bims-prodis 2018-07-15 papers

bims-prodis

Biomed News

on Proteomics in disease

Issue of 2018–07–15
seven papers selected by
Nancy Gough, Bioserendipity

Urinary peptidomic biomarkers of renal function in heart transplant recipients.
Proteome profiling in the hippocampus, medial prefrontal cortex, and striatum of aging rat.
Predictors of Treatment Response in Rheumatoid Arthritis.
Antibodies to PfsEGXP, An Early Gametocyte Enriched Phosphoprotein, Predict Decreased Plasmodium falciparum Gametocyte Density In Humans.
Protein biomarkers and coronary microvascular dilatation assessed by rubidium-82 PET in women with angina pectoris and no obstructive coronary artery disease.
cAMP Regulated EPAC1 Supports Microvascular Density, Angiogenic and Metastatic Properties in a Model of Triple Negative Breast Cancer.
EPH receptor signaling as a novel therapeutic target in NF2-deficient meningioma.

Nephrol Dial Transplant. 2018 Jul 02.

Urinary peptidomic biomarkers of renal function in heart transplant recipients.

Qi-Fang Huang, Zhen-Yu Zhang, Jan Van Keer, Sander Trenson, Esther Nkuipou-Kenfack, Wen-Yi Yang, Lutgarde Thijs, Johan Vanhaecke, Lucas N L Van Aelst, Johan Van Cleemput, Stefan Janssens, Peter Verhamme, Harald Mischak, Jan A Staessen.

Background: Chronic kidney disease (CKD) is common in patients after heart transplantation (HTx). We assessed whether in HTx recipients the proteomic urinary classifier CKD273 or sequenced urinary peptides revealing the parental proteins correlated with the estimated glomerular filtration rate (eGFR).
Methods: In 368 HTx patients, we measured the urinary peptidome and analysed CKD273 and 48 urinary peptides with a detectable signal in >95% of participants. After 9.1 months (median), eGFR and the urinary biomarkers were reassessed.
Results: In multivariable Bonferroni-corrected analyses of the baseline data, a 1-SD increase in CKD273 was associated with a 11.4 [95% confidence interval (CI) 7.25-15.5] mL/min/1.73 m2 lower eGFR and an odds ratio of 2.63 (1.56-4.46) for having eGFR <60 mL/min/1.73 m2. While relating eGFR category at follow-up to baseline urinary biomarkers, CKD273 had higher (P = 0.007) area under the curve (0.75; 95% CI 0.70-0.80) than 24-h proteinuria (0.64; 95% CI 0.58-0.69), but additional adjustment for baseline eGFR removed significance of both biomarkers. In partial least squares analysis, the strongest correlates of the multivariable-adjusted baseline eGFR were fragments of collagen I (positive) and the mucin-1 subunit α (inverse). Associations between the changes in eGFR and the urinary markers were inverse for CKD273 and mucin-1 and positive for urinary collagen I.
Conclusions: With the exception of baseline eGFR, CKD273 was more closer associated with imminent renal dysfunction than 24-h proteinuria. Fragments of collagen I and mucin-1-respectively, positively and inversely associated with eGFR and change in eGFR-are single-peptide markers associated with renal dysfunction.

DOI: https://doi.org/10.1093/ndt/gfy185
Exp Gerontol. 2018 Jul 04. pii: S0531-5565(18)30309-7. [Epub ahead of print]

Proteome profiling in the hippocampus, medial prefrontal cortex, and striatum of aging rat.

Hamizah Shahirah Hamezah, Lina Wati Durani, Daijiro Yanagisawa, Nor Faeizah Ibrahim, Wan Mohd Aizat, Jean Pierre Bellier, Suzana Makpol, Wan Zurinah Wan Ngah, Hanafi Ahmad Damanhuri, Ikuo Tooyama.

  Decrease in multiple functions occurs in the brain with aging, all of which can contribute to age-related cognitive and locomotor impairments. Brain atrophy specifically in hippocampus, medial prefrontal cortex (mPFC), and striatum, can contribute to this age-associated decline in function. Our recent metabolomics analysis showed age-related changes in these brain regions. To further understand the aging processes, analysis using a proteomics approach was carried out. This study was conducted to identify proteome profiles in the hippocampus, mPFC, and striatum of 14-, 18-, 23-, and 27-month-old rats. Proteomics analysis using ultrahigh performance liquid chromatography coupled with Q Exactive HF Orbitrap mass spectrometry identified 1074 proteins in the hippocampus, 871 proteins in the mPFC, and 241 proteins in the striatum. Of these proteins, 97 in the hippocampus, 25 in mPFC, and 5 in striatum were differentially expressed with age. The altered proteins were classified into three ontologies (cellular component, molecular function, and biological process) containing 44, 38, and 35 functional groups in the hippocampus, mPFC, and striatum, respectively. Most of these altered proteins participate in oxidative phosphorylation (e.g. cytochrome c oxidase and ATP synthase), glutathione metabolism (e.g. peroxiredoxins), or calcium signaling pathway (e.g. protein S100B and calmodulin). The most prominent changes were observed in the oldest animals. These results suggest that alterations in oxidative phosphorylation, glutathione metabolism, and calcium signaling pathway are involved in cognitive and locomotor impairments in aging.

