Can urinary caspase-3 and cytochrome c levels be used as predictive biomarkers in the management of unilateral antenatal hydronephrosis?

PURPOSE: We aimed to investigate the urinary caspase-3 and cytochrome c levels in patients with unilateral antenatal hydronephrosis and to determine whether changes in urinary biomarker levels could be useful for both predicting the need for surgical intervention due to ureteropelvic junction obstruction (UPJO) and postoperative surgical success. METHODS: Sixty-five children with a history of unilateral antenatal hydronephrosis and postnatal anteroposterior diameter ≥ 10 mm were included in this prospective case-control study between January 2013 and December 2021. The obstruction group consisted of 33 patients (28 boys, 84.8%) who underwent open dismembered pyeloplasty due to UPJO. The non-obstructive dilatation (NOD) group consisted of 32 patients (27 boys, 84.4%) with stable or improving hydronephrosis and no significant reduction in ipsilateral split renal function during follow-up, whereas 34 healthy children were enrolled in the study as a control group. Urinary urinary caspase-3 and cytochrome c levels using ELISA were measured. RESULTS: The median preoperative urinary caspase-3 level was significantly higher in the obstruction group when compared to the NOD group (4.82 ng/mgCr vs. 2.61 ng/mgCr, p = 0.013) as well as the control group (4.82 ng/mgCr vs. 1.72 ng/mgCr, p = 0.002). In the postoperative period, urinary caspase-3 levels significantly decreased compared to preoperative measurements (4.82 ng/mgCr vs. 2.51 ng/mgCr, p = 0.006) and became similar to the control group (2.51 ng/mgCr vs. 1.72 ng/mgCr, p = 0.422). On the other hand, no significant differences were observed in urinary cytochrome c levels between the groups. All patients who underwent pyeloplasty achieved postoperative resolution in hydronephrosis and improved drainage on MAG-3, so none of the patients required re-do pyeloplasty. Postoperative decrease in caspase-3 level was found to be compatible with adequate urine drainage on MAG-3 scan. The cut-off value of urinary caspase-3 to predict patients requiring pyeloplasty was found to be 3.31 ng/mg creatinine with 63.6% sensitivity, 62.5% specificity (AUC = 0.679). In the multivariable analysis, urinary caspase-3 level (OR: 1.653, p = 0.019), anteroposterior pelvic diameter (OR: 1.401, p = 0.001), and split renal function on MAG-3 (OR: 1.277, p = 0.011) were found to be independent factors in determining patients who require surgery. CONCLUSION: Based on our preliminary findings, urinary caspase-3 levels could be a useful biomarker not only for predicting the need for surgical intervention but also for determining the postoperative surgical success in children with UPJO.

Urinary HSP70 can predict the indication of surgery in unilateral ureteropelvic junction obstruction.

BACKGROUND: Distinguishing hydronephrosis that requires surgical intervention is a clinical challenge. The aim of this study is to determine the level of urinary heat shock protein 70 (HSP70) in children who required surgery for ureteropelvic junction obstruction and its potential use as a biomarker for prediction of surgery in children with isolated unilateral hydronephrosis. METHODS: The data of 43 children with ureteropelvic junction obstruction who underwent pyeloplasty, 25 patients with non-obstructive dilation (NOD) and 30 healthy children (control group) were collected prospectively for this study. Preoperative and postoperative urinary HSP70/Cr levels were also analyzed in 30 children in the pyeloplasty group who had available follow-up information. HSP70 levels were assessed using ELISA. RESULTS: The median age of the pyeloplasty group was 13 months (IQR 7-36 months), NOD group was 42.5 months (IQR 16-73) and it was 36 months (IQR 24-47.5) in the control group. The mean preoperative urinary HSP70/Cr was significantly higher in the pyeloplasty group when compared to controls as well as the NOD group (150.6 pg/mgCr vs. 65.0 pg/mgCr and vs. 64.7 pg/mgCr, p < 0.001 and p < 0.001, respectively). The urinary HSP70 levels significantly decreased in the postoperative period (151.5 vs 79.5, p < 0.001). Using the cutoff value of 94.7 pg/mgCr, the sensitivity and specificity of urinary HSP70 for predicting the risk of surgical intervention were 69.7% and 68%, respectively (AUC = 0.689). CONCLUSION: Urinary HSP70 may be used as an adjunct tool to clinical parameters to identify patients that would require surgery due to ureteropelvic junction obstruction.

Effects of systemic androgens on late-stage urethral wound healing: An animal study.

