Home Medicine Evaluation of E2F3 and survivin expression in peripheral blood as potential diagnostic markers of prostate cancer
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Evaluation of E2F3 and survivin expression in peripheral blood as potential diagnostic markers of prostate cancer

  • Ahmed M. Wadaa Allah ORCID logo , Fatma F. Abdel Hamid , Ahmed F. Soliman EMAIL logo , Noha Ibrahim , Ibrahim Malash and Iman A. Abdelgawad
Published/Copyright: July 12, 2020
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Turkish Journal of Biochemistry
From the journal Turkish Journal of Biochemistry Volume 45 Issue 5

Abstract

Background

Prostate cancer (PC) incidence has risen globally. As there are no current independent biomarkers with high diagnostic efficiency to detect PC, this study was performed to investigate the relative gene expression levels of E2F3 and survivin in the whole blood of PC, benign prostate hyperplasia (BPH), and normal control individuals and to explore their diagnostic value.

Material and methods

Participants of the study were divided into three groups; normal control group (n=25), BPH patients (n=25), and PC patients (n=75). The E2F3 and survivin gene expression levels were assessed using real-time qPCR in addition to the measurement of free and total levels of prostate-specific antigen (PSA) using electrochemiluminescence assays.

Results

Survivin relative gene expression was over-expressed in PC and BPH patients compared to the normal control group, whereas, E2F3 did not differ significantly among the studied groups. Compared to PSA, E2F3 and survivin mRNA expression levels had lower diagnostic efficacy to differentiate PC from normal and BPH individuals with an area under curve (AUC) of 0.471 and 0.727, respectively. Further, survivin expression level was associated with increased the risk of PC.

Conclusion

Survivin and E2F3 relative expression levels in peripheral blood had low diagnostic performance to detect PC and individuals with high survivin expression levels may have higher risk to develop PC.

Öz

Amaç

Prostat kanseri insidansı global olarak artmaktadır. Prostat kanserini saptayacak yüksek tanısal etkinlikte güncel bağımsız biyobelirteçler olmaması nedeniyle, bu çalışma E2F3 ve survivin genlerinin göreceli ekspresyon düzeylerinin tam kanda benign prostat hiperplazisi (BPH), prostat kanseri (PC) ve normal kontrollerde incelenmesi amacıyla yapılmıştır.

Gereç ve Yöntem

Katılımcılar normal kontrol (n=25), BPH hastaları (n=25) ve PC hastalrı olarak üç gruba ayrılmıştır. E2F3 ve surviving gen ekspresyonları gerçek zamanlı qPCR yöntemiyle, serbest ve total prostat spesifik antijen (PSA) düzeyleri ise elektrokemilüminesans yöntemi ile ölçülmüştür.

Bulgular

Survivin geminin ekspresyonu PC ve BPH hastalarında normal kontrollere göre artmış bulunup, E2F3 gen ekspresyonunda çalışma grupları arasında anlamlı fark bulunamamıştır PSA ile kıyaslandığında, E2F3 ve surviving mRNA ekspresyon düzeylerinin PC hastalarını normal kontrol ve BPH hastalarından ayırıcılığının düşük tanısal etkinliği olduğu sırasıyla AUC değerlerinin 0,727 ve 0,471 bulunması ile gösterilmiştir. Ayrıca, survivin ekspresyon düzeyinin prostat kanseri riskini arttırdığı gösterilmiştir.

Sonuç

Survivin ve E2F3 genlerinin periferik kandaki göreceli ekspresyon düzeyleri prostat kanserinin saptanmasında düşük tanısal performanslıdır ve yüksek survivin ekspresyon düzeyleri olan bireylerde prostat kanseri gelişme riski daha yüksektir.

Keywords: E2F3; prostate cancer; prostate-specific antigen (PSA); survivin
Anahtar kelimeler: E2F3; prostat kanseri; survivin

Introduction

Prostate cancer (PC) is ranked as the fifth leading cause of cancer mortality in men; it is diagnosed in 1.6 million subjects and causes the death of 366 thousand patients per year [1], [2]. In Egypt, PC age-standardized incidence rate (ASIR) was 9.5/100,000, while age-standardized mortality rate (ASMR) was 4.3/100,000 [3], [4].

