Research Outputs

Stratum corneum and systemic biomarkers in infantile AD

DATE - 2019 August 08

Abstract

Atopic Dematitis (AD), also known as eczema, is a common inflammatory skin disease which usually appears during the early stages of life. It is estimated that approximately 15 million people in the UK are currently living with AD, affecting up to 20% of children. Indicators, such as a specific protein level in the body which is related to the presence or seriousness of a disease in a patient, may be important in ensuring proper treatment. Indicators of the seriousness of AD have been described for adults, however there is a need for similar indicators which could be used to define the seriousness of AD in infants, as this is usually when onset of the condition occurs. This study aimed to identify easily obtainable indicators from the skin of infants which could be used to predict AD. 100 children who had just developed moderate to severe AD which had not yet been treated and 20 children without AD were sampled as part of this study. The level of seriousness of AD in the affected children was graded at the start of the study and samples of the outer‐most layer of skin were taken from all participants. In total, 31 out of 66 indicators measured showed different levels in infants with AD than infants without AD. These indicators are known to be involved in various processes including the body's natural defence and the formation of new blood vessels. The authors of this study concluded that these results demonstrate easily obtainable indicators can be used to predict AD in infants, and that natural defence responses in the outer layer of skin are essential in preventing development of AD in infants.

Authors

Analysis of health-related biomarkers between vegetarians and non-vegetarians: A multi-biomarker approach

DATE - 2019 July 17

Abstract

This study was performed in a group of adult vegetarians (N = 40) and matched non-vegetarian subjects (N = 40) in order to analyse differences in health-related biomarkers. Obtained results revealed differences in various biomarkers between subjects on a traditional mixed and vegetarian diet, indicating that vegetarians have a lower nutritional status of some nutrients (Ca, Cu and Zn, and vitamins B12 and D) accompanied with a lower antioxidant defence system (glutathione) and higher homocysteine and genome damage (micronuclei and DNA strand breaks), along with shorter telomeres. This suggests that the supplementation of animal derived nutrients to this particular dietary group would be beneficial for the improvement of some measured health-related biomarkers. However, the level of certain toxic metals (As and Hg) was higher in non-vegetarians. The presented multi-biomarker approach implies the necessity of evaluating a large number of different health-related biomarkers in order to obtain clear insight into dietary preferences and health outcomes.

Authors

Clinical Proteomics: Closing the Gap from Discovery to Implementation.

DATE - 2019 July 09

Abstract

Clinical proteomics, the application of proteome analysis to serve a clinical purpose, represents a major field in the area of proteome research. Over 1000 manuscripts on this topic are published each year, with numbers continuously increasing. However, the anticipated outcome, the transformation of the reported findings into improvements in patient management, is not immediately evident.

In this article, the value and validity of selected clinical proteomics findings are investigated, and it is assessed how far implementation has progressed. A main conclusion from this assessment is that to achieve implementation, well-powered clinical studies are required in the appropriate population, addressing a specific clinical need and with a clear context-of-use. Efforts toward implementation, to be feasible, must be supported by the key players in science: publishers and funders.

The authors propose a change on objectives, from additional discovery studies toward studies aiming at validation of the plethora of potential biomarkers that have been described, to demonstrate practical value of clinical proteomics. All elements required, potential biomarkers, technologies, and bio-banked samples are available (based on today’s literature), hence a change in focus from discovery toward validation and application is not only urgently necessary, but also possible based on resources available today.

Authors

Systematic review on recent potential biomarkers of chronic obstructive pulmonary disease.

DATE - 2019 July 09

Abstract

Introduction:
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide and associated with decreased lung function and inflammation. The heterogeneity of COPD and its molecular and clinical features hinder efficient patient stratification and introduction of personalized therapeutic approaches. The available clinical tools do not efficiently predict the progression and exacerbations of the disease.

Areas covered:
An overview of the most recent studies on putative COPD protein biomarkers and the challenges for implementing their use in the clinical setting is presented.

Expert commentary:
Proteomics biomarker discovery in COPD has mostly focused on approaches evaluating specific proteins on a limited number of samples. The most promising protein candidates can be classified into five main biological categories: extracellular matrix (ECM) remodeling, inflammation/immune response, oxidative stress response, vascular tone regulation, and lipid metabolism. To efficiently stratify COPD patients and predict exacerbations, it will be necessary to implement biomarker panels to better represent the complex pathophysiology of this disease. The application of unbiased proteomics and bioinformatics followed by appropriate clinical validation studies will contribute to the achievement of this aim while increasing the number of validated biomarkers that can enter the qualification processes by the regulatory entities.

Authors

Handbook of Biomarkers and Precision Medicine.

DATE - 2019 May 01

Summary

"Handbook of Biomarkers and Precision Medicine" provides comprehensive insights into biomarker discovery and development which has driven the new era of Precision Medicine. A wide variety of renowned experts from government, academia, teaching hospitals, biotechnology and pharmaceutical companies share best practices, examples and exciting new developments. The handbook aims to provide in-depth knowledge to research scientists, students and decision makers engaged in Biomarker and Precision Medicine-centric drug development.

