bims-prodis 2019-02-17 papers

bims-prodis

Biomed News

on Proteomics in disease

Issue of 2019–02–17
35 papers selected by
Nancy Gough, Bioserendipity

Proteomic and genomic profiling of pancreatic cancer.
Shotgun proteomic analysis reveals proteome alterations in HDL of patients with cholesteryl ester transfer protein deficiency.
Microvesicle Proteomic profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.
Altered Molecular Pathways in the Proteome of Cryopreserved Sperm in Testicular Cancer Patients before Treatment.
Proteomic Investigations of Autism Spectrum Disorder: Past Findings, Current Challenges, and Future Prospects.
Proteomic evidence that ABCA4 is vital for traumatic proliferative vitreoretinopathy formation and development.
Proteomics and Visual Health Research: Proteome of the Human Sclera Using High-Resolution Mass Spectrometry.
Toward Candidate Proteomic Biomarkers in Clinical Monitoring of Acute Promyelocytic Leukemia Treatment with Arsenic Trioxide.
Inflammasome Signaling and Impaired Vascular Health in Psoriasis.
New biomarkers of Kawasaki disease identified by urine proteomic analysis.
Differentially expressed proteins identified by TMT proteomics analysis in bone marrow microenvironment of osteoporotic patients.
Integrated Fourier Transform Infrared Imaging and Proteomics for Identification of a Candidate Histochemical Biomarker in Bladder Cancer.
MALDI-TOF-MS Analysis in the Identification of Urine Proteomic Patterns of Gestational Trophoblastic Disease.
Mass spectrometry-based analysis of cerebrospinal fluid from arthritis patients-immune-related candidate proteins affected by TNF blocking treatment.
Intra-surgical Protein Layer on Titanium Arthroplasty Explants: From the Big Twelve To The Implant Proteome.
Proteomics for clinical assessment of kidney disease.
Development of a sensitive, scalable method for spatial, cell-type-resolved proteomics of the human brain.
The complementary role of histology and proteomics for diagnosis and typing of systemic amyloidosis.
Lymphocyte mass cytometry identifies a CD3-CD4+ cells subset with a potential role in psoriasis.
The Role of Biomarkers in Psychiatry.
MicroRNA-143 is Associated With Pathological Complete Response and Regulates Multiple Signaling Proteins in Breast Cancer.
Clinical proteomics on the path towards implementation: first promises delivered.
Proteomic Markers for Depression.
Chronic Obstructive Pulmonary Disease Phenotype Dictates Cancer-Promoting Stromal Gene Expression Programs.
Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function.
Male Infertility, Precision Medicine and Systems Proteomics.
Interactome Studies of Psychiatric Disorders.
Early Detection and Treatment of Patients with Alzheimer's Disease: Future Perspectives.
Proteomics and Metabolomics in Pregnancy-An Overview.
Advances in Biomarker Studies in Autism Spectrum Disorders.
Multimodel inference for biomarker development: an application to schizophrenia.
Mutations in Hepatitis D Virus Allow it to Escape Detection by CD8+ T Cells and Evolve at the Population Level.
A Pregnancy Cohort to Study Multidimensional Correlates of Preterm Birth in India: Study Design, Implementation, and Baseline Characteristics of the Participants.
A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic- and molecular-phenotypes of epithelial ovarian cancer.
Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TGF-β Signaling and Epigenomics.

Cell Biol Toxicol. 2019 Feb 15.

Proteomic and genomic profiling of pancreatic cancer.

Daniel Ansari, William Torén, Qimin Zhou, Dingyuan Hu, Roland Andersson.

  Pancreatic cancer remains the most fatal human tumor type. The aggressive tumor biology coupled with the lack of early detection strategies and effective treatment are major reasons for the poor survival rate. Collaborative research efforts have been devoted to understand pancreatic cancer at the molecular level. Large-scale genomic studies have generated important insights into the genetic drivers of pancreatic cancer. In the post-genomic era, protein sequencing of tumor tissue, cell lines, pancreatic juice, and blood from patients with pancreatic cancer has provided a fundament for the development of new diagnostic and prognostic biomarkers. The integration of mass spectrometry and genomic sequencing strategies may help characterize protein identities and post-translational modifications that relate to a specific mutation. Consequently, proteomic and genomic techniques have become a compulsory requirement in modern medicine and health care. These types of proteogenomic studies may usher in a new era of precision diagnostics and treatment in patients with pancreatic cancer.

Keywords:  Biomarkers; Genomics; Pancreatic cancer; Proteogenomics; Proteomics

DOI:  https://doi.org/10.1007/s10565-019-09465-9
J Clin Lipidol. 2019 Jan 11. pii: S1933-2874(19)30002-9. [Epub ahead of print]

Shotgun proteomic analysis reveals proteome alterations in HDL of patients with cholesteryl ester transfer protein deficiency.

Takeshi Okada, Tohru Ohama, Kazuaki Takafuji, Kotaro Kanno, Hibiki Matsuda, Masami Sairyo, Yinghong Zhu, Ayami Saga, Takuya Kobayashi, Daisaku Masuda, Masahiro Koseki, Makoto Nishida, Yasushi Sakata, Shizuya Yamashita.

   BACKGROUND: We previously reported that the patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) show marked changes in the size and lipid compositions of high-density lipoprotein (HDL) and that they are not protected from atherosclerotic cardiovascular diseases, despite increased serum HDL-cholesterol (HDL-C) levels. HDL particles carry a variety of proteins, some of which are known to have antiatherogenic functions.
OBJECTIVE: This study aimed to investigate the protein composition of HDL particles in patients with CETP-D.
METHODS: Eight patients with complete deficiency of CETP and 8 normolipidemic healthy subjects were enrolled. We performed shotgun proteomic analysis to investigate the proteome of ultracentrifugally isolated HDL.
RESULTS: We identified 79 HDL-associated proteins involved in lipid metabolism, protease inhibition, complement regulation, and acute-phase response, including 5 potential newly identified HDL-associated proteins such as angiopoietin-like3 (ANGPTL3). Spectral counts of apolipoprotein (apo) E were increased in patients with CETP-D compared with controls (60.3 ± 6.9 vs 43.7 ± 2.5, P < .001), which is concordant with our previous report. Complement regulatory proteins such as C3, C4a, C4b, and C9 were also significantly enriched in HDL from patients with CETP-D. Furthermore, apoC-III and ANGPTL3, both of which are now known to associate with increased atherosclerotic cardiovascular diseases, were enriched in patients with CETP-D compared with normolipidemic subjects (35.9 ± 5.3 vs 27.1 ± 3.7, 2.3 ± 1.1 vs 0.4 ± 1.1, respectively; P < .01).
CONCLUSION: We have characterized HDL-associated proteins in patients with CETP-D. We identified a significant increase in the amount of apoE, apoC-III, ANGPTL3, and complement regulatory proteins. These proteomic changes might be partly responsible for the enhanced atherogenicity of patients with CETP-D.

Keywords:  Cholesteryl ester transfer protein deficiency; High density lipoprotein; LC-MS/MS analysis; Shotgun proteomic analysis; Ultracentrifugation

DOI:  https://doi.org/10.1016/j.jacl.2019.01.002
Mol Cell Proteomics. 2019 Feb 13. pii: mcp.RA119.001362. [Epub ahead of print]

Microvesicle Proteomic profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.

Georgina D Barnabas, Keren Bahar-Shany, Stav Sapoznik, Limor Helpman, Yfat Kadan, Mario Beiner, Omer Weitzner, Nissim Arbib, Jacob Korach, Tamar Perri, Guy Katz, Anna Blecher, Benny Brandt, Eitan Friedman, David Stockheim, Ariella Jakobson-Setton, Ram Eitan, Shunit Armon, Hadar Brand, Oranit Zadok, Sarit Aviel-Ronen, Michal Harel, Tamar Geiger, Keren Levanon.