Keywords:  Aging; Brain; Proteomics

DOI:  https://doi.org/10.1016/j.exger.2018.07.002
Joint Bone Spine. 2018 Jul 04. pii: S1297-319X(18)30130-1. [Epub ahead of print]

Predictors of Treatment Response in Rheumatoid Arthritis.

Thierry Lequerré, Pascal Rottenberg, Céline Derambure, Pascal Cosette, Olivier Vittecoq.

  The expanding array of drugs available for treating rheumatoid arthritis is creating challenges in drug selection for the individual patient. The identification of biomarkers that predict the treatment response prior to drug exposure is therefore a current priority. This new approach, known as theranostics, is a component of personalized medicine, which involves selecting the management strategies that are most effective for a given patient at a given point in time. Antibodies to citrullinated peptides, rheumatoid factor, and the interferon signature are the most robust and best validated biomarkers identified to date. Matrices containing clinical or laboratory parameters of diagnostic or prognostic relevance may help to select the best treatment for the individual patient. Furthermore, the development of large-scale approaches requiring no a priori knowledge, such as functional genomics and metabolomics, hold considerable promise, despite persistent difficulties in replicating findings. The complexity of the treatment response in a given patient and substantial variability across patients suggest that biomarkers may be more helpful in combination than singly. The objectives of this review article are to discuss the approaches used to identify theranostic biomarkers and to present an overview of currently available biomarkers and of their performance in everyday clinical practice. However, the range of biomarkers suitable for use in daily practice remains extremely narrow.

Keywords:  Rheumatoid arthritis. Biomarkers. Response prediction. Theranostics. Transcriptome. Proteome.

DOI:  https://doi.org/10.1016/j.jbspin.2018.03.018
J Infect Dis. 2018 Jul 06.

Antibodies to PfsEGXP, An Early Gametocyte Enriched Phosphoprotein, Predict Decreased Plasmodium falciparum Gametocyte Density In Humans.

Christian P Nixon, Christina E Nixon, Ian C Michelow, Rayna A Silva-Viera, Bonnie Colantuono, Aisha S Obeidallah, Ambrish Jha, Dominique Dockery, Dipak Raj, Sangshin Park, Patrick E Duffy, Jonathan D Kurtis.

Background: Anti-gametocyte specific immune responses may regulate Plasmodium falciparum gametocyte density, providing the rationale for pursuing transmission blocking vaccines (TBVs) that target gametocytes in the human host.
Methods: To identify novel anti-gametocyte TBV antigens, we interrogated the gametocyte proteome with our whole proteome differential screening method using plasma from a treatment-reinfection study conducted in western Kenya. At the start of the high transmission season, 144 males (12-35 years) were enrolled, treated with quinine and doxycycline, peripheral venous blood sample were obtained, and volunteers were followed with weekly blood films for 18 weeks to quantify gametocytemia. Using plasma pooled from individuals with low versus high gametocyte carriage, we differentially screened a P. falciparum gametocyte stage cDNA expression library.
Results: We identified eight parasite genes uniquely recognized by gametocyte-resistant but not by gametocyte-susceptible individuals. Antibodies to one of these antigens, PfsEGXP, predicted lower gametocytemia measured over the 18-week transmission season (P = 0.021). When analyzed dichotomously, anti-PfsEGXP responders had 31% lower gametocyte density over 18 weeks of follow-up, compared to non-responders (P = 0.04).
Conclusions: PfsEGXP is one of the first reported gametocyte-specific target of antibodies that predict decreased gametocyte density in humans and supports our novel TBV antigen discovery platform.

DOI: https://doi.org/10.1093/infdis/jiy416
Atherosclerosis. 2018 Jun 19. pii: S0021-9150(18)31176-6. [Epub ahead of print]275 319-327

Protein biomarkers and coronary microvascular dilatation assessed by rubidium-82 PET in women with angina pectoris and no obstructive coronary artery disease.

Jakob Schroder, Rikke Zethner-Moller, Kira Bang Bové, Naja Dam Mygind, Philip Hasbak, Marie Mide Michelsen, Ida Gustafsson, Jens Kastrup, Eva Prescott.

