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Clinica Chimica Acta

Current research reports and chronological list of recent articles..




The international scientific journal Clinica Chimica Acta publishes original Research Communications in the field of clinical chemistry and laboratory medicine, defined as the application of chemistry, biochemistry, immunochemistry, biochemical aspects of hematology, toxicology, and molecular biology to the study of human disease in body fluids, cells or tissues.

The publisher is Elsevier. The copyright and publishing rights of specialized products listed below are in this publishing house. This is also responsible for the content shown.

To search this web page for specific words type "Ctrl" + "F" on your keyboard (Command + "F" on a Mac). Then: type the word you are searching for in the window that pops up!

Additional research articles see Current Chemistry Research Articles. Magazines with similar content (clinical chemistry):

 - Clinical Biochemistry.

 - Clinical Chemistry and Laboratory Medicine.

 - Clinical Chemistry Online.

 - Clinical Science.

 - Clinical Toxicology.

 - Journal of Medicinal Chemistry.

 - Journal of Laboratory Medicine.



Clinica Chimica Acta - Abstracts



Evaluation of potential biomarkers for the diagnosis and monitoring of Systemic Lupus Erythematosus using the Cytometric Beads Array (CBA)

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): L.C.V. Alves, M.G. Carvalho, F.F.C. Nunes, E.A. Reis, G.A. Ferreira, D.C. Calderaro, J.S. Carvalho, P.M. Pádua, W.B. Cicarini, I.M. Gondim, L.F. Ferreira, T.M.P.D. Guimarães, V.P.C.P. Toledo

Abstract
Background

Systemic Lupus Erythematosus (SLE) is an autoimmune, multisystemic disease. Currently diagnosis depends on complex criteria developed by the American College of Rheumatology. Moreover, the lack of specific biomarkers also challenges the diagnosis.

Methods

Inflammatory biomarkers such as IL-8, IP-10, MIG, MIP-1α and RANTES were measured in serum samples from SLE patients and subjects in control groups (patients with other autoimmune diseases and healthy individuals). Forty-six SLE patients (22 patients with low activity, SLEDAI-2 K ≤ 4, 24 patients with moderate/high activity, SLEDAI-2 K > 4), 42 patients with other autoimmune diseases (OAD group), and 8 healthy volunteers participated in this study.

Results

MIG (p < .001) and RANTES (p < .001) concentrations in SLE patients and healthy controls, and IP-10 concentrations in SLE patients with different disease activities (low activity, p < .01, moderate/high activity, p < .05) differed significantly. IL-8 (p < .001) and MIP-1α (p < .001) concentrations in SLE patients differed from those in patients from the OAD group. IL-8 (p < .05), IP-10 (p < .01), MIG (p < .05), MIP-1α (p < .001), and RANTES (p < .05) were correlated with SLE activity; their concentrations in SLE patients with low and moderate/high activity differed significantly.

Conclusions

Given the findings of this study, one can envision the possibility of future use of some of these cytokines to assist in the screening of SLE patients, or even in monitoring disease activity.


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Long noncoding RNA OIP5-AS1 in cancer

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Yuwei Li, Xiao Han, Hong Feng, Junqing Han

Abstract

Long noncoding RNAs (lncRNAs) can be over two hundred nucleotides in length and lack an obvious open reading frame (ORF). Interestingly, these RNAs form a group of nucleic acids involved in a variety of diverse cellular mechanisms involving proliferation, differentiation, apoptosis,and senescence. Given these characteristics, it is not unexpected that the aberrant expression of certain lncRNAs is strongly linked to oncogenesis and tumor advancement. OIP5-AS1, a prominent tumor-associated lncRNA, contributes to intricate cellular mechanisms during the evolution of malignant tumors. For example, it not only represses cyclin G-associated kinase (GAK) expression thus impacting mitosis, but also regulates cell proliferation and apoptosis in many cancers, including lung adenocarcinoma, breast, glioma and hepatoblastoma. In this paper, we review our current understanding of OIP5-AS1 in carcinogenesis and its potential application as a clinical biomarker or therapeutic target in malignancy.


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Estimated glomerular filtration rate using a point of care measure of creatinine in patients with iohexol determinate GFR

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Violeta Stojkovic, Pierre Delanaye, Gregory Collard, Nunzio Ferrante, Caroline Le Goff, Laurence Lutteri, Etienne Cavalier

Abstract
Introduction

Determination of creatinine and estimation of Glomerular Filtration Rate (GFR) rapidly before injection of contrast media provides early detection of high-risk patients for acute kidney failure. Hence, a rapid point-of-care (POC) device (result in 30 s) allowing creatinine measurement and eGFR could be of interest. To validate this method, we considered a population referred for measuring GFR.

Methods

Iohexol plasma clearance was used to measure GFR. For each subject, enzymatic creatinine was quantified with two different devices: in plasma with the Roche Cobas analyzer and in capillary blood with the Nova Biomedical POC device. Both values of creatinine were used in the CKD-EPI equation for estimated glomerular filtration rate (eGFR). eGFR using POC was compared to eGFR using Cobas and to mGFR by Passing Bablok regression, calculation of bias, precision and accuracy (or concordance) within 30%. Also, we calculated the rate of discrepant staging (eGFR >60 or ≤ 60 when mGFR is actually ≤60 and > 60) with both creatinine methods.

Results

120 subjects (52 ± 13 years, 49% of women) were included. Mean mGFR was 77 ± 27 mL/min/1.73m2 with 29 patients presenting mGFR <60 mL/min/1.73m2. Passing- Bablok regression comparing eGFR obtained with the POC and the Cobas was: eGFRPOC = −0.1 (95% CI: −7.4; 3.0) + 1.06 (95% CI: 1.00; 1.15) x eGFRCOBAS. Mean bias was 3.7 ± 14.1 mL/min/1.73m2. Concordance within 30% was 82%. Compared to mGFR, Passing-Bablok with POC was: eGFRPOC = −11.5 (95% CI: −22.9; −0.7) + 1.15 (95% CI: 1.02; 1.29) x mGFR. Mean bias was 0.1 ± 17.6 mL/min/1.73m2. Accuracy within 30% was 81%. Between eGFRCOBAS and mGFR, mean bias was −3.7 ± 12.5 mL/min/1.73m2. Accuracy within 30% was 95%. With POC (and Cobas), 3.3% (0.8%) of patients would have been considered with GFR > 60 mL/min/1.73m2 whereas mGFR it was ≤60 and 10% (9.2%) of them would have been considered with GFR ≤60 mL/min/1.73m2 when mGFR was >60.

Conclusion

Creatinine measured with the POC has an acceptable performance when used with the CKD-EPI equation to estimate GFR. Its ability to detect GFR <60 mL/min/1.73m2 is not significantly different from the classical Roche assay. StatSensor Creatinine (Nova Biomedical) can be used for GFR screening before contrast media injection.


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High fluorescence cell count in pleural fluids for malignant effusion screening

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Jhonatan Wong-Arteta, Eva Gil-Rodríguez, Raquel Cabezon-Vicente, Edurne Bereciartua-Urbieta, Luis Bujanda

Abstract

Malignant pleural effusion (MPE) is mainly secondary to pleural metastasis. Its prevalence is 15 to 35% of all the pleural effusions, and the median of survival oscillates between 4 and 6 months, reason why it is very important to know how to diagnose it. The Sysmex XN-350® is an automated hematological analyzer that allows white blood cell count and differentiation, as well as high fluorescence cells (HFC) which includes macrophages, mesothelial and neoplastic cells.

For MPE screening, the best combinations obtained were HF-BF# ≥ 17/μL and HF-BF# > 10/μL, both in the absence of heart failure and/or low respiratory infection.

The results of this study show that the automated analysis of the pleural fluid with the Sysmex XN-350® analyzer is effective for the screening of the MPE.


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Data mining of reference intervals for coagulation screening tests in adult patients

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Jakob Zierk, Thomas Ganslandt, Manfred Rauh, Markus Metzler, Erwin Strasser

Abstract
Background

Appropriate reference intervals are essential when evaluating laboratory test results. However, establishment of reference intervals is challenging, especially for coagulation screening tests, and uncertainty exists regarding age- and sex-dependency of test results. Data mining of laboratory information systems is an emerging approach to reference interval determination, and we evaluated its applicability to coagulation tests.

Methods

We analyzed measurements of activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR), thrombin time (TT), and fibrinogen performed during clinical care in the University Hospital Erlangen, Germany (1,778,738 samples from 116,754 adult patients, 45,577-509,859 samples per analyte). We identified the proportion of samples from healthy individuals using an established statistical approach (Reference Limit Estimator), in which the distribution of physiological test results is approximated using a parametrical function, and used for the calculation of reference intervals.

Results

We established age- and sex specific reference intervals for aPTT, PT, INR, TT, and fibrinogen, and created batch- and reagent-specific aPTT-reference intervals. Additionally, we evaluated the sensitivity of the established aPTT reference intervals for the detection of factor VIII, IX, XI, XII deficiencies.

