bims-prodis Biomed News
on Proteomics in disease
Issue of 2018–12–16
forty papers selected by
Nancy Gough, Bioserendipity
  1. Analysis of the differential urinary protein profile in IgA nephropathy patients of Uygur ethnicity.
  2. A Combination of Proteomic Approaches Identifies A Panel of Circulating Extracellular Vesicle Proteins Related to the Risk of Suffering Cardiovascular Disease in Obese Patients.
  3. Proteome-wide tyrosine phosphorylation analysis reveals dysregulated signaling pathways in ovarian tumors.
  4. Anti-fibrosis activity of combination therapy with epigallocatechin gallate, taurine and genistein by regulating glycolysis, gluconeogenesis, and ribosomal and lysosomal signaling pathways in HSC-T6 cells.
  5. An integrated quantitative proteomic and metabolomics approach to reveal the negative regulation mechanism of LamB in antibiotics resistance.
  6. Proteomic Analysis of the initial Oral Pellicle in Caries-Active and Caries-Free Individuals.
  7. Dynamic changes of urinary proteins in a rat model of acute hypercoagulable state induced by tranexamic acid.
  8. Quantitative Proteomic Analysis Identifies MAPK15 as a Potential Regulator of Radioresistance in Nasopharyngeal Carcinoma Cells.
  9. Proteomic Evidence of Biological Ageing in a Child with a Compound Heterozygous ZMPSTE24 Mutation.
  10. Quantitative Proteomics by SWATH-MS Suggest an Association Between Circulating Exosomes and Maternal Metabolic Changes in Gestational Diabetes Mellitus.
  11. Development of a class prediction model to discriminate pancreatic ductal adenocarcinoma from pancreatic neuroendocrine tumor by MALDI mass spectrometry imaging.
  12. Proteomic analysis of protein homeostasis and aggregation.
  13. A proteomic approach to identify novel disease biomarkers in LCAT deficiency.
  14. Network proteomics of human dermal wound healing.
  15. Integration of Proteomics and Metabolomics Revealed Metabolite-Protein Networks in ACTH-Secreting Pituitary Adenoma.
  16. The contribution and perspectives of proteomics to uncover ovarian cancer tumor markers.
  17. Rapid Detection and Identification of Antimicrobial Peptide Fingerprints of Nasal Fluid by Mesoporous Silica Particles and MALDI-TOF/TOF Mass Spectrometry: From the Analytical Approach to the Diagnostic Applicability in Precision Medicine.
  18. Plasma Proteome Profiling Reveals Dynamics of Inflammatory and Lipid Homeostasis Markers after Roux-En-Y Gastric Bypass Surgery.
  19. Identification and validation of differentially expressed proteins in serum of CSU patients with different duration of wheals using an iTRAQ labeling, 2D-LC-MS/MS.
  20. Interstitial Fluid in Gynecologic Tumors and Its Possible Application in the Clinical Practice.
  21. Protein-Based Salivary Profiles as Novel Biomarkers for Oral Diseases.
  22. Identification of salivary peptidomic biomarkers in chronic kidney disease patients undergoing haemodialysis.
  23. Proteomic analysis of olfactory bulb suggests CACNA1E as a promoter of CREB signaling in microbiota-induced depression.
  24. The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury.
  25. Prospective exosome-focused translational research for afatinib study of non-small cell lung cancer patients expressing EGFR (EXTRA study).
  26. figHigh Spatial Resolution MALDI-MS Imaging in the Study of Membranous Nephropathy.
  27. Proteomic analyses reveal lower expression of TEX40 and ATP6V0A2 proteins related to calcium ion entry and acrosomal acidification in asthenozoospermic males.
  28. A Complete Proteomic Workflow to Study Brain-Related Disorders via Postmortem Tissue.
  29. Xiao-Xu-Ming decoction extract regulates differentially expressed proteins in the hippocampus after chronic cerebral hypoperfusion.
  30. The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy.
  31. Discovery and qualification of candidate urinary biomarkers of disease activity in lupus nephritis.
  32. Mass spectrometry-based peptidome profiling of human serous ovarian cancer tissues.
  33. Mitoproteomics: Tackling Mitochondrial Dysfunction in Human Disease.
  34. Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis.
  35. Detection of Malignancy-Associated Phosphoproteome Changes in Human Colorectal Cancer Induced by Cell Surface Binding of Growth-Inhibitory Galectin-4.
  36. Beyond the Message: Advantages of Snapshot Proteomics with Single-Cell Mass Cytometry in Solid Tumors.
  37. Omics approach reveals metabolic disorders associated with the cytotoxicity of airborne particulate matter in human lung carcinoma cells.
  38. A review of lifestyle, metabolic risk factors and blood-based biomarkers for early diagnosis of pancreatic ductal adenocarcinoma.
  39. Differentially expressed serum host proteins in hepatitis B and C viral infections.
  40. Immunoproteomic Identification of Non-carbohydrate Antigens Eliciting Graft-Specific Adaptive Immune Responses in Patients with Bovine Pericardial Bioprosthetic Heart Valves.
  1. BMC Nephrol. 2018 Dec 14. 19(1): 358
    Analysis of the differential urinary protein profile in IgA nephropathy patients of Uygur ethnicity.
    Zhengguang Guo, Zhao Wang, Chen Lu, Shufen Yang, Haidan Sun, Reziw, Yu Guo, Wei Sun, Hua Yue.
       BACKGROUND: IgA nephropathy (IgAN) is one of the most common forms of idiopathic glomerular diseases and might lead to end-stage kidney disease. Accurate and non-invasive biomarkers for early diagnosis are required for early intervention and consequent therapy for IgAN patients. Because variance in the disease incidence and predisposing genes of IgAN has been detected among different ethnicities, the ethnicity factor should be considered in IgAN biomarker discovery. The differences in the protein profiles and pathological mechanisms of IgAN in patients of Uygur ethnicity need to be clearly illustrated.
    METHODS: In this study, we used urinary proteomics to discover candidate biomarkers of IgAN in patients of Uygur ethnicity. The urinary proteins from Uygur normal control and Uygur IgAN patients were extracted and analyzed using 2D-LC-MS/MS and isobaric tags for relative and absolute quantitation (iTRAQ) analysis.
    RESULTS: A total of 277 proteins were found to be differentially represented in Uygur IgAN compared with the respective normal controls. The bioinformatics analysis revealed that the immune response, cell survival, and complement system were activated in Uygur IgAN. Many differentially expressed proteins were found to be related to nephropathy and kidney injuries. Four candidate biomarkers were validated by Western blot, and these results were consistent with the iTRAQ results. ICAM1, TIMP1, SERPINC1 and ADIPOQ were upregulated in Uygur IgAN. Bioinformatic analysis revealed that the increase of ICAM1 and TIMP1 might be caused by IgAN, but the increase of SERPINC1 and ADIPOQ might be caused by proteinuria. SERPINC1 and ICAM1 were identified as the candidate biomarkers with excellent area-under-the-curve (AUC) values (0.84) for distinguishing Uygur IgAN from normal controls.
    CONCLUSIONS: Using urinary proteomic analysis, we identified several candidate biomarkers for IgAN in patients of Uygur ethnicity. These results will prove helpful for exploring the pathological mechanism of IgAN in patients of Uygur ethnicity and for developing better treatments for these patients.
    Keywords:  Biomarker; IgA nephropathy; Urinary proteomics; Uygur
    DOI:  https://doi.org/10.1186/s12882-018-1139-3
  2. Proteomics. 2018 Dec 07. e1800248
    A Combination of Proteomic Approaches Identifies A Panel of Circulating Extracellular Vesicle Proteins Related to the Risk of Suffering Cardiovascular Disease in Obese Patients.
    María N Barrachina, Aurelio M Sueiro, Vanessa Casas, Irene Izquierdo, Lidia Hermida-Nogueira, Esteban Guitián, Felipe F Casanueva, Joaquín Abián, Montserrat Carrascal, María Pardo, Ángel García.
      Plasma-derived extracellular vesicles (EVs) have been extensively described as putative biomarkers in different diseases. Interestingly, increased levels of EVs subpopulations are well-known to associate with obesity. The goal of this study was to identify EVs-derived biomarkers in plasma from obese patients in order to predict the development of pathological events associated with obesity. Samples were obtained from 22 obese patients and their lean-matched controls which were divided into two cohorts: one for a 2D-DIGE-based study, and the other one for a label free LC-MS/MS-based approach. EVs were isolated following a serial ultracentrifugation protocol. We detected 22 and 23 differentially regulated features from 2D-DIGE and label free LC-MS/MS, respectively; most of them involved in the coagulation and complement cascades. Remarkably, there was an up-regulation of complement C4, complement C3 and fibrinogen in obese patients following both approaches, the latter two also validated by 2D-western-blotting in an independent cohort. These results correlate with a pro-inflammatory and prothrombotic state of those individuals. On the other hand, we showed a down-regulation of adiponectin leading to an increased risk of suffering cardiovascular diseases. Our results suggest the relevance of plasma-derived-EVs proteins as a source of potential biomarkers for the development of atherothrombotic events in obesity. This article is protected by copyright. All rights reserved.
    Keywords:  2D-DIGE; biomarkers; extracellular vesicles; label-free quantitation; obesity; plasma
    DOI:  https://doi.org/10.1002/pmic.201800248
  3. Mol Cell Proteomics. 2018 Dec 06. pii: mcp.RA118.000851. [Epub ahead of print]
    Proteome-wide tyrosine phosphorylation analysis reveals dysregulated signaling pathways in ovarian tumors.
    Guang Song, Lily Chen, Bai Zhang, Qifeng Song, Yu Yu, Cedric Moore, Tian-Li Wang, Ie-Ming Shih, Hui Zhang, Daniel Chan, Zhen Zhang, Heng Zhu.
