bims-prodis Biomed News
on Proteomics in disease
Issue of 2018–12–23
forty-nine papers selected by
Nancy Gough, Bioserendipity
  1. Quantitative proteomic profiling of cerebrospinal fluid to identify candidate biomarkers for Alzheimer's disease.
  2. Probing the Virtual Proteome to Identify Novel Disease Biomarkers.
  3. Neuroanatomical Quantitative Proteomics Reveals Common Pathogenic Biological Routes between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
  4. Urinary Proteomics in Biomarker Discovery of Kidney-Related Disorders: Diabetic Nephropathy and Drug-Induced Nephrotoxicity in Chronic Headache.
  5. Integrating proteomic and phosphoproteomic data for pathway analysis in breast cancer.
  6. Analysis of the Effect of Intestinal Ischemia and Reperfusion on the Rat Neutrophils Proteome.
  7. Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy.
  8. Vero Cell Proteomic Changes Induced by Zika Virus Infection.
  9. FBP2 and Talin-1 are potential protein markers for Mongolian medicine symptom evaluation in viral infectious diseases.
  10. Proteomics Applications in Health: Biomarker and Drug Discovery and Food Industry.
  11. Cancer biomarker discovery and translation: proteomics and beyond.
  12. iTRAQ-based phosphoproteomic analysis reveals host cell's specific responses to Toxoplasma gondii at the phases of invasion and prior to egress.
  13. Haptoglobin degradation product as a novel serum biomarker for hematopoietic stem cell transplant-associated thrombotic microangiopathy.
  14. Proteomics in the Diagnosis of Endometriosis: Opportunities and Challenges.
  15. Systematic review on recent potential biomarkers of chronic obstructive pulmonary disease.
  16. Oncogenic Regulation Of Extracellular Vesicle Proteome And Heterogeneity.
  17. Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots.
  18. High-dimensional single-cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis.
  19. Proteomic Analysis of Zn Depletion/Repletion in the Hormone-Secreting Thyroid Follicular Cell Line FRTL-5.
  20. Urinary proteome in inherited nephrolithiasis.
  21. Analysing the Secretome of Gut Microbiota as the Next Strategy For Early Detection of Colorectal Cancer.
  22. Identification of Novel Therapeutic Targets for Pulmonary Arterial Hypertension.
  23. An Optimised Method for the Proteomic Analysis of Low Volumes of Cell Culture Media and the Secretome: The Application and the Demonstration of Altered Protein Expression in iPSC-Derived Neuronal Cell Lines from Parkinson's Disease Patients.
  24. Plasma-Derived Inflammatory Proteins Predict Oral Squamous Cell Carcinoma.
  25. Proteomics, Bioinformatics and Structure-Function Antigen Mining For Gonorrhea Vaccines.
  26. Mass spectrometry and proteomics in hematology.
  27. High Throughput Chemical Screening Reveals Multiple Regulatory Proteins on FOXA1 in Breast Cancer Cell Lines.
  28. Plasma Protein Pattern Correlates With Pain Intensity and Psychological Distress in Women With Chronic Widespread Pain.
  29. Proteomic analysis of heart failure hospitalization among patients with chronic kidney disease: The Heart and Soul Study.
  30. The Challenge to Search for New Nervous System Disease Biomarker Candidates: the Opportunity to Use the Proteogenomics Approach.
  31. Tissue proteomics outlines AGR2 AND LOX5 as markers for biochemical recurrence of prostate cancer.
  32. A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer.
  33. Proteomic Profiling of Primary Human Acute Myeloid Leukemia Cells Does Not Reflect Their Constitutive Release of Soluble Mediators.
  34. Clinically Relevant Post-Translational Modification Analyses-Maturing Workflows and Bioinformatics Tools.
  35. Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles.
  36. Dissecting the molecular effects of cigarette smoke on proteasome function.
  37. Impairment of chaperone-mediated autophagy affects neuronal homeostasis through altered expression of DJ-1 and CRMP-2 proteins.
  38. Deep sequencing salivary proteins for periodontitis using proteomics.
  39. The Effect of Myosin Light Chain Kinase on the Occurrence and Development of Intracranial Aneurysm.
  40. Shotgun proteomics data on the impact of hyperglycaemia on platelet protein acetylation by aspirin.
  41. New antigens for the serological diagnosis of human visceral leishmaniasis identified by immunogenomic screening.
  42. Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C.
  43. Harmonization of pipeline for preclinical multicenter plasma protein and miRNA biomarker discovery in a rat model of post-traumatic epileptogenesis.
  44. Plasma TNF alpha is a predictor of persisting symptoms post-concussion in children.
  45. A multiomic approach to characterize the temporal sequence in Alzheimer's disease-related pathology.
  46. Protein production is an early biomarker for RNA-targeted therapies.
  47. TBIcare Investigator's response to "Raising the Bar for Traumatic Brain Injury Biomarker Research: Methods Make a Difference" by Papa and Wang.
  48. ATM-Mediated Phosphorylation of Cortactin Involved in Actin Polymerization Promotes Breast Cancer Cells Migration and Invasion.
  49. GJA1 (connexin43) is a key regulator of Alzheimer's disease pathogenesis.
  1. Proteomics Clin Appl. 2018 Dec 21. e1800105
    Quantitative proteomic profiling of cerebrospinal fluid to identify candidate biomarkers for Alzheimer's disease.
    Gajanan Sathe, Chan Hyun Na, Santosh Renuse, Anil K Madugundu, Marilyn Albert, Abhay Moghekar, Akhilesh Pandey.
       PURPOSE: Development of novel biomarkers for AD is essential for early diagnosis, monitoring disease progression and therapeutic response. The aim of this study was to identify the potential CSF biomarkers for Alzheimer's disease (AD) and to evaluate these markers on independent CSF samples using parallel reaction monitoring assays.
    EXPERIMENTAL DESIGN: In this study, we employed high-resolution mass spectrometry and tandem mass tag (TMT) multiplexing technology to identify proteins that might be biomarkers for Alzheimer's disease. Some of the identified potential biomarkers were validated using a parallel reaction monitoring assays.
    RESULTS: We identified 2,327 proteins in the cerebrospinal fluid (CSF) of which 139 were observed to be significantly different in their abundance in the CSF of AD patients versus controls. The proteins whose abundance was altered in AD included a number of known AD marker proteins such as MAPT, NPTX2, SCG2, VGF, GFAP, SST and NCAM1 as well as novel biomarkers such as GSN, PKM and YWHAG. We then sought to validate these findings in a separate set of CSF specimens from AD dementia patients and controls. For the AD group, significant increases were found for YWHAG and PKM, and a significant decrease was observed for VGF by multiplexed targeted parallel reaction monitoring experiments. NPTX2, in combination with PKM or YWHAG, led to the best results with AUCs of 0.935 and 0.933, respectively.
    CONCLUSIONS AND CLINICAL RELEVANCE: The proteins that were found to be altered in the CSF of patients with AD could be used for monitoring disease progression and therapeutic response and perhaps also for early detection once they are validated in larger studies. This article is protected by copyright. All rights reserved.
    Keywords:  Alzheimer's disease; TMT; biomarker; cerebrospinal fluid; mass spectrometry; parallel reaction monitoring; proteome
    DOI:  https://doi.org/10.1002/prca.201800105
  2. Circulation. 2018 Nov 27. 138(22): 2469-2481
    Probing the Virtual Proteome to Identify Novel Disease Biomarkers.
    Jonathan D Mosley, Mark D Benson, J Gustav Smith, Olle Melander, Debby Ngo, Christian M Shaffer, Jane F Ferguson, Matthew S Herzig, Catherine A McCarty, Christopher G Chute, Gail P Jarvik, Adam S Gordon, Melody R Palmer, David R Crosslin, Eric B Larson, David S Carrell, Iftikhar J Kullo, Jennifer A Pacheco, Peggy L Peissig, Murray H Brilliant, Terrie E Kitchner, James G Linneman, Bahram Namjou, Marc S Williams, Marylyn D Ritchie, Kenneth M Borthwick, Krzysztof Kiryluk, Frank D Mentch, Patrick M Sleiman, Elizabeth W Karlson, Shefali S Verma, Yineng Zhu, Ramachandran S Vasan, Qiong Yang, Josh C Denny, Dan M Roden, Robert E Gerszten, Thomas J Wang.
       BACKGROUND: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals.
    METHODS: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651).
    RESULTS: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-β.
    CONCLUSIONS: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.
    Keywords:  atherosclerosis; biomarkers; electronic health records; proteomics
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.118.036063
  3. Int J Mol Sci. 2018 Dec 20. pii: E4. [Epub ahead of print]20(1):
    Neuroanatomical Quantitative Proteomics Reveals Common Pathogenic Biological Routes between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
    Marina Oaia Iridoy, Irene Zubiri, María Victoria Zelaya, Leyre Martinez, Karina Ausín, Mercedes Lachen-Montes, Enrique Santamaría, Joaquín Fernandez-Irigoyen, Ivonne Jericó.
      (1) Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with an overlap in clinical presentation and neuropathology. Common and differential mechanisms leading to protein expression changes and neurodegeneration in ALS and FTD were studied trough a deep neuroproteome mapping of the spinal cord. (2) Methods: A liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the spinal cord from ALS-TAR DNA-binding protein 43 (TDP-43) subjects, ubiquitin-positive frontotemporal lobar degeneration (FTLD-U) subjects and controls without neurodegenerative disease was performed. (3) Results: 281 differentially expressed proteins were detected among ALS versus controls, while 52 proteins were dysregulated among FTLD-U versus controls. Thirty-three differential proteins were shared between both syndromes. The resulting data was subjected to network-driven proteomics analysis, revealing mitochondrial dysfunction and metabolic impairment, both for ALS and FTLD-U that could be validated through the confirmation of expression levels changes of the Prohibitin (PHB) complex. (4) Conclusions: ALS-TDP-43 and FTLD-U share molecular and functional alterations, although part of the proteostatic impairment is region- and disease-specific. We have confirmed the involvement of specific proteins previously associated with ALS (Galectin 2 (LGALS3), Transthyretin (TTR), Protein S100-A6 (S100A6), and Protein S100-A11 (S100A11)) and have shown the involvement of proteins not previously described in the ALS context (Methanethiol oxidase (SELENBP1), Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN-1), Calcyclin-binding protein (CACYBP) and Rho-associated protein kinase 2 (ROCK2)).
    Keywords:  amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); motor neuron; proteomics
    DOI:  https://doi.org/10.3390/ijms20010004
  4. EJIFCC. 2018 Dec;29(4): 290-297
    Urinary Proteomics in Biomarker Discovery of Kidney-Related Disorders: Diabetic Nephropathy and Drug-Induced Nephrotoxicity in Chronic Headache.
    Elisa Bellei, Emanuela Monari, Stefania Bergamini, Luigi Alberto Pini, Tomasi Aldo, Tomris Ozben.
