Beta-2-glycoprotein-1 and alpha-1-antitrypsin as urinary markers of renal cancer in von Hippel–Lindau patients

Context: Von Hippel–Lindau disease (VHLD) is a rare inherited neoplastic syndrome. Among all the VHLD-associated tumors, clear cell renal cell carcinoma (ccRCC) is the major cause of death.

Objective: The aim of this paper is the discovery of new non-invasive biomarker for the monitoring of VHLD patients.

Materials and methods: We compared the urinary proteome of VHLD patients, ccRCC patients and healthy volunteers.

Results: Among all differentially expressed proteins, alpha-1-antitrypsin (A1AT) and APOH (beta-2-glycoprotein-1) are strongly over-abundant only in the urine of VHLD patients with a history of ccRCC.

Discussion and conclusion: A1AT and APOH could be promising non-invasive biomarkers.     

Serum adenosine deaminase,catalase, and carbonic anhydrase activities in patients with renal cell carcinoma

Objectives: To determine whether serum levels of adenosine deaminase (AD), catalase (CAT), and carbonic anhydrase (CA) enzymes may be useful biomarkers in the diagnosis of renal tumors and may lead to early diagnosis of renal tumors.

Material and methods: The study included 33 patients with renal cell carcinoma (RCC) and 31 healthy controls. The activity of serum AD, CA, and CAT was determined and analyzed using the Giusti spectrophotometric method, H₂O₂ substrate, and C0₂ hydration, respectively.

Results: Serum AD and CA activity were significantly higher in patients with RCC than in controls. However, serum CAT activity was significantly lower in patients with RCC than in controls.

Conclusion: These markers might be potentially important as an additional biochemical tool for diagnosing RCC. We believe multidisciplinary studies are needed to plan patients’ preoperative and postoperative treatment and to create follow-up protocols.     

Validation of a protein panel for the noninvasive detection of recurrent non-muscle invasive bladder cancer

Context: About 50–70% of patients with non-muscle invasive bladder cancer (NMIBC) experience relapse of disease.

Objective: To establish a panel of protein biomarkers incorporated in a multiplexed microarray (BCa chip) and a classifier for diagnosing recurrent NMIBC.

Materials and methods: Urine samples from 45 patients were tested. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis.

Results: A multi biomarker panel (ECadh, IL8, MMP9, EN2, VEGF, past recurrences, BCG therapies and stage at diagnosis) was identified yielding an area under the curve of 0.96.

Discussion and conclusion: This biomarker panel represents a potential diagnostic tool for noninvasive diagnosis of recurrent NMIBC.     

Circulating levels of apoptotic markers and oxidative stress parameters in women with polycystic ovary syndrome: a case-controlled descriptive study

Context: Apoptotic dysregulation plays a role in the pathogenesis of polycystic ovary syndrome (PCOS).

Objective: To evaluate circulatory apoptotic markers and oxidative stress in patients with PCOS.

Materials and methods: Forty-four women with PCOS, and 44 healthy women as controls were enrolled in the study. Oxidative stress parameters and caspases levels were measured in serum.

Results: The caspase 9 level was significantly lower and related with oxidant status in patients with PCOS, while the circulating levels of caspases 3 and 7 were statistically similar in both groups.

Discussion: This study is the first report demonstrating the circulating levels of apoptotic markers and their relationship with oxidant status in PCOS.

Conclusion: The circulating caspase 9 and oxidant status might contribute to apoptotic dysregulation in PCOS.     

Differential expression of circulating vascular cell adhesion molecule-1 in subjects with coronary artery disease and cardiac syndrome X without known diabetes mellitus

Context: Inflammation is one of the mechanisms underlying cardiac syndrome X (CSX).

Objectives: Few studies have compared the expression of inflammatory or adhesion molecules between coronary artery disease (CAD) versus CSX.

Materials and methods: Ninety-two CSX and 145 CAD subjects without known diabetes mellitus underwent coronary angiogram for angina.

Results: Vascular cell adhesion molecule (VCAM)-1 (median, 507 versus 431?ng/ml, p?=?0.001) was significantly higher in the CAD group. In the binary regression, VCAM-1 was a significant differential factor for CAD versus CSX.

Discussion and conclusion: Adhesion molecules might be implicated in the differential expression of macro versus microvascular coronary disease.

Trial registration number: NCT01198730 at https://clinicaltrials.gov     

H19 non-coding RNA in urine cells detects urothelial carcinoma: a pilot study

Context: Urothelial carcinoma (UC) is common and highly recurrent. Diagnosis and follow-up involve invasive cystoscopies.

