Showing papers on "Biomarker (medicine) published in 2007"
TL;DR: Findings indicate that gene expression in cytologically normal large-airway epithelial cells can serve as a lung cancer biomarker, potentially owing to a cancer-specific airway-wide response to cigarette smoke.
Abstract: Lung cancer is the leading cause of death from cancer in the US and the world 1 . The high mortality rate (80–85% within 5 years) results, in part, from a lack of effective tools to diagnose the disease at an early stage 2–4 . Given that cigarette smoke creates a field of injury throughout the airway 5–11 , we sought to determine if gene expression in histologically normal large-airway epithelial cells obtained at bronchoscopy from smokers with suspicion of lung cancer could be used as a lung cancer biomarker. Using a training set (n ¼ 77) and gene-expression profiles from Affymetrix HG-U133A microarrays, we identified an 80-gene biomarker that distinguishes smokers with and without lung cancer. We tested the biomarker on an independent test set (n ¼ 52), with an accuracy of 83% (80% sensitive, 84% specific), and on an additional validation set independently obtained from five medical centers (n ¼ 35). Our biomarker had B90% sensitivity for stage 1 cancer across all subjects. Combining cytopathology of lower airway cells obtained at bronchoscopy with the biomarker yielded 95% sensitivity and a 95% negative predictive value. These findings indicate that gene expression in cytologically normal large-airway epithelial cells can serve as a lung cancer biomarker, potentially owing to a cancer-specific airway-wide response to cigarette smoke.
560 citations
TL;DR: These studies show that, in some circumstances, CFDNA alterations are detectable ahead of cancer diagnosis, raising the possibility of exploiting them as biomarkers for monitoring cancer occurrence.
Abstract: The presence of small amounts of tumor DNA in cell free DNA (CFDNA) circulating in the plasma or serum of cancer patients was first demonstrated 30 years ago. Since then, overall plasma DNA concentration in cancer patients and genetic or epigenetic alterations specific to tumor DNA have been investigated in patients diagnosed with different types of cancer. The proportion of patients with altered CFDNA varies with the pathology and the nature of the marker. However, several studies have reported the presence of altered CFDNA in over 50% of cancer patients, suggesting that this marker may be common and amenable for a variety of clinical and epidemiological studies. Because the mechanisms and timing of CFDNA release in the blood stream are poorly understood, only few studies have addressed the use of CFDNA for early cancer detection or as a biomarker for mutagenesis and tumourigenesis in molecular epidemiology. In this review, we discuss the technical issues involved in obtaining, using and analyzing CFDNA in cancer or healthy subjects. We also summarize the literature available on the mechanisms of CDNA release as well as on cross-sectional or prospective studies aimed at assessing the clinical and biological significance of CFDNA. These studies show that, in some circumstances, CFDNA alterations are detectable ahead of cancer diagnosis, raising the possibility of exploiting them as biomarkers for monitoring cancer occurrence. Testing these hypotheses will require well-designed studies, assessing multiple markers with quantitative and sensitive methods, with adequate follow-up of subjects, and we provide recommendations for the development of such studies.
462 citations
TL;DR: Emerging data suggests that measurement of survivin can aid the early diagnosis of bladder cancer, determine prognosis in multiple cancer types and predict response to diverse anti-cancer therapies.
258 citations
TL;DR: The IRMA can detect GDF15 in human serum and plasma with excellent sensitivity and specificity, and the reference limits and confounding variables defined for apparently healthy elderly individuals and the favorable preanalytic characteristics of GDF 15 are expected to facilitate future studies of G DF15 as a biomarker in various disease settings, including CHF.
