Polymorphisms of glutathione-S-transferase M1 and T1 and prostate cancer risk in a Tunisian population

Several genes involved in the metabolism of carcinogenesis have been found to be polymorphic in the human population, and specific alleles are associated with increase risk of cancer of various sites. This study is focused on the polymorphic enzymes glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) that involved in the detoxification of many xenobiotics involved in the etiology of prostate cancer. Objective. To evaluate whether GSTM1 and/or GSTT1 contribute to prostate cancer (CaP) etiology, we studied 110 incident CaP cases and 122 controls. Results. The probability of having CaP was increased in men who had homozygous deleted (non-functional) genotypes at GSTT1 (OR = 2.17; 95% CI = 1–3.79) but not GSTM1 (OR = 0.89; 95% CI = 0.66–1.88). Hence, individuals lacking the GSTT1 gene are at approximately twofold higher risk of developing prostate cancer in comparison with individuals with at least one active allele in the GSTT1 locus. Conclusion. These results suggest that GSTT1 is associated with CaP risk. The effect of smoking associated with the GSTT10/0 genotype was not found to affect the risk of prostate cancer.     

CYP1AI, glutathione S-transferase gene polymorphisms and risk of Polycythemia vera

Background: Associations between polymorphisms for gene encoding enzymes involved in biotransformation of xenobiotics and susceptibility to several cancers have been shown in several studies. The aim of the present study was to evaluate the association of polymorphisms of cytochrome P450 (CYP1A1) and GST deletions with the incidence of Polycythemia vera (PV) among the Jordanian population. Methods: The study included 61 PV patients and 70 cancer-free healthy controls. CYP1A1 (m1, m2, m3, m4) and GST (T1, M1) genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism. The risk of cancer associated with gene polymorphisms was estimated by calculations of odds ratio (ORs) and confidence intervals (95% CIs) using Mantel–Haenszel statistics. Results: A statistically significant difference between the PV group and the control group was observed in the case of GSTM1 null genotype with 3.38 fold increase in risk of developing PV (95% CI = 1.63–7.01, p = 0.001) while GSTT1 null genotype showed no significance (OR = 1.11; 95% CI = 0.50–2.44, p = 0.38). No significant association was found between the CYP1A1 mutant genotypes (m1, m2, m4) and PV. The m3 genotype was absent in both patients and controls. Interestingly, a substantial significant increase of PV risk for the combination of GSTM1 null genotype and CYP1A1 m1 (T6235C) genotype was observed (OR = 4.38; 95% CI = 1.15–16.73, p = .02). Furthermore, the present case–control study showed that the studied Jordanian population generally resembles Caucasian populations with respect to the frequencies of CYP1A1 polymorphisms. Conclusion: Our data suggests that GSTM1 null genotype alone and in combination with CYP1A1 m1 genotype may be predisposing risk factors for PV in the Jordanian population.     

Serum interleukin-6 concentration reflects the extent of asymptomatic left ventricular dysfunction and predicts progression to heart failure in patients with stable coronary artery disease

BackgroundLeft ventricular ejection fraction (LVEF) remains one of the strongest predictors of long-term prognosis in patients with stable coronary artery disease (CAD). Asymptomatic left ventricular systolic dysfunction (LVSD) often precedes clinically overt heart failure (HF) and is an area of extensive research nowadays. We studied the association between serum IL-6 concentrations and the extent of LV dysfunction in patients with asymptomatic LVSD. We aimed to investigate the diagnostic value of serum IL-6 concentrations in predicting the risk of progression to HF. Seventy-one patients entered the study and were divided into three groups based on LVEF: group 1 – patients with LVEF <30% (N = 7), group 2 – patients with LVEF 30–50% (N = 37) and group 3 – patients with LVEF >50% (N = 27).ResultsDemographics were similar in all three groups. IL-6 concentration was the highest in group 1 (median 8.6 pg/mL) and the lowest in group 3 (median 2.6 pg/mL), whereas IL-6 concentration in group 2 was intermediate (median 3.7 pg/mL) (P = 0.002). We found a significant, inverse correlation between IL-6 concentration and ejection fraction. During 18-month follow-up clinically overt HF developed in 71.4% of patients in group 1 and in 37.5% of patients in group 2. None of the patients in group 3 manifested HF symptoms (P < 0.001). ROC analysis revealed high diagnostic value of serum IL-6 and LVEF in predicting progression to HF. We also found a strong, inverse correlation between IL-6 and the time of progression to HF.ConclusionsThere is a strong correlation between IL-6 and the extent of asymptomatic LVSD in patients with documented CAD. Elevated IL-6 concentrations preceded progression to clinically overt HF. Moreover, the higher the IL-6 concentration the earlier the manifestation of HF symptoms.     

