Recent advances in proteomic profiling of pancreatic ductal adenocarcinoma and the road ahead

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide. However, there remain many unmet clinical needs, from diagnosis to treatment strategies. The inherent complexity of the molecular characteristics of PDAC has made it difficult to meet these challenges, rendering proteomic profiling of PDAC a critical area of research.

Area covered: In this review, we present recent advances in mass spectrometry (MS) and its current application in proteomic studies on PDAC. In addition, we discuss future directions for research that can efficiently incorporate current MS-based technologies that address key issues of PDAC proteomics.

Expert commentary: Compared with other cancer studies, little progress has been made in PDAC proteomics, perhaps attributed to the difficulty in performing in-depth and large-scale clinical studies on PDAC. However, recent advances in mass spectrometry can advance PDAC proteomics past the fundamental research stage.     

Platelet proteomics applied to the search for novel antiplatelet therapeutic targets

Introduction: Unwanted platelet activation is associated with numerous diseases, mainly thrombosis-related. In this context, proteomics has emerged as a novel tool with potential for drug target discovery and to scrutinize the effects of antiplatelet drugs.

Areas covered: The present review presents the main findings of platelet proteomic studies to date in the context of drug target discovery and perspectives for the future ahead. It includes data and evidences obtained from literature searches on PubMed as well as commentaries derived from the authors’ experience and opinions.

Expert commentary: Platelet proteomics applied to drug target discovery is a young field. Recent studies have shown promising data, especially in the context of coronary artery disease. However, challenges remain such as establishing definitive guidelines for blood collection and platelet isolation, essential to guarantee data reproducibility. Recent advances in quantitative platelet proteomics should lead to novel studies with higher clinical impact in the near future.     

Biomarker discovery for drug-induced phospholipidosis: phenylacetylglycine to hippuric acid ratio in urine and plasma as potential markers

Context: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable.

Objective: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach.

Method: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs.

Results: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation.

Conclusion: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis.     

Progress and prospects for the discovery of biomarkers for gastric cancer: a focus on proteomics

Introduction: Patient outcomes from gastric cancer vary due to the complexity of stomach carcinogenesis. Recent research using proteomic technologies has targeted components of all of these systems in order to develop biomarkers to aid the early diagnosis of gastric cancer and to assist in prognostic stratification.

Areas covered: This review is comprised of evidence obtained from literature searches from PubMed. It covers the evidence of diagnostic, prognostic, and predictive biomarkers for gastric cancer using proteomic technologies, and provides up-to-date references.

Expert commentary: The proteomic technologies have not only enabled the screening of a large number of samples, but also enabled the identification of diagnostic, prognostic and predictive biomarkers for gastric cancer. While major challenges still remain, to date, proteomic studies in gastric cancer have provided a wealth of information in revealing proteome alterations associated with the disease.     

MicroRNAs as possible biomarkers for screening of aortic aneurysms: a systematic review and validation study

Context: There is an urgent need to identify non-invasive biomarkers for the early detection of aortic aneurysms, preceding a fatal event. The potential role for MicroRNAs (miRNAs) as diagnostic markers for aortic aneurysms was investigated through the present systematic review.

Objective: To perform a comprehensive review on published studies examining the association of miRNAs with aortic aneurysms and further validate these results with plasma samples collected from thoracic aortic aneurysm (TAA) patients.

Methods: The literature search was performed via numerous databases and articles were only included if they fulfilled the predefined eligibility criteria. The miRNAs reported three times or more with expression consistency were validated using plasma samples from TAA patients collected before and following surgery.

Results: Twenty-four articles were selected from the literature search and 11 miRNAs were chosen for validation using our samples. The miRNAs which were further validated were found to follow the trend in the regulation pattern as with the majority of the published data. MiRNA hsa-miR-193a-5p was found to be significantly down-regulated in the plasma samples collected before the aneurysmal removal when compared with postsurgical serum samples.

