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1.  Comment on “Validation of a Blood-Based Laboratory Test to Aid in the Confirmation of a Diagnosis of Schizophrenia” 
Biomarker Insights  2014;9:7.
COMMENT ON
Schwarz et al. Validation of a Blood-Based Laboratory Test to Aid in the Confirmation of a Diagnosis of Schizophrenia. Biomarker Insights. 2010:5 39–47 doi:10.4137/BMI.S4877.
doi:10.4137/BMI.S15196
PMCID: PMC3964184  PMID: 24678240
schizophrenia; biomarker; diagnosis; clinical test
2.  Utility of C-terminal Telopeptide in Evaluating Levothyroxine Replacement Therapy-Induced Bone Loss 
Biomarker Insights  2014;9:1-6.
BACKGROUND
Levothyroxine (LT4) therapy has shown to have effects on bone metabolism though its deleterious effect on bone remodeling is debatable. This study was aimed at assessing the diagnostic utility of the bone remodeling marker C-terminal telopeptide (CTx) in detecting early bone loss.
MATERIALS AND METHODS
In this case–control study, 84 premenopausal women of 30–45 years of age were selected. Out of them, 28 were recently diagnosed of hypothyroidism (not on LT4), 28 were on LT4 replacement therapy (100–200 μg/day) for more than five years, and 28 had euthyroid. Plasma CTx levels were estimated. Bone mineral density (BMD) was measured by quantitative ultrasound (QUS) method. Pearson’s coefficient of correlation and ANOVA were used for statistical analysis.
RESULTS
CTx was most elevated in LT4-treated group (0.497 ± 0.209 ng/mL). It showed a significant negative correlation with T-score and Z-score of BMD values. In the treatment group of more than 150 μg/day, CTx showed significantly negative correlation with TSH (r = −0.462, P = 0.047).
CONCLUSION
LT4 therapy induces bone loss in hypothyroid patients. CTx levels can measure such bone loss along with BMD. Regular monitoring of CTx with adjustment in LT4 doses may help delay osteoporosis induced by prolonged LT4 replacement therapy.
doi:10.4137/BMI.S13965
PMCID: PMC3948734  PMID: 24634578
hypothyroidism; bone loss; C-terminal telopeptide; LT4 - levothyroxine therapy; Bone mineral density; bone remodeling; osteoporosis
3.  Quantification of Plasma miRNAs by Digital PCR for Cancer Diagnosis 
Biomarker Insights  2013;8:127-136.
Analysis of plasma microRNAs (miRNAs) by quantitative polymerase chain reaction (qPCR) provides a potential approach for cancer diagnosis. However, absolutely quantifying low abundant plasma miRNAs is challenging with qPCR. Digital PCR offers a unique means for assessment of nucleic acids presenting at low levels in plasma. This study aimed to evaluate the efficacy of digital PCR for quantification of plasma miRNAs and the potential utility of this technique for cancer diagnosis. We used digital PCR to quantify the copy number of plasma microRNA-21-5p (miR-21–5p) and microRNA-335–3p (miR-335–3p) in 36 lung cancer patients and 38 controls. Digital PCR showed a high degree of linearity and quantitative correlation with miRNAs in a dynamic range from 1 to 10,000 copies/μL of input, with high reproducibility. qPCR exhibited a dynamic range from 100 to 1×107 copies/μL of input. Digital PCR had a higher sensitivity to detect copy number of the miRNAs compared with qPCR. In plasma, digital PCR could detect copy number of both miR-21–5p and miR-335–3p, whereas qPCR was only able to assess miR-21–5p. Quantification of the plasma miRNAs by digital PCR provided 71.8% sensitivity and 80.6% specificity in distinguishing lung cancer patients from cancer-free subjects.
doi:10.4137/BMI.S13154
PMCID: PMC3836484  PMID: 24277982
digital PCR; miRNAs; plasma; diagnosis; lung cancer
4.  Perspectives on the Value of Biomarkers in Acute Cardiac Care and Implications for Strategic Management 
Biomarker Insights  2013;8:115-126.
Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management.
doi:10.4137/BMI.S12703
PMCID: PMC3771707  PMID: 24046510
biomarker; acute cardiac care; point-of-care; management; assays
5.  Decreased Hepatocyte Growth Factor (HGF) and Gamma Aminobutyric Acid (GABA) in Individuals with Obsessive-Compulsive Disorder (OCD) 
Biomarker Insights  2013;8:107-114.
Introduction
There is support for the role of gamma aminobutyric acid (GABA) in the etiology of mood disorders. Recent research has shown that hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility. This study was designed to determine and correlate plasma levels of HGF and GABA as well as symptom severity in individuals with obsessive-compulsive disorder (OCD).
