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.
personalized medicine; early detection; colorectal cancer; lung cancer; breast cancer; prostate cancer
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.
acute myocardial infarction; lipid profile; inflammation; biomarker
To measure levels of the collagen V formation marker CO5-1230 during liver fibrosis progression and regression.
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.
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.
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.
biochemical markers; type V collagen; liver fibrosis; propeptide; reversible carbon tetrachloride
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.
ovarian cancer; familial cancer predisposition; cancer genetics; single nucleotide polymorphism; signaling pathway
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.
colonic neoplasms; inflammation; biomarkers
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.
arsenic; disulfide bond; environmental response genes; functional annotation; hyperpigmentation; iron uptake; keratinocyte; melanocyte; RAC1; SNPs; skin cancer; TFRC; toxicogenomics; vicinal cysteines Isokpehi et al
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.
collagen; extracellular matrix remodeling; biochemical marker; neoepitope; chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; matrix metalloproteinases
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.
serum marker; liver fibrosis; extracellular matrix; neo-epitope
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.
GFAP; GFAP-BDP; traumatic brain injury; human
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.
breast cancer; biomarkers; prognostic biomarker models; treatment response; global gene expression analysis; systems biology
The concept of the cardiovascular continuum, introduced during the early 1990s, created a holistic view of the chain of events connecting cardiovascular-related risk factors with the progressive development of pathological-related tissue remodelling and ultimately, heart failure and death. Understanding of the tissue-specific changes, and new technologies developed over the last 25–30 years, enabled tissue remodelling events to be monitored in vivo and cardiovascular disease to be diagnosed more reliably than before. The tangible product of this evolution was the introduction of a number of biochemical markers such as troponin I and T, which are now commonly used in clinics to measure myocardial damage. However, biomarkers that can detect specific earlier stages of the cardiovascular continuum have yet to be generated and utilised. The majority of the existing markers are useful only in the end stages of the disease where few successful intervention options exist. Since a large number of patients experience a transient underlying developing pathology long before the signs or symptoms of cardiovascular disease become apparent, the requirement for new markers that can describe the early tissue-specific, matrix remodelling process which ultimately leads to disease is evident. This review highlights the importance of relating cardiac biochemical markers with specific time points along the cardiovascular continuum, especially during the early transient phase of pathology progression where none of the existing markers aid diagnosis.
biomarkers; cardiovascular disease; extracellular matrix remodeling; ECMr; diagnostic markers; cardiovascular continuum; biomarker continuum; cardiac matrikine
It has been suggested that soluble urokinase plasminogen activator (suPAR) can be used as a marker of disease severity and risk of mortality in sepsis. The aim with the present study was to compare plasma levels of suPAR in patients with severe sepsis to control subjects and correlate it with the level of inflammatory activation, severity and mortality. Samples were collected from 27 sepsis patients at the intensive care unit (ICU), Lund, Sweden; 90-day mortalities were registered. The suPAR level was significantly elevated in sepsis patients compared to controls, but not significantly higher in nonsurvivors than survivors. Plasma levels of suPAR did correlate weakly with the SOFA score and myeloperoxidase (MPO) but not with CRP, PCT, IL-6 or IL-10 in patients with severe sepsis. The weak correlation between suPAR and other inflammatory markers might suggest that suPAR reflects general activation of the immune system rather than exerting inflammatory actions.
inflammatory markers; sepsis; SIRS; soluble urokinase plasminogen activator receptor; suPAR
Early stages of esophageal cancer lack a specific symptom, a reliable biomarker and accurate non-invasive diagnostic modalities prompting the pressing need for identification of a marker for early diagnosis of this disease.
In the present study we investigated the levels of circulating and tissue mRNAs of Oct-3/4, Sox-2, Nanog and Bmi-1 in esophageal cancer patients using Reverse-Transcription Polymerase Chain Reaction (RT-PCR) with the aim of evaluating their potential as minimally invasive diagnostic markers.