The perioperative granulocyte/lymphocyte ratio is a clinically relevant marker of surgical stress in patients with colorectal cancer

PurposeThis study was to assess the clinical relevance of the blood granulocytes to lymphocytes (G/L) ratio as an early marker of surgical stress in patients with colorectal cancer.MethodsThirty-three patients with colorectal cancer were prospectively to undergo laparoscopic-assisted (n = 12) or open (n = 21) surgical resection. Granulocyte and lymphocyte counts were used to calculate the G/L ratios in blood samples from all patients before the operation and post-operatively on days 1, 3 and 7. Additionally, serum inflammatory cytokines, interleukin (IL)-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF) and macrophage (M)-CSF were assayed as markers of surgical stress.ResultsSeven of 33 patients developed unexpected complications. Serum IL-6 (P < 0.0001), G-CSF (P = 0.0257), and M-CSF (P < 0.0001) were higher on day 1 vs before the operation. Similarly, the G/L ratios were higher on days 1–3 vs before the operation (P < 0.0001) and then gradually decreased together with the surgical stress levels. The G/L ratios and the numbers of granulocytes and lymphocytes in the blood showed no correlation with serum IL-1β or TNF-α. In contrast, the G/L ratios and the numbers of granulocytes in the blood showed significant correlation with IL-6 (Rs = 0.710, P < 0.0001, Rs = 0.653, P < 0.0001, respectively), with G-CSF (Rs = 0.626, P < 0.0001, Rs = 0.578, P < 0.0001), with M-CSF (Rs = 0.470, P < 0.0001, Rs = 0.372, P < 0.0001). However, the number of lymphocytes showed inverse correlation with IL-6 (Rs = ?0.493, P < 0.0001), G-CSF (Rs = ?0.440, P < 0.0001) and M-SCF (Rs = ?0.443, P < 0.0001).ConclusionThe G/L ratio appears to be a simple and clinically relevant parameter for the assessment of perioperative stress in patients undergoing colorectal surgery.     

Association of systemic inflammation markers with the presence and extent of coronary artery calcification

BackgroundCoronary artery calcification (CAC) is a marker for the presence and extent of coronary atherosclerotic plaques and can be detected non-invasively by multi-detector row CT (MDCT). Well known predictors of CAC are age, gender, and the classical atherogenic risk factors. CAC is associated with atherosclerotic plaque burden, but it is still elusive if atherosclerosis-relevant cytokines and chemokines are also associated with CAC.MethodsWe conducted a clinical study among 455 consecutive individuals who underwent coronary calcium assessment performed by MDCT. Before MDCT, blood was drawn and subsequently analyzed for 20 different atherosclerosis-relevant cytokines and chemokines using a Luminex-laser-based fluorescence analysis.ResultsUsing univariate analyses, CAC patients revealed significantly higher levels of the chemokines IP-10 (P = 0.047) and eotaxin (P = 0.031) as compared to non-CAC patients. In multivariate analyses using common thresholds for calcium burden, the three cytokines interleukin-6 (P = 0.028), interleukin-8 (P = 0.009), and interleukin-13 (P = 0.024) were associated with high coronary calcium levels after adjustment for classical variables and risk factors.ConclusionsIn a large group of individuals with atypical chest pain and a low to intermediate likelihood for coronary artery disease elevated plasma levels of IL-6 and reduced levels of IL-8 and IL-13 were predictive for distinct coronary artery calcification. These findings support a specific role of these cytokines in coronary calcification.     