       Objective: Urinary proteomics is primarily applied to the study of renal and urogenital tract disorders. Here are reported two distinct successful examples of this approach for the discovery of early urinary biomarkers of kidney-related dysfunctions: diabetic nephropathy (DN), a well-known complication of diabetes frequently leading to dialysis, and drug-induced nephrotoxicity, a possible condition caused by medication-overuse headache (MOH). Early detection of kidney disorders based on selective biomarkers could permit to diagnose patients at the initial stage of the disease, where the therapy may be suspended or prevent disease advancement.
    Methods: Urine samples were first concentrated and desalted. Subsequently, they were subjected to two-dimensional gel electrophoresis (2-DE) coupled to mass spectrometry (MS) for protein identification. Furthermore, some proteins were verified by Western blot and ELISA test.
    Results: In diabetes-related study, 11 differentially expressed proteins were detected (8 up-regulated and 3 down-regulated) in type 2 diabetic (T2D) and T2DN patients compared to the healthy control subjects. In the MOH study, a total of 21 over-excreted proteins were revealed in urine of non-steroidal anti-inflammatory drugs (NSAIDs) and mixtures abusers vs controls. Particularly, 4 proteins were positively validated by immunob-lotting and EUSA.
    Conclusion: Urinary proteomics allows non-invasive assessment of renal diseases at an early stage by the identification of characteristic protein pattern.
    Keywords:  biomarkers; diabetic nephropathy; drug-induced nephrotoxicity; urinary proteomics
  5. BMC Syst Biol. 2018 Dec 21. 12(Suppl 8): 130
    Integrating proteomic and phosphoproteomic data for pathway analysis in breast cancer.
    Jie Ren, Bo Wang, Jing Li.
       BACKGROUND: As protein is the basic unit of cell function and biological pathway, shotgun proteomics, the large-scale analysis of proteins, is contributing greatly to our understanding of disease mechanisms. Proteomics study could detect the changes of both protein expression and modification. With the releases of large-scale cancer proteome studies, how to integrate acquired proteomic and phosphoproteomic data in more comprehensive pathway analysis becomes implemented, but remains challenging. Integrative pathway analysis at proteome level provides a systematic insight into the signaling network adaptations in the development of cancer.
    RESULTS: Here we integrated proteomic and phosphoproteomic data to perform pathway prioritization in breast cancer. We manually collected and curated breast cancer well-known related pathways from the literature as target pathways (TPs) or positive control in method evaluation. Three different strategies including Hypergeometric test based over-representation analysis, Kolmogorov-Smirnov (K-S) test based gene set analysis and topology-based pathway analysis, were applied and evaluated in integrating protein expression and phosphorylation. In comparison, we also assessed the ranking performance of the strategy using information of protein expression or protein phosphorylation individually. Target pathways were ranked more top with the data integration than using the information from proteomic or phosphoproteomic data individually. In the comparisons of pathway analysis strategies, topology-based method outperformed than the others. The subtypes of breast cancer, which consist of Luminal A, Luminal B, Basal and HER2-enriched, vary greatly in prognosis and require distinct treatment. Therefore we applied topology-based pathway analysis with integrating protein expression and phosphorylation profiles on four subtypes of breast cancer. The results showed that TPs were enriched in all subtypes but their ranks were significantly different among the subtypes. For instance, p53 pathway ranked top in the Basal-like breast cancer subtype, but not in HER2-enriched type. The rank of Focal adhesion pathway was more top in HER2- subtypes than in HER2+ subtypes. The results were consistent with some previous researches.
    CONCLUSIONS: The results demonstrate that the network topology-based method is more powerful by integrating proteomic and phosphoproteomic in pathway analysis of proteomics study. This integrative strategy can also be used to rank the specific pathways for the disease subtypes.
    Keywords:  Breast cancer; Integration; Pathway analysis; Phosphoproteomics; Proteomics
    DOI:  https://doi.org/10.1186/s12918-018-0646-y
  6. Front Mol Biosci. 2018 ;5 89
    Analysis of the Effect of Intestinal Ischemia and Reperfusion on the Rat Neutrophils Proteome.
    Muhammad Tahir, Samina Arshid, Belchor Fontes, Mariana S Castro, Isabelle S Luz, Katyelle L R Botelho, Simone Sidoli, Veit Schwämmle, Peter Roepstorff, Wagner Fontes.
      Intestinal ischemia and reperfusion injury is a model system of possible consequences of severe trauma and surgery, which might result into tissue dysfunction and organ failure. Neutrophils contribute to the injuries preceded by ischemia and reperfusion. However, the mechanisms by which intestinal ischemia and reperfusion stimulate and activate circulating neutrophils is still not clear. In this work, we used proteomics approach to explore the underlying regulated mechanisms in Wistar rat neutrophils after ischemia and reperfusion. We isolated neutrophils from three different biological groups; control, sham laparotomy, and intestinal ischemia/reperfusion. In the workflow, we included iTRAQ-labeling quantification and peptide fractionation using HILIC prior to LC-MS/MS analysis. From proteomic analysis, we identified 2,045 proteins in total that were grouped into five different clusters based on their regulation trend between the experimental groups. A total of 417 proteins were found as significantly regulated in at least one of the analyzed conditions. Interestingly, the enzyme prediction analysis revealed that ischemia/reperfusion significantly reduced the relative abundance of most of the antioxidant and pro-survival molecules to cause more tissue damage and ROS production whereas some of the significantly up regulated enzymes were involved in cytoskeletal rearrangement, adhesion and migration. Clusters based KEGG pathways analysis revealed high motility, phagocytosis, directional migration, and activation of the cytoskeletal machinery in neutrophils after ischemia and reperfusion. Increased ROS production and decreased phagocytosis were experimentally validated by microscopy assays. Taken together, our findings provide a characterization of the rat neutrophil response to intestinal ischemia and reperfusion and the possible mechanisms involved in the tissue injury by neutrophils after intestinal ischemia and reperfusion.
    Keywords:  LC-MS/MS; ischemia reperfusion; neutrophils; proteomics; systemic inflammatory response
    DOI:  https://doi.org/10.3389/fmolb.2018.00089
  7. Circ Genom Precis Med. 2018 Dec;11(12): e001974
    Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy.
    Caroline J Coats, Wendy E Heywood, Alex Virasami, Nadia Ashrafi, Petros Syrris, Cris Dos Remedios, Thomas A Treibel, James C Moon, Luis R Lopes, Christopher G A McGregor, Michael Ashworth, Neil J Sebire, William J McKenna, Kevin Mills, Perry M Elliott.
       BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by a complex phenotype that is only partly explained by the biological effects of individual genetic variants. The aim of this study was to use proteomic analysis of myocardial tissue to explore the postgenomic phenotype.
    METHODS: Label-free proteomic analysis was used initially to compare protein profiles in myocardial samples from 11 patients with HCM undergoing surgical myectomy with control samples from 6 healthy unused donor hearts. Differentially expressed proteins of interest were validated in myocardial samples from 65 unrelated individuals (HCM [n=51], controls [n=7], and aortic stenosis [n=7]) by the development and use of targeted multiple reaction monitoring-based triple quadrupole mass spectrometry.
    RESULTS: In this exploratory study, 1586 proteins were identified with 151 proteins differentially expressed in HCM samples compared with controls ( P<0.05). Protein expression profiling showed that many proteins identified in the initial discovery study were associated with metabolism, muscle contraction, calcium regulation, and oxidative stress. Proteins downregulated in HCM versus controls included creatine kinase M-type, fructose-bisphosphate aldolase A, and phosphoglycerate mutase ( P<0.001). Proteins upregulated in HCM included lumican, carbonic anhydrase 3, desmin, α-actin skeletal, and FHL1 (four and a half LIM domain protein 1; P<0.01). Myocardial lumican concentration correlated with the left atrial area (ρ=0.34, P=0.015), late gadolinium enhancement on cardiac magnetic resonance imaging ( P=0.03) and the presence of a pathogenic sarcomere mutation ( P=0.04).
    CONCLUSIONS: The myocardial proteome of HCM provides supporting evidence for dysregulation of metabolic and structural proteins. The finding that lumican is raised in HCM hearts provides insight into the myocardial fibrosis that characterizes this disease.
    Keywords:  cardiomyopathies; fibrosis; hypertrophy; proteome
    DOI:  https://doi.org/10.1161/CIRCGEN.117.001974
  8. Proteomics. 2018 Dec 22. e1800309
    Vero Cell Proteomic Changes Induced by Zika Virus Infection.
    Kathleen K M Glover, Ang Gao, Ali Zahedi-Amiri, Kevin M Coombs.
      The re-emergence, and recent spread of Zika virus (ZIKV), has raised significant global concerns due to lack of information in patient diagnosis and management. Thus, in addition to gaining more basic information about ZIKV biology, appropriate interventions and management strategies are being sought to control ZIKV-associated diseases and its spread. This study's objective was to identify host cell proteins that are significantly dysregulated during ZIKV infection. We used SOMAScan® , a novel aptamer-based assay, to simultaneously screen >1300 host proteins to detect ZIKV-induced host protein dysregulation at multiple time points during infection. A total of 125 Vero cell host proteins, including cytokines such as CXCL11 and CCL5, interferon stimulated gene 15, and translation initiation factors EIF5A and EIF4G2, were significantly dysregulated after ZIKV infection. Bioinformatic analyses of 77 host proteins that were significantly dysregulated ≥ 1.25-fold identified several activated biological processes, including the JAK/STAT, Tec kinase and complement cascade pathways. This article is protected by copyright. All rights reserved.
    Keywords:  RNA virus infection; SOMAScan; aptamers; proteomics
    DOI:  https://doi.org/10.1002/pmic.201800309
  9. Medicine (Baltimore). 2018 Dec;97(51): e13526
    FBP2 and Talin-1 are potential protein markers for Mongolian medicine symptom evaluation in viral infectious diseases.
    Li Li, Xiaoying Wu, Eerdunchaolu, Wenyan Qin, Yuqiu Yang, Geriletu Wang, Huili He, Husileng Zhang.
       BACKGROUND: Influenza, measles, and mumps are common viral infectious diseases in Mongolia. The traditional Mongolian medicine (TMM) classified them as warm disease, and still plays a major role in the diagnoses and treatments.
    METHODS: To interpret the connotation of the complex theoretical system in TMM with scientific technique, in this study, a high throughput mass spectrometry was used to identify potential protein markers of TMM symptom types. Fifty venous blood samples were drawn from influenza, measles and mumps patients. Differential proteins between samples of patients diagnosed as immature and mature heat in TMM were detected by mass spectrometry.
    RESULTS: After proteomics analysis, 1500 proteins and 7619 polypeptides were identified and 1323 in total showed differential expression between those 2 symptom types; then enrichment analysis of the differentially expressed proteins revealed the significant biological functions related to the differentially expressed proteins, including cardiomyopathy, several bacterial and parasitic infections, bacterial invasion of epithelial cells, insulin signaling pathway, and regulation of actin cytoskeleton. The network analysis showed that FBP2 and Talin-1 were critical points and might determine the evolution directions of TMM warm disease symptom.
    CONCLUSIONS: This study suggests that the identified core differential proteins may be regarded as potential biomarkers, and benefit to evaluate the evolutionary tendency of TMM warm disease symptoms.