Abstract: Background: Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor β (TGF-β) cytokine superfamily. There has been increasing interest in using circulating GDF15 as a biomarker in patients, for example those with cardiovascular disease. Methods: We developed an IRMA that uses a polyclonal, affinity chromatography–purified goat antihuman GDF15 IgG antibody, assessed the preanalytic characteristics of GDF15, and determined circulating GDF15 concentrations in 429 apparently healthy elderly individuals and 153 patients with chronic heart failure (CHF). Results: The assay had a detection limit of 20 ng/L, an intraassay imprecision of ≤10.6%, and an interassay imprecision of ≤12.2%. Specificity was demonstrated with size-exclusion chromatography, parallel measurements with polyclonal and monoclonal anti-GDF15 antibody, and lack of cross-reactivity with TGF-β. The assay was not appreciably influenced by the anticoagulant matrix or unrelated biological substances. GDF15 was stable at room temperature for 48 h and resistant to 4 freeze-thaw cycles. Apparently healthy, elderly individuals presented with a median GDF15 concentration of 762 ng/L (25th–75th percentiles, 600–959 ng/L). GDF15 concentrations were associated with age and with cystatin C and C-reactive protein concentrations. CHF patients had increased GDF15 concentrations that were closely related to disease severity. Conclusion: The IRMA can detect GDF15 in human serum and plasma with excellent sensitivity and specificity. The reference limits and confounding variables defined for apparently healthy elderly individuals and the favorable preanalytic characteristics of GDF15 are expected to facilitate future studies of GDF15 as a biomarker in various disease settings, including CHF.
250 citations
TL;DR: A statistically valid test for a biomarker-defined subset effect can be prospectively incorporated into a randomized phase III design without compromising the ability to detect an overall effect if the intervention is beneficial in a broad population.
Abstract: Human cancers are heterogeneous with regard to their molecular and genomic properties. Recent advances in biotechnology have resulted in a shift toward molecularly targeted anticancer agents. These new therapeutics are likely to benefi t only a subset of the patients with a given cancer. Defi nitive testing of such targeted agents requires the identifi cation of the appropriate “sensitive” population. When biomarkers to identify the patients who are likely to benefi t from the new therapy are available, targeted clinical trials that restrict eligibility to sensitive patients should be used ( 1 ). However, reliable assays to identify sensitive patients are often unavailable. In the absence of a reliable biomarker, broad-eligibility clinical trials are used routinely. Most of these trials use a conventional design, in which the primary analysis is based on comparison of all randomly assigned patients. This often leads to the failure to recognize effective agents due to dilution of the treatment effect by the presence of the patients who do not benefi t from the agent. Retrospective analysis of trials with a conventional design can be used as an initial step in identifying biomarkers for the sensitive subpopulation. However, retrospectively identifi ed biomarkers
233 citations
TL;DR: Diagnostic and therapeutic trials that measure CSF levels should control for the time of CSF sampling to minimize variability, indicating that similar processes likely regulate the level of these species.
Abstract: Objective: To investigate the stability and time course of human CSF amyloid-β (Aβ) levels over hours. Methods: Fifteen nondemented participants had CSF sampled hourly for up to 36 hours via indwelling lumbar catheter. CSF Aβ 1-x , Aβ 1-40 , and Aβ 1-42 were measured by ELISA in each hourly CSF sample. Results: Significant variation in Aβ levels of 1.5- to fourfold was detected over 36 hours of serially sampling in individual subjects. Aβ 40 , Aβ 42 , and Aβ 1-X are highly correlated over time indicating that similar processes likely regulate the level of these species. On average, the fluctuations of Aβ levels appear to be time of day or activity dependent. Conclusion: Diagnostic and therapeutic trials that measure Aβ should control for the time of CSF sampling to minimize variability.
230 citations
TL;DR: In this paper, a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance (1H NMR) spectroscopy was performed to identify early stages of the Huntington disease.
Abstract: Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD have not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance (1H NMR) spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. 1H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.
224 citations
TL;DR: PMP technology can be useful in identifying potential biomarkers in patients with COPD and panels of selected serum markers are associated with important clinical predictors of outcome in these patients.
Abstract: Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with significant systemic consequences. Recognition of the systemic manifestations has stimulated interest in identifying circulating biomarkers in these patients. A systematic analysis was undertaken of multiple protein analytes in the serum of well characterised patients with COPD and matched controls using novel protein microarray platform (PMP) technology. Methods: Forty-eight patients (65% men) with COPD (forced expiratory volume in 1 s Results: Thirty biomarker clusters were identified and ranked by computing the predictive value of each cluster for COPD (partial least squares discriminant analysis). From the 19 best predictive clusters, 2–3 biomarkers were selected based on their pathophysiological profile (chemoattractants, inflammation, tissue destruction and repair) and the statistical significance of their relationship with clinically important end points was tested. The selected panel of 24 biomarkers correlated (p Conclusion: PMP technology can be useful in identifying potential biomarkers in patients with COPD. Panels of selected serum markers are associated with important clinical predictors of outcome in these patients.