BACKGROUND: There are limited data regarding the effects of systemic androgens on late-stage urethral wound healing. OBJECTIVE: To evaluate the effects of systemic androgens on fibrosis and scar formation in late-stage urethral wound healing. MATERIALS AND METHODS: Forty-five male Sprague Dawley rats were divided into three groups. First group consisted of 15 rats that were castrated on 23 days of age and were given 5 mg/kg testosterone undecanoate with 1/25 ml cottonseed oil intraperitoneally at weekly intervals for 3 weeks (castrated and replaced with testosterone rats [CAS+T] group). The castrated rats (CAS) group included 15 castrated rats. The remaining 15 rats underwent sham surgery. CAS and sham groups also received 1/25 ml cottonseed oil intraperitoneally at weekly intervals for 3 weeks. Furthermore, all groups were divided into three subgroups after testosterone/placebo administration (urethroplasty performed after first, second, and third weeks) in accordance with the urethroplasty timing. All animals were sacrificed 6 weeks after urethroplasty. Serum testosterone level was measured, tissue samples were investigated using hematoxylin and eosin and Masson's trichrome. Alpha-SMA, Coll 1 and Coll 3 primary antibodies were applied for immunohistochemical examination. Expression of cytokines and growth factors, such as Bax, Bcl2, IL-10, IP-10, TNF-alpha, TGFb1, MMP9, Col-I, Col-III, TIMP-1, fibronectin, fibroblast growth factor 10, platelet-derived growth factor, alpha-SMA, were also evaluated in the tissues. RESULTS: The blood testosterone levels were significantly higher in CAS+T group at the time of urethroplasty compared with the levels in CAS group; however, this difference was not observed at the time of sacrification (p < 0.001 and 0.97, respectively). Histological analysis with hematoxylin and eosin and Masson's trichrome staining revealed a significantly higher fibrosis in the sham group compared with the others. Significantly lower fibrosis was detected in the CAS group in the pairwise comparison of the pathological fibrosis area between the CAS and CAS+T groups (p < 0.001). Furthermore, tissue collagen-1, collagen-3, and alpha-SMA expression levels were statistically different between CAS and CAS+T groups (p < 0.001, <0.05, and <0.001, respectively). The tissue levels of BAX, TIM-1, MMP-9, Coll-I, Coll-III, TGF-beta, TNF-alpha, and IL-10 mRNA expressions in the CAS+T group were different than the levels in CAS group (as <0.5-fold and >1.5-fold changes, respectively). The expressions of all these markers were significantly higher in the sham group. The subgroup analysis of CAS+T group (urethroplasty performed after first, second, and third weeks) revealed similar histopathological wound healing findings. DISCUSSION: Debate continues on the effects and benefits of androgen use regarding urethral healing. There are two main routes for administration as systemic or local. This study focuses on the late-stage histologic and biochemical effects of systemic androgens. CONCLUSION: Systemic androgens adversely affect wound healing and cause abnormal extracellular matrix as well as scar formation.

Urinary biomarkers can identify the need for pyeloplasty in presence of supranormal differential renal function in antenatally diagnosed unilateral hydronephrosis.

INTRODUCTION: Decision for surgery can be challenging in children with AH (Antenatal Hydronephrosis) especially in the setting of supranormal differential renal function (SnDRF). OBJECTIVE: Aim of this study is to investigate whether IP-10 (interferon gamma-induced protein 10), MCP-1 (monocyte chemotactic protein-1), NGAL (neutrophil gelatinase-associated lipocalin), CA 19-9 (carbohydrate antigen 19-9), and KIM-1 (kidney injury molecule-1) can identify the need for pyeloplasty in presence of SnDRF in antenatally diagnosed unilateral hydronephrosis. STUDY DESIGN: A prospectively collected urinary biomarker database was used for the study. There was a total of 53 patients in the AH group. Nineteen children with no history of AH and a normal urinary ultrasonography were taken as controls. Patients with initial ipsilateral DRF (Differential Renal Function) over 50% were included in the SnDRF group while the remaining were named as non-SnDRF. Patients that didn't undergo surgery were classified as non-obstructive dilation (NOD) in both groups. RESULTS: Pyeloplasty was performed in 6/20 patients in SnDRF group, and in 19/33 patients in non-SnDRF group. Biomarker levels in the pyeloplasty and NOD groups were not affected by the presence or absence of SnDRF (p = 1.00, for both). Urinary NGAL, and CA 19-9 could determine the need for surgery in SnDRF group with 83% and 100% sensitivity, 86% and 79% specificity, respectively whereas urinary IP-10 and KIM-1 could with 84% and 83% sensitivity, 57% and 71% specificity, respectively. Urinary MCP-1 could differentiate patients who underwent surgery with 83% sensitivity and 50% specificity in SnDRF groups. CONCLUSION: Our results showed that biomarker levels were not affected whether the kidney has SnDRF. Furthermore, in patients with SnDRF, NGAL and CA 19-9 appear to better estimate requirement for surgical correction before deterioration of renal function.