   BACKGROUND AND AIMS: While a plethora of biomarkers have been shown to be associated with coronary artery disease, studies assessing biomarkers in coronary microvascular dysfunction (CMD) are few. We investigated associations between cardiovascular protein biomarkers and non-endothelium dependent CMD assessed by positron emission tomography (PET).
METHODS: In 97 women with angina pectoris and no significant obstructive coronary artery disease (<50% stenosis on invasive coronary angiography), CMD was defined as myocardial blood flow reserve (MBFR) < 2.5 by rubidium-82 PET. Blood samples were analyzed with a cardiovascular disease proteomic panel encompassing 92 biomarkers. The relation between MBFR and biomarkers was evaluated with age-adjusted regression analysis.
RESULTS: Median age was 62 years (range 31-79), median MBFR was 2.7 (range 1.2-4.7) and 32% had non-endothelium dependent CMD (MBFR<2.5). Four biomarkers were significantly correlated with MBFR: Galectin-4 (Gal4, p = 0.008), growth differentiation factor 15 (GDF15, p = 0.026), tissue-type plasminogen activator (tPA, p = 0.030) and von Willebrand factor (vWF, p = 0.018), while 12 biomarkers showed a trend for correlation (0.05 ≤ p < 0.15). Of the 16 identified biomarkers, 10 are involved in pro-inflammatory pathways.
CONCLUSIONS: In a panel of 92 cardiovascular protein biomarkers, 4 were significantly associated with non-endothelium dependent CMD in women: Gal4, GDF15, tPA and vWF, suggesting that inflammatory status and coagulation changes are associated with impaired microvascular dilatation. Further confirmatory studies are needed to corroborate these findings.

Keywords:  Coronary microvascular dysfunction; Myocardial blood flow; PET; Positron emission tomography; Protein biomarkers; Women

DOI:  https://doi.org/10.1016/j.atherosclerosis.2018.06.864
Carcinogenesis. 2018 Jul 05.

cAMP Regulated EPAC1 Supports Microvascular Density, Angiogenic and Metastatic Properties in a Model of Triple Negative Breast Cancer.

Naveen Kumar, Peeyush Prasad, Eshna Jash, Smruthi Jayasundar, Itender Singh, Neyaz Alam, Nabendu Murmu, S P Somashekhar, Aaron Goldman, Seema Sehrawat.

Breast cancer is a leading cause of cancer-related mortality in women. Triple-negative breast cancer (TNBC; HER2-, ER-/PR-) is an aggressive subtype prone to drug resistance and metastasis, which is characterized by high intratumor microvascular density (iMVD) resulting from angiogenesis. However, the mechanisms contributing to the aggressive phenotypes of TNBC remain elusive. We recently reported that down-regulation of exchange factor directly activated by Cyclic AMP (cAMP), also known as EPAC1, leads to a reduction in metastatic properties including proliferation and cell migration in TNBC cell lines. Here, we report that EPAC1 supports TNBC-induced angiogenesis, tumor cell migration and invasiveness as well as pro-metastatic phenotypes in endothelial cells induced through the tumor secretome. Using an approach that integrates proteomics with bioinformatics and gene ontologies, we elucidate that EPAC1 supports a tumor-secreted network of angiogenic, cell adhesion and cell migratory pathways. Using confocal microscopy we show that signaling molecules involved in focal adhesion, including Paxillin and MENA, are down-regulated in the absence of EPAC1, and electric cell substrate impedance sensing technique confirmed a role for EPAC1 on TNBC-induced endothelial cell permeability. Finally, to provide a translational bridge, we studied iMVD and therapy response using a primary human tumor explant assay, CANscriptTM, which suggests a link between therapy-modulated neovascularization and drug sensitivity. These data provide mechanistic insight into the role of EPAC1 in regulating the tumor microenvironment, iMVD and cancer cell-induced angiogenesis, a dynamic mechanism under drug pressure that may associate to treatment failure.

DOI: https://doi.org/10.1093/carcin/bgy090
Neuro Oncol. 2018 Mar 21.

EPH receptor signaling as a novel therapeutic target in NF2-deficient meningioma.

Children’s Tumor Foundation Synodos for NF2 Consortium

Background: Meningiomas are the most common primary brain tumor in adults, and somatic loss of the neurofibromatosis 2 (NF2) tumor suppressor gene is a frequent genetic event. There is no effective treatment for tumors that recur or continue to grow despite surgery and/or radiation. Therefore, targeted therapies that either delay tumor progression or cause tumor shrinkage are much needed. Our earlier work established mammalian target of rapamycin complex mTORC1/mTORC2 activation in NF2-deficient meningiomas.
Methods: High-throughput kinome analyses were performed in NF2-null human arachnoidal and meningioma cell lines to identify functional kinome changes upon NF2 loss. Immunoblotting confirmed the activation of kinases and demonstrated effectiveness of drugs to block the activation. Drugs, singly and in combination, were screened in cells for their growth inhibitory activity. Antitumor drug efficacy was tested in an orthotopic meningioma model.
Results: Erythropoietin-producing hepatocellular receptor tyrosine kinases (EPH RTKs), c-KIT, and Src family kinase (SFK) members, which are biological targets of dasatinib, were among the top candidates activated in NF2-null cells. Dasatinib significantly inhibited phospho-EPH receptor A2 (pEPHA2), pEPHB1, c-KIT, and Src/SFK in NF2-null cells, showing no cross-talk with mTORC1/2 signaling. Posttreatment kinome analyses showed minimal adaptive changes. While dasatinib treatment showed some activity, dual mTORC1/2 inhibitor and its combination with dasatinib elicited stronger growth inhibition in meningiomas.
Conclusion: Co-targeting mTORC1/2 and EPH RTK/SFK pathways could be a novel effective treatment strategy for NF2-deficient meningiomas.

DOI: https://doi.org/10.1093/neuonc/noy046