203 citations
TL;DR: Findings identify global tissue hypoxia as an important contributor to the early inflammatory response and support the role of hemodynamic optimization in supplementing other established therapies during this diagnostic and therapeutic “window of opportunity.”
Abstract: Background:Despite abundant experimental studies of biomarker patterns in early severe sepsis and septic shock, human data are few. Further, the impact of the severity of global tissue hypoxia resulting from resuscitative strategies on these early biomarker patterns remains unknown.Methods:The tempo
198 citations
TL;DR: Monitoring of glycaemic control using HbA1c could have additional benefits of identifying diabetic patients who are at a greater risk of cardiovascular complications, as well as a good predictor of lipid profile.
Abstract: Impaired lipid metabolism resulting from uncontrolled hyperglycaemia has been implicated in cardiovascular complications in diabetes patients. The aim of this study was to examine the impact of glycaemic control on the lipid profile of diabetic patients. We also determined the ability of glycated haemoglobin (HbA1c) as an indirect marker of dyslipidaemia. A total of 1011 type 2 diabetic patients (males, 574; females, 437; mean age, 59.76 years) were included in this study. Venous blood samples were collected from all the subjects after at least 8 h fasting. The sera were analysed for HbA1c, fasting blood glucose (FBG), total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL). The levels of HbA1c, FBG and LDL did not differ significantly between males and females. Female patients showed significantly higher serum cholesterol and HDL but significantly lower TG levels as compared to males. There was a highly significant correlation between HbA1c and FBG. Both HbA1c and FBG exhibited direct correlations with cholesterol, TG and LDL and inverse correlation with HDL; the magnitude of significance for all these lipid parameters being greater with HbA1c than FBG. There was a linear relationship between HbA1c and dyslipidaemia. The levels of serum cholesterol and TG were significantly higher and of HDL significantly lower in patients with worse glycaemic control as compared to patients with good glycaemic control. The findings of this study clearly indicate that HbA1c is not only a useful biomarker of long-term glycaemic control but also a good predictor of lipid profile. Thus, monitoring of glycaemic control using HbA1c could have additional benefits of identifying diabetic patients who are at a greater risk of cardiovascular complications.
197 citations
TL;DR: It is concluded that NSE, S100B, and MBP concentrations obtained at the time of TBI may be useful in predicting outcome and future studies should focus on assessing the differential benefit of biomarkers compared with clinical variables.
Abstract: Predicting outcome after pediatric traumatic brain injury (TBI) is important for providing information to families and prescribing rehabilitation services. The study objective was to assess whether biomarkers concentrations obtained at the time of injury are associated with outcome. Serial serum concentrations of neuron-specific enolase (NSE), S100B and myelin basic protein (MBP) were measured in 152 children with acute TBI. Outcome was assessed with the Glasgow Outcome Scale (GOS) score and/or GOS-Extended Pediatric (GOS-E Peds). Spearman's rank correlation and binary logistic regression assessed the relationship between biomarker concentrations and outcome. For all biomarkers and time points, higher biomarker concentrations were associated with worse outcome. Initial and peak NSE concentrations and initial MBP concentrations were more strongly correlated with outcome in children 4 years of age. Using binary logistic regression to evaluate the simultaneous affect of all biomarkers on outcome, there was significant overall model fit predicting a dichotomous GOS from biomarker concentrations with a 77% correct classification rate and a negative and positive predictive value of 97% and 75%, respectively. We conclude that NSE, S100B, and MBP concentrations obtained at the time of TBI may be useful in predicting outcome. Future studies should focus on assessing the differential benefit of biomarkers compared with clinical variables and in assessing a continuous rather than categorical outcome variable.