Conclusions: Numerous miRNAs have been associated with aortic aneurysms, and specifically hsa-miR-193a-5p and hsa-miR-30b-5p; therefore they warrant further investigation as potential biomarkers.

Registration: The protocol of the review was registered in Prospero Databases (ID: CRD42016039953)     

Beta-2-glycoprotein-1 and alpha-1-antitrypsin as urinary markers of renal cancer in von Hippel–Lindau patients

Context: Von Hippel–Lindau disease (VHLD) is a rare inherited neoplastic syndrome. Among all the VHLD-associated tumors, clear cell renal cell carcinoma (ccRCC) is the major cause of death.

Objective: The aim of this paper is the discovery of new non-invasive biomarker for the monitoring of VHLD patients.

Materials and methods: We compared the urinary proteome of VHLD patients, ccRCC patients and healthy volunteers.

Results: Among all differentially expressed proteins, alpha-1-antitrypsin (A1AT) and APOH (beta-2-glycoprotein-1) are strongly over-abundant only in the urine of VHLD patients with a history of ccRCC.

Discussion and conclusion: A1AT and APOH could be promising non-invasive biomarkers.     

Proteomics applied to pediatric medicine: opportunities and challenges

Introduction: Care in pediatrics often refers to treatments directed to adults. However, childhood is a specific life period, with molecular pathways connected to development and thereby it requires distinctive considerations and special treatments under disease. Proteomics can help to elucidate the molecular mechanisms underlying the human development and disease onset in pediatric age and this review is devoted to underline the results recently obtained in the field.

Areas covered: The contribution of proteomics to the characterization of physiological modifications occurring during human development is presented. The proteomic studies carried out to elucidate the molecular mechanisms underlying different pediatric pathologies and to discover new markers for early diagnosis and prognosis of disease, comprising genetic and systemic pathologies, sepsis and pediatric oncology are thereafter reported. The investigations concerning milk composition in human and farm mammals are also presented. Finally, the chances offered by the integration of different -omic platforms are discussed.

Expert commentary: The growing utilization of holistic technologies such as proteomics, metabolomics and microbiomics will allow, in the near future, to define at the molecular level the complexity of human development and related diseases, with great benefit for future generations.     

Functional proteomic insights in B-cell chronic lymphocytic leukemia

Introduction: B cell chronic lymphocytic leukemia (B-CLL) is a hematological malignancy considered as the most common leukemia in the Western world. The understanding of B cell differentiation is crucial for the diagnosis, prognosis, and treatment of the disease.

Areas covered: In this review, B-cell ontogeny and its relation with the CLL development, in combination with the proteomic approaches which could provide a deep characterization of the disease through the characterization of the cellular signaling pathways involved in the pathological cells is described.

Expert commentary: Although conventional strategies (genome sequencing, morphology assays, and immunophenotyping by flow cytometry and/or immunochemistry) have allowed the establishment of the disease stage based on different parameters, it is still necessary to utilize novel approaches (e.g., proteomics) that have the potential to simultaneously analyze thousands of molecules to improve understanding of CLL.     

Circulating levels of apoptotic markers and oxidative stress parameters in women with polycystic ovary syndrome: a case-controlled descriptive study

Context: Apoptotic dysregulation plays a role in the pathogenesis of polycystic ovary syndrome (PCOS).

Objective: To evaluate circulatory apoptotic markers and oxidative stress in patients with PCOS.

Materials and methods: Forty-four women with PCOS, and 44 healthy women as controls were enrolled in the study. Oxidative stress parameters and caspases levels were measured in serum.

Results: The caspase 9 level was significantly lower and related with oxidant status in patients with PCOS, while the circulating levels of caspases 3 and 7 were statistically similar in both groups.

Discussion: This study is the first report demonstrating the circulating levels of apoptotic markers and their relationship with oxidant status in PCOS.

Conclusion: The circulating caspase 9 and oxidant status might contribute to apoptotic dysregulation in PCOS.     