Subjects and methods
Plasma from 15 individuals with OCD (9 males, 6 females;, mean age 38.7 years) and 17 neurotypical controls (10 males, 7 females; mean age 35.2 years) was assessed for HGF, GABA, urokinase plasminogen activator (uPA), and urokinase plasminogen activator receptor (uPAR) concentration using enzyme-linked immunosorbest assays ELISAs. Symptom severity was assessed in these OCD individuals and compared with HGF and GABA concentrations.
Results
In this preliminary study, individuals with OCD had significantly decreased HGF levels, decreased plasma levels of GABA and decreased uPA. We found that both uPA and uPAR levels correlate with HGF. Both low uPA and low uPAR levels correlate with high symptom severity in individuals with OCD. Low GABA levels in OCD individuals also correlate with high symptom severity.
Discussion
These results demonstrate a preliminary association between HGF, GABA, uPA levels, and OCD and suggest that plasma GABA and uPA levels are related to symptom severity in individuals with OCD.
doi:10.4137/BMI.S11931
PMCID: PMC3762604  PMID: 24023510
GABA; HGF; obsessive-compulsive disorder; OCD; uPA; uPAR; symptom severity
6.  Markers that can Reflect Asthmatic Activity before and after Reduction of Inhaled Corticosteroids: A Pilot Study 
Biomarker Insights  2013;8:97-105.
Evaluation of airway inflammation is important in achieving adequate dosing of inhaled corticosteroids (ICS) for treating bronchial asthma. However, there is no evaluation tool that can be used in clinical settings. We examined biomarkers that can precisely reflect airway inflammation when ICS are decreased in stable asthmatic patients. This was a 12-week, single-arm, open-label clinical study performed at a single university hospital. Twenty-five patients (6 male and 19 female) with stable asthma were included in this study. We investigated whether the levels of nitrite and nitrate in exhaled breath condensate (EBC) increase after ICS reduction. We also investigated whether blood eosinophils, serum immunoglobulin E (IgE), high-sensitivity C reactive protein (hs-CRP), interleukin (IL)-13, IL-17, and periostin are different before and after ICS reduction. Peak expiratory flow (PEF), pulmonary function tests, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were also examined. We considered an unscheduled hospital visit due to asthmatic symptoms and decline in average PEF over one week by more than 10% to indicate disease instability, and compared patients with stable and unstable disease for analysis. Unstable status was detected in 5 patients. Age, sex, asthma duration, ACT and AQLQ scores, and the level of serum IgE did not differ between stable and unstable groups. In the unstable group, the total concentration of nitrite and nitrate at the last visit was 9.84 (6.65–11.24) μM. Surprisingly, this was similar to the concentration at the first visit (5.58 (2.94–17.29) μM). Serum periostin before ICS reduction (141.9 [107.7–147.7] pg/mL) was higher in the unstable group than in the stable group (91.5 [78.75–103.5] pg/mL). The unstable group had a higher peripheral blood eosinophil count and wider diurnal variation of PEF at the first visit compared to the stable group. Higher eosinophils in peripheral blood and wider diurnal variation of PEF were predictive markers for unstable disease after ICS reduction. Serum periostin is another candidate for the predictive marker.
doi:10.4137/BMI.S12537
PMCID: PMC3738382  PMID: 23943655
bronchial asthma; inhaled corticosteroid; exhaled breath condensate; nitric oxides; periostin
7.  Identification of Potential Prognostic Markers for Knee Osteoarthritis by Serum Proteomic Analysis 
Biomarker Insights  2013;8:85-95.
Background
As osteoarthritis (OA) is a highly heterogeneous disease in terms of progression, establishment of prognostic biomarkers would be highly beneficial for treatment. The present study was performed to identify novel biomarkers capable of predicting the progression of knee OA.
Methods
A total of 69 plasma samples (OA patients undergoing radiographic progression, n = 25; nonprogression, n = 33; healthy donors, n = 11) were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), and ion peaks of interest were identified by liquid chromatography and matrix-assisted laser desorption/ionization (MALDI)-TOF MS. The identities of these proteins were further validated by immunoprecipitation combined with SELDI-TOF MS analysis.
Results
SELDI-TOF MS analysis indicated that the intensities of 3 ion peaks differed significantly between progressors and nonprogressors. Subsequent analyses indicated that these peaks corresponded to apolipoprotein C-I, C-III, and an N-terminal truncated form of transthyretin, respectively. The identities of these proteins were confirmed by the loss of ion peaks in SELDI-TOF MS spectra by immunoprecipitation using specific antibodies for the respective proteins.