  High-grade ovarian cancer (HGOC) is the leading cause of mortality from gynecological malignancies, due to diagnosis at a metastatic stage. Current screening options fail to improve mortality due to the absence of early-stage-specific biomarkers. We postulated that a liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Furthermore, while mutation-based assays are challenged by the rarity of tumor DNA within non-mutated DNA, analyzing the proteomic profile, is expected to enable earlier detection, as it reveals perturbations in both the tumor as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we applied our method for microvesicle proteomics to the UtL samples. Liquid biopsies from HGOC patients (n=49) and controls (n=127) were divided into a discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8,578 UtL proteins in total, and on average ~3,000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 70% sensitivity and 76.2% specificity. The signature correctly identified all Stage I lesions. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis.

Keywords:  Biofluids*; Biomarker: Diagnostic; Cancer biomarker(s); Mass Spectrometry; Ovarian cancer

DOI:  https://doi.org/10.1074/mcp.RA119.001362
Int J Mol Sci. 2019 Feb 05. pii: E677. [Epub ahead of print]20(3):

Altered Molecular Pathways in the Proteome of Cryopreserved Sperm in Testicular Cancer Patients before Treatment.

Manesh Kumar Panner Selvam, Ashok Agarwal, Peter N Pushparaj.

  Testicular cancer (TC) represents the most common cancer affecting men within the reproductive age and is often accompanied by major disturbances in semen parameters. Cryopreservation is recommended in these patients before initiating cancer treatment. Currently, there are no studies reporting the molecular mechanisms associated with altered semen quality in these men. The main objective of this study was to compare the sperm proteome of normozoospermic (motility >40%) and asthenozoospermic (motility <40%) TC patients with normozoospermic infertile men without cancer (control group). Pooled sperm samples from normozoospermic (n = 20), asthenozoospermic (n = 11) TC, and a control group (n = 9) were used for quantitative global proteomic profiling using liquid chromatography-tandem mass spectrometry. A total of 1085, 846, and 982 proteins were identified in normozoospermic TC, asthenozoospermic TC, and control groups, respectively. Functional analysis revealed mitochondrial dysfunction and altered cellular pathways in both normozoospermic and asthenozoospermic TC patients. Comparison of pathway analysis showed no significant difference in fertility-associated proteins/mechanism between the normozoospermic TC patients and infertile men. Western blot analysis revealed under-expression of NDUFS1 associated with mitochondrial dysfunction and overexpression of CD63 involved in sperm maturation in both normozoospermic and asthenozoospermic TC patients. Our proteomic results confirm that defective cellular pathways are associated with reproductive functions in both normozoospermic and asthenozoospermic TC patients before the start of cancer treatment.

Keywords:  cryopreservation; proteomics; sperm; testicular cancer; unexplained infertility

DOI:  https://doi.org/10.3390/ijms20030677
Adv Exp Med Biol. 2019 ;1118 235-252

Proteomic Investigations of Autism Spectrum Disorder: Past Findings, Current Challenges, and Future Prospects.

Joseph Abraham, Nicholas Szoko, Marvin R Natowicz.

  Proteomics is a powerful tool to study biological systems and is potentially useful in identifying biomarkers for clinical screening and diagnosis, for monitoring treatment, and for exploring pathogenetic mechanisms in autism. Unlike numerous other experimental approaches employed in autism research, there have been few proteomic-based analyses. Herein, we discuss the findings of studies regarding autism that utilized a proteomic approach and review key considerations in sample acquisition, processing, and analysis. Most proteomic studies on autism used blood or other peripheral tissues. Few studies used brain tissue, the main site of biological difference between persons with autism and others. The findings have varied and are not yet replicated. Some showed abnormalities of synaptic proteins or proteins of mitochondrial bioenergetics. Various abnormalities of proteins relating to immune processes and lipid metabolism have also been noted. Whether any of the proteomic differences between autism and control cases are primary or secondary phenomena is currently unclear. Consequently, no definitive biomarkers for autism have been identified, and the pathophysiological insights provided by proteomic studies to date are uncertain in the absence of replication. Based on this body of work and the challenges in using proteomics to study autism, we suggest considerations for future study design. These include attention to subject and specimen inclusion/exclusion criteria, attention to the state of specimens prior to proteomic analysis, and use of a replicate set of specimens. We end by discussing especially promising applications of proteomics in the study of autism pathobiology.

Keywords:  ASD; Autism; Mass spectrometry; Neuroproteomics; Proteomic; Proteomics

DOI:  https://doi.org/10.1007/978-3-030-05542-4_12
Exp Eye Res. 2019 Feb 06. pii: S0014-4835(18)30439-1. [Epub ahead of print]

Proteomic evidence that ABCA4 is vital for traumatic proliferative vitreoretinopathy formation and development.

Menghua Wang, Qiuming Li, Hongtao Dong.

  Proliferative vitreoretinopathy (PVR) is the leading cause of retinal detachment failure. The mechanism of PVR development is complex and still not completely elucidated. There are no proven methods for early prevention or clinical treatment. Retinal proteins are abnormally expressed during the entire PVR disease process. Due to limitations of research methods and techniques, we do not fully understand the retinal protein changes in PVR. This proteomics study systemically analyzed and identified differential protein expression between retinas of PVR and non-PVR (normal) eyes. Retinal samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) coupled with mass spectrometry. Raw data were processed and analyzed by Maxquant software and then searched against the human UniProKB (201510) protein database. Differentially expressed proteins were selected and further validated in a human retinal pigment epithelial (RPE) cell line. The effects of dysregulated proteins on cell proliferation, apoptosis, and migration were studied. Systemic proteomics analysis identified several PVR-enriched proteins. The differentially expressed proteins were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation to find abnormal pathways involved in PVR. Retinal-specific ATP-binding cassette transporter (ABCA4) expression was one of the most increased proteins in PVR tissue. ABCA4 knockdown significantly reduced proliferation and affected the cell cycle in the human RPE cell line. ABCA4 knockdown also induced apoptosis and inhibited retinal cell migration. In conclusion, systemic proteomics analysis identified differentially expressed proteins in traumatic PVR, with ABCA4 being highly expressed. Disruption of ABCA4 expression induced apoptosis and inhibited cell proliferation and migration in a human RPE cell line.

Keywords:  ABCA4; Migration; Proliferation; Proliferative vitreoretinopathy (PVR); Proteomics; Retinal pigment epithelial (RPE) cells

DOI:  https://doi.org/10.1016/j.exer.2019.02.006
OMICS. 2019 Feb;23(2): 98-110

Proteomics and Visual Health Research: Proteome of the Human Sclera Using High-Resolution Mass Spectrometry.

Varshasnata Mohanty, Yashwanth Subbannayya, Mohammed Altaf Najar, Sneha M Pinto, Sandeep Kasaragod, Hilda Karuppiah, Bhuvaragavan Sreeramulu, Kunal Kumar Singh, Sunita Dalal, Shyamjith Manikkoth, Cynthia Arunachalam, Thottethodi Subrahmanya Keshava Prasad, Krishna R Murthy.

  Eye disorders and resulting visual loss are major public health problems affecting millions of people worldwide. In this context, the sclera is an opaque, thick outer coat covering more than 80% of the eye, and essential in maintaining the shape of the eye and protecting the intraocular contents against infection and the external environment. Despite efforts undertaken to decipher the scleral proteome, the functional and structural picture of the sclera still remain elusive. Recently, proteomics has arisen as a powerful tool that enables identification of proteins playing a critical role in health and disease. Therefore, we carried out an in-depth proteomic analysis of the human scleral tissue using a high-resolution Orbitrap Fusion Tribrid mass spectrometer. We identified 4493 proteins using SequestHT and Mascot as search algorithms in Proteome Discoverer 2.1. Importantly, the proteins, including radixin, synaptopodin, paladin, netrin 1, and kelch-like family member 41, were identified for the first time in human sclera. Gene ontology analysis unveiled that the majority of proteins were localized to the cytoplasm and involved in cell communication and metabolism. In sum, this study offers the largest catalog of proteins identified in sclera with the aim of facilitating their contribution to diagnostics and therapeutics innovation in visual health and autoimmune disorders. This study also provides a valuable baseline for future investigations so as to map the dynamic changes that occur in sclera in various pathological conditions.