Objective: To evaluate H19 RNA in urine cells as diagnostic tool for UC.

Materials and methods: RT-PCR analysis of urine samples from healthy volunteers and UC patients.

Results: H19 RNA was unequivocally detected in the urine of 90.5% of patients and 25.9% of controls. H19 copies were three orders of magnitude higher in patients. Receiver operating characteristic analysis showed an area under the curve of 0.933.

Conclusions: This pilot study shows that urinary cell H19 is a highly sensitive test for UC and pending verification could transform patient management.     

Matrix metalloproteinase multiplex screening identifies increased MMP-2 urine concentrations in women predicted to develop preeclampsia

Background: Preeclampsia, a pregnancy disorder characterized by hypertension and proteinuria, represents the leading cause of fetal and maternal morbidity and mortality in developing countries. The identification of novel and accurate biomarkers that are predictive of preeclampsia is necessary to improve the prognosis of patients with preeclampsia.

Objective: The objective of this study is to evaluate the usefulness of nine urinary metalloproteinases to predict the risk of preeclampsia development.

Methods: MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12 and MMP-13 were analyzed in urine (early-pregnancy) from 17 women predicted to develop preeclampsia and 48 controls using the Bio-Plex Pro-Human MMP panel (Bio-Rad, Hercules, CA).

Results: Urinary MMP-2 showed differences between groups which allowed us to calculate an increased risk for PE development of up to 20 times among the study population.

Conclusion: Increased urinary concentration of MMP-2 at 12 and 16 weeks of gestation predicted an increased risk of developing preeclampsia in the study population.     

MicroRNAs as possible biomarkers for screening of aortic aneurysms: a systematic review and validation study

Context: There is an urgent need to identify non-invasive biomarkers for the early detection of aortic aneurysms, preceding a fatal event. The potential role for MicroRNAs (miRNAs) as diagnostic markers for aortic aneurysms was investigated through the present systematic review.

Objective: To perform a comprehensive review on published studies examining the association of miRNAs with aortic aneurysms and further validate these results with plasma samples collected from thoracic aortic aneurysm (TAA) patients.

Methods: The literature search was performed via numerous databases and articles were only included if they fulfilled the predefined eligibility criteria. The miRNAs reported three times or more with expression consistency were validated using plasma samples from TAA patients collected before and following surgery.

Results: Twenty-four articles were selected from the literature search and 11 miRNAs were chosen for validation using our samples. The miRNAs which were further validated were found to follow the trend in the regulation pattern as with the majority of the published data. MiRNA hsa-miR-193a-5p was found to be significantly down-regulated in the plasma samples collected before the aneurysmal removal when compared with postsurgical serum samples.

Conclusions: Numerous miRNAs have been associated with aortic aneurysms, and specifically hsa-miR-193a-5p and hsa-miR-30b-5p; therefore they warrant further investigation as potential biomarkers.

Registration: The protocol of the review was registered in Prospero Databases (ID: CRD42016039953)     

Elevated serum YKL-40 levels in patients with Kawasaki disease

Context: YKL-40 is an inflammatory biomarker for endothelial dysfunction that may have a role in Kawasaki disease (KD).

Objectives: We investigated the association of serum YKL-40 levels with KD and established laboratory parameters for YKL-40 levels and other inflammatory markers.

Methods: YKL-40 levels and other inflammatory markers of 23 KD patients, 9 disease control patients and 11 age-matched healthy controls.

Results: YKL-40 concentration in the serum of KD patients significantly increased during the acute disease phase compared with those of disease controls and healthy controls.

Conclusions: Increased YKL-40 levels may provide a useful inflammatory marker for patients with KD.     

Potential of lysophosphatidylinositol as a prognostic indicator of cardiac arrest using a rat model

Aims: The potential of a lysophosphatidylinositol species, LPI(18:0), as a biomarker of ischaemia was tested using a rat model of cardiac arrest (CA).

Methods: Male Sprague-Dawley rats were subjected to asphyxia-induced CA or CA followed by cardiopulmonary bypass (CPB) resuscitation. The brain, heart, kidney and liver tissues were harvested from rats after 0, 5, 10, 20, 30 and 60?min CA and 30?min CA followed by 60?min CPB resuscitation. Blood samples were collected from inferior vena cava and hepatic veins following 30?min CA. Phospholipids were extracted from the four tissues and blood and analysed by HPLC-MS.