Increased transcript levels of Oct-4, Sox-2, Bmi-1 and Nanog were detected in (92%), (95%), (75%) and (67%) of the esophageal cancer tissues, respectively as compared with the matched distant normals.
Interestingly, most of the preneoplastic tissues exhibited increased transcript levels of these stemness markers suggesting their role in early stages of esophageal tumorigenesis. Furthermore, the detection of elevated levels of circulating mRNAs of Oct-4 and Nanog in sera of esophageal cancer patients emphasizes their potential as minimally invasive diagnostic markers for esophageal cancer.
Oct3/4; Sox-2; Bmi-1; Nanog; pluripotent
To investigate whether serum ischemia-modified albumin or C-reactive protein is reliable for predicting type 2 diabetic patients with ketosis.
One hundred and four diabetic patients, 48 with diabetic ketosis, and 33 controls were enrolled in the study. Serum ischemia-modified albumin and C-reactive protein were measured and evaluated for their ability to distinguish diabetic ketosis.
Compared to the controls, the ischemia-modified albumin and C-reactive protein levels were higher in patients with diabetic ketosis and type 2 diabetes at the baseline. The levels of ischemia-modified albumin were higher in patients with type 2 diabetes than in the controls. C-reactive protein and ischemia-modified albumin levels were reduced after insulin treatment. The level of ischemia-modified albumin was an independent risk marker for diabetic ketosis (OR = 1.085, P = 0.008, 95% CI: 1.022–1.152). Receiver operating characteristic curves revealed that the areas under the curve were 0.917 for the modified albumin and 0.357 for C-reactive protein.
This study indicates that ischemia-modified albumin was significantly associated with diabetic ketosis and was more sensitive than C-reactive protein in reflecting diabetic ketosis.
diabetic ketosis; ischemia-modified albumin; C-reactive protein; biomarker
1p/19q (1p and/or 19q) deletions are prognostic factors in oligodendroglial tumors (OT) and predict better survival after both chemotherapy and radiotherapy. While studying 1p/19q status as a potential variable within multivariate prognosis models for OT, we have frequently encountered unknown 1p/19q status within our glioma sample database due to lack of paired blood samples for loss of heterozygosity (LOH) assay and/or failure to perform fluorescence in situ hybridization (FISH). We realized that a 1p and 19q deletion assay that could be reliably performed solely on tumor DNA samples would allow us to fill in these molecular biology data “holes”. We built recombinant DNA with fragments of the selected “marker” genes in 1p (E2F2, NOTCH2), and 19q (PLAUR) and “reference” genes (ERC2, SPOCK1, and SPAG16 ) and used it as quantification standard in real-time PCR to gain absolute ratios of marker/reference gene copy numbers in tumor DNA samples, thus called comparative quantitative PCR (CQ-PCR). Using CQ-PCR, we identified 1p and/ or 19q deletions in majority of pure low-grade oligodenroglioma (OG) tumors (17/21, 81%), a large portion of anaplastic oligodendroglioma (AO) tumors (6/15, 47%), but rarely found in mixed oligoastrcytomas (OA) tumors (1/8, 13%). These data are consistent with results of LOH and FISH assays generally reported for these tumor types. In addition, 15 out 18 samples showed concordant results between FISH and CQ-PCR. We conclude that CQ-PCR is a potential means to gain 1p/19q deletion information, which prognostic and predictive values of CQ-PCR-derived 1p/19q status will be determined in a future study.
glioma; oligodendroglial tumors; glioblastoma multiforme; 1p19q deletion; real-time comparative quantitative PCR
Using multiplex bead assays to measure urine proteins has a great potential for biomarker discovery, but substances in urine (the matrix) can interfere with assay measurements. By comparing the recovery of urine spiked with known quantities of several common analytes, this study demonstrated that the urine matrix variably interfered with the accurate measurement of low abundance proteins. Dilution of the urine permitted a more accurate measure of these proteins, equivalent to the standard dilution technique when the diluted analytes were above the limits of detection of the assay. Therefore, dilution can be used as an effective technique for over-coming urine matrix effects in urine immunoassays. These results may be applicable to other biological fluids in which matrix components interfere with assay performance.
biomarkers; body fluids urine; analysis/urine; standard addition; assay validation
A previous study based on NHANES 2001–2002 observed that increased levels of urinary perchlorate were associated with increased levels of thyroid stimulating hormone among all women, and with decreased levels of thyroxine among women with low urinary iodine. No associations were observed for men.