      The recent accomplishment of comprehensive proteogenomic analysis of high-grade serous ovarian carcinoma (HGSOC) tissues reveals cancer associated molecular alterations were not limited to variations among DNA, and mRNA/protein expression, but are a result of complex reprogramming of signaling pathways/networks mediated by the protein and post-translational modification (PTM) interactomes. A systematic, multiplexed approach interrogating enzyme-substrate relationships in the context of PTMs is fundamental in understanding the dynamics of these pathways, regulation of cellular processes, and their roles in disease processes. Here, as part of Clinical Proteomic Tumor Analysis Consortium (CPTAC) project, we established a multiplexed PTM assay (tyrosine phosphorylation, and lysine acetylation, ubiquitylation and SUMOylation) method to identify protein probes' PTMs on the human proteome array. Furthermore, we focused on the tyrosine phosphorylation and identified 19 kinases are potentially responsible for the dysregulated signaling pathways observed in HGSOC. Additionally, elevated kinase activity was observed when 14 ovarian cancer cell lines or tumor tissues were subjected to test the autophosphorylation status of PTK2 (pY397) and PTK2B (pY402) as a proxy for kinase activity. Taken together, this report demonstrates that PTM signatures based on lysate reactions on human proteome array is a powerful, unbiased approach to identify dysregulated PTM pathways in tumors.
    Keywords:  CPTAC; Ovarian cancer; Phosphorylation; Protein array; Proteogenomics; Tyrosine Kinases*
    DOI:  https://doi.org/10.1074/mcp.RA118.000851
  4. Exp Ther Med. 2018 Dec;16(6): 4329-4338
    Anti-fibrosis activity of combination therapy with epigallocatechin gallate, taurine and genistein by regulating glycolysis, gluconeogenesis, and ribosomal and lysosomal signaling pathways in HSC-T6 cells.
    Yan Li, Min Zhu, Yani Huo, Xuerong Zhang, Ming Liao.
      A previous study by our group indicated that combined treatment with taurine, epigallocatechin gallate (EGCG) and genistein protects against liver fibrosis. The aim of the present study was to elucidate the antifibrotic mechanism of this combination treatment using isobaric tag for relative and absolute quantification (iTRAQ)-based proteomics in an activated rat hepatic stellate cell (HSC) line. In the present study, HSC-T6 cells were incubated with taurine, EGCG and genistein, and cellular proteins were extracted and processed for iTRAQ labeling. Quantification and identification of proteins was performed using two-dimensional liquid chromatography coupled with tandem mass spectrometry. Proteomic analysis indicated that the expression of 166 proteins were significantly altered in response to combination treatment with taurine, EGCG and genistein. A total 76 of these proteins were upregulated and 90 were downregulated. Differentially expressed proteins were grouped according to their association with specific Kyoto Encyclopedia of Genes and Genomes pathways. The results indicated that the differentially expressed proteins hexokinase-2 and lysosome-associated membrane glycoprotein 1 were associated with glycolysis, gluconeogenesis and lysosome signaling pathways. The expression of these proteins was validated using western blot analysis; the expression of hexokinase-2 was significantly decreased and the expression of lysosome-associated membrane glycoprotein 1 was significantly increased in HSC-T6 cells treated with taurine, EGCG and genistein compared with the control, respectively (P<0.05). These results were in accordance with the changes in protein expression identified using the iTRAQ approach. Therefore, the antifibrotic effect of combined therapy with taurine, EGCG and genistein may be associated with the activation of several pathways in HSCs, including glycolysis, gluconeogenesis, and the ribosome and lysosome signaling pathways. The differentially expressed proteins identified in the current study may be useful for treatment of liver fibrosis in the future.
    Keywords:  epigallocatechin gallate; genistein; isobaric tags for relative and absolute quantitation; proteomics; rat hepatic stellate cell; taurine
    DOI:  https://doi.org/10.3892/etm.2018.6743
  5. J Proteomics. 2018 Dec 04. pii: S1874-3919(18)30420-2. [Epub ahead of print]
    An integrated quantitative proteomic and metabolomics approach to reveal the negative regulation mechanism of LamB in antibiotics resistance.
    Wanxin Li, Guibin Wang, Song Zhang, Yuying Fu, Yuhang Jiang, Xiaojun Yang, Xiangmin Lin.
      Previously, a maltose-specific channel porin, LamB was found to be associate with multi-drug resistance in a lamB deleted strain, but the exact mechanisms require further elucidation. Herein, differential protein expression between the Escherichia coli mutant strain ΔlamB and the wild type strain BW25113, with and without ciprofloxacin (CFLX), was identified using iTRAQ based liquid chromatography-tandem mass spectrometry (LC-MS/MS); while differential metabolite expression was examined using gas chromatography-mass spectrometry (GC-MS). Further Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that lamB deletion leads to a decrease in several key metabolic pathways such as tricarboxylic acid (TCA) cycle, pentose phosphate pathway and glycolysis/gluconeogenesis. When examining the ΔlamB strain without CFLX, many aminoacyl-tRNA biosynthesis and pyrimidine metabolism-related proteins were unaltered, but the addition of CFLX resulted in reduced levels. These findings indicate that a lamB deletion may confer antibiotic resistance by relieving the pressure of protein translation and DNA replication. To further examine antibiotic resistance, exogenous metabolites, including maltose, and several amino acids metabolites were evaluated to determine whether the resistance level could be reduced in the presence of CFLX. The obtained results indicate that lamB knockout may increase bacterial antibiotics resistance by decreasing metabolic pathway activity levels. BIOLOGICAL SIGNIFICANCE: An integrated metabonomic-proteomic method was performed to systematically compare the profiles of metabolites and proteins between ΔlamB and its wild type strain, with and without ciprofloxacin (CFLX) treatment. Following bioinformatics analysis showed that lamB deletion in CFLX stress leads to the decreasing of several key metabolic pathways. Many amino acid-tRNA biosynthesis and pyrimidine metabolism related proteins didn't change in ΔlamB strain but largely decreased after treated with CFLX. Further exogenous metabolites addition assay reveals that maltose and several amino acids metabolites contribute to the CFLX resistance mediated by LamB. Our results indicate that the down-regulation of LamB may increase bacterial antibiotics resistance by decreasing the intracellular metabolism pathways.
    Keywords:  Antibiotics resistance; LamB; Outer membrane protein; Quantitative proteomics
    DOI:  https://doi.org/10.1016/j.jprot.2018.11.022
  6. Proteomics Clin Appl. 2018 Dec 08. e1800143
    Proteomic Analysis of the initial Oral Pellicle in Caries-Active and Caries-Free Individuals.
    Simone Trautmann, Ahmad Barghash, Claudia Fecher-Trost, Pascal Schalkowsky, Christian Hannig, Jasmin Kirsch, Stefan Rupf, Andreas Keller, Volkhard Helms, Matthias Hannig.
       PURPOSE: To 1) elucidate individual proteomic profiles of the 3-min biofilm of caries-active and caries-free individuals and 2) compare these proteomic profiles against the background of caries.
    EXPERIMENTAL DESIGN: The initial oral pellicle of 12 caries-active and 12 caries-free individuals was generated in situ on ceramics specimens. The individual, host-specific proteomic profiles of this basic pellicle layer were analyzed by a chemical elution protocol combined with an elaborate mass spectrometry and evaluated bioinformatically.
    RESULTS: A total of 1188 different proteins were identified. 68 proteins were present in the profiles of all individuals, suggesting them as ubiquitously occurring base-proteins of the initial human pellicle. Thereof, the single profiles exhibit high inter-individual differences independent of their group affiliation, stating the initial pellicle to represent a rather "individual fingerprint". Quantitative analyses imply slight indication for 23 proteins potentially capable of counting for caries-specific biomarkers.
    CONCLUSIONS AND CLINICAL RELEVANCE: The introduced protocol enables the individual analysis of minimal protein amounts and allows for highly precise characterizations and comparisons of individual proteomic profiles. The results contain a considerable higher extent of protein identifications and might serve as a base for future large scale analyzes to identify discrimination factors for the development of caries-susceptibility-tests. This article is protected by copyright. All rights reserved.
    Keywords:  3-min pellicle; caries-related biomarkers; enriched molecular functions; individual proteomic profiles; ubiquitous base proteins
    DOI:  https://doi.org/10.1002/prca.201800143
  7. J Cell Physiol. 2018 Dec 07.
    Dynamic changes of urinary proteins in a rat model of acute hypercoagulable state induced by tranexamic acid.
    Jian Jing, Zhenhuan Du, Zhang Wen, Bo Jiang, Bixi He.
      The hypercoagulable state leads to the development of thrombotic diseases, but it is difficult to diagnose due to the lack of available biomarkers. This study aimed to investigate systematic changes of the urinary proteome in the acute hypercoagulable state. A rat model of the acute hypercoagulable state was induced by an antifibrinolytic agent tranexamic acid and urine samples were collected for proteomic analysis by liquid chromatography-tandem mass spectrometry. A total of 28 differential proteins were detected in the urinary proteome of the model rats, of which 12 had been previously considered as candidate biomarkers such as myoglobin, and 10 had been considered stable in healthy human urine. Of the 28 differentially expressed proteins 18 had counterparts in humans. Of these 18 proteins, 10 were members of the human core urinary proteome distributed in a variety of human tissues but concentrated in the urinary and digestive systems. Fumarylacetoacetase was verified as a potential marker of the acute hypercoagulable state by Western blot analysis. In conclusion, urine proteome analysis is a powerful approach to identify potential biomarkers of acute hypercoagulable state.
    Keywords:  antifibrinolytics tranexamic acid (TXA); biomarkers; hypercoagulable state; urine proteome
    DOI:  https://doi.org/10.1002/jcp.27904
  8. Front Oncol. 2018 ;8 548
    Quantitative Proteomic Analysis Identifies MAPK15 as a Potential Regulator of Radioresistance in Nasopharyngeal Carcinoma Cells.
    Zhanzhan Li, Na Li, Liangfang Shen, Jun Fu.