Keywords:  eye proteome; omics technology; ophthalmology; proteomics; tandem mass spectrometry; visual health

DOI:  https://doi.org/10.1089/omi.2018.0185
OMICS. 2019 Feb;23(2): 119-130

Toward Candidate Proteomic Biomarkers in Clinical Monitoring of Acute Promyelocytic Leukemia Treatment with Arsenic Trioxide.

Fenglin Cao, Xingang Li, Yiju Yang, Honghong Fang, Haixia Qu, Naibai Chang, Qingwei Ma, Weifan Cao, Jin Zhou, Wei Wang.

  The introduction of arsenic trioxide (ATO) in treatment of acute promyelocytic leukemia (APL) has resulted in high clinical complete remission (CR) rates over 90%. On the contrary, the risk for early death (ED) in APL patients treated with ATO continues to have a negative impact for optimization of APL therapeutics. There is an urgent need for precision medicine and biomarkers in clinical monitoring of ATO toxicity in APL, and ED in particular. This retrospective case series cohort proteomics study was conducted as a hypothesis generation effort and provides here several potential molecular leads on serum peptides expressed at different times after treatment with ATO in patients with APL. In 12 patients with a de novo APL diagnosis, and treated with single-agent ATO as frontline remission induction therapy, serum peptides were fractionated by weak cation exchange magnetic beads and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Ten peptides (m/z 2075.5, 2084.2, 2203.0, 2265.2, 2872.8, 2916.6, 3145.2, 3153.4, 3953.4, and 3964.8) were significantly downregulated in serum after ATO treatment. Among them, four peptides were identified as (1) Immunoglobulin heavy chain V-III region BUT, (2) RRP15-like protein, (3) filaggrin, and (4) protein SON isoform F. To the best of our knowledge, this is the first clinical oncology proteomic biomarker study with a view to future rational therapeutic monitoring of patients with APL in the course of single-agent ATO treatment and hematological CR.

Keywords:  acute promyelocytic leukemia; arsenic trioxide; biomarkers; precision medicine; proteomics; therapeutic drug monitoring

DOI:  https://doi.org/10.1089/omi.2018.0178
Arterioscler Thromb Vasc Biol. 2019 Feb 14. ATVBAHA118312246

Inflammasome Signaling and Impaired Vascular Health in Psoriasis.

Michael S Garshick, Tessa Barrett, Todd Wechter, Sarah Azarchi, Jose Scher, Andrea Neimann, Stuart Katz, Judilyn Fuentes-Duculan, Maria V Cannizzaro, Sanja Jelic, Edward A Fisher, James G Krueger, Jeffrey S Berger.

  Objective- Psoriasis is an inflammatory skin disease which heightens the risk of cardiovascular disease. This study directly investigated vascular endothelial health and systemically altered pathways in psoriasis and matched controls. Approach and Results- Twenty patients (mean age, 40 years; 50% male) with active psoriasis and 10 age-, sex-matched controls were recruited. To investigate systemically alerted pathways, a deep sequencing omics approach was applied, including unbiased blood transcriptomic and targeted proteomic analysis. Vascular endothelial health was assessed by transcriptomic profiling of endothelial cells obtained from the brachial veins of recruited participants. Blood transcriptomic profiling identified inflammasome signaling as the highest differentially expressed canonical pathway ( Z score 1.6; P=1×10-7) including upregulation of CASP5 and interleukin ( IL) -1β. Proteomic panels revealed IL-6 as a top differentially expressed cytokine in psoriasis with pathway analysis highlighting IL-1β( Z score 3.7; P=1.02×10-23) as an upstream activator of the observed upregulated proteins. Direct profiling of harvested brachial vein endothelial cells demonstrated inflammatory transcript (eg, IL-1β, CXCL10, VCAM-1, IL-8, CXCL1, Lymphotoxin beta, ICAM-1, COX-2, and CCL3) upregulation between psoriasis versus controls. A linear relationship was seen between differentially expressed endothelial inflammatory transcripts and psoriasis disease severity. IL-6 levels correlated with inflammatory endothelial cell transcripts and whole blood inflammasome-associated transcripts, including CASP5 and IL-1β. Conclusions- An unbiased sequencing approach demonstrated the inflammasome as the most differentially altered pathway in psoriasis versus controls. Inflammasome signaling correlated with psoriasis disease severity, circulating IL-6, and proinflammatory endothelial transcripts. These findings help better explain the heightened risk of cardiovascular disease in psoriasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03228017.

Keywords:  cardiovascular disease; endothelium; inflammasome; inflammation; psoriasis

DOI:  https://doi.org/10.1161/ATVBAHA.118.312246
FEBS Open Bio. 2019 Feb;9(2): 265-275

New biomarkers of Kawasaki disease identified by urine proteomic analysis.

Hui-Min Hu, Hong-Wu Du, Jia-Wen Cui, De-Qin Feng, Zhong-Dong Du.

  Kawasaki disease (KD) is an acute systemic vasculitis that mainly afflicts infants and young children. The symptoms of KD are similar to those of various febrile diseases. Here, we attempted to develop accurate diagnostic biomarkers of KD by performing urine proteomic analysis of samples from healthy controls, patients with KD, and patients with another febrile disease, pneumonia (two patients). We identified differentially expressed proteins (DEPs) in KD as compared to normal controls. We also constructed functional annotation and protein-protein interaction (PPI) networks of DEPs in KD and pneumonia. DEPs common to both KD and pneumonia were identified, as well as DEPs specific to KD. Compared to normal control, 43 and 62 DEPs were identified in KD and pneumonia, respectively. Serine hydroxymethyltransferase 1 is a hub protein of the KD-specific PPI network. Thirteen DEPs common to both KD and pneumonia and 30 DEPs specific to KD were identified. Of these, the expression of eight DEPs could cluster normal and pneumonia samples into one group and cluster KD samples into another group based on hierarchical clustering. Our study identified several DEPs that may play a role in KD and that may serve as diagnostic biomarkers to distinguish patients with KD from both normal control and other febrile diseases.

Keywords:  Kawasaki disease; biomarker; pneumonia; protein; urine proteomics

DOI:  https://doi.org/10.1002/2211-5463.12563
Osteoporos Int. 2019 Feb 09.

Differentially expressed proteins identified by TMT proteomics analysis in bone marrow microenvironment of osteoporotic patients.

Q Zhou, F Xie, B Zhou, J Wang, B Wu, L Li, Y Kang, R Dai, Y Jiang.

  We applied tandem mass tag (TMT)-based proteomics to investigate protein changes in bone marrow microenvironment of osteoporotic patients undergoing spine fusion. Multiple bioinformatics tools were used to identify and analyze 219 differentially expressed proteins. These proteins may be associated with the pathogenesis of osteoporosis.
INTRODUCTION: Bone marrow microenvironment is indispensable for the maintenance of bone homeostasis. We speculated that alterations of some factors in the microenvironment of osteoporotic subjects might influence the homeostasis. This study aimed to investigate the changes in the expression of protein factors in the bone marrow environment of osteoporosis.
METHODS: We performed a proteomics analysis in the vertebral body-derived bone marrow supernatant fluid from 8 Chinese patients undergoing posterior lumbar interbody fusion (4 osteoporotic vs. 4 non-osteoporotic) and used micro-CT to analyze the microstructural features of spinous processes from these patients. We further performed western blotting to validate the differential expressions of some proteins.
RESULTS: There was deteriorated bone microstructure in osteoporotic patients. Based on proteomics analysis, 172 upregulated and 47 downregulated proteins were identified. These proteins had multiple biological functions associated with osteoblast differentiation, lipid metabolism, and cell migration, and formed a complex protein-protein interaction network. We identified five major regulatory mechanisms, splicing, translation, protein degradation, cytoskeletal organization, and lipid metabolism, involved in the pathogenesis of osteoporosis.
CONCLUSIONS: There are various protein factors, such as DDX5, PSMC2, CSNK1A1, PLIN1, ILK, and TPM4, differentially expressed in the bone marrow microenvironment of osteoporotic patients, providing new ideas for finding therapeutic targets for osteoporosis.