Conclusions
Three potential biomarkers were identified whose serum levels differed significantly between OA progressors and nonprogressors. These biomarkers are expected to be prognostic biomarkers for knee OA and to facilitate the development of novel disease-modifying treatments for OA.
doi:10.4137/BMI.S11966
PMCID: PMC3735238  PMID: 23935359
osteoarthritis; biomarker; proteomics; surface-enhanced laser desorption/ionization (SELDI)
8.  CIINE Reflects Collagenase-Specific CII Breakdown in Cartilage Explant and Whole Body of Canine 
Biomarker Insights  2013;8:77-83.
To evaluate collagenase inhibitors for the treatment of osteoarthritis and to correlate them with clinical pathology, canine cartilage explant and anterior cruciate ligament transection (ACLT) models were examined by quantifying the CII neoepitope (CIINE). This peptide is a putative marker for collagenase-specific type II collagen (CII) degradation, which is a critical step in osteoarthritis pathology.
The concentration of CIINE in supernatants of canine cartilage explants showed increase upon IL-1β—stimulation and collagenase inhibitors suppressed this elevation of CIINE. In the canine ACLT model, levels of CIINE in urine (uCIINE) increased as lesions of knee joint cartilage developed and decreased in response to collagenase inhibitors.
Our results suggest that CIINE reflects collagenase-specific CII degradation in canine explants and whole bodies. It is anticipated that these data will establish a tool for clarifying and bridging the efficacy and mechanism of collagenase inhibitors at the preclinical stage of drug discovery.
doi:10.4137/BMI.S11627
PMCID: PMC3694827  PMID: 23825438
CII neoepitope; collagenase; type II collagen; osteoarthritis; biomarker; matrix metalloproteinase
9.  Correlation Between Hepatocyte Growth Factor (HGF) and Gamma-Aminobutyric Acid (GABA) Plasma Levels in Autistic Children 
Biomarker Insights  2013;8:69-75.
There is much support for the role of Gamma-Aminobutyric acid (GABA) in the etiology of autism. Recent research has shown that hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility. This study was designed to determine and correlate plasma levels of HGF, GABA, as well as symptom severity, in autistic children and neurotypical controls. Plasma from 48 autistic children and 29 neurotypical controls was assessed for HGF and GABA concentration using ELISAs. Symptom severity was assessed in these autistic individuals and compared to HGF and GABA concentrations. We previously reported that autistic children had significantly decreased levels of HGF. In this study, the same autistic children had significantly increased plasma levels of GABA (P = 0.002) and decreased HGF levels correlated with these increased GABA levels (r = 0.3; P = 0.05). High GABA levels correlated with increasing hyperactivity (r = 0.6; P = 0.0007) and impulsivity severity (r = 0.5; P = 0.007), tip toeing severity (r = 0.35; P = 0.03), light sensitivity (r = 0.4; P = 0.02), and tactile sensitivity (r = 0.4; P = 0.01). HGF levels did not correlate significantly with any symptom severity. These results suggest an association between HGF and GABA levels and suggest that plasma GABA levels are related to symptom severity in autistic children.
doi:10.4137/BMI.S11448
PMCID: PMC3694825  PMID: 23825437
GABA; HGF; autism; symptom severity
10.  Biomarkers of Dose and Effect of Inhaled Ozone in Resting versus Exercising Human Subjects: Comparison with Resting Rats 
Biomarker Insights  2013;8:53-67.
To determine the influence of exercise on pulmonary dose of inhaled pollutants, we compared biomarkers of inhaled ozone (O3) dose and toxic effect between exercise levels in humans, and between humans and rats. Resting human subjects were exposed to labeled O3 (18O3, 0.4 ppm, for 2 hours) and alveolar O3 dose measured as the concentration of excess 18O in cells and extracellular material of nasal, bronchial, and bronchoalveolar lavage fluid (BALF). We related O3 dose to effects (changes in BALF protein, LDH, IL-6, and antioxidant substances) measurable in the BALF. A parallel study of resting subjects examined lung function (FEV1) changes following O3. Subjects exposed while resting had 18O concentrations in BALF cells that were 1/5th of those of exercising subjects and directly proportional to the amount of O3 breathed during exposure. Quantitative measures of alveolar O3 dose and toxicity that were observed previously in exercising subjects were greatly reduced or non-observable in O3 exposed resting subjects. Resting rats and resting humans were found to have a similar alveolar O3 dose.
doi:10.4137/BMI.S11102
PMCID: PMC3663491  PMID: 23761957
ozone; inhalation toxicology; exercise; animal human extrapolation
11.  Oxidative Stress and DNA Damage Induced by Chromium in Liver and Kidney of Goldfish, Carassius auratus 
Biomarker Insights  2013;8:43-51.