Improved prediction of all-cause mortality by a combination of serum total testosterone and insulin-like growth factor I in adult men

ObjectiveLower levels of anabolic hormones in older age are well documented. Several studies suggested that low insulin-like growth factor I (IGF-I) or testosterone levels were related to increased mortality. The aim of the present study was to investigate the combined influence of low IGF-I and low testosterone on all-cause mortality in men.Methods and resultsFrom two German prospective cohort studies, the DETECT study and SHIP, 3942 men were available for analyses. During 21,838 person-years of follow-up, 8.4% (n = 330) of men died. Cox model analyses with age as timescale and adjusted for potential confounders revealed that men with levels below the 10th percentile of at least one hormone [hazard ratio (HR) 1.38 (95% confidence-interval (CI) 1.06–1.78), p = 0.02] and two hormones [HR 2.88 (95% CI 1.32–6.29), p < 0.01] showed a higher risk of all-cause mortality compared to men with non-low hormones. The associations became non-significant by using the 20th percentile as cut-off showing that the specificity increased with lower cut-offs for decreased hormone levels. The inclusion of both IGF-I and total testosterone in a mortality prediction model with common risk factors resulted in a significant integrated discrimination improvement of 0.5% (95% CI 0.3–0.7%, p = 0.03).ConclusionsOur results prove that multiple anabolic deficiencies have a higher impact on mortality than a single anabolic deficiency and suggest that assessment of more than one anabolic hormone as a biomarker improve the prediction of all-cause mortality.     

Glutathione S-transferase polymorphisms and survival in African-American and White colorectal cancer patients

Background: Glutathione S-transferase (GST) enzymes are involved in electrophile detoxification. The authors investigated the association between GST genotype and survival in a racially diverse, population-based cohort of colorectal cancer (CRC) patients followed for a median of 9.6 years. Methods: Interviews were conducted with 315 African-American and White CRC patients in Connecticut, 1987–1991. Tumor tissue (n = 197) was later retrieved from hospital of diagnosis and assayed using multiplex PCR (GSTM1 and GSTT1) and PCR and RFLP analysis (GSTP1). Cox proportional hazards models provided adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: Individuals with Ile/Val or Val/Val GSTP1 genotypes had a decreased risk of death (multivariate adjusted HR = 0.72, 95% CI: 0.48, 1.09) relative to those with wild type (Ile/Ile). Among those who received chemotherapy, this benefit was more pronounced (HR = 0.35, 95% CI: 0.16, 0.79); the interaction of reduced function GSTP1 genotype and chemotherapy was significant (P = 0.05). GSTM1 and GSTT1 genotype were not associated with survival. GSTM1, GSTT1, and GSTP1 genotype did not vary by race and did not contribute significantly to the survival disadvantage observed in African-Americans. Conclusions: In summary, GSTP1 genotype may play a role in CRC survival in African-Americans and Whites, particularly among those who receive chemotherapy.     

The association between genetic damage in peripheral blood lymphocytes and polymorphisms of three glutathione S-transferases in Chinese workers exposed to 1,3-butadiene

1,3-Butadiene (BD) has been classified as a human carcinogen, group I; however, the relationship between polymorphisms of glutathione S-transferases that metabolize BD and chromosomal damage is not clear. The present study used sister chromatid exchange (SCE) and cytokinesis-block micronucleus (CBMN) assays to detect chromosomal damage in peripheral lymphocytes of 44 BD-exposed workers and 39 non-exposed healthy controls. PCR and PCR-RFLP were employed to detect three known glutathione S-transferase polymorphisms GSTT1, GSTM1, and GSTP1 (Ile105Val). The data demonstrated that the micronucleus (CBMN) frequency in BD-exposed workers was significantly higher than that in controls (frequency ratio (FR) = 1.48, 95% CI: 1.14–1.91, P < 0.01), and the CBMN frequency was higher in workers exposed to higher cumulative BD levels (FR = 1.70, 95% CI: 1.28–2.27, P < 0.01). However, differences in SCE frequency were not observed (FR = 1.14, 95% CI: 0.81–1.61, P > 0.05). Among exposed workers, chromosomal damage was related to BD exposure levels (FR = 1.35, 95% CI: 1.02–1.80, P < 0.05); age, older workers exhibited higher MN frequencies than younger workers (FR = 1.45, 95% CI: 1.14–1.84, P < 0.05); and years of work, those with more years of work exhibited higher MN frequencies than those with fewer years (FR = 1.40, 95% CI: 1.10–1.77, P < 0.05). Multivariate Poisson regression analysis showed that those who carried GSTM1 (?) (FR = 1.48, 95% CI: 1.14–1.92) or GSTT1 (?) (FR = 1.42, 95% CI: 1.10–1.83) genotypes, and especially those who carried both (FR = 2.10, 95% CI: 1.43–3.09) exhibited significantly higher MN frequencies than those carrying GSTM1 (+), GSTT1 (+) genotypes or their combination. The GSTP1 Val genotype did not affect MN frequency (P > 0.05). Our results suggested that higher levels of BD exposure in the workplace resulted in increased chromosomal damage, and that polymorphisms in GSTT1 and GSTM1 genes might modulate the genotoxic effects of BD exposure. Furthermore, the GSTT1 and GSTM1 polymorphisms exhibited an additive effect. Finally, urinary DHBMA was found to provide a biomarker that correlated with airborne BD levels.     