Keywords:  Bone marrow microenvironment; Bone marrow supernatant fluid; Bone microstructure; Osteoporosis; Proteomics

DOI:  https://doi.org/10.1007/s00198-019-04884-0
Am J Pathol. 2019 Feb 09. pii: S0002-9440(18)30739-9. [Epub ahead of print]

Integrated Fourier Transform Infrared Imaging and Proteomics for Identification of a Candidate Histochemical Biomarker in Bladder Cancer.

Kathrin E Witzke, Frederik Großerueschkamp, Hendrik Jütte, Melanie Horn, Florian Roghmann, Nicolas von Landenberg, Thilo Bracht, Angela Kallenbach-Thieltges, Heiko Käfferlein, Thomas Brüning, Karin Schork, Martin Eisenacher, Katrin Marcus, Joachim Noldus, Andrea Tannapfel, Barbara Sitek, Klaus Gerwert.

Histopathological differentiation between severe urocystitis with reactive urothelial atypia and carcinoma in situ (CIS) can be difficult, particularly after a treatment that deliberately induces an inflammatory reaction, such as intravesical instillation of Bacillus Calmette-Guèrin. However, precise grading in bladder cancer is critical for therapeutic decision making and thus requires reliable immunohistochemical biomarkers. Herein, an exemplary potential biomarker in bladder cancer was identified by the novel approach of Fourier transform infrared imaging for label-free tissue annotation of tissue thin sections. Identified regions of interest are collected by laser microdissection to provide homogeneous samples for liquid chromatography-tandem mass spectrometry-based proteomic analysis. This approach afforded label-free spatial classification with a high accuracy and without interobserver variability, along with the molecular resolution of the proteomic analysis. Cystitis and invasive high-grade urothelial carcinoma samples were analyzed. Three candidate biomarkers were identified and verified by immunohistochemistry in a small cohort, including low-grade urothelial carcinoma samples. The best-performing candidate AHNAK2 was further evaluated in a much larger independent verification cohort that also included CIS samples. Reactive urothelial atypia and CIS were distinguishable on the basis of the expression of this newly identified and verified immunohistochemical biomarker, with a sensitivity of 97% and a specificity of 69%. AHNAK2 can differentiate between reactive urothelial atypia in the setting of an acute or chronic cystitis and nonmuscle invasive-type CIS.

DOI: https://doi.org/10.1016/j.ajpath.2018.11.018
Metabolites. 2019 Feb 09. pii: E30. [Epub ahead of print]9(2):

MALDI-TOF-MS Analysis in the Identification of Urine Proteomic Patterns of Gestational Trophoblastic Disease.

Paulina Banach, Paweł Dereziński, Eliza Matuszewska, Jan Matysiak, Hubert Bochyński, Zenon J Kokot, Ewa Nowak-Markwitz.

  Gestational trophoblastic disease (GTD) is a group of highly aggressive, rare tumors. Human chorionic gonadotropin is a common biomarker used in the diagnosis and monitoring of GTD. To improve our knowledge of the pathology of GTD, we performed protein-peptide profiling on the urine of patients affected with gestational trophoblastic neoplasm (GTN). We analyzed urine samples from patients diagnosed with GTN (n = 26) and from healthy pregnant and non-pregnant controls (n = 17) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Ions were examined in a linear mode over a m/z range of 1000⁻10,000. All GTN urine samples were analyzed before and after treatment and compared with those of the controls. The statistical analyses included multivariate classification algorithms as well as ROC curves. Urine sample analyses revealed there were significant differences in the composition of the ions between the evaluated groups. Comparing the pre-treatment and group with the pregnant controls, we identified two discriminatory proteins: hemoglobin subunit α (m/z = 1951.81) and complement C4A (m/z = 1895.43). Then, comparing urine samples from the post-treatment cases with those from the non-pregnant controls, we identified the peptides uromodulin fragments (m/z = 1682.34 and 1913.54) and complement C4A (m/z = 1895.43).

Keywords:  MALDI-TOF-MS; biomarkers; gestational trophoblastic disease; protein–peptide profiling

DOI:  https://doi.org/10.3390/metabo9020030
Arthritis Res Ther. 2019 Feb 15. 21(1): 60

Mass spectrometry-based analysis of cerebrospinal fluid from arthritis patients-immune-related candidate proteins affected by TNF blocking treatment.

Johanna Estelius, Johan Lengqvist, Elena Ossipova, Helena Idborg, Erwan Le Maître, Magnus L A Andersson, Lou Brundin, Mohsen Khademi, Elisabet Svenungsson, Per-Johan Jakobsson, Jon Lampa.

   BACKGROUND: Signs of inflammation in cerebrospinal fluid (CSF) of rheumatoid arthritis patients correlate positively with fatigue, a central nervous system (CNS)-related symptom that can be partially suppressed by TNF blockade. This suggests a possible role for CNS inflammation in arthritis that may be affected by TNF blockade. We therefore investigated the effects of TNF blockade on the arthritis CSF proteome and how candidate proteins related to clinical measures of disease activity and inflammation.
METHODS: Mass spectrometry-based quantitative proteomic analysis was performed on CSF from seven polyarthritis patients before and during infliximab treatment. Treatment-associated proteins were identified using univariate (Wilcoxon signed rank test) and multivariate (partial least squares discriminant analysis (PLS-DA)) strategies. Relations between selected candidate proteins and clinical measures were investigated using the Spearman correlations. Additionally, selected proteins were cross-referenced to other studies investigating human CSF in a thorough literature search to ensure feasibility of our results.
RESULTS: Univariate analysis of arthritis CSF proteome revealed a decrease of 35 proteins, predominantly involved in inflammatory processes, following TNF blockade. Seven candidate proteins, Contactin-1 (CNTN1), fibrinogen gamma chain (FGG), hemopexin (HPX), cell adhesion molecule-3 (CADM3), alpha-1B-glycoprotein (A1BG), complement factor B (CFB), and beta-2-microglobulin (B2M), were selected for further studies based on identification by both univariate and multivariate analyses and reported detection in human CSF and known associations to arthritis. Decreased levels of FGG and CFB in CSF after treatment showed strong correlations with both erythrocyte sedimentation rate and disability scores, while CNTN1 and CADM3 were associated with pain.
CONCLUSION: Several immune-related proteins in the CSF of arthritis patients decreased during TNF blockade, including FGG and CFB that both correlated strongly with systemic inflammation. Our findings stress that also intrathecal inflammatory pathways are related to arthritis symptoms and may be affected by TNF blockade.

Keywords:  Ankylosing spondylitis; Anti-TNF; CSF; Chronic inflammation; Intrathecal inflammation; Juvenile chronic arthritis; Proteomics; Psoriatic arthritis; Rheumatoid arthritis

DOI:  https://doi.org/10.1186/s13075-019-1846-6
Proteomics Clin Appl. 2019 Feb 15. e1800168

Intra-surgical Protein Layer on Titanium Arthroplasty Explants: From the Big Twelve To The Implant Proteome.

Marcus Jäger, Herbert P Jennissen, Marcel Haversath, André Busch, Thomas Grupp, Andrea Sowislok, Monika Herten.

