bims-prodis Biomed News
on Proteomics in disease
Issue of 2019‒05‒05
eighteen papers selected by
Nancy Gough
Bioserendipity
  1. Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities.
  2. Quantitative proteomic profiling of tumor-associated vascular endothelial cells in colorectal cancer.
  3. Accelerating Biomarker Discovery Through Electronic Health Records, Automated Biobanking, and Proteomics.
  4. Variability of serum novel serum peptide biomarkers correlates with the disease states of multiple myeloma.
  5. iTRAQ-based proteomics reveals SOD2 as a potential salivary biomarker in liver cancer.
  6. Molecular Network Analysis of the Urinary Proteome of Alzheimer's Disease Patients.
  7. Proteomics Profiling of Pancreatic Cancer and Pancreatitis for Biomarkers Discovery.
  8. Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma.
  9. Association of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C) with T2DM.
  10. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts.
  11. Serum proteomics identify potential biomarkers for nasopharyngeal carcinoma sensitivity to radiotherapy.
  12. SpotLight Proteomics-A IgG-Enrichment Phenotype Profiling Approach with Clinical Implications.
  13. Plasma proteome profiling reveals differentially expressed lipopolysaccharide-binding protein among leptospirosis patients.
  14. Identification of key transcription factors in endometrial cancer by systems bioinformatics analysis.
  15. Exosome-enriched fractions from MS B cells induce oligodendrocyte death.
  16. Corrigendum: Discovery of Novel and Clinically Relevant Markers in Formalin-Fixed Paraffin-Embedded Esophageal Cancer Specimen.
  17. Author Correction: Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients.
  18. A multiplex liquid chromatography tandem mass spectrometry method for the quantification of seven therapeutic monoclonal antibodies: Application for adalimumab therapeutic drug monitoring in patients with Crohn's disease.
  1. Cell. 2019 May 02. pii: S0092-8674(19)30292-2. [Epub ahead of print]177(4): 1035-1049.e19
    Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities.
    Suhas Vasaikar, Chen Huang, Xiaojing Wang, Vladislav A Petyuk, Sara R Savage, Bo Wen, Yongchao Dou, Yun Zhang, Zhiao Shi, Osama A Arshad, Marina A Gritsenko, Lisa J Zimmerman, Jason E McDermott, Therese R Clauss, Ronald J Moore, Rui Zhao, Matthew E Monroe, Yi-Ting Wang, Matthew C Chambers, Robbert J C Slebos, Ken S Lau, Qianxing Mo, Li Ding, Matthew Ellis, Mathangi Thiagarajan, Christopher R Kinsinger, Henry Rodriguez, Richard D Smith, Karin D Rodland, Daniel C Liebler, Tao Liu, Bing Zhang, .
      We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
    Keywords:  RB1; SOX9; biomarkers; colon cancer; drug targets; glycolysis; immune evasion; proteogenomics; proteomics; tumor antigen
    DOI:  https://doi.org/10.1016/j.cell.2019.03.030
  2. Biol Open. 2019 Apr 29. pii: bio.042838. [Epub ahead of print]
    Quantitative proteomic profiling of tumor-associated vascular endothelial cells in colorectal cancer.
    Guoqiang Wang, Qiongzhi Yang, Maoyu Li, Ye Zhang, Yu-Xiang Cai, Xujun Liang, Ying Fu, Zhefeng Xiao, Minze Zhou, Zhongpeng Xie, Huichao Huang, Yahui Huang, Yongheng Chen, Qiongqiong He, Fang Peng, Zhuchu Chen.