    DOI:  https://doi.org/10.1097/MD.0000000000013526
  10. Iran J Pharm Res. 2018 ;17(4): 1523-1536
    Proteomics Applications in Health: Biomarker and Drug Discovery and Food Industry.
    Nasrin Amiri-Dashatan, Mehdi Koushki, Hojjat-Allah Abbaszadeh, Mohammad Rostami-Nejad, Mostafa Rezaei-Tavirani.
      Advancing in genome sequencing has greatly propelled the understanding of the living world; however, it is insufficient for full description of a biological system. Focusing on proteomics has emerged as another large-scale platform for improving the understanding of biology. Proteomic experiments can be used for different aspects of clinical and health sciences such as food technology, biomarker discovery and drug target identification. Since proteins are main constituents of foods, proteomic technology can monitor and characterize protein content of foods and their change during production process. The proteomic biomarker discovery is advanced in various diseases such as cancer, cardiovascular diseases, AIDS, and renal diseases which provide non-invasive methods by the use of body fluids such as urine and serum. Proteomics is also used in drug target identification using different approaches such as chemical proteomics and protein interaction networks. The development and application of proteomics has increased tremendously over the last decade. Advances in proteomics methods offer many promising new directions of studying in clinical fields. In this regard, we want to discuss proteomics technology application in food investigations, drug, and biomarker discovery.
    Keywords:  Biomarker; Drug discovery; Foodomics; Proteome profiling; Proteomics
  11. Expert Rev Proteomics. 2018 Dec 17.
    Cancer biomarker discovery and translation: proteomics and beyond.
    Ventzislava A Hristova, Daniel W Chan.
       INTRODUCTION: Cancer is often diagnosed at late stages when the chance of cure is relatively low and although research initiatives in oncology discover many potential cancer biomarkers, few transition to clinical applications. This review addresses the current landscape of cancer biomarker discovery and translation with a focus on proteomics and beyond. Areas covered: The review examines proteomic and genomic techniques for cancer biomarker detection and outlines advantages and challenges of integrating multiple omics approaches to achieve optimal sensitivity and address tumor heterogeneity. This discussion is based on a systematic literature review and direct participation in translational studies. Expert commentary: Identifying aggressive cancers early on requires improved sensitivity and implementation of biomarkers representative of tumor heterogeneity. During the last decade of genomic and proteomic research, significant advancements have been made in next generation sequencing (NGS) and mass spectrometry (MS) techniques. This in turn has led to a dramatic increase in identification of potential genomic and proteomic cancer biomarkers. However, limited successes have been shown with translation of these discoveries into clinical practice. We believe that the integration of these omics approaches is the most promising molecular tool for comprehensive cancer evaluation, early detection and transition to Precision Medicine in oncology.
    Keywords:  biomarker discovery; cancer biomarker; multi-omics; proteomics; translational research
    DOI:  https://doi.org/10.1080/14789450.2019.1559062
  12. Biochim Biophys Acta Proteins Proteom. 2018 Dec 18. pii: S1570-9639(18)30213-9. [Epub ahead of print]
    iTRAQ-based phosphoproteomic analysis reveals host cell's specific responses to Toxoplasma gondii at the phases of invasion and prior to egress.
    Cheng He, Ling Kong, Santhosh Puthiyakunnon, Hai-Xia Wei, Li-Juan Zhou, Hong-Juan Peng.
      Protein phosphorylation plays a key role in host cell-T. gondii interaction. However, the phosphoproteome data of host cell at various phases of T. gondii infection has not been thoroughly described. In this study, we assessed the host phosphoproteome data with isobaric tags for relative and absolute quantification (iTRAQ) method during the phases of T. gondii invasion (30 min post infection, PI) and prior to egress (28 h PI). Our iTRAQ analysis revealed a total of 665 phosphoproteins, among which the significantly regulated phosphoproteins in different between-group comparisons were further analyzed. Functional analysis of these significantly regulated phosphoproteins suggested that T. gondii modulated host cell processes through phosphorylation including cell cycle regulation, inducing apoptosis, blocking the synthesis of some inflammatory factors, mediating metabolism to support its proliferation at the infection phase prior to egress, and utilizing membrane and energy from host cell, reorganizing cytoskeleton to favor its invasion and PV formation at the phase of invasion. The phosphorylation level of Smad2, CTNNA1, and HSPB1 identified with western blot revealed a consistent trend of change with iTRAQ result. These newly identified and significantly regulated phosphoproteins from our phosphoproteome data may provide new clues to unravel the host cell's complex reaction against T. gondii infection and the interaction between the host cell and T. gondii.
    Keywords:  Apoptosis; Host cell immunity; Phosphoproteomic analysis; Toxoplasma gondii; iTRAQ
    DOI:  https://doi.org/10.1016/j.bbapap.2018.12.004
  13. Pediatr Nephrol. 2018 Dec 19.
    Haptoglobin degradation product as a novel serum biomarker for hematopoietic stem cell transplant-associated thrombotic microangiopathy.
    Meredith P Schuh, Michael R Bennett, Adam Lane, Sonata Jodele, Benjamin L Laskin, Prasad Devarajan.
       BACKGROUND: Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a well-known complication of HSCT and carries high risk of morbidity and mortality. A lack of consistent non-invasive diagnostic criteria can delay diagnosis and lead to irreversible organ damage.
    METHODS: Serum samples of 100 patients that underwent HSCT at Cincinnati Children's Hospital were serially collected. Unbiased proteomic profiling by SELDI-TOF-MS was performed on serum from TA-TMA patients at baseline (pre-HSCT), 2 weeks before TMA diagnosis (pre-TMA), and at clinical TMA diagnosis. Two proteins with mass to charge ratios of 12-13 kDa were consistently elevated at the 2 week pre-TMA time point by SELDI-TOF, compared to control samples. Potential peptides were isolated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the Linear Trap Quadropole (LTQ). A MASCOT search identified haptoglobin fragments in the 12-17-kDa range. Western blot was performed to validate haptoglobin fragments as a potential biomarker.
    RESULTS: Western blot of TA-TMA patients showed haptoglobin fragments at 12, 14, and 17 kDa that varied between baseline, pre-TMA, and TMA time points for each patient. By densitometric analysis, the 17-kDa fragment in the pre-TMA samples differed significantly from TMA diagnosis (p < 0.0001). There was no significant difference in the concentrations of the 12-kDa and 14-kDa fragments.
    CONCLUSION: The 17-kDa haptoglobin degradation product may represent a novel early serum biomarker for TA-TMA that could potentially allow for earlier diagnosis and intervention.
    Keywords:  Biomarker; Haptoglobin; Hematopoietic stem cell transplant; Thrombotic microangiopathy
    DOI:  https://doi.org/10.1007/s00467-018-4178-x
  14. Proteomics Clin Appl. 2018 Dec 17. e1800183
    Proteomics in the Diagnosis of Endometriosis: Opportunities and Challenges.
    Simone Ferrero.
      The non-surgical diagnosis of endometriosis is still challenging for the clinician. Ultrasonography and magnetic resonance imaging can be used to diagnose ovarian endometriotic cysts and deep infiltrating endometriosis; but their performance is poor in the diagnosis of initial stages of endometriosis. CA-125 and other serum markers (such as CA 19-9, serum protein PP14, interleukins and angiogenetic factors) have been measured in women with endometriosis but they are not reliable for the diagnosis of the disease. Although several studies used proteomics technologies to identify plasmatic markers of endometriosis, the non-invasive diagnosis of endometriosis is far from being achieved. In this issue, Manousopoulou et al. compared the integrated quantitative proteomic profile of eutopic endometrium and serum of women with endometriosis and controls. 1,214 proteins were differentially expressed in the eutopic endometrium and 404 proteins in the serum of the two study groups. 21 proteins were aberrantly expressed in both eutopic endometrium and serum of women with endometriosis. More work is needed to assess if the differentially expressed proteins identified in this study can be used as clinical markers of endometriosis. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/prca.201800183
  15. Expert Rev Mol Diagn. 2018 Dec 18. 1-9
    Systematic review on recent potential biomarkers of chronic obstructive pulmonary disease.
    Eda Aydindogan, Deborah Penque, Jerome Zoidakis.
       INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide and associated with decreased lung function and inflammation. The heterogeneity of COPD and its molecular and clinical features hinder efficient patient stratification and introduction of personalized therapeutic approaches. The available clinical tools do not efficiently predict the progression and exacerbations of the disease. Areas covered: An overview of the most recent studies on putative COPD protein biomarkers and the challenges for implementing their use in the clinical setting is presented. Expert commentary: Proteomics biomarker discovery in COPD has mostly focused on approaches evaluating specific proteins on a limited number of samples. The most promising protein candidates can be classified into five main biological categories: extracellular matrix (ECM) remodeling, inflammation/immune response, oxidative stress response, vascular tone regulation, and lipid metabolism. To efficiently stratify COPD patients and predict exacerbations, it will be necessary to implement biomarker panels to better represent the complex pathophysiology of this disease. The application of unbiased proteomics and bioinformatics followed by appropriate clinical validation studies will contribute to the achievement of this aim while increasing the number of validated biomarkers that can enter the qualification processes by the regulatory entities.
    Keywords:  COPD; Protein biomarkers; biomarkers; exacerbations; mortality; proteomics
    DOI:  https://doi.org/10.1080/14737159.2018.1559054
  16. Proteomics. 2018 Dec 18. e1800169
    Oncogenic Regulation Of Extracellular Vesicle Proteome And Heterogeneity.
    Dongsic Choi, Cristiana Spinelli, Laura Montermini, Janusz Rak.
      Mutational and epigenetic driver events profoundly alter intercellular communication pathways in cancer. This effect includes deregulated release, molecular composition, and biological activity of extracellular vesicles (EVs), membranous cellular fragments ranging from a few microns to less than 100 nanometers in diameter and filled with bioactive molecular cargo (proteins, lipids and nucleic acids). While EVs are usually classified on the basis of their physical properties and biogenetic mechanisms recent analyses of their proteome suggest a larger than expected molecular diversity, a notion that is also supported by multicolour nano-flow cytometry and other emerging technology platforms designed to analyze single EVs. Both protein composition and EV diversity are markedly altered by oncogenic transformation, epithelial to mesenchymal transition and differentiation of cancer stem cells. Interestingly, only a subset of EVs released from mutant cells may carry oncogenic proteins (e.g. EGFRvIII), hence these EVs are often referred to as "oncosomes". Indeed, oncogenic transformation alters the repertoire of EV-associated proteins, increases the presence of pro-invasive cargo, and alters the composition of distinct EV populations. Molecular profiling of single EVs may reveal a more intricate effects of transforming events on the architecture of EV populations in cancer and shed new light on their biological role and diagnostic utility. This article is protected by copyright. All rights reserved.
    Keywords:  ectosomes; exosomes; heterogeneity; nano flow cytometry; oncogenes; proteomics; subtypes
    DOI:  https://doi.org/10.1002/pmic.201800169
  17. Front Immunol. 2018 ;9 2756
    Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots.