The landscape of viral proteomics and its potential to impact human health

Introduction: Advances in mass spectrometry-based proteomic technologies are enhancing studies of viral pathogenesis. Identification and quantification of host and viral proteins and modifications in cells and extracellular fluids during infection provides useful information about pathogenesis, and will be critical for directing clinical interventions and diagnostics.

Areas covered: Herein we review and discuss a broad range of global proteomic studies conducted during viral infection, including those of cellular responses, protein modifications, virion packaging, and serum proteomics. We focus on viruses that impact human health and focus on experimental designs that reveal disease processes and surrogate markers.

Expert commentary: Global proteomics is an important component of systems-level studies that aim to define how the interaction of humans and viruses leads to disease. Viral-community resource centers and strategies from other fields (e.g., cancer) will facilitate data sharing and platform-integration for systems-level analyses, and should provide recommended standards and assays for experimental designs and validation.     

Current state of the art for enhancing urine biomarker discovery

Introduction: Urine is a highly desirable biospecimen for biomarker analysis because it can be collected recurrently by non-invasive techniques, in relatively large volumes. Urine contains cellular elements, biochemicals, and proteins derived from glomerular filtration of plasma, renal tubule excretion, and urogenital tract secretions that reflect, at a given time point, an individual’s metabolic and pathophysiologic state.

Areas covered: High-resolution mass spectrometry, coupled with state of the art fractionation systems are revealing the plethora of diagnostic/prognostic proteomic information existing within urinary exosomes, glycoproteins, and proteins. Affinity capture pre-processing techniques such as combinatorial peptide ligand libraries and biomarker harvesting hydrogel nanoparticles are enabling measurement/identification of previously undetectable urinary proteins.

Expert commentary: Future challenges in the urinary proteomics field include a) defining either single or multiple, universally applicable data normalization methods for comparing results within and between individual patients/data sets, and b) defining expected urinary protein levels in healthy individuals.     

The progress and potential of proteomic biomarkers for type 1 diabetes in children

Introduction: Although it is possible to identify the genetic risk for type 1 diabetes (T1D), it is not possible to predict who will develop the disease. New biomarkers are needed that would help understand the mechanisms of disease onset and when to administer targeted therapies and interventions.

Areas covered: An overview is presented of international study efforts towards understanding the cause of T1D, including the collection of several extensive temporal sample series that follow the development of T1D in at risk children. The results of the proteomics analysis of these materials are presented, which have included bodily fluids, such as serum or plasma and urine, as well as tissue samples from the pancreas.

Expert commentary: Promising recent reports have indicated detection of early proteomic changes in the serum of patients prior to diagnosis, potentially providing new measures for risk assessment. Similarly, there has been evidence that post-translational modification (PTM) may result in the recognition of islet cell proteins as autoantigens; modified proteins could thus be used as targets for immunomodulation to overcome the threat of the autoimmune response.     

Cancer biomarker discovery and translation: proteomics and beyond

Introduction: Cancer is often diagnosed at late stages when the chance of cure is relatively low and although research initiatives in oncology discover many potential cancer biomarkers, few transition to clinical applications. This review addresses the current landscape of cancer biomarker discovery and translation with a focus on proteomics and beyond.

Areas covered: The review examines proteomic and genomic techniques for cancer biomarker detection and outlines advantages and challenges of integrating multiple omics approaches to achieve optimal sensitivity and address tumor heterogeneity. This discussion is based on a systematic literature review and direct participation in translational studies.

Expert commentary: Identifying aggressive cancers early on requires improved sensitivity and implementation of biomarkers representative of tumor heterogeneity. During the last decade of genomic and proteomic research, significant advancements have been made in next generation sequencing and mass spectrometry techniques. This in turn has led to a dramatic increase in identification of potential genomic and proteomic cancer biomarkers. However, limited successes have been shown with translation of these discoveries into clinical practice. We believe that the integration of these omics approaches is the most promising molecular tool for comprehensive cancer evaluation, early detection and transition to Precision Medicine in oncology.     