Chromium (Cr) is an abundant element in the Earth’s crust. It exhibits various oxidation states, from divalent to hexavalent forms. Cr has diverse applications in various industrial processes and inadequate treatment of the industrial effluents leads to the contamination of the surrounding water resources. Hexavalent chromium (Cr (VI)) is the most toxic form, and its toxicity has been associated with oxidative stress. The present study was designed to investigate the toxic potential of Cr (VI) in fish. In this research, we investigated the role of oxidative stress in chromium-induced genotoxicity in the liver and kidney cells of goldfish, Carassius auratus. Goldfish were acclimatized to the laboratory conditions and exposed them to 5% and 10% of 96 hr-LC50 (85.7 mg/L) of aqueous Cr (VI) in a continuous flow through system. Fish were sampled every 7 days for a period of 28 days to analyze the lipid hydroperoxides (LHP) levels and genotoxic potentials in the liver and kidney. LHP levels were analyzed by spectrophotometry while genotoxicity was assessed by single cell gel electrophoresis (comet) assay. LHP levels in the liver increased significantly at week 1, followed by a decrease. LHP levels in the kidney increased significantly at weeks 1, 2, and 3, and decreased at week 4 compared to the control. The percentage of DNA damage increased in both liver and kidney at both test concentrations. The results clearly indicate that Cr (VI) induces significant levels of DNA damage in liver and kidney cells of goldfish. The induced LHP levels in both organs were concentration-dependent and were directly correlated with the levels of DNA damage. The two tested Cr (VI) concentrations induced significant levels of oxidative stress in both organs, however the kidney appears to be more vulnerable and sensitive to Cr-induced toxicity than the liver.
doi:10.4137/BMI.S11456
PMCID: PMC3653851  PMID: 23700361
chromium; goldfish; sub-chronic exposure; oxidative stress; DNA damage
12.  Decreased Epidermal Growth Factor (EGF) Associated with HMGB1 and Increased Hyperactivity in Children with Autism 
Biomarker Insights  2013;8:35-41.
Background
Autism spectrum disorders (ASDs), characterized by impaired social interactions and deficits in verbal and nonverbal communication, are thought to affect 1 in 88 children in the United States. There is much support for the role of growth factors in the etiology of autism. Recent research has shown that epithelial growth factor (EGF) is decreased in young autistic children (2–4 years of age). This study was designed to determine plasma levels of EGF in an older group of autistic children (mean age 10.6 years) and to correlate these EGF levels with putative biomarkers HGF, uPA, uPAR, GAD2, MPO GABA, and HMGB1, as well as symptom severity of 19 different symptoms.
Subjects and methods
Plasma from 38 autistic children, 11 children with pervasive developmental disorder (PDD-NOS) and 40 neurotypical, age and gender similar controls was assessed for EGF concentration using ELISAs. Severity of 19 symptoms (awareness, expressive language, receptive language, (conversational) pragmatic language, focus/attention, hyperactivity, impulsivity, perseveration, fine motor skills, gross motor skills, hypotonia (low muscle tone), tiptoeing, rocking/pacing, stimming, obsessions/fixations, eye contact, sound sensitivity, light sensitivity, and tactile sensitivity) was assessed and then compared to EGF concentrations.
Results
In this study, we found EGF levels in autistic children and those with PDD-NOS to be significantly lower when compared with neurotypical controls. EGF levels correlated with HMGB1 levels but not the other tested putative biomarkers, and EGF correlated negatively with hyperactivity, gross motor skills, and tiptoeing but not other symptoms.
Conclusions
These results suggest an association between decreased plasma EGF levels and selected symptom severity. We also found a strong correlation between plasma EGF and HMGB1, suggesting inflammation is associated with decreased EGF.
doi:10.4137/BMI.S11270
PMCID: PMC3623607  PMID: 23645980
EGF; HMGB1; GABA; autism; PDD; symptom severity
13.  Quantitative Appraisal of Ventricular Cerebrospinal Fluid Biomarkers in Neuropathologically Diagnosed Parkinson’s Disease Cases Lacking Alzheimer’s Disease Pathology 
Biomarker Insights  2013;8:19-28.