    Christopher J Collins, Irene J Chang, Sunhee Jung, Remwilyn Dayuha, Jeffrey R Whiteaker, Gesmar R S Segundo, Troy R Torgerson, Hans D Ochs, Amanda G Paulovich, Si Houn Hahn.
      Background: Primary immunodeficiency disorders (PIDD) comprise a group of life-threatening congenital diseases characterized by absent or impaired immune responses. Despite the fact that effective, curative treatments are available with optimal clinical outcomes when diagnosed early, newborn screening does not exist for the majority of these diseases due to the lack of detectable, specific biomarkers or validated methods for population-based screening. Peptide immunoaffinity enrichment coupled with selected reaction monitoring mass spectrometry (immuno-SRM) is a sensitive proteomic assay, involving antibody-mediated peptide capture, that allows for concurrent quantification of multiple analytes. This assay has promise for use in potential newborn screening of PIDDs that lead to diminished or absent target proteins in the majority of cases. Objective: To determine and evaluate if a multiplex assay based on immuno-SRM is able to reliably and precisely distinguish affected patients with X-linked agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), and CD3ϵ-associated severe combined immunodeficiency (SCID) from one another and from unaffected normal control dried blood spot (DBS) samples. Methods: We performed a blinded, multiplexed analysis of proteolytically-generated peptides from WASp, BTK, and CD3ϵ (for WAS, XLA, and SCID, respectively) in DBS samples from 42 PIDD patients, 40 normal adult controls, and 62 normal newborns. The peptide ATPase copper transporting protein (ATP7B) 1056 was simultaneously monitored for quality assurance purposes. Results: The immuno-SRM assays reliably quantified the target peptides in DBS and accurately distinguished affected patients from normal controls. Analysis of signature peptides found statistically significant reduction or absence of peptide levels in affected patients compared to control groups in each case (WASp and BTK: p = 0.0001, SCID: p = 0.05). Intra and inter-assay precision ranged from 11 to 22% and 11 to 43% respectively; linearity (1.39-2000 fmol peptide), and stability (≤ 0.09% difference in 72 h) showed high precision for the multiplexed assay. Inter-laboratory assay comparison showed high concordance for measured peptide concentrations, with R2 linearity ≥ 0.97 for the WASp 274, CD3ϵ 197, BTK 407, and ATP7B 1056 peptides. Conclusion: Immuno-SRM-based quantification of proteotypic peptides from WASp, BTK, and CD3ϵ in DBS distinguishes relevant PIDD cases from one another and from controls, raising the possibility of employing this approach for large-scale multiplexed newborn screening of selective PIDDs.
    Keywords:  Dried Blood Spot (DBS); Primary Immunodeficiency Disorders (PIDD); Severe Combined Immunodeficiency (SCID); Stable Isotope Standards and Capture by Anti-Peptide Antibodies (SISCAPA); Wiskott-Aldrich Syndrome (WAS); X-linked Agammaglobulinemia (XLA); newborn screening (NBS); peptide immunoaffinity enrichment coupled to SRM (immuno-SRM)
    DOI:  https://doi.org/10.3389/fimmu.2018.02756
  18. Eur J Immunol. 2018 Dec 22.
    High-dimensional single-cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis.
    Sebastian Fuchs, Nadia Sawas, Nicolas Staedler, David A Schubert, Annalisa D'Andrea, Robert Zeiser, Luca Piali, Petr Hruz, Andreas P Frei.
      Immune checkpoints are regulators of immune cells and play key roles in the modulation of immune responses. The role of checkpoints in autoimmune disease is poorly understood but likely to be central since checkpoint inhibition during cancer treatment can cause autoimmunity. We generated a high-dimensional single-cell proteomics data set from PBMCs of healthy individuals and patients with ulcerative colitis (UC) by mass cytometry, enabling systems-wide analyses of immune cell frequencies and cell type-specific expression patterns of 12 immune checkpoints. Subtle but significant changes in immune cell frequencies and checkpoint expression were observed between UC patients on different treatment regimens and between patients and healthy controls. Most strikingly, UC patients showed a reduced number of peripheral NK-cells and those cells showed an altered phenotype including increased TIGIT expression. Based on these results, we modulated NK-cell function ex vivo through targeting of TIGIT pathway members. In summary, we describe a pattern of changes in immune cell abundance and checkpoint expression as a basis for UC patient stratification and we show modulation of a corresponding immune cell subset through checkpoint targeting. Our approach can be used for the identification of pathogenic immune cell subsets and guide target selection in autoimmunity and chronic inflammation. This article is protected by copyright. All rights reserved.
    Keywords:  CyTOF; Single-cell proteomics; immune checkpoints; inflammation; ulcerative colitis
    DOI:  https://doi.org/10.1002/eji.201847862
  19. Nutrients. 2018 Dec 14. pii: E1981. [Epub ahead of print]10(12):
    Proteomic Analysis of Zn Depletion/Repletion in the Hormone-Secreting Thyroid Follicular Cell Line FRTL-5.
    Barbara Guantario, Angela Capolupo, Maria Chiara Monti, Guido Leoni, Giulia Ranaldi, Alessandra Tosco, Liberato Marzullo, Chiara Murgia, Giuditta Perozzi.
      Zinc deficiency predisposes to a wide spectrum of chronic diseases. The human Zn proteome was predicted to represent about 10% of the total human proteome, reflecting the broad array of metabolic functions in which this micronutrient is known to participate. In the thyroid, Zn was reported to regulate cellular homeostasis, with a yet elusive mechanism. The Fischer Rat Thyroid Cell Line FRTL-5 cell model, derived from a Fischer rat thyroid and displaying a follicular cell phenotype, was used to investigate a possible causal relationship between intracellular Zn levels and thyroid function. A proteomic approach was applied to compare proteins expressed in Zn deficiency, obtained by treating cells with the Zn-specific chelator N,N,N',N'-tetrakis (2-pyridylmethyl) ethylene-diamine (TPEN), with Zn repleted cells. Quantitative proteomic analysis of whole cell protein extracts was performed using stable isotope dimethyl labelling coupled to nano-ultra performance liquid chromatography-mass spectrometry (UPLC-MS). TPEN treatment led to almost undetectable intracellular Zn, while decreasing thyroglobulin secretion. Subsequent addition of ZnSO₄ fully reversed these phenotypes. Comparative proteomic analysis of Zn depleted/repleted cells identified 108 proteins modulated by either treatment. Biological process enrichment analysis identified functions involved in calcium release and the regulation of translation as the most strongly regulated processes in Zn depleted cells.
    Keywords:  calcium channels; endocrine tissues; metal ion; ribosomes; zinc transport
    DOI:  https://doi.org/10.3390/nu10121981
  20. Urolithiasis. 2018 Dec 18.
    Urinary proteome in inherited nephrolithiasis.
    Giovanna Capolongo, Miriam Zacchia, Alessandra Perna, Davide Viggiano, Giovambattista Capasso.
      In the last decades, proteomics has been largely applied to the Nephrology field, with the double aim to (1) elucidate the biological processes underlying renal diseases; (2) identify disease-specific biomarkers, predictor factors of therapeutic efficacy and prognostic factors of disease progression. Kidney stone disease, and in particular, inherited nephrolithiasis (INL) are not an exception. Given the multifactorial origin of these disorders, the combination of genomics and proteomics studies may complement each other, with the final objective to give a global and comprehensive mechanistic view. In this review, we summarize the results of recent proteomic studies which have expanded our knowledge about INL, focusing the attention on monogenic forms of nephrolithiasis (cystinuria, Dent's disease, Bartter syndrome, distal renal tubular acidosis and primary hyperoxaluria), on polygenic hypercalciuria and on medullary sponge kidney disease.
    Keywords:  Biomarker; Genetic nephrolithiasis; Proteomics; Urine
    DOI:  https://doi.org/10.1007/s00240-018-01104-y
  21. Proteomics. 2018 Dec 17. e1800176
    Analysing the Secretome of Gut Microbiota as the Next Strategy For Early Detection of Colorectal Cancer.
    Putri-Intan-Hafizah Megat Mohd Azlan, Siok-Fong Chin, Teck Yew Low, Neoh Hui-Min, Rahman Jamal.
      Dysbiosis of gut microbiome can contribute to inflammation, and subsequently initiation and progression of colorectal cancer (CRC). Throughout these stages, various proteins and metabolites are secreted to the external environment by microorganisms or the hosts themselves. Studying these proteins may help enhance our understanding of the host-microorganism relationship or they may even serve as useful biomarkers for CRC. However, secretomic studies of gut microbiome of CRC patients, until now, are scarcely performed. In this viewpoint article, we focus on the roles of gut microbiome in CRC, highlight the current findings on CRC secretome and address the emerging challenges and strategies to drive forward this area of research. This article is protected by copyright. All rights reserved.
    Keywords:  colorectal cancer; gut microbiome; mass spectrometry; metaproteomics; secretome
    DOI:  https://doi.org/10.1002/pmic.201800176
  22. Int J Mol Sci. 2018 Dec 17. pii: E4081. [Epub ahead of print]19(12):
    Identification of Novel Therapeutic Targets for Pulmonary Arterial Hypertension.
    Kimio Satoh, Nobuhiro Kikuchi, Taijyu Satoh, Ryo Kurosawa, Shinichiro Sunamura, Mohammad Abdul Hai Siddique, Junichi Omura, Nobuhiro Yaoita, Hiroaki Shimokawa.
      Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are fatal diseases; however, their pathogenesis still remains to be elucidated. We have recently screened novel pathogenic molecules and have performed drug discovery targeting those molecules. Pulmonary artery smooth muscle cells (PASMCs) in patients with PAH (PAH-PASMCs) have high proliferative properties like cancer cells, which leads to thickening and narrowing of distal pulmonary arteries. Thus, we conducted a comprehensive analysis of PAH-PASMCs and lung tissues to search for novel pathogenic proteins. We validated the pathogenic role of the selected proteins by using tissue-specific knockout mice. To confirm its clinical significance, we used patient-derived blood samples to evaluate the potential as a biomarker for diagnosis and prognosis. Finally, we conducted a high throughput screening and found inhibitors for the pathogenic proteins.
    Keywords:  biomarker; drug discovery; pathogenesis; pulmonary hypertension
    DOI:  https://doi.org/10.3390/ijms19124081
  23. J Proteome Res. 2018 Dec 18.
    An Optimised Method for the Proteomic Analysis of Low Volumes of Cell Culture Media and the Secretome: The Application and the Demonstration of Altered Protein Expression in iPSC-Derived Neuronal Cell Lines from Parkinson's Disease Patients.
    Anna Baud, Daniel Little, Teo Qi Wen, Wendy E Heywood, Paul Gissen, Kevin Mills.