Conclusion

Data mining of laboratory test results allows the creation of age- and sex-reference intervals for coagulation tests that are specific to the examined population, analytical framework, and reagent. This approach can complement conventional methods when establishing reference intervals and improve clinical decision-making based on coagulation tests. The reference intervals established in this study show only minor variation with sex and age, supporting the practice of providing a common reference interval for adult women and men.


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Determination of serum tissue kallikrein levels after traumatic brain injury

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Jian-Jun Huang, Shen-Zhong Qiu, Guan-Rong Zheng, Bin Chen, Jia Shen, Huai-Ming Yin, Wei Mao

Abstract
Background

Tissue kallikrein (TK) plays an important role in the kallikrein-kinin system. Its protective role has been demonstrated in traumatic brain injury (TBI). We attempted to determine relationship between serum TK levels and trauma severity in addition to clinical outcome in TBI.

Methods

We recruited 112 patients with severe TBI (Glasgow coma scale score < 9) and 112 controls. We configured 2 multivariate models to assess the relationship between serum TK levels and 30-day death. Its prognostic predictive ability was analyzed under receiver operating characteristic curve.

Results

TK levels were significantly lower in patients than in controls (median 0.148 mg/l, the upper - lower quartiles 0.121–0.185 vs. median 0.258 mg/l, the upper - lower quartiles 0.207–0.342, P < 0.001). TK levels were closely and positively correlated with Glasgow coma scale score (r = 0.550). TK levels <0.148 mg/l independently predicted 30-day mortality with odds ratio value of 4.752 (95% confidence interval (CI), 1.166–19.367) and 30-day overall survival with hazard ratio value of 3.698 (95% CI, 1.026–13.333). TK levels significantly discriminated 30-day mortality with area under curve of 0.822 (95% CI, 0.738–0.887).

Conclusions

Serum TK can represent a potential predictor of clinical outcome in TBI patients.


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Application of IFN-γ/IL-2 FluoroSpot assay for distinguishing active tuberculosis from non-active tuberculosis: A cohort study

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Lifan Zhang, Shijun Wan, Susu Ye, Xinhe Cheng, Yueqiu Zhang, Xiaochun Shi, Baotong Zhou, Xiaochuan Sun, Xiaoqing Liu

Abstract

Currently available Interferon-γ release assay cannot reliably differentiate active TB (ATB) from non-active TB (non-ATB). This study aimed to evaluate the diagnostic accuracy of the IFN-γ/IL-2 FluoroSpot assay, which can simultaneously detect IFN-γ and IL-2 secretion, for differentiating ATB from non-ATB. 191 suspected ATB patients with positive T-SPOT.TB results were consecutively recruited. 64 (33.5%) participants had ATB, including 22 (34.4%) microbiologically or histologically confirmed TB and 42 (65.6%) clinically diagnosed TB. 119 (62.3%) cases were non-ATB and 8 (4.2%) were clinically indeterminate. After being stimulated with ESAT-6 and CFP-10 antigens, the median frequency and proportion of IFN-γ+IL-2 T cells were significantly higher in the ATB group than the non-ATB group (P < .001). The areas under the ROC curves of IFN-γ+IL-2 T cells were larger than those of total IFN-γ+ T cells (0.788 vs. 0.739, p = .323). With a cutoff value of 25 SFCs/250,000 PBMCs for frequency, sensitivity and specificity of this assay were 73.4% and 69.8% respectively. When combining the frequency and proportions of IFN-γ+IL-2 T cells, the sensitivity and specificity were increased to 95.3% in parallel testing and 83.2% in serial testing respectively. In conclusion, IFN-γ/IL-2 FluoroSpot assay is conducive for the diagnosis of ATB in patients with positive T-SPOT.TB results.


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Proteomic approaches in the discovery of potential urinary biomarkers of mucopolysaccharidosis type II

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Xiaozhou Yuan, Yan Meng, Chen Chen, Shuang Liang, Yating Ma, Wencan Jiang, Jinyan Duan, Chengbin Wang

Abstract

Mucopolysaccharindosis type II (MPS II) is a rare lysosomal storage disorder caused by deficient or absent activity of the iduronate-2-sulfatase (IDS) enzyme, which leads to pathological accumulation of the glycosaminoglycans(GAGs). The absence of early diagnosis can result in irreversible developmental, neurological, and physiological damage. The lack of clear understanding of the etiology of physiological dysfunction in MPS II has been a major obstacle to the development of new treatment. Therefore, a reliable biomarker for early diagnosis and exploration of pathogenic mechanism are of great importance. Proteomics provides powerful tool for protein expression alterations and study of complicated pathological process. This study was performed to identify the differential protein profile in urine of MPS II patients using two-dimensional gel electrophoresis(2D-PAGE)combining with MALDI-TOF/TOF and a total of 15 differentially expressed proteins were identified. Content of alpha1-antitrypsin, Gm2 activator and lipocalin-type prostaglandin D synthase was measured by ELISA method. The value of urinary α1-AT/Cr in MPS II group was 0.79 ± 0.10 mg/mmol, significantly higher than 0.42 ± 0.05 mg/mmol in healthy control group; whereas the value of GM2A/Cr and L-PGDS/Cr in MPS II group was 1.30 ± 0.12 μg/mmol and 9.86 ± 1.16 ng/mmol respectively, which was significantly lower than 2.19 ± 0.19 μg/mmol and 13.98 ± 1.48 ng/mmol in healthy control group. The proteins can be considered as accessory diagnostic biomarkers for MPS II. This approach helped to discover early diagnostic markers and provided a better understanding of the pathogenic mechanism of MPS II.


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Determination of 6-thioguanine and 6-methylmercaptopurine in dried blood spots using liquid chromatography-tandem mass spectrometry: Method development, validation and clinical application

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Kristina Lampič, Jurij Trontelj, Helena Prosen, David Drobne, Alenka Šmid, Tomaž Vovk

Abstract
Background

Therapeutic drug monitoring of azathioprine metabolites is required for pharmacotherapy individualisation in patients with inflammatory bowel disease. Currently mainly hemolysates are used, requiring long sample preparation and showing limited analytes stability. Therefore, a quantitative LC-MS/MS method for determination of 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) in dried blood spot samples (DBS) was developed.

Methods

Analysis involves liquid extraction from 30 μL blood spot, hydrolysis and quantification with LC-MS/MS.

Results

Method met the validation criteria in terms of selectivity, linearity, accuracy, and precision in a range from 50 to 5300 pmol/8 × 108 Ery for 6-TG and from 260 to 5300 pmol/8 × 108 Ery for 6-MMP. Range can be increased to 8000 pmol/8 × 108 Ery. No matrix effect was observed and the recovery was >80%. DBS specific validation parameters were confirmed: spot homogeneity, no influence of blood spot volume (>30 μL) on 6 mm DBS disk, and absence of haematocrit effect. DBS samples were stable for at least one month at temperatures from −20 to 40 °C. Clinical validation confirmed that DBS method and routine clinical method with hemolysate samples give comparable results and enable similar clinical decisions.

Conclusions

The newly developed DBS method is simple and presents an alternative to conventional methods for therapeutic drug monitoring of azathioprine metabolites.


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Biomarkers and their relative contributions to identifying coronary artery stenosis based on coronary computed tomography angiography in asymptomatic adults

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): A. Ra Cho, Sang Yeoup Lee

Abstract
Background

Coronary computed tomography angiography (CCTA) has emerged as an important, non-invasive imaging modality for the assessment of coronary vascular disease. However, CCTA as a screening tool still has issues with radiation exposure and cost in asymptomatic adults. In this study, we investigated the relationship between cardio-metabolic biomarkers and coronary artery stenosis on CCTA in asymptomatic, apparently healthy adults.

Methods

Data for this cross-sectional study were obtained from 306 subjects who underwent a comprehensive medical check-up including CCTA. A 128-slice CT device was used to detect earlier stages of coronary stenosis, which was defined as > 25% luminal reduction in the most severe stenosis in the calcified segments of the coronary arteries.

Results

On multivariate analysis, after adjustment for age, only γ-glutamyl transferase (GGT) was significantly and independently associated with CCTA stenosis (OR 1.006, 95% CI 1.001–1.011, P = .026). In a subgroup analysis of 103 subjects with brachial-ankle pulse wave velocity (baPWV) data, baPWV was significantly associated with CCTA stenosis (OR 1.005; 95% CI 1.003–1.008, P < .001).

Conclusions

GGT and baPWV were associated independently with the presence of CCTA stenosis in apparently healthy adults. Further research is needed to re-confirm on these findings.


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Thiamine phosphokinase deficiency and mutation in TPK1 presenting as biotin responsive basal ganglia disease

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): William L. Nyhan, Karen McGowan, Bruce A. Barshop

Abstract

The product of thiamine phosphokinase is the cofactor for many enzymes, including the dehydrogenases of pyruvate, 2-ketoglutarate and branched chain ketoacids. Its deficiency has recently been described in a small number of patients, some of whom had a Leigh syndrome phenotype. The patient who also had a Leigh phenotype was initially found to have a low concentration of biotin in plasma and massive urinary excretion of biotin. Despite treatment with biotin and thiamine, her disease was progressive. Mutations c.311delG and c.426G > C were found in the TPK1 gene.