      To investigate the global proteomic profiles of vascular endothelial cells (VECs) in the tumor microenvironment and antiangiogenic therapy for colorectal cancer (CRC), matched pairs of normal (NVECs) and tumor-associated VECs (TVECs) were purified from CRC tissues by laser capture microdissection and subjected to iTRAQ based quantitative proteomics analysis. Here, 216 differentially expressed proteins (DEPs) were identified and performed bioinformatics analysis. Interestingly, these proteins were implicated in epithelial mesenchymal transition (EMT), ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, angiogenesis and HIF-1 signaling pathway, which may play important roles in CRC angiogenesis. Among these DEPs, we found that Tenascin-C (TNC) was upregulated in TVECs of CRC and correlated with CRC multistage carcinogenesis and metastasis. Furthermore, the reduction of tumor-derived TNC could attenuate human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation through ITGB3/FAK/Akt signaling pathway. Based on the present work, we provided a large-scale proteomic profiling of VECs in CRC with quantitative information, a certain number of potential antiangiogenic targets and a novel vision in the angiogenesis bio-mechanism of CRC.
    Keywords:  Angiogenesis; Colorectal cancer; Quantitative proteomics; Tenascin-C
    DOI:  https://doi.org/10.1242/bio.042838
  3. J Am Coll Cardiol. 2019 May 07. pii: S0735-1097(19)33945-2. [Epub ahead of print]73(17): 2195-2205
    Accelerating Biomarker Discovery Through Electronic Health Records, Automated Biobanking, and Proteomics.
    Quinn S Wells, Deepak K Gupta, J Gustav Smith, Sean P Collins, Alan B Storrow, Jane Ferguson, Maya Landenhed Smith, Jill M Pulley, Sarah Collier, Xiaoming Wang, Dan M Roden, Robert E Gerszten, Thomas J Wang.
      BACKGROUND: Circulating biomarkers can facilitate diagnosis and risk stratification for complex conditions such as heart failure (HF). Newer molecular platforms can accelerate biomarker discovery, but they require significant resources for data and sample acquisition.OBJECTIVES: The purpose of this study was to test a pragmatic biomarker discovery strategy integrating automated clinical biobanking with proteomics.
    METHODS: Using the electronic health record, the authors identified patients with and without HF, retrieved their discarded plasma samples, and screened these specimens using a DNA aptamer-based proteomic platform (1,129 proteins). Candidate biomarkers were validated in 3 different prospective cohorts.
    RESULTS: In an automated manner, plasma samples from 1,315 patients (31% with HF) were collected. Proteomic analysis of a 96-patient subset identified 9 candidate biomarkers (p < 4.42 × 10-5). Two proteins, angiopoietin-2 and thrombospondin-2, were associated with HF in 3 separate validation cohorts. In an emergency department-based registry of 852 dyspneic patients, the 2 biomarkers improved discrimination of acute HF compared with a clinical score (p < 0.0001) or clinical score plus B-type natriuretic peptide (p = 0.02). In a community-based cohort (n = 768), both biomarkers predicted incident HF independent of traditional risk factors and N-terminal pro-B-type natriuretic peptide (hazard ratio per SD increment: 1.35 [95% confidence interval: 1.14 to 1.61; p = 0.0007] for angiopoietin-2, and 1.37 [95% confidence interval: 1.06 to 1.79; p = 0.02] for thrombospondin-2). Among 30 advanced HF patients, concentrations of both biomarkers declined (80% to 84%) following cardiac transplant (p < 0.001 for both).
    CONCLUSIONS: A novel strategy integrating electronic health records, discarded clinical specimens, and proteomics identified 2 biomarkers that robustly predict HF across diverse clinical settings. This approach could accelerate biomarker discovery for many diseases.
    Keywords:  biomarkers; electronic health records; heart failure; proteomics
    DOI:  https://doi.org/10.1016/j.jacc.2019.01.074
  4. Clin Proteomics. 2019 ;16 17
    Variability of serum novel serum peptide biomarkers correlates with the disease states of multiple myeloma.
    Ju Bai, Yun Yang, Jianli Wang, Lei Zhang, Fangxia Wang, Aili He.
      Background: The bone marrow microenvironment provides an optimal substrate for multiple myeloma (MM) initiation and progression. The soluble component of MM niche is dynamic with the disease states of MM. We formerly employed proteomic profiling to construct a MM model. Four peptides constituting the model were selected by supervised neural network algorithm (SNN).Methods: 62 Newly diagnosed (ND) MM and 64 healthy controls (HCs) were picked up for validating the distinguishing capability of the SNN model. Nano-liquid chromatography-electrospray ionization-tandem mass spectrometry was used for peptide identification. MM in different disease states and HCs were choosed for peptides relative intensities comparison. Western blot and ELISA were employed to validate the variability.