      Since resistance to radiotherapy remains refractory for the clinical management of nasopharyngeal cancer (NPC), further understanding the mechanisms of radioresistance is necessary in order to develop more effective NPC treatment and improve prognosis. In this study, an integrated quantitative proteomic approach involving tandem mass tag labeling and liquid chromatograph-mass spectrometer was used to identify proteins potentially responsible for the radioresistance of NPC. The differential radiosensitivity in NPC model cells was examined through clonogenic survival assay, CCK-8 viability assay, and BrdU incorporation analysis. Apoptosis of NPC cells after exposure to irradiation was detected using caspase-3 colorimetric assay. Intracellular reactive oxygen species (ROS) was detected by a dichlorofluorescin diacetate fluorescent probe. In total, 5,946 protein groups were identified, among which 5,185 proteins were quantified. KEGG pathway analysis and protein-protein interaction enrichment analysis revealed robust activation of multiple biological processes/pathways in radioresistant CNE2-IR cells. Knockdown of MAPK15, one up-regulated protein kinase in CNE2-IR cells, significantly impaired clonogenic survival, decreased cell viability and increased cell apoptosis following exposure to irradiation, while over-expression of MAPK15 promoted cell survival, induced radioresistance and reduced apoptosis in NPC cell lines CNE1, CNE2, and HONE1. MAPK15 might regulate radioresistance through attenuating ROS accumulation and promoting DNA damage repair after exposure to irradiation in NPC cells. Quantitative proteomic analysis revealed enormous metabolic processes/signaling networks were potentially involved in the radioresistance of NPC cells. MAPK15 might be a novel potential regulator of radioresistance in NPC cells, and targeting MAPK15 might be useful in sensitizing NPC cells to radiotherapy.
    Keywords:  MAPK15; nasopharyngeal carcinoma; quantitative proteomics; radioresistance; radiosensitivity
    DOI:  https://doi.org/10.3389/fonc.2018.00548
  9. Proteomics Clin Appl. 2018 Dec 13. e1800135
    Proteomic Evidence of Biological Ageing in a Child with a Compound Heterozygous ZMPSTE24 Mutation.
    Angela K Lucas-Herald, Petra Zürbig, Avril Mason, Esther Kinning, Catriona E Brown, Bahareh Mansoorian, William Mullen, Syed Faisal Ahmed, Christian Delles.
       BACKGROUND: Progeria-like syndromes offer a unique insight into ageing. Here we present the case of a boy affected with mandibuloacral dysplasia and compound heterozygous mutations in ZMPSTE24.
    METHODS: Capillary electrophoresis-mass spectroscopy was used for proteome analysis to analyse peptides previously found to be differentially regulated in chronic kidney disease (273 peptides defining the CKD273 classifier), coronary artery disease (238 peptides defining the CAD238 classifier) and ageing (116 peptides defining the AGE116 classifier).
    RESULTS: No evidence of renal disease was identified. Although the boy has no overt cardiovascular disease other than a raised carotid intima media thickness relative to his age, a proteomic classifier for the diagnosis of coronary artery disease was mildly raised. The biological age based on the proteomic AGE116 classifier was 24 years compared to the chronological ages of 5 and 10 years. In contrast, a control group of healthy children had a significantly lower (p<0.0001) calculated mean age of 13.
    CONCLUSION: Urinary proteomic analysis is effective in confirming advanced biological age and to identify early evidence of renal or cardiovascular damage. Our case highlights the value of proteomic approaches in ageing research and may represent a method for non-invasive monitoring of the effects of early ageing. This article is protected by copyright. All rights reserved.
    Keywords:  biomarkers; capillary electrophoresis-mass spectroscopy; progeria
    DOI:  https://doi.org/10.1002/prca.201800135
  10. Proteomics. 2018 Dec 07. e1800164
    Quantitative Proteomics by SWATH-MS Suggest an Association Between Circulating Exosomes and Maternal Metabolic Changes in Gestational Diabetes Mellitus.
    Nanthini Jayabalan, Andrew Lai, Soumyalekshmi Nair, Dominic Guanzon, Katherin Scholz-Romero, Carlos Palma, Harold David McIntyre, Martha Lappas, Carlos Salomon.
      Several factors including placental hormones (PH) released from the human placenta have been associated with the development of insulin resistance and gestational diabetes mellitus (GDM). However, circulating levels of PH do not correlate well with maternal insulin sensitivity across gestation, suggesting that other, previously unrecognized, mechanisms may be involved. The levels of circulating exosomes are higher in GDM compared to normal. GDM derived exosomes produce greater release of pro-inflammatory cytokines from endothelial cells compared to exosomes from normal, suggesting that their contents may differ compared to normal pregnancies. Using a quantitative, information-independent acquisition (Sequential Windowed Acquisition of All Theoretical Mass Spectra [SWATH]) approach, we identify differentially abundance circulating exosome proteins in women with normal glucose tolerance (NGT) and GDM at the time of GDM diagnosis. A total of 78 statistically significant proteins in the relative expression of exosomal proteins in GDM compared with NGT. Bioinformatic analysis showed the exosomal proteins in GDM target pathways were mainly associated with energy production, inflammation, and metabolism. Finally, we used an independent cohort of patients to validate some of the proteins identified by SWATH. The data obtained may be of utility in elucidating the underlying physiological mechanisms associated with insulin resistant in GDM. This article is protected by copyright. All rights reserved.
    Keywords:  extracellular vesicles; insulin resistant; pregnancy; proteomics
    DOI:  https://doi.org/10.1002/pmic.201800164
  11. Proteomics Clin Appl. 2018 Dec 13. e1800046
    Development of a class prediction model to discriminate pancreatic ductal adenocarcinoma from pancreatic neuroendocrine tumor by MALDI mass spectrometry imaging.
    Rita Casadonte, Mark Kriegsmann, Aurel Perren, Gustavo Baretton, Sören-Oliver Deininger, Katharina Kriegsmann, Thilo Welsch, Christian Pilarsky, Jörg Kriegsmann.
       PURPOSE: To define proteomic differences between pancreatic ductal adenocarcinoma (pDAC) and pancreatic neuroendocrine tumor (pNET) by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI).
    EXPERIMENTAL DESIGN: 93 pDAC and 126 pNET individual tissues were assembled in tissue microarrays and analyzed by MALDI MSI. The cohort was separated in a training (52 pDAC and 83 pNET) and validation set (41 pDAC and 43 pNET). Subsequently, a linear discriminant analysis (LDA) model based on 46 peptide ions was performed on the training set and evaluated on the validation cohort. Additionally, two liver metastases and a whole slide of pDAC were analyzed by the same LDA algorithm.
    RESULTS: Classification of pDAC and pNET by the LDA model was correct in 95% (39/41) and 100% (43/43) of patients in the validation cohort, respectively. The two liver metastases and the whole slide of pDAC were also correctly classified in agreement with the histopathological diagnosis.
    CONCLUSION AND CLINICAL RELEVANCE: In the preset study, we investigated a large dataset of pDAC and pNET by MALDI MSI, we developed a class prediction model that allowed separation of both entities with high accuracy, and we highlighted differential peptide peaks with potential diagnostic, prognostic and predictive value. This article is protected by copyright. All rights reserved.
    Keywords:  FFPE; MALDI MSI; Pancreas; neuroendocrine-tumor; tumor typing
    DOI:  https://doi.org/10.1002/prca.201800046
  12. J Proteomics. 2018 Dec 06. pii: S1874-3919(18)30425-1. [Epub ahead of print]
    Proteomic analysis of protein homeostasis and aggregation.
    Ewa Laskowska, Dorota Kuczyńska-Wiśnik, Barbara Lipińska.
      Protein homeostasis (proteostasis) refers to the ability of cells to preserve the correct balance between protein synthesis, folding and degradation. Proteostasis is essential for optimal cell growth and survival under stressful conditions. Various extracellular and intracellular stresses including heat shock, oxidative stress, proteasome malfunction, mutations and aging-related modifications can result in disturbed proteostasis manifested by enhanced misfolding and aggregation of proteins. To limit protein misfolding and aggregation cells have evolved various strategies including molecular chaperones, proteasome system and autophagy. Molecular chaperones assist folding of proteins, protect them from denaturation and facilitate renaturation of the misfolded polypeptides, whereas proteasomes and autophagosomes remove the irreversibly damaged proteins. The impairment of proteostasis results in protein aggregation that is a major pathological hallmark of numerous age-related disorders, such as cataract, Alzheimer's, Parkinson's, Huntington's, and prion diseases. To discover protein markers and speed up diagnosis of neurodegenerative diseases accompanied by protein aggregation, proteomic tools have increasingly been used in recent years. Systematic and exhaustive analysis of the changes that occur in the proteomes of affected tissues and biofluids in humans or in model organisms is one of the most promising approaches to reveal mechanisms underlying protein aggregation diseases, improve their diagnosis and develop therapeutic strategies. Significance: In this review we outline the elements responsible for maintaining cellular proteostasis and present the overview of proteomic studies focused on protein-aggregation diseases. These studies provide insights into the mechanisms responsible for age-related disorders and reveal new potential biomarkers for Alzheimer's, Parkinson's, Huntigton's and prion diseases.
    Keywords:  biomarkers; heat shock proteins; protein aggregation diseases; proteostasis
    DOI:  https://doi.org/10.1016/j.jprot.2018.12.003
  13. J Proteomics. 2018 Dec 06. pii: S1874-3919(18)30427-5. [Epub ahead of print]
    A proteomic approach to identify novel disease biomarkers in LCAT deficiency.
    Sara Simonelli, Alice Ossoli, Cristina Banfi, Chiara Pavanello, Laura Calabresi, Elisabetta Gianazza.