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Extracellular vesicles in vascular calcification

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Wenling Yang, Bu Zou, Yangfeng Hou, Wei Yan, Tao Chen, Shunlin Qu

Abstract

Vascular calcification is associated with adverse cardiovascular events that increase the risk of cardiovascular death. Unfortunately, the pathogenesis of vascular calcification is complex and incompletely understood. As important intercellular signaling molecules, the role of extracellular vesicles (EVs) in vascular calcification has attracted wide attention in recent years. This review will briefly describe the role of EVs (mainly including exosomes and microvesicles) in the process of vascular wall calcification focusing on the specific mechanisms of smooth muscle cell (SMC) differentiation and calcium-phosphorus balance to illustrate the relationship between EVs and vascular calcification. It is likely that EVs may be prognostic markers in some cardiovascular diseases and have potential therapeutic potential.


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Evaluation of MALDI-TOF MS for the measurement of glycated hemoglobin

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Anping Xu, Yajun Wang, Jie Li, Guiping Liu, Xiaofeng Li, Weidong Chen, Ling Ji

Abstract
Background

Glycated hemoglobin (Hemoglobin A1c, HbA1c) plays a key role in monitoring long-term blood glucose levels in diabetics mellitus. Therefore, it is of great importance to ensure test quality of HbA1c methods.

Objectives

We aimed to evaluate analytical performances of a matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) system for the measurement of HbA1c.

Methods

We assessed the analytical performances of the method including imprecision, accuracy, and linearity. In addition, comparison with Variant II Turbo 2.0 and Capillarys3 TERA, correlation between glycation rate of α and β globin as well as the influence of most frequent analytical interferences in HbA1c assays were also investigated.

Results

As measurement of imprecision, within-run CVs and total CVs were lower than 1.6% and 2.4%, respectively. Discrepancy of test results (<0.2%) of IFCC value-assigned external quality control samples indicated a good accuracy of the method. The linearity was excellent with a correlation coefficient of 0.999. The QuanTOF results were well correlated with those obtained by Variant II Turbo 2.0 and Capillarys3 TERA. Good correlation between glycation rates of α and β globin were found. QuanTOF was not prone to common interferences including bilirubin, triglyceride, labile A1c, and carbamylated hemoglobin. However, unacceptable positive bias was observed when the amount of HbF were greater than approximately 8.0% or in the presence of HbS.

Conclusions

QuanTOF perform well for the determination of HbA1c and meet quality criteria requested for clinical use.


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The presence of S-sulfonated transthyretin in commercial human serum albumin solutions: Potential contribution to neuropathy

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Leonard T. Rael, Raphael Bar-Or, Kaysie L. Banton, Charles W. Mains, Robert M. Madayag, Gary T. Marshall, I.I. Allen Tanner, Michael Waxman, David L. Acuna, David Bar-Or

Abstract
Background

Commercial solutions of human serum albumin (HSA) are administered to critically ill patients for the treatment of shock, restoration of blood volume, and the acute management of burns. Previously, conflicting results on the effects of HSA administration have been reported varying from a favorable increase in total plasma antioxidant capacity to a higher mortality rate in traumatic brain injury (TBI) patients. These results could be partially explained due to the known heterogeneity of HSA solutions. We report the discovery of S-sulfonated human transthyretin (hTTR) in HSA solutions.

Methods

Proteomics was performed on commercially available solutions of 5% HSA by LC-MS analysis. The MS charge envelope for hTTR was deconvolved to the uncharged native hTTR parent mass (13,762 Da). The parent mass was then integrated, and relative proportions of the 2 major species of hTTR, native and S-sulfonated hTTR (13,842 Da), were calculated.

Results

The majority of hTTR found in 5% commercial HSA solutions is in the S-sulfonated form regardless of the age of the HSA solution. S-sulfonation of hTTR at the free cysteine residue in position 10 appears to be the result of a mixed disulfide exchange possibly with S-cysteinylated hTTR or S-cysteinylated HSA. hTTR is a tetramer composed of four identical monomers each containing a reduced cysteine residue in position 10. S-sulfonation of hTTR at this cysteine residue can destabilize the hTTR tetramer, an important step in the formation of TTR-related amyloid fibrils.

Conclusions

Administration of a commercial HSA solution that already contains S-sulfonated hTTR could potentially contribute to the development of amyloid-related/polyneuropathy in the critically ill.


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Chronic kidney disease: Biomarker diagnosis to therapeutic targets

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Yan-Ni Wang, Shi-Xing Ma, Yuan-Yuan Chen, Lin Chen, Bao-Li Liu, Qing-Quan Liu, Ying-Yong Zhao

Abstract

Chronic kidney disease (CKD), characterized as renal dysfunction, is recognized as a major public health problem with high morbidity and mortality worldwide. Unfortunately, there are no obvious clinical symptoms in early stage disease until severe damage has occurred. Further complicating early diagnosis and treatment is the lack of sensitive and specific biomarkers. As such, novel biomarkers are urgently needed. Metabolomics has shown an increasing potential for identifying underlying disease mechanisms, facilitating clinical diagnosis and developing pharmaceutical treatments for CKD. Recent advances in metabolomics revealed that CKD was closely associated with the dysregulation of numerous metabolites, such as amino acids, lipids, nucleotides and glycoses, that might be exploited as potential biomarkers. In this review, we summarize recent metabolomic applications based on animal model studies and in patients with CKD and highlight several biomarkers that may play important roles in diagnosis, intervention and development of new therapeutic strategies.


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The cross-talk between adipokines and miRNAs in health and obesity-mediated diseases

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Ahmad Ghasemi, Seyed Isaac Hashemy, Mohsen Azimi-Nezhad, Alireza Dehghani, Jafar Saeidi, Mahnaz Mohtashami

Abstract
Background

Multiple studies have revealed a direct correlation between obesity and the development of multiple comorbidities, including metabolic diseases, cardiovascular disorders, chronic inflammatory disease, and cancers. However, the molecular mechanism underlying the link between obesity and the progression of these diseases is not completely understood. Adipokines are factors that are secreted by adipocytes and play a key role in whole body homeostasis. Collaboratively, miRNAs are suggested to have key functions in the development of obesity and obesity-related disorders. Based on recently emerging evidence, obesity leads to the dysregulation of both adipokines and obesity-related miRNAs. In the present study, we described the correlations between obesity and its related diseases that are mediated by the mutual regulatory effects of adipokines and miRNAs.

Methods

We reviewed current knowledge of the modulatory effects of adipokines on miRNAs activity and their relevant functions in pathological conditions and vice versa.

Results

Our research reveals the ability of adipokines and miRNAs to control the expression and activity of the other class of molecules, and their effects on obesity-related diseases.

Conclusions

This study may help researchers develop a roadmap for future investigations and provide opportunities to develop new therapeutic and diagnostic methods for treating obesity-related diseases.


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The Warburg effect: A new insight into atrial fibrillation

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Yaozhong Liu, Fan Bai, Na Liu, Feifan Ouyang, Qiming Liu

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. Atrial remodeling, including electrical/structural/autonomic remodeling, plays a vital role in AF pathogenesis. All of these have been shown to contribute continuously to the self-perpetuating nature of AF. The Warburg effect was found to play important roles in tumor and non-tumor disease. Recently, lots of studies documented altered atrial metabolism in AF, but the specific mechanism and the impact of these changes upon AF initiation/progression remain unclear. In this article, we review the metabolic consideration in AF comprehensively and observe the footprints of the Warburg effect. We also summarize the signaling pathway involved in the Warburg effect during AF—HIF-1α and AMPK, and discuss their potential roles in AF maintenance and progression. In conclusion, we give the innovative idea that the Warburg effect exists in AF and promotes the progression of AF. Targeting it may provide new therapies for AF treatment.


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Vortioxetine use may cause false positive immunoassay results for urine methadone

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Sacha Uljon, Yachana Kataria, James G. Flood

Abstract
Background

Urine immunoassays are frequently employed for methadone screening because they are relatively inexpensive and widely available. However, immunoassays are notoriously prone to false positives. We report that the use of vortioxetine (Trintellix® in the USA and Canada, Brintellix® worldwide) could cause false positives in the Roche KIMS Methadone II Urine immunoassay (MDN2).

Methods

We performed a spiking study using a parent drug vortioxetine concentration of 7500 ng/ml.

Results

Urine specimens from seven patients on typical vortioxetine doses tested positive for methadone in the Roche assay but negative for methadone in a confirmatory (GC/MS) assay and two other immunoassay platforms. Because of the pharmacokinetics of vortioxetine and the high cross-reactivity of a metabolite in the MDN2 assay, routine use of the drug could cause false positives even without detectible parent drug in the urine.

Conclusions

Vortioxetine is commonly prescribed for mood disorders, which have high prevalence in patients treated for opioid addiction. For that reason, it is important that clinicians are aware of this interference.