Role of proinflammatory markers and NT-proBNP in patients with an implantable cardioverter-defibrillator and an electrical storm

BackgroundSeveral studies have attempted to identify risk factors for the development of an electrical storm (ES), which is defined as ⩾3 separate ventricular tachyarrhythmic (VT/VF) events, but in the majority of studies no triggers have been found. However, little is known about the role of inflammation and NT-proBNP in patients with ES. The aim of this study was therefore to assess the relationship of Interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) and NT-proBNP serum concentrations in ICD-patients with or without single spontaneous ventricular tachyarrhythmic events (VT/VF) and in ES.MethodsMarkers were determined in 51 patients without ICD-intervention, in 15 ICD-patients with single VT/VF-episodes during 9-months follow-up and in 20 ICD-patients with ES (blood sampling performed within 60 min after fulfilling ES criteria). VT/VF-episodes were analysed by stored ICD-electrograms.ResultsAll patients had idiopathic dilated cardiomyopathy (n = 23) or coronary artery disease (n = 63). Patients with ES revealed significantly higher mean serum concentrations of all markers (IL-6 15.19 ± 10.34 pg/mL, hs-CRP 20.12 ± 14.4 mg/L, NT-proBNP 4799 ± 4596 pg/mL) compared to baseline values of patients with single VT/VF-events during follow-up (IL-6 8.37 ± 5.8 pg/mL (p = 0.03), hs-CRP 4.7 ± 5.3 mg/dL (p < 0.001), NT-proBNP 1913 ± 2665 pg/mL (p = 0.04)) and compared to baseline values of ICD-patients without device intervention (IL-6 4.62 ± 3.66 pg/mL (p < 0.001), hs-CRP 4.1 ± 3.4 mg/L (p < 0.001), NT-proBNP 1461 ± 2281 pg/mL (p < 0.001)). In 9/20 patients presenting with ES (45%) baseline values were available. All markers were significantly higher during ES compared to event-free determination (IL-6 14.54 ± 10.43 vs. 7.03 ± 2.83 pg/mL (p = 0.04), hs-CRP 19.07 ± 16.07 vs. 6.5 ± 3.9 mg/L (p = 0.02), NT-proBNP 4218 ± 2561 vs. 2099 ± 1279 pg/mL (p = 0.03)).ConclusionsElectrical storm is associated with significantly elevated IL-6, hs-CRP and NT-proBNP serum concentrations in ICD-patients with structural heart disease. Thus, ES may be triggered by proinflammatory activity. Combined intraindividual elevation of determined markers might help to identify patients at risk of impending electrical storm.     

Influence of related donor age on outcomes after peripheral blood stem cell transplantation

