Proteasome inhibitor MG132 enhances TRAIL-induced apoptosis and inhibits invasion of human osteosarcoma OS732 cells

MG132 as a proteasome inhibitor could induce apoptosis in various cancer cells. This study aimed to discuss the effect of proteasome inhibitor MG132 on the TRAIL-induced apoptosis of human osteosarcoma OS732 cells. MG132 and TRAIL were applied on OS732 cells respectively or jointly. Cell survival rates, changes of cellular shape, cell apoptosis and cell invasion were analyzed, respectively, by 3-(4,5)-dimethylthiahiazo(-z-y1)-2,5-di-phenytetrazoliumromide (MTT) assay, inverted phase contrast microscope, flow cytometry, and transwell invasion chamber methods. The protein levels of DR5, caspase-3, caspase-8, p27^kip1 and MMP-9 were measured by Western blot analysis. The results indicated that combination of MG132 and TRAIL had the effect of up-regulating expression of DR5, caspase-3, caspase-8 and p27^kip1, down-regulating expression of MMP-9 and inducing apoptosis as well as suppressing the ability of invasion of OS732 cells. The survival rate of combined application of 10 μM MG132 and 100 ng/ml TRAIL on OS732 cells was significantly lower than that of the individual application (p < 0.01). Changes of cellular shape and apoptotic rates also indicated the apoptosis-inducing effect of combined application was much stronger than that of individual application. Cell cycle analysis showed combination of MG132 and TRAIL mostly caused OS732 cells arrested at G2–M-phase. The invasion ability of OS732 cells was restrained significantly in the combined group compared with the individual group and control group.     

Association between interleukin-6 gene − 174 G/C polymorphism and the risk of coronary heart disease: A meta-analysis of 20 studies including 9619 cases and 10,919 controls

Interleukin-6 (IL-6) gene − 174 G/C polymorphism has been reported to be associated with coronary heart disease (CHD), but the results remain inconclusive. The present meta-analysis was therefore designed to clarify these controversies. This meta-analysis was performed by searching PubMed, Embase and Web of Science databases. A total of 20 studies including 9619 CHD cases and 10,919 controls were combined showing no evidence of association between IL-6 gene − 174 G/C polymorphism and CHD risk (for C/C + C/G vs. G/G: OR = 1.10, 95% CI = 0.99–1.22, p = 0.07; for C/C vs. C/G + G/G: OR = 1.08, 95% CI = 0.93–1.24, p = 0.33; for C/C vs. G/G: OR = 1.16, 95% CI = 0.97–1.39, p = 0.11; for C allele vs. G allele: OR = 1.10, 95% CI = 1.00–1.21, p = 0.06). Moreover, we also did not find significant association between IL-6 gene − 174 G/C polymorphism and myocardial infarction (MI) risk. However, in the subgroup analysis by ethnicity, significant association was found among Asians (for C/C + C/G vs. G/G: OR = 1.35, 95% CI = 1.05–1.63, p = 0.02). In summary, the present meta-analysis suggests that IL-6 gene − 174 G/C polymorphism is associated with increased CHD risk among Asians. However, due to the small subjects included in the subgroup analysis of Asians, the results should be interpreted with caution.     

Association of the interleukin-10 − 592A/C, − 1082G/A and − 819T/C gene polymorphisms with type 2 diabetes: A meta-analysis

There is more evidence that interleukin-10 (IL-10), as a multifunctional regulatory cytokine of inflammatory responses, may have an important role in type 2 diabetes (T2D). However, genetic association studies that evaluated the relationship between IL-10 gene variants and T2D have produced conflicting results. The aim of this study was to determine whether the IL-10 gene polymorphisms (− 592A/C, − 1082G/A, − 819T/C) conferred susceptibility to T2D through a meta-analysis. A comprehensive search was conducted to examine all the eligible studies. A total of 9 studies involving 2838 T2D patients and 2773 controls were considered in the meta-analysis. Overall, there was no significant association between IL-10 − 592A/C and T2D (A vs C: OR = 0.93, P = 0.625; AA + AC vs CC: OR = 0.89, P = 0.511; AA vs AC + CC: OR = 0.93, P = 0.821). We failed to find the association between the IL-10 − 1082G allele and T2D (OR = 1.04, P = 0.430), but the genotypes of the IL-10 − 1082G/A polymorphism conferred a risk for the development of T2D (GA vs AA: OR = 1.21, P = 0.027; GG + GA vs AA: OR = 1.17, P = 0.048). Analysis of the − 819T/C polymorphism revealed no significant association with T2D (T vs C: OR = 1.04, P = 0.853; TT + TC vs CC: OR = 1.07, P = 0.834; TT vs TC + CC: OR = 1.08, P = 0.824). In conclusion, the present meta-analysis suggests association between the IL-10 − 1082G/A polymorphism and T2D. However, additional well-designed and larger scale primary studies are required to further evaluate the IL-10 gene polymorphisms and T2D.     

