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PubMed2004

Clinical proteomics and biomarker discovery.

Early detection of disease generally provides much-improved outcomes by a definitive medical procedure or through lifestyle modification along with specific medical management strategies. For serum biomarkers, which are central to the diagnosis of many diseases, to become truly useful sentinels of pathogenesis, their sensitivity and specificity in both early detection and recurrence monitoring must be improved. Currently, the detection and monitoring of disease markers is based on solitary proteins, and this approach is not always reliable. New classes of biomarkers derived from mass spectroscopy analysis of the low molecular weight proteome have shown improved abilities in the early detection of disease and hence in patient risk stratification and outcome. The development of a modular platform technology with sufficient flexibility and design abstractions allowing for concurrent experimentation, test, and refinement will help speed the progress of mass spectroscopy-derived proteomic pattern-based diagnostics from the scientific laboratory to the medical clinic. For acceptance by scientists, physicians, and regulatory personnel, new bioinformatic tools are essential system components for data management, analysis, and intuitive display of these new and complex data. Clinically engineered mass spectroscopy systems are essential for the further development and validation of multiplexed biomarkers that have shown tremendous promise for the early detection of disease.

Biomarkers↗
PubMed1995

Sensitivity of cytochrome P450 1A induction in dab (Limanda limanda) of different age and sex as a biomarker for environmental contaminants in the southern North Sea.

The sensitivity of cytochrome P450 1A (CYPIA) induction as a biomarker for environmental contaminants in the flatfish dab (Limanda limanda) was evaluated by studying fish of different age and sex from the southern North Sea. Mature and juvenile dab from both sexes were collected in autumn and winter during two surveys from four different stations with varying levels of polychlorinated biphenyls (PCBs) contamination in the southern North Sea. All groups of fish exhibited highest muscle PCB concentrations near the Dutch coast. CB153 was always the dominant congener. Since the concentrations of the other congeners measured covaried to a large degree with CB153, this congener appears to be a good marker for general differences in PCB concentrations. In summer, bottom water temperature differences of up to 10 degrees C can occur between stratified and vertically mixed areas. This was previously shown to have a strong effect on CYPIA expression. In autumn and winter, stratification has disappeared, resulting in almost equal water temperatures between stations of the same survey. CYPIA levels were measured as 7-ethoxyresorufin of O-deethylase (EROD) activity and immunoquantitated CYPIA protein concentrations. Highest levels were also found close to the Dutch coast for mature fish from both sexes in October and for juvenile female and mature male fish in February during the spawning season. During this season, gravid female fish had significantly lowered contents of CYPIA protein and EROD activity compared to mature males and juveniles of both sexes. The sensitivity of CYPIA induction in dab as a biomarker for halogenated aromatic hydrocarbons is highest in mature males when stratification during autumn is lacking.

Age Factors↗
PubMed2005

Pulmonary embolism: impact of right ventricular dysfunction.

PURPOSE OF REVIEW: The appropriate treatment of patients with acute pulmonary embolism who present with right ventricular dysfunction but normal arterial blood pressure, and particularly the potential benefits of thrombolytic treatment in this setting, continue to be highly controversial. In the past year, several well designed studies improved our understanding of subclinical right ventricular dysfunction in pulmonary embolism, and emerging risk stratification algorithms now appear to identify high-risk patients reliably. RECENT FINDINGS: A meta-analysis confirmed that echocardiographically diagnosed right ventricular dysfunction is an independent predictor of early mortality in normotensive patients with pulmonary embolism. Retrospective studies suggest that similar information can also be obtained by multidetector-row chest computed tomography. Recent data indicate that biomarker (particularly troponin) testing followed by echocardiographic imaging of the right ventricle is an efficient and reliable strategy both for excluding (ruling out) and for predicting (ruling in) a poor outcome in patients with pulmonary embolism. SUMMARY: Novel risk stratification algorithms may help identify possible candidates for early thrombolytic treatment in pulmonary embolism and thus provide the background for a large international multicenter study that will hopefully resolve the 30-year-old debate on the benefits of thrombolysis in normotensive patients with pulmonary embolism and right ventricular dysfunction.

Algorithms↗
PubMed2006

[Acute coronary syndrome with and without ST elevation].