Background aimsThe rising use of allogeneic transplantation in older recipients necessitates considering older related donors. The effect of related donor age for peripheral blood stem cell allografts (PBSC) on graft maintenance and outcomes, independent of CD34⁺cell dose, has not been well-characterized.MethodsHLA-related donors (98% siblings) underwent a uniform filgrastim-based mobilization regimen aiming to collect and infuse 5 × 10⁶ CD34⁺ cells/recipient kg. Donor and recipient age were modeled in multiple ways to account for the correlation, and outcomes reported by decade of donor age.ResultsThe median donor and recipient ages were 52 years and 54 years, respectively. The mean CD34⁺ cell dose infused was 5.6 × 10⁶ CD34⁺/kg and 75% of patients received a narrow range between 4.4 and 6.6 × 10⁶ CD34⁺ cells/kg. Neither better PBSC mobilization nor higher CD34⁺ content of allografts was significantly associated with engraftment or transplant outcomes. After adjusting for recipient age and other prognostic factors, older donor age by decade conferred a lower risk of non-relapse mortality (NRM) [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.45–0.91, P = 0.013] and borderline improvement in overall survival (OS) (HR = 0.76, 95% CI 0.58–0.99, P = 0.045) without altering progression-free survival (PFS) (HR = 0.85, 95% CI 0.66–1.07, P = 0.18).ConclusionsOlder donor age does not worsen outcome after matched related donor PBSC transplantation in patients receiving a narrow range CD34⁺ cells. The relatively small sample size mandates that the finding of similar to improved outcomes for older related donor age must be confirmed in larger studies.     

Comparison and relationship of thyroid hormones,IL-6, IL-10 and albumin as mortality predictors in case-mix critically ill patients

ObjectiveTo compare the ability of thyroid hormones, IL-6, IL-10, and albumin to predict mortality, and to assess their relationship in case-mix acute critically ill patients.MethodsAPACHE II scores and serum thyroid hormones (FT3, FT4, and TSH), IL-6, IL-10, and albumin were obtained at EICU admission for 79 cases of mix acute critically ill patients without previous history of thyroid disease. Patients were followed for 28 days with patient’s death as the primary outcome. All mean values were compared, correlations assessed with Pearson’ test, and mortality prediction assessed by multivariate logistic regression and ROC.ResultsNon survivors were older, with higher APACHE II score (p = 0.000), IL-6 (p < 0.05), IL-10 (p = 0.000) levels, and lower albumin (p = 0.000) levels compared to survivors at 28 days. IL-6 and IL-10 had significant negative correlation with albumin (p = 0.001) and FT3 (p ⩽ 0.05) respectively, while low albumin had a direct correlation with FT3 (p < 0.05). In the mortality prediction assessment, IL-10, albumin and APACHE II were independent morality predictors and showed to have a good (0.70–0.79) AUC-ROC (p < 0.05). Despite that the entire cohort showed low FT3 serum levels (p = 0.000), there was not statistical difference between survivors and non-survivors; neither showed any significance as mortality predictor.ConclusionsIL-6 and IL-10 are correlated with Low FT3 and hypoalbuminemia. Thyroid hormones assessed at EICU admission did not have any predictive value in our study. And finally, high levels of IL-6 and IL-10 in conjunction with albumin could improve our ability to evaluate disease’s severity and predict mortality in the critically ill patients. When use in combination with APACHE II scores, our model showed improved mortality prediction.     

Preliminary observations on the association between serum IL-6 and hydration status and cardiovascular risk in patients treated with peritoneal dialysis

IntroductionSystemic inflammation, as defined by elevated blood IL-6, is a strong independent predictor of peritoneal dialysis (PD) patient survival. The present study has aimed to determine whether there exists a particular “phenotype” associated with high systemic IL-6 that characterizes PD patients in terms of their fluid status and cardiac parameters.MethodsFifty-seven prevalent PD patients were classified according to serum concentrations of IL-6. The degree of overhydration was assessed by bioimpedance analysis (BIA). Echocardiography and serum concentrations of NT-proBNP and troponin T were used to assess cardiovascular risk.ResultsPatients with high serum IL-6 were older, more often diabetic, treated with PD for longer, and significantly more overhydrated. There was a significant correlation between serum IL-6, hydration status (r = 0.38; p = 0.002) and serum albumin (r = −0.35; p = 0.009). Multivariate regression analysis confirmed a strong association of overhydration, hypoalbuminemia, and systemic IL-6 concentration. Patients with high IL-6 had significantly increased levels of both NT-proBNP (r = 0.36; p = 0.006) and TnT (r = 0.50; p < 0.001) in the absence of abnormalities in echocardiography.ConclusionsHigh systemic IL-6 identifies PD patients with increased cardiovascular risk that is significantly related to overhydration. Thus, the measurement of serum IL-6 may contribute to the more accurate assessment of cardiovascular status in patients undergoing PD.     

