Biomarker Commons

Scripps researchers develop technology for biomarker identification in ulcerative colitis.

Bioanalysis. 2012 Nov;4(22):2667

Authors: Potticary J

PMID: 23346562 [PubMed - indexed for MEDLINE]

Serum leucine-rich alpha-2 glycoprotein is a disease activity biomarker in ulcerative colitis.

Inflamm Bowel Dis. 2012 Nov;18(11):2169-79

Authors: Serada S, Fujimoto M, Terabe F, Iijima H, Shinzaki S, Matsuzaki S, Ohkawara T, Nezu R, Nakajima S, Kobayashi T, Plevy SE, Takehara T, Naka T

Abstract
BACKGROUND: Reliable biomarkers for monitoring disease activity have not been clinically established in ulcerative colitis (UC). This study aimed to investigate whether levels of serum leucine-rich alpha-2 glycoprotein (LRG), identified recently as a potential disease activity marker in Crohn's disease and rheumatoid arthritis, correlate with disease activity in UC.
METHODS: Serum LRG concentrations were determined by enzyme-linked immunosorbent assay (ELISA) in patients with UC and healthy controls (HC) and were evaluated for correlation with disease activity. Expression of LRG in inflamed colonic tissues from patients with UC was analyzed by western blotting and immunohistochemistry. Interleukin (IL)-6-independent induction of LRG was investigated using IL-6-deficient mice by lipopolysaccharide (LPS)-mediated acute inflammation and dextran sodium sulfate (DSS)-induced colitis.
RESULTS: Serum LRG concentrations were significantly elevated in active UC patients compared with patients in remission (P < 0.0001) and HC (P < 0.0001) and were correlated with disease activity in UC better than C-reactive protein (CRP). Expression of LRG was increased in inflamed colonic tissues in UC. Tumor necrosis factor alpha (TNF-α), IL-6, and IL-22, serum levels of which were elevated in patients with active UC, could induce LRG expression in COLO205 cells. Serum LRG levels were increased in IL-6-deficient mice with LPS-mediated acute inflammation and DSS-induced colitis.
CONCLUSIONS: Serum LRG concentrations correlate well with disease activity in UC. LRG induction is robust in inflamed colons and is likely to involve an IL-6-independent pathway. Serum LRG is thus a novel serum biomarker for monitoring disease activity in UC and is a promising surrogate for CRP.

PMID: 22374925 [PubMed - indexed for MEDLINE]

Quantitative proteomic approaches in biomarker discovery of inflammatory bowel disease.

J Dig Dis. 2012 Oct;13(10):497-503

Authors: Han NY, Kim EH, Choi J, Lee H, Hahm KB

Abstract
Proteomics offers considerable opportunities for either enhancing our biological understanding or discovering biomarkers, blood and biopsied specimen-based proteomic approaches, provide reproducible and quantitative tools that can complement clinical assessments and aid clinicians in the diagnosis and treatment of inflammatory bowel disease (IBD). Sometimes a differential diagnosis of Crohn's disease (CD) and ulcerative colitis (UC) and the prediction of treatment response can be deduced by finding meaningful biomarkers, for which the central platform for proteomics is tandem mass spectrometry (MS/MS). A range of workflows are available for protein (or peptide) separation prior to MS/MS as well as bioinformatics analysis to achieve protein identification, for which two-dimensional electrophoresis (2-DE) and subsequent mass spectrometry (MS), liquid chromatography-MS, difference gel electrophoresis following 2-DE, isobaric tags for relative and absolute quantification (iTRAQ), stable isotope labeling by amino acids and label-free quantification are under development. In this article, the current status and perspective of these advanced proteomic technologies are introduced, with examples of recent biomarkers focused on the diagnosis, treatment response, prognosis of IBD, and even colitis-associated carcinogenesis in both animal models and human patients.

PMID: 22988922 [PubMed - indexed for MEDLINE]

PDCD4/miR-21 dysregulation in inflammatory bowel disease-associated carcinogenesis.

Virchows Arch. 2013 Jan;462(1):57-63

Authors: Ludwig K, Fassan M, Mescoli C, Pizzi M, Balistreri M, Albertoni L, Pucciarelli S, Scarpa M, Sturniolo GC, Angriman I, Rugge M