      Traditionally, cell culture medium in iPSC-derived cell work is not the main focus of research and often considered as just "food for cells". We demonstrate that by manipulation of the media and optimised methodology, it is possible to use this solution to study the proteins that the cell secretes ("secretome"). This is particularly useful in the study of iPSC-derived neurons, which require long culture time. We demonstrate that media can be considered as the cellular equivalent of cerebrospinal fluid and can be used to model diseases with optimised incubation and sampling times. The ability not to sacrifice cells allows significant cost and research benefits. In this manuscript we describe an optimised method for the analysis of the cell media from iPSC-derived neuronal lines from control and Parkinson's disease patients. We have evaluated the use of standard and supplement B27-free cell media as well as five different sample preparation techniques for proteomic analysis of the cell secretome. Mass spectral analysis of culture media allowed for the identification of > 500 proteins, in 500 µL of media which is 20-40 less volume than reported previously. Using shorter incubation times and our optimized methodology, we describe the use of this technique to study and describe potential disease mechanisms in Parkinson's disease.
    DOI:  https://doi.org/10.1021/acs.jproteome.8b00831
  24. Front Oncol. 2018 ;8 585
    Plasma-Derived Inflammatory Proteins Predict Oral Squamous Cell Carcinoma.
    Kelly Yi Ping Liu, Xian Jun David Lu, Yuqi Sarah Zhu, Nhu Le, Hugh Kim, Catherine F Poh.
      Oral squamous cell carcinoma (OSCC) is a major concern with high morbidity and mortality worldwide, even with the current knowledge and the advancement in treatment. OSCCs diagnosed at late-stage often require wide-excision with or without neck dissection, radiotherapy, or chemotherapy. When deemed successful, treatment often results in diminished quality of life, impaired function, and disfigurement. Strategies for early detection are urgently needed for patients afflicted with this disease. Inflammatory protein plasma biomarkers have shown to be potential tests for early detection and disease monitoring in several cancers. There has been no study on inflammation-related plasma biomarkers in OSCC. The objectives of the study were to use a multiplex approach to screen plasma-derived biomarkers and to examine the association of measurable proteins with OSCC. A total of 260 plasma samples (210 OSCC and 50 normal controls) were collected to measure for concentration of inflammatory related biomarkers using electrochemiluminescence multiplex assay. After screening of 82 potential biomarkers of the first 160 OSCC, 16 cytokines, chemokines, and growth factors were identified and verified in the second set of samples containing 50 OSCC and 50 normal. After adjustment of age and batch effects, the adjusted differential expression analysis showed that the OSCCs were markedly lower in 14 biomarkers and significantly higher level of interleukin 1 receptor antagonist (IL1Ra). By performing unsupervised clustering analysis, we observed distinctive groups of normal and two subgroups of OSCC. Linear regression of IL2, IL1Ra, and macrophage inhibitory factor (MIF) showed high accuracy in classifying OSCC with sensitivity of 0.96 and specificity of 0.92. In conclusion, this is the first paper to identify potential inflammatory plasma protein biomarkers of patients with OSCC. With further validation, the set of biomarkers can potentially be used to assist in early detection of OSCC when the disease is localized and in more treatable stage.
    Keywords:  biomarker; clinical outcomes; inflammation; oral carcinogenesis; plasma; protein expression
    DOI:  https://doi.org/10.3389/fonc.2018.00585
  25. Front Immunol. 2018 ;9 2793
    Proteomics, Bioinformatics and Structure-Function Antigen Mining For Gonorrhea Vaccines.
    Benjamin I Baarda, Fabian G Martinez, Aleksandra E Sikora.
      Expanding efforts to develop preventive gonorrhea vaccines is critical because of the serious health consequences combined with the prevalence and the dire possibility of untreatable gonorrhea. Reverse vaccinology, which includes genome and proteome mining, has proven successful in the discovery of vaccine candidates against many pathogenic bacteria. Here, we describe proteomic applications including comprehensive, quantitative proteomic platforms and immunoproteomics coupled with broad-ranging bioinformatics that have been applied for antigen mining to develop gonorrhea vaccine(s). We further focus on outlining the vaccine candidate decision tree, describe the structure-function of novel proteome-derived antigens as well as ways to gain insights into their roles in the cell envelope, and underscore new lessons learned about the fascinating biology of Neisseria gonorrhoeae.
    Keywords:  Neisseria gonorrhoeae; antigen; bioinformatics; membrane vesicles; protein structure-function; proteomics; reverse vaccinology; vaccine
    DOI:  https://doi.org/10.3389/fimmu.2018.02793
  26. Semin Hematol. 2019 Jan;pii: S0037-1963(18)30057-X. [Epub ahead of print]56(1): 52-57
    Mass spectrometry and proteomics in hematology.
    Delphine C M Rolland, Megan S Lim, Kojo S J Elenitoba-Johnson.
      Mass spectrometry-based techniques now enable the unbiased identification of proteins in complex mixtures including proteins isolated from cells and tissues. These powerful tools permit near-complete annotation of proteins expressed in cells, tissues or organs. Further, these techniques permit the interrogation of the numerous posttranslational modifications that govern cell-specific responses to signaling cues and underlie the functional heterogeneity of cellular composition and contribute to biological complexity. Parallel developments in technologies such as mass cytometry and multicolor ion-beam imaging which permit multi-parameter detection of numerous proteins at the single-cell and in situ level respectively, are poised to radically impact our understanding of the functional and translational importance of proteins in hematologic conditions. Importantly, the field of proteomics is poised to realize the immensely powerful opportunities in integration with genomic information that is being discovered at an unprecedented pace for many hematologic conditions.
    Keywords:  Hematology; Mass spectrometry; Proteomics
    DOI:  https://doi.org/10.1053/j.seminhematol.2018.05.009
  27. Int J Mol Sci. 2018 Dec 19. pii: E4123. [Epub ahead of print]19(12):
    High Throughput Chemical Screening Reveals Multiple Regulatory Proteins on FOXA1 in Breast Cancer Cell Lines.
    Shixiong Wang, Sachin Kumar Singh, Madhumohan R Katika, Sandra Lopez-Aviles, Antoni Hurtado.
      Forkhead box A1 (FOXA1) belongs to the forkhead class transcription factor family, playing pioneering function for hormone receptors in breast and prostate cancers, and mediating activation of linage specific enhancers. Interplay between FOXA1 and breast cancer specific signaling pathways has been reported previously, indicating a regulation network on FOXA1 in breast cancer cells. Here in this study, we aimed to identify which are the proteins that could potentially control FOXA1 function in breast cancer cell lines expressing different molecular markers. We first established a luciferase reporter system reflecting FOXA1 binding to DNA. Then, we applied high throughput chemical screening of multiple protein targets and mass spectrometry in breast cancer cell lines expressing different molecular markers: ER positive/HER2 negative (MCF-7), ER positive/HER2 positive (BT474), and ER negative/HER2 positive (MDA-MB-453). Regardless of estrogen receptor status, HER2 (human epidermal growth factor receptor 2) enriched cell lines showed similar response to kinase inhibitors, indicating the control of FOXA1 by cell signaling kinases. Among these kinases, we identified additional receptor tyrosine kinases and cyclin-dependent kinases as regulators of FOXA1. Furthermore, we performed proteomics experiments from FOXA1 inmunoprecipitated protein complex to identify that FOXA1 interacts with several proteins. Among all the targets, we identified cyclin-dependent kinase 1 (CDK1) as a positive factor to interact with FOXA1 in BT474 cell line. In silico analyses confirmed that cyclin-dependent kinases might be the kinases responsible for FOXA1 phosphorylation at the Forkhead domain and the transactivation domain. These results reveal that FOXA1 is potentially regulated by multiple kinases. The cell cycle control kinase CDK1 might control directly FOXA1 by phosphorylation and other kinases indirectly by means of regulating other proteins.
    Keywords:  FOXA1; breast cancer; drug screening and proteomics
    DOI:  https://doi.org/10.3390/ijms19124123
  28. Front Psychol. 2018 ;9 2400
    Plasma Protein Pattern Correlates With Pain Intensity and Psychological Distress in Women With Chronic Widespread Pain.
    Karin Wåhlén, Bijar Ghafouri, Nazdar Ghafouri, Björn Gerdle.
      Objectives: Although generalized muscle pain, tiredness, anxiety, and depression are commonly present among chronic widespread pain (CWP) patients, the molecular mechanisms behind CWP are not fully elucidated. Moreover, the lack of biomarkers often makes diagnosis and treatment problematic. In this study, we investigated the correlation between pain intensity, psychological distress, and plasma proteins among CWP patients and controls (CON). Methods: The plasma proteome of CWP (n = 15) and CON (n = 23) was analyzed using two-dimensional gel electrophoresis. Orthogonal Partial Least Square analysis (OPLS) was used to determine proteins associated with pain intensity (numeric rating scale) in CWP and psychological distress (Hospital and Depression Scale, HADS) in CWP and CON. Significant proteins were identified by MALDI-TOF and tandem MS. Results: In CWP, pain intensity was associated with plasma proteins mostly involved in metabolic and immunity processes (e.g., kininogen-1, fibrinogen gamma chain, and ceruloplasmin), and psychological distress was associated with plasma proteins related to immunity response, iron ion, and lipid metabolism (e.g., complement factor B, complement C1r subcomponent, hemopexin, and clusterin). Discussion: This study suggests that different plasma protein patterns are associated with different pain intensity and psychological distress in CWP. Proteins belonging to the coagulation cascade and immunity processes showed strong associations to each clinical outcome. Using the plasma proteome profile of CWP to study potential biomarker candidates provides a snapshot of ongoing systemic mechanisms in CWP.
    Keywords:  biomarker; fibromyalgia; inflammation; pain; psychological distress
    DOI:  https://doi.org/10.3389/fpsyg.2018.02400
  29. PLoS One. 2018 ;13(12): e0208042
    Proteomic analysis of heart failure hospitalization among patients with chronic kidney disease: The Heart and Soul Study.
    Ruth F Dubin, Mary Whooley, Alexander Pico, Peter Ganz, Nelson B Schiller, Craig Meyer.
       BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk for heart failure (HF). We aimed to investigate differences in proteins associated with HF hospitalizations among patients with and without CKD in the Heart and Soul Study.
    METHODS AND RESULTS: We measured 1068 unique plasma proteins from baseline samples of 974 participants in The Heart and Soul Study who were followed for HF hospitalization over a median of 7 years. We sequentially applied forest regression and Cox survival analyses to select prognostic proteins. Among participants with CKD, four proteins were associated with HF at Bonferroni-level significance (p<2.5x10-4): Angiopoietin-2 (HR[95%CI] 1.45[1.33, 1.59]), Spondin-1 (HR[95%CI] 1.13 [1.06, 1.20]), tartrate-resistant acid phosphatase type 5 (HR[95%CI] 0.65[0.53, 0.78]) and neurogenis locus notch homolog protein 1 (NOTCH1) (HR[95%CI] 0.67[0.55, 0.80]). These associations persisted at p<0.01 after adjustment for age, estimated glomerular filtration and history of HF. CKD was a significant interaction term in the associations of NOTCH1 and Spondin-1 with HF. Pathway analysis showed a trend for higher representation of the Cardiac Hypertrophy and Complement/Coagulation pathways among proteins prognostic of HF in the CKD sub-group.
    CONCLUSIONS: These results suggest that markers of heart failure differ between patients with and without CKD. Further research is needed to validate novel markers in cohorts of patients with CKD and adjudicated HF events.