Results: The relative content of LPI(18:0) compared to a phosphatidylinositol species, PI(18:0,22:4), was significantly increased in the brain, heart, liver and kidney following 30?min CA and decreased following CPB resuscitation. In addition, the increase of the LPI(18:0)/PI(18:0,22:4) ratio in the four tissues was proportional to the duration of ischaemia for CA lasting up to 60?min. The ratio was also found to be increased in plasma from the hepatic vein following 30?min CA.

Conclusion: LPI(18:0) is a good indicator of CA downtime and has a potential to be used for early prognostication of outcome in CA.     

miR-200b-3p in plasma is a potential diagnostic biomarker in oral squamous cell carcinoma

Context: Circulating MicroRNAs (miRNAs) are emerging as novel biomarkers for tumour.

Objective: Evaluate the diagnostic potential of plasma miR-200b-3p in oral squamous cell carcinoma (OSCC).

Materials and methods: miR-200b-3p was detected by qRT-PCR in paired pre-operative and post-operative plasmas from 80 OSCC patients and 80 healthy controls.

Results: Plasma miR-200b-3p was significantly upregulated in OSCC, and it was higher in WHO II/III grade than WHO I grade. The AUC of miR-200b-3p for OSCC was 0.9173. miR-200b-3p was significantly downregulated after surgery. High miR-200b-3p expression was associated with poor prognosis.

Discussion and conclusion: Plasma miR-200b-3p could be a potential diagnostic biomarker for OSCC.     

The role of urinary KIM-1, NGAL,CA19-9 and β2-microglobulin in the assessment of ureteropelvic junction obstruction in adults

Purpose: The objective of this study is to evaluate the diagnostic properties of urinary biomarkers in adults with ureteropelvic junction obstruction: KIM-1, NGAL, CA19-9, and β2-microglobulin. We also assessed urinary biomarker concentrations following pyeloplasty.

Material and methods: We prospectively studied adults from December 2013 to February 2015. We included 47 patients with a mean age of 38.6?±?12.7 years. Each patient provided four samples of voided urine for biomarker measurement, one at pre-operative consultation and the others at 1, 3, and 6 months of post-operative follow-up. The control group consisted of 40 healthy individuals with no hydronephrosis on ultrasound evaluation.

Results: KIM-1 had an area under the curve of 0.79 (95% CI 0.70–0.89), NGAL 0.71 (95% CI 0.61–0.83), CA19-9 0.70 (95% CI 0.60–0.81), and β2-microgloblin 0.61 (95% CI 0.50–0.73). KIM-1 was the most sensitive marker with a cut-off of 170.4?pg/mg creatinine (sensitivity 91.4%, specificity 59.1%), whereas CA19-9 was the most specific with a cut-off of 51.3?U/mg creatinine (sensitivity 48.9%, specificity 88.0%). Urinary concentrations of biomarkers decreased after pyeloplasty.

Conclusions: The evaluation of urinary biomarkers is useful in adults undergoing pyeloplasty. KIM-1, NGAL, and CA19-9 were elevated and significantly decreased after surgery.     

Sleep-disordered breathing is associated with higher carboxymethyllysine level in elderly women but not elderly men in the cardiovascular health study

Context: Carboxymethyl-lysine (CML) results from oxidative stress and has been linked to cardiovascular disease.

Objective: The objective of this study is to investigate the association between sleep-disordered breathing (SDB) – a source of oxidative stress – and CML.

Materials and methods: About 1002 participants in the Cardiovascular Health Study (CHS) were studied.

Results: Women with SDB had significantly higher CML concentration compared with those without SDB (OR?=?1.63, 95%CI?=?1.03–2.58, p?=?0.04). The association was not significant among men.

Discussion: SDB was associated with CML concentration among elderly women but not men in the Cardiovascular Health Study.

Conclusion: Accumulation of CML may be an adverse health consequence of SDB     

Quantification of 1-hydroxypyrene, 1- and 2-hydroxynaphthalene, 3-hydroxybenzo[a]pyrene and 6-hydroxynitropyrene by HPLC-MS/MS in human urine as exposure biomarkers for environmental and occupational surveys

Context: Several urinary PAHs metabolites can be detected by HPLC-MS/MS for individual exposure assessment.

Objective: Quantitation of urinary metabolites of four PAHs, selected on the basis of their significance, with reduced costs and high sensitivity.

Materials and methods: HPLC-MS/MS was used and pure standards and isotope-labeled internal analogs of the analytes. Two hundred samples were tested after enzymatic hydrolysis.

Results: Accuracy was higher than 90% and variability lower than 19%; LODs permit to measure 1-hydroxypyrene, 1 and 2-hydroxynaphthalene in all subjects, 6-hydroxynitropyrene in the 65% and 3-hydroxybenzo[a]pyrene in the 70%.