Prostate-specific antigen (PSA) seems to be a useful marker for staging and monitoring PC, however, it lacks specificity thus an invasive procedure involving multiple biopsies examination is needed for histological confirmation of the disease [5], [6]. Recent studies evaluated new biomarkers to non-invasively detect PC including ghrelin-O-acyl transferase (GOAT) which was elevated in PC urine and plasma samples, and engrailed variant-2 (EN2) which, compared to control samples, was found to be increased in PC tissues and tumor cell lines. Additionally, neuroendocrine marker level was higher in serum samples of PC patients, while both homeobox C6 (HOXC6) and distal-less homeobox1 (DLX1) were associated with PC grade [7], [8], [9], [10].

PC stages are correlated with various molecular mechanisms [11]. Much attempt has recently been made to find new genes that could serve as credible markers for early diagnosis and prognosis as well as prospective therapeutic targets.

E2F3 is a transcriptional activator belonging to the E2F family, which activates the growth-promoting genes necessary for the progression of the cell cycle. During normal cell division, cyclin-dependent kinases (CDKs) phosphorylates retinoblastoma protein (pRB) and prevent its binding to E2F, therefore, the mutation of RB1 gene results in non-functional pRB which leads in turn to an increase in the free E2F throughout the cell cycle causing constitutive expression of growth-promoting genes. Any down-regulation of the E2F pathway surveillance is thus considered an essential step in the development of cancer, illustrating why E2F appears to be a main regulator of a normal cell cycle [12], [13].

Over-expression of E2F3 was found in about two-thirds of human PC samples with a worse overall survival rate in patients with high E2F3 expression than those with lower expression levels [14], [15].

E2F3 could bind to the promoter of survivin causing its transcription [16]. Survivin is a member of the family of apoptosis inhibitors (IAP) that is found in most human tumors and has many roles in malignancy, immunity, and differentiation, and is essential for homeostasis, and T-cell maturation and proliferation at different development stages [16], [17], [18], [19]. Moreover, survivin induces molecular processes concerning the inflammation process in extracellular fluids by binding to leukocytes where it contributes to the activation of the latter [20]. Further, survivin has roles in cancer immunity as it can act as a tumor-associated antigen or modulate the immune environment to permit tumor growth [17]. In addition, survivin was suggested to have a major role in cell cycle stimulation [21]. Thus, survivin was viewed as a possibly significant therapeutic target because of its elevated expression in most human cancers and its roles in promoting cell proliferation [22].

Since E2F3 and survivin gene expression in the peripheral blood of PC patients had not been systematically studied before, this study was performed to evaluate the relative expression of these genes in peripheral blood of PC patients as well as their diagnostic efficacy to detect the presence of the disease.

Material and methods

Patients

Seventy-five patients suffered from a histologically, and radiologically proven PC and did not receive any medical or surgical therapeutic intervention, in addition to 25 patients with benign prostate hyperplasia (BPH) were recruited from the medical oncology clinic at the National Cancer Institute (NCI), Cairo University from December 2017 to September 2018. Twenty-five volunteers were included as a normal control group. Patients who received any line of treatment, and those with pathologies other than adenocarcinoma were excluded.

Informed written consent was obtained from all participants included in the study. This work was performed according to the declaration of Helsinki for experiments involving humans, and the study protocol was approved by the institutional review board of NCI (Organization no. IORG0003381) under IRB number of IRB00004025 with a Federal Wide Assurance (FWA) number of FWA00007284 and approval number of 201617029.4

Seven milliliters of 12 h fasting venous blood samples were collected from all subjects and were aseptically divided into two parts; the first was collected on EDTA contained tubes and was used for molecular analyses while the second was collected on plain vacutainer tubes, left to clot and centrifuged at 1000×g for 5 min to obtain sera for biochemical analyses.