Can urinary biomarkers detect obstruction defined by renal functional loss in antenatal hydronephrosis?

INTRODUCTION: Diagnosing obstruction and thus, assessment of need for surgery in the management of antenatal hydronephrosis may be challenging. Current diagnostic tests are not capable of indicating which patients are at risk for obstructive nephropathy. Biomarkers may play an important role in distinguishing these patients. OBJECTIVE: The aim of this study is to evaluate if urinary biomarkers could differentiate obstruction (OBS) from non-obstructive dilation (NOD) in patients with antenatal hydronephrosis (AH) that underwent pyeloplasty due to loss of differential renal function (DRF). STUDY DESIGN: Children with a history of AH and postnatal anteroposterior (AP) diameter ≥15 mm were included in this study of prospectively collected data between 2010 and 2018. The OBS group included patients who underwent pyeloplasty due to solely ≥10% subsequent decrease in DRF on a MAG-3 scan during follow-up. Patients with stable or improving hydronephrosis with no significant reduction in ipsilateral DRF (<10%) during follow-up formed the NOD group. Healthy children with no history of AH and a normal urinary ultrasound were taken as the control group. Urinary IP-10, MCP-1, KIM-1, NGAL, and Ca19-9 levels using ELISA were measured. In the OBS group, urine samples were obtained preoperatively and at 3rd post operative-month whereas in the NOD and control groups, samples were collected at the time of enrollment. RESULTS: There were 24 children in the OBS and 27 children in the NOD groups. The control group consisted of 27 healthy children. The pre-operative bladder urine levels of biomarkers of the OBS group were significantly higher than in the NOD and control group (p < 0.05, for all). In terms of differentiating OBS from NOD, results of ROC analyses for the given cut-off values were as follows: 135.06 ng/mgCr (sensitivity 75%; specificity 66%, AUC = 0.735) for IP-10, 0.89 ng/mgCr (sensitivity 79.2%; specificity 88%, AUC = 0.802) for KIM-1, 367.65 pg/mgCr (sensitivity 62.5%; specificity 52%, AUC = 0.660) for MCP-1, 16.15 ng/mgCr (sensitivity 70.8%; specificity 70.4%, AUC = 0.669) for NGAL, and 55.5 U/mgCr (sensitivity 75%; specificity 66%, AUC = 0.676) for Ca 19-9. Moreover, when KIM-1 was combined with IP-10 and Ca19-9, sensitivity and specificity levels were 83% and 85% (AUC = 0.919), respectively. CONCLUSION: In this novel study, which focused on scintigraphic DRF loss, KIM-1 was the most successful among all the biomarkers evaluated. Combination of IP-10, Ca19-9 and KIM-1 resulted increased diagnostic ability.

Effect of low-energy shockwave therapy on angiogenic factors in the penile tissue of diabetic rats.

OBJECTIVE: The aim of this study is to investigate the effect of low-energy shock wave therapy (LESWT) on angiogenesis factors at penile tissue in a diabetic rat model. MATERIAL AND METHODS: A total of 30 male Sprague-Dawley rats which were allocated into three equal groups were included study. Group 1 (control group) included 10 male rats which did not receive any treatment were randomly chosen to serve as normal control. The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce diabetes. Diabetic rats were divided into two equal group which constituted diabetic control, and LESWT treatment (DM+LESWT) group. Each rat in the DM+LESWT group received L-ESWT therapy. Endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) mRNA expression levels of penile tissue were evaluated. RESULTS: Following STZ dosing eNOS level dropped in the diabetic control group relative to the control group. Statistically significant increase in eNOS levels were seen in the LESWT+DM group. Similarly, in the diabetic control group STZ treatment decreased VEGF levels, while in the LESWT+DM group VEGF nearly approached to baseline levels. However variations in VEGF levels were not statistically significant. CONCLUSION: Mechanism action of ESWT in the penile tissue seems to involve angiogenic factors.

Effects of Cilostazol and Diltiazem Hydrochloride on Ischemia-Reperfusion Injury in a Rat Hindlimb Model.