      Genetic LCAT deficiency is a rare recessive autosomal disease due to loss-of-function mutations in the gene coding for the enzyme lecithin:cholesterol acyltransferase (LCAT). Homozygous carriers are characterized by corneal opacity, haemolytic anaemia and renal disease, which represent the first cause of morbidity and mortality in these subjects. Diagnostic and prognostic markers capable of early detecting declining kidney function in these subjects are not available, and the specific serum or urine proteomic signature of LCAT deficient carriers has never been assessed. Taking advantage of a proteomic approach, we performed 2-DE analysis of carriers' plasma and identified proteins present at different concentration in samples from homozygous carriers. Our data confirm the well-known alterations in the concentration of circulating apolipoproteins, with a statistically significant decrease of both apoA-I and apoA-II and a statistically significant increase of apoC-III. Furthermore, we observed increased level of alpha-1-antitrypsin, zinc-alpha-2-glycoprotein and retinol-binding protein 4, and reduced level of clusterin and haptoglobin. Interestingly, only beta but not alpha subunit of haptoglobin is significant reduced in homozygous subjects. Despite the limited sample size, our findings set the basis for assessing the identified protein in a larger population and for correlating their levels with clinical markers of renal function and anaemia. SIGNIFICANCE: This investigation defines the effects of LCAT deficiency on the level of the major plasma proteins in homozygous and heterozygous carriers. Increase for some proteins, with different function, together with a drop for haptoglobin, and specifically for haptoglobin beta chains, are reported for the first time as part of a coherent signature. We are glad to have the opportunity to report our findings on this subject, which is one of the main interests for our research group, when Journal of Proteomics celebrates its 10th anniversary. With its various sections devoted to different areas of research, this journal is a privileged forum for publishing proteomic investigations without restrictions either in sample type or in technical approach. It is as well a privileged forum for reviewing literature data on various topics related to proteomics investigation, as colleagues in our research group have done over the years; by the way, a good share of the reviewed papers were as well reports published in Journal of Proteomics itself. The journal also offers opportunities for focused surveys through thematic issues devoted to a variety of subjects, timely selected for their current relevance in research; it was an honour for colleagues in our group to recently act as editors of one of those. Out of this diverse experience, we express our appreciation for the endeavour of Journal of Proteomics in its first 10 years of life - and wish identical and possibly greater success for the time to come.
    Keywords:  Apolipoproteins; Haemolysis; Haptoglobin; LCAT deficiency
    DOI:  https://doi.org/10.1016/j.jprot.2018.12.005
  14. Physiol Meas. 2018 Nov 05.
    Network proteomics of human dermal wound healing.
    Xi Gao, Emmanuel F Petricoin Iii, Kevin R Ward, Stephanie R Goldberg, Therese M Duane, Danail Bonchev, Tomasz Arodz, Robert F Diegelmann.
      Healing of wounds is critical to maintaining protection of human body against environmental factors. The mechanisms involving protein expression during this complex physiological process have not been fully elucidated. Here, we use the reverse-phase protein microarrays involving 94 phosphoproteins to study tissue samples from tubes implanted into healing dermal wounds in 7 human subjects tracked over 2 weeks. We compare the proteomic profiles to proteomes of controls obtained from skin biopsy from the same subjects. Compared to previous proteomic studies of wound healing, our approach is focused on wound tissue instead of wound fluid, and has the sensitivity to go beyond measuring only high-abundance proteins. To study the temporal dynamics of networks involved in wound healing, we applied two network analysis methods that integrate the experimental results with prior knowledge about protein-protein physical and regulatory interactions, as well as higher-level biological processes and associated pathways. We uncovered densely connected networks of proteins that are up- or down-regulated during human wound healing, as well as their relationships to microRNAs and to proteins outside of our set of targets we measured with proteomic microarrays.
    Keywords:  Network physiology; Protein-protein interaction networks; Systems biology; Wound healing
    DOI:  https://doi.org/10.1088/1361-6579/aaee19
  15. Front Endocrinol (Lausanne). 2018 ;9 678
    Integration of Proteomics and Metabolomics Revealed Metabolite-Protein Networks in ACTH-Secreting Pituitary Adenoma.
    Jie Feng, Qi Zhang, Yang Zhou, Shenyuan Yu, Lichuan Hong, Sida Zhao, Jingjing Yang, Hong Wan, Guowang Xu, Yazhuo Zhang, Chuzhong Li.
      An effective treatment for the management of adrenocorticotropic hormone-secreting pituitary adenomas (ACTH-PA) is currently lacking, although surgery is a treatment option. We have integrated information obtained at the metabolomic and proteomic levels to identify critical networks and signaling pathways that may play important roles in the metabolic regulation of ACTH-PA and therefore hopefully represent potential therapeutic targets. Six ACTH-PAs and seven normal pituitary glands were investigated via gas chromatography-mass spectrometry (GC-MS) analysis for metabolomics. Five ACTH-PAs and five normal pituitary glands were subjected to proteomics analysis via nano liquid chromatography tandem-mass spectrometry (nanoLC-MS/MS). The joint pathway analysis and network analysis was performed using MetaboAnalyst 3.0. software. There were significant differences of metabolites and protein expression levels between the ACTH-PAs and normal pituitary glands. A proteomic analysis identified 417 differentially expressed proteins that were significantly enriched in the Myc signaling pathway. The protein-metabolite joint pathway analysis showed that differentially expressed proteins and metabolites were significantly enriched in glycolysis/gluconeogenesis, pyruvate metabolism, citrate cycle (TCA cycle), and the fatty acid metabolism pathway in ACTH-PA. The protein-metabolite molecular interaction network identified from the metabolomics and proteomics investigation resulted in four subnetworks. Ten nodes in subnetwork 1 were the most significantly enriched in cell amino acid metabolism and pyrimidine nucleotide metabolism. Additionally, the metabolite-gene-disease interaction network established nine subnetworks. Ninety-two nodes in subnetwork 1 were the most significantly enriched in carboxylic acid metabolism and organic acid metabolism. The present study clarified the pathway networks that function in ACTH-PA. Our results demonstrated the presence of downregulated glycolysis and fatty acid synthesis in this tumor type. We also revealed that the Myc signaling pathway significantly participated in the metabolic changes and tumorigenesis of ACTH-PA. This data may provide biomarkers for ACTH-PA diagnosis and monitoring, and could also lead to the development of novel strategies for treating pituitary adenomas.
    Keywords:  ACTH; metabolite–protein networks; metabolomics; pituitary adenoma; proteomics
    DOI:  https://doi.org/10.3389/fendo.2018.00678
  16. Transl Res. 2018 Nov 20. pii: S1931-5244(18)30214-7. [Epub ahead of print]
    The contribution and perspectives of proteomics to uncover ovarian cancer tumor markers.
    Vinícius Pereira de Carvalho, Mariana Lopes Grassi, Camila de Souza Palma, Helio Humberto Angotti Carrara, Vitor Marcel Faça, Francisco José Candido Dos Reis, Aline Poersch.
      Despite all the advances in understanding the mechanisms involved in ovarian cancer (OC) development, many aspects still need to be unraveled and understood. Tumor markers (TMs) are of special interest in this disease. Some aspects of clinical management of OC might be improved by the use of validated TMs, such as differentiating subtypes, defining the most appropriate treatment, monitoring the course of the disease, or predicting clinical outcome. The Food and Drug Administration (FDA) has approved a few TMs for OC: CA125 (cancer antigen 125; monitoring), HE4 (Human epididymis protein; monitoring), ROMA (Risk Of Malignancy Algorithm; HE4+CA125; prediction of malignancy) and OVA1 (Vermillion's first-generation Multivariate Index Assay [MIA]; prediction of malignancy). Proteomics can help advance the research in the field of TMs for OC. A variety of biological materials are being used in proteomic analysis, among them tumor tissues, interstitial fluids, tumor fluids, ascites, plasma, and ovarian cancer cell lines. However, the discovery and validation of new TMs for OC is still very challenging. The enormous heterogeneity of histological types of samples and the individual variability of patients (lifestyle, comorbidities, drug use, and family history) are difficult to overcome in research protocols. In this work, we sought to gather relevant information regarding TMs, OC, biological samples for proteomic analysis, as well as markers and algorithms approved by the FDA for use in clinical routine.
    DOI:  https://doi.org/10.1016/j.trsl.2018.11.001
  17. Int J Mol Sci. 2018 Dec 12. pii: E4005. [Epub ahead of print]19(12):
    Rapid Detection and Identification of Antimicrobial Peptide Fingerprints of Nasal Fluid by Mesoporous Silica Particles and MALDI-TOF/TOF Mass Spectrometry: From the Analytical Approach to the Diagnostic Applicability in Precision Medicine.
    Mariaimmacolata Preianò, Giuseppina Maggisano, Maria Stella Murfuni, Chiara Villella, Carmela Colica, Annalisa Fregola, Corrado Pelaia, Nicola Lombardo, Girolamo Pelaia, Rocco Savino, Rosa Terracciano.
       BACKGROUND: Antimicrobial peptides (AMP) play a pivotal role in innate host defense and in immune response. The delineation of new MS-based profiling tools, which are able to produce panels of AMP of the nasal fluid (NF), may be attractive for the discovery of new potential diagnostic markers of respiratory disorders.
    METHODS: Swabs collected NF from healthy patients and from patients with respiratory disorders. We used a fast procedure based on mesoporous silica particles (MPS) to enrich NF in its AMP component in combination with MALDI-TOF/TOF MS as a key tool for rapidly analyzing clinical samples.
    RESULTS: Reproducible MS peptide fingerprints were generated for each subject and several AMP were detected including (Human Neutrophil Peptides) HNPs, Statherin, Thymosin-β4, Peptide P-D, II-2, β-MSP, SLPI, Lysozyme-C, and their proteo-forms. In particular, Statherin, Thymosin-β4, and Peptide P-D were accurately identified by direct MS/MS sequencing. Examples of applicability of this tool are shown. AMP fingerprints were obtained before and after a nasal polypectomy as well as before and post-treatment with azelastine/fluticasone in one case of allergic rhinitis.
    CONCLUSION: The potential of our platform to be implemented by new mesoporous materials for capturing a wider picture of AMP might offer an amazing opportunity for diagnostic clinical studies on individual and population scales.
    Keywords:  MALDI-TOF MS; antimicrobial peptides; biomarker; biomarkers; enrichment; mass spectrometry; nasal fluid; nasal polyposis; peptidomics; precision medicine
    DOI:  https://doi.org/10.3390/ijms19124005
  18. Cell Syst. 2018 Nov 30. pii: S2405-4712(18)30437-X. [Epub ahead of print]
    Plasma Proteome Profiling Reveals Dynamics of Inflammatory and Lipid Homeostasis Markers after Roux-En-Y Gastric Bypass Surgery.
    Nicolai J Wewer Albrechtsen, Philipp E Geyer, Sophia Doll, Peter V Treit, Kirstine N Bojsen-Møller, Christoffer Martinussen, Nils B Jørgensen, Signe S Torekov, Florian Meier, Lili Niu, Alberto Santos, Eva C Keilhauer, Jens J Holst, Sten Madsbad, Matthias Mann.