Biochemical analyses

Total and free PSA were quantitatively determined by Elecsys dual monoclonal antibody Sandwich assays (Roche Diagnostics) based on electrochemiluminescence technology. Low detection limits were 0.011 ng/mL and 0.018 ng/mL for total and free PSA, respectively. The intra- and inter-assay coefficient of variation (CV) for total PSA assay were 2.62 and 2.94% respectively while they were 1.38 and 4.1% for free PSA assay. The reactions were performed on Cobas e411 analyzer (Roche Diagnostics, IN, USA). PSA ratio was then calculated as free PSA/total PSA.

Molecular analyses

Mononuclear cells including lymphocytes, and monocytes in addition to circulating tumor cells were isolated from the whole blood using Ficoll-Paque™ density gradient media (GE Healthcare UK Ltd, Buckinghamshire, UK), cells were resuspended in phosphate buffered saline (pH 7.4), and finally, RNA was extracted from the cell suspension using QIAamp RNA Blood Mini Kit (Cat no. 52304, Qiagen) according to manufacturer’s instructions. Spectrophotometric determination of RNA purity and concentration was made at 260 and 280 nm.

QuantiTect® Reverse Transcription Kit (Cat no. 205311, Qiagen) was used to reversely transcribe total RNA and to synthesize the first cDNA strand. Firstly, genomic DNA was removed by using entire genomic DNA elimination mixture that consisted of 2 μL of 7x genomic DNA Wipeout Buffer and one μg of template RNA; the volume was then completed to 14 μL with RNase-free water. The mixture was incubated at 42 °C for 10 min then the reverse transcription was carried out in a reaction mixture (20 μL) containing the elimination mixture, 4 μL of 5x Quantiscript RT Buffer, 1 μL of RT Primer Mix, and 1 μL of Quantiscript Reverse Transcriptase.

QuantiTect® Primer Assays for E2F3, and survivin (Cat no. QT00081186, and QT02451946, respectively; Qiagen) were used for real-time reactions in a final volume of 25 μL with 2 μL of cDNA as a template, 2.5 μL 10x QuantiTect® primer assay, 12.5 μL 2x QuantiTect SYBR ® green PCR master mix (Qiagen) and 8 μL of RNase-free water. The PCR cycles were as follows: 15 min for initial denaturation at 95 °C, followed by 45 amplification cycles of 15 s for denaturation at 95 °C, 30 s for annealing at 55 °C and 30 s for extension at 72 °C. MicroAmp® fast optical plate with MicroAmp® optical adhesive film (Applied Biosystems) was used for PCR reaction. The plate was loaded into the PCR system in Step One Real-Time device (Applied Biosystems, CA, USA). The melting curve analyses of all real-time PCR yields were conducted and shown to produce a single DNA duplex. 2−ΔΔCt method was used for quantitative calculations [23]. The expression of mRNAs was normalized to the expression of β-actin (Cat no. QT00095431) purchased from Qiagen (Hilden, Germany).

Statistical analysis

Data analysis was implemented by using IBM SPSS advanced statistics version 25 (IBM Corp, NY, US). For categorical data, the descriptive measures were presented in frequencies and percentages. For quantitative data, Shapiro-Wilk test was performed to identify the type of data distribution, normally distributed data were presented as mean ± SD and non-normally distributed data as median and interquartile ranges (25th and 75th percentile). Continuous variables were compared between groups using ANOVA followed by Tukey’s post hoc for multiple comparisons or Kruskal-Wallis test followed by Mann-Whitney U test as a post hoc for multiple comparisons as appropriate. Chi-square test was performed to compare the differences between categorical variables. Correlation between two variables was evaluated with Spearman’s rho correlation analysis. Unconditional logistic regression analysis was used to evaluate the strength of the association between E2F3, and survivin relative expression levels and the susceptibility to PC. To determine the diagnostic value of E2F3 as well as survivin relative expression, receiver operating characteristic (ROC) curve analysis was performed. Significant difference was considered when p-value <0.05.

Table 1:

General characteristics of study population.