Glutathione S-transferase M1, T1, and P1 polymorphisms and thyroid cancer risk: A meta-analysis

Glutathione S-transferases (GSTs) genetic variants have been explored extensively as a predictive factor for cancer etiology. This meta-analysis aimed to examine the associations GSTM1, GSTT1, and GSTP1 genetic polymorphisms with thyroid cancer risk. PubMed, EMBASE, Cochrane Library, and HuGNet database were searched up to November 2011 using the appropriate terms. Twelve studies regarding GSTM1 null polymorphism (1569 cases and 2907 controls), 11 studies concerning GSTT1 null polymorphism (1515 cases and 2863 controls), and 8 studies on GSTP1 Ile105Val (965 cases and 1604 controls) were included in the meta-analysis. The random effects odds ratio was 1.07 (95% CI: 0.88–1.31; I² = 54.1%, P for heterogeneity = 0.013) for the GSTM1 null vs. present genotype and 1.08 (95% CI: 0.75–1.57; I² = 81.4%, P for heterogeneity < 0.001) for the GSTT1 null vs. present genotype, and 1.02 (95% CI: 0.70–1.49; I² = 74.6%, P for heterogeneity < 0.001) for the GSTP1 Val/Val + Val/Ile vs. Ile/Ile genotype. Similarly, no significant associations were demonstrated for subgroup analyses performed by ethnicity and histological type. In conclusion, these three polymorphisms are unlikely to be major determinants of susceptibility to thyroid cancer. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation. The relationship between these three genes and thyroid carcinoma must be evaluated further with gene–gene and gene–environment interactions.     

Increased serum TWEAK levels in Psoriatic arthritis: relationship with disease activity and matrix metalloproteinase-3 serum levels

ObjectivesWe measured serum levels of Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), interleukin 15 (IL-15), monocyte chemoattractant protein 1 (MCP-1), and matrix metalloproteinase (MMP)-3 for patients with Psoriatic arthritis (PsA), and investigated whether TWEAK levels are associated with clinical disease activity and expression of proinflammatory cytokines.MethodsForty five patients with PsA and forty five patients with osteoarthritis (OA) were involved in this study between January 2008 and December 2009. At the time of blood sample collection, the disease activity of patients with PsA was assessed according to the 28-joint count Disease Activity Score (DAS28). Serum levels of TWEAK, IL-15, MCP-1, and MMP-3 were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturers’ protocol.ResultsIn patients with PsA, serum TWEAK, IL-15, MCP-1 and MMP-3 levels were significantly elevated, and serum TWEAK levels showed a significant correlation with DAS28 (r = 0.405, p = 0.006) and serum MMP-3 levels (r = 0.375, p = 0.011).ConclusionsSerum TWEAK levels positively correlate with disease activity of PsA and confirm that TWEAK plays a crucial role in the pathogenesis of PsA. TWEAK may be a new important target for therapy in PsA.     

A simple method for identifying bone marrow mesenchymal stromal cells with a high immunosuppressive potential

Background aimsThe beneficial activity of mesenchymal stromal cells (MSC) in allogeneic hematopietic stem cell transplantation requires correct use in terms of cell dose and timing of infusion and the identification of biomarkers for selection. The immunosuppressive bone marrow (BM)-derived MSC (BM-MSC) functions have been associated with the production of soluble HLA-G molecules (sHLA-G) via interleukin (IL)-10. We have established a reliable method for evaluating BM-MSC HLA-G expression without the influence of peripheral blood mononuclear cells (PBMC).MethodsThirteen BM-MSC from donors were activated with recombinant IL-10 or co-cultured with 10 different phytohemagglutinin (PHA)-treated PBMC (PHA-PBMC). Membrane-bound and sHLA-G expression was evaluated by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively; lymphoproliferation was measured by (methyl-³H)thymidine.ResultsThe results demonstrated the ability of IL-10 to stimulate both membrane-bound and sHLA-G production by BM-MSC. The levels of HLA-G expression induced by IL-10 in BM-MSC were associated with the inhibition of PHA-PBMC proliferation (sHLA-G, P = 0.0008, r = 0.9308; membrane HLA-G, P = 0.0005, r = 0.9502).ConclusionsWe propose the evaluation of sHLA-G production in IL-10-treated BM-MSC cultures as a possible marker of immunoregulatory function.     