      Obesity-related diseases affect half of the global population, and bariatric surgery is one of the few interventions with long-lasting weight loss and cardio-metabolic effects. Here, we investigated the effect of Roux-en-Y gastric bypass surgery on the plasma proteome, hypothesizing that specific proteins or protein patterns may serve as key mediators and markers of the metabolic response. We performed mass spectrometry (MS)-based proteomics on two longitudinal studies encompassing 47 morbidly obese patients, generating quantitative information on more than 1,700 proteins. A global correlation matrix incorporating about 200,000 relationships revealed functional connections between proteins and assigned them to physiological processes. The main classes of significantly altered proteins were markers of systemic inflammation and those involved in lipid metabolism. Our data highlight robust correlative and anti-correlative behaviors of circulating proteins to each other and to clinical parameters. A group of inflammation-related proteins showed distinct inverse relationships to proteins consistently associated with insulin sensitivity.
    Keywords:  biomarker; diabetes; gastric bypass surgery; global correlation profiles; insulin resistance; mass spectrometry; obesity; plasma proteome profiling; serum; shot gun proteomics
    DOI:  https://doi.org/10.1016/j.cels.2018.10.012
  19. Exp Ther Med. 2018 Dec;16(6): 4527-4536
    Identification and validation of differentially expressed proteins in serum of CSU patients with different duration of wheals using an iTRAQ labeling, 2D-LC-MS/MS.
    Yanyun Cao, Shunming Xu, Wei Kong, Haibin Cai, Yang Xu.
      Chronic spontaneous urticaria (CSU) is one of the most common types of chronic urticaria (CU), with symptoms that recur easily, migrate and are refractory. It is unclear whether association between the differentiation of protein expression levels in the serum of CSU patients and the different duration of wheals exists. In the present study the samples were divided according to the duration of the wheals into group A (wheal duration <2 h) and group B (wheal duration 12-24 h). Differentially expressed proteins in sera of CSU patients with different durations of wheals were identified and validated with isobaric tags for relative and absolute quantitation (iTRAQ) in combination with two-dimensional liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS). Three hundred and seventy CSU serum-related proteins were initially identified. Among these proteins, ~30 had significant differences between the groups. According to the classification of biological functions and upregulated/downregulated values, serum amyloid A (SAA), CFL1, TPM4 and monocyte differentiation antigen (CD14) were chosen and validated by enzyme-linked immunosorbent assay (ELISA). The expression levels of CD14 in sera were not significantly different among the groups. SAA, CFL1 and TPM4 were associated with the wheal duration in CSU patients and therefore could be considered as new potential inflammatory biomarkers associated with CSU.
    Keywords:  chronic spontaneous urticaria; cofilin-1; isobaric tags for relative and absolute quantitation; serum amyloid A protein
    DOI:  https://doi.org/10.3892/etm.2018.6818
  20. Int J Mol Sci. 2018 Dec 12. pii: E4018. [Epub ahead of print]19(12):
    Interstitial Fluid in Gynecologic Tumors and Its Possible Application in the Clinical Practice.
    Blendi Ura, Giovanni Di Lorenzo, Federico Romano, Lorenzo Monasta, Giuseppe Mirenda, Federica Scrimin, Giuseppe Ricci.
      Gynecologic cancers are an important cause of worldwide mortality. The interstitium consists of solid and fluid phases, situated between the blood vessels and cells. The interstitial fluid (IF), or fluid phase, is an extracellular fluid bathing and surrounding the tissue cells. The TIF (tumor interstitial fluid) is a dynamic fluid rich in lipids, proteins and enzyme-derived substances. The molecules found in the IF may be associated with pathological changes in tissues leading to cancer growth and metastatization. Proteomic techniques have allowed an extensive study of the composition of the TIF as a source of biomarkers for gynecologic cancers. In our review, we analyze the composition of the TIF, its formation process, the sampling methods, the consequences of its accumulation and the proteomic analyses performed, that make TIF valuable for monitoring different types of cancers.
    Keywords:  biomarker; gynecologic tumors; proteomics; tumor interstitial fluid
    DOI:  https://doi.org/10.3390/ijms19124018
  21. Dis Markers. 2018 ;2018 6141845
    Protein-Based Salivary Profiles as Novel Biomarkers for Oral Diseases.
    Alejandro I Lorenzo-Pouso, Mario Pérez-Sayáns, Susana B Bravo, Pía López-Jornet, María García-Vence, Manuela Alonso-Sampedro, Javier Carballo, Abel García-García.
      The Global Burden of Oral Diseases affects 3.5 billion people worldwide, representing the number of people affected by the burden of untreated dental caries, severe periodontal disease, and edentulism. Thus, much more efforts in terms of diagnostics and treatments must be provided in the fight of these outcomes. In this sense, recently, the study of saliva as biological matrix has been identified as a new landmark initiative in the search of novel and useful biomarkers to prevent and diagnose these conditions. Specifically, saliva is a rich reservoir of different proteins and peptides and accessible due to recent advances in molecular biology and specially in targeted and unbiased proteomics technologies. Nonetheless, emerging barriers are an obstacle to the study of the salivary proteome in an effective way. This review aims at giving an overall perspective of salivary biomarkers identified in several oral diseases by means of molecular biology approaches.
    DOI:  https://doi.org/10.1155/2018/6141845
  22. Clin Chim Acta. 2018 Dec 07. pii: S0009-8981(18)30622-3. [Epub ahead of print]
    Identification of salivary peptidomic biomarkers in chronic kidney disease patients undergoing haemodialysis.
    Peiyuan Tong, Chao Yuan, Xiangyu Sun, Qi Yue, Xiaoling Wang, Shuguo Zheng.
       BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health problem. To detect discriminating salivary peptide profiles between CKD patients undergoing haemodialysis (HD) and healthy controls (HCs) and to screen candidate biomarkers for CKD, we preliminarily explored the diagnostic potentiality of saliva.
    METHODS: Saliva samples from 30 CKD HD patients and 35 HCs were analysed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) combined with weak cation exchange magnetic beads. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was performed to identify the potential biomarkers.
    RESULTS: The HD group showed higher salivary pH. We chose 3 significantly different (p < 0.01) peptides to establish an effective discrimination model which was validated by a decision tree and ROC curve. Statistically significant correlations (p < 0.05) between the candidate salivary peptidomic biomarkers and serum parameters were found. Eight differentially expressed peptides were identified as segments of Histatin-1, Mucin-7, salivary acidic proline-rich phosphoprotein 1/2 (aPRP 1/2), submaxillary gland androgen-regulated protein 3B, and Histatin-3.
    CONCLUSIONS: Our findings substantiate the pivotal role of peptidomic methods in identifying biomarkers for CKD. Histatin-1, Mucin-7 and aPRP 1/2 are expected to be candidate salivary biomarkers of CKD HD patients. Furthermore, saliva might be a promising non-invasive diagnostic biofluid.
    Keywords:  Chronic kidney disease (CKD); Haemodialysis; MALDI-TOF MS; Salivary peptidomic biomarkers; UPLC-MS/MS
    DOI:  https://doi.org/10.1016/j.cca.2018.12.003
  23. J Proteomics. 2018 Dec 04. pii: S1874-3919(18)30421-4. [Epub ahead of print]
    Proteomic analysis of olfactory bulb suggests CACNA1E as a promoter of CREB signaling in microbiota-induced depression.
    Cheng Huang, Xun Yang, Benhua Zeng, Li Zeng, Xue Gong, Chanjuan Zhou, Jinjun Xia, Bin Lian, Yinhua Qin, Lining Yang, Lanxiang Liu, Peng Xie.
      Major depressive disorders impact approximately 17% of the population worldwide, whose high morbidity and considerable adversity have resulted in enormous social and economic burden. In addition, clinically depressed patients often show reduced volume of olfactory bulb (OB) and decreased olfactory sensitivity. Although mounting evidence conveyed that the gut microbiota may implicate the pathophysiology of major depressive disorder (MDD) via the microbe-gut-brain axis, knowledge about its distinctive molecular mechanism is rudimentary. Herein, iTRAQ coupled with LC-MS/MS was applied to compare the OB proteome between "pathological microbiota" and "healthy microbiota" germ-free mice. A set of 367 proteins were differentially identified in the OB, including 119 up-regulated and 248 down-regulated proteins compared with the levels in controls. A combined analysis with significantly changed OB proteins from CUMS depression model supported the role of CREB signaling, whose dysregulation is likely to disrupt the axonogenesis of OB under microbiota condition. With that, the down-regulated CACNA1E and its downstream proteins (CALM/ CaMKII/ CREB/ BDNF) in CREB pathway were validated by Western blot. Meanwhile, the canonical pathways involved Nuclear Receptor Signaling highlighted the fecal microbiota transplantation (FMT) model, which would be a new breakthrough for depressive research. These findings enrich the previous research achievements about the gut microbiota in psychiatric disorders, providing a creative insight into the intricate mechanisms of OB dysfunction in depression. SIGNIFICANCE: Emerging evidence has shown that gut microbiota can greatly influence brain functions and even behaviors. As one of the post-developmental neurogenesis areas for the adult brain, the OB is becoming increasingly important in the study of the pathogenesis of depression. Using an iTRAQ-based proteomics, we identified 367 altered proteins in the OB of fecal microbiota transplanted mouse, which provide a novel insight for further research of the "microbiota-gut-brain axis". In addition, combined analyses with the CUMS depression model and the validation of key proteins by Western blot may assist in the investigation of OB dysfunction in mental sickness.
    Keywords:  CACNA1E; Gut microbiota; Major depressive disorder; Olfactory bulb; iTRAQ
    DOI:  https://doi.org/10.1016/j.jprot.2018.11.023
  24. Kidney Int. 2018 Nov 29. pii: S0085-2538(18)30644-6. [Epub ahead of print]
    The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury.
    Martin R Späth, Malte P Bartram, Nicolàs Palacio-Escat, K Johanna R Hoyer, Cedric Debes, Fatih Demir, Christina B Schroeter, Amrei M Mandel, Franziska Grundmann, Giuliano Ciarimboli, Andreas Beyer, Jayachandran N Kizhakkedathu, Susanne Brodesser, Heike Göbel, Jan U Becker, Thomas Benzing, Bernhard Schermer, Martin Höhne, Volker Burst, Julio Saez-Rodriguez, Pitter F Huesgen, Roman-Ulrich Müller, Markus M Rinschen.