Features:
- Detailed insights into biomarker discovery, validation and diagnostic development with implementation strategies.
- Lessons-learned from successful Precision Medicine case studies.
- A variety of exciting and emerging biomarker technologies.
- The next frontiers and future challenges of biomarkers in Precision Medicine.

Edited by

Identification of 4-Hydroxyproline at the Xaa Position in Collagen by Mass Spectrometry.

DATE - 2019 Apr 12

Abstract

Collagen has a triple helix form, structured by a [-Gly-Xaa-Yaa-] repetition, where Xaa and Yaa are amino acids. This repeating unit can be post-translationally modified by enzymes, where proline is often hydroxylated into hydroxyproline (Hyp). Two Hyp isomers occur in collagen: 4-hydroxyproline (4Hyp, Gly-Xaa-Pro, substrate for 4-prolyl hydroxylase) and 3-hydroxyproline (3Hyp, Gly-Pro-4Hyp, substrate for 3-prolyl hydroxylase). If 4Hyp is lacking at the Yaa position, then Pro at the Xaa position should remain unmodified. Nevertheless, in literature 41 positions have been described where Hyp occurs at the Xaa position (?xHyp) lacking an adjacent 4Hyp. We report four additional positions in liver and colorectal liver metastasis tissue (CRLM). We studied the sequence commonalities between the 45 known positions of ?xHyp. Alanine and glutamine were frequently present adjacent to ?xHyp. We showed that proline, position 584 in COL1A2, had a lower rate of modification in CRLM than in healthy liver. The isomeric identity of ?xHyp, that is, 3- and/or 4Hyp, remains unknown. We present a proof of principle identification of ?xHyp. This identification is based on liquid chromatography retention time differences and mass spectrometry using ETD-HCD fragmentation, complemented by ab initio calculations. Both techniques identify ?xHyp at position 584 in COL1A2 as 4-hydroxyproline (4xHyp).

Authors

Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics.

DATE - 2019 Apr

Abstract

OBJECTIVE: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). METHODS: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. RESULTS: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. INTERPRETATION: We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.

Authors

Neoantigens in Chronic Obstructive Pulmonary Disease and Lung Cancer: A Point of View.

DATE - 2019 Feb 11

Abstract

The goal of this manuscript is to explore the role of clinical proteomics for detecting mutations in chronic obstructive pulmonary disease (COPD) and lung cancer by mass spectrometry-based technology. COPD and lung cancer caused by smoke inhalation are most likely linked by challenging the immune system via partly shared pathways. Genome-wide association studies have identified several single nucleotide polymorphisms which predispose an increased susceptibility to COPD and lung cancer. In lung cancer, this leads to coding mutations in the affected tissues, development of neoantigens, and different functionality and abundance of proteins in specific pathways. If a similar reasoning can also be applied in COPD will be discussed. The technology of mass spectrometry has developed into an advanced technology for proteome research detecting mutated peptides or proteins and finding relevant molecular mechanisms that will enable predicting the response to immunotherapy in COPD and lung cancer patients.

Authors

The future of protein biomarker research in type 2 diabetes mellitus.

DATE - 2018 Nov 27

Abstract

The onset of type 2 diabetes mellitus (T2DM) is strongly associated with obesity and subsequent perturbations in immuno-metabolic responses. To understand the complexity of these systemic changes and better monitor the health status of people at risk, validated clinical biomarkers are needed. Omics technologies are increasingly applied to measure the interplay of genes, proteins and metabolites in biological systems, which is imperative in understanding molecular mechanisms of disease and selecting the best possible molecular biomarkers for clinical use. Areas covered: This review describes the complex onset of T2DM, the contribution of obesity and adipose tissue inflammation to the T2DM disease mechanism, and the output of current biomarker strategies. A new biomarker approach is described that combines published and new self-generated data to merge multiple -omes (i.e. genome, proteome, metabolome etc.) toward understanding of mechanism of disease on the individual level and design multiparameter biomarker panels that drive significant impacts on personalized healthcare. Expert commentary: We here propose an approach to use cross-omics analyses to contextualize published biomarker data and better understand molecular mechanisms of health and disease. This will improve the current and future innovation gaps in translation of discovered putative biomarkers to clinically applicable biomarker tests.

Authors

Up-regulation of collagen proteins in colorectal liver metastasis compared with normal liver tissue.