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Association of cerebrospinal fluid kappa free light chains with the intrathecal polyspecific antiviral immune response in multiple sclerosis

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): André Huss, Fatemeh Mojib-Yezdani, Franziska Bachhuber, Tanja Fangerau, Jan Lewerenz, Markus Otto, Hayrettin Tumani, Makbule Senel

Abstract

The polyspecific B-lymphocyte response to neurotropic viruses such as measles (M), rubella (R) and varicella zoster (Z), known as MRZ reaction, is to-date the most specific neurochemical marker for multiple sclerosis (MS). The aim of this study was to investigate a possible association of immunoglobulin (Ig) kappa (κ-) and lambda (λ-) free light chains (FLC) with the presence of the MRZ reaction in multiple sclerosis.

Immunoglobulin κ- and λ-FLC, MRZ reaction, oligoclonal IgG bands (OCB), and cerebrospinal fluid (CSF) routine parameters were measured in 65 MS patients.

OCB were detected in 97% of MS patients, intrathecal IgG synthesis according to Reiber was detectable in 57%, an elevated IgG index (>0.7) in 66% and the MRZR was positive in 45%. All investigated κ-values (CSF κFLC, CSF-serum ratio of κFLCs (QκFLC), and κFLC index (κFLC/QAlbumin)) were significantly higher in patients with positive MRZ reaction as compared to MRZ negative MS patients. In contrast, λ-values showed no significant differences.

Additionally to the putative diagnostic sensitivity and prognostic value of κFLC, the association of κFLC with a highly specific neurochemical marker for MS – the MRZ reaction, especially the determination of κFLCs is an informative tool to assess the B-cell response and determine its extent in MS patients.


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Long-term quality control testing on a high-sensitivity cardiac troponin I assay

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Peter A. Kavsak, Kelsey MacEachern, Eleonora Petryayeva, Lorna Clark


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The future of laboratory medicine: Navigating between technology and professionalism

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Mario Plebani


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Mevalonate kinase deficiency masked by cytomegalovirus infection and obscure liver disease

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Tumelo M. Satekge, Olivia Kiabilua, Alta J. Terblanche, Meshack Bida, Tahir S. Pillay

Abstract
Background

Chronic liver disease with conjugated hyperbilirubinaemia and failure to thrive can have multifactorial aetiologies. Investigations can be complex and difficult especially when obscured by a viral infection affecting liver function.

Methods

A 5 month old male infant was referred for investigation of chronic liver disease and a history of jaundice with multiple febrile episodes. Liver function tests were performed followed by a liver biopsy and microbiological workup for infectious disease. In addition, urine analysis of organic acids was also performed.

Results

There was marked conjugated hyperbilirubinaemia with markedly elevated hepatocellular enzymes and normal ductal enzymes. Proteinuria and near normal renal function suggested early renal impairment. There was also leukocytosis and bicytopenia. An extensive bacteriological investigation including TB workup was negative. CMV infection was confirmed by viral load and antibody reactivity. There was prolonged PT and PTT and high INR.

The liver biopsy showed giant cell transformation of hepatocytes with mild cholestasis, portal and peri-cellular fibrosis with alpha-1-antitrypsin positive granules in the hepatocyte cytoplasm suggesting alpha-1-antitrypsin deficiency. Urine organic acids revealed significantly elevated mevalonolactone.

Conclusions

We confirmed the genetic diagnosis of mevalonic aciduria caused by MVK deficiency which had been masked by liver disease and the possible misdiagnosis of alpha-1-antitrypsin deficiency.


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Melatonin is not stored in platelets

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Martijn van Faassen, Marloes A.M. Peters, Annemiek M. Walenkamp, Elisabeth G.E. de Vries, Sjoukje F. Oosting, Ido P. Kema

Abstract
Background

Melatonin is one of numerous biologically active compounds reported to be stored in platelets. As melatonin is increasingly linked to several diseases, we wanted to confirm the storage of melatonin in platelets using sensitive liquid chromatography in combination with isotope dilution tandem mass spectrometry (LC-MS/MS). The difference between melatonin levels analyzed in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) served as proxy for platelet levels of melatonin.

Methods

Melatonin concentrations were analyzed in PRP and PPP from nineteen healthy volunteers by ELISA and LC-MS/MS. A Wilcoxon signed-rank test was performed to assess if the melatonin levels measured in PRP and PPP were different. Results for melatonin concentrations obtained by LC-MS/MS or ELISA were compared using Passing-Bablok regression.

Results

Comparison of the ELISA with the LC-MS/MS method showed poor agreement for melatonin concentrations in PRP and PPP. No indication was found for storage of melatonin in platelets by either LC-MS/MS or ELISA (P = .89 and P = .53 for the LC-MS/MS and ELISA analysis, respectively).

Conclusion

In this study we could find no evidence for melatonin storage in platelets.


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Screening and mutation analysis of hyperphenylalaninemia in newborns from Xiamen, China

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Xudong Wang, Ying He, Yancheng Jiang, Xiaomei Feng, Guowang Zhang, Zhongmin Xia, Yulin Zhou

Abstract

In this study, we evaluated the incidence and genetic characteristics of hyperphenylalaninemia (HPA) in Xiamen, China. We analyzed the newborn screening data of HPA, obtained using a fluorometric method and tandem mass spectrometry (MS/MS), from 2013 to 2017. The suspected positive samples were further diagnosed using MassArray technology, multiplex ligation-dependent probe amplification (MLPA), and Sanger sequencing. A total of 418,831 newborns were screened, of whom 19 were diagnosed as HPA patients, with an incidence of 1:22,044. Of these HPA patients, 15 tested positive for phenylketonuria (PKU, 1:27922), and 4 tested positive for tetrahydrobiopterin deficiency (BH4D, 1:104,708). A total of 17 mutations were identified among 38 alleles in the 19 patients, with a detection rate of 94.74%, including 13 PAH and 4 PTS mutations. Among these, the c.721C>T, c.728G>A, c.1197A>T, c.611A>G and c.331C>T mutations, and the c.259C>T and c.155A>G mutations were the most prevalent PAH and PTS mutations in Xiamen, respectively. Therefore, this study systematically demonstrated the incidence and mutation spectrum of HPA in Xiamen. This information would contribute to genetic counseling, prenatal diagnosis, and management of HPA patients. Moreover, combining MS/MS technology with molecular genetic diagnosis is an effective strategy for future newborn HPA screening in Xiamen.


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Plasma MicroRNA as a novel diagnostic

Publication date: December 2019

Source: Clinica Chimica Acta, Volume 499

Author(s): Rafal Szelenberger, Michal Kacprzak, Joanna Saluk-Bijak, Marzenna Zielinska, Michal Bijak

Abstract

MicroRNAs (miRNAs) are small, single-stranded, endogenous, non-coding RNAs necessary for proper gene expression. Their mechanism of action controls translation by base-pairing with target messenger RNA (mRNAs) thus leading to translation blockage or mRNA degradation. Many studies have shown that miRNAs play pivotal roles in cancer, cardiovascular disease and neurodegenerative disorders. The lack of blood-derived biomarkers and those markers of poor specificity and sensitivity significantly impact the ability to diagnose in general and at early disease stage specifically. As such, new, non-invasive and quantifiable biomarkers are needed. As post-transcriptional regulators of gene expression, miRNAs have been confirmed to be notably stable in cells, tissues and body fluids. These and other advantages make miRNAs ideal candidates as potential biomarkers and early experimental findings support this finding. This review examines the use of miRNAs as biomarkers in cancer, neurodegenerative, cardiovascular and liver disease and viral infection.


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Evaluation of the automated indirect immunofluorescence test for anti-dsDNA antibodies

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Shiji Wu, Feng Wang, Jin Huang, Botao Yin, Min Huang, Wei Wei, Minxia Zhang, Renren Ouyang

Abstract
Background

Anti-dsDNA antibody is a specific antibody in systemic lupus erythematosus (SLE). Indirect immunofluorescence test (IIFT) is a highly specific method in detecting anti-dsDNA antibody. The application of automated system has gained better consistency than manual operation. This study detected anti-dsDNA antibodies using EUROPattern Computer-aided immunofluorescence microscopy (EPA), and evaluated the performance of the automated system.

Methods

The sera of 96 patients with suspected SLE and 102 control patients were examined using IIFT. The consistency between the EPA and manual reading was analyzed.

Results

Analysis of 198 samples showed that the overall consistency of the negative/positive results between the EPA and manual reading was 94.95%. Based on the manual reading results, the sensitivity and specificity of EPA were 95.70% and 94.29%, respectively. The analysis of 57 samples with non-specific fluorescence showed that the overall consistency of the negative/positive results was 96.49%. The analysis of the antibody titer of 89 positive samples showed that the consistency between the EPA and manual reading was 97.75%.

Conclusion

EPA was consistent with the manual reading with regard to qualitative reading and antibody titer. With low-exposure function, EPA could read samples with non-specific fluorescence. EPA was superior to manual reading in automation and standardization.