      Acute kidney injury (AKI) leads to significant morbidity and mortality; unfortunately, strategies to prevent or treat AKI are lacking. In recent years, several preconditioning protocols have been shown to be effective in inducing organ protection in rodent models. Here, we characterized two of these interventions-caloric restriction and hypoxic preconditioning-in a mouse model of cisplatin-induced AKI and investigated the underlying mechanisms by acquisition of multi-layered omic data (transcriptome, proteome, N-degradome) and functional parameters in the same animals. Both preconditioning protocols markedly ameliorated cisplatin-induced loss of kidney function, and caloric restriction also induced lipid synthesis. Bioinformatic analysis revealed mRNA-independent proteome alterations affecting the extracellular space, mitochondria, and transporters. Interestingly, our analyses revealed a strong dissociation of protein and RNA expression after cisplatin treatment that showed a strong correlation with the degree of damage. N-degradomic analysis revealed that most posttranscriptional changes were determined by arginine-specific proteolytic processing. This included a characteristic cisplatin-activated complement signature that was prevented by preconditioning. Amyloid and acute-phase proteins within the cortical parenchyma showed a similar response. Extensive analysis of disease-associated molecular patterns suggested that transcription-independent deposition of amyloid P-component serum protein may be a key component in the microenvironmental contribution to kidney damage. This proof-of-principle study provides new insights into the pathogenesis of cisplatin-induced AKI and the molecular mechanisms underlying organ protection by correlating phenotypic and multi-layered omics data.
    Keywords:  acute kidney injury; complement; preconditioning; proteomic analysis; transcriptomic analysis
    DOI:  https://doi.org/10.1016/j.kint.2018.08.037
  25. Thorac Cancer. 2018 Dec 08.
    Prospective exosome-focused translational research for afatinib study of non-small cell lung cancer patients expressing EGFR (EXTRA study).
    Yusuke Okuma, Kei Morikawa, Hisashi Tanaka, Takuma Yokoyama, Hidetoshi Itani, Kazuya Horiuchi, Hideyuki Nakagawa, Nobumasa Takahashi, Akihiro Bessho, Kenzo Soejima, Kazuma Kishi, Akira Togashi, Yae Kanai, Koji Ueda, Katsuhisa Horimoto, Noriyuki Matsutani, Nobuhiko Seki.
      Patients with EGFR-mutated non-small cell lung cancer (NSCLC) exhibit resistance to EGFR-tyrosine kinase inhibitors (TKIs) within 9-14 months of therapy. Recently, EGFR-mutated NSCLC has demonstrated the potential for heterogeneity; therefore, the manner of clonal heterogeneity may impact the duration of progression-free and overall survival and other parameters affecting EGFR-TKI treatment efficacy. However no predictive biomarker of these favorable treatment efficacies has been identified to date. The exosome-focused translational research for afatinib (EXTRA) study aims to identify a novel predictive biomarker and a resistance marker for afatinib by analyzing data from association studies of the clinical efficacy of afatinib and four "OMICs" (genomics, proteomics, epigenomics, and metabolomics) using peripheral blood from patients treated with afatinib. This study aims to: (i) conduct comprehensive multi-OMIC analyses in a prospective clinical trial, and (ii) focus on both sera/plasma and exosome as a source for OMIC analyses to identify a novel predictor of the efficacy of a specific drug. To eliminate the carryover bias of prior treatment, systemic treatment-naïve patients were enrolled. The candidates to be screened for biomarkers comprise a discovery cohort of 60 patients and an independent validation cohort of 40 patients. The EXTRA study is the first trial to screen novel biomarkers of longer treatment efficacy of EGFR-TKIs using four-OMICs analyses, focusing on both "naked or free" molecules and "capsulated" exosomal components in serially collected peripheral blood.
    Keywords:  Afatinib; OMIC; epidermal growth factor receptor; exosome; translational research
    DOI:  https://doi.org/10.1111/1759-7714.12923
  26. Proteomics Clin Appl. 2018 Dec 07. e1800016
    figHigh Spatial Resolution MALDI-MS Imaging in the Study of Membranous Nephropathy.
    Andrew Smith, Vincenzo L'Imperio, Vanna Denti, Mariafrancesca Mazza, Mariia Ivanova, Martina Stella, Isabella Piga, Clizia Chinello, Elena Ajello, Federico Pieruzzi, Fabio Pagni, Fulvio Magni.
      MALDI-MSI technology has advanced rapidly during recent years with the development of instruments equipped with low-diameter lasers that are suitable for high spatial resolution imaging. This may provide significant advantages in certain fields of molecular pathology where more specific protein fingerprints of individual cell types are required, such as renal pathology. Here we performed MALDI-MSI analysis of a cohort of MN patients among which patients either responded favourably (R; n = 6), or unfavourably (NR; n = 4), to immunosuppressive treatment (Ponticelli Regimen), employing a 10μm laser spot diameter. Specific tryptic peptide profiles of the different cellular regions within the glomerulus could be generated, similarly for the epithelial cells belonging to the proximal and distal tubules. Conversely, specific glomerular and sub-glomerular profiles could not be obtained whilst using the pixel size performed in previous studies (50μm). Furthermore, we highlight two proteins, Sonic Hedgehog (SHH) and α-smooth muscle actin (α-SMA), whose signal intensity and spatial localisation within the sub-glomerular and tubulointerstitial compartments differed between treatment responders and non-responders. The current study exemplifies the advantage of using high spatial resolution MALDI-MSI for the study of MN and highlights that such findings have the potential to provide complimentary support in the routine prognostic assessment of MN patients. This article is protected by copyright. All rights reserved.
    Keywords:  MALDI-MSI; high spatial resolution; high-throughput; membranous nephropathy; proteomics
    DOI:  https://doi.org/10.1002/prca.201800016
  27. Life Sci. 2018 Dec 11. pii: S0024-3205(18)30799-9. [Epub ahead of print]
    Proteomic analyses reveal lower expression of TEX40 and ATP6V0A2 proteins related to calcium ion entry and acrosomal acidification in asthenozoospermic males.
    Ashima Sinha, Virendra Singh, Sarman Singh, Savita Yadav.
       AIMS: Idiopathic nature of male infertility disorder needs to be investigated by different horizons of molecular biology for its treatment and to device male contraceptive. Further, it can also aid in advancement of assisted reproductive technology (ART), as nowadays the failure and disquiets of ART are consistent. Herein, we have attempted to find out proteins responsible for male infertility by comparing proteome profile of sperms collected from normal control and asthenozoospermic (AS) males.
    MAIN METHODS: Differential proteome profiles were studied by 2-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry. The confirmation of proteome profiling results was done by western blotting and ELISA. Quantitative reverse-transcription-PCR was also performed in an independent cohort of AS and normal individuals to investigate the transcriptional regulation of proteins.
    KEY FINDINGS: Although seven differentially regulated proteins were identified, highpoints of the study were two proteins, TEX40 and ATP6V0A2. Lower expression of a crucial sperm motility related protein, TEX40 is reported for the first time in clinically diagnosed AS males in the present investigation. Most likely with reference to previous findings the down regulation of TEX40 leads to fewer entries of calcium ions in the sperm and lower expression of ATP6V0A2 is responsible for acrosomal de-acidification.
    SIGNIFICANCE: Conclusively, the down regulation of these two proteins in AS males might result in diminished sperm motility. The findings can be worthwhile for male contraception and ART management besides their use for male infertility therapy.
    Keywords:  ATP6V0A2; Asthenozoospermia; Male infertility; TEX40
    DOI:  https://doi.org/10.1016/j.lfs.2018.12.016
  28. Methods Mol Biol. 2019 ;1916 319-328
    A Complete Proteomic Workflow to Study Brain-Related Disorders via Postmortem Tissue.
    Guilherme Reis-de-Oliveira, Mariana Fioramonte, Daniel Martins-de-Souza.
      Here we describe a mass spectrometry-based proteomics workflow to discovery proteins differentially regulated in brains collected postmortem from mental, neurological, or substance abuse disorders (MNS) patients. One way to maximize protein detection is to carry out enrichment of cellular compartments such as the nucleus, mitochondria and cytosol. Subcellular fractionation improves proteome coverage and may shed light on the role of these organelles in the pathophysiology of MNS.
    Keywords:  Brain; Mass spectrometry-based proteomics; Mental health disorders; Postmortem brain; Proteomics; Sample enrichment; Subcellular fractionation
    DOI:  https://doi.org/10.1007/978-1-4939-8994-2_31
  29. Neural Regen Res. 2019 Mar;14(3): 470-479
    Xiao-Xu-Ming decoction extract regulates differentially expressed proteins in the hippocampus after chronic cerebral hypoperfusion.
    Yue-Hua Wang, Ying-Lin Yang, Xiao Cheng, Jun Zhang, Wan Li, Guan-Hua Du.
      Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2a, Ptpn1, Ppm1e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MT-ND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.
    Keywords:  Morris water maze test; Nano-LC-ESI LTQ-Orbitrap MS/MS technology; Xiao-Xu-Ming decoction; bilateral common carotid artery occlusion; chronic cerebral hypoperfusion; label-free quantitative proteomics; nerve regeneration; neural regeneration; vascular dementia
    DOI:  https://doi.org/10.4103/1673-5374.245471
  30. Blood. 2018 Dec 10. pii: blood-2018-07-866830. [Epub ahead of print]
    The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy.
    Tatjana Bilich, Annika Nelde, Leon Bichmann, Malte Roerden, Helmut R Salih, Daniel J Kowalewski, Heiko Schuster, Chih-Chiang Tsou, Ana Marcu, Marian C Neidert, Maren Lübke, Jonas Rieth, Mirle Schemionek, Tim H Brümmendorf, Vladan Vucinic, Dietger Niederwieser, Jens Bauer, Melanie Märklin, Janet K Peper, Reinhild Klein, Oliver Kohlbacher, Lothar Kanz, Hans-Georg Rammensee, Stefan Stevanović, Juliane S Walz.