Coronary artery disease accounts for most deaths in western communities. The acute coronary syndrome subsidizes ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina pectoris. They are characterized by an acute onset of chest pain. The high number of acute coronary syndromes of more than 400,000 per year in Germany demonstrates the necessity of guidelines. Such guidelines are available from different cardiac societies. The implementation of the guidelines of the German Cardiac Society and the European Society of Cardiology in the daily clinical practice are demonstrated in this review by means of two case presentations. Special attention has been given to diagnostic measures, risk stratification, and different therapeutic options. For the diagnostic work-up in the acute phase, the ECG and the assessment of cardiac biomarkers play the central role. For patients with ST elevation myocardial infarction, primary interventional diagnostics and therapy are the first choice. For patients presenting with acute coronary syndromes without ST elevation, a risk-adapted therapeutic approach should be chosen. High-risk patients (elevated troponins, clinical, rhythmologic, and hemodynamic instability, ST depression, or diabetes mellitus) should be treated with an early invasive approach within 48-72 h. Low-risk patients can be treated primarily conservatively. For all patients who undergo interventional treatment, administration of an aggressive antiaggregatory therapy, including acetylsalicylic acid, clopidogrel, glycoprotein IIb/IIIa receptor antagonists, and heparin, is indicated in the acute phase. In the chronic phase, an adequate treatment of cardiovascular risk factors is of paramount importance.

Acute Disease↗
PubMed2005

SELDI-TOF-MS proteomics of breast cancer.

The detection, diagnosis, and management of breast cancer rely on an integrated approach using clinical history, physical examination, imaging, and histopathology. The discovery and validation of novel biomarkers will aid the physician in more effectively achieving this integration. This review discusses efforts in surface-enhanced laser desorption/ionization (SELDI)-based proteomics to address various clinical questions surrounding breast cancer, including diagnosis, monitoring, and stratification for treatment. Emphasis is placed on examining how study design and execution influence the discovery and validation process, which is critical to the proper development of potential clinical tests.

Biomarkers, Tumor↗
PubMed2003

Usefulness of prodromal unstable angina pectoris in predicting better survival and smaller infarct size in acute myocardial infarction (The InTIME-II Prodromal Symptoms Substudy).

Prodromal unstable angina on presentation is a significant predictor of smaller infarct size, reflected by smaller creatine kinase-MB and creatine kinase total measurements and lower 30-day, 6-month, and 5-year mortality. These findings suggest that prodromal unstable angina is an important physiologic marker that should be routinely collected for risk stratification.

Angina, Unstable↗
PubMed1998

Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis comparing published studies.

Controversy exists as to the clinical roles and relative specificities of cardiac troponin T or I in patients with unstable angina pectoris (UAP). We measured troponin T and I levels on admission in 123 patients with UAP. Of the 107 patients with normal creatine kinase during the first 24 hours, troponin T and I were elevated in 14 and 13 patients, respectively. At 30 days, 5 of 14 patients (36%) with elevated troponin T and 3 of 93 patients (3.2%) with normal troponin T had acute myocardial infarction (odds ratio [OR], 16.7; 95% confidence interval [CI] 3.4 to 81.5; p <0.001). Of 13 patients with elevated troponin I, 5 patients (39%) and 3 of 94 patients (3.2%) with normal troponin I had acute myocardial infarction (odds ratio, 21.7; 95% CI 4.3 to 110; p <0.001). No deaths occurred within 30 days. Both markers demonstrated equivalent sensitivity (63%) and specificities (troponin T: 91%; troponin I: 92%) for myocardial infarction. Meta-analysis of 12 published troponin T and 9 troponin I studies in patients with UAP produced risk ratios of 4.2 (95% CI 2.7 to 6.4, p <0.001) for troponin I compared with 2.7 (95% CI 2.1 to 3.4, p <0.001) for troponin T. Comparison of the sensitivities and specificities of both markers using summary receiver operating characteristic curves showed no significant difference in their abilities to predict acute myocardial infarction and cardiac death. Troponin T and I show similar prognostic significance for acute myocardial infarction or death in the same patients with UAP. The 2 markers are equally sensitive and specific, as confirmed by meta-analysis, and this supports a role in risk stratification.

Aged↗
PubMed2003

Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment.

PURPOSE OF REVIEW: Myeloperoxidase, an abundant leukocyte protein that generates reactive oxidant species, is present and catalytically active within atherosclerotic lesions. Numerous lines of evidence suggest mechanistic links between myeloperoxidase, inflammation and both acute and chronic manifestations of cardiovascular disease. RECENT FINDINGS: Myeloperoxidase generates reactive oxidant species as part of its function in innate host defense mechanisms. The reactive species formed, however, may also damage normal tissues, contributing to inflammatory injury. Recent studies suggest that MPO-generated oxidants participate in multiple processes relevant to cardiovascular disease development and outcomes, including induction of foam cell formation, endothelial dysfunction, development of vulnerable plaque, and ventricular remodeling following acute myocardial infarction. Of note, measurements of myeloperoxidase mass and activity may be useful in cardiac risk stratification, both for chronic disease assessment, as well as in identification of patients at risk in the acute setting. SUMMARY: The inflammatory protein myeloperoxidase is present, active and mechanistically poised to participate in the initiation and progression of cardiovascular disease. The many links between myeloperoxidase, oxidation and cardiovascular disease suggest this leukocyte protein may have clinical utility in risk stratification for cardiovascular disease status and outcomes.