OBJECTIVE: Free radicals and neutrophils are potent sources of ischemia-reperfusion injury (I/R) and they can be limited by the use of exogenous application of some therapeutic agents. The objective of this study was to compare the effects of cilostazol and diltiazem hydrochloride in a rat hind limb model of I/R injury. Methods: Skeletal muscles submitted to 2 hours of ischemia by placing an aneurysm clip to femoral artery and reperfused after 1, 2 and 4 hours. Seventy-two Wistar-Albino rats were randomly divided into mainly four groups according to treatment agents:  Group I (control group) was treated with saline; Group II was treated with diltiazem hydrochloride; Group III was treated with cilostazol in 30% dimethyl sulphoxide; and Group IV was treated with 30% dimethyl sulphoxide intraperitoneally. These four main groups also subdivided into three subgroups according to duration of the reperfusion times.  Blood samples were taken and all rats were sacrificed. Results: Cilostazol-treated groups demonstrated a significant decrease in tissue and serum malondialdehyde (MDA) levels, and tissue myeloperoxidase (MPO ) activity compared with other groups. Increase in serum nitric oxide (NOx) level was significantly higher in all subgroups of cilastazol, diltiazem hydrochloride, and dimethyl sulphoxide groups versus the control group. CONCLUSION: Although these results suggest the beneficial effects of cilostazol and diltiazem hydrochloride on I/R injury, the effect of cilostazol on I/R injury seems to be more efficient than diltiazem hydrochloride.

Urinary IP-10, MCP-1, NGAL, Cystatin-C, and KIM-1 Levels in Prenatally Diagnosed Unilateral Hydronephrosis: The Search for an Ideal Biomarker.

OBJECTIVE: To investigate the urinary interferon gamma-induced protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin-C, and kidney injury molecule-1 (KIM-1) levels in the management of children with prenatally diagnosed unilateral hydronephrosis. MATERIALS AND METHODS: Twenty-seven children with antenatally diagnosed hydronephrosis were enrolled into the study. The controls consisted of 9 healthy children (6 boys, 3 girls; mean age: 41.77 ± 5.30 months). Thirteen children (9 boys, 4 girls; mean age: 48.46 ± 21.11 months) underwent pyeloplasty on follow-up; the remaining 14 (13 boys, 1 girl; mean age: 36.57 ± 14.02 months) were followed up after being diagnosed as having nonobstructive dilatation (NOD). The urinary marker levels were measured in the pyeloplasty, the NOD, and the control groups. RESULTS: The preoperative concentrations of IP-10, MCP-1, NGAL, and KIM-1 were significantly higher in the pyeloplasty group than in the control group (P = .024, P = .002, P = .032, P = .001, respectively). The urinary IP-10 and MCP-1 levels were also significantly higher in the pyeloplasty group than in the NOD group (P = .038, P = .037, respectively). There was no significant difference between the pyeloplasty group and the NOD group regarding urinary NGAL and KIM-1. In the pyeloplasty group, urinary marker levels except cystatin-C were significantly decreased in the postoperative period. CONCLUSION: A decrease in levels of IP-10, MCP-1, NGAL, and KIM-1 after pyeloplasty may be used as a predictor of surgical outcome. Additionally, IP-10 and MCP-1 were superior to NGAL and KIM-1 in predicting who required surgery.

The roles of serum and urinary carbohydrate antigen 19-9 in the management of patients with antenatal hydronephrosis.

INTRODUCTION: Serum carbohydrate antigen (CA) 19-9 has been clinically applied as a valuable tumor marker for pancreatic and gastrointestinal carcinoma. CA 19-9 is expressed in normal excretory epithelium tissues. Increased CA 19-9 has also been observed in uroepithelial tumors as well as in nonmalignant conditions including hydronephrosis secondary to ureteral stones. OBJECTIVE: The purpose of this article is to evaluate the role of urinary CA 19-9 as a non-invasive biomarker in the postnatal differentiation of obstructive and non-obstructive hydronephrosis in patients with unilateral antenatal hydronephrosis. STUDY DESIGN: Infants with isolated renal pelvic dilatation, defined as the presence of anteroposterior pelvic diameter (APPD) equal to or greater than 7 mm based on antenatal ultrasound after 28 weeks' gestation, underwent systematic investigation for uropathies and were prospectively followed up. The pyeloplasty group consisted of 17 patients with ureteropelvic junction (UPJ) obstruction who had undergone pyeloplasty. The non-obstructive dilatation (NOD) group consisted of 17 patients with non-obstructive hydronephrosis, and the control group consisted of 21 healthy children. Commercial enzyme-linked immunosorbent assay (ELISA) kits were used to measure the urinary and serum CA 19-9 levels. In both hydronephrosis groups (pyeloplasty and non-obstructive dilatation), the correlations between urinary and serum CA 19-9 levels with the anteroposterior pelvic diameter measured at the third trimester and the postnatal initial evaluation and differential renal function were investigated. RESULTS: The initial median urinary CA 19-9 levels were significantly greater in children who underwent pyeloplasty than in both the non-obstructive hydronephrosis (143 ± 38 vs. 68 ± 23, respectively; p = 0.007) and the healthy control groups (143 ± 38 vs. 13 ± 3, respectively; p = 0.001) (Figure). Three months after surgery, the urinary CA 19-9 levels had decreased significantly according to the preoperative levels in the pyeloplasty group (143 ± 38 vs. 55 ± 16, p = 0.039). In both the pyeloplasty and NOD groups, there was a correlation of urinary CA 19-9 levels with differential renal function and a correlation of serum CA 19-9 levels with the initial anteroposterior pelvic diameter. Receiver operator characteristic (ROC) analysis revealed a better diagnostic profile for the urinary CA 19-9 level than for the serum CA 19-9 level in terms of identifying obstruction in the hydronephrosis groups (areas under the curve = 0.8 and 0.7, respectively). The best cut-off value of for urinary CA 19-9 was 85.5 U/mL with 76% sensitivity, 85% specificity. The negative predictive value was 80%. DISCUSSION: The results suggest that voided urine CA 19-9 levels seems to be a more useful marker than serum CA 19-9 in obstructive dilatation. An appropriate decrease in urinary CA 19-9 levels after pyeloplasty may be used as a predictor of surgical outcome. In addition, the results have a number of important diagnostic implications that should be further validated in a larger study population. CONCLUSIONS: Based on these results, we suggest that a high urinary CA 19-9 level is a non-invasive clinically applicable marker for differentiating between obstruction and non-obstructive dilatation.