    Results: The sensitivity and specificity of the independent testing data set for blind validation were 93.55% and 92.19%. The relative intensities of three out of the four peptides were increased in ND and refractory and relapse patients but decreased to that level of HCs in complete remission and very good partial remission patients. Relative intensity of the remaining peptide was negatively associated with MM remission. The peptides sequencing results showed that they were derived from dihydropyrimidinase-like 2, fibrinogen alpha chain, platelet factor 4 and alpha-fetoprotein.
    Conclusions: The potential value of the four peptides in monitoring MM treatment response was arised from their close correlation with MM disease states.
    Keywords:  Biomarkers; Bone marrow microenvironment; Multiple myeloma; Proteomic profiling; Treatment response
    DOI:  https://doi.org/10.1186/s12014-019-9238-0
  5. Int J Biol Markers. 2019 May 01. 1724600819841619
    iTRAQ-based proteomics reveals SOD2 as a potential salivary biomarker in liver cancer.
    Feng Ding, Kehuan Sun, Ningning Sun, Qianqian Jiang, Meiqun Cao, Zhengzhi Wu.
      BACKGROUND: Salivary proteomic analysis has been extensively used in a wide range of cancer, but not in hepatocellular carcinoma. The aim of this study was to identify potential salivary biomarkers for hepatocellular carcinoma clinical screening.METHODS: In this study, we performed isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics analysis to detect differentially expressed proteins between saliva samples from 15 hepatocellular carcinoma patients and 15 healthy controls. Enzyme-linked immunosorbent assay (ELISA) verification was undertaken in saliva samples from 14 hepatocellular carcinoma patients and 14 healthy controls.
    RESULTS: Overall, 133 proteins with significant differential expression level (ratio > 1.5 or < 0.67) were detected. Using bioinformatic analysis, two candidate proteins were selected and subsequently verified by ELISA. The increased expression of superoxide dismutase 2, mitochondrial (SOD2) in hepatocellular carcinoma patients was confirmed by ELISA, with an area under the curve value of 0.9082.
    CONCLUSIONS: iTRAQ-based quantitative proteomics revealed that SOD2 might serve as a potential salivary biomarker for hepatocellular carcinoma detection. Our results indicated that a noninvasive and inexpensive salivary test might be established for hepatocellular carcinoma detection.
    Keywords:  Hepatocellular carcinoma; SOD2; iTRAQ; salivary biomarker
    DOI:  https://doi.org/10.1177/1724600819841619
  6. Dement Geriatr Cogn Dis Extra. 2019 Jan-Apr;9(1):9(1): 53-65
    Molecular Network Analysis of the Urinary Proteome of Alzheimer's Disease Patients.
    Yumi Watanabe, Yoshitoshi Hirao, Kensaku Kasuga, Takayoshi Tokutake, Yuka Semizu, Kaori Kitamura, Takeshi Ikeuchi, Kazutoshi Nakamura, Tadashi Yamamoto.
      Background/Aims: The identification of predictive biomarkers for Alzheimer's disease (AD) from urine would aid in screening for the disease, but information about biological and pathophysiological changes in the urine of AD patients is limited. This study aimed to explore the comprehensive profile and molecular network relations of urinary proteins in AD patients.Methods: Urine samples collected from 18 AD patients and 18 age- and sex-matched cognitively normal controls were analyzed by mass spectrometry and semiquantified with the normalized spectral index method. Bioinformatics analyses were performed on proteins which significantly increased by more than 2-fold or decreased by less than 0.5-fold compared to the control (p < 0.05) using DAVID bioinformatics resources and KeyMolnet software.
    Results: The levels of 109 proteins significantly differed between AD patients and controls. Among these, annotation clusters related to lysosomes, complement activation, and gluconeogenesis were significantly enriched. The molecular relation networks derived from these proteins were mainly associated with pathways of lipoprotein metabolism, heat shock protein 90 signaling, matrix metalloproteinase signaling, and redox regulation by thioredoxin.