TL;DR: The results show that a staged pipeline employing shotgun-based comparative proteomics for biomarker discovery and multiple reaction monitoring for confirmation of biomarker candidates is capable of finding novel tissue and plasma biomarkers in a mouse model of breast cancer.
Abstract: Despite their potential to impact diagnosis and treatment of cancer, few protein biomarkers are in clinical use. Biomarker discovery is plagued with difficulties ranging from technological (inability to globally interrogate proteomes) to biological (genetic and environmental differences among patients and their tumors). We urgently need paradigms for biomarker discovery. To minimize biological variation and facilitate testing of proteomic approaches, we employed a mouse model of breast cancer. Specifically, we performed LC-MS/MS of tumor and normal mammary tissue from a conditional HER2/Neu-driven mouse model of breast cancer, identifying 6758 peptides representing >700 proteins. We developed a novel statistical approach (SASPECT) for prioritizing proteins differentially represented in LC-MS/MS datasets and identified proteins over- or under-represented in tumors. Using a combination of antibody-based approaches and multiple reaction monitoring-mass spectrometry (MRM-MS), we confirmed the overproduction of multiple proteins at the tissue level, identified fibulin-2 as a plasma biomarker, and extensively characterized osteopontin as a plasma biomarker capable of early disease detection in the mouse. Our results show that a staged pipeline employing shotgun-based comparative proteomics for biomarker discovery and multiple reaction monitoring for confirmation of biomarker candidates is capable of finding novel tissue and plasma biomarkers in a mouse model of breast cancer. Furthermore, the approach can be extended to find biomarkers relevant to human disease.
TL;DR: Assessment of hepatic scarring may be performed with a combination of these novel fibrosis biomarkers, thus eliminating the need for liver biopsy, further evaluation of these candidate markers needs to be performed in larger patient populations.
Abstract: BACKGROUND: Liver biopsy is currently the gold standard for assessing liver fibrosis, and no reliable noninvasive diagnostic approach is available. Therefore a suitable serologic biomarker of liver fibrosis is urgently needed. METHODS: We used a proteomics method based on 2-dimensional gel electrophoresis to identify potential fibrosis biomarkers. Serum samples from patients with varying degrees of hepatic scarring induced by infection with the hepatitis C virus (HCV) were analyzed and compared with serum from healthy controls. RESULTS: We observed the most prominent differences when we compared serum samples from cirrhotic patients with healthy control serum. Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) fragments, alpha1 antichymotrypsin, apolipoprotein L1 (Apo L1), prealbumin, albumin, paraoxonase/arylesterase 1, and zinc-alpha2-glycoprotein were decreased in cirrhotic serum, whereas CD5 antigen-like protein (CD5L) and beta2 glycoprotein I (beta2GPI) were increased. In general, alpha2 macroglobulin (a2M) and immunoglobulin components increased with hepatic fibrosis, whereas haptoglobin and complement components (C3, C4, and factor H-related protein 1) decreased. Novel proteins associated with HCV-induced fibrosis included ITIH4 fragments, complement factor H-related protein 1, CD5L, Apo L1, beta2GPI, and thioester-cleaved products of a2M. CONCLUSIONS: Assessment of hepatic scarring may be performed with a combination of these novel fibrosis biomarkers, thus eliminating the need for liver biopsy. Further evaluation of these candidate markers needs to be performed in larger patient populations. Diagnosis of fibrosis during early stages will allow early treatment, thereby preventing fibrosis progression.
TL;DR: It is concluded that T-tau, P-t Tau and Abeta42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients, suggesting that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness in clinical trials with drug candidates with disease-modifying potential.
TL;DR: Gene methylation in saliva is a promising biomarker for the follow-up and early detection of still curable relapses of head and neck squamous cell carcinoma patients.