Control (n=25)BPH (n=25)PC (n=75)p-Value between groups
Age, years35.00 ± 5.9765.70 ± 6.1a67.40 ± 7.56a<0.001
Total PSA, ng/mL1.04 (0.75–1.56)2.47 (1.24–6.80)a50.54(11.00–115)a, b<0.001
Free PSA, ng/mL0.27 ± 0.0850.69 (0.41–1.36)a8.41 (1.83–17.37)a, b<0.001
PSA ratio0.28 (0.16–0.36)0.30 ± 0.100.17 (0.10–0.24)a, b<0.001
Relative gene expression of E2F31.27 (0.79–1.58)0.89 (0.61–1.05)0.90 (0.45–1.91)0.272
Relative gene expression of survivin1.03 ± 0.371.43 (1.23–1.70)a2.14 (1.11–5.46)a, b<0.001
Gleason score
<720 (26.7%)
≥755 (73.3%)
Tumor’s localization
Localized42 (56%)
metastatic33 (44%)

Data are expressed as mean ± SD for Gaussian data, median (interquartile range) for non-Gaussian data, and frequency (percentage) for categorical data.

BPH, Benign prostate hyperplasia; PC, Prostate cancer; PSA, Prostate-specific antigen. In multiple comparisons, ap<0.05 vs. control, and bp<0.05 vs. BPH.

Results

Basic features of the studied groups

Basic characteristics of the studied groups are shown in Table 1. Compared to the control group, BPH and PC patients were older (p<0.001) with considerably high serum concentrations of total PSA (p=0.001, and p<0.001; respectively) and free PSA (p<0.001) with a significant decreased PSA ratio in cancer patients only (p=0.014). With respect to gene expression levels, survivin showed a significant up-regulation in peripheral blood of BPH and PC patients compared to controls (p=0.016, and p<0.001; respectively). On the other hand, E2F3 showed only a borderline significant down-regulation in BPH patients (p=0.05) with no significant difference in cancer patients (p=0.247).

PC patients exhibited significantly elevated levels of serum total PSA and free PSA (p<0.001) with a significant decrease in the PSA ratio (p<0.001) in comparison with BPH patients. In contrast, they were age-matched with BPH patients and showed no significant difference regarding gene expression levels of E2F3 (p=0.765), and survivin (p=0.086). Almost half of the cancer patients suffered from metastasized tumors, and more than 70% had a high Gleason score (≥7).

Correlation between relative expression of E2F3, survivin, and the studied parameters

In BPH group, positive significant correlations were found between relative expression level of survivin and circulating levels of both total and free PSA. In PC patients, a positive significant correlation was observed between the relative expression levels of E2F3 and survivin (Table 2).

Table 2:

Correlation analysis of the studied parameters with relative expression of E2F3 and survivin genes in different groups.

Relative expression of E2F3 gene
ControlBPHPC
rp-Valuerp-ValueRp-Value
Age, years−0.2350.257−0.2530.222−0.0210.859
Total PSA, ng/mL0.2390.2500.0050.981−0.2140.066
Free PSA, ng/mL−0.1720.4110.0580.783−0.1510.195
PSA ratio−0.3840.0580.0010.9970.0190.873
Relative expression of survivin gene0.3120.1290.2780.1790.3310.004
Relative expression of survivin gene
ControlBPHPC
rp-Valuerp-ValueRp-Value
Age, years0.1550.4590.1770.5770.0540.648
Total PSA, ng/mL0.1940.3530.5650.003−0.0100.398
Free PSA, ng/mL−0.1350.5210.5300.006−0.1610.168
PSA ratio−0.1820.385−0.0740.726−0.0410.726
Relative expression of E2F3 gene0.3120.1290.2780.1790.3310.004

BPH, Benign prostate hyperplasia; PC, Prostate cancer; PSA, Prostate-specific antigen.

Association of E2F3 and survivin mRNA expression levels with the studied parameters

PC patients were divided into two sub-groups (high vs low) according to the median value of the relative gene expression level. E2F3 gene expression did not associate with any of the studied parameter. In contrast, PC patients in the low survivin expression sub-group had lower free PSA level and higher Gleason score than those in the high expression sub-group (Table 3).

Table 3:

Association of E2F3 and survivin expression levels with the studied parameters in PC group.