    Conclusion: Our findings suggest that changes in the urinary proteome of AD patients reflect systemic changes related to AD pathophysiology.
    Keywords:  Alzheimer's disease; Case-control study; Label-free mass spectrometry; Proteomics; Urine
    DOI:  https://doi.org/10.1159/000496100
  7. J Cell Sci Ther. 2018 ;pii: 287. [Epub ahead of print]9(4):
    Proteomics Profiling of Pancreatic Cancer and Pancreatitis for Biomarkers Discovery.
    N Sanh, H Fadul, N Hussein, B D Lyn-Cook, G Hammons, X E Ramos-Cardona, K Mohamed, S I Mohammed.
      Pancreatic cancer is one of the most aggressive malignancies with an increase in incidence predicted, particularly in African Americans. Pancreatic cancer is considered a silent disease with poor prognosis and a lack of early biomarkers for detection. Proteomics has been applied in many diseases for identifying or discovering biomarkers. It has long been suggested that chronic pancreatitis may be a risk factor for developing pancreatic cancer. This study identified proteins that are altered in expression in pancreatic cancer and pancreatitis compared to normal using proteomic technology. Proteins were extracted from laser captured micro-dissected tissues and separated in 2-DPAGE and imaged. The protein profiles of pancreatic cancer and pancreatitis are similar but differed with the protein profile of normal adjacent tissues. Representative proteins, overexpressed in tumor and pancreatitis but not normal tissues, were excised from gels, subjected to in-gel digestion, and analyzed by MALDI-TOF mass spectrometry. Proteins identified included transferrin, ER-60 protein, proapolipoprotein, tropomyosin 1, alpha 1 actin precursor, ACTB protein, and gamma 2 propeptide, aldehyde dehydrogenase 1A1, pancreatic lipase and annexin A1. Several proteins, which were shown in pancreatic cancer, were also observed in pancreatitis samples. Understanding the role of these specific proteins and their mechanistic action will give insights into their involvement in pancreatic cancers.
    Keywords:  2D-gel; Biomarkers; Lipase; Pancreatic cancer; Pancreatitis; Proteomic
    DOI:  https://doi.org/10.4172/2157-7013.1000287
  8. Genome Med. 2019 Apr 30. 11(1): 28
    Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma.
    Markus W Löffler, Christopher Mohr, Leon Bichmann, Lena Katharina Freudenmann, Mathias Walzer, Christopher M Schroeder, Nico Trautwein, Franz J Hilke, Raphael S Zinser, Lena Mühlenbruch, Daniel J Kowalewski, Heiko Schuster, Marc Sturm, Jakob Matthes, Olaf Riess, Stefan Czemmel, Sven Nahnsen, Ingmar Königsrainer, Karolin Thiel, Silvio Nadalin, Stefan Beckert, Hans Bösmüller, Falko Fend, Ana Velic, Boris Maček, Sebastian P Haen, Luigi Buonaguro, Oliver Kohlbacher, Stefan Stevanović, Alfred Königsrainer, , Hans-Georg Rammensee.
      BACKGROUND: Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs.METHODS: In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data.
    RESULTS: The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations.
    CONCLUSIONS: This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
    Keywords:  HLA; HLA ligandomics; Hepatocellular carcinoma; Immunoinformatics; Immunotherapy; Liver cancer; Mass spectrometry; Multi-omics; Neoantigen; Next-generation sequencing; Peptide prediction; Personalized medicine
    DOI:  https://doi.org/10.1186/s13073-019-0636-8
  9. Gene. 2019 Apr 27. pii: S0378-1119(19)30434-2. [Epub ahead of print]
    Association of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C) with T2DM.
    Rabab Asghar Abdulwahab, Abdul Ameer A Allaith, Zakia Shinwari, Ayodele Alaiya, Hayder A Giha.