Abstract: Purpose: Our goal was to define tumor and saliva gene methylation profile of head and neck squamous cell carcinoma and to evaluate its prognostic significance and its biomarker potential for early detection of relapse. Experimental Design: We prospectively analyzed 11 genes by methylation-specific PCR on primary tumors, histologically normal adjacent mucosa, and saliva from 90 French patients at diagnosis and during follow-up as well as on 30 saliva specimens from control-matched patients with nonmalignant head and neck pathology. Five additional genes were analyzed on 50 tumors of the series. Results: Methylation of TIMP3, ECAD, p16, MGMT, DAPK , and RASSF1 was the most frequently observed in tumors and paired saliva samples were analyzed at diagnosis, with an excellent agreement between both samples. At least one of these six genes was methylated in >75% of the samples without additional positive samples when other genes were analyzed. Methylation profile was similar in newly diagnosed and second primary cancers. Aberrant methylation was not associated with a worse prognosis. Ninety percent of normal adjacent mucosa and all control saliva samples were negative. Twenty-two patients were followed after treatment; abnormal methylation was detectable in the saliva of five patients few months before clinical and 2-deoxy-2[ 18 F]fluoro-d-glucose-positron emission tomography signs of relapse, allowing curable surgery. Saliva samples were negative for the 17 other patients: 16 were in remission and only 1 relapsed. Conclusions: Gene methylation in saliva is a promising biomarker for the follow-up and early detection of still curable relapses of head and neck squamous cell carcinoma patients.
TL;DR: IMA blood levels may be a biomarker for early identification of acute stroke, and further studies are required to investigate the role of IMA in the early detection of acute strokes.
Abstract: Background: Ischemia-modified albumin (IMA)is a new biological marker of ischemia Previous studies have found increased serum IMA levels after myocardial ischemia, but no study has
TL;DR: Induction of necrotic cell death may explain the clinical efficacy of anthracycline-based therapy for breast carcinomas with defective apoptosis pathways and is suggested to be useful biomarkers for clinical trials.
Abstract: Purpose: With a widening arsenal of cancer therapies available, it is important to develop therapy-specific predictive markers and methods to rapidly assess treatment efficacy. We here evaluated the use of cytokeratin-18 (CK18) as a serum biomarker for monitoring chemotherapy-induced cell death in breast cancer. Experimental Design: Different molecular forms of CK18 (caspase cleaved and total) were assessed by specific ELISA assays. Drug-induced release of CK18 was examined from breast carcinoma cells and tissue. CK18 protein composition was examined in serum. CK18 levels were determined in serum from 61 breast cancer patients during docetaxel or cyclophosphamide/epirubicin/5-fluorouracil (CEF) therapy. Results: Caspase-cleaved CK18 molecules were released from monolayer cultures and tumor organ cultures to the extracellular compartment. CK18 was present in complexes with other cytokeratins in serum. Such CK18 protein complexes are remarkably stable, leading to favorable performance of CK18 biomarker assays for clinical investigations. Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis. CEF therapy led to increases predominantly in uncleaved CK18, indicating induction of necrotic cell death in many tumors. The increase in total CK18 at 24 h of the first treatment cycle correlated to the clinical response to CEF therapy ( P Conclusions: Induction of necrotic cell death may explain the clinical efficacy of anthracycline-based therapy for breast carcinomas with defective apoptosis pathways. We suggest that CK18 biomarkers are useful for early prediction of the response to CEF therapy in breast cancer and may be useful biomarkers for clinical trials.
TL;DR: A simple test based on gene-expression patterns may be used as a biomarker of cure while identifying patients who are at risk for relapse, which would facilitate the introduction of new tuberculosis drugs.
Abstract: BACKGROUND: The majority of patients with tuberculosis who comply with appropriate treatment are cured. However, approximately 5% subsequently have a repeat disease episode, usually within 2 years of successful combination therapy. Presently, there is no way of predicting which patients will experience a relapse. METHODS: We identified 10 subjects who had previously experienced recurrent tuberculosis and carefully matched them to cured subjects who had had only 1 episode of tuberculosis, to patients with active tuberculosis, and to latently infected healthy subjects. We compared their ex vivo whole-blood gene-expression profiles by use of DNA array technology and confirmed the results by use of quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). RESULTS: The 4 clinical tuberculosis groups exhibited distinct patterns of gene expression. The gene-transcript profiles of the patients with recurrent tuberculosis were more similar to those of the patients with active tuberculosis than to those of the cured or latently infected subjects. Discriminant analysis of a training data set showed that 9 genes were sufficient to classify the subjects. We confirmed that measurement of the expression of these genes by qRT-PCR can accurately discriminate between subjects in a test set of samples. CONCLUSIONS: A simple test based on gene-expression patterns may be used as a biomarker of cure while identifying patients who are at risk for relapse. This would facilitate the introduction of new tuberculosis drugs.