   PURPOSE: Aseptic loosening in total joint replacement due to insufficient osteointegration is an unsolved problem in orthopaedics. The purpose of our study was to obtain a picture of the initial protein adsorption layer on femoral endoprosthetic surfaces as the key to the initiation of osseointegration.
EXPERIMENTAL DESIGN: This paper describes the first study of femoral stem explants from patients for proteome analysis of the primary protein layer. After 2 min. in situ the stems were explanted and frozen in liquid nitrogen. Proteins were eluted under reducing conditions and analyzed by LC-MS/MS.
RESULTS: After exclusion of proteins identified by a single peptide the implant proteome was found to consist of 2,802 unique proteins. Of these 77% were of intracellular origin, 9% were derived from the plasma proteome, 8% from the bone proteome and 4 proteins with highest specificity score could be assigned to the bone marrow proteome (Transcriptome). The most abundant protein in the adsorbed total protein layer was haemoglobin (8-11%) followed by serum albumin (3.6-6%).
CONCLUSIONS: A detailed knowledge of the initial protein film deposited onto the implants, as demonstrated here for the first time, may help to understand and predict the response of the osseous microenvironment to implant surfaces. This article is protected by copyright. All rights reserved.

Keywords:  Total hip arthroplasty; osteointegration; protein adsorption

DOI:  https://doi.org/10.1002/prca.201800168
Proteomics Clin Appl. 2019 Feb 15. e1900004

Proteomics for clinical assessment of kidney disease.

Alberto Ortiz.

Kidney disease is one of the fastest growing causes of death worldwide, disclosing an unmet clinical need for early diagnosis and optimized risk stratification that allows high risk patient selection for clinical trials and for more intensive nephroprotective interventions in the clinic. The current issue of PROTEOMICS - Clinical Applications contains four manuscripts that explore different aspects of clinical proteomics implementation in the context of acute kidney injury, chronic kidney disease and, more specifically, diabetic kidney disease, and kidney transplantation from a diagnostic and risk stratification point of view. Overall, the evidence discussed suggests that chronic kidney disease is an example where clinical proteomics has become a valuable tool ready for clinical implementation, expected to have a major impact in patient management. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/prca.201900004
J Proteome Res. 2019 Feb 15.

Development of a sensitive, scalable method for spatial, cell-type-resolved proteomics of the human brain.

Simon Davis, Connor Scott, Olaf Ansorge, Roman Fischer.

While nearly comprehensive proteome coverage can be achieved from bulk tissue or cultured cells, the data usually lacks spatial resolution. As a result, tissue based proteomics averages protein abundance across multiple cell types and/or localisations. With proteomics platforms lacking sensitivity and throughput to undertake deep single-cell proteome studies in order to resolve spatial or cell type dependent protein expression gradients within tissue, proteome analysis has been combined with sorting techniques to enrich for certain cell populations. However, the spatial resolution and context is lost after cell sorting. Here, we report an optimised method for the proteomic analysis of neurons isolated from post-mortem human brain by Laser Capture Microdissection (LCM). We tested combinations of sample collection methods, lysis buffers and digestion methods to maximize the number of identifications and quantitative performance, identifying 1500 proteins from 60,000 µm2 of 10 µm thick cerebellar molecular layer with excellent reproducibility. To demonstrate the ability of our workflow to resolve cell type specific proteomes within human brain tissue, we isolated sets of individual Betz and Purkinje cells. Both neuronal cell types are involved in motor coordination and were found to express highly specific proteomes to a depth of 2800 to 3600 proteins.

DOI: https://doi.org/10.1021/acs.jproteome.8b00981
J Pathol Clin Res. 2019 Feb 11.

The complementary role of histology and proteomics for diagnosis and typing of systemic amyloidosis.

Tamer Rezk, Janet A Gilbertson, P Patrizia Mangione, Dorota Rowczenio, Nigel Rendell, Diana Canetti, Helen J Lachmann, Ashutosh D Wechalekar, Paul Bass, Philip N Hawkins, Vittorio Bellotti, Graham W Taylor, Julian D Gillmore.

  The tissue diagnosis of amyloidosis and confirmation of fibril protein type, which are crucial for clinical management, have traditionally relied on Congo red (CR) staining followed by immunohistochemistry (IHC) using fibril protein specific antibodies. However, amyloid IHC is qualitative, non-standardised, requires operator expertise, and not infrequently fails to produce definitive results. More recently, laser dissection mass spectrometry (LDMS) has been developed as an alternative method to characterise amyloid in tissue sections. We sought to compare these techniques in a real world setting. During 2017, we performed LDMS on 640 formalin-fixed biopsies containing amyloid (CR+ve) comprising all 320 cases that could not be typed by IHC (IHC-ve) and 320 randomly selected CR+ve samples that had been typed (IHC+ve). In addition, we studied 60 biopsies from patients in whom there was a strong suspicion of amyloidosis, but in whom histology was non-diagnostic (CR-ve). Comprehensive clinical assessments were conducted in 532 (76%) of cases. Among the 640 CR+ve samples, 602 (94%) contained ≥ 2 of 3 amyloid signature proteins (ASPs) on LDMS (ASP+ve) supporting the presence of amyloid. 49 of the 60 CR-ve samples were ASP-ve; 7/11 that were ASP+ve were glomerular. The amyloid fibril protein was identified by LDMS in 255/320 (80%) of the IHC-ve samples and in a total of 545/640 (85%) cases overall. The LDMS and IHC techniques yielded discordant results in only 7/320 (2%) cases. CR histology and LDMS are corroborative for diagnosis of amyloid, but LDMS is superior to IHC for confirming amyloid type. This article is protected by copyright. All rights reserved.

Keywords:  Amyloid; Immunohistochemistry; Mass Spectrometry; Proteomics

DOI:  https://doi.org/10.1002/cjp2.126
JCI Insight. 2019 Feb 12. pii: 125306. [Epub ahead of print]

Lymphocyte mass cytometry identifies a CD3-CD4+ cells subset with a potential role in psoriasis.

Ruru Guo, Ting Zhang, Xinyu Meng, Zhen Lin, Jinran Lin, Yu Gong, Xuesong Liu, Yuetian Yu, Guilin Zhao, Xianting Ding, Xiaoxiang Chen, Liangjing Lu.

  Psoriasis (PS) is a systemic, immune-mediated inflammatory disorder. However, the whole lymphocyte compartment and the potential pathologies of PS have not been fully characterized. In the present study, we examined whole lymphocyte subsets and signal transduction proteins using high-dimensional single-cell mass cytometry and a bioinformatics pipeline for an in-depth characterization of the immune cell subsets and protein profiles involved in pathways in the peripheral blood of patients with PS. We identified 15 major immune cell populations in T cell lineages, and characterized various CD3+CD4+T helper and CD3+CD8+T cytotoxic cell populations simultaneously across 24 leukocyte markers and 7 proteins related to the signal transduction pathways. High-dimensional analysis identified three new subsets that are abundant in PS peripheral blood, resembling CD3-CD4+ lymphoid tissue inducer cells, Tc17, and CD8+CXCR3+ Tregs. We confirmed the CD3-CD4+ cells, and their features and functions, in an independent PS cohort. The use of single-cell mass cytometry allows systemic-level characterization of lymphocyte subpopulations and dysregulated signaling pathways in the blood of patients with PS, identifying abnormalities of different immune cell subsets. We validated that the CD3-CD4+ cells had elevated OX40 and decreased FRA2 expression, which were positively associated with the psoriasis area and severity index.

Keywords:  Autoimmune diseases; Autoimmunity; Inflammation

DOI:  https://doi.org/10.1172/jci.insight.125306
Adv Exp Med Biol. 2019 ;1118 135-162

The Role of Biomarkers in Psychiatry.