      Proteins differential expression in type 2 diabetes mellitus (T2DM) can be due to etiological factors or pathological changes, such proteins can be utilized as biomarkers. Identification of a marker protein out of thousands became a feasible task during the proteomics era by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, blood samples were obtained from 80 Bahraini subjects with and without T2DM, a subset was used for proteomic analysis by LC-MS/MS, while all samples were used for ELISA analysis of 3 proteins, TATA-box binding protein-associated factor RNA polymerase-1-C (TAF1C), ceruloplasmin (CERP) and fibronectin (FN). The former 2 proteins were selected from the T2DM-protein-panel identified by LC-MS/MS, and the latter was analyzed for validation of the setting. The main findings of the proteomic analysis are i. Identifications of 62 differentially expressed proteins in T2DM, ii. Upregulation of 71% of the identified proteins. While the ELISA analysis showed that; both TAF1C and FN were significantly increased in T2DM (P0.015 and P0.001, respectively), while CERP was not (P0.088). Logistic regression analysis: i. confirmed the above associations after correction for covariates, ii. Revealed an interaction between age and gender that affect the association of the proteins with T2DM. In conclusion, knowing that TAF1C is a prerequisite in ribosomal biogenesis, our ELISA results are suggestive of increased protein synthesis in T2DM, explaining the observed upregulation of the proteins identified by LC-MSMS. The association between T2DM and TAF1C is a novel finding that might open a new avenue in DM research.
    Keywords:  Fibronectin; LC-MS/MS; Peptides; Proteomics; Ribosomal biogenesis; T2DM; TAF1C
    DOI:  https://doi.org/10.1016/j.gene.2019.04.076
  10. Nature. 2019 May 01.
    Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts.
    Mark A Eckert, Fabian Coscia, Agnieszka Chryplewicz, Jae Won Chang, Kyle M Hernandez, Shawn Pan, Samantha M Tienda, Dominik A Nahotko, Gang Li, Ivana Blaženović, Ricardo R Lastra, Marion Curtis, S Diane Yamada, Ruth Perets, Stephanie M McGregor, Jorge Andrade, Oliver Fiehn, Raymond E Moellering, Matthias Mann, Ernst Lengyel.
      High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer1,2, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.
    DOI:  https://doi.org/10.1038/s41586-019-1173-8
  11. Biosci Rep. 2019 Apr 30. pii: BSR20190027. [Epub ahead of print]
    Serum proteomics identify potential biomarkers for nasopharyngeal carcinoma sensitivity to radiotherapy.
    Guangying Zhang, Kun Zhang, Chao Li, Yanyan Li, Zhanzhan Li, Na Li, Qin Zhou, Liangfang Shen.
      Radiotherapy is the primary treatment option for nasopharyngeal carcinoma (NPC). Local recurrence and metastasis caused by radioresistance become a bottleneck of curative effect for patients with NPC. Currently, serum predictive biomarkers of radioresistance are scare. We enrolled NPC patients who underwent radiotherapy in the Department of Oncology, Xiangya Hospital, Central Southern University, and analyzed the serum proteins profiles in NPC patients using with quantitative label-free proteomics using ultra-definition MS. Patients were divided into those who were radioresistant and radiosensitive by the overall reduction (≤50% or >50%, respectively) in tumor extent. The MS/MS spectrum database search identified 911 proteins and 809 proteins are quantifiable. Eight proteins significantly up-regulated and twelve serum proteins were significantly downregulated in the radioresistance group compared with radiosensitivity group ( P <0.05). Finally, five proteins entered the optimal models, including secreted protein acidic and cysteine rich (SPARC) ( P =0.032), serpin family D member 1S (ERPIND1) ( P =0.040), Complement C4B (C4B) ( P =0.017), Peptidylprolyl Isomerase B (PPIB) ( P =0.042), and FAM173A ( P =0.017). In all patient, the AUCs for SPARC, SERPIND, C4B, PPIB and FAM173A were 0.716 (95%CI: 0.574-0.881), 0.697(95%CI: 0.837-0.858), 0.686(95%CI: 0.522-0.850), 0.668 (95%CI: 0.502-0.834) and 0.657(95%CI: 0.512-0.825), respectively. The AUC of five selected proteins was 0.968 (95%CI: 0.918-1.000) with the sensitivity of 0.941 and the specificity of 0.926.  Our result indicated that a panel including five serum protein (SPARC SERPIND1 C4B PPIB FAM173A) based on serum proteomics provided a high discrimination ability for radiotherapy effects in NPC patients. Studies with larger sample size and longer follow-up outcome are required.