Diagnostic utility of serum and pleural levels of adenosine deaminase 1-2, and interferon-γ in the diagnosis of pleural tuberculosis.

BACKGROUND: To evaluate and compare the diagnostic efficiency of serum (s) and pleural (p) levels of adenosine deaminase (ADA)-1, ADA-2, total ADA, and interferon-gamma (IFN-γ) for the differential diagnosis of pleural tuberculosis (TB). METHODS: Clinical and analytic data of 93 consecutive patients with pleural effusions from May 2012 to February 2013 were prospectively evaluated. The study population included 43 pleural TB, 23 malignancies, and 27 other exudates. The median and interquartile range of ADA-1, ADA-2, total ADA, and IFN-γ were evaluated according to their underlying diseases. RESULTS: There were no significant differences in sADA-1 and sIFN-γ values among each group. pADA-1, pADA-2, total pADA, and pIFN-γ levels were significantly higher in patients with pleural TB than in other patients (p < 0.0001). As for pleural TB receiving operating characteristic (ROC) curves identified the following results. The best cut-off value for pADA-2 was 20.37 U/L and it yielded a sensitivity and specificity of 95.35% and 86%, respectively. Taking a cut-off value of 40.68 U/L for total pADA, the sensitivity and the specificity were found to be 88.37% and 88%, respectively. ROC curve identified 110 U/L as the best cut-off value for pµg/ml, while the sensitivity and the specificity were 74.42% and 68%, respectively. Finally, the best cut-off value for pADA-1 was 16.8 U/L and yielded a sensitivity and specificity of 69.77% and 68%, respectively. CONCLUSIONS: To distinguish pleural TB, pleural levels of ADA-2 have the highest sensitivity among the different diagnostic parameters and may find a place as routine investigation for early detection of TB in the future.

Manganese superoxide dismutase Ile58Thr, catalase C-262T and myeloperoxidase G-463A gene polymorphisms in patients with prostate cancer: relation to advanced and metastatic disease.

OBJECTIVE: To evaluate the relationship between manganese superoxide dismutase (MnSOD) Ile58Thr, catalase (CAT) C-262T and myeloperoxidase (MPO) G-463A gene polymorphisms and the susceptibility and clinicopathological characteristics of prostate cancer. PATIENTS AND METHODS: In all, 155 patients diagnosed with prostate cancer and 195 controls with negative digital rectal examinations and PSA levels of <4 ng/dL were enrolled in this study. MnSOD, CAT and MPO gene polymorphisms were identified by polymerase chain reaction restriction-fragment length polymorphism methods. RESULTS: The TT genotype in MnSOD Ile58Thr polymorphism, CC genotype in the CAT C-262T polymorphism and the GG genotype in the MPO G-463A polymorphism were the predominant genotypes amongst this Turkish male population. There was no association between MnSOD Ile58Thr polymorphism and prostate cancer. For the CAT C-262T polymorphism, the TT genotype had significantly increased prostate cancer risk compared with the CC genotype. Similarly, the TT genotype had a 1.94- and 3.83-fold increased risk for high-stage disease and metastasis, respectively, when compared with the CC genotype. For the MPO G-463A polymorphism, the GG genotype had 1.78-fold increased risk of prostate cancer compared with the AA genotype. However, no association was found regarding Gleason score, advanced and metastatic prostate cancer risk. CONCLUSIONS: It seems that there is no association of prostate cancer with MnSOD Ile58Thr polymorphism, whereas the TT genotype in the CAT C-262T polymorphism and the GG genotype in the MPO G-463A polymorphism may be associated with increased prostate cancer risk. The TT genotype in the CAT C-262T gene polymorphism may also be a risk factor in tumour progression and metastasis among Turkish men.