Toxicoproteomics in human health and disease: an update

Introduction: Toxicoproteomics is an emerging area of omics, intended to explore the changes in protein expression and modifications in biological samples exposed to toxicants. The development of techniques that utilize sophisticated instruments in proteomics has facilitated the exploration of a wide-range of protein coverage and assisted the quantitative and qualitative evaluation of protein changes as a result of the toxic effects of toxic substances.

Areas covered: Studies on toxicoproteomics have an immense potential to explore the molecular mechanism of action of a variety of toxic substances through deciphering the proteomic map altered as a result of toxicant exposure. Here, we provide an overview of toxicoproteomic approaches and the current paradigm of toxicoproteomics.

Expert commentary: Research in this area continues to increase our understanding of the role of toxicants in worsening human health and toxicity driven diseases. The progress in toxicoproteomics may realize the development of novel biomarkers, drug targets and personalized medicines by incorporating the advanced proteomic applications in this field.     

Release kinetics of high-sensitivity cardiac troponins I and T and troponin T upstream open reading frame peptide (TnTuORF) in clinically induced acute myocardial infarction

Context: Troponin T upstream open reading frame peptide (TnTuORF) may be useful as a novel biomarker in acute cardiac syndromes.

Objective: The study examined the early release kinetics of TnTuORF.

Materials and methods: We analyzed the time course of the release of cardiac troponins I and T and TnTuORF in patients (n?=?31) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH).

Results: Fifteen minutes after TASH, the levels of both troponins increased significantly (cTnT median: 18?ng/L versus 27?ng/L; cTnI median: 15?ng/L versus 25?ng/L). TnTuORF showed no variation.

Discussion: We observed a significantly greater increase in cTnI compared with cTnT.

Conclusion: Our results demonstrate that troponin assays allow early detection of myocardial injury, whereas TnTuORF levels remain unchanged in this setting.     

Circulating miRNA-33: a potential biomarker in patients with coronary artery disease

Background: Circulating microRNAs (miRNA) are present in body fluids in stable, cell-free form. Likewise, these miRNAs can be identified in various stages of coronary artery disease (CAD) such as inflammation, endothelial dysfunction, proliferation and atherosclerosis among others. miRNA expression levels can be identified.

Aims and objectives: To determine the expression of circulating miRNAs (miR-126, miR-92, miR-33, miR-145 and miR-155) in CAD patients of Indian origin.

Material and methods: miRNA profiling analysis in blood plasma was performed by quantitative real-time-PCR (qRT-PCR) in 60 angiographically verified subjects including 30 CAD patients and 30 age- and gender-matched controls. Association between the expression of all five circulating miRNAs and clinical characteristics of patients with CAD were analysed using Medcalc statistics. The severity of CAD was assessed using SYNTAX score (SS).

Results: Expression of plasma miR-33 increased by 2.9 folds in CAD patients than in control group (p value ≥0.002) also it was found that miR-33 expression levels in mild cases (SS: ≤22) were significantly higher than CAD controls. There was a modest negative correlation between miR-33 and total cholesterol/high density lipoprotein ratio, triglycerides and very low density lipoprotein.

Conclusion: The study reports a significant association between increased levels of plasma miR-33 and CAD. Thus, plasma miR-33 appears to be a promising non-invasive biomarker, but requires further validation in a large cohort.     

Mapping and analyzing the human liver proteome: progress and potential

Introduction: The liver is an important organ in humans. Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world. Progress in the Human Liver Proteome Project (HLPP) has improved understanding of the liver and the liver cancer proteome.

Areas covered: Here, we summarize the recent progress in liver proteome modification profiles, proteomic studies in liver cancer, proteomic study in the search for novel liver cancer biomarkers and drug targets, and progress of the Chromosome Centric Human Proteome Project (CHPP) in the past five years in the Institutes of Biomedical Sciences (IBS) of Fudan University.

Expert commentary: Recent advances and findings discussed here provide great promise of improving the outcome of patients with liver cancer.