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Current status of urinary diagnostic biomarkers for colorectal cancer

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Hiroyasu Iwasaki, Takaya Shimura, Hiromi Kataoka

Abstract

Fecal occult blood test (FOBT) and flexible sigmoidoscopy are the currently using screening methods for colorectal cancer (CRC). However, these methods still have problems of high false positive rates in FOBT and increased invasiveness and cost associated with endoscopy. The development of non-invasive biomarkers is thus important for the diagnosis of CRC. Urine is one of the most commonly used samples for mass screening owing to its non-invasive and simple process of collection; however, the discovery of urinary diagnostic biomarkers for malignancies is still challenging and developing. Since urine contains abundant substances reflecting systemic body condition, urinary biomarker might contribute to detect CRC in a completely non-invasive manner. In this review, we describe the current utility of urinary diagnostic biomarkers for CRC.


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Glycosylation products in prostate diseases

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Priscila Marcelino dos Santos Silva, Priscilla Barbosa Sales Albuquerque, Weslley Felix de Oliveira, Luana Cassandra Breitenbach Barroso Coelho, Maria Tereza dos Santos Correia

Abstract

Although prostate cancer is notable for its high incidence and mortality in men worldwide, its identification remains a challenge. Biomarkers have been useful tools for the specific detection of prostate cancer. Unfortunately, benign prostate diseases cause similar alterations in screening assays thus reducing the potential for early and specific diagnosis. Changes in glycan and glycoprotein expression have often been associated with the onset and progression of cancer. Abnormal glycans and glycoproteins have been reported as new biomarkers of prostate metabolism that can distinguish benign prostate disease and cancer in non-aggressive and aggressive stages. Carbohydrate-binding proteins known as lectins have been valuable tools to detect these changes, investigate potential biomarkers and improve our understanding aberrant glycosylation in cancer. Here we review progress in elucidating prostate disease and discuss the roles of glycans in the differential detection of benign and cancerous prostate disease. We also summarize the lectin-based tools for detecting glycosylation changes.


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Evaluation of algorithm development approaches: Development of biomarker panels for early detection of colorectal lesions

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Susan H. Gawel, Michael Lucht, Heather Gomer, Patrick Treado, Ib J. Christensen, Hans J. Nielsen, Gerard J. Davis, for the Danish Research Group on Early Detection of Colorectal Cancer

Abstract
Introduction

Colorectal cancer (CRC) is the third most common cancer in the U.S. Early detection of CRC can substantially increase survival rates. Test compliance may be improved by offering a blood-based test option.

Methods

Endoscopy II trial specimens were tested for AFP, CA19-9, CEA, hs-CRP, CyFra 21-1, Ferritin, Galectin-3, and TIMP-1 levels. These biomarkers, as well as patient demographic information (e.g., age, gender), were included in algorithm development. Six statistical methods were utilized to develop algorithms that would discriminate cancer vs. noncancers. Statistical methods included logistic regression, adaptive index modeling, partial least-squares discriminant analysis, feature vector (weighted and unweighted), and random forest. The performance of these algorithms was compared against benchmark criteria established for stool-based tests.

Results

Using several statistical methods, the presence of CRC and high-risk adenomas was detected with an AUCs of at least 0.65–0.76, with a few of models approaching the stool-based tests benchmark performance. Further, common markers were utilized across the different statistical techniques, with model complexities ranging from 3 to 9 markers.

Conclusions

Predictive models identified subjects with CRC and high-risk adenomas with the similar levels of statistical accuracy. Clinical performance differences were minimal across the statistical techniques, although the intuitive interpretations, model complexity, clinical adoption and implementation varied.


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Automation of chromatographic peak review and order to result data transfer in a clinical mass spectrometry laboratory

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Faye B. Vicente, David C. Lin, Shannon Haymond

Abstract
Introduction

Mass spectrometry-based assays have increasingly been implemented in clinical laboratories for their multiplexing capacity and high specificity and sensitivity. However, these methods are often associated with labor-intensive and error-prone data-related workflows, due to the volume of data generated that is often manually reviewed and resulted. We aimed to establish a system within our clinical mass spectrometry laboratory to facilitate data ‘flow’ from electronic medical record order to result and to automate processes for chromatogram peak review. The processes and validation are described for a 25-hydroxyvitamin D assay.

Methods

Automating chromatogram review and order to result data transfer required flat file interfacing, file transfers of standardized data formats, barcode scanning, and software for peak processing and review. Validation of the automated workflow involved (1) correlation of quantified results generated by two chromatogram analysis methods: Waters TargetLynx and Indigo Bioautomation ASCENT, (2) manual verification of quality assurance flags applied in ASCENT, and (3) testing data flow and integrity across all the systems from order to result. Efficiency and quality improvements were assessed through calculation of batch review times and rates for autoverification and manual manipulations.

Results

The correlation of TargetLynx and ASCENT quantitation methods for 25-hydroxyvitamin D2 in patient samples yielded slope of 0.99 (95% CI: 0.989 to 0.996), intercept of 0.46 (95% CI: 0.363 to 0.565), with r = 0.999. The correlation for the D3 fraction showed Deming regression slope of 0.98 (95% CI: 0.969 to 0.989), intercept of 0.06 (95% CI: −0.115 to 0.313), and r = 0.995. Results from both quantitation approaches were also compared to the assigned value in CDC reference samples. The mean bias relative to the CDC was 4.6% for ASCENT and 2.5% for TargetLynx. The median time for chromatogram review of a full 96-well plate of vitamin D results is reduced from approximately 2 h to 14 min and 80% of batches were reviewed within 30 min. Instead of 100% peak review, technologists review only the peaks that have been flagged by the system based on applied rules. Analysis of full plate batches showed that 2–20% of peaks per batch were flagged for manual review. Manipulations made by technologists during chromatogram review were reduced by 75% when using the automated versus manual system.

Conclusions

We describe a system to facilitate data ‘flow’ from electronic order to result and to automate chromatogram peak review in a clinical liquid chromatography mass spectrometry assay for 25-hydroxyvitamin D. This eliminated manual result entry, repetitive transcription, and unnecessary review of high quality data while enabling systematic evaluation of data quality indicators. The new processes were accurate, improved the data review and processing times, and helped to reduce manual manipulations during chromatogram review.


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A single-center investigational study of CD36 antigen deficiency and platelet alloantibody distribution in different populations in Northern China as well as platelet alloantibodies effect on pregnancy

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Chunya Ma, Jinhui Wang, Lu Yang, Yannan Feng, Lihui Fu, Xiaozhen Guan, Shufang Wang, Yang Yu, Deqing Wang

Abstract
Background

Platelet antibodies can lead to clinical diseases such as platelet transfusion refractoriness (PTR), fetal/neonatal alloimmune thrombocytopenia (FNAIT), etc. This study is aimed at understanding CD36 expression, platelet alloantibody distribution in different populations in Northern China, and effects of platelet alloantibodies on pregnancy.

Study design and methods

Whole blood samples of 612 subjects including hematological patients, pregnant women, and blood donors were collected at a single center, then CD36 expressions were determined, followed by platelet antibody screening and characterization of platelet antibody specificity. A retrospective analysis was performed in 1552 pregnant women admitted to Department of Obstetrics, in order to investigate FNAIT occurrence.

Results

Rate of CD36 deficiency expression was 2.12% (13/612), all cases exhibited type II deficiency without type I deficiency being detected, and such rate is lower than that in Southern China (3.43%), Japanese (4.87%) and in the black people (4.18%), and higher than that in the White people (0.09%). Positive rates of platelet antibody screening in hematological patient group (6.86%, 14/204) and in pregnant women group (6.31%, 13/206) are higher than that in blood donor group (0.49%, 1/202), P < .01. Out of 1552 pregnant women, there were not children with FNAIT.

Conclusion

The frequency of CD36 deficiency in northern China was low, all of them were type II deficiency, and no CD36 antibody was detected. It is speculated that the risk of immune-related thrombocytopenia caused by CD36 deficiency in this population is very low. Platelet antibodies should be monitored early in patients with hematological and multiple miscarriages pregnant.


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Red blood cell distribution width provides additional prognostic value beyond severity scores in adult critical illness

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Yan-Qiu Han, Li Yan, Lei Zhang, Pei-Heng Ouyang, Peng Li, Hemant Goyal, Zhi-De Hu

Abstract
Background

The prognostic value of red blood cell distribution width (RDW) in critical illness remains controversial. The aim of this study was to investigate the prognostic value of on-admission RDW for in-hospital and 4-year mortality in adults with critical illness.

Methods

This is a retrospective cohort study from the Medical Information Mart for Intensive Care III (MIMIC III) database (version 1.4). Patients admitted to the intensive care unit (ICU) for the first time were included. Their on-admission RDW and severity scores were extracted with the Structured Query Language (SQL). The patients were categorized into a training set and a validation set. The relation of RDW to in-hospital and 4-year all-cause mortality was analyzed using receiver operating characteristic (ROC) curve, Kaplan-Meier curve, Cox model, net reclassification index (NRI), integrated discriminatory index (IDI) and nomogram.