    DOI:  https://doi.org/10.1371/journal.pone.0208042
  30. J Mol Neurosci. 2018 Dec 15.
    The Challenge to Search for New Nervous System Disease Biomarker Candidates: the Opportunity to Use the Proteogenomics Approach.
    Thais Guimarães Martins Nery, Esdras Matheus Silva, Raphael Tavares, Fabio Passetti.
      Alzheimer's disease, Parkinson's disease, prion diseases, schizophrenia, and multiple sclerosis are the most common nervous system diseases, affecting millions of people worldwide. The current scientific literature associates these pathological conditions to abnormal expression levels of certain proteins, which in turn improved the knowledge concerning normal and affected brains. However, there is no available cure or preventive therapy for any of these disorders. Proteogenomics is a recent approach defined as the data integration of both nucleotide high-throughput sequencing and protein mass spectrometry technologies. In the last years, proteogenomics studies in distinct diseases have emerged as a strategy for the identification of uncharacterized proteoforms, which are all the different protein forms derived from a single gene. For many of these diseases, at least one protein used as biomarker presents more than one proteoform, which fosters the analysis of publicly available data focusing proteoforms. Given this context, we describe the most important biomarkers for each neurodegenerative disease and how genomics, transcriptomics, and proteomics separately contributed to unveil them. Finally, we present a selection of proteogenomics studies in which the combination of nucleotide and proteome high-throughput data, from cell lines or brain tissue samples, is used to uncover proteoforms not previously described. We believe that this new approach may improve our knowledge about nervous system diseases and brain function and an opportunity to identify new biomarker candidates.
    Keywords:  Nervous system diseases; Proteoform; Proteogenomics; Proteomics; RNA-Seq
    DOI:  https://doi.org/10.1007/s12031-018-1220-1
  31. Oncotarget. 2018 Nov 23. 9(92): 36444-36456
    Tissue proteomics outlines AGR2 AND LOX5 as markers for biochemical recurrence of prostate cancer.
    Giovanny Rodríguez-Blanco, Lona Zeneyedpour, Diederick Duijvesz, A Marije Hoogland, Esther I Verhoef, Charlotte F Kweldam, Peter C Burgers, Peter Sillevis Smitt, Chris H Bangma, Guido Jenster, Geert J L H van Leenders, Lennard J M Dekker, Theo M Luider.
      Although many patients are cured from prostate cancer (PCa) by surgery only, there are still patients who will experience rising prostate-specific antigen (PSA) levels after surgery, a condition known as biochemical recurrence (BCR). Novel protein prognostic markers in PCa tissue might enable finding better treatment for those patients experiencing BCR with a high chance of metastasis. In this study, we aimed to identify altered proteins in prostate cancer tissue, and to evaluate their potential role as prognostic markers. We used two proteomics strategies to analyse 34 prostate tumours (PCa) and 33 normal adjacent prostate (NAP) tissues. An independent cohort of 481 samples was used to evaluate the expression of three proteins: AGR2, FASN and LOX5 as prognostic markers of the disease. Tissue microarray immunohistochemical staining indicated that a low percentage of positive tumour cells for AGR2 (HR (95% CI) = 0.61 (0.43-0.93)), and a low percentage of positive tumour cells for LOX5 expression (HR (95% CI) = 2.53 (1.23-5.22)) are predictors of BCR after RP. In contrast, FASN expression had no prognostic value for PCa.
    Keywords:  arachidonic acid; mass spectrometry; prostate cancer
    DOI:  https://doi.org/10.18632/oncotarget.26342
  32. Gynecol Oncol. 2018 Dec 18. pii: S0090-8258(18)31515-4. [Epub ahead of print]
    A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer.
    David Mysona, Adam Pyrzak, Sharad Purohit, Wenbo Zhi, Ashok Sharma, Lynn Tran, Paul Tran, Shan Bai, Bunja Rungruang, Sharad Ghamande, Jin-Xiong She.
       OBJECTIVE: To investigate the utility of a combined panel of protein biomarkers and clinical factors to predict recurrence in serous ovarian cancer patients.
    METHODS: Women at Augusta University diagnosed with ovarian cancer were enrolled between 2005 and 2015 (n = 71). Blood was drawn at enrollment and follow-up visits. Patient serum collected at remission was analyzed using the SOMAscan array (n = 35) to measure levels of 1129 proteins. The best 26 proteins were confirmed using Luminex assays in the same 35 patients and in an additional 36 patients (ntotal = 71) as orthogonal validation. The data from these 26 proteins was combined with clinical factors using an elastic net multivariate model to find an optimized combination predictive of progression-free survival (PFS).
    RESULTS: Of the 26 proteins, Brain Derived Neurotrophic Factor and Platelet Derived Growth Factor molecules were significant for predicting PFS on both univariate and multivariate analyses. All 26 proteins were combined with clinical factors using the elastic net algorithm. Ten components were determined to predict PFS (HR of 6.55, p-value 1.12 × 10-6, CI 2.57-16.71). This model was named the serous high grade ovarian cancer (SHOC) score.
    CONCLUSION: The SHOC score can predict patient prognosis in remission. This tool will hopefully lead to early intervention and consolidation therapy strategies in remission patients destined to recur.
    Keywords:  Biomarkers; Ovarian neoplasm; Prognosis; Serum proteomics
    DOI:  https://doi.org/10.1016/j.ygyno.2018.12.015
  33. Proteomes. 2018 Dec 20. pii: E1. [Epub ahead of print]7(1):
    Proteomic Profiling of Primary Human Acute Myeloid Leukemia Cells Does Not Reflect Their Constitutive Release of Soluble Mediators.
    Elise Aasebø, Maria Hernandez-Valladares, Frode Selheim, Frode S Berven, Annette K Brenner, Øystein Bruserud.
      Acute myeloid leukemia (AML) is a heterogeneous disease, and communication between leukemic cells and their neighboring leukemia-supporting normal cells is involved in leukemogenesis. The bone marrow cytokine network is therefore important, and the mediator release profile seems more important than single mediators. It is not known whether the characterization of primary AML cell proteomes reflects the heterogeneity of the broad and dynamic constitutive mediator release profile by these cells. To address this, we compared the intracellular levels of 41 proteins in 19 AML patients with the constitutive extracellular release during in vitro culture, including chemokines, growth factors, proteases, and protease regulators. The constitutive release of most mediators showed a wide variation (up to 2000-fold differences) between patients. Detectable intracellular levels were seen for 10 of 41 mediators, but for most of these 10 mediators we could not detect significant correlations between the constitutive release during in vitro culture and their intracellular levels. Intracellular protein levels in primary human AML cells do not reflect the dynamics, capacity, and variation between patients in constitutive mediator release profiles. Measurements of these profiles thus add complementary information to proteomic detection/quantification regarding the heterogeneity of the AML cell contributions to the bone marrow cytokine network.
    Keywords:  acute myeloid leukemia; constitutive secretion; cytokine; protease; proteomics
    DOI:  https://doi.org/10.3390/proteomes7010001
  34. Int J Mol Sci. 2018 Dec 20. pii: E16. [Epub ahead of print]20(1):
    Clinically Relevant Post-Translational Modification Analyses-Maturing Workflows and Bioinformatics Tools.
    Dana Pascovici, Jemma X Wu, Matthew J McKay, Chitra Joseph, Zainab Noor, Karthik Kamath, Yunqi Wu, Shoba Ranganathan, Vivek Gupta, Mehdi Mirzaei.
      Post-translational modifications (PTMs) can occur soon after translation or at any stage in the lifecycle of a given protein, and they may help regulate protein folding, stability, cellular localisation, activity, or the interactions proteins have with other proteins or biomolecular species. PTMs are crucial to our functional understanding of biology, and new quantitative mass spectrometry (MS) and bioinformatics workflows are maturing both in labelled multiplexed and label-free techniques, offering increasing coverage and new opportunities to study human health and disease. Techniques such as Data Independent Acquisition (DIA) are emerging as promising approaches due to their re-mining capability. Many bioinformatics tools have been developed to support the analysis of PTMs by mass spectrometry, from prediction and identifying PTM site assignment, open searches enabling better mining of unassigned mass spectra-many of which likely harbour PTMs-through to understanding PTM associations and interactions. The remaining challenge lies in extracting functional information from clinically relevant PTM studies. This review focuses on canvassing the options and progress of PTM analysis for large quantitative studies, from choosing the platform, through to data analysis, with an emphasis on clinically relevant samples such as plasma and other body fluids, and well-established tools and options for data interpretation.
    Keywords:  PTM; body fluids; clinical samples; post translational modification; quantitative proteomics
    DOI:  https://doi.org/10.3390/ijms20010016
  35. Mol Cancer. 2018 Dec 21. 17(1): 177
    Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles.
    Robin Imperial, Zaheer Ahmed, Omer M Toor, Cihat Erdoğan, Ateeq Khaliq, Paul Case, James Case, Kevin Kennedy, Lee S Cummings, Niklas Melton, Shahzad Raza, Banu Diri, Ramzi Mohammad, Bassel El-Rayes, Timothy Pluard, Arif Hussain, Janakiraman Subramanian, Ashiq Masood.
      Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.
    Keywords:  Clonal evolution; Hotspot mutations; Left-sided colon cancer; Proteomics; Rectal cancers; Right-sided colon cancer
    DOI:  https://doi.org/10.1186/s12943-018-0923-9
  36. J Proteomics. 2018 Dec 14. pii: S1874-3919(18)30444-5. [Epub ahead of print]
    Dissecting the molecular effects of cigarette smoke on proteasome function.
    Ilona E Kammerl, Anne Caniard, Juliane Merl-Pham, Gili Ben-Nissan, Christoph H Mayr, Alessandra Mossina, Arie Geerlof, Oliver Eickelberg, Stefanie M Hauck, Michal Sharon, Silke Meiners.
      Proteasome dysfunction is emerging as a novel pathomechanism for the development of chronic obstructive pulmonary disease (COPD), a major leading cause of death in the world. Cigarette smoke, one of the main risk factors for COPD, impairs proteasome function in vitro and in vivo. In the present study, we dissected the molecular changes induced by cigarette smoke on the proteasome in lung epithelial cells and mouse lungs. 26S proteasome pull-down, MS interactome, and stoichiometry analyses indicated that 26S proteasome complexes become instable in cigarette smoke-treated lung epithelial cells as well as in lungs of mice after three day smoke exposure. The interactome of the 26S was clearly altered in mouse lungs upon smoke exposure but not in cells after 24 h of smoke exposure. Using native MS analysis of purified 20S proteasomes, we observed some destabilization of 20S complexes purified from cigarette smoke-exposed cells in the absence of any dominant and inhibitory modification of proteasomal proteins. Taken together, our results suggest that cigarette smoke induces minor but detectable changes in the stability of 20S and 26S proteasome complexes which might contribute to imbalanced proteostasis in a chronic setting as observed in chronic lung diseases associated with cigarette smoking.
    Keywords:  26S proteasome interactome; Cigarette smoke; Native MS analysis; Proteasome
    DOI:  https://doi.org/10.1016/j.jprot.2018.12.015
  37. Mol Cell Neurosci. 2018 Dec 15. pii: S1044-7431(18)30182-9. [Epub ahead of print]
    Impairment of chaperone-mediated autophagy affects neuronal homeostasis through altered expression of DJ-1 and CRMP-2 proteins.