Identifying biomarkers that distinguish Parkinson’s disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subjects lacking Alzheimer’s disease (AD) neuropathology. In the present study, we assessed these biomarkers as well as p-tau181, Aβ42, and S100B by ELISA in PD (n = 43) and NC (n = 49) cases. The p-tau181/Aβ42 ratio and ApoA-1 showed statistically significant differences between groups. Multiple regression analysis demonstrated that p-tau181/Aβ42 had a significant odds ratio: OR = 1.42 (95% confidence interval [CI], 1.12–1.84), P = 0.006. Among the molecules investigated, intriguing correlations were observed that require further investigation. Our results suggest coexistent AD CSF biomarkers within the PD group notwithstanding that it was selected to minimize AD neuropathological lesions.
doi:10.4137/BMI.S11422
PMCID: PMC3603385  PMID: 23533154
Parkinson’s disease; biomarkers; ventricular cerebrospinal fluid; apolipoprotein A-1; p-tau181/Aβ42 ratio
14.  A Further Study of the Role of Copper in Regard to the Antimutagenic Action of Sodium Copper Chlorophyllin (SCC) in Somatic Cells of Drosophila melanogaster 
Biomarker Insights  2013;8:29-33.
Previous findings suggest that copper plays a crucial role in the antimutagenic effect of sodium copper chlorophyllin (SCC). The objective of the current research was to compare the antimutagenic effects of two SCC compounds with different amounts of copper (3.7% and 5.4%, respectively) on the genetic damage induced by gamma rays in somatic cells of Drosophila. Data indicate that an increase in copper content of 31.5% in SCC-5.4 resulted in a greater inhibition of gamma ray genetic damage of 49% whereas only a 2% inhibition with SCC-3.7 occurred. Of greater interest is the association of SCC with a variety of uses in humans, such as a chemo preventive agent and food supplement. A greater attention to the concentration of copper in the SCC product in use should be required.
doi:10.4137/BMI.S11081
PMCID: PMC3603386  PMID: 23531495
copper; chlorophyllin; gamma ray mutagenesis; Drosophila; somatic mutation
15.  Urine Biomarkers Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule-1 (KIM-1) Have Different Patterns in Heart Failure Exacerbation 
Biomarker Insights  2013;8:15-18.
Individuals with acute heart failure exacerbation often experience a deterioration in renal function. We sought to determine whether this deterioration is ischemic in nature and detectable by sensitive urine biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). We measured serial biomarker levels and evaluated the associations of these biomarkers with renal recovery in a cohort of hospitalized patients with acute heart failure exacerbation.
doi:10.4137/BMI.S11479
PMCID: PMC3603387  PMID: 23531625
acute kidney injury; urine biomarkers; heart failure
16.  Personalized Medicine in Screening for Malignant Disease: A Review of Methods and Applications 
Biomarker Insights  2013;8:9-14.
Personalized medicine (PM) is currently a hot topic in the professional world. It is often called the medicine of the future and has already achieved resounding success in the area of targeted therapy. Nevertheless, integration of the concepts of PM into routine clinical practice is slow. This review is intended to give an overview of current and potential applications of PM in oncology. PM could soon play a decisive role, especially in screening. The relevance of PM in screening was examined in the case of four common cancers (colorectal cancer, lung cancer, breast cancer, and prostate cancer). A literature search was performed. This showed that biomarkers in particular play a crucial role in screening. In summary, it can be emphasized that there are already numerous known promising biomarkers in malignant disease. This results in several possibilities for individualizing and revolutionizing screening.
doi:10.4137/BMI.S11153
PMCID: PMC3583264  PMID: 23471146
personalized medicine; early detection; colorectal cancer; lung cancer; breast cancer; prostate cancer
17.  Lipid Profile of Patients with Acute Myocardial Infarction and its Correlation with Systemic Inflammation 
Biomarker Insights  2013;8:1-7.
The biomarker potential of using various lipids fractions for predicting risk of acute myocardial infarction (AMI) is controversial. We therefore compared the lipid profiles, including serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL) and triglycerides (TG), in 67 AMI patients. Patients included 28 STEMI (ST-elevated myocardial infarction) patients, 39 NSTEMI (non-ST-elevated myocardial infarction) patients and 25 patients with chest pain. Control group included 54 age- and gender-matched normal subjects. We also studied the correlation between lipid profile and systemic inflammation in these subjects. There were significant decreases in TC, LDL and HDL levels in both STEMI and NSTEMI patients as compared to normal subjects; however, patients with chest pain did not show any significant change in these lipids. Serum TG levels did not differ significantly among the study groups. There were significant increases in serum high-sensitive C-reactive protein (hs-CRP) levels in STEMI and NSTEMI patients, as compared to control group. Serum hs-CRP showed significant inverse correlation with HDL; however, hs-CRP was not correlated with TC, LDL, and TG. In conclusion, our findings suggest that reduction in serum TC does not prevent the risk of AMI, whereas a decrease in serum HDL and increase in hs-CRP strongly predisposes the risky individuals to an AMI event. We emphasize the importance of HDL and CRP measurements for the assessment of a combined lipid-inflammation risk factor that could be a useful predictor of high risk individuals, as well as a prognostic marker in AMI patients.
doi:10.4137/BMI.S11015
PMCID: PMC3561938  PMID: 23400110
acute myocardial infarction; lipid profile; inflammation; biomarker
18.  Circulating Levels of a Collagen Type V Propeptide Fragment in a Carbon Tetrachloride Reversible Model of Liver Fibrosis 
Biomarker Insights  2012;7:159-166.