    Keywords:  Nasopharyngeal carcinoma; biomarkers; radioresistance; serum proteomics
    DOI:  https://doi.org/10.1042/BSR20190027
  12. Int J Mol Sci. 2019 May 01. pii: E2157. [Epub ahead of print]20(9):
    SpotLight Proteomics-A IgG-Enrichment Phenotype Profiling Approach with Clinical Implications.
    Susanna L Lundström, Tina Heyder, Emil Wiklundh, Bo Zhang, Anders Eklund, Johan Grunewald, Roman A Zubarev.
      Sarcoidosis is a systemic interstitial lung disease of unknown aetiology. Less invasive diagnostics are needed to decipher disease pathology and to distinguish sub-phenotypes. Here we test if SpotLight proteomics, which combines de novo MS/MS sequencing of enriched IgG and co-extracted proteins with subsequent label-free quantification of new and known peptides, can differentiate controls and sarcoidosis phenotypes (Löfgrens and non-Löfgrens syndrome, LS and nonLS). Intra-individually matched IgG enriched from serum and bronchial lavage fluid (BALF) from controls (n = 12), LS (n = 11) and nonLS (n = 12) were investigated. High-resolution mass-spectrometry SpotLight proteomics and uni- and multivariate-statistical analyses were used for data processing. Major differences were particularly observed in control-BALF versus sarcoidosis-BALF. However, interestingly, information obtained from BALF profiles was still present (but less prominent) in matched serum profiles. By using information from orthogonal partial least squares discriminant analysis (OPLS-DA) differentiating 1) sarcoidosis-BALF and control-BALF and 2) LS-BALF vs. nonLS-BALF, control-serum and sarcoidosis-serum (p = 0.0007) as well as LS-serum and nonLS-serum (p = 0.006) could be distinguished. Noteworthy, many factors prominent in identifying controls and patients were those associated with Fc-regulation, but also features from the IgG-Fab region and novel peptide variants. Differences between phenotypes were mostly IgG-specificity related. The results support the analytical utility of SpotLight proteomics which prospectively have potential to differentiate closely related phenotypes from a simple blood test.
    Keywords:  IgG; Löfgrens syndrome; biomarker; sarcoidosis
    DOI:  https://doi.org/10.3390/ijms20092157
  13. J Microbiol Immunol Infect. 2019 Apr 13. pii: S1684-1182(18)30447-X. [Epub ahead of print]
    Plasma proteome profiling reveals differentially expressed lipopolysaccharide-binding protein among leptospirosis patients.
    Cheng-Yee Fish-Low, Leslie Thian Lung Than, King-Hwa Ling, Qingsong Lin, Zamberi Sekawi.
      BACKGROUND: Human leptospirosis, or commonly known as "rat urine disease" is a zoonotic disease that is caused by the bacteria called Leptospira sp. The incidence rate of leptospirosis has been under-reported due to its unspecific clinical symptoms and the limitations of current laboratory diagnostic methods. Leptospirosis can be effectively treated with antibiotics in the early stage, and it is a curable disease but the accuracy to diagnose the infection is rarely achieved.METHODS: The present pilot study investigated plasma protein profiles of leptospirosis patients and compared them against two control groups which consisted of dengue patients and healthy individuals. The plasma protein digests were analyzed using shotgun approach by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein abundances were estimated from the exponentially modified protein abundance index (emPAI) values. Plasma proteins in leptospirosis patients with at least two-fold differential expression compared to dengue and healthy control groups (p < 0.05, ANOVA) were identified.
    RESULTS: Lipopolysaccharide (LPS)-binding protein (LBP) was found to be the only protein that has significant different expression between leptospirosis and the two control groups. The expression levels of leucine-rich alpha-2-glycoprotein (LRG1) and alpha-1-antichymotrypsin (ACT) were different significantly between leptospirosis and healthy group but not to the dengue control group.