Association study of CD36 single nucleotide polymorphisms with essential hypertension in the Northeastern Han Chinese

We found that cluster determinant 36 (CD36) gene is up-regulated in essential hypertension (EH) patients in our former research, but the association between CD36 gene variations and EH has not yet been clearly demonstrated. The relationship between CD36 gene single nucleotide polymorphisms (SNPs) and EH in the northeastern Han Chinese was examined in the present study through direct sequencing and genotype-detection. A total of 589 unrelated northeastern Han Chinese including 276 with EH and 313 controls were studied. SNPs in exon 7, exon 13 and intron 4 were detected using PCR-sequencing. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). + 216T/C, + 273A/G, + 132C/T, + 217T/C, + 212T/G and + 233T/C polymorphisms were identified. Distributions of genotypes AA, GA and GG of + 273A/G polymorphism were significantly different between EH group and the control group (χ²: 9.056, p = 0.011) and G allelic frequency was higher in EH (p = 0.006, OR = 1.629, 95% CI [1.224–2.168]). Logistic regression analysis showed that + 273A/G polymorphism was closely associated with blood pressure (BP) after adjusting for ages. When subclassified by sex, the genotype distribution of + 273A/G (p = 0.011) and allelic frequency of G allele (p = 0.006) were significantly different between EH participants and controls in males, but not in females. Subgroup analysis performed by body mass index (BMI) suggested that the genotype distribution of + 273A/G and allelic frequency were significantly different in non-obese group and non-obese men, but the associations were not significant (non-obese group: p = 0.016, OR = 1.664, 95% CI [1.459–2.409]; non-obese men: p = 0.073, OR = 1.898, 95% CI [1.033–3.487]). + 273A/G polymorphism in CD36 gene was associated with EH, and + 273G could be an independent predictor.     

The interleukin-4 − 589C/T polymorphism and the risk of asthma: A meta-analysis including 7345 cases and 7819 controls

Background

A number of studies assessed the association of − 589C/T polymorphism in the promoter region of interleukin-4 (IL-4) with asthma in different populations. However, the results were contradictory. A meta-analysis was conducted to investigate the association between polymorphism in the IL-4 and asthma susceptibility.

Methods

Databases including Pubmed, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

Thirty-four studies involving 7345 cases and 7819 controls were included. Overall, significant association between − 589C/T polymorphism and asthma was observed for TT + CT vs. CC (OR = 1.26; 95% CI 1.12–1.42; P = 0.0001; I² = 26%). In the subgroup analysis by ethnicity, significant associations were found among Asians (OR = 1.36; 95% CI 1.07–1.73; P = 0.01; I² = 0%) and Caucasians (OR = 1.30; 95% CI 1.09–1.54; P = 0.004; I² = 53%) but not among African Americans (OR = 1.20; 95% CI 0.72–2.00; P = 0.48; I² = 48%). In the subgroup analysis by atopic status, no significant association was found among atopic asthma patients (OR = 1.20; 95% CI 0.92–1.34; P = 0.27; I² = 6%) and non-atopic asthma patients (OR = 0.97; 95% CI 0.73–1.28; P = 0.81; I² = 0%).

Conclusions

This meta-analysis suggested that the IL-4 − 589C/T polymorphism was a risk factor of asthma.     

Influence of interleukin-6 gene − 174G>C polymorphism on development of atherosclerosis: A meta-analysis of 50 studies involving 33,514 subjects

Increasing epidemiological studies have focused on the associations between interleukin-6 (IL-6) gene − 174G>C polymorphism and atherosclerotic diseases, but the results are still controversial. This meta-analysis was designed to identify whether this association exists. PubMed, Embase, Web of Science, Cochrane database, Clinicaltrials.gov and Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. The crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the IL-6 gene − 174G>C polymorphism and atherosclerosis ( AS ) risk. The subgroup analyses were made on the following: ethnicity, atherosclerotic diseases and source of controls. Finally, 50 studies (15,029 cases and 18,485 controls) were included in this meta-analysis. Overall, no significant association was found between the IL-6 gene − 174G>C polymorphism and AS risk (for C allele vs. G allele: OR = 1.02, 95% CI = 0.94–1.11, p = 0.64; for C/C vs. G/G: OR = 1.01, 95% CI = 0.85–1.21, p = 0.88; for C/C vs. C/G + G/G: OR = 0.97, 95% CI = 0.84–1.12, p = 0.68; for C/C + C/G vs. G/G: OR = 1.07, 95% CI = 0.97–1.17, p = 0.18). In the subgroup analyses, significant associations were found between the IL-6 gene − 174G>C polymorphism and AS in non-Caucasian group (for CC + CG vs. GG: OR = 1.22, 95% CI = 1.06–1.41, p = 0.005), other atherosclerotic diseases group (for C allele vs. G allele: OR = 0.75, 95% CI = 0.61–0.93, p = 0.008; for C/C vs. G/G: OR = 0.56, 95% CI = 0.38–0.81, p = 0.002; for C/C vs. C/G + G/G: OR = 0.60, 95% CI = 0.45–0.79, p = 0.0004) and population-based group (for C allele vs. G allele: OR = 1.09, 95% CI = 1.00–1.18, p = 0.04; for CC + CG vs. GG: OR = 1.15, 95% CI = 1.04–1.27, p = 0.005). In summary, the present meta-analysis suggests that the IL-6 gene − 174G C polymorphism is associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution.     