Using the same NHANES 2001–2002 data, associations of urinary perchlorate with indirect biomarkers of thyroid hormone disruption were investigated. Decreased levels of hemoglobin (HGB), hematocrit (HCT), and high density lipoprotein (HDL) have been observed among subjects with subclinical hypothyroidism. To investigate the suitability of these indicators for use in observational studies, subjects were divided into six groups: boys, age 6–19; men, age 20–85; girls, age 6–14; non-pregnant women, age 15–49; women, age 50–85; and pregnant women. Use of perchlorate quintiles (Q1-Q5) and continuous log-transformed perchlorate in the regression models allowed investigation of both non-linear and linear associations. Adjustments were made for age, urinary creatinine, race/ethnicity, body mass index, cotinine, poverty index, hours of fasting, thiocyanate, nitrate, daily kcal intake, C-reactive protein. Adjustment for alcohol consumption depended on availability. Adjustment for prescription drugs (beta-blockers, sex hormones, antihyperlipidemic and antidiabetic drugs) was made if it changed the perchlorate estimate by ≥10%.
Statistically significant decreases were observed for HGB and HCT among boys, men, women age 15–49, and pregnant women, and for HDL among men.
Although the mean response biomarkers were within normal range, their association with urinary perchlorate is of interest. HGB and HCT among pregnant women showed a stronger association with urinary perchlorate than non-pregnant women age 15–49. Statistically significant associations were observed for individual perchlorate quintiles. Assumption of linearity of log-transformed perchlorate may result in underestimation of some associations.
perchlorate; biomarkers; endocrine disruption; hypothyroidism; HDL; haemoglobin; hematocrit
To assess plasma zinc and copper concentration in individuals with Asperger’s Syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) and autistic disorder, and to analyze the efficacy of zinc therapy on the normalization of zinc and copper levels and symptom severity in these disorders.
Subjects and methods
Plasma from 79 autistic individuals, 52 individuals with PDD-NOS, 21 individuals with Asperger’s Syndrome (all meeting DSM-IV diagnostic criteria), and 18 age and gender similar neurotypical controls, were tested for plasma zinc and copper using inductively-coupled plasma-mass spectrometry.
Autistic and PDD-NOS individuals had significantly elevated plasma levels of copper. None of the groups (autism, Asperger’s or PDD-NOS) had significantly lower plasma zinc concentrations. Post zinc and B-6 therapy, individuals with autism and PDD-NOS had significantly lower levels of copper, but individuals with Asperger’s did not have significantly lower copper. Individuals with autism, PDD-NOS and Asperger’s all had significantly higher zinc levels. Severity of symptoms decreased in autistic individuals following zinc and B-6 therapy with respect to awareness, receptive language, focus and attention, hyperactivity, tip toeing, eye contact, sound sensitivity, tactile sensitivity and seizures. None of the measured symptoms worsened after therapy. None of the symptoms in the Asperger’s patients improved after therapy.
These results suggest an association between copper and zinc plasma levels and individuals with autism, PDD-NOS and Asperger’s Syndrome. The data also indicates that copper levels normalize (decrease to levels of controls) in individuals with autism and PDD-NOS, but not in individuals with Asperger’s. These same Asperger’s patients do not improve with respect to symptoms after therapy, whereas many symptoms improved in the autism group. This may indicate an association between copper levels and symptom severity.