      Anti-leukemia immunity plays an important role in disease control and maintenance of tyrosine kinase inhibitor (TKI)-free remission in chronic myeloid leukemia (CML). Thus, antigen-specific immunotherapy holds promise to strengthen immune control in CML, but requires the identification of CML-associated targets. In this study, we used a mass spectrometry-based approach to identify naturally presented, HLA class I- and class II-restricted peptides in primary CML samples. Comparative HLA ligandome profiling using a comprehensive dataset of different hematological benign specimen and samples of CML patients in deep molecular remission delineated a panel of novel, frequently presented, CML-exclusive peptides. These non-mutated target antigens are of particular relevance since our extensive data mining approach suggests absence of naturally presented, BCR-ABL- and ABL-BCR-derived, HLA-restricted peptides and lack of frequent, tumor-exclusive presentation of known cancer/testis and leukemia-associated antigens. Functional characterization revealed spontaneous T-cell responses against the newly identified CML-associated peptides in CML patient samples and their ability to induce multifunctional and cytotoxic antigen-specific T cells de novo in samples of healthy volunteers and CML patients. These antigens are thus prime candidates for T cell-based immunotherapeutic approaches that may prolong TKI-free survival and even mediate cure of CML patients.
    DOI:  https://doi.org/10.1182/blood-2018-07-866830
  31. J Proteome Res. 2018 Dec 10.
    Discovery and qualification of candidate urinary biomarkers of disease activity in lupus nephritis.
    Veronica G Anania, Kebing Yu, Francesco Pingitore, Qingling Li, Christopher M Rose, Peter Liu, Wendy Sandoval, Ann E Herman, Jennie R Lill, W Rodney Mathews.
      Lupus nephritis (LN) is a severe clinical manifestation of systemic lupus erythematosus (SLE) associated with significant morbidity and mortality. Assessment of severity and activity of renal involvement in SLE requires a kidney biopsy, an invasive procedure with limited prognostic value. Non-invasive biomarkers are needed to inform treatment decisions and to monitor disease activity. Proteinuria is associated with disease progression in LN, however, the composition of the LN urinary proteome remains incompletely characterized. To address this, we profiled LN urine samples using complementary mass spectrometry-based methods: SDS-PAGE gel fractionation, chemical labeling using tandem mass tags (TMT), and data-independent acquisition (DIA). Combining results from these approaches yielded quantitative information on 2,573 unique proteins in urine from LN patients. A multiple reaction monitoring (MRM) method was established to confirm eight proteins in an independent cohort of LN patients, and seven proteins (transferrin, alpha-2-macroglobulin, haptoglobin, afamin, alpha-1-antitrypsin, vimentin, and ceruloplasmin) were confirmed to be elevated in LN urine compared to HC. In this study, we demonstrate that deep mass spectrometry profiling of a small number of patient samples can identify high quality biomarkers that replicate in an independent LN disease cohort. These biomarkers are being used to inform clinical biomarker strategies to support longitudinal and interventional studies focused on evaluating disease progression and treatment efficacy of novel LN therapeutics.
    DOI:  https://doi.org/10.1021/acs.jproteome.8b00874
  32. Int J Biochem Cell Biol. 2018 Dec 10. pii: S1357-2725(18)30258-9. [Epub ahead of print]
    Mass spectrometry-based peptidome profiling of human serous ovarian cancer tissues.
    Juan Xu, Xusu Wang, Pengfei Xu, Siyu Liu, Fang Teng, Xiaoguang Liu, Qiaoying Zhu, Xiangdong Hua, Zhen Gong, Xuemei Jia.
       BACKGROUND: Bioactive peptides existing in vivo have been considered an important class of natural medicines for the treatment of diseases. Peptidome analysis of tissues and biofluids had provided important information about the differentially expressed bioactive peptides in vivo.
    METHODS: Here, we analyzed the peptidome of serous ovarian cancer tissue samples and normal ovarian epithelial tissue samples by mass spectrometry and further investigated the possible bioactive peptides that were differentially expressed.
    RESULTS: We identified 634 differentially expressed peptides, 508 of these peptides were highly abundant in serous ovarian cancer tissues, a result consistent with higher protease activity in ovarian cancer patients. The difference in preferred cleavage sites between the serous ovarian cancer tissues and normal ovarian epithelium indicates the characteristic peptidome of ovarian cancer and the nature of cancer-associated protease activity. Interestingly, KEGG pathway analysis of the peptide precursors indicated that the differentially regulated pathways in ovarian cancer are highly consistent with the pathways discovered in other cancers. Besides, we found that a proportion of the differentially expressed peptides are similar to the known immune-regulatory peptides and anti-bacterial peptides. Then we further investigated the function of the two down-regulated peptides in ovarian cancer cells and found that the peptide P1DS significantly inhibited the invasion and migration of OVCAR3 and SKOV3 ovarian cancer cells.
    CONCLUSIONS: Our results are the first to identify the differentially expressed peptides between the serous ovarian cancer tissue and the normal ovarian epithelium. Our results indicate that bioactive peptides involved in tumorigenesis are existed in vivo.
    Keywords:  Cleavage sites; Liquid Chromatography/Mass Spectrometry; Ovarian cancer; P1 derived from S38AA protein; endogenous peptides
    DOI:  https://doi.org/10.1016/j.biocel.2018.12.004
  33. Oxid Med Cell Longev. 2018 ;2018 1435934
    Mitoproteomics: Tackling Mitochondrial Dysfunction in Human Disease.
    María Gómez-Serrano, Emilio Camafeita, Marta Loureiro, Belén Peral.
      Mitochondria are highly dynamic and regulated organelles that historically have been defined based on their crucial role in cell metabolism. However, they are implicated in a variety of other important functions, making mitochondrial dysfunction an important axis in several pathological contexts. Despite that conventional biochemical and molecular biology approaches have provided significant insight into mitochondrial functionality, innovative techniques that provide a global view of the mitochondrion are still necessary. Proteomics fulfils this need by enabling accurate, systems-wide quantitative analysis of protein abundance. More importantly, redox proteomics approaches offer unique opportunities to tackle oxidative stress, a phenomenon that is intimately linked to aging, cardiovascular disease, and cancer. In addition, cutting-edge proteomics approaches reveal how proteins exert their functions in complex interaction networks where even subtle alterations stemming from early pathological states can be monitored. Here, we describe the proteomics approaches that will help to deepen the role of mitochondria in health and disease by assessing not only changes to mitochondrial protein composition but also alterations to their redox state and how protein interaction networks regulate mitochondrial function and dynamics. This review is aimed at showing the reader how the application of proteomics approaches during the last 20 years has revealed crucial mitochondrial roles in the context of aging, neurodegenerative disorders, metabolic disease, and cancer.
    DOI:  https://doi.org/10.1155/2018/1435934
  34. Cell. 2018 Dec 13. pii: S0092-8674(18)31553-8. [Epub ahead of print]175(7): 1931-1945.e18
    Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis.
    Priya S Shah, Nichole Link, Gwendolyn M Jang, Phillip P Sharp, Tongtong Zhu, Danielle L Swaney, Jeffrey R Johnson, John Von Dollen, Holly R Ramage, Laura Satkamp, Billy Newton, Ruth Hüttenhain, Marine J Petit, Tierney Baum, Amanda Everitt, Orly Laufman, Michel Tassetto, Michael Shales, Erica Stevenson, Gabriel N Iglesias, Leila Shokat, Shashank Tripathi, Vinod Balasubramaniam, Laurence G Webb, Sebastian Aguirre, A Jeremy Willsey, Adolfo Garcia-Sastre, Katherine S Pollard, Sara Cherry, Andrea V Gamarnik, Ivan Marazzi, Jack Taunton, Ana Fernandez-Sesma, Hugo J Bellen, Raul Andino, Nevan J Krogan.
      Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms.
    Keywords:  ANKLE2; Drosophila; PAF1C; Sec61; Zika virus; dengue virus; endoplasmic reticulum; flavivirus; interferon stimulated genes; microcephaly; proteomics
    DOI:  https://doi.org/10.1016/j.cell.2018.11.028
  35. IUBMB Life. 2018 Dec 14.
    Detection of Malignancy-Associated Phosphoproteome Changes in Human Colorectal Cancer Induced by Cell Surface Binding of Growth-Inhibitory Galectin-4.
    Malwina Michalak, Uwe Warnken, Martina Schnölzer, Hans-Joachim Gabius, Jürgen Kopitz.
      Emerging evidence on efficient tumor growth regulation by endogenous lectins directs interest to determine on a proof-of-principle level the range of information on alterations provided by full-scale analysis using phosphoproteomics. In our pilot study, we tested galectin-4 (gal-4) that is a growth inhibitor for colon cancer cells (CRC), here working with the LS 180 line. In order to cover monitoring of short- and long-term effects stable isotope labeling by amino acids in cell culture-based quantitative phosphoproteomic analyses were conducted on LS 180 cell preparations collected 1 and 72 h after adding gal-4 to the culture medium. After short-term treatment, 981 phosphosites, all of them S/T based, were detected by phosphoproteomics. Changes higher than 1.5-fold were seen for eight sites in seven proteins. Most affected were the BET1 homolog (BET1), whose level of phosphorylation at S50 was about threefold reduced, and centromere protein F (CENPF), extent of phosphorylation at S3119 doubling in gal-4-treated cells. Phosphoproteome analysis after 72 h of treatment revealed marked changes at 33 S/T-based phosphosites from 29 proteins. Prominent increase of phosphorylation was observed for cofilin-1 at position S3. Extent of phosphorylation of the glutamine transporter SLC1A5 at position S503 was decreased by a factor of 3. Altered phosphorylation of BET1, CENPF, and cofilin-1 as well as a significant effect of gal-4 treatment on glutamine uptake by cells were substantiated by independent methods in the Vaco 432, Colo 205, CX 1, and HCT 116 cell lines. With the example of gal-4 which functions as a tumor suppressor in CRC cells, we were able to prove that cell surface binding of the lectin not only markedly influences the cell proteome, but also has a bearing on malignancy-associated intracellular protein phosphorylation. These results underscore the potential of this approach to give further work on elucidating the details of signaling underlying galectin-triggered growth inhibition a clear direction. © 2018 IUBMB Life, 9999(9999):1-12, 2018.