E2F3 expressionSurvivin expression
High expression (n=36)Low expression (n=39)p-ValueHigh expression (n=38)Low expression (n=37)p-Value
Total PSA, ng/mL
<43 (8.33)2 (5.13)0.8374 (10.53)1 (2.70)0.302
4–106 (16.67)6 (15.38)7 (18.42)5 (13.51)
>1027 (75)31 (79.49)27 (71.05)31 (83.78)
Free PSA, ng/mL
>0.930 (83.33)32 (82.05)0.88326 (68.42)36 (97.30)0.01
<0.96 (16.67)7 (17.95)12 (31.58)1 (2.70)
PSA ratio
>0.259 (25)9 (23.08)0.8469 (23.68)9 (24.32)0.948
<0.2527 (75)30 (76.92)29 (76.32)28 (75.68)
Gleason score
<711 (30.56)9 (23.08)0.46414 (36.84)6 (16.22)0.043
≥725 (69.44)30 (76.92)24 (63.16)31 (83.78)
Distant metastasis
Present14 (38.9)18 (46.15)0.52515 (39.47)17 (45.95)0.571
Absent22 (61.1)21 (53.85)23 (60.53)20 (54.05)

Data are expressed as frequency (percentage). PC, Prostate cancer; PSA, Prostate-specific antigen.

Potential relative risk factors among the studied markers

Logistic regression analysis showed that older age, elevated levels of both total and free PSA, high expression of survivin in the peripheral blood, in addition to decreased PSA ratio were associated with increasing the risk of PC development, whereas expression level of E2F3 showed no association (Table 4).

Table 4:

Logistic regression analysis for potential relative risk factors for prostate cancer (PC).

OR95% CIp-Value
Lower boundUpper bound
Age, Years1.121.0701.164<0.001
Total PSA, ng/mL1.401.1981.635<0.001
Free PSA, ng/mL2.301.4543.640<0.001
PSA ratio0.00600.1240.001
Relative gene expression of E2F31.000.9991.0020.660
Relative gene expression of survivin1.821.2212.7010.003

OR, Odds ratio; 95%CI, 95% Confidence interval; PSA, Prostate-specific antigen.

Efficacy of E2F3 and survivin gene expression as potential diagnostic biomarkers for PC

Figure 1 illustrates the ROC curves of E2F3 and survivin relative expression levels in addition to the concentrations of total PSA, free PSA and PSA ratio. Survivin showed a diagnostic value for PC with an area under curve (AUC) of 0.727 (95%CI: 0.639–0.815, p<0.001) at an optimum cut-off point of 1.38 which could yield sensitivity and specificity of 65.30 and 62%, respectively. However, this ability was lower than the diagnostic efficacy of PSA. On the other hand, E2F3 relative expression in peripheral blood failed to discriminate between patients with PC and those with BPH and healthy individuals.

Figure 1: Receiver operating characteristic (ROC) curves of (A) E2F3, survivin, total prostate-specific antigen (PSA), and free PSA, (B) PSA ratio for discriminating prostate cancer (PC) patients from healthy controls and Benign prostate hyperplasia (BPH) patients. AUC: Area under curve, 95% CI: 95% confidence interval.
Figure 1:

Receiver operating characteristic (ROC) curves of (A) E2F3, survivin, total prostate-specific antigen (PSA), and free PSA, (B) PSA ratio for discriminating prostate cancer (PC) patients from healthy controls and Benign prostate hyperplasia (BPH) patients. AUC: Area under curve, 95% CI: 95% confidence interval.

Discussion

Because PC is considered as one of the most common non-cutaneous malignancies, represents a major cause of cancer fatality in men, and is rarely symptomatic early in its course, it is extremely critical to detect and diagnose PC in its earliest stages [24], [25]. Therefore, this study was designed to examine the relative expression levels of E2F3 and survivin in the peripheral blood of PC patients and to test their diagnostic abilities as non-invasive biomarkers of PC occurrence.