autism; PDD-NOS; Asperger’s disorder; zinc; copper
The soluble urokinase plasminogen activator receptor (suPAR) has been detected in blood, plasma, serum, urine, ovarian cystic fluid, and cerebrospinal fluid. Elevated suPAR levels in plasma have been associated with negative outcomes in various diseases, such as bacteremia, sepsis, SIRS, cardiovascular disease, cancer, and tuberculosis. The primary aim of this study was to investigate whether suPAR can be detected in saliva from healthy individuals and thus, if saliva suPAR can be related to plasma suPAR, CRP, BMI, or gender. Blood and unstimulated whole saliva was collected from 20 healthy individuals (10 female and 10 male, median age of 28 years; range 21–41). CRP and suPAR were measured with ELISA in saliva and serum/plasma. suPAR was detected in all saliva samples in the 5.2–28.1 ng/mL range, with a median value of 17.1 ng/mL. Saliva suPAR was significantly higher (P < 0.001) but not correlated to plasma suPAR in healthy young adults with normal plasma suPAR levels. suPAR and CRP levels were correlated in blood but not in saliva. No correlation was found between BMI, age, or gender and suPAR in saliva.
plasma suPAR; saliva biomarkers; saliva CRP; saliva suPAR
A pivotal role in guiding mesenchymal stem cell (MSC) differentiation has recently been attributed to the primary cilium. This solitary, non-motile microtubule-based organelle emerging from the cell surface acts as a sensorial membrane structure reflecting developmental and adaptive processes associated with pathologies including human cystic kidney disease, skeletal malformations, obesity and cancer. Given that the intrinsic hypoxic adaptation of MSC remains poorly understood within ischemic tissues or hypoxic tumours, we questioned whether the hypoxia inducible factor-1α (HIF-1α) might be a downstream effector regulating cilium maintenance. We show that murine bone marrow-derived MSC cultured under hypoxic conditions (1.2% O2) lose their primary cilia in a time-dependent manner. Gene silencing of HIF-1α prevented cilia loss in hypoxic cultures, and generation of MSC expressing a constitutively active HIF-1α (MSC-HIF) was found to decrease primary cilium formation. A Wnt pathway-related gene expression array was also performed on MSC-HIF and indicated that the secreted Frizzled-related proteins (sFRP)-1, -3 and -4 were down-regulated, while sFRP-2 was up-regulated. Overexpression of recombinant sFRP-2 or gene silencing of sFRP-1, -3 and -4 in MSC led to primary cilium disruption. These results indicate a molecular signalling mechanism for the hypoxic disruption of the primary cilium in MSC involving an HIF-1α/sFRP axis. This mechanism contributes to our understanding of the adaptive processes possibly involved in the oncogenic transformation and tumour-supporting potential of MSC. Our current observations also open up the possibility for the primary cilia to serve as a biomarker in MSC adaptation to low oxygen tension within (patho)physiological microenvironments.
cilia; hypoxia; mesenchymal stem cells; hypoxia-inducible factor (HIF)
Arterial extracellular matrix (ECM) remodeling by matrix metalloproteinases (MMPs) is one of the major hallmarks of atherosclerosis. Mimecan, also known as osteoglycin has been implicated in the integrity of the ECM. This study assessed the validity of an enzyme-linked immunosorbent assay (ELISA) developed to measure a specific MMP12-derived fragment of mimecan, MMCN-151, in apolipoprotein-E knockout (ApoE-KO) mice.
Methods and results:
A mouse monoclonal antibody raised against MMCN-151 was used to develop a competitive ELISA. The assay was validated using samples from 20 ApoE-KO and 20 wild type [C57 BL/6] male mice fed a normal or high-fat diet (HFD) for up to 20 weeks. The technical reliability of the assay was established with intra-assay variability <2% and inter-assay variability <10%. The lowest limit of quantification of MMCN-151 was 0.5 ng/ml. ApoE-KO mice fed a HFD for 20 weeks had four-fold increased circulating levels of MMCN-151 compared to baseline, whereas MMCN-151 levels in control mice on HFD increased two-fold compared with baseline. After 10 weeks of a HFD, a significant difference in MMCN-151 levels was observed between ApoE-KO and control mice (P = 0.005) and became more significant at 20 weeks (P = 0.002).