Animals↗
PubMed2003

Admission troponin T as a prognostic marker and it relationship to streptokinase treatment patients with acute myocardial infarction.

The relationship between the admission troponinT (TnT) level and the response to streptokinase (SK) was examined in 76 patients with acute myocardial infarction (AMI). Of 27 TnT positive patients, 10 (37%) showed a response to SK as suggested by a non-invasive criterion for reperfusion, while 24 (49%) were 'responders' among 49 TnT negative patients. There appeared to be a trend towards a better response to SK in the TnT negative group but the difference lacked statistical power due to the small sample size. The mean time-interval between the onset of symptoms and thrombolytic treatment among TnT positive 'non-responders' was significantly (P < 0.005) higher than the TnT negative 'non-responders' (5.23 + 3.42 h versus 2.38 +/- 1.37 h). An 18 month follow up on 61 patients revealed a higher mortality (33%) among TnT positive patients than TnT negative patients (10%). Mortality among TnT positive 'non-responders' was significantly higher (P = 0.0494) than mortality among TnT-negative 'non-responders' (43% versus 9%), indicating that TnT positive patients, non-responsive to SK were at a greater risk of cardiac death. The data suggest that the admission TnT level can be of value in risk stratification of patients with AMI.

Biomarkers↗
PubMed2005

Establishment and characterization of primary and subsequent subcultures of normal mouse urothelial cells.

In this study, we report a reliable technique for the harvest, cultivation and expansion of monoculture of NMU. The NMU were harvested by two methods, directly from the urothelium in vivo and indirectly from the urothelial outgrowths of bladder explant cultures. Primary cultures and subsequent subcultures were propagated in the mixture of media MCDB 153 and Advanced-DMEM, and conditioned medium. Primary urothelial cells required an initial plating density of 1 x 10(5) viable cells/cm2 for survival, while passaged cells needed lower plating densities (1 x 10(4) viable cells per cm2). The cultured cells were identified as urothelial by their epithelioid morphology and by the positive immunofluorescence labelling of tight junctional proteins, occludin and ZO-1, adherens protein E-cadherin and cytoskeletal protein cytokeratin 7. Markers of highly differentiated urothelial cells, cytokeratin 20 and uroplakins, were not expressed. Furthermore, the immunofluorescence labelling of occludin and cytokeratin 7 was not detected in later passages when urothelial cells replicated at a high rate. In spite of the use of conditioned medium derived from V79 fibroblast cell culture supernatant, the NMU in the primary cultures and subsequent subcultures expressed a basal/intermediate cell phenotype. In conclusion, we demonstrate that homogeneous long-term culture of NMU can be developed. Since powerful transgenic tools exist to manipulate the mouse genome, our findings should help design the mouse in vitro systems for studying the control mechanisms of urothelial cell proliferation, stratification and differentiation in health and disease.

Animals↗
PubMed2002

A pilot study of cardiac troponin I in patients with acute myocardial infarction and unstable angina.