Association between genetic variants of DNA repair genes and coronary artery disease.

Polymorphisms in DNA repair genes may be associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of atherosclerosis. Genetic research on coronary artery disease (CAD) has traditionally focused on investigation aimed at identifying disease-susceptibility genes. The aim of this study was to investigate the relationship between AP-endonuclease-1 (Asp148Glu), XRCC1 (Arg399Gln), XRCC3 (Thr241Met), XPD (Lys751Gln), XPG (Asp1104His), and hOGG1 (Ser326Cys), gene polymorphisms and the risk of developing CAD in a Turkish population. The study population consisted of 197 patients with acute coronary syndrome (ACS) with chronic CAD and 135 healthy subjects' age and sex matched. Gene polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism method. We demonstrated for the first time, a positive association of XRCC3 and hOGG1 DNA repair gene variants with CAD risk. XRCC3 Thr/Thr genotype and Thr allele frequencies were significantly increased in ACS and chronic CAD patients compared with the control group (p<0.05). It was also observed that there is a protective role of XRCC3 Met alleles against both ACS and chronic CAD (p<0.05). hOGG1 Cys alleles were found significantly higher in ACS patients than in the control group and carriers of the Cys allele had a 1.7-fold increased risk for ACS. In addition, we confirmed the association of XRCC3 Thr241Met and hOGG1 Ser326Cys gene variants with CAD by haplotype analysis. We found that CAD risk is associated with XRCC3 Thr: hOGG1 Cys haplotype, whereas XRCC3 Met: hOGG1 Ser haplotype was found to be protective against the disease. The preliminary results suggested that XRCC3 and hOGG1 genetic variants may be risk factors by affecting the enzyme's function that may lead to development of CAD.

Nitric oxide synthase (eNOS4a/b) gene polymorphism is associated with tumor recurrence and progression in superficial bladder cancer cases.

PURPOSE: We investigated the relationship between the distribution of the eNOS4a/b polymorphism and the clinical features of superficial bladder cancer. MATERIALS AND METHODS: This study included 201 healthy controls with a mean ± SD age of 62.35 ± 7.96 years and 123 patients with a mean age of 64.03 ± 11.00 years diagnosed with histopathologically confirmed superficial bladder cancer. The eNOS4a/b polymorphism genotype (aa, bb or ab) was identified by polymerase chain reaction. Blood glutathione and plasma malondialdehyde levels were measured by spectrophotometry as an indicator of oxidative stress. We estimated total plasma levels of nitric oxide metabolites using a colorimetric assay kit. RESULTS: There were no significant differences in age or body mass index between patients and controls. Malondialdehyde and nitric oxide metabolite levels were statistically significantly increased (p = 0.000 and 0.024, respectively) and glutathione levels were decreased (p = 0.000) in patients with superficial bladder cancer. The bb genotype of the eNOS4a/b polymorphism is the most frequent one in the Turkish population and the aa genotype was significantly more common in patients with superficial bladder cancer (p = 0.000). Also, the aa plus ab genotype was significantly more common in patients with high grade tumors (p = 0.013) and in those with more progression to muscle invasive disease (p = 0.000). This genotype was also a significant independent risk factor for recurrence after adjusting for smoking status, stage, grade and the presence of carcinoma in situ on logistic regression analyses (OR 3.095, 95% CI 1.21-7.86, p = 0.018). CONCLUSIONS: The current study suggests that a genotype containing the a allele of the eNOS4a/b polymorphism may be a risk factor for bladder cancer. Additionally, patients harboring the aa plus ab genotype are more likely to experience tumor recurrence and progression.

Association between SDF1-3'A or CXCR4 gene polymorphisms with predisposition to and clinicopathological characteristics of prostate cancer with or without metastases.