TL;DR: Research indicates that a transient increase in serum CC16 is not associated with measurable pulmonary damage or impairment of pulmonary function, and a lack of specificity limits the use of serumCC16 as a biomarker of specific exposures.
Abstract: Biomarkers associated with asthma aetiology and exacerbation have been sought to shed light on this multifactorial disease. One candidate is the serum concentration of the Clara cell secretory protein (CC16, sometimes referred to as CC10 or uteroglobin). In this review, we examine serum CC16's relation to asthma aetiology and exacerbation. There is evidence that acute exposures to certain pulmonary irritants can cause a transient increase in serum CC16 levels, and limited evidence also suggests that a transient increase in serum CC16 levels can be caused by a localized pulmonary inflammation. Research also indicates that a transient increase in serum CC16 is not associated with measurable pulmonary damage or impairment of pulmonary function. The biological interpretation of chronic changes in serum CC16 is less clear. Changes in serum CC16 concentrations (either transient or chronic) are not specific to any one agent, disease state, or aetiology. This lack of specificity limits the use of serum CC16 as a biomarker of specific exposures. To date, many of the critical issues that must be understood before serum CC16 levels can have an application as a biomarker of effect or exposure have not been adequately addressed.
TL;DR: The need for biomarkers and surrogate endpoints for future clinical trials in individuals at risk for Huntington's disease is discussed and data is presented suggesting that striatal volumes, as measured on MRI scans, meet the criteria for a biomarker.
TL;DR: The data presented show that simultaneous testing using a multiplexed panel of serum biomarkers may present a promising new approach for the early detection of head and neck cancer.
Abstract: Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease that has been linked to altered immune, inflammatory, and angiogenesis responses. A better understanding of these aberrant responses might improve early detection and prognosis of SCCHN and provide novel therapeutic targets. Previous studies examined the role of multiplexed serum biomarkers in small cohorts or SCCHN sera. We hypothesized that an expanded panel comprised of multiple cytokines, chemokines, growth factors, and other tumor markers, which individually may show some promising correlation with disease status, might provide higher diagnostic power if used in combination. Thus, we evaluated a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple serum biomarkers. Concentrations of 60 cytokines, growth factors, and tumor antigens were measured in the sera of 116 SCCHN patients before treatment (active disease group), 103 patients who were successfully treated (no evidence of disease group), and 117 smoker controls without evidence of cancer. The multimarker panel offering the highest diagnostic power was comprised of 25 biomarkers, including epidermal growth factor, epidermal growth factor receptor, interleukin (IL)-8, tissue plasminogen activator inhibitor-1, alpha-fetoprotein, matrix metalloproteinase-2, matrix metalloproteinase-3, IFN-alpha, IFN-gamma, IFN-inducible protein-10, regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein-1alpha, IL-7, IL-17, IL-1 receptor-alpha, IL-2 receptor, granulocyte colony-stimulating factor, mesothelin, insulin-like growth factor binding protein 1, E-selectin, cytokeratin-19, vascular cell adhesion molecule, and cancer antigen-125. Statistical analysis using an ADE algorithm resulted in a sensitivity of 84.5%, specificity of 98%, and 92% of patients in the active disease group correctly classified from a cross-validation serum set. The data presented show that simultaneous testing using a multiplexed panel of serum biomarkers may present a promising new approach for the early detection of head and neck cancer.
TL;DR: Even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.
Abstract: This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau181 (P-tau181) and amyloid-β1−42 (Aβ1−42). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau181 levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group ( p< 0.01), while baseline Aβ1−42 levels were lower ( p< 0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 ( p< 0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.
TL;DR: Those biomarkers found in biological fluids, blood in particular, apparently hold the best promise for fast development of screening assays, and it is expected that technologies developed for breast cancer detection will be useful for other types of cancer.