Abstract
Inflammatory bowel diseases (IBDs; both ulcerative colitis [UC] and Crohn's colitis [CC]) are well-established predisposing pathological conditions for colorectal cancer (CRC) development. In IBDs, both the endoscopy and the histology assessment of CRC precursors (i.e., dysplasia, also defined as intraepithelial neoplasia) are associated with low interobserver consistency, and no reliable dysplasia-specific biomarker is available. The programmed cell death 4 (PDCD4) tumor suppressor gene is involved in sporadic colorectal oncogenesis, but scanty information is available on its involvement in IBD-associated colorectal oncogenesis. One hundred twenty tissue samples representative of active and inactive IBD and of flat dysplasia were obtained from 30 cases of UC and 30 of CC who undergone colectomy. Twenty additional biopsy samples obtained from patients with irritable bowel syndrome acted as normal controls. PDCD4 expression was assessed by immunohistochemistry; the expression of miR-21 (a major PDCD4 regulator) was investigated by quantitative real-time PCR and in situ hybridization in different series of a hundred samples. Tissue specimens from both controls and inactive IBD consistently featured strong PDCD4 nuclear immunostain; conversely, lower PDCD4 nuclear expression was featured by both active IBD and IBD-associated dysplastic lesions. Significant PDCD4 down-regulation distinguished IBD-associated dysplasia (p < 0.001) versus active IBD. In both active IBD and dysplasia, PDCD4 down-regulation was significantly associated with miR-21 up-regulation. PDCD4 nuclear down-regulation (which parallels miR-21 up-regulation) is involved in the molecular pathway of IBD-associated carcinogenesis. PDCD4 nuclear expression may be usefully applied as ancillary maker in the histological assessment of IBD-associated dysplastic lesions.

PMID: 23224068 [PubMed - indexed for MEDLINE]

Role of serum cytokine profile in ulcerative colitis assessment.

Inflamm Bowel Dis. 2012 Oct;18(10):1864-71

Authors: Rodríguez-Perlvárez ML, García-Sánchez V, Villar-Pastor CM, González R, Iglesias-Flores E, Muntane J, Gómez-Camacho F

Abstract
BACKGROUND: Several cytokines are overexpressed in the colonic mucosa of patients with ulcerative colitis (UC). The measurement of these parameters in plasma could be useful in diagnosis and disease assessment.
METHODS: In all, 67 UC patients and 21 healthy controls were enrolled. At inclusion, clinical, endoscopic, and histological disease activity were assessed using the Ulcerative Colitis Activity Index (UCAI) and the Baron and Geboes scales, respectively. Serum cytokine concentrations were analyzed with a multiplex system (Bio-Plex pro, Bio-Rad) measuring interleukin (IL)-1-β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17, interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). Multiple logistic regression was used to design a serum cytokines profile.
RESULTS: In the UC group the disease activity was moderate to severe based on clinical evaluation in 35 patients (52.2%), by endoscopic appearance in 45 (67.2%), and in 53 patients (81.6%) using histology. With respect to controls, the multivariate analysis identified that UC patients had higher IL-8 (odds ratio [OR] = 1.37; P = 0.002) and IL-10 concentrations (OR = 3.88; P = 0.012) with lower levels of IFN-γ (OR = 0.95; P = 0.002). The model had an accuracy of 77.3%, which increased to 94.6% when only newly diagnosed patients were considered. Patients with moderate to severe disease according to their clinical score showed a higher concentration of IL-8 (OR = 1.16; P = 0.012) and IL-10 (OR = 1.76; P = 0.039) with lower levels of IL-17 (OR = 0.97; P = 0.021). The IL-8 serum concentration was also related to endoscopic and histological severity (OR = 1.10; P = 0.026 and OR = 1.33, P = 0.017, respectively).
CONCLUSIONS: A serum cytokine profile may be an auxiliary tool for the diagnosis and severity assessment of UC. IL-8 seems to be a reliable biomarker, closely related to disease activity.

PMID: 22238172 [PubMed - indexed for MEDLINE]

Early patient stratification and predictive biomarkers in drug discovery and development: a case study of ulcerative colitis anti-TNF therapy.

Adv Exp Med Biol. 2012;736:645-53

Authors: Laifenfeld D, Drubin DA, Catlett NL, Park JS, Van Hooser AA, Frushour BP, de Graaf D, Fryburg DA, Deehan R

Abstract
The current drug discovery paradigm is long, costly, and prone to failure. For projects in early development, lack of efficacy in Phase II is a major contributor to the overall failure rate. Efficacy failures often occur from one of two major reasons: either the investigational agent did not achieve the required pharmacology or the mechanism targeted by the investigational agent did not significantly contribute to the disease in the tested patient population. The latter scenario can arise due to insufficient study power stemming from patient heterogeneity. If the subset of disease patients driven by the mechanism that is likely to respond to the drug can be identified and selected before enrollment begins, efficacy and response rates should improve. This will not only augment drug approval percentages, but will also minimize the number of patients at risk of side effects in the face of a suboptimal response to treatment. Here we describe a systems biology approach using molecular profiling data from patients at baseline for the development of predictive biomarker content to identify potential responders to a molecular targeted therapy before the drug is tested in humans. A case study is presented where a classifier to predict response to a TNF targeted therapy for ulcerative colitis is developed a priori and verified against a test set of patients where clinical outcomes are known. This approach will promote the tandem development of drugs with predictive response, patient selection biomarkers.

PMID: 22161357 [PubMed - indexed for MEDLINE]