In the present study, we aimed to investigate the association between SDF1-3'A and CXCR4 gene polymorphisms and the susceptibility and clinicopathological development of prostate cancer. SDF1-3'A and CXCR4 gene polymorphisms were assessed by polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP) in 149 healthy subjects and 152 patients with prostate cancer. There were no significant differences in the distributions of SDF-1 and CXCR4 genotypes between controls and prostate cancer patients. However, the patients with AA genotype of SDF1-3'A gene presented a higher risk for developing an advanced disease status as compared to patients with GG homozygotes (aOR = 2.02; 95 % CI = 1.05-3.90; P = 0.035). In addition, the distribution of AA genotype of SDF1-3'A gene was found significantly increased in the patients with bone metastasis in comparison to those without bone metastasis (aOR = 2.94; 95 % CI = 1.26-6.82; P = 0.012). On the other hand, CXCR4 gene polymorphism was not associated with the clinicopathological characteristics of prostate cancer. Our results suggest that SDF1-3'A and CXCR4 gene polymorphisms may not be risk factors for the susceptibility to prostate cancer. However, SDF1-3'A gene polymorphism may be associated with the progression and bone metastasis of prostate cancer in a Turkish men population.

The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer.

The gene variants of the chemokine and chemokine receptor genes associated with inflammation may be involved in cancer initiation and progression. The aim of this study was to explore the possible association of monocyte chemoattractant protein-1 (MCP-1) A2518G, stromal cell derived factor 1 (SDF-1) 3'A and chemokine receptors CCR2A V64I, CCR5 Δ32, CCR5 59029 and CXCR4 gene polymorphisms with the risk and clinicopathological characteristics of bladder cancer (BC) in a Turkish population. The genotyping was done by PCR and PCR-Restriction Fragment Length Polymorphism (RFLP) methods in 142 histologically confirmed BC patients and 197 controls. The SDF-1 3'AA genotype conferred significantly increased susceptibility to BC. The carriers with AA genotype or at least one A allele of CCR2 had an increased risk of developing BC. CCR5 wt/Δ32 genotype and CCR5 Δ32 allele were also observed to be involved in the susceptibility to BC. Additionally, the combination of CCR2 V64I and CCR5 Δ32 (i.e., GG-wt/Δ32) was found to be associated with BC risk. With respect to the stage of BC, the AA genotype of SDF-1 and at least one T allele of CXCR4 were significantly associated with high T stage as compared to GG genotype of SDF-1 and CC genotype of CXCR4. Furthermore, BC patients with AA genotype or at least one A allele of CCR2 had an increased risk of high grade and stage tumors as compared to those with GG genotype. Our results suggest that the genetic variants of SDF-1 3'A, CCR2A V64I and CCR5 Δ32 gene polymorphisms may modify the BC risk. Furthermore, SDF-1 3'A, CCR2A V64I and CXCR4 gene polymorphisms may contribute to the muscle invasive BC in a Turkish population.

Association of polymorphisms in MCP-1, CCR2, and CCR5 genes with the risk and clinicopathological characteristics of prostate cancer.

The aim of our study was to determine the effect of monocyte chemotactic protein-1 (MCP-1), CC chemokine receptor 2 (CCR2), and CC chemokine receptor 5 (CCR5) gene polymorphisms on the susceptibility and clinicopathological characteristics of prostate cancer. Genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method in 156 histopathologically confirmed prostate cancer patients and 152 healthy subjects. Individuals with AA genotype or at least one A allele of CCR2 V64I gene polymorphism had a higher risk for prostate cancer as compared with those with GG genotype (p=0.010 and p=0.028, respectively). CCR5 Δ32/wt genotype and CCR5 Δ32 allele were also found to be involved in the susceptibility to prostate cancer (p=0.028 and p=0.030, respectively). However, there was no significant association between MCP-1-2518 A/G gene polymorphism and prostate cancer risk. Prostate cancer patients carrying AA genotype or at least one A allele of CCR2 V64I had significantly increased risk for high stage disease (p=0.002 and p=0.039, respectively) and metastasis (p=0.004 and p=0.022, respectively). The CCR2 A allele (64I allele) was significantly associated with high T stage (p=0.001) and metastasis (p=0.005) as compared with CCR2 G allele (64V allele). Our data indicate that gene polymorphism of CCR2 V64I may influence the susceptibility and clinicopathological characteristics of prostate cancer and CCR5 Δ32 allele may also be an important risk factor for prostate cancer in Turkish men population.

Increased risk of advanced prostate cancer associated with MnSOD Ala-9-Val gene polymorphism.