Madia Lozupone, Maddalena La Montagna, Francesca D'Urso, Antonio Daniele, Antonio Greco, Davide Seripa, Giancarlo Logroscino, Antonello Bellomo, Francesco Panza.

  Psychiatric illnesses are cognitive and behavioral disorders of the brain. At present, psychiatric diagnosis is based on DSM-5 criteria. Even if endophenotype specificity for psychiatric disorders is discussed, it is difficult to study and identify psychiatric biomarkers to support diagnosis, prognosis, or clinical response to treatment. This chapter investigates the innovative biomarkers of psychiatric diseases for diagnosis and personalized treatment, in particular post-genomic data and proteomic analyses.

Keywords:  Biomarker; Bipolar disorder; Depressive disorder; Epigenetics; Lifestyle; Microbiota; Post-genomic diagnostics; Proteomics; Psychiatric disease; Schizophrenia

DOI:  https://doi.org/10.1007/978-3-030-05542-4_7
Technol Cancer Res Treat. 2019 Jan 01. 18 1533033819827309

MicroRNA-143 is Associated With Pathological Complete Response and Regulates Multiple Signaling Proteins in Breast Cancer.

Raúl García-Vázquez, Laurence A Marchat, Erika Ruíz-García, Horacio Astudillo-de la Vega, Abelardo Meneses-García, Claudia Arce-Salinas, Enrique Bargallo-Rocha, Ángeles Carlos-Reyes, José Sullivan López-González, Carlos Pérez-Plasencia, Rosalío Ramos-Payán, Maribel Aguilar-Medina, César López-Camarillo.

  Almost 55% to 80% of patients with breast cancer have an unfavorable pathological complete response to chemotherapy. MicroRNAs are small noncoding RNAs involved in cancer progression; however, their utility as predictors of pathological complete response to neoadjuvant chemotherapy is unclear. Here, we investigated if miR-143 could discriminate between pathological complete response and no-polymerase chain reaction of patients with locally advanced triple negative breast cancer that have received a fluorouracil-cisplatin/paclitaxel-based neoadjuvant treatment. Data showed that miR-143 exhibited a significant low expression ( P < .0006) in patients that achieved pathological complete response in comparison to nonresponder group. Receiver operating characteristic curve analysis suggested that miR-143 could be a good predictor of pathological complete response (area under curve = 0.849, P < .0006). Moreover, Kaplan-Meier analysis indicated that before neoadjuvant therapy low levels of miR-143 were associated to increased disease free survival. To gain insights into cellular functions of miR-143, we firstly showed that miR-143 was severely repressed in breast cancer cell lines and tumors in comparison to normal mammary cells and tissues. Ectopic restoration of miR-143 using RNA mimics inhibited both cell proliferation and migration and sensitized breast cancer cells to cisplatin therapy in vitro. To decipher the signaling networks regulated by miR-143, we used a high-throughput enzyme-linked immunosorbent assay-based phosphorylation antibody array. Phospho-proteomic profiling revealed that miR-143 coordinately reduced the protein levels and phosphorylation status of multiple oncoproteins involved in AKT, WNT/β-catenin, SAPK/JNK, FAK, and JAK/STAT signaling pathways. Moreover, low miR-143 and high GSK3-β, RAF1, paxillin, and p21CIP1 expression levels in a large cohort of patients with breast cancer were associated with worst outcome. In summary, miR-143 could be a potential predictor of response to neoadjuvant therapy and it may function as a divergent regulator of diverse signaling networks to suppress cell proliferation and migration in breast cancer.

Keywords:  breast cancer; cell migration; cell proliferation; miR-143; neoadjuvant therapy; pathological complete response; signaling pathways

DOI:  https://doi.org/10.1177/1533033819827309
Proteomics Clin Appl. 2019 Feb 14. e1800094

Clinical proteomics on the path towards implementation: first promises delivered.

Maria Frantzi, Harald Mischak, Agnieszka Latosinska.

DOI: https://doi.org/10.1002/prca.201800094
Adv Exp Med Biol. 2019 ;1118 191-206

Proteomic Markers for Depression.

Licia C Silva-Costa, Pamela T Carlson, Paul C Guest, Valéria de Almeida, Daniel Martins-de-Souza.

  Major depressive disorder is a multifactorial disease, with molecular mechanisms not fully understood. A breakthrough could be reached with a panel of diagnostic biomarkers, which could be helpful to stratify patients and guide physicians to a better therapeutic choice, reducing the time between diagnostic and remission. This review brings the most recent works in proteomic biomarkers and highlights several potential proteins that could compose a panel of biomarkers to diagnostic and response to medication. These proteins are related to immune, inflammatory, and coagulatory systems and may also be linked to energy metabolism, oxidative stress, cell communication, and oligodendrogenesis.

Keywords:  Antidepressants; Drug response; Major depressive disorder; Mass spectrometry

DOI:  https://doi.org/10.1007/978-3-030-05542-4_10
Ann Am Thorac Soc. 2018 Dec;15(Supplement_4): S290-S291

Chronic Obstructive Pulmonary Disease Phenotype Dictates Cancer-Promoting Stromal Gene Expression Programs.

Chris H Wendt, Brian J Sandri, Laia Masvidal, Carl Murie, Margarita Bartish, Svetlana Avdulov, LeeAnn Higgins, Todd Markowski, Mark Peterson, Jonas Bergh, Ping Yang, Charlotte Rolny, Andrew H Limper, Timothy J Griffin, Peter B Bitterman, Ola Larsson.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that stromal cells comprising the COPD lung contain pathological gene expression programs supporting oncogenesis.
OBJECTIVES: To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer.
METHODS: Study subjects included patients with COPD with (n = 30) or without (n = 30) lung cancer across a spectrum of COPD severity. We conducted multi-omics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome.
RESULTS: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation impacting protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these procancer translation programs differed on the basis of COPD severity. In mild or no COPD, the mammalian target of rapamycin pathway served as an upstream driver; whereas in advanced COPD, pathways downstream of pathological extracellular matrix emerged. Both the mammalian target of rapamycin and extracellular matrix gene expression programs paralleled activation of previously identified secretomes that can be independently induced and promote cancer initiation in mouse models. These included the senescence secretome in mild to no COPD and the ETS2 (erythroblast transformation-specific 2) secretome in moderate to severe COPD. Furthermore, in situ examination of COPD lung tissue documented stromal fibroblasts expressing key cancer-associated proteins from procancer secretomes including IL-6 (senescence secretome) in mild COPD and bone morphogenetic protein-1 (ETS2 secretome) in advanced COPD.
CONCLUSIONS: Two distinct stromal gene expression programs promoting cancer initiation are activated in patients with lung cancer depending on the severity of COPD as measured by lung function. Our work has implications both for screening strategies and personalized approaches to prevent cancer in COPD.

DOI: https://doi.org/10.1513/AnnalsATS.201806-421MG
Am J Respir Crit Care Med. 2019 Feb 11.

Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function.

Brian J Sandri, Laia Masvidal, Carl Murie, Margarita Bartish, Svetlana Avdulov, LeeAnn Higgins, Todd Markowski, Mark Peterson, Jonas Bergh, Ping Yang, Charlotte Rolny, Andrew H Limper, Timothy J Griffin, Peter B Bitterman, Chris H Wendt, Ola Larsson.

   RATIONALE: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs supporting oncogenesis.
OBJECTIVE: To identify molecular mechanisms operating in the lung stroma that support development of lung cancer.
METHODS: Study subjects included patients with- or without- lung cancer across a spectrum of lung function. We conducted multi-omics analysis of non-malignant lung tissue to quantify the transcriptome, translatome and proteome.
MEASUREMENTS AND MAIN RESULTS: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation modulating protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these cancer-associated translation programs differed based on lung function. In subjects with normal to mildly impaired lung-function, the mammalian target of rapamycin (mTOR) pathway served as an upstream driver; whereas in severe airflow obstruction, pathways downstream of pathological extracellular matrix (ECM) emerged. Consistent with a role during cancer initiation, both the mTOR and ECM gene expression programs paralleled activation of previously identified pro-cancer secretomes. Furthermore, in situ examination of lung tissue documented that stromal fibroblasts express cancer-associated proteins from the two pro-cancer secretomes including IL6 in mild or no airflow obstruction and BMP1 in severe airflow obstruction.
CONCLUSION: Two distinct stromal gene expression programs promoting cancer initiation are activated in lung cancer patients depending on lung function. Our work has implications both for screening strategies and personalized approaches to cancer treatment.