Aim:
To measure levels of the collagen V formation marker CO5-1230 during liver fibrosis progression and regression.
Methods:
Monoclonal antibodies were raised against the sequence TAALGDIMGH located at the start of the C-terminal propeptide between amino acid position 1230′ and 1239′ (CO5-1230). An assay developed using the biotin-streptavidin system was evaluated in a rat reversible model of fibrosis. Animals were treated for duration of 4, 6 and 8 weeks. Animals that were treated for 8 weeks were left to regress for a period of 14, 20 and 26 weeks.
Results:
Mean CO5-1230 level for control animals was found to be 8.7 ng/mL. CO5-1230 marker levels, at termination points, for CCl4 treated animals was be 8.7 ng/mL at 4 weeks (P < 0.05, ROC: 0.83), 11.4 ng/mL at 6 weeks (P < 0.001, ROC: 0.93) and 10.8 ng/mL at 8 weeks (P < 0.05, ROC: 0.82). During regression phase, marker levels were statistically significantly decreased when compared with the marker levels at 8 weeks of treatment. Marker levels were found to be 5.9 ng/mL (P < 0.001, ROC: 0.8) after 14 weeks of regression, 3.9 ng/mL (P < 0.001, ROC: 0.95) after 20 weeks and 4.5 ng/mL (P < 0.001, ROC: 0.97) after 26 weeks of regression.
Conclusions:
The data indicates that CO5-1230 levels are statistically significantly increased when CCl4 intoxication stimulus is applied in all treatment time points. CO5-1230 levels return back to control levels when the stimulus is removed. The above finding adds to our previous evaluation of the marker and suggests that CO5-1230 may be a promising potential marker for liver fibrosis staging and monitoring in both disease progression and regression.
doi:10.4137/BMI.S10975
PMCID: PMC3572874  PMID: 23440040
biochemical markers; type V collagen; liver fibrosis; propeptide; reversible carbon tetrachloride
19.  Variants in the Signaling Protein TSAd are Associated with Susceptibility to Ovarian Cancer in BRCA1/2 Negative High Risk Families 
Biomarker Insights  2012;7:151-157.
A substantial fraction of familial ovarian cancer cases cannot be attributed to specific genetic factors. The discovery of additional susceptibility genes will permit a more accurate assessment of hereditary cancer risk and allow for monitoring of predisposed women in order to intervene at the earliest possible stage. We focused on a population with elevated familial breast and ovarian cancer risk. In this study, we identified a SNP rs926103 whose minor allele is associated with predisposition to ovarian but not breast cancer in a Caucasian high-risk population without BRCA1/BRCA2 mutations. We have found that the allelic variation of rs926103, which alters amino acid 52 of the encoded protein SH2D2A/TSAd, results in differences in the activity of this protein involved in multiple signal transduction pathways, including regulation of immune response, tumor vascularization, cell growth, and differentiation. Our observation provides a novel candidate genetic biomarker of elevated ovarian cancer risk in members of high-risk families without BRCA1/2 mutations, as well as a potential therapeutic target, TSAd.
doi:10.4137/BMI.S10815
PMCID: PMC3528110  PMID: 23300341
ovarian cancer; familial cancer predisposition; cancer genetics; single nucleotide polymorphism; signaling pathway
20.  Associations of Circulating Inflammatory Biomarkers with Risk Factors for Colorectal Cancer in Colorectal Adenoma Patients 
Biomarker Insights  2012;7:143-150.