We aimed to investigate the association between manganese superoxide dismutase (MnSOD) Ala-9-Val gene polymorphism and the initiation and/or progression of prostate cancer (PCa) as well as to evaluate its potential interactions with advanced age and smoking status. MnSOD Ala-9-Val gene polymorphism was carried out in 134 (mean age 64.1±7.48) PCa patients and 159 (mean age 62.5±7.53) healthy controls with serum prostate specific antigen (PSA) levels (<4 ng/ml) and normal digital rectal examination (DRE) findings in this prospectively designed study. PCa patients were classified as low stage disease (T1 or T2 and N0M0 stages) and high stage disease (T3 or T4 and N0M0 or N1 or M1 stages). Genotypes for MnSOD Ala-9-Val gene polymorphism were identified by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFPL). Despite lack of association between different genotypes of MnSOD Ala-9-Val gene polymorphism and the presence of PCa, patients with Ala/Ala genotype were at an increased risk of high stage disease compared with those with the Val/Val genotype [odds ratio (OR), 3.77; 95% CI, 1.30-10.94; P=0.012]. However, no significant difference was observed in the distribution of each genotype among PCa patients, with respect to tumor grade. On the other hand, smoking status and aging did not seem to change the association between genotypes and PCa risk. Ala/Ala genotype of MnSOD polymorphism may have an effect on adverse features of PCa such as high stage disease.

Genetic variants of MnSOD and GPX1 and susceptibility to bladder cancer in a Turkish population.

This study was conducted to investigate the association of genetic polymorphisms in the MnSOD and GPX1 genes with the risk and invasiveness of bladder cancer in a Turkish population. This prospectively designed study enrolled 157 patients with bladder cancer (mean age 63.2 ± 10.86 years) and 224 healthy controls (mean age 61.7 ± 8.39 years). Genotyping of the MnSOD Ala-9Val and GPX1 Pro198Leu polymorphisms was carried out by PCR-RFLP. No significant difference was found in MnSOD genotype distributions between the controls and the bladder cancer patients. However, the Leu/Leu genotype of GPX1 was associated with a significantly higher risk of bladder cancer than the Pro/Pro genotype. When stratified according to tumor stage, the Leu/Leu genotype of GPX1 was more frequently observed in bladder cancer patients with high-stage tumors than those with low-stage tumors. Additionally, patients carrying both Ala/Ala of MnSOD and Leu/Leu of GPX1 had the highest risk of developing bladder cancer. In conclusion, the present study indicates that the GPX1 Pro198Leu polymorphism may be associated with the risk and development of invasive bladder cancer. In addition, the combination of the MnSOD Ala/Ala and GPX1 Leu/Leu genotypes may have a synergistic effect on disease risk.

Despite the lack of association between different genotypes and the presence of prostate cancer, endothelial nitric oxide synthase a/b (eNOS4a/b) polymorphism may be associated with advanced clinical stage and bone metastasis.

OBJECTIVES: To investigate the relationship between the distribution of endothelial NO synthase (eNOS4a/b) gene polymorphism and clinical features of prostate cancer (PCa). METHODS AND MATERIALS: One hundred thirty-two patients with PCa (mean age 64.10 ± 7.23 years) and 158 healthy controls (mean age 62.50 ± 7.53 years) with normal serum total prostate specific antigen (PSA) levels (<4 ng/ml) and digital rectal examinations (DRE) were enrolled in this prospectively designed study. PCa patients were classified as clinical T1 and T2 stages (Group 1), clinical T3 and T4 stages without bone metastasis (Group 2), and patients with bone metastasis (Group 3). Genotypes (aa, bb, ab) for eNOS4a/b gene polymorphisms were identified by polymerase chain reaction analysis. Meanwhile, plasma nitrate and nitrite levels (NO(x)) were used to estimate the amounts of endogenous NO formation for both groups of patients. RESULTS: Despite lack of statistically significant differences between PCa patients and the control group in terms of distribution of genotypes and frequency of alleles, plasma NO(x) levels were found to be significantly increased in PCa patients compared with controls. Meanwhile, there was no significant difference between the group of PCa patients with high and low grade tumors (Gleason score ≥ 7 vs. < 7) in terms of genotype (aa + ab genotypes or a-allele vs. bb genotype) distribution. However, bb genotype was observed to be present at a higher frequency (85.1% vs. 60%) in Group 1; whereas a-allele was more frequent in Group 2 (13.3% vs. 5.7%) and Group 3 (26.7 vs. 9.2). In addition, patients with a-allele had a 3.79-fold risk of having advanced disease and bone metastasis in comparison with bb genotype. Moreover, multivariable logistic regression analysis revealed that eNOS4a/b polymorphism and plasma NOx levels were predictive factors for developing bone metastasis and high stage disease after adjustment for age and BMI. CONCLUSIONS: Our data did not reveal any relationship between any of these genotypes and the presence of PCa. However, the finding that PCa patients with bb genotype generally manifest localized disease and develop bone metastasis less frequently in comparison patients with a-allele may indicate an important role for this polymorphism in the molecular pathophysiology of PCa.