Keywords:  COPD; cancer; extracellular matrix; secretome; translation

DOI:  https://doi.org/10.1164/rccm.201801-0080OC
J Reprod Infertil. 2018 Oct-Dec;19(4):19(4): 185-192

Male Infertility, Precision Medicine and Systems Proteomics.

Niloofar Agharezaee, Mehrdad Hashemi, Minoo Shahani, Kambiz Gilany.

Precision medicine (PM) is an approach that has the power to create the best effect and safety of medicine and treatment with the least side effects for each person. PM is very helpful as sometimes due to inaccurate or late diagnosis or toxicities of the drugs irreversible side effect for patient's health are generated. This seemingly new and emerging science is also effective in preventing disease, due to differences in the genes, environment, and lifestyles of any particular person. PM can be a prominent criterion in infertility research. To achieve this goal, there should be information from a healthy human body, including genetic and molecular information. A PM is an evolution in health care, which is very helpful even economically. The guarantor of the PM success is the examination of the molecular profile of the patient, including genes, proteins, metabolites, etc. Therefore, genomics, proteomics, and metabolomics-based techniques are very important in this regard. Unfortunately, despite extensive studies on PM practice in various fields, male infertility has remained unresponsive. Given that around 20% of couples around the world suffer from infertility, and almost half of them are related to men's problems, the PM approach has a high potential for male infertility. In this study, with the help of proteomics and metabolomics, PM information on male infertility was explored.

Keywords: Infertility; Male; Precision medicine; Proteomics
Adv Exp Med Biol. 2019 ;1118 163-173

Interactome Studies of Psychiatric Disorders.

Dong Ik Park, Christoph W Turck.

  High comorbidity and complexity have precluded reliable diagnostic assessment and treatment of psychiatric disorders. Impaired molecular interactions may be relevant for underlying mechanisms of psychiatric disorders but by and large remain unknown. With the help of a number of publicly available databases and various technological tools, recent research has filled the paucity of information by generating a novel dataset of psychiatric interactomes. Different technological platforms including yeast two-hybrid screen, co-immunoprecipitation-coupled with mass spectrometry-based proteomics, and transcriptomics have been widely used in combination with cellular and molecular techniques to interrogate the psychiatric interactome. Novel molecular interactions have been identified in association with different psychiatric disorders including autism spectrum disorders, schizophrenia, bipolar disorder, and major depressive disorder. However, more extensive and sophisticated interactome research needs to be conducted to overcome the current limitations such as incomplete interactome databases and a lack of functional information among components. Ultimately, integrated psychiatric interactome databases will contribute to the implementation of biomarkers and therapeutic intervention.

Keywords:  Co-immunoprecipitation-coupled mass spectrometry-based proteomics; Interactome; Protein-protein interaction; Psychiatric disorders; Psychiatric interactome; Transcriptomics; Yeast two-hybrid screen

DOI:  https://doi.org/10.1007/978-3-030-05542-4_8
Adv Exp Med Biol. 2019 ;1118 295-317

Early Detection and Treatment of Patients with Alzheimer's Disease: Future Perspectives.

Francesca L Guest.

  Alzheimer's disease affects approximately 6% of people over the age of 65 years. It is characterized as chronic degeneration of cortical neurons, with loss of memory, cognition and executive functions. As the disease progresses, it is accompanied by accumulation of amyloid plaques and neurofibrillary tangles in key areas of the brain, leading to a loss of neurogenesis and synaptic plasticity in the hippocampus, along with changes in the levels of essential neurotransmitters such as acetylcholine and glutamate. Individuals with concomitant diseases such as depression, diabetes and cardiovascular disorders have a higher risk of developing Alzheimer's disease, and those who have a healthier diet and partake in regular exercise and intellectual stimulation have a lower risk of developing the disorder. This chapter describes the advances made in early diagnosis of Alzheimer's disease as this could help to improve outcomes for the patients by facilitating earlier treatment.

Keywords:  Alzheimer’s disease; Biomarkers; Imaging; Lab-on-a-chip; Metabolomics; Proteomics; Smartphone monitoring

DOI:  https://doi.org/10.1007/978-3-030-05542-4_15
Obstet Gynecol Surv. 2019 Feb;74(2): 111-125

Proteomics and Metabolomics in Pregnancy-An Overview.

Niraj Vora, Ram Kalagiri, Lea H Mallett, Jin Ho Oh, Umaima Wajid, Saef Munir, Natalie Colon, Venkata Nakta Raju, Madhava R Beeram, M Nasir Uddin.

Importance: Pregnancy is getting more and more complex due to increasing number of complications that may affect fetal outcomes. The introduction of newer "proteomics and metabolomics" technologies in the field of obstetrics and gynecology may allow physicians to identify possible associated etiologies that affect the mother during pregnancy and lead to associated complications affecting the offspring.
Objective: The principal objective of this review article is to provide a comprehensive evaluation of the use of proteomics and metabolomics in complicated pregnancies. Future studies that incorporate data from multiple technologies may allow the development of an integrated biological system approach to maternal genomes, proteomes, and metabolomes in pregnancy.
Evidence Acquisition and Results: We conducted a substantial MEDLINE, EBSCOhost, and Cochrane database search for all the relevant articles containing use of "omics" technologies in pregnancy. We identified 197 relevant articles, following standardized systematic review process along with grading systems; 69 eligible articles were identified.
Conclusion/Relevance: We sought to provide a comprehensive review in this emerging field of "omics" in pregnancy and associated complications. This article focuses mainly on use of proteomics and metabolomics identification techniques and possible interventions for early pregnancy complications to improve neonatal outcomes.

DOI: https://doi.org/10.1097/OGX.0000000000000646
Adv Exp Med Biol. 2019 ;1118 207-233

Advances in Biomarker Studies in Autism Spectrum Disorders.

Liming Shen, Yuxi Zhao, Huajie Zhang, Chengyun Feng, Yan Gao, Danqing Zhao, Sijian Xia, Qi Hong, Javed Iqbal, Xu Kun Liu, Fang Yao.

  Autism spectrum disorder (ASD) is a neurological and developmental condition that begins early in childhood and lasts throughout life. The epidemiology of ASD is continuously increasing all over the world with huge social and economical burdens. As the etiology of autism is not completely understood, there is still no medication available for the treatment of this disorder. However, some behavioral interventions are available to improve the core and associated symptoms of autism, particularly when initiated at an early stage. Thus, there is an increasing demand for finding biomarkers for ASD. Although diagnostic biomarkers have not yet been established, research efforts have been carried out in neuroimaging and biological analyses including genomics and gene testing, proteomics, metabolomics, transcriptomics, and studies of the immune system, inflammation, and microRNAs. Here, we will review the current progress in these fields and focus on new methods, developments, research strategies, and studies of blood-based biomarkers.

Keywords:  Autism spectrum disorder; Biomarker; Diagnosis; Prediction; Proteomics

DOI:  https://doi.org/10.1007/978-3-030-05542-4_11
Transl Psychiatry. 2019 Feb 11. 9(1): 83

Multimodel inference for biomarker development: an application to schizophrenia.

Jason D Cooper, Sung Yeon Sarah Han, Jakub Tomasik, Sureyya Ozcan, Nitin Rustogi, Nico J M van Beveren, F Markus Leweke, Sabine Bahn.