    Keywords:  Glutamine transporter; colorectal cancer; galectin-4; growth-inhibition; phosphoproteome; tumor suppressor
    DOI:  https://doi.org/10.1002/iub.1987
  36. FEBS J. 2018 Dec 13.
    Beyond the Message: Advantages of Snapshot Proteomics with Single-Cell Mass Cytometry in Solid Tumors.
    Akshitkumar M Mistry, Allison R Greenplate, Rebecca A Ihrie, Jonathan M Irish.
      Single-cell technologies that can quantify features of individual cells within a tumor are critical for treatment strategies aiming to target cancer cells while sparing or activating beneficial cells. Given that key players in protein networks are often the primary targets of precision oncology strategies, it is imperative to transcend the nucleic acid message and read cellular actions in human solid tumors. Here, we review the advantages of single-cell mass cytometry. Leveraging its multiplexing capability, mass cytometry can quantitatively probe nearly any cellular feature or target, for tissue and solid tumor investigations. In discussing the ability of mass cytometry to reveal and characterize a broad spectrum of cell types, identify rare cells, and study functional behavior through protein signaling networks in millions of individual cells from a tumor, this review surveys publications of scientific advances in solid tumor biology made with the aid of mass cytometry. Advances discussed include functional identification of rare tumor-infiltrating immune cells and dissecting cellular mechanisms of immunotherapy in solid tumors and the periphery. The review concludes by highlighting ways to incorporate single-cell mass cytometry in solid tumor precision oncology efforts and rapidly developing cytometry techniques for quantifying cell location and sequenced nucleic acids. This article is protected by copyright. All rights reserved.
    Keywords:  immune cell; immunotherapy; mass cytometry; proteomics; signaling; single cell
    DOI:  https://doi.org/10.1111/febs.14730
  37. Environ Pollut. 2018 Dec 01. pii: S0269-7491(18)34134-4. [Epub ahead of print]246 45-52
    Omics approach reveals metabolic disorders associated with the cytotoxicity of airborne particulate matter in human lung carcinoma cells.
    Chao Zhao, Lin Zhu, Ruijin Li, Hailin Wang, Zongwei Cai.
      Exposure to airborne particulate matter (PM) 2.5 induced various adverse health effects, such as metabolic syndrome, systemic inflammation and respiratory infection. However, a global influence of PM2.5-induced metabolic and proteomic disorders remains confusing, and the underlying mechanism is still under-explored. Herein, LC-MS/MS-based metabolomics, lipidomics and isobaric tags for relative and absolute quantification (iTRAQ)-based proteomics were applied to analyze the toxicological characteristics of PM2.5 from Taiyuan City in China (Taiyuan-PM2.5) on human lung carcinoma cells (A549) after the 24-h treatment. Metabolites, lipids and proteins that have distinctive differences were screened by SIEVE, LipidSearch and Proteome Discoverer, respectively. The abundance of 56 metabolites (40 increased and 16 decreased), 22 lipids (19 increased and 3 decreased) and 81 proteins (55 up-regulated and 26 down-regulated) were significantly changed upon the PM2.5 treatment. Among the proteomics analysis, 16 proteins were specifically related to RNA splicing, mainly including up-regulated serine/arginine-rich splicing factor 1 (SRSF1), SRSF2, small nuclear ribonucleoprotein 70 kDa (snRNP70), small nuclear ribonucleoprotein polypeptide B (SNRPB), SNRPC, SNRPE and down-regulated heterogeneous nuclear ribonucleoprotein U-like 2 (hnRNP UL2). At the metabolic level, PM2.5 exposure significantly altered the sphingolipid metabolism, including ceramide, serine, sphingosine and sphingomyelin. It was proposed that excessive accumulation of ceramide and expression of key enzymes (ceramide synthases, phingomyelinase, sphingosine kinase types 2 and protein phosphatase-1) induced the secretion of pro-inflammatory cytokines, generation of lipotoxicity and alterations of RNA splicing in PM2.5-treated A549  cells. In general, our results demonstrated that ceramide accumulation and altered RNA splicing could becritical contributors to PM2.5-induced cytotoxicity at metabolic and proteomic level, which might be considered as potential markers for toxicological evaluation of PM2.5 samples.
    Keywords:  Human lung carcinoma cells; LC-MS/MS; Lipidomics; Metabolomics; Proteomics
    DOI:  https://doi.org/10.1016/j.envpol.2018.11.108
  38. J Gastroenterol Hepatol. 2018 Dec 14.
    A review of lifestyle, metabolic risk factors and blood-based biomarkers for early diagnosis of pancreatic ductal adenocarcinoma.
    Yuanjie Pang, Michael V Holmes, Zhengming Chen, Christiana Kartsonaki.
      We aimed to review the epidemiologic literature examining lifestyle, metabolic risk factors, and blood-based biomarkers including multi-omics (genomics, proteomics, and metabolomics) and to discuss how these predictive markers can inform early diagnosis of pancreatic ductal adenocarcinoma (PDAC). A search of the PubMed database was conducted in June 2018 to review epidemiologic studies of (1) lifestyle and metabolic risk factors for PDAC, genome-wide association studies (GWAS), and risk prediction models incorporating these factors and (2) blood-based biomarkers for PDAC (conventional diagnostic markers, metabolomics, and proteomics). Prospective cohort studies have reported at least twenty possible risk factors for PDAC, including smoking, heavy alcohol drinking, adiposity, diabetes, and pancreatitis, but the relative risks (RR) and population attributable fractions of individual risk factors are small (mostly <10%). High-throughput technologies have continued to yield promising genetic, metabolic, and protein biomarkers in addition to conventional biomarkers such as carbohydrate antigen 19-9 (CA 19-9). Nonetheless, most studies have utilised a hospital-based case-control design, and the diagnostic accuracy is low in studies that collected pre-diagnostic samples. Risk prediction models incorporating lifestyle and metabolic factors as well as other clinical parameters have shown good discrimination and calibration. Combination of traditional risk factors, genomics and blood-based biomarkers can help identify high-risk populations and inform clinical decisions. Multi-omics investigations can provide valuable insights into disease aetiology, but prospective cohort studies that collect pre-diagnostic samples and validation in independent studies are warranted.
    Keywords:  biomarkers; early diagnosis; metabolomics; pancreatic ductal adenocarcinoma; proteomics; risk factors
    DOI:  https://doi.org/10.1111/jgh.14576
  39. Virusdisease. 2018 Dec;29(4): 468-477
    Differentially expressed serum host proteins in hepatitis B and C viral infections.
    Kruti Dalal, Priyanka Khorate, Bhavik Dalal, Rahul Chavan, Shobna Bhatia, Avinash Kale, Akash Shukla, Aruna Shankarkumar.
      Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection often lead to hepatocellular carcinoma (HCC), which is mostly detected in advanced stage. Hence, its early detection is of paramount importance using a biomarker having sensitivity and specificity both. The present study highlights differentially expressed host proteins in response to HBV/HCV infection at different stages. Comparative proteomic study was done by two-dimensional gel electrophoresis followed by mass spectrometry. Sera from each of chronically infected, liver cirrhosis and HCC in HBV or HCV infection along with controls were selected. Analysis of functional association between differentially expressed proteins with viral hepatitis was extensively carried out. Forty-three differentially expressed spots (≥ 1.5 fold; P < 0.05) on two-dimensional gel electrophoresis were corresponded to 28 proteins by mass spectrometry in variable liver diseases. Haptoglobin protein levels were decreased upon disease progression to HCC due to HBV infection. The other proteins expressed differentially are ceruloplasmin, serum paraoxonase 1, retinol binding protein and leucine rich alpha 2 proteins in plasma maybe associated to HBV HCC. Whereas, upregulation of C4a/C4b showed it as a reliable marker in patients with end stage liver disease related to HCV infection. ApolipoproteinA1 levels in liver diseases in both HBV and HCV infection corresponding to healthy controls may be a common marker for early diagnosis and disease monitoring. Protein interaction studies by extensive pathway analysis using bioinformatics tools such as EnrichNet application and STRING revealed significant associations with specific infections.
    Keywords:  Hepatitis B virus; Hepatitis C virus; Hepatocellular carcinoma; Protein biomarkers
    DOI:  https://doi.org/10.1007/s13337-018-0484-y
  40. Proteomics Clin Appl. 2018 Dec 13. e1800129
    Immunoproteomic Identification of Non-carbohydrate Antigens Eliciting Graft-Specific Adaptive Immune Responses in Patients with Bovine Pericardial Bioprosthetic Heart Valves.
    Katherine V Gates, Qi Xing, Leigh G Griffiths.
       PURPOSE: The purpose of this case-control retrospective discovery study is to identify antigenic bovine pericardium (BP) proteins that stimulate graft-specific humoral immune response in patients implanted with glutaraldehyde fixed bovine pericardial (GFBP) heart valves.
    EXPERIMENTAL DESIGN: Banked serum was collected from age and sex matched patients who had received either a GFBP or mechanical heart valve replacement. Serum IgG was isolated and used to generate poly-polyclonal antibody affinity chromatography columns from each patient. Native and deglycosylated BP protein extracts were separately added to individual patient affinity chromatography columns, with unbound proteins washed through the column. Proteins captured in the affinity chromatography columns were submitted for LC-MS/MS. Differences between GFBP and mechanical heart valve replacement recipients were analyzed with Gaussian linearized modeling.
    RESULTS: Carbohydrate antigens overwhelmed protein capture in the affinity chromatography column, requiring BP protein deglycosylation prior to affinity chromatography. Nineteen BP protein antigens, which stimulated graft-specific IgG production, were identified in patients who received GFBP valve replacements. Identified antigens were significantly over-represented for calcium binding proteins.
    CONCLUSIONS AND CLINICAL RELEVANCE: Patients implanted with GFBP valves develop a graft-specific humoral immune response toward BP protein antigens, with 19 specific antigens identified in this work. The molecular functions of over-represented antigens, specifically calcium-binding proteins, may aid in understand the underlying factors that contribute to structural valve deterioration. This article is protected by copyright. All rights reserved.
    Keywords:  antigens; deglycosylation; heart valves; immunoproteomics; structural valve deterioration
    DOI:  https://doi.org/10.1002/prca.201800129
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