Results

A total of 36,532 patients (21,090 in training and 15,442 in validation set) were included in this study. Increased RDW was significantly associated with higher in-hospital and 4-year mortality. The prognostic value of RDW for 4-year mortality was independent of conventional severity scores. Using conventional severity scores as covariates the continuous NRI and IDI of RDW for in-hospital mortality were around 0.3–0.5 and 0.01–0.03, respectively. For 4-year mortality the NRI was around 0.2–0.3 and IDIs was around 0.03–0.08.

Conclusions

Admission RDW predicts both in-hospital and 4-year mortality in adult patients with critical illness admitted in the ICU, and can provide additional prognostic values beyond conventional clinical severity scores.


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A high-throughput LC-MS/MS method for the quantification of four immunosu- ppressants drugs in whole blood

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Zi-Shan Gong, Zhong-Hao Wu, Shu-Xin Xu, Wen-Nian Han, Xiao-Mei Jiang, Hai-Pei Liu, Yan-Li, Wei-Hu, Yan-Wang

Abstract
Background

Immunoassays and liquid chromatography tandem mass spectrometry (LC-MS/MS) are two major methods for therapeutic drug monitoring (TDM) of immunosuppressant drugs. Compared to the relatively limited analytical performance and cross reactivities of immunoassays, the LC-MS/MS method is considered as a gold standard; however, the lack of systematic evaluation and standardization needs to be addressed.

Methods

A LC-MS/MS method for the determination of cyclosporine A, sirolimus, tacrolimus, and everolimus was developed. One-step protein precipitation was used to prepare blood samples. The newly developed method was systematically evaluated and validated according to the standard guidelines.

Results

The quantitative method for four immunosuppressant drugs in human whole blood was validated according to the guidelines. The lower limits of the measuring interval (LLMI) for cyclosporine A, sirolimus, tacrolimus, and everolimus were 5, 0.5, 0.5, and 0.5 ng/mL, respectively. Linear correlation coefficients were all >0.999. Internal standard-normalized (IS-normalized) matrix correction factor was within the range 0.88–1.17. The average spiked recoveries of five replicates for the four immunosuppressant drugs were in the range 87.4–109.6%.

Conclusion

An LC-MS/MS method combined with one-step protein precipitation was developed, providing short sample preparation and chromatographic run time, thus allowing easy clinical diagnosis.


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Signal-to-cutoff ratios of current anti-HCV assays and a suggestion of new algorithm of supplementary testing

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Jihye Ha, Younhee Park, Hyon-Suk Kim

Abstract
Background

The detection of hepatitis C virus antibody (anti-HCV) is known to have high false-positive rates. Using signal-to-cutoff (S/Co) ratios in reflex supplemental testing, however, could reduce false-positive rates. Here, we analyzed the 2-year data of an anti-HCV assay to understand the significance of the S/Co ratio and make a new algorithm by confirming with a second anti-HCV assay.

Methods

We reviewed 32,573 samples of the Architect assay (Abbott Diagnostics) from a tertiary hospital. Retests with the Elecsys (Roche Diagnostics) and Vitros (Ortho Clinical Diagnostics) assays were performed in 346 anti-HCV-positive samples. HCV RNA PCR and recombinant immunoblot assay (RIBA) were performed in 147 and 11 anti-HCV-positive samples, respectively.

Results

Among 32,573 samples, 446 (1.37%) yielded positive results and 32,127 (98.6%) yielded negative results. Concordance rates in low S/Co samples (0.9–10.0) were 35.2%, 43.8%, and 81.9% for the Architect-Elecsys, Architect-Vitros, and Elecsys-Vitros comparisons, respectively. Correlation coefficients of S/Co ratios were as follows: Architect-Elecsys, 0.20; Architect-Vitros, 0.42; and Elecsys-Vitros, 0.46. In logistic regression, the S/Co value for predicting positivity with 95% probability was 3.13, while that for predicting 50% probability was 8.85. S/Co ratios of 1.70–3.34 showed one reactive antigen out of five antigens, and S/Co ratios of 13.54–17.72 showed three to five positive reactions out of five antigens used in the RIBA.

Conclusions

Supplementary testing of anti-HCV screening results is necessary to distinguish between true positivity and biological false positivity for anti-HCV. In this study, we presented an algorithm of supplementary testing by a retest with a second reagent, which could be useful in clinical laboratories.


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Commutability of proficiency testing material containing amitriptyline and nortriptyline: A study within the framework of the Dutch Calibration 2.000 project

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Karen Robijns, Niels W. Boone, Rob T.P. Jansen, Aldy W.H.M. Kuypers, Cees Neef, Daan J. Touw

Abstract
Background

External quality assessment schemes (EQAS) can provide important information regarding accuracy and comparability of different measurement methods if the sample matrices are composed of commutable material. The aim of this study was to assess the commutability of different matrices for the material used in an EQAS for amitriptyline and nortriptyline.

Methods

Proficiency testing material (PTM) and patient samples containing amitriptyline and nortriptyline were prepared, collected, pooled, and distributed to participating laboratories for analysis. Low, medium and high concentrations of both drugs in liquid pooled human, lyophilized human and lyophilized bovine serum were tested in this study. The measurement deviation of the PTM results to the patient serum regression line were normalized by dividing trough the average within-laboratory SD (SDwl) derived from the results reported in the official EQAS, resulting in a relative residual. The commutability decision limit was set at 3 SDwl.

Results

With 10 laboratories participating in this study, 45 laboratory couples were formed. All matrix types delivered several relative residuals outside the commutability decision limit. The number and the magnitude of relative residuals for both drugs were lower for liquid human sera as compared to lyophilized human and bovine sera.

Conclusions

The PTM used for amitriptyline and nortriptyline is preferably prepared with human serum, although not all relative residuals are within the commutability decision limit.


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E2 ubiquitin-conjugating enzymes in cancer: Implications for immunotherapeutic interventions

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Seyed Mohammad Hosseini, Isobel Okoye, Mitra Ghasemi Chaleshtari, Bita Hazhirkarzar, Javad Mohamadnejad, Gholamreza Azizi, Mohammad Hojjat-Farsangi, Hamed Mohammadi, Siamak Sandoghchian Shotorbani, Farhad Jadidi-Niaragh

Abstract

Despite the medical advances of the 21st century, the incidence of cancer continues to increase and the search for a universal cure remains a major health challenge. Our lack of understanding the complex pathophysiology of the tumor microenvironment has hindered the development and efficiency of anti-cancer therapeutic strategies. The tumor microenvironment, composed of multiple cellular and non-cellular components, enables tumor-promoting processes such as proliferation, angiogenesis, migration and invasion, metastasis, and drug resistance. The ubiquitin-mediated degradation system is involved in several physiologic processes including cell cycling, signal transduction, receptor downregulation, endocytosis and transcriptional regulation. Ubiquitination includes attachment of ubiquitin to target proteins via E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. Several studies have shown that E2 enzymes are dysregulated in variety of cancers. Multiple investigations have demonstrated the involvement of E2s in various tumor-promoting processes including DNA repair, cell cycle progression, apoptosis and oncogenic signaling. E2 enzymes consist of 40 members that facilitate ubiquitin-substrate conjugation thereby modulating the stability and interaction of various proteins. As such, E2s are potential biomarkers as diagnostic, prognostic and therapeutic tools. In this review, we discuss the role of E2s in modulating various types of cancer.


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Executive summary of the Japan Osteoporosis Society Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition)

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Yoshiki Nishizawa, Masakazu Miura, Shoichi Ichimura, Masaaki Inaba, Yasuo Imanishi, Masataka Shiraki, Junichi Takada, Osamu Chaki, Hiroshi Hagino, Masao Fukunaga, Saeko Fujiwara, Takami Miki, Noriko Yoshimura, Hiroaki Ohta, from the Japan Osteoporosis Society Bone Turnover Marker Investigation Committee

Abstract

With the aging of society, the number of osteoporosis-related fractures is increasing. Prevention of osteoporosis and maintenance of the quality of life of osteoporosis patients require early diagnosis, effective treatment, and highly precise treatment monitoring. Although bone biopsy is clinically one of the essential techniques for diagnosis of osteoporosis, it is invasive and difficult to perform in general clinical practice. Bone mineral density measurement is another essential technique available in clinical practice that provides good precision. However, it is not effective for determining the appropriate treatment options or evaluating short-term treatment efficacy. On the other hand, bone turnover markers (BTMs) have gained attention because they provide information that is valuable for both the selection of treatment and short-term monitoring.

BTMs are now positioned to become a tool for clinically assessing bone turnover outcomes. Since the Japan Osteoporosis Society issued its Guidelines for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis in 2012, new drugs, drug formulations, and combination drug therapies have been approved; therefore, we updated the 2012 guidelines in the Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition).