TL;DR: A large battery of transcriptomic tests explored as state biomarker candidates were described, in an attempt to exploit the known neuroinflammatory and transcriptional perturbations of disease, and measured relevant mRNAs in peripheral blood cells.
Abstract: Highly quantitative biomarkers of neurodegenerative disease remain an important need in the urgent quest for disease-modifying therapies. For Huntington's disease (HD), a genetic test is available (trait marker), but necessary state markers are still in development. In this report, we describe a large battery of transcriptomic tests explored as state biomarker candidates. In an attempt to exploit the known neuroinflammatory and transcriptional perturbations of disease, we measured relevant mRNAs in peripheral blood cells. The performance of these potential markers was weak overall, with only one mRNA, immediate early response 3 (IER3), showing a modest but significant increase of 32% in HD samples compared with controls. No statistically significant differences were found for any other mRNAs tested, including a panel of 12 RNA biomarkers identified in a previous report [Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, et al. (2005) Proc Natl Acad Sci USA 102:11023-11028]. The present results may nonetheless inform the future design and testing of HD biomarker strategies.
TL;DR: The presence and titer of high risk human papilloma virus and expression of epidermal growth factor receptor in pre-treatment biopsies, as well as smoking and gender were examined in oropharynx cancer patients enrolled in an organ sparing trial.
Abstract: Induction chemotherapy and concurrent chemoradiation for responders or immediate surgery for non-responders is an effective treatment strategy head and neck squamous cell carcinoma (HNSCC) of the larynx and oropharynx Biomarkers that predict outcome would be valuable in selecting patients for therapy In this study, the presence and titer of high risk human papilloma virus (HPV) and expression of epidermal growth factor receptor (EGFR) in pre-treatment biopsies, as well as smoking and gender were examined in oropharynx cancer patients enrolled in an organ sparing trial HPV16 copy number was positively associated with response to therapy and with overall and disease specific survival, whereas EGFR expression, current or former smoking behavior, and female gender (in this cohort) were associated with poor response and poor survival in multivariate analysis Smoking cessation and strategies to target EGFR may be useful adjuncts for therapy to improve outcome in the cases with the poorest biomarker profile
TL;DR: CSF levels of Ab1^42,T -tau and P-tau 181P were not associated with e4, tangle or plaque burden in 50 autopsy-confirmed Alzheimer’s disease patients, and the concept of in vivo surrogate biomarkers should be further explored.
Abstract: The CSF biomarkers b-amyloid peptide (Ab1^42), total tau protein (T-tau) and tau phosphorylated at threonine 181 (P-tau181P) were determined in autopsy-confirmed Alzheimer’s disease patients in order to study possible associations with the e4 allele of APOE and density and spread of plaques (SP) and tangles (NFT). CSF levels of Ab1^42, T-tau and P-tau181P were determined in 50 Alzheimer’s disease patients using commercially available single parameter ELISA kits (INNOTEST ). Genomic DNA was extracted from whole blood and the APOE genotype was determined using standard methods. Tangle burden was assessed by means of Braak’s NFT stages (I^VI), whereas the plaque burden was assessed by means of Braak’s SP stages (A^C). CSF biomarker levels were not different when comparing e4 carriers (n^21) and non-carriers (n^29) (P`0.05 for all comparisons). No significant correlations between the number of e 4a lleles (0, 1 or 2) and CSF levels of Ab1^42 (Spearman Rank Order: r^20.057, P^0.695), T-tau (r^0.104, P^0.472) and P-tau181P (r^0.062, P^0.668) were found. Braak’s SP (Ab1^42: r^20.155, P ¼ 0.280; T-tau: r^20.044, P ¼ 0.763; P-tau181P: r^20.010, P^0.947) and NFT (Ab1^42: r^20.145, P^0.315; T-tau: r^0.117, P^0.415; P-tau181P: r^0.150, P^0.296) stages were not significantly correlated with CSF biomarker levels. In conclusion, CSF levels of Ab1^42 ,T -tau and P-tau 181P were not associated with e4, tangle or plaque burden in 50 autopsy-confirmed Alzheimer’s disease patients. In the light of future biomarker applications like monitoring of disease progression and as allocortical neuropathological changes significantly contribute to clinical symptoms, the concept of in vivo surrogate biomarkers should be further explored.