    CONCLUSION: This is the first plasma proteome-based study on leptospirosis that reports the differential expression of LBP compared to both dengue and healthy controls, which has not been previously reported in the context of leptospirosis.
    Keywords:  Leptospirosis; Lipopolysaccharide-binding protein; Plasma proteome
    DOI:  https://doi.org/10.1016/j.jmii.2018.12.015
  14. J Cell Biochem. 2019 Apr 29.
    Identification of key transcription factors in endometrial cancer by systems bioinformatics analysis.
    Yong Song, Qiu-Tong Chen, Qi-Qiang He.
      Endometrial cancer (EC) is one of the most common malignant diseases worldwide. Although many studies have been performed on EC, a systems analysis between transcription factors (TFs) and EC relationship remains poorly characterized. Here, we present a systems bioinformatics analysis of TFs in EC patient samples to identify key TFs in EC. First, dysregulated and survival-related TFs were identified in EC using data from The Cancer Genome Atlas database and Gene Expression Omnibus. Second, we investigated the mechanisms of dysregulated TFs and tested whether their expression is correlated with prognosis of EC. Finally, we addressed new perspectives in EC biomarker research, including comprehensive knowledge of previously suggested candidate biomarkers in conjunction with novel mass spectrometry-based proteomic technologies with enhanced sensitivity and specificity not yet applied to EC studies, enabling a directed clinical perspective of the study design. Our study identified three promising TFs, E2F1, HMGA1, and PGR, which closely correlate with EC. Although treatments targeting TFs are not always efficient, these TFs may be useful as biomarkers for the diagnosis and prognosis of EC. Furthermore, we found that these dysregulated TFs and their target genes are primarily involved in the cell cycle and may promote endometrial carcinoma occurrence and development. Using integrated bioinformatic analysis, we identified candidate genes and pathways in EC, which could improve our understanding of the etiology and underlying molecular events of EC. Furthermore, these candidate genes and pathways could be therapeutic targets for EC.
    Keywords:  The Cancer Genome Atlas; bioinformatics; endometrial cancer; transcription factors
    DOI:  https://doi.org/10.1002/jcb.28811
  15. Neurol Neuroimmunol Neuroinflamm. 2019 May;6(3): e550
    Exosome-enriched fractions from MS B cells induce oligodendrocyte death.
    Joyce A Benjamins, Liljana Nedelkoska, Hanane Touil, Paul M Stemmer, Nicholas J Carruthers, Bhanu P Jena, Akshata R Naik, Amit Bar-Or, Robert P Lisak.
      Objective: To identify whether factors toxic to oligodendrocytes (OLs), released by B cells from patients with MS, are found in extracellular microvesicles enriched in exosomes.Methods: Conditioned medium (Sup) was obtained from cultures of blood B cells of patients with MS and normal controls (NCs). Exosome-enriched (Ex-En) fractions were prepared by solvent precipitation from Sup containing bovine serum and from serum-free Sup by ultracentrifugation (UC) or immunoprecipitation (IP) with antibodies to CD9. Ex-En fractions were diluted 1:4 with OL culture medium and screened for toxic effects on cultured rat OLs as measured by trypan blue uptake. Proteomic analysis was performed on Sup fractions.
    Results: MS B cell-derived Ex-En fractions prepared from Sup by solvent extraction, UC, or IP induced OL death, whereas corresponding Ex-En fractions from NC showed little toxicity. Proteomic analysis of Sup demonstrated enrichment of proteins characteristic of exosomes from both NC and MS B-cell Sup. Ontology enrichment analysis suggested differences in the types and cargo of exosomes from MS Sup compared with NC, with proteins related to cell surface, extracellular plasma membrane, and gliogenesis enriched in MS.
    Conclusions: Much of the in vitro toxicity of Sup from B cells of patients with relapsing-remitting MS is found in Ex-En fractions, as confirmed by 3 methods. Proteomic analysis of B-cell Sup indicates multiple differences between MS and NC.