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Heat shock proteins in infection

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Azam Bolhassani, Elnaz Agi

Abstract

Heat shock proteins (HSPs) are constitutively expressed under physiological conditions in most organisms but their expression can significantly enhance in response to four types of stimuli including physical (e.g., radiation or heat shock), chemical and microbial (e.g., pathogenic bacteria, viruses, parasites and fungi) stimuli, and also dietary. These proteins were identified for their role in protecting cells from high temperature and other forms of stress. HSPs control physiological activities or virulence through interaction with various regulators of cellular signaling pathways. Several roles were determined for HSPs in the immune system including intracellular roles (e.g., antigen presentation and expression of innate receptors) as well as extracellular roles (e.g., tumor immunosurveillance and autoimmunity). It was observed that exogenously administered HSPs induced various immune responses in immunotherapy of cancer, infectious diseases, and autoimmunity. Moreover, virus interaction with HSPs as molecular chaperones showed important roles in regulating viral infections including cell entry and nuclear import, viral replication and gene expression, folding/assembly of viral protein, apoptosis regulation, and host immunity. Viruses could regulate host HSPs at different levels such as transcription, translation, post-translational modification and cellular localization. In this review, we attempt to overview the roles of HSPs in a variety of infectious diseases.


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Plasma metabolites Xanthine, 4-Pyridoxate, and <span class="small-caps">d</span>-glutamic acid as novel potential biomarkers for pulmonary tuberculosis

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Huai Huang, Li-Ying Shi, Li-Liang Wei, Yu-Shuai Han, Wen-Jing Yi, Zhi-Wen Pan, Ting-Ting Jiang, Jing Chen, Hui-Hui Tu, Zhi-Bin Li, Yu-Ting Hu, Ji-Cheng Li

Abstract
Background

The lack of rapid and efficient diagnostic methods has been one of the most frustrating challenges in controlling the pulmonary tuberculosis (TB) epidemic. This study was aimed to identify novel non-invasive biomarkers for pulmonary TB.

Methods

The subjects in this study were divided into four groups: the pulmonary TB group, the community-acquired pneumonia (CAP) group, the lung cancer (LC) group, and the normal control (NC) group. Plasma small molecule metabolites were investigated in each group by using ultra-high performance liquid chromatography coupled with Q Exactive mass spectrometry. Multivariate statistical methods and bioinformatics were used to analyze the data.

Results

We identified three differential plasma metabolites such as, Xanthine, 4-Pyridoxate and d-glutamic acid in the pulmonary TB group, compared to the other groups (CAP, LC and NC). The pathway enrichment analysis indicated that the energy source in pulmonary TB was multi-center, which might be involved in maintaining the reproductive ability and virulence of Mycobacterium tuberculosis.

Conclusion

The results suggested that Xanthine, 4-Pyridoxate, and d-glutamic acid may serve as potential biomarkers for pulmonary TB. The present study provides experimental basis for developing potential biomarkers of pulmonary TB.


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Eight novel mutations detected from eight Chinese patients with isovaleric acidemia

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Yanhan Li, Ming Shen, Ying Jin, Yi Liu, Lulu Kang, Ruxuan He, Jinqing Song, Leiming Luo, Yanling Yang

Abstract
Background

Isovaleric acidemia (IVA), a rare autosomal recessive disorder in leucine metabolism caused by defected IVD gene, is characterized by episodes of acute metabolic crisis and psychomotor development retardation. This study aimed to determine the clinical, biochemical, and mutation spectrum of patients with IVA from mainland China.

Methods

Eight patients (three boys and five girls) from eight unrelated families were collected, IVD gene mutations and phenotypes were examined.

Results

The patients were admitted because of vomiting, feeding difficulty, psychomotor retardation and “dirty sock” odor. Elevated blood isovaleryl (C5)-carnitine and urine isovalerylglycine were detected from all our patients. Fourteen mutations of the IVD gene were detected, eight of them are novel, c.145C>T (p.Q49Ter), c.359G>A (p.R120Q), c.424C>T (p.R142C), c.458T>C (p.L153P), c.466-1G>T, c.676_677insA (p.T226Nfs*13), c.1039G>A (p.A347T) and c.1076A>G (p.D359G). With this study, a total of 34 alleles were studied in the Chinese population. c.1208A>G (p.Y403C), the common mutation in Taiwan, accounts for 9/34 alleles (7 in previous reports and 2 in this study).

Conclusions

We described eight novel mutations detected from eight unrelated Chinese patients and provided evidence to support that the p.Y403C is the hotspot mutation in this population.


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Biochemical diagnostics of pancreatic cancer - Present and future

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Wojciech Jelski, Barbara Mroczko

Abstract

Pancreatic cancer is one of the deadliest cancers having an exceptionally high mortality rate. Despite a relatively low incidence (10th among cancers), it is the fourth leading cause of cancer-related deaths in most developed countries. Improving early diagnosis of pancreatic cancer and strengthening the standardised comprehensive treatment remain the main focus of pancreatic cancer research. Tumor markers are usually tumor-associated proteins of clinical relevance in these patients. Although tumor markers carbohydrate antigen (CA 19–9) and carcino-embryonic antigen (CEA) are commonly used, neither demonstrate high diagnostic accuracy. Recently, hematopoietic growth factors (HGFs) and various enzymes have been reported as potential biomarkers for pancreatic cancer. These include macrophage-colony stimulating factor (M-CSF) and granulocyte-colony stimulating factor (G-CSF), interleukin-3 (IL-3), macrophage inhibitory cytokine (MIC-1) and various enzymes (alcohol dehydrogenase, aldehyde dehydrogenase, lysosomal exoglycosidases). With the development of molecular technology, detecting K-ras mutation in serum via polymerase chain reaction (PCR) is becoming more common and efficient. Because K-ras mutation rates are high in many cancers, some regard it as a potential tumor marker. Others have shown the value of serum miRNAs in detection of pancreatic cancer. Unfortunately, there are currently no effective methods of sufficient diagnostic accuracy to detect early-stage surgically resectable pancreatic cancer. In this article we highlight these biomarkers and summarise recent developments in the diagnosis and treatment of pancreatic cancer.


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Proteogenomics: From next-generation sequencing (NGS) and mass spectrometry-based proteomics to precision medicine

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Mia Yang Ang, Teck Yew Low, Pey Yee Lee, Wan Fahmi Wan Mohamad Nazarie, Victor Guryev, Rahman Jamal

Abstract

One of the best-established area within multi-omics is proteogenomics, whereby the underpinning technologies are next-generation sequencing (NGS) and mass spectrometry (MS). Proteogenomics has contributed significantly to genome (re)-annotation, whereby novel coding sequences (CDS) are identified and confirmed. By incorporating in-silico translated genome variants in protein database, single amino acid variants (SAAV) and splice proteoforms can be identified and quantified at peptide level. The application of proteogenomics in cancer research potentially enables the identification of patient-specific proteoforms, as well as the association of the efficacy or resistance of cancer therapy to different mutations. Here, we discuss how NGS/TGS data are analyzed and incorporated into the proteogenomic framework. These sequence data mainly originate from whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-Seq. We explain two major strategies for sequence analysis i.e., de novo assembly and reads mapping, followed by construction of customized protein databases using such data. Besides, we also elaborate on the procedures of spectrum to peptide sequence matching in proteogenomics, and the relationship between database size on the false discovery rate (FDR). Finally, we discuss the latest development in proteogenomics-assisted precision oncology and also challenges and opportunities in proteogenomics research.


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Fibroblast growth factor 21 in lipid metabolism and non-alcoholic fatty liver disease

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Xin Su, Yi Kong, Daoquan Peng

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in several developed countries, ranging from simple non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. Currently, NAFLD has been confirmed to be associated with dyslipidemia, insulin resistance, and pre-diabetes, which are always grouped together as metabolic syndrome. Fibroblast growth factor 21 (FGF21) plays an important role in liver pathophysiology with multiple metabolic functions. Accumulating evidence has shown that FGF21 could directly modulate lipid metabolism and reduce lipid accumulation in hepatocytes through an insulin-independent pathway, thus suppressing the pathogenesis of NAFLD. Furthermore, treatment with FGF21 could obviously reverse NAFLD and synergistically alleviate obesity and counteract insulin resistance. In this review, we summarize the current knowledge of FGF21 and the evidence of FGF21 as an important regulator in hepatic lipid metabolism. The mechanisms by which FGF21 affects the pathogenesis of NAFLD would also be proposed for the further understanding of FGF21.


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eGFR, cystatin C and creatinine in shrunken pore syndrome

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

Author(s): Hua Zhou, Min Yang, Xiaozhou He, Ning Xu

Abstract

Shrunken pore syndrome (SPS) is a condition in which the estimated glomerular filtration rate (eGFR) based on serum/plasma cystatin C concentration is significantly lower than the eGFR based on creatinine. According to the literatures, the diagnosis of SPS could be defined when the eGFRcystatin C is <70% of eGFRcreatinine. Although the incidence of SPS varies in different patient populations and healthy seniors, it has been demonstrated that patients with SPS have poor prognosis. The present review has summarized its diagnosis, epidemiology, prognosis and possible pathophysiology basis. Moreover, we discuss the prevention and treatment of SPS in clinical practice as future challenges.


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Editorial board member, Aims and Scope, Publication Info.