OBJECTIVE: To assess the value of cardiac troponin I in the initial management of acute myocardial infarction and unstable angina, as well as the concordance between creatine phosphokinase-cardiac isoenzyme and cardiac troponin I. METHODS: We reviewed retrospectively the charts of 32 patients with acute myocardial infarction or unstable angina admitted to the Intensive Care Unit from the Emergency Room of King Khalid Military City Hospital, Hafar-Al-Batin, Kingdom of Saudi Arabia from April 1998 to September 2000. The time of admission to the intensive care unit, which corresponds to the beginning of thrombolytic therapy, the time when cardiac enzymes (creatine phosphokinase-cardiac isoenzyme and cardiac troponin I) are available as well as number of cardiac troponin I determinations before obtaining a significant positive result (>2ng/ml) and the delay between admission and the first significant positive result of cardiac troponin I, were evaluated. RESULTS: Sixteen patients had confirmed acute myocardial infarction based on the association of typical chest pain, electrocardiographic findings with ST segment elevation and significant increase of the ratio creatine phosphokinase-cardiac isoenzyme/creatine phosphokinase > 10%. Sixteen patients had unstable angina and out of the 16 patients (81.25%) with acute myocardial infarction, 13 received thrombolytic therapy which was initiated on the basis of typical clinical history and electrocardiographic features, before the availability of cardiac enzymes. Troponin I was available in only 13 cases. The number of tests performed in these patients was 32. The first positive result of cardiac troponin I was available within a mean time of 16.66 20.8 hours from admission. The number of negative tests performed before obtaining a frank positive result was 9 in 12 patients. The number of positive tests after having obtained the first frank positive cardiac troponin I result was 10 in 12 patients. In all cases of cardiac troponin I, results were concordant with creatine phosphokinase-cardiac isoenzyme. In the 16 patients with unstable angina, only 11 patients had cardiac troponin I serum level. A total of 21 tests were performed. In 9 patients 14 cardiac troponin I tests were < 2 ng/ml. This was correlated with normal creatine phosphokinase-cardiac isoenzyme/creatine phosphokinase ratio. In 2 patients, 7 cardiac troponin I tests were positive. Both of them had significant increase of creatine phosphokinase-cardiac isoenzyme/creatine phosphokinase ratio and electrocardiographic features of myocardial ischemia and were referred for urgent coronary angiography. CONCLUSION: Cardiac troponin I levels are not helpful in the initial management of patients with acute myocardial infarction. Thrombolytic therapy should be therefore instituted before the availability of cardiac troponin I results. However, cardiac troponin I results are concordant with creatine phosphokinase-cardiac isoenzyme in retrospective confirmation of the diagnosis of acute myocardial infarction a few hours after onset. In patients with unstable angina, cardiac troponin I should be used mainly for risk stratification.

Adult↗
PubMed1998

Progress in the diagnosis of unstable angina and perspectives for treatment.

Unstable angina is a high-risk phase of coronary heart disease defined by clinical symptoms. Electrocardiographic findings are heterogeneous and creatine kinase is only rarely elevated. However, troponin T and troponin I are found in about 30-40% of patients with angina at rest disclosing minor myocardial cell injury. Several studies in recent years have documented that troponins are the best markers to identify high-risk patients when other life-threatening, non-cardiac diseases are excluded. In addition, first evidence is provided that only these patients benefit from prolonged treatment with low molecular weight heparin or glycoprotein IIb/IIIa receptor blockers. Therefore, this new diagnostic potential should be made available to emergency rooms for risk stratification and in the future to guide therapeutic decision making.

Angina, Unstable↗
PubMed2025

Integrating multi-omics approaches in acute myeloid leukemia (AML): Advancements and clinical implications.

Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hematologic malignancy characterized by clonal proliferation of myeloid precursors. Despite significant advancements in genomic profiling and targeted therapies, patient outcomes remain suboptimal due to disease complexity, resistance mechanisms, and high relapse rates. The integration of multi-omics approaches-spanning genomics, epigenomics, transcriptomics, proteomics, and metabolomics-has revolutionized AML research, offering a comprehensive understanding of leukemogenesis, tumor heterogeneity, and therapeutic vulnerabilities. Recent studies leveraging high-throughput sequencing, mass spectrometry, and advanced computational tools have uncovered novel biomarkers, clonal evolution dynamics, and microenvironmental interactions that drive AML progression and resistance. For instance, single-cell multi-omics has revealed chemotherapy-resistant leukemic stem cell populations, while proteogenomic analyses have identified actionable targets such as MCL1 and metabolic dependencies like OXPHOS. Clinically, integrated omics platforms are refining risk stratification, minimal residual disease (MRD) monitoring, and personalized therapy selection. However, challenges such as data integration complexity, cost barriers, and ethical considerations remain. This review highlights the transformative potential of multi-omics in AML, emphasizing recent advancements in technology, biomarker discovery, and therapeutic innovation. By bridging the gap between molecular insights and clinical practice, multi-omics integration promises to redefine AML management, paving the way for precision oncology and improved patient outcomes.

Humans↗
PubMed2005

B-type natriuretic peptide in organic mitral regurgitation: determinants and impact on outcome.