In the current study, survivin was over-expressed in peripheral blood of PC patients in comparison with BPH and control individuals which seems to be in line with the results of previous studies which reported an over-expression of survivin in lung, colorectal, esophageal, and gastric carcinomas peripheral blood [26], [27], [28], [29]. Survivin has high potential to be expressed in most types of human cancers [21]. It is expressed and up-regulated in PC to protect the tumor microenvironment against apoptosis and oxidative stress-induced damage [30]. A gradual, but consistent, upsurge of survivin expression from normal control prostate samples to PC was observed when its expression was compared between healthy, malignant prostate and lymph node tissues using immunohistochemistry with the highest expression found in metastatic lymph nodes [31], [32].

Survivin and E2F3 relative expression were positively correlated in the PC group of this study. This could be ascribed for the molecular link between survivin transcription regulation and RB/E2F protein family that can be proved by the interaction of both RB1 and retinoblastoma-like protein 2 (p130) with the survivin promoter suppressing the latter’s transcription. Moreover, E2F3 could stimulate the transcription of survivin by binding to its promoter [16].

Additionally, this work showed that survivin expression might be a risk factor for the occurrence of PC which appears to be consistent with the results of Gunaldi et al., who revealed that individuals with high survivin expression in serum are 4.2 times more susceptible to develop cancer [29]. Moreover, the results of the present study shows that survivin relative expression had diagnostic value for PC consistent with the results of previous studies which showed that survivin levels were higher in malignant pleural effusion (MPE) patients than non-MPE patients with a sensitivity of 57.5% and using its level in urine to detect bladder cancer yielded 64% sensitivity [33], [34].

Regarding E2F3, there was no significant difference in its relative expression level in peripheral blood between the groups. In contrast, Foster et al. [14] detected high levels of E2F3 in 67% of human PC tissues. Additionally, Olsson et al. [35] showed that E2F3 was over-expressed in prostate and bladder tissues. This contradiction may be due to different sample types, demographic characteristics or techniques used in the gene measurement. Furthermore, the current work disclosed that the expression of E2F3 in the peripheral blood was not related with PC predisposition.

There is a debate about the diagnostic efficiency of total PSA in detecting PC, although several studies revealed that total PSA has high sensitivity but lacks specificity [36], [37], [38], Holmström et al. [39] revealed that total PSA have low sensitivity and high specificity. Furthermore, there is an argument about the diagnostic efficiency of PSA ratio; some studies revealed that PSA ratio enhance sensitivity and specificity for PC diagnosis than that of total PSA [40], [41], on the other hand, Huang et al. [42] and Thakur et al. [43] suggested that PSA ratio lacks the efficiency to diagnose PC. This concurs with results of the present study which showed that PSA ratio had the lowest diagnostic efficacy compared to total and free PSA levels.

In conclusion, survivin expression might be considered as a risk factor for the development of PC. Moreover, both survivin and E2F3 have lower diagnostic efficiency than PSA in discriminating patients with PC. PSA is still the most sensitive and specific non-invasive biomarker to detect PC compared to the studied markers.

Corresponding author: Ahmed F. Soliman, Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt, Phone: +20 1007383005, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Informed consent: Informed consent was obtained from all individuals included in this study.

  4. Competing interests: Authors state no conflict of interest.

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Received: 2019-08-31
Accepted: 2020-01-21
Published Online: 2020-07-12