Publication date: November 2019

Source: Clinica Chimica Acta, Volume 498

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Circulating ectodysplasin A is a potential biomarker for nonalcoholic fatty liver disease

Publication date: Available online 14 September 2019

Source: Clinica Chimica Acta

Author(s): Ji Yang, Wenjing Zhou, Jinzhou Zhu, Yue Wu, Liqian Xu, Yuming Wang, Qin Zhang, Yunmei Yang

Abstract
Background

Ectodysplasin A (EDA), a new hepatokine, may be involved in energy metabolism. This study aims to 1) investigate the role of EDA in hepatic steatosis in C57BL/6 mice and HepG2 cells; 2) evaluate serum EDA in nonalcoholic fatty liver disease (NAFLD) in human.

Methods

This study comprises an experimental study in vitro and in vivo and a hospital based case-control study. Western blotting, qPCR and ELISA were used to measure EDA levels. siRNA and shRNA were performed to knockdown EDA. An Adipokine Magnetic Bead Panel was performed to measure serum adipokines.

Results

Increased levels of hepatic and secreted EDA were detected in steatosis, in vivo and in vitro. Steatosis was ameliorated by EDA knockdown in vitro, while intrahepatic triglycerides content and liver enzymes were improved in vivo. Furthermore, knockdown of EDA upregulated lipolytic genes and suppressed lipogenic genes. Serum EDA in subjects with NAFLD was higher. Moreover, it reveals associations between circulating EDA and higher odds of NAFLD, while circulating EDA presented a practicable performance to identify NAFLD. Lastly, serum EDA level was dependent on BMI, TNF-α, T2DM and obesity.

Conclusions

EDA aggravates steatosis by striking balance between lipid deposition and elimination. It was a potential biomarker of NAFLD.


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Role of apelin/APJ system in hypothalamic-pituitary axis

Publication date: Available online 13 September 2019

Source: Clinica Chimica Acta

Author(s): Na Yang, Tianping Li, Jun Cheng, Qinhui Tuo, Jian Shen

Abstract

Apelin and its G protein-coupled receptor APJ are specifically expressed in endocrine organs.

As well known, the hypothalamus is the regulatory center of endocrine activity, which combined with the pituitary and other gonads form regulatory axes involved in endocrine function. Evidence to date has shown that the apelin/APJ system plays an important role in mediating these axes, such as food intake, acute stress, steroid release, as well as, an anti-depressant-like activity. Here we review the effect of the apelin/APJ system on hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. Although the apelinergic system exerts a positive effect on these axes, there are contradictory reports on the role of apelin in endocrine disease caused by hypothalamic-pituitary disorders. Thus, as research continues to evolve we expect that apelin-related drugs can be used as a treatment for clinical diseases resulting from hypothalamic-pituitary dysfunction.


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Sex hormone-binding globulin and polycystic ovary syndrome

Publication date: Available online 13 September 2019

Source: Clinica Chimica Acta

Author(s): Jing-ling Zhu, Zhuo Chen, Wen-jie Feng, Shuang-lian Long, Zhong-Cheng Mo

Abstract

Polycystic ovary syndrome (PCOS), one of the most common endocrine diseases that causes infertility in reproductive women, is characterized by hyperandrogenemia, chronic anovulation, and polycystic ovary morphology (PCOM), and most women with PCOS have metabolic abnormalities. A reduction in plasma sex hormone-binding globulin (SHBG), a transport carrier that binds estrogen and androgens and regulates their biological activities, is often used as an indicator of hyperandrogenism in women with PCOS. Low serum SHBG levels are considered a biomarker of abnormal metabolism and are related to insulin resistance (IR), compensatory hyperinsulinemia and abnormalities in glucose and lipid metabolism in PCOS patients. SHBG is also associated with the long-term prognosis of PCOS. SHBG gene polymorphism is correlated with the risk of PCOS. As SHBG plays a vital role in the occurrence and development of PCOS, knowledge regarding its role in PCOS is helpful for further understanding the molecular mechanism of SHBG in PCOS development and providing new ideas for the treatment of female infertility. Hepatocyte nuclear factor-4α (HNF-4α) is a vital transcription factor in the SHBG synthesis process. HNF-4α binds to the cis-type element DR1 in the SHBG promoter to initiate transcription and regulates hepatic SHBG levels by modulating glucose and lipid metabolism and inflammatory factors. However, it remains unclear whether HNF-4α is indirectly involved in the pathogenesis of PCOS via regulation of hepatic SHBG synthesis. Therefore, this review discusses the interaction between SHBG and the various complications of PCOS as well as the regulatory effect of HNF-4α on SHBG expression.


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A cross-reactive monoclonal antibody as universal detection antibody in autoantibody diagnostic assays

Publication date: Available online 4 September 2019

Source: Clinica Chimica Acta

Author(s): Steffi Lütkecosmann, Thomas Faupel, Silvia Porstmann, Tomas Porstmann, Burkhard Micheel, Katja Hanack

Abstract

Diagnostics of Autoimmune Diseases involve screening of patient samples for containing autoantibodies against various antigens. To ensure quality of diagnostic assays a calibrator is needed in each assay system. Different calibrators as recombinant human monoclonal antibodies as well as chimeric antibodies against the autoantigens of interest are described. A less cost-intensive and also more representative possibility covering different targets on the antigens is the utilization of polyclonal sera from other species. Nevertheless, the detection of human autoantibodies as well as the calibration reagent containing antibodies from other species in one assay constitutes a challenge in terms of assay calibration. We therefore developed a cross-reactive monoclonal antibody which binds human as well as rabbit sera with similar affinities in the nanomolar range. We tested our monoclonal antibody S38CD11B12 successfully in the commercial Serazym® Anti-Cardiolipin-ß2-GPI IgG/IgM assay and could thereby prove the eligibility of S38CD11B12 as detection antibody in autoimmune diagnostic assays using rabbit derived sera as reference material.


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Storage of urine specimens in point of care (POC) urine drug testing cups reduces concentrations of many drugs

Publication date: Available online 3 September 2019

Source: Clinica Chimica Acta

Author(s): Mehran Haidari, Sravan Mansani, Dezaray Ponds, Lissett Romero, Christine Cobb, Saad Alsaab

Abstract
Background

Many clinical toxicology laboratories receive urine specimens in urine cups that contain point of care (POC) drug testing strips. We conducted this study to evaluate the effect on the stability of commonly measured drugs in the clinical toxicology laboratory when urine is exposed to POC urine drug testing cups.

Methods

Drug free urine was spiked with 85 drugs that were measured by a validated liquid chromatography mass spectrometry (LCMS) method after exposure to POC urine drug testing cups at ambient and 2–6 °C temperatures. Alterations ≥20% were defined as significant changes in the drugs concentration.

Results

Concentrations of amitriptyline, cyclobenzaprine, fentanyl, fluoxetine, flunitrazepam, nortriptyline, paroxetine, and sertraline were significantly reduced when urine specimens were stored inside POC urine drug testing cups for 24 h at ambient temperature. Storage of urine in urine chemistry dipsticks reduced the concentration of several drugs. When spiked urine was exposed to an increasing number of POC urine drug testing strips, the concentrations of some drugs were reduced in a dose-dependent manner. The drugs that were absorbed by POC urine drug testing strips were partially back extracted from the strips.

Conclusion

Exposure of urine specimens to POC urine drug testing strips reduces the concentration of several drugs measured by LCMS method.


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Genistein upregulates cyclin D1 and CDK4 expression and promotes the proliferation of ovarian cancer OVCAR-5 cells

Publication date: Available online 26 August 2019

Source: Clinica Chimica Acta

Author(s): Yali Wang, Wen Li, Zhongwei Wang, Hongtao Ren, Yi Li, Yang Zhang, Pengtao Yang, Shupei Pan

Abstract
Background

Ovarian epithelial cancer is the leading cause of deaths associated with gynecologic malignancies. Genistein represents a major type of phytoestrogens widely found in foods and herbal medicines. Although multiple epidemiological studies indicated that the consumption of genistein or other isoflavones is associated with a decreased ovarian cancer risk, the cellular effects and underlying mechanisms are not fully understood. This study focuses on the effect of genistein on the proliferation and cell cycle regulation of ovarian cancer cells.

Methods

Ovarian cancer OVCAR-5 cells were treated with genistein in an estrogen-free condition. Cell counting and MTS assays were performed to determine the cell proliferation alterations. Real-time PCR and Western blotting were conducted to examine the expression changes in key cell cycle regulators.

Results

Genistein significantly promoted the proliferation and the viability of OVCAR-5 cells. Upon genistein treatment, cellular mRNA and protein expression levels of PCNA, Cyclin D1 and CDK4 were increased, but those of p21 and p27 were decreased.

Conclusion

In contrary to results of many previous studies, we observed that genistein was able to upregulate the proliferation and G1-S transition of ovarian cancer OVCAR-5 cells. The discrepancy could be caused by diverged experimental conditions and/or different ER expression patterns of cell lines. The findings may provide basic information for in-depth analysis on the role(s) and mechanisms by which genistein confers its effect on ovarian cancer progression.


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Category: Current Chemistry Research

Last update: 28.03.2018.






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