BACKGROUND: B-type natriuretic peptide (BNP) activation observed in cardiac diseases is a predictor of poor outcome; however, in organic mitral regurgitation (MR), BNP determinants and prognostic value are unknown. METHODS AND RESULTS: We prospectively enrolled 124 patients with chronic organic MR (aged 63+/-15 years, 60% males) in whom we measured BNP level and simultaneously quantified MR degree, left ventricular (LV) remodeling, and left atrial (LA) volumes and analyzed long-term outcome. Baseline BNP level (54+/-67 pg/mL, median 31 pg/mL) was associated univariately with multiple clinical and echocardiographic characteristics, but in multivariate analysis, independent determinants of BNP, beyond age and sex (both P< or =0.01), were LV end-systolic volume index, LA volume, atrial fibrillation, and symptoms (all P<0.02). Conversely, MR degree was not independently associated with BNP. During follow-up, patients with high versus low BNP (> or =31 versus <31 pg/mL) displayed lower survival rates (at 5 years, 72+/-10% versus 95+/-5%, P=0.03) and higher rates of the combined end point of death and heart failure (at 5 years, 42+/-10% versus 16+/-7%, P=0.03). In multivariate analysis, with adjustment for age, sex, functional class, MR severity, and ejection fraction, BNP was independently predictive of mortality (hazard ratio per 10 pg/mL, 1.23 [95% CI 1.07 to 1.48], P=0.004) and of death or heart failure (hazard ratio per 10 pg/mL, 1.09 [95% CI 1.001 to 1.19], P=0.04). CONCLUSIONS: BNP activation in organic MR reflects primarily ventricular and atrial consequences rather than degree of MR. Higher BNP level in patients with organic MR independently predicts adverse events under conservative management. Therefore, BNP activation in organic MR is an emerging biomarker of severity of MR consequences and of poor clinical outcome, and its assessment should be considered in the clinical evaluation and risk stratification of patients with MR.

Aged↗
PubMed2006

Unstable angina and non-ST-segment myocardial infarction: an evidence-based approach to management.

Unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) represent two common, closely related acute coronary syndromes with potentially high morbidity and mortality. Integration of information from the history, physical exam, electrocardiogram, and cardiac biomarkers is used to formulate both the diagnosis of UA/NSTEMI and the overall assessment of patient prognosis and risk. Early diagnosis and risk stratification of patients with UA/NSTEMI enable the physician to initiate timely, appropriate treatment. (There is strong clinical evidence supporting the tailoring of specific therapies to the risk profile of the patient.) In recent years, powerful new medical and invasive therapies have been developed. Pharmaceutical agents for UA/NSTEMI may be broadly grouped into one of three categories: anti-ischemic, anti-platelet, and anti-thrombotic agents. Standard therapy for UA/NSTEMI has commonly included oxygen, aspirin, nitrates, morphine, beta-blockers and heparin. Potent new anti-platelet agents, including inhibitors of platelet adenosine diphosphate and glycoprotein IIb/IIIa receptors, play important, expanding roles in the management of these syndromes. Low-molecular-weight heparins have been shown to be an effective alternative to unfractionated heparin in their treatment. Major advances in invasive techniques and devices over the last decade include revascularization with percutaneous coronary intervention and drug-eluting intracoronary stents. Strong interest exists in studying the potential benefits and risks associated with an early invasive therapeutic strategy rather than an aggressive medical regimen for patients with UA/NSTEMI. As new treatments are rapidly added to our growing arsenal of management options, clinicians are constantly challenged with incorporating complex new information and guidelines into their practices in a timely fashion. To assist clinicians with this challenge, this article will review the evidence to support the use of current therapeutic options for UA/NSTEMI, with an emphasis on summarizing the most recent clinical guidelines jointly published by the American College of Cardiology and the American Heart Association.

Angina, Unstable↗
PubMed2006

Anti-glycan antibodies as biomarkers for diagnosis and prognosis.

Glycans (sugars or carbohydrates) are predominant surface components of cells such as erythrocytes, immune cells and microorganisms. As such, they give rise to high levels of anti-glycan antibodies of all classes. Antibodies to certain defined mono, di and oligosaccharides that are common in bacterial, fungal and parasite cells exist in human sera and can be profiled using glycan arrays. The use of glycan arrays for systematic screening of blood samples from multiple sclerosis (MS) and Crohn's disease (CD) patients in versus to blood samples from control groups, have lead to the discovery of a few anti glycan antibodies biomarkers enabling diagnosis and prognosis in MS and CD patients. Anti-Glc(alpha1,4)Glc(alpha) IgM antibodies were found to be specific for MS patients, enabling differentiation between MS patients and patients with other neurological diseases, with 54% sensitivity and 85% specificity. Anti-Glc(alpha1,4)Glc(alpha) IgM were found to be predictive for the conversion of patients in first acute neurological event to clinically defined MS. Anti-laminaribioside (ALCA), anti-mannobioside (AMCA) and anti-chitobioside (ACCA) antibodies were found to be specific for CD. The combined use of these antibodies enables improved diagnosis of CD versus ulcerative colitis and other gastrointestinal diseases, as well as stratification of CD patients with a more complicated disease and high risk for surgery. Anti-glycan antibodies profiling (AGAP) is a new and promising approach for development of biomarkers for diagnosis and prognosis.

Antibodies↗