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Review Article
  3. Newly developed diagnostic methods for SARS-CoV-2 detection
  4. Short Communication
  5. Effect of hemolysis on prealbumin assay
  6. Research Articles
  7. BioVar: an online biological variation analysis tool
  8. High dose ascorbic acid treatment in COVID-19 patients raised some problems in clinical chemistry testing
  9. Immunoassay biomarkers of first and second trimesters: a comparison between pregnant Syrian refugees and Turkish women
  10. Association of maternal serum trace elements with newborn screening-thyroid stimulating hormone
  11. PIK3CA and TP53 MUTATIONS and SALL4, PTEN and PIK3R1 GENE EXPRESSION LEVELS in BREAST CANCER
  12. Evaluation of E2F3 and survivin expression in peripheral blood as potential diagnostic markers of prostate cancer
  13. Age, gender and season dependent 25(OH)D levels in children and adults living in Istanbul
  14. Original Article
  15. Fractional excretion of magnesium as an early indicator of renal tubular damage in normotensive diabetic nephropathy
  16. Research Articles
  17. Diagnostic value of laboratory results in children with acute appendicitis
  18. Evaluation of thiol disulphide levels in patients with pulmonary embolism
  19. Relationship between renal tubulointerstitial fibrosis and serum prolidase enzyme activity
  20. Comparison of test results obtained from lithium heparin gel tubes and serum gel tubes
  21. MHC Class I related chain A (MICA), Human Leukocyte Antigen (HLA)-DRB1, HLA-DQB1 genotypes in Turkish patients with ulcerative colitis
  22. An overview of procalcitonin in Crimean-Congo hemorrhagic fever: clinical diagnosis, follow-up, prognosis and survival rates
  23. Comparison of different equations for estimation of low-density lipoprotein (LDL) – cholesterol
  24. Case-Report
  25. A rare case of fructose-1,6-bisphosphatase deficiency: a delayed diagnosis story
  26. Research Articles
  27. Atypical cells in sysmex UN automated urine particle analyzer: a case report and pitfalls for future studies
  28. Investigation of the relationship cellular and physiological degeneration in the mandible with AQP1 and AQP3 membrane proteins
  29. In vitro assessment of food-derived-glucose bioaccessibility and bioavailability in bicameral cell culture system
  30. Letter to the Editor
  31. The weighting factor of exponentially weighted moving average chart
https://doi.org/10.1515/tjb-2019-0323
Keywords for this article
E2F3; prostate cancer; prostate-specific antigen (PSA); survivin

Articles in the same Issue

  1. Frontmatter
  2. Review Article
  3. Newly developed diagnostic methods for SARS-CoV-2 detection
  4. Short Communication
  5. Effect of hemolysis on prealbumin assay
  6. Research Articles
  7. BioVar: an online biological variation analysis tool
  8. High dose ascorbic acid treatment in COVID-19 patients raised some problems in clinical chemistry testing
  9. Immunoassay biomarkers of first and second trimesters: a comparison between pregnant Syrian refugees and Turkish women
  10. Association of maternal serum trace elements with newborn screening-thyroid stimulating hormone
  11. PIK3CA and TP53 MUTATIONS and SALL4, PTEN and PIK3R1 GENE EXPRESSION LEVELS in BREAST CANCER
  12. Evaluation of E2F3 and survivin expression in peripheral blood as potential diagnostic markers of prostate cancer
  13. Age, gender and season dependent 25(OH)D levels in children and adults living in Istanbul
  14. Original Article
  15. Fractional excretion of magnesium as an early indicator of renal tubular damage in normotensive diabetic nephropathy
  16. Research Articles
  17. Diagnostic value of laboratory results in children with acute appendicitis
  18. Evaluation of thiol disulphide levels in patients with pulmonary embolism
  19. Relationship between renal tubulointerstitial fibrosis and serum prolidase enzyme activity
  20. Comparison of test results obtained from lithium heparin gel tubes and serum gel tubes
  21. MHC Class I related chain A (MICA), Human Leukocyte Antigen (HLA)-DRB1, HLA-DQB1 genotypes in Turkish patients with ulcerative colitis
  22. An overview of procalcitonin in Crimean-Congo hemorrhagic fever: clinical diagnosis, follow-up, prognosis and survival rates
  23. Comparison of different equations for estimation of low-density lipoprotein (LDL) – cholesterol
  24. Case-Report
  25. A rare case of fructose-1,6-bisphosphatase deficiency: a delayed diagnosis story
  26. Research Articles
  27. Atypical cells in sysmex UN automated urine particle analyzer: a case report and pitfalls for future studies
  28. Investigation of the relationship cellular and physiological degeneration in the mandible with AQP1 and AQP3 membrane proteins
  29. In vitro assessment of food-derived-glucose bioaccessibility and bioavailability in bicameral cell culture system
  30. Letter to the Editor
  31. The weighting factor of exponentially weighted moving average chart
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