DATE - 2018 Nov 08

Abstract

Changes to extracellular matrix (ECM) structures are linked to tumor cell proliferation and metastasis. We previously reported that naturally occurring peptides of collagen type I are elevated in urine of patients with colorectal liver metastasis (CRLM). In the present study, we took an MS-based proteomic approach to identify specific collagen types that are up-regulated in CRLM tissues compared with healthy, adjacent liver tissues from the same patients. We found that 19 of 22 collagen-α chains are significantly up-regulated (p < 0.05) in CRLM tissues compared with the healthy tissues. At least four collagen-α chains were absent or had low expression in healthy colon and adjacent tissues, but were highly abundant in both colorectal cancer (CRC) and CRLM tissues. This expression pattern was also observed for six noncollagen colon-specific proteins, two of which (CDH17 and PPP1R1B/DARP-32) had not previously been linked to CRLM. Furthermore, we observed CRLM-associated up-regulation of 16 proteins (of 20 associated proteins identified) known to be required for collagen synthesis, indicating increased collagen production in CRLM. Immunohistochemistry validated that collagen type XII is significantly up-regulated in CRLM. The results of this study indicate that most collagen isoforms are up-regulated in CRLM compared with healthy tissues, most likely as a result of an increased collagen production in the metastatic cells. Our findings provide further insight into morphological changes in the ECM in CRLM and help explain the finding of tumor metastasis-associated proteins and peptides in urine, suggesting their utility as metastasis biomarkers.

Authors

Integrated Chemometrics and Statistics to Drive Successful Proteomics Biomarker Discovery.

DATE - 2018 Apr 26

Abstract

Protein biomarkers are of great benefit for clinical research and applications, as they are powerful means for diagnosing, monitoring and treatment prediction of different diseases. Even though numerous biomarkers have been reported, the translation to clinical practice is still limited. This mainly due to: (i) incorrect biomarker selection, (ii) insufficient validation of potential biomarkers, and (iii) insufficient clinical use. In this review, we focus on the biomarker selection process and critically discuss the chemometrical and statistical decisions made in proteomics biomarker discovery to increase to selection of high value biomarkers. The characteristics of the data, the computational resources, the type of biomarker that is searched for and the validation strategy influence the decision making of the chemometrical and statistical methods and a decision made for one component directly influences the choice for another. Incorrect decisions could increase the false positive and negative rate of biomarkers which requires independent confirmation of outcome by other techniques and for comparison between different related studies. There are few guidelines for authors regarding data analysis documentation in peer reviewed journals, making it hard to reproduce successful data analysis strategies. Here we review multiple chemometrical and statistical methods for their value in proteomics-based biomarker discovery and propose to include key components in scientific documentation.

Authors

Decreased Neuro-Axonal Proteins in CSF at First Attack of Suspected Multiple Sclerosis.

DATE - 2017 Sep 20

Abstract

PURPOSE: The pathology of multiple sclerosis is located in the central nervous system, therefore cerebrospinal fluid (CSF) is an attractive biofluid for biomarker research for proteins related to the early stages of this disease. In this study, the CSF proteome of patients with a Clinically Isolated Syndrome of demyelination (CIS, a first attack of Multiple Sclerosis) was compared to the CSF proteome of control patients to identify differentially abundant proteins.

Authors

Immunohistochemistry for predictive biomarkers in non-small cell lung cancer

DATE - 2017 JUL 18

Abstract

PURPOSE: In the era of targeted therapy, predictive biomarker testing has become increasingly important for non-small cell lung cancer. Of multiple predictive biomarker testing methods, immunohistochemistry (IHC) is widely available and technically less challenging, can provide clinically meaningful results with a rapid turn-around-time and is more cost efficient than molecular platforms. In fact, several IHC assays for predictive biomarkers have already been implemented in routine pathology practice. In this review, we will discuss: (I) the details of anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) IHC assays including the performance of multiple antibody clones, pros and cons of IHC platforms and various scoring systems to design an optimal algorithm for predictive biomarker testing; (II) issues associated with programmed death-ligand 1 (PD-L1) IHC assays; (III) appropriate pre-analytical tissue handling and selection of optimal tissue samples for predictive biomarker IHC.

Authors

  • MARI MINO-KENUDSON
  • Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA

Serum Protein Markers for the Early Detection of Lung Cancer: A Focus on Autoantibodies.

DATE - 2017 Jan 06

Abstract

Lung cancer has the highest mortality rate among cancer patients in the world, in particular because most patients are only diagnosed at an advanced and noncurable stage. Computed tomography (CT) screening on high-risk individuals has shown that early detection could reduce the mortality rate. However, the still high false-positive rate of CT screening may harm healthy individuals because of unnecessary follow-up scans and invasive follow-up procedures. Alternatively, false-negative and indeterminate results may harm patients due to the delayed diagnosis and treatment of lung cancer. Noninvasive biomarkers, complementary to CT screening, could lower the false-positive and false-negative rate of CT screening at baseline and thereby reduce the number of patients that need follow-up and diagnose patients at an earlier stage of lung cancer. Lung cancer tissue generates lung cancer-associated proteins to which the immune system might produce high-affinity autoantibodies. This autoantibody response to tumor-associated antigens starts during early stage lung cancer and may endure over years. Identification of tumor-associated antigens or the corresponding autoantibodies in body fluids as potential noninvasive biomarkers could thus be an effective approach for early detection and monitoring of lung cancer. We provide an overview of differentially expressed protein, antigen, and autoantibody biomarkers that combined with CT imaging might be of clinical use for early detection of lung cancer.

Authors