TL;DR: Safety and efficacy pharmacogenetics can be applied successfully to the drug discovery and development pipeline at multiple phases and is currently being used across the pipeline to prevent attrition and to create safer and more effective medicines.
Abstract: Safety and efficacy pharmacogenetics can be applied successfully to the drug discovery and development pipeline at multiple phases. We review drug-target screening using high throughput SNP associations with complex diseases testing more than 1,800 candidate targets with approximately 7,000 SNPs. Alzheimer's disease data are provided as an example. The supplementation of target-selected screening with genome-wide SNP association, to also define susceptibility genes and relevant disease pathways for human diseases, is discussed. Applications for determining predictive genetic or genomic profiles, or derived biomarkers, for drug efficacy and safety during clinical development are exemplified by several successful experiments at different phases of development. A Phase I-IIA study of side effects using an oral drug for the treatment of breast cancer is used as an example of early pipeline pharmacogenetics to predict side effects and allow optimization of dosing. References are provided for several other recently published genetic association studies of adverse events during drug development. We illustrate the early identification of gene variant candidates related to efficacy in a Phase IIA obesity drug trial to generate hypotheses for testing in subsequent development. How these genetic data generated in Phase IIA are subsequently incorporated as hypotheses into later Phase clinical protocols is discussed. A Phase IIB clinical trial for Alzheimer's disease is described that exemplifies the major pipeline decision between program attrition and further clinical development. In this case, there was no significant improvement in 511 intention-to-treat patients but, applying a confirmed prognostic biomarker (APOE4) to segment the clinical trial population, all three doses of rosiglitazone demonstrated improvement in patients who did not carry the APOE4 allele. The data for the APOE4 carriers demonstrated no significant improvement but suggested that there may be a need for higher doses. Thus, a development program that would have been terminated progressed to Phase III registration trials based on the results of prospective efficacy pharmacogenetic analyses. The implications of using APOE genotype as a biomarker to predict efficacy and possibly dose, as well as supporting the basic neurobiology and pharmacology that provided the original target validation, is discussed. Citations are provided that support a slow neurotoxic effect over many years of a specific fragment of apoE protein (over-produced by apoE4 substrate compared to apoE3) on mitochondria and the use of rosiglitazone to increase mitochondrial biogenesis and improve glucose utilization. Pharmacogenetics is currently being used across the pipeline to prevent attrition and to create safer and more effective medicines.
TL;DR: The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability and the newly described associations will need to be replicated in other studies.
Abstract: Background
Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations.
TL;DR: The current state of knowledge of the FGF receptor 3 (FGFR3) receptor in urothelial carcinoma (UC) is summarized.
Abstract: Although non-invasive bladder tumours (pTa) are the most common group of bladder tumours at presentation, there has until recently been relatively little information on their molecular biology. Thus it was of great interest when mutations in the FGF receptor 3 (FGFR3) were identified in bladder tumours and it became apparent that these were most common in tumours of low grade and stage. Since the initial description of activating mutations of FGFR3, there have been numerous studies confirming the frequency and spectrum of these mutations in bladder cancers of all grades and stages. Mutation screening techniques have evolved and improved. FGFR3 mutation has been assessed as a predictive biomarker in tumour tissues and as a diagnostic biomarker in urine. Efforts have been made to understand the function of FGFR3 in urothelial and other cells. Although our understanding of FGFR3 function is incomplete, it is already apparent that this may represent an important therapeutic target not only in non-invasive bladder cancer but also in a significant number of invasive tumours. This review summarises the current state of knowledge of this interesting receptor in urothelial carcinoma (UC).
TL;DR: An array-based DASL assay to identify molecular signatures for predicting prostate cancer relapse in formalin-fixed, paraffin-embedded (FFPE) prostate cancers, through gene expression profiling of 512 prioritized genes suggests that the approach used is effective for expression profiling in heterogeneous FFPE tissues for cancer diagnosis/prognosis biomarker discovery and validation.