Family history of non-hematologic cancers among Waldenstrom macroglobulinemia patients: a preliminary study

BackgroundLittle is known about the epidemiology and etiology of Waldenstrom macroglobulinemia (WM). Despite several studies of the relation between family history and B-cell disorders and WM, family history of non-hematologic cancers has not been systematically investigated. We thus examined associations of family history of breast, colorectal, lung, ovarian, and prostate cancers with WM.MethodsAll probands aged 20–79 years with bone marrow biopsy-confirmed diagnosis of WM between May 1, 1999 and January 1, 2010 at the Bing Center for Waldenstrom Macroglobulinemia were eligible for inclusion in our analysis. We reviewed medical records for eligible probands to determine family history of cancer (defined as a cancer diagnosis for ≥1 first-degree relative(s) of the proband). Using expected values constructed from the United States National Health Interview Survey, we estimated age- and race-standardized rate ratios (RRs) for family history of breast, colorectal, lung, ovarian, and prostate cancers by WM subtype.ResultsFamily history of prostate cancer had the largest overall rate ratio (RR = 1.4, 95% confidence limits [CL]: 1.1, 1.7), and among sporadic cases, family history of prostate and breast cancer had the largest rate ratios (prostate: RR = 1.3, 95% CL: 1.1, 1.7; breast: RR = 1.3, 95% CL: 1.2, 1.6).ConclusionOur study suggests that it may be worthwhile to pursue these associations in a case–control study with uniform selection and data collection for cases and controls, and at least some record-based information on family history.     

Low serum zinc levels in patients undergoing coronary angiography correlate with immune activation and inflammation

IntroductionLow serum zinc concentrations are associated with adverse outcomes. To explain this phenomenon we aimed to investigate whether low zinc levels are related to immune activation, renal function and coronary artery disease (CAD).MethodsSerum concentrations of zinc and the immune activation markers neopterin and C-reactive protein (CRP) were measured in 2048 patients derived from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, a cohort study among patients referred for coronary angiography.ResultsZinc concentrations did not differ between patients with CAD (mean ± SD: 13.3 ± 2.4 μmol/L) and controls (13.3 ± 2.2 μmol/L; Welch's t test: p = n.s.) but CAD patients had higher neopterin (8.6 ± 7.4 nmol/L) and CRP (9.7 ± 19.6 mg/L) concentrations compared to controls (neopterin: 7.5 ± 4.8 nmol/L, p = 0.0005; CRP: 5.5 ± 10.0 mg/L, p < 0.0001). There was an inverse correlation between serum zinc concentrations and neopterin (Spearman's rank correlation: r_s = ?0.222) and CRP (r_s = ?0.166; both p < 0.0001) concentrations.ConclusionsOur results indicate increased inflammatory processes in patients with low zinc levels. Further studies should clarify whether inflammation related processes such as renal wasting contribute to zinc deficiency and underlie the adverse health consequences of low serum zinc levels.     

Expression of IL-32 modulates NF-κB and p38 MAP kinase pathways in human esophageal cancer

BackgroundEsophageal cancer is the seventh leading cause of cancer death in males in USA, and there is a strong link has been demonstrated between inflammation and esophageal cancer, interleukin (IL)-32 is a recently described pro-inflammatory cytokine characterized by the induction of nuclear factor NF-κB activation, the p38MAPK also plays an important role in key cellular processes related to inflammation and cancer. We investigated whether the IL-32 expression may be involved in esophageal carcinogenesis through modulates the activity of NF-κB and p-p38 MAPK.MethodMalignant esophageal tissue and blood samples were obtained from 65 operated untreated patients, normal samples was obtained from 35 patients operated for other reasons as control. IL-32 expression visualized by immunohistochemistry, Real time RT–PCR for IL-32 mRNA expression, NF-κB phosphorylation and phosphorylated p38mapk were analyzed by immunoblotting, ELISA for further detection IL-32 and cytokines (TNF-α, IL-1β, IL-6 and IL-8) concentration in the patient’s sera.ResultsIL-32 expression was increased in immunohistochemical staining for malignant esophageal tissue and it’s correlated with the relative expression level of IL-32 mRNA P = 0.007, the P-NF-κB level elevated in tumor tissue compared with control and no difference in the total NF-κB level P = 0.003 while the IL-32 up-regulated the P-pNF-κB in the esophageal tumor P = 0.005. There is increase in p-p38MAPK activation underlying IL-32 expression in tumor P = 0.004, but no change in total p38 MAPK in malignant esophagus. The plasma level of IL-32 expression was increased in malignant esophageal patients P = 0.01, with increased in the levels of the cytokines TNF-α, IL-6, and IL-1β P<0.05.ConclusionsUnderstanding the pathway of IL-32 expression to stimulate the secretion cytokines via the activation of NF-κB and up-regulation of p-p38MAPK may or may not prove to be a therapeutic target, or a biomarker, and future studies will finally answer this hypothesis generated.     