    Oeystein Roed Brekk, Manousos Makridakis, Panagiota Mavroeidi, Antonia Vlahou, Maria Xilouri, Leonidas Stefanis.
      Chaperone-mediated autophagy (CMA) is a substrate-specific mode of lysosomal proteolysis, with multiple lines of evidence connecting its dysfunction to both ageing and disease. We have recently shown that CMA impairment through knock-down of the lysosomal receptor LAMP2A is detrimental to neuronal viability in vivo; however, it is not clear which subset of proteins regulated by the CMA pathway mediate such changes. In this study, we have manipulated CMA function through alterations of LAMP2A abundance of utilizing primary rat cortical neurons, to identify potential changes to the neuronal proteome occurring prior to actual toxic effects. We have identified a list of proteins with significant, >2-fold change in abundance following our manipulations, of which PARK7/DJ-1 - an anti-oxidant implicated in hereditary forms of Parkinson's Disease (PD), and DPYSL2/CRMP-2 - a microtubule-binding phosphoprotein involved in schizophrenia pathogenesis - were both found to have measurable effects on neuronal homeostasis and phenotype. Taken together, this study describes alterations in the abundance of neuronal proteins involved in neuropsychiatric disorders upon CMA manipulation, and suggests that such alterations may in part be responsible for the neurodegeneration observed upon CMA impairment in vivo.
    Keywords:  Chaperone-mediated autophagy (CMA); DPYSL2/CRMP-2; LAMP2A; PARK7/DJ-1; Parkinson's Disease (PD); Proteomics; Schizophrenia
    DOI:  https://doi.org/10.1016/j.mcn.2018.12.006
  38. Clin Oral Investig. 2018 Dec 15.
    Deep sequencing salivary proteins for periodontitis using proteomics.
    Myung-Seop Shin, Yun-Gon Kim, Yoo Jin Shin, Byoung Joon Ko, Sungtae Kim, Hyun-Duck Kim.
       OBJECTIVES: Saliva is a bodily fluid transuded from gingival crevice fluid and blood and contains many proteins. Proteins in saliva have been studied as markers for periodontal diseases. Mass spectrometric analysis is applied to investigate biomarker proteins that are related to periodontitis.
    MATERIAL AND METHODS: Saliva samples were collected from 207 participants including 36 pairs matched for age, sex, and smoking who joined Yangpyeong health cohort. Periodontitis was defined by 2005 5th European guideline. Shotgun proteomics was applied to detect proteins from saliva samples. Principal component analysis and Ingenuity Pathway Analysis for canonical pathway and protein pathway were applied. Protein-protein interaction was also applied. Enzyme-linked immunosorbent assay (ELISA) was used to verify the candidate protein markers among another matched participants (n = 80).
    RESULTS: Shotgun proteomics indicated that salivary S100A8 and S100A9 were candidate biomarkers for periodontitis. ELISA confirmed that both salivary S100A8 and S100A9 were higher in those with periodontitis compared to those without periodontitis (paired-t test, p < 0.05).
    CONCLUSION: Our proteomics data showed that S100A8 and S100A9 in saliva could be candidate biomarkers for periodontitis. The rapid-test-kit using salivary S100A8 and S100A9 will be a practical tool for reducing the risk of periodontitis and promotion of periodontal health.
    CLINICAL RELEVANCE: A rapid-test-kit using salivary biomarkers, S100A8 and S100A9, could be utilized by clinicians and individuals for screening periodontitis, which might reduce the morbidity of periodontitis and promote periodontal health.
    Keywords:  Ingenuity Pathway Analysis; Periodontitis; Protein biomarker; Proteomics; Saliva
    DOI:  https://doi.org/10.1007/s00784-018-2779-1
  39. Front Cell Neurosci. 2018 ;12 416
    The Effect of Myosin Light Chain Kinase on the Occurrence and Development of Intracranial Aneurysm.
    Yaying Song, Peixi Liu, Zongwei Li, Yuan Shi, Jun Huang, Sichen Li, Yingjun Liu, Zhijun Zhang, Yongting Wang, Wei Zhu, Guo-Yuan Yang.
      Myosin light chain kinase is a key enzyme in smooth muscle cell contraction. However, whether myosin light chain kinase plays a role in the occurrence or development of intracranial aneurysms is not clear. The present study explored the function of myosin light chain kinase in human intracranial aneurysm tissues. Five aneurysm samples and five control samples were collected, and smooth muscle cells (SMCs) were dissociated and cultured. A label-free proteomic analysis was performed to screen the differentially expressed proteins between aneurysm and control samples. The expression and function of myosin light chain kinase in aneurysms were examined. We found that 180 proteins were differentially expressed between the aneurysm and control samples, among which 88 were increased and 92 (including myosin light chain kinase) were decreased in aneurysms compared to control tissues. In a model of the inflammatory environment, contractility was weakened and apoptosis was increased in aneurysm SMCs compared to human brain SMCs (p < 0.05). The knock down of myosin light chain kinase in human brain SMCs caused effects similar to those observed in aneurysm SMCs. These results indicated that myosin light chain kinase plays an important role in maintaining smooth muscle contractility, cell survival and inflammation tolerance.
    Keywords:  aneurysm; myosin light chain kinase; phenotype switch; proteomic; smooth muscle cell
    DOI:  https://doi.org/10.3389/fncel.2018.00416
  40. Data Brief. 2018 Dec;21 2475-2481
    Shotgun proteomics data on the impact of hyperglycaemia on platelet protein acetylation by aspirin.
    Francesco Finamore, Jean-Luc Reny, Sarah Malacarne, Pierre Fontana, Jean-Charles Sanchez.
      This data article associated with the manuscript "A high glucose levels is associated with decreased aspirin-mediated acetylation of platelet cyclooxygenase (COX)-1 at serine 529: a pilot study" (Finamore et al., 2018) refers to the shotgun proteomics approach carried out on platelet protein extracts from diabetic patients and healthy controls. Platelet proteins were in vitro incubated with 500 µM aspirin for 30 min at 37 °C to enhance the acetylation process. After protein digestion with trypsin, DDA data were acquired on a Thermo QExactive plus using 3 technical replicate injections per sample. Here, we were able to elucidate the preferential sites of aspirin-induced acetylation on a significant fraction of the platelet proteome and to quantify the impact of diabetes on the effect of aspirin on several platelet proteins. Data are available via ProteomeXchange with identifier PXD011582.
    DOI:  https://doi.org/10.1016/j.dib.2018.11.082
  41. PLoS One. 2018 ;13(12): e0209599
    New antigens for the serological diagnosis of human visceral leishmaniasis identified by immunogenomic screening.
    Ana Maria Ravena Severino Carvalho, Tiago Antônio de Oliveira Mendes, Eduardo Antonio Ferraz Coelho, Mariana Costa Duarte, Daniel Menezes-Souza.
      Visceral leishmaniasis (VL) still represents a serious public health problem in Brazil due to the inefficiency of the control measures currently employed, that included early diagnosis and treatment of human cases, vector control, euthanasia of infected dogs and, recently approved in Brazil, treatment with Milteforam drug. Effective clinical management depend largely on early and unequivocal diagnosis, however, cross-reactivity have also been described in serological tests, especially when it refers to individuals from areas where Chagas' disease is also present. Thus, to discover new antigens to improve the current serological tests for VL diagnosis is urgently needed. Here, we performed an immunogenomic screen strategy to identify conserved linear B-cell epitopes in the predicted L. infantum proteome using the following criteria: i) proteins expressed in the stages found in the vertebrate host, amastigote stage, and secreted/excreted, to guarantee greater exposure to the immune system; ii) divergent from proteins present in other infectious disease pathogens with incidence in endemic areas for VL, as T. cruzi; iii) highly antigenic to humans with different genetic backgrounds, independently of the clinical stage of the disease; iv) stable and adaptable to quality-control tests to guarantee reproducibility; v) using statistical analysis to determine a suitable sample size to evaluate accuracy of diagnostic tests established by receiver operating characteristic strategy. We selected six predicted linear B-cell epitopes from three proteins of L. infantum parasite. The results demonstrated that a mixture of peptides (Mix IV: peptides 3+6) were able to identify VL cases and simultaneously able to discriminate infections caused by T. cruzi parasite with high accuracy (100.00%) and perfect agreement (Kappa index = 1.000) with direct methods performed by laboratories in Brazil. The results also demonstrated that peptide-6, Mix III (peptides 2+6) and I (peptides 2+3+6) are potential antigens able to used in VL diagnosis, represented by high accuracy (Ac = 99.52%, 99.52% and 98.56%, respectively). This study represents an interesting strategy for discovery new antigens applied to serologic diagnosis which will contribute to the improvement of the diagnosis of VL and, consequently, may help in the prevention, control and treatment of the disease in endemic areas of Brazil.
    DOI:  https://doi.org/10.1371/journal.pone.0209599
  42. Int J Mol Sci. 2018 Dec 17. pii: E4072. [Epub ahead of print]19(12):
    Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C.
    Silvia Cipriani, Vietxuan Phan, Jean-Jacques Médard, Rita Horvath, Hanns Lochmüller, Roman Chrast, Andreas Roos, Sally Spendiff.
      The neuromuscular junction (NMJ) appears to be a site of pathology in a number of peripheral nerve diseases. Charcot-Marie-Tooth (CMT) 4C is an autosomal recessive, early onset, demyelinating neuropathy. Numerous mutations in the SH3TC2 gene have been shown to underlie the condition often associated with scoliosis, foot deformities, and reduced nerve conduction velocities. Mice with exon 1 of the Sh3tc2 gene knocked out demonstrate many of the features seen in patients. To determine if NMJ pathology is contributory to the pathomechanisms of CMT4C we examined NMJs in the gastrocnemius muscle of SH3TC2-deficient mice. In addition, we performed proteomic assessment of the sciatic nerve to identify protein factors contributing to the NMJ alterations and the survival of demyelinated axons. Morphological and gene expression analysis of NMJs revealed a lack of continuity between the pre- and post-synaptic apparatus, increases in post-synaptic fragmentation and dispersal, and an increase in expression of the gamma subunit of the acetylcholine receptor. There were no changes in axonal width or the number of axonal inputs to the NMJ. Proteome investigations of the sciatic nerve revealed altered expression of extracellular matrix proteins important for NMJ integrity. Together these observations suggest that CMT4C pathology includes a compromised NMJ even in the absence of changes to the innervating axon.
    Keywords:  Charcot-Marie-Tooth disease 4C; SH3TC2; demyelination; mouse models; neuromuscular junction; peripheral neuropathy
    DOI:  https://doi.org/10.3390/ijms19124072
  43. Epilepsy Res. 2018 Nov 26. pii: S0920-1211(18)30479-0. [Epub ahead of print]149 92-101
    Harmonization of pipeline for preclinical multicenter plasma protein and miRNA biomarker discovery in a rat model of post-traumatic epileptogenesis.