    DOI:  https://doi.org/10.1212/NXI.0000000000000550
  16. Front Oncol. 2019 ;9 273
    Corrigendum: Discovery of Novel and Clinically Relevant Markers in Formalin-Fixed Paraffin-Embedded Esophageal Cancer Specimen.
    Joe Abdo, Christopher S Wichman, Nicholas E Dietz, Pawel Ciborowski, John Fleegel, Sumeet K Mittal, Devendra K Agrawal.
      [This corrects the article DOI: 10.3389/fonc.2018.00157.].
    Keywords:  SWATH analysis; chemoresistance markers; formalin-fixed paraffin-embedded tissue; mass spectrometry; molecular oncology; proliferation markers; proteomics
    DOI:  https://doi.org/10.3389/fonc.2019.00273
  17. Transl Psychiatry. 2019 May 03. 9(1): 146
    Author Correction: Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients.
    Akira Yoshimi, Shinnosuke Yamada, Shohko Kunimoto, Branko Aleksic, Akihiro Hirakawa, Mitsuki Ohashi, Yurie Matsumoto, Kazuhiro Hada, Norimichi Itoh, Yuko Arioka, Hiroki Kimura, Itaru Kushima, Yukako Nakamura, Tomoko Shiino, Daisuke Mori, Satoshi Tanaka, Shuko Hamada, Yukihiro Noda, Taku Nagai, Kiyofumi Yamada, Norio Ozaki.
      The original Article required a few updates; one co-author name, which was given as Hiroki Kiumura, has been updated to Hiroki Kimura. Furthermore, supplementary information has been updated, and grant numbers have been added. These updates have been made to both the PDF and HTML versions of this Article.
    DOI:  https://doi.org/10.1038/s41398-019-0479-5
  18. Anal Chim Acta. 2019 Aug 27. pii: S0003-2670(19)30322-8. [Epub ahead of print]1067 63-70
    A multiplex liquid chromatography tandem mass spectrometry method for the quantification of seven therapeutic monoclonal antibodies: Application for adalimumab therapeutic drug monitoring in patients with Crohn's disease.
    Théo Willeman, Jean-François Jourdil, Elodie Gautier-Veyret, Bruno Bonaz, Françoise Stanke-Labesque.
      The use of therapeutic monoclonal antibodies (mAbs) is steadily increasing. Previous studies have reported the clinical interest of mAb therapeutic-drug monitoring (TDM), including that of adalimumab, for patients with Crohn's disease (CD). Proof of concept mAb-quantification studies by liquid chromatography mass spectrometry (LC-MS/MS) have been published, but a specific and reliable routine-suited multiplex quantification method is still needed to facilitate mAb TDM. We describe an electrospray ionization LC-MS/MS method for the simultaneous quantification of seven mAbs (adalimumab, cetuximab, infliximab, rituximab, secukinumab, tocilizumab, and trastuzumab) in human plasma. Sample preparation was performed using protein-G purification and trypsin digestion to obtain proteotypic peptides. We retrospectively measured the adalimumab concentration in 65 plasma samples from 56 CD patients and determined the adalimumab therapeutic cut-off concentration associated with biological remission. Calibration curves were linear from 1 to 100 μg mL-1, except for rituximab (5-100 μg mL-1). This method was reproducible, repeatable, and accurate (coefficient of variation and bias < 20%), with no cross contamination. Adalimumab concentrations were significantly higher (p = 0.0198) for patients with biological remission (median: 11.3 μg mL-1 [4.6; 18.3]) than that for patients without a biological response (9.5 μg mL-1 [3.94;17.0]). An adalimumab cut-off concentration of 8.0 μg mL-1 correctly discriminated patients with or without biological remission (sensitivity: 74.1%, specificity: 57.9%). This validated LC-MS/MS routine-suited method is the first allowing simultaneous quantification of up to seven mAbs acting against different pharmacological targets. It opens the field of TDM to numerous mAbs.
    Keywords:  Adalimumab; Crohn's disease; Liquid chromatography tandem mass spectrometry; Therapeutic drug monitoring; Therapeutic monoclonal antibodies
    DOI:  https://doi.org/10.1016/j.aca.2019.03.033
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