The newly developed assay is a reliable detector of MMCN-151 levels which ultimately may be useful indicators of arterial remodeling in patients affected by atherosclerotic disease.
MMCN-151; mimecan; biomarker; atherosclerosis; proteoglycans; extracellular matrix; matrix metalloproteinases
In this prospective study we investigated the role of plasma levels of soluble urokinase plasminogen activator receptor (suPAR) in children with urinary tract infection.
Material and methods:
We measured the levels of plasma suPAR during admission in 42 children with suspected acute pyelonephritis and compared the results to acute DMSA scintigraphy.
The mean level of plasma suPAR at admission was significantly elevated in children with renal involvement (7.3 ng/ml) assessed by the DMSA scintigraphy compared to children without renal involvement (4.4 ng/ml, P = 0.010). The positive predictive value of suPAR seems high, since all patients without renal involvement had low suPAR values. During treatment the mean level of plasma suPAR decreased.
We conclude that plasma suPAR could be of clinical use for the diagnosis of acute pyelonephritis and that high levels of plasma suPAR might reflect the level of renal involvement and could therefore be a new indicator for renal scarring.
biomarker; urinary tract infection; suPAR
A widely held viewpoint in the field of predictive biomarkers for disease holds that no single marker can provide high enough discrimination and that a panel of markers, combined in some type of algorithm, will be needed. Motivated by a recent study where 27 additional markers for ovarian cancer, many of which had good predictive value alone, failed to substantially increase the predictive ability of the primary marker of CA125, we explore the effect of additional markers on the area under the ROC curve (AUC). We develop a statistical model based on the multivariate normal distribution and linear algorithms and use it to explore how the magnitude and direction of statistical correlation among the markers (in diseased and in non-diseased) is critical in determining the added predictive value of additional markers. We show mathematically and empirically that if the additional marker(s) is negatively correlated with the primary marker, then it will always be able to provide increased AUC when combined with the primary marker (as compared to that obtained with the primary marker alone), even if it has little predictive ability on its own. In contrast, if the additional marker(s) is positively correlated with the primary marker, then it is unlikely to substantially increase the AUC when combined with the primary marker, even when it has good predictive ability on its own. Thus, univariate analyses alone may not be the best approach in choosing which markers to combine in a predictive panel of markers; patterns of statistical correlation should be considered in ranking top-performing biomarkers.
correlation; ROC AUC; biomarkers; multivariate normal distribution; linear algorithm
Background and aim:
Mucopolysaccharidosis IVA (MPS IVA) leads to skeletal dysplasia through excessive storage of chondroitin-6-sulfate and keratan sulfate (KS). KS is synthesized mainly in cartilage and released into circulation, making it a critical biomarker for MPS IVA to evaluate clinical course and effectiveness of therapies. Therefore, an accurate and sensitive method is required to measure KS levels.
Material and methods:
Using sandwich ELISA and liquid chromatography tandem mass spectrometry (LC/MS/MS) assays, we measured KS levels in blood and urine from MPS IVA patients and healthy controls to evaluate comparability of results. Blood (patients, n = 110; controls, n = 364) and urine (patients, n = 103; controls, n = 326) specimens were obtained.
Plasma and urine KS measurements in patients were age-dependent and higher than age-matched controls. We observed a moderate correlation (r = 0.666; P < 0.001) between urine KS measurements and a weak correlation (r = 0.333; P = 0.002) between plasma KS measurements by ELISA and LC/MS/MS methods in patients. No correlation was found between plasma KS measurements in controls. The difference between KS measurements assayed by LC/MS/MS and ELISA was greater in controls than in patients. A moderate correlation between blood and urine KS measurements in the same individual was observed.
These findings indicate that both methods to measure blood and urine KS are suitable for diagnosis, monitoring therapies, and longitudinal assessment of the disease course in MPS IVA, but the LC/MS/MS method measures over 10 times more KS present in body fluids.
biomarker; clinical severity; correlation; monitor therapy; MPS IVA; Mucopolysaccharidosis IVA