    Alaa Kamnaksh, Noora Puhakka, Idrish Ali, Gregory Smith, Roxanne Aniceto, Jesse McCullough, Shalini Das Gupta, Xavier Ekolle Ndode-Ekane, Rhys Brady, Pablo Casillas-Espinosa, Matt Hudson, Cesar Santana-Gomez, Riikka Immonen, Pedro Andrade de Abreu, Nigel Jones, Sandy Shultz, Richard J Staba, Terence J O'Brien, Denes Agoston, Asla Pitkänen.
      The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is an international, multicenter, multidisciplinary study aimed at preventing epileptogenesis (EpiBioS4Rx: https://epibios.loni.usc.edu/). One of the study's major objectives is the discovery of diagnostic, prognostic, and predictive plasma protein and microRNA (miRNA) biomarkers that are sensitive, specific, and translatable to the human condition. Epilepsy due to structural brain abnormalities, secondary to neurological insults such as traumatic brain injury (TBI), currently represents ∼50% of all epilepsy cases. In the preclinical EpiBioS4Rx study, TBI was induced in adult male Sprague Dawley rats using a standardized protocol for lateral fluid-percussion injury. Whole blood was collected from the tail vein at baseline and 2, 9 and 30 days post-injury and processed for plasma separation. Biomaterial properties, sample preparation and integrity, and choice of analysis platform can significantly impact measured marker levels and, in turn, interpretation with respect to injury and/or other variables. We present here the results of procedural harmonization for the first 320 rats included in the EpiBioS4Rx study study, from three international research centers, and preliminary proteomic and miRNA analyses. We also discuss experimental considerations for establishing rigorous quality controls with the goal of harmonizing operating procedures across study sites, and delivering high-quality specimens for preclinical biomarker discovery in a rat model of post-traumatic epilepsy (PTE).
    Keywords:  Case report form; Common data elements; Post-traumatic epilepsy; Quality control; Standardization; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.eplepsyres.2018.11.009
  44. J Neurotrauma. 2018 Dec 20.
    Plasma TNF alpha is a predictor of persisting symptoms post-concussion in children.
    Georgia M Parkin, Cathriona Clarke, Michael Takagi, Stephen J C Hearps, Franz Babl, Gavin Davis, Vicki Anderson, Vera Ignjatovic.
      Mild traumatic brain injury (mTBI)-associated blood proteomics has become an emerging focus in the past decade, with the U.S Food and Drug Administration (FDA) recently approving the use of a blood test to determine the necessity of a CT scan following adult mTBI. We now also know that the blood proteome of children is different to that of adults and new evidence suggests that children may take longer to recover from an mTBI. Despite this, comparatively fewer studies have analyzed changes in blood protein expression following pediatric mTBI. Concussions, an mTBI subset, often go under-reported, despite the potential for post-concussive symptoms to last more than one month in up to 30% of children. In the current study, we used a multiplex immunoassay to measure blood protein expression of apoE, enolase 2, GFAP, IL-1B, IL-6, IL-8, IL-10, S100B, tau and TNFα at admission, 1-4 days, 2 weeks and 3 months post-pediatric concussion, comparing patients with normal recovery (n = 9) to those with persisting symptoms (n = 9). We identified significant differences in IL-6 (p < 0.001) and tau (p = 0.048) protein expression across time post-injury irrespective of clinical outcome and in IL-8 protein expression (p = 0.041) across time post-injury specific to children with persisting symptoms. Significantly, we have identified an increase in TNFα protein expression at 1-4 days post-injury (p = 0.031) in children with persisting symptoms compared to normal recovery. To our knowledge, this is the first study to identify TNFα as a potential blood biomarker for persisting symptoms post-pediatric concussion.
    Keywords:  BIOMARKERS; HUMAN STUDIES; PEDIATRIC BRAIN INJURY; PROTEOMICS; TRAUMATIC BRAIN INJURY
    DOI:  https://doi.org/10.1089/neu.2018.6042
  45. Neurobiol Dis. 2018 Dec 14. pii: S0969-9961(18)30479-0. [Epub ahead of print]
    A multiomic approach to characterize the temporal sequence in Alzheimer's disease-related pathology.
    Mikael Marttinen, Jussi Paananen, Antonio Neme, Vikram Mitra, Mari Takalo, Teemu Natunen, Kaisa M A Paldanius, Petra Mäkinen, Michael Bremang, Mitja I Kurki, Tuomas Rauramaa, Ville Leinonen, Hilkka Soininen, Annakaisa Haapasalo, Ian Pike, Mikko Hiltunen.
      No single-omic approach completely elucidates the multitude of alterations taking place in Alzheimer's disease (AD). Here, we coupled transcriptomic and phosphoproteomic approaches to determine the temporal sequence of changes in mRNA, protein, and phosphopeptide expression levels from human temporal cortical samples, with varying degree of AD-related pathology. This approach highlighted fluctuation in synaptic and mitochondrial function as the earliest pathological events in brain samples with AD-related pathology. Subsequently, increased expression of inflammation and extracellular matrix-associated gene products was observed. Interaction network assembly for the associated gene products, emphasized the complex interplay between these processes and the role of addressing post-translational modifications in the identification of key regulators. Additionally, we evaluate the use of decision trees and random forests in identifying potential biomarkers differentiating individuals with different degree of AD-related pathology. This multiomic and temporal sequence-based approach provides a better understanding of the sequence of events leading to AD.
    Keywords:  Alzheimer's disease; Human brain; Phosphoproteomics; Systems biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.nbd.2018.12.009
  46. Ann Clin Transl Neurol. 2018 Dec;5(12): 1492-1504
    Protein production is an early biomarker for RNA-targeted therapies.
    Wade K Self, Kathleen M Schoch, Jacob Alex, Nicolas Barthélemy, James G Bollinger, Chihiro Sato, Tracy Cole, Holly B Kordasiewicz, Eric Swayze, Randall J Bateman, Timothy M Miller.
       Objectives: Clinical trials for progressive neurodegenerative disorders such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA-targeted therapies.
    Methods: Transgenic animal models expressing human proteins implicated in neurodegenerative disorders - microtubule-associated protein tau (hTau) or superoxide dismutase-1 (hSOD1) - were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13C6-leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics.
    Results: ASO treatment lowered hTau mRNA and protein production (measured by 13C6-leucine-labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30 days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment.
    Interpretation: Measures of newly generated protein show earlier pharmacodynamics changes for RNA-lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA-targeted therapeutics.
    DOI:  https://doi.org/10.1002/acn3.657
  47. J Neurotrauma. 2018 Dec 20.
    TBIcare Investigator's response to "Raising the Bar for Traumatic Brain Injury Biomarker Research: Methods Make a Difference" by Papa and Wang.
    Jussi P Posti, Riikka Sk Takala, Olli Tenovuo.
      No abstract.
    Keywords:  BIOMARKERS; CLINICAL TRIAL; GLIA CELL RESPONSE TO INJURY; PROTEOMICS; TRAUMATIC BRAIN INJURY
    DOI:  https://doi.org/10.1089/neu.2017.5209
  48. Cell Physiol Biochem. 2018 Dec 14. 51(6): 2972-2988
    ATM-Mediated Phosphorylation of Cortactin Involved in Actin Polymerization Promotes Breast Cancer Cells Migration and Invasion.
    Lei Lang, Yixuan Hou, Yanlin Chen, Gang Tu, Jing Tao, Dan Yang, Lei Xi, Lixin Fu, Kexin Sun, Jiali Yin, Rui Chen, Meixi Peng, Shuiqing Liu, Manran Liu.
       BACKGROUND/AIMS: The ataxia-telangiectasia mutated (ATM) protein kinase is critical for the maintenance of genomic stability and acts as tumor suppressor. Although evidence shows that a DNA damage-independent ATM (oxidized ATM) may be involved in cancer progression, the underlying mechanism is still unclear.
    METHODS: Immunohistochemistry, immunofluorescence and western blotting were applied to detect the levels of oxidized ATM. Transwell assay was used to detect the cell migration and invasion abilities in different treatments. Quantitative phosphoproteome analysis was performed using hypoxic BT549 cells, in the presence or absence of Ku60019, a specific inhibitor of ATM kinase. The phosphorylated cortactin, the target protein of oxidized ATM, was confirmed by immunoprecipitation-western blots and in vitro kinase assay. The functions of phosphorylated cortactin were studied by specific short hairpin RNA, site-directed mutation, transwell assay, and actin polymerization assay.
    RESULTS: Enhanced oxidized ATM proteins were present not only in the advanced and invasive breast tumor tissues but also malignant hypoxic breast cancer cells, in the absence of DNA damage. Loss of ATM expression or inhibiting oxidized ATM kinase activity reduced breast cancer cell migration and invasion. Using quantitative phosphoproteomics approach, 333 oxidized ATM target proteins were identified, some of these proteins govern key signaling associated with gap junction, focal adhesion, actin cytoskeleton rearrangement. Cortactin, one of the biggest changed phospho-protein, is a novel oxidized ATM-dependent target in response to hypoxia. Mechanically, we reveal that hypoxia-activated ATM can enhance the binding affinity of cortactin with Arp2/3 complex by phosphorylating cortactin at serine 113, and as a result, in favor of breast cancer cell migration and invasion.
    CONCLUSION: Oxidized ATM can phosphorylate cortactin at serine 113, playing a critical role in promoting breast tumor cell mobility and invasion via actin polymerization.
    Keywords:  ATM; Cortactin; Hypoxia; Invasion; Phosphorylation
    DOI:  https://doi.org/10.1159/000496048
  49. Acta Neuropathol Commun. 2018 Dec 21. 6(1): 144
    GJA1 (connexin43) is a key regulator of Alzheimer's disease pathogenesis.
    Yuji Kajiwara, Erming Wang, Minghui Wang, Wun Chey Sin, Kristen J Brennand, Eric Schadt, Christian C Naus, Joseph Buxbaum, Bin Zhang.
      GJA1 (connexin43) has been predicted as the top key driver of an astrocyte enriched subnetwork associated with Alzheimer's disease (AD). In this study, we comprehensively examined GJA1 expression across 29 transcriptomic and proteomic datasets from post-mortem AD and normal control brains. We demonstrated that GJA1 was strongly associated with AD amyloid and tau pathologies and cognitive functions. RNA sequencing analysis of Gja1-/- astrocytes validated that Gja1 regulated the subnetwork identified in AD, and many genes involved in Aβ metabolism. Astrocytes lacking Gja1 showed reduced Apoe protein levels as well as impaired Aβ phagocytosis. Consistent with this, wildtype neurons co-cultured with Gja1-/- astrocytes contained higher levels of Aβ species than those with wildtype astrocytes. Moreover, Gja1-/- astrocytes was more neuroprotective under Aβ stress. Our results underscore the importance of GJA1 in AD pathogenesis and its potential for further investigation as a promising pharmacological target in AD.
    Keywords:  Alzheimer’s disease; Astrocyte; Cx43; GJA1; Gene networks; amyloidβ; connexin43
    DOI:  https://doi.org/10.1186/s40478-018-0642-x
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