Obesity and central adiposity are associated with colorectal cancer risk and have been linked to inflammation. Inflammation is a complex, interactive response that may most accurately be summarized through multiple, simultaneously measured cytokines. In this cross-sectional analysis, we investigated associations of circulating plasma levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1β (IL-1β), and a combined inflammation z score with risk factors for colorectal cancer in colorectal adenoma patients (n = 92). Multivariable logistic regression was used to investigate associations between cytokine levels and known risk factors for colorectal neoplasms. Mean cytokine levels tended to increase with increasing body mass index (BMI), with statistically significant trends in relation to CRP, IL-6, and the combined inflammation z score (P for trend < 0.001, 0.02, and <0.001, respectively). The odds ratios for associations of the inflammation z score with being overweight (BMI 25–29.9 kg/m2), obese (BMI ≥ 30 kg/m2), or having a high waist-to-hip ratio were 4.33 (95% CI [confidence interval], 1.04–18.00), 5.54 (95% CI, 1.37–22.42), and 4.09 (95% CI, 1.67–9.98), respectively. Our findings support (1) associations of inflammation with increased general and central adiposity and (2) investigation of a combined inflammation score as a risk factor for colorectal neoplasms.
doi:10.4137/BMI.S10092
PMCID: PMC3498968  PMID: 23170065
colonic neoplasms; inflammation; biomarkers
21.  Knowledge Building Insights on Biomarkers of Arsenic Toxicity to Keratinocytes and Melanocytes 
Biomarker Insights  2012;7:127-141.
Exposure to inorganic arsenic induces skin cancer and abnormal pigmentation in susceptible humans. High-throughput gene transcription assays such as DNA microarrays allow for the identification of biological pathways affected by arsenic that lead to initiation and progression of skin cancer and abnormal pigmentation. The overall purpose of the reported research was to determine knowledge building insights on biomarker genes for arsenic toxicity to human epidermal cells by integrating a collection of gene lists annotated with biological information. The information sets included toxicogenomics gene-chemical interaction; enzymes encoded in the human genome; enriched biological information associated with genes; environmentally relevant gene sequence variation; and effects of non-synonymous single nucleotide polymorphisms (SNPs) on protein function. Molecular network construction for arsenic upregulated genes TNFSF18 (tumor necrosis factor [ligand] superfamily member 18) and IL1R2 (interleukin 1 Receptor, type 2) revealed subnetwork interconnections to E2F4, an oncogenic transcription factor, predominantly expressed at the onset of keratinocyte differentiation. Visual analytics integration of gene information sources helped identify RAC1, a GTP binding protein, and TFRC, an iron uptake protein as prioritized arsenic-perturbed protein targets for biological processes leading to skin hyperpigmentation. RAC1 regulates the formation of dendrites that transfer melanin from melanocytes to neighboring keratinocytes. Increased melanocyte dendricity is correlated with hyperpigmentation. TFRC is a key determinant of the amount and location of iron in the epidermis. Aberrant TFRC expression could impair cutaneous iron metabolism leading to abnormal pigmentation seen in some humans exposed to arsenicals. The reported findings contribute to insights on how arsenic could impair the function of genes and biological pathways in epidermal cells. Finally, we developed visual analytics resources to facilitate further exploration of the information and knowledge building insights on arsenic toxicity to human epidermal keratinocytes and melanocytes.
doi:10.4137/BMI.S7799
PMCID: PMC3480875  PMID: 23115478
arsenic; disulfide bond; environmental response genes; functional annotation; hyperpigmentation; iron uptake; keratinocyte; melanocyte; RAC1; SNPs; skin cancer; TFRC; toxicogenomics; vicinal cysteines Isokpehi et al
22.  Serological Investigation of the Collagen Degradation Profile of Patients with Chronic Obstructive Pulmonary Disease or Idiopathic Pulmonary Fibrosis 
Biomarker Insights  2012;7:119-126.
In both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), abnormally high collagen remodeling occurs within the lung tissue. Matrix metalloproteinase (MMP)-degraded type I, III, IV, V and VI collagen and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-degraded type III collagen were assessed in serum of patients diagnosed with mild COPD (n = 10) or IPF (n = 30), and healthy controls (n = 15). The collagen degradation markers C1M, C3M, C5M and C6M were significantly elevated in serum of both mild COPD and IPF patients, versus controls. C3A and C4M were only elevated in patients with mild COPD, compared with controls. The most reliable indicators of mild COPD versus controls were: C1M (area under the receiver-operating characteristics (AUROC = 0.94, P < 0.0001), C3M (AUROC = 0.95, P < 0.0001), and C5M (AUROC = 0.95, P < 0.0001). The most reliable markers for the diagnosis of IPF were achieved by C1M (AUROC = 0.90, P < 0.0001) and C3M (AUROC = 0.93, P < 0.0001). Collagen degradation was highly up-regulated in patients with IPF and mild COPD, indicating that degradation fragments of collagens are potential markers of pulmonary diseases. Interestingly, C4M and C3A were only elevated in patients with mild COPD, indicating that these markers could be used to distinguish between the two pathologies.
doi:10.4137/BMI.S9415
PMCID: PMC3448496  PMID: 23012495
collagen; extracellular matrix remodeling; biochemical marker; neoepitope; chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; matrix metalloproteinases
23.  Molecular Serum Markers of Liver Fibrosis 
Biomarker Insights  2012;7:105-117.