Discussion and conclusion: The method is suitable both for occupational and for environmental studies. This is the first paper reporting urinary levels of 6-hydroxynitropyrene in European subjects, nonoccupationally exposed to nitro-PAHs.     

Effect of confounding factors on a phospho-flow assay of ribosomal S6 protein for therapeutic drug monitoring of the mTOR-inhibitor everolimus in heart transplanted patients

Context: Several assays of monitoring immune cell function have been developed to enhance therapeutic drug monitoring.

Objective: An in vitro-validated whole-blood assay of phosphorylated ribosomal protein S6 (pS6RP) was evaluated for confounders to monitor the mTOR-inhibitor everolimus (ERL).

Materials and methods: Whole blood samples from 87 heart transplant recipients were analyzed for pS6RP-expression in CD3-positive T-cells by phospho-flow analysis.

Results: ERL blood concentration, laboratory parameters, co-medications, demographic and clinical data were reviewed.

Conclusion: Evaluating the pS6RP-assay revealed that pS6RP is influenced by cyclosporine A (CsA) blood concentration, duration of ERL treatment, co-medication with thiazide diuretics and different metabolic parameters.     

Association of IL-10 (-819T/C, -592A/C and -1082A/G) and IL-6 -174G/C gene polymorphism and the risk of pneumonia-induced sepsis

Context: Association between inherited variants and the risks of sepsis is controversial.

Objective: To evaluate the risk of pneumonia-induced sepsis by examining its linkage with polymorphisms of IL-6 and IL-10.

Materials and methods: Samples were obtained from 188 pneumonia-induced sepsis patients, 162 pneumonia patients and 200 healthy controls.

Results: Subjects with IL-10 -1082 AA genotypes and IL-6 -174?CC genotype had a higher risk of sepsis and increased mRNA levels.

Conclusion: The variants of IL-10 -1082 A allele and IL-6 -174 C allele contributed to an increased risk of pneumonia-induced sepsis.     

Biomarker discovery for drug-induced phospholipidosis: phenylacetylglycine to hippuric acid ratio in urine and plasma as potential markers

Context: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable.

Objective: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach.

Method: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs.

Results: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation.

Conclusion: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis.     

The relationship of single-strand breaks in DNA to breast cancer risk and to tissue concentrations of oestrogens

Context: Clinical study of breast cancer patients in Chicago, IL, USA.

Objective: Ascertain the utility of measurements of single-strand breaks (SSB) in DNA for assessment of breast cancer risk.

Methods: Fine-needle aspirates of the breast, SSB by nick translation, percent breast density (PBD), Gail model risk, cumulative methylation index (CMI), enzymes of DNA repair and tissue antioxidants.

Results: DNA repair enzymes and 4-hydroxyestradiol were negatively associated with SSB; CMI and PBD were positively associated.

Conclusions: Quantitative measurement of SSBs by this procedure indicates the relative number of SSBs and is related to promoter methylation, antioxidant availability and percent breast density.     

Release kinetics of high-sensitivity cardiac troponins I and T and troponin T upstream open reading frame peptide (TnTuORF) in clinically induced acute myocardial infarction

Context: Troponin T upstream open reading frame peptide (TnTuORF) may be useful as a novel biomarker in acute cardiac syndromes.

Objective: The study examined the early release kinetics of TnTuORF.

Materials and methods: We analyzed the time course of the release of cardiac troponins I and T and TnTuORF in patients (n?=?31) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH).

Results: Fifteen minutes after TASH, the levels of both troponins increased significantly (cTnT median: 18?ng/L versus 27?ng/L; cTnI median: 15?ng/L versus 25?ng/L). TnTuORF showed no variation.

Discussion: We observed a significantly greater increase in cTnI compared with cTnT.

Conclusion: Our results demonstrate that troponin assays allow early detection of myocardial injury, whereas TnTuORF levels remain unchanged in this setting.     

Improved reliability of the urine lactate concentration under controlled hydration after maximal exercise

Context: Urine lactate may be a novel biomarker of lactate production capacity but its reliability has been unsatisfactory so far.

Objective: To compare the reliability of urine lactate between controlled hydration and no hydration after maximal exercise.

Material and methods: Athletes performed swimming exercise four times: two followed by consumption of 1?L of water and two followed by no water intake. Blood and urine lactate was measured.

Results: The reliability of urine lactate was good and similar to that in blood only after controlled hydration. Blood and urine lactate were correlated under both hydration conditions.

Discussion and conclusion: Controlled hydration after exercise provides satisfactory reliability of urine lactate.