In the present study, to improve the predictive performance of a model and its reproducibility when applied to an independent data set, we investigated the use of multimodel inference to predict the probability of having a complex psychiatric disorder. We formed training and test sets using proteomic data (147 peptides from 77 proteins) from two-independent collections of first-onset drug-naive schizophrenia patients and controls. A set of prediction models was produced by applying lasso regression with repeated tenfold cross-validation to the training set. We used feature extraction and model averaging across the set of models to form two prediction models. The resulting models clearly demonstrated the utility of a multimodel based approach to make good (training set AUC > 0.80) and reproducible predictions (test set AUC > 0.80) for the probability of having schizophrenia. Moreover, we identified four proteins (five peptides) whose effect on the probability of having schizophrenia was modified by sex, one of which was a novel potential biomarker of schizophrenia, foetal haemoglobin. The evidence of effect modification suggests that future schizophrenia studies should be conducted in males and females separately. Future biomarker studies should consider adopting a multimodel approach and going beyond the main effects of features.

DOI: https://doi.org/10.1038/s41398-019-0419-4
Gastroenterology. 2019 Feb 12. pii: S0016-5085(19)30366-X. [Epub ahead of print]

Mutations in Hepatitis D Virus Allow it to Escape Detection by CD8+ T Cells and Evolve at the Population Level.

Hadi Karimzadeh, Muthamia M Kiraithe, Valerie Oberhardt, Elahe Salimi Alizei, Jan Bockmann, Julian Schulze Zur Wiesch, Bettina Budeus, Daniel Hoffmann, Heiner Wedemeyer, Markus Cornberg, Adalbert Krawczyk, Jassin Rashidi-Alavijeh, Francisco Rodríguez-Frías, Rosario Casillas, Maria Buti, Antonina Smedile, Seyed Moayed Alavian, Andreas Heinold, Florian Emmerich, Marcus Panning, Emma Gostick, David A Price, Jörg Timm, Maike Hofmann, Bijan Raziorrouh, Robert Thimme, Ulrike Protzer, Michael Roggendorf, Christoph Neumann-Haefelin.

   BACKGROUND & AIMS: Hepatitis D virus (HDV) super-infection in patients with hepatitis B virus (HBV) is associated with rapid progression to liver cirrhosis and hepatocellular carcinoma. Treatment options are limited, and no vaccine is available. Although HDV-specific CD8+ T cells are thought to control the virus, little is known about which HDV epitopes are targeted by virus-specific CD8+ T cells or why these cells ultimately fail to control the infection. We aimed to define how HDV escapes the CD8+ T cell-mediated response.
METHODS: We collected plasma and DNA samples from 104 patients with chronic HDV and HBV infection at medical centers in Europe and Asia, sequenced HDV, typed HLA class I alleles from patients, and searched for polymorphisms in HDV RNA associated with specific HLA class I alleles. We predicted epitopes in HDV that would be recognized by CD8+ T cells and corresponded with the identified virus polymorphisms in patients with resolved (n = 12) or chronic (n = 13) HDV infection.
RESULTS: We identified 21 polymorphisms in HDV that were significantly associated with specific HLA class I alleles (P<.005). Five of these polymorphisms were found to correspond to epitopes in HDV that are recognized by CD8+ T cells; we confirmed that CD8+ T cells in culture targeted these HDV epitopes. HDV variant peptides were only partially cross-recognized by CD8+ T cells isolated from patients, indicating that the virus had escaped detection by these cells. These newly identified HDV epitopes were restricted by relatively infrequent HLA class I alleles, and bound most frequently to HLA-B. In contrast, frequent HLA class I alleles were not associated with HDV sequence polymorphisms.
CONCLUSIONS: We analyzed sequences of HDV RNA and HLA class I alleles that present epitope peptides to CD8+ T cells in patients with persistent HDV infection. We identified polymorphisms in the HDV proteome that associate with HLA class I alleles. Some variant peptides in epitopes from HDV were only partially recognized by CD8+ T cells isolated from patients-these could be mutations that allow HDV to escape the immune response, resulting in persistent infection. HDV escape from the immune response was associated with uncommon HLA class I alleles, indicating that HDV evolves, at the population level, to evade recognition by common HLA class I alleles.

Keywords:  MHC class I; TCR; antigen presentation; cytotoxic T cell

DOI:  https://doi.org/10.1053/j.gastro.2019.02.003
Am J Epidemiol. 2019 Feb 16. pii: kwy284. [Epub ahead of print]

A Pregnancy Cohort to Study Multidimensional Correlates of Preterm Birth in India: Study Design, Implementation, and Baseline Characteristics of the Participants.

Interdisciplinary Group for Advanced Research on Birth Outcomes—DBT India Initiative (GARBH-Ini)

  Globally, preterm birth is a major public health problem. In India, 3.6 million of the 27 million infants born annually are preterm. Risk stratification of women based on multidimensional risk factors assessed during pregnancy is critical for prevention of preterm birth. A cohort study of pregnant women was initiated in May 2015 at the civil hospital in Gurugram, Haryana, India. Women are enrolled within 20 weeks of gestation and are followed until delivery and once postpartum. The objectives are to identify clinical, epidemiologic, genomic, epigenomic, proteomic, and microbial correlates; discover molecular-risk markers by using an integrative -omics approach; and generate a risk-prediction algorithm for preterm birth. We describe here the longitudinal study design, methodology of data collection, and the repositories of data, biospecimens, and ultrasound images being created. A total of 4,326 pregnant women, with documented evidence of recruitment before 20 weeks of gestation, have been enrolled through March 2018. We report baseline characteristics and outcomes of the first 2,000 enrolled participants. A high frequency of preterm births (14.9% among 1,662 live births) is noteworthy. The cohort database and the repositories will become global resources to answer critical questions on preterm birth and other birth outcomes.

Keywords:  India; cohort studies; fetal growth retardation; pregnancy outcome; premature birth; risk factors

DOI:  https://doi.org/10.1093/aje/kwy284
Nat Commun. 2019 Feb 15. 10(1): 764

A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic- and molecular-phenotypes of epithelial ovarian cancer.

Haonan Lu, Mubarik Arshad, Andrew Thornton, Giacomo Avesani, Paula Cunnea, Ed Curry, Fahdi Kanavati, Jack Liang, Katherine Nixon, Sophie T Williams, Mona Ali Hassan, David D L Bowtell, Hani Gabra, Christina Fotopoulou, Andrea Rockall, Eric O Aboagye.

The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35-40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name "Radiomic Prognostic Vector" (RPV). RPV reliably identifies the 5% of patients with median overall survival less than 2 years, significantly improves established prognostic methods, and is validated in two independent, multi-center cohorts. Furthermore, genetic, transcriptomic and proteomic analysis from two independent datasets elucidate that stromal phenotype and DNA damage response pathways are activated in RPV-stratified tumors. RPV and its associated analysis platform could be exploited to guide personalized therapy of EOC and is potentially transferrable to other cancer types.

DOI: https://doi.org/10.1038/s41467-019-08718-9
Cell Mol Gastroenterol Hepatol. 2018 Oct 24. pii: S2352-345X(18)30157-7. [Epub ahead of print]7(2): 411-431

Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TGF-β Signaling and Epigenomics.

CoHEART Consortium

   BACKGROUND & AIMS: A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed.
METHODS: To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-β (TGF-β) signaling, and immunohistochemistry in CAID patient gut biopsy specimens.
RESULTS: Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-β pathway in CAID pathogenesis. Canonical TGF-β signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism.
CONCLUSIONS: Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-β signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.

Keywords:  CAID Syndrome (Chronic Atrial and Intestinal Dysrhythmia); Chronic Intestinal Pseudo-obstruction; Epigenetics; TGF-β Signaling

DOI:  https://doi.org/10.1016/j.jcmgh.2018.10.011