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Clinics and Research in Hepatology and... Jun 2016Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological... (Review)
Review
Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such as bile acid induced diarrhea, bile acid induced cholestasis or nonalcoholic steatohepatitis. Changes in bile acid homeostasis are also linked to various types of drug-induced liver injury (DILI). However, the key question whether bile acids are surrogate markers for monitoring DILI or key pathogenic players in the onset and progression of DILI is under intense investigation. The purpose of this review is to summarize the different facets of bile acids in the context of normal physiology, hereditary defects of bile acid transport and DILI.
Topics: Bile Acids and Salts; Bile Ducts; Biological Transport; Biomarkers; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Enterohepatic Circulation; Homeostasis; Humans
PubMed: 26874804
DOI: 10.1016/j.clinre.2015.12.017 -
American Heart Journal Jun 2022The contribution of gut dysfunction to heart failure (HF) pathophysiology is not routinely assessed. We sought to investigate whether biomarkers of gut dysfunction would...
BACKGROUND
The contribution of gut dysfunction to heart failure (HF) pathophysiology is not routinely assessed. We sought to investigate whether biomarkers of gut dysfunction would be useful in assessment of HF (eg, severity, adverse outcomes) and risk stratification.
METHODS
A panel of gut-related biomarkers including metabolites of the choline/carnitine- pathway (acetyl-L-carnitine, betaine, choline, γ-butyrobetaine, L-carnitine and trimethylamine-N-oxide [TMAO]) and the gut peptide, Trefoil factor-3 (TFF-3), were investigated in 1,783 patients with worsening HF enrolled in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort and associations with HF severity and outcomes, and use in risk stratification were assessed.
RESULTS
Metabolites of the carnitine-TMAO pathway (acetyl-L-carnitine, γ-butyrobetaine, L-carnitine, and TMAO) and TFF-3 were associated with the composite outcome of HF hospitalization or all-cause mortality at 3 years (hazards ratio [HR] 2.04-2.93 [95% confidence interval {CI} 1.30-4.71] P≤ .002). Combining the carnitine-TMAO metabolites with TFF-3, as a gut dysfunction panel, showed a graded association; a greater number of elevated markers was associated with higher New York Heart Association class (P< .001), higher plasma concentrations of B-type natriuretic peptide (P< .001), and worse outcome (HR 1.90-4.58 [95% CI 1.19-6.74] P≤ 0.008). Addition of gut dysfunction biomarkers to the contemporary BIOSTAT HF risk model also improved prediction for the aforementioned composite outcome (C-statistics P≤ .011, NRI 13.5-21.1 [95% CI 2.7-31.9] P≤ .014).
CONCLUSIONS
A panel of biomarkers of gut dysfunction showed graded association with severity of HF and adverse outcomes. Biomarkers as surrogate markers are potentially useful for assessment of gut dysfunction to HF pathophysiology and in risk stratification.
Topics: Acetylcarnitine; Biomarkers; Carnitine; Choline; Chronic Disease; Heart Failure; Humans
PubMed: 35278373
DOI: 10.1016/j.ahj.2022.03.002 -
Clinical Trials (London, England) Aug 2015A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the...
BACKGROUND
A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the unobserved true endpoint. A prognostic marker is a marker for predicting the risk of an event given a control treatment; it informs treatment decisions when there is information on anticipated benefits and harms of a new treatment applied to persons at high risk. A predictive marker is a marker for predicting the effect of treatment on outcome in a subgroup of patients or study participants; it provides more rigorous information for treatment selection than a prognostic marker when it is based on estimated treatment effects in a randomized trial.
METHODS
We organized our discussion around a different theme for each topic.
RESULTS
"Fundamentally an extrapolation" refers to the non-statistical considerations and assumptions needed when using surrogate endpoints to evaluate a new treatment. "Decision analysis to the rescue" refers to use the use of decision analysis to evaluate an additional prognostic marker because it is not possible to choose between purely statistical measures of marker performance. "The appeal of simplicity" refers to a straightforward and efficient use of a single randomized trial to evaluate overall treatment effect and treatment effect within subgroups using predictive markers.
CONCLUSION
The simple themes provide a general guideline for evaluation of surrogate endpoints, prognostic markers, and predictive markers.
Topics: Algorithms; Biomarkers; Data Interpretation, Statistical; Forecasting; Humans; Outcome Assessment, Health Care
PubMed: 25385934
DOI: 10.1177/1740774514557725 -
Journal of Biochemistry Feb 2022Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as...
Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as surrogate markers for therapy response. N-glycanase 1 (NGLY1) deficiency is an ultra-rare autosomal recessive disorder characterized by developmental delay, peripheral neuropathy, elevated liver transaminases, hyperkinetic movement disorder and (hypo)-alacrima. We demonstrate that N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA), is the analyte most closely associated with NGLY1 deficiency, showing consistent separation in levels between patients and controls. GNA accumulation is directly linked to the absence of functional NGLY1, presenting strong potential for its use as a biomarker. In agreement, a quantitative liquid chromatography with tandem mass spectrometry assay, developed to assess GNA from 3 to 3000 ng/ml, showed that it is conserved as a marker for loss of NGLY1 function in NGLY1-deficient cell lines, rodents (urine, cerebrospinal fluid, plasma and tissues) and patients (plasma and urine). Elevated GNA levels differentiate patients from controls, are stable over time and correlate with changes in NGLY1 activity. GNA as a biomarker has the potential to identify and validate patients with NGLY1 deficiency, act as a direct pharmacodynamic marker and serve as a potential surrogate endpoint in clinical trials.
Topics: Asparagine; Biomarkers; Congenital Disorders of Glycosylation; Humans; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
PubMed: 34697629
DOI: 10.1093/jb/mvab111 -
Arquivos de Neuro-psiquiatria Mar 2014The challenges for establishing an early diagnosis of Alzheimer's disease (AD) have created a need for biomarkers that reflect the core pathology of the disease. The... (Review)
Review
The challenges for establishing an early diagnosis of Alzheimer's disease (AD) have created a need for biomarkers that reflect the core pathology of the disease. The cerebrospinal fluid (CSF) levels of total Tau (T-tau), phosphorylated Tau (P-Tau) and beta-amyloid peptide (Aβ₄₂) reflect, respectively, neurofibrillary tangle and amyloid pathologies and are considered as surrogate markers of AD pathophysiology. The combination of low Aβ₄₂ and high levels of T-tau and P-Tau can accurately identify patients with AD at early stages, even before the development of dementia. The combined analysis of the CSF biomarkers is also helpful for the differential diagnosis between AD and other degenerative dementias. The development of these CSF biomarkers has evolved to a novel diagnostic definition of the disease. The identification of a specific clinical phenotype combined with the in vivo evidence of pathophysiological markers offers the possibility to make a diagnosis of AD before the dementia stage with high specificity.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Diagnosis, Differential; Early Diagnosis; Humans; Sensitivity and Specificity; tau Proteins
PubMed: 24676441
DOI: 10.1590/0004-282x20130233 -
American Society of Clinical Oncology... 2013Alterations in PI3K signaling are common in gynecologic malignancies. Alterations detected vary with gynecologic cancer type, histologic subtypes within these, and... (Review)
Review
Alterations in PI3K signaling are common in gynecologic malignancies. Alterations detected vary with gynecologic cancer type, histologic subtypes within these, and clinical phenotypes. The distinction into type I and type II endometrial and ovarian carcinomas is reflected in distribution of changes detected in several of the PI3K members. PIK3CA mutations and amplifications are common in endometrial, ovarian, and cervical cancers. PTEN mutations and deletions are frequent in endometrial cancers. Several immunohistochemical studies of protein expression have explored these and other potential surrogate markers for PI3K pathway activation. Biomarkers to measure level of PI3K activity in clinical samples are not established. Whether amplifications, mutations, and deletions of the PI3K pathway members, and in particular change in their expression levels, result in clinically relevant pathway activation needs to be further explored. Also, to what extent these alterations drive the tumor behavior and are critical targets for therapeutics to improve patient survival needs to be further tested to establish predictive biomarkers for response to PI3K inhibition.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Female; Gene Amplification; Gene Deletion; Genetic Predisposition to Disease; Genital Neoplasms, Female; Humans; Molecular Targeted Therapy; Mutation; Phenotype; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Precision Medicine; Protein Kinase Inhibitors; Signal Transduction
PubMed: 23714506
DOI: 10.14694/EdBook_AM.2013.33.e218 -
Cardiovascular Diabetology Feb 2021Clinical trials are often performed to investigate the effects of various types of cardiometabolic therapies on cardiovascular surrogate markers, including vascular...
Clinical trials are often performed to investigate the effects of various types of cardiometabolic therapies on cardiovascular surrogate markers, including vascular function and biomarkers. This study platform has the potential to provide information on the suspected actions of drugs and mechanistic insights into their prognostic impact. However, despite using the same class of drugs and similar study designs we are often faced with inconsistent and even conflicting results, possibly leading to some confusion in the clinical setting. When interpreting these results, it is important to investigate what caused the differences and carefully assess the information, taking into account the research situation and the patient population investigated. Using this approach, assessment of the impact on cardiovascular surrogate markers observed in clinical studies from multiple perspectives should help to better understand the potential cardiovascular effects. In this commentary we discuss how we should interpret the effects of cardiometabolic therapeutics on vascular surrogate markers, based on viewpoints learned from the results of clinical trials on dipeptidyl peptidase-4 inhibitors. This learning strategy could also be helpful for appropriate selection of drugs for evidence-based, patient-centric, tailored medication.