Interactions between Glutathione-S-Transferase M1, T1 and P1 polymorphisms and smoking,and increased susceptibility to esophageal squamous cell carcinoma

Background: A complex of genetic and environmental factors is involved in carcinogenesis of the esophageal squamous cell carcinoma (ESCC). Glutathione-S-Transferases (GSTs) are phase-II enzymes playing role in detoxification of carcinogen electrophiles. Genetic polymorphisms of GSTM1, GSTT1 and GSTP1 in association with some environmental factors and their impact on esophageal cancer susceptibility were assessed in the Iranian population. Methods: Genomic DNA of peripheral blood leukocytes from 148 confirmed esophageal cancer cases and 137 healthy individuals as control group was assayed for restriction fragment length polymorphisms in the GSTP1 loci by PCR amplification followed by digestion with Alw26I. Deletion of the GSTM1 and GSTT1 genes was detected by multiplex PCR. A data-mining method based on decision trees was applied to produce a predictive model of interactions between genotypes. Results: Smoking was independently associated with ESCC (p < 0.05, OR: 2.286, 95% CI = 1.311–3.983). Smoking along with GSTP1 Val/Val genotype was associated to ESCC (p < 0.001, OR: 3.886, 95% CI = 1.830–8.251), while non-smokers with GSTP1 Val/Val were significantly more frequent in non-cancerous group. (p = 0.007, OR: 0.507, 95% CI = 0.309–0.830). Conclusions: Data-mining methods are useful tools to map out a scheme for predicting complex relations and combinations of different genotypes. Genotyping analysis of GSTP1 together with assessment of smoking seems to be important in determining the risk of ESCC in the Iranian population.     

Th1/Th2 cytokine profile in childhood-onset systemic lupus erythematosus

ObjectiveTo determine the serum levels of Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines in childhood-onset SLE, first-degree relatives and healthy controls. To elucidate their association with disease activity, laboratory and treatment features.MethodsWe included 60 consecutive childhood-onset SLE patients [median age 18 years (range 10–37)], 64 first-degree relatives [median 40 (range 28–52)] and 57 healthy [median age 19 years (range 6–30 years)] controls. Controls were age and sex-matched to SLE patients. SLE patients were assessed for clinical and laboratory SLE manifestations, disease activity (SLEDAI), damage (SDI) and current drug exposures. Mood and anxiety disorders were determined through Becks Depression (BDI) and Anxiety Inventory (BAI). Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines levels were measured by ELISA and compared by non-parametric tests.ResultsSerum TNF-α (p = 0.004), IL-6 (p = 0.007) and IL-10 (p = 0.03) levels were increased in childhood-onset SLE patients when compared to first-degree relatives and healthy controls. TNF-α levels were significantly increased in patients with active disease (p = 0.014) and correlated directly with SLEDAI scores (r = 0.39; p = 0.002). IL-12 (p = 0.042) and TNF-α (p = 0.009) levels were significantly increased in patients with nephritis and TNF-α in patients with depression (p = 0.001). No association between cytokine levels and SDI scores or medication was observed.ConclusionTh1 cytokines may play a role in the pathogenesis of neuropsychiatric and renal manifestations in childhood-onset SLE. The correlation with SLEDAI suggests that TNF-α may be a useful biomarker for disease activity in childhood-onset SLE, however longitudinal studies are necessary to determine if increase of this cytokine may predict flares in childhood-onset SLE.