Fibrosis is a hallmark histologic event of chronic liver diseases and is characterized by the excessive accumulation and reorganization of the extracellular matrix (ECM). The gold standard for assessment of fibrosis is liver biopsy. As this procedure has various limitations, including risk of patient injury and sampling error, a non-invasive serum marker for liver fibrosis is desirable. The increasing understanding of the pathogenesis of hepatic fibrosis has suggested several markers which could be useful indicators of hepatic fibrogenesis and fibrosis. These markers include serum markers of liver function, ECM synthesis, fibrolytic processes, ECM degradation and fibrogenesis related cytokines. Recently, neo-epitopes, which are post-translational modifications of proteins, have been successfully used in bone and cartilage diseases which are characterized by extensive ECM remodeling. Increasing numbers of studies are being undertaken to identify neo-epitopes generated during liver fibrosis, and which ultimately might be useful for diagnosing and monitoring fibrogenesis. To date, the metalloproteinases generated fragment of collagen I, III, IV and VI have been proven to be elevated in two rat models of fibrosis. This review summarizes the recent efforts that have been made to identify potentially reliable non-invasive serum markers. We used the recently proposed BIPED (Burden of disease, Investigative, Prognostic, Efficacy and Diagnostic) system to characterize potential serum markers and neo-epitope markers that have been identified to date.
doi:10.4137/BMI.S10009
PMCID: PMC3412619  PMID: 22872786
serum marker; liver fibrosis; extracellular matrix; neo-epitope
24.  Characterization of Antibodies that Detect Human GFAP after Traumatic Brain Injury 
Biomarker Insights  2012;7:71-79.
After traumatic brain injury (TBI), glial fibrillary acidic protein (GFAP) and other brain-derived proteins and their breakdown products are released into biofluids such as CSF and blood. Recently, a sandwich ELISA was constructed that measured GFAP concentrations in CSF or serum from human mild-moderate TBI patients. The goals of the present study were to characterize the same two antibodies used in this ELISA, and to determine which GFAP bands are detected by this antibody combination. Here, both antibodies recognized GFAP specifically in human brain and post-TBI CSF in a cluster of bands ranging from 50–38 kDa, that resembled bands from calpain-cleaved GFAP. By immunoprecipitation, the anti-GFAP Capture antibody recovered full length GFAP and its breakdown products from human brain lysate and post-TBI CSF. These findings demonstrate that the anti-GFAP ELISA antibodies non-preferentially detect intact GFAP and GFAP breakdown products, underscoring their utility for detecting brain injury in human patients.
doi:10.4137/BMI.S9873
PMCID: PMC3394595  PMID: 22798722
GFAP; GFAP-BDP; traumatic brain injury; human
25.  Prognosis of Treatment Response (Pathological Complete Response) in Breast Cancer 
Biomarker Insights  2012;7:59-70.
Pertaining to the female population in the USA, breast cancer is the leading cancer in terms of annual incidence rate and, in terms of mortality, the second most lethal cancer. There are currently no biomarkers available that can predict which breast cancer patients will respond to chemotherapy with both sensitivity and specificity > 80%, as mandated by the latest FDA requirements. In this study, we have developed a prognostic biomarker model (complex mathematical function) that—based on global gene expression analysis of tumor tissue collected during biopsy and prior to the commencement of chemotherapy—can identify with a high accuracy those patients with breast cancer (clinical stages I–III) who will respond to the paclitaxel-fluorouracil-doxorubicin-cyclophosphamide chemotherapy and will experience pathological complete response (Responders), as well as those breast cancer patients (clinical stages I–III) who will not do so (Non-Responders). Most importantly, both the application and the accuracy of our breast cancer prognostic biomarker model are independent of the status of the hormone receptors ER, PR, and HER2, as well as of the ethnicity and age of the subjects. We developed our prognostic biomarker model with 50 subjects [10 responders (R) and 40 non-responders (NR)], and we validated it with 43 unknown (new and different) subjects [10 responders (R) and 33 non-responders (NR)]. All 93 subjects were recruited at five different clinical centers around the world. The overall sensitivity and specificity of our prognostic biomarker model were 90.0% and 91.8%, respectively. The nine most significant genes identified, which comprise the input variables to the mathematical function, are involved in regulation of transcription; cell proliferation, invasion, and migration; oncogenesis; suppression of immune response; and drug resistance and cancer recurrence.
doi:10.4137/BMI.S9387
PMCID: PMC3355866  PMID: 22619502
breast cancer; biomarkers; prognostic biomarker models; treatment response; global gene expression analysis; systems biology

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