Topics: Biomarkers; Blood Glucose; Cardiometabolic Risk Factors; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Endpoint Determination; Humans; Research Design; Risk Assessment; Treatment Outcome
PubMed: 33573675
DOI: 10.1186/s12933-021-01234-5 -
TheScientificWorldJournal 2012Preclinical atherosclerosis represents a crucial period associated with several pathophysiological reactions in the vascular wall. Failure to diagnose preclinical... (Review)
Review
Preclinical atherosclerosis represents a crucial period associated with several pathophysiological reactions in the vascular wall. Failure to diagnose preclinical atherosclerosis at this stage misses a major opportunity to prevent the long-term consequences of this disease. Surrogate biological and structural vascular markers are available to determine the presence and the extension of preclinical vascular injury in the general population. Examples of surrogate markers are carotid intima media thickness and biomarkers including high-sensitivity C-reactive protein, cell adhesion molecules and matrix metalloproteinases, and leukotrienes. Recently, leukotrienes have been implicated as mediators, biomarkers, and possible therapeutic targets in the context of subclinical atherosclerosis. The aim of this short paper is to focus on the relation between preclinical atherosclerosis and leukotrienes, with particular attention to the recent development on the use of leukotriene modifiers in the treatment of atherosclerosis.
Topics: Animals; Arachidonate 5-Lipoxygenase; Atherosclerosis; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Carotid Intima-Media Thickness; Disease Progression; Humans; Inflammation; Leukotrienes; Mice; Models, Biological; Placebos; Risk
PubMed: 22645425
DOI: 10.1100/2012/490968 -
Journal of Atherosclerosis and... 2016This study aimed to evaluate the cross-sectional association between serum phosphorus and arterial stiffness among a health checkup population.
AIM
This study aimed to evaluate the cross-sectional association between serum phosphorus and arterial stiffness among a health checkup population.
METHODS
The study population included 26791 individuals without impaired kidney function. Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV), ankle brachial index (ABI), and augmentation index (AI) by the radial artery waveform analysis. Linear or logistic regression model was used to appropriately evaluate the association between phosphorus levels and arterial stiffness markers.
RESULTS
The mean age of the population was 49 years and 67% were male. The phosphorus level was divided into quintiles. After multivariate adjustments, participants in the fourth (3.90-4.17 mg/dL) and fifth quintile (≥ 4.18 mg/dL) of serum phosphorus had increased the level of baPWV with linear regression coefficients of 11.9 [95% confidence interval (CI): 5.6-18.2] and 17.2 (95% CI: 10.9-23.5), respectively, compared with those in the first quintile (<3.34 mg/dL). No significant associations were found between each quintile of phosphorus and ABI <0.9. However, participants in the fifth quintile of phosphorus had an increased risk of ABI ≥ 1.3 with an odds ratio (OR) of 1.2 (95% CI: 1.0-1.5) compared with the reference quintile. Furthermore, the increased risks could be observed for AI >97% throughout the second to fifth quintile of phosphorus and the ORs were 1.1 (95% CI: 1.0-1.3), 1.2 (95% CI: 1.0-1.4), 1.3 (95% CI: 1.1-1.5), and 1.5 (95% CI: 1.3-1.7), respectively.
CONCLUSIONS
Higher serum phosphorus levels, even within the normal range, are associated with markers of arterial stiffness among general population with normal kidney function.
Topics: Adult; Aged; Ankle Brachial Index; Anthropometry; Biomarkers; Cardiovascular Diseases; Female; Glomerular Filtration Rate; Humans; Kidney; Linear Models; Male; Middle Aged; Phosphorus; Pulse Wave Analysis; Regression Analysis; Vascular Stiffness
PubMed: 26347182
DOI: 10.5551/jat.31153 -
Journal of the Neurological Sciences Jun 2005This review on the role of neurofilaments as surrogate markers for axonal degeneration in neurological diseases provides a brief background to protein synthesis,... (Review)
Review
This review on the role of neurofilaments as surrogate markers for axonal degeneration in neurological diseases provides a brief background to protein synthesis, assembly, function and degeneration. Methodological techniques for quantification are described and a protein nomenclature is proposed. The relevance for recognising anti-neurofilament autoantibodies is noted. Pathological implications are discussed in view of immunocytochemical, cell-culture and genetic findings. With reference to the present symposium on multiple sclerosis, the current literature on body fluid levels of neurofilaments in demyelinating disease is summarised.
Topics: Animals; Axons; Biomarkers; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Glycosylation; Humans; Immunohistochemistry; Models, Biological; Nerve Degeneration; Neurofilament Proteins; Phosphorylation; Protein Isoforms
PubMed: 15896809
DOI: 10.1016/j.jns.2005.03.015