Association of peroxisome proliferator activated receptor-γ gene with non-alcoholic fatty liver disease in Asian Indians residing in north India

Background

Genetics of non-alcoholic fatty liver (NAFLD) in Asian Indians has been inadequately studied. We investigated the association of polymorphisms C161T and Pro12Ala of peroxisome proliferator-activated receptor gamma (PPARγ) with clinical and biochemical parameters in Asian Indians with NAFLD.

Methods

In this case–control study, 162 NAFLD cases and 173 controls were recruited. Abdominal ultrasound, clinical and biochemical profiles, fasting insulin levels and value of homeostasis model assessment of insulin resistance were determined. Polymerase chain reaction–restriction fragment length polymorphisms of two polymorphisms were performed. The association of these polymorphisms with clinical and biochemical parameters was analysed.

Results

Higher frequency of Ala and T alleles of PPARγ was obtained in cases. Ala/Ala genotype of PPARγ (Pro12Ala) was associated with significantly higher serum triglycerides (TG), alkaline phosphatase (ALK) and waist–hip ratio in cases as compared to controls. In C161T polymorphism, TT genotype was significantly increased TG (p = 0.04), total cholesterol (p = 0.01), ALK (p = 0.04) and gamma-glutamyl transpeptidase (p = 0.007) in cases. The linkage disequilibrium for these two single-nucleotide polymorphisms of PPARγ was differed in cases (D1 = 0.1; p = 0.006) and controls (D1 = 0.07; p = 0.1). Using a multivariate analysis after adjusting for age, sex and body mass index, the presence of NAFLD was linked to these two polymorphisms (odds ratio 1.64 (95% CI: 1.09–2.45, p = 0.05)].

Conclusion

Asian Indians in north India carrying the alleles Ala and T of PPARγ (Pro12Ala and C161T) polymorphisms are predisposed to develop NAFLD.     

Association between -251A>T polymorphism in the interleukin-8 gene and oral cancer risk: A meta-analysis

Background

Emerging evidence showed that the most common functional polymorphism (-251A>T, rs4073) in the promoter region of the interleukin-8 (IL-8) gene is involved in the regulation of the activities of interleukin-8, thus increasing an individual's susceptibility to oral cancer; but individually published results are inconclusive. The aim of this meta-analysis was to investigate the associations between IL-8 -251A>T polymorphism and oral cancer risk.

Methods

The PubMed, Embase, Web of Science and CBM databases were searched for all articles published up to October 1st, 2012 that addressed IL-8 -251A>T polymorphism and oral cancer risk. Statistical analyses were performed using STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

Six case–control studies were included with a total of 1324 oral cancer cases and 1879 healthy controls. When all available studies were pooled into the meta-analysis, the results showed that the AA and AT genotypes of IL-8 -251A>T polymorphism were associated with increased risk of oral cancer (OR = 1.23, 95% CI: 1.03–1.46, P = 0.025; OR = 1.25, 95% CI: 1.07–1.47, P = 0.006; respectively). In the subgroup analysis by ethnicity, significant associations were observed between the AA and AT genotypes of IL-8 -251A>T polymorphism and increased risk of oral cancer among Caucasian populations (OR = 1.40, 95% CI: 1.14–1.72, P = 0.001; OR = 1.29, 95% CI: 1.06–1.57, P = 0.011; respectively). However, no statistically significant associations were found between IL-8 -251A>T polymorphism and oral cancer risk among Asian populations.

Conclusions

Results from the current meta-analysis indicate that the AA and AT genotypes of IL-8 -251A>T polymorphism might increase the risk of oral cancer, especially among Caucasian populations.     

Proteasome Inhibitors Cause Induction of Heat Shock Proteins and Trehalose, Which Together Confer Thermotolerance in Saccharomyces cerevisiae

An accumulation in cells of unfolded proteins is believed to be the common signal triggering the induction of heat shock proteins (hsps). Accordingly, in Saccharomyces cerevisiae, inhibition of protein breakdown at 30°C with the proteasome inhibitor MG132 caused a coordinate induction of many heat shock proteins within 1 to 2 h. Concomitantly, MG132, at concentrations that had little or no effect on growth rate, caused a dramatic increase in the cells’ resistance to very high temperature. The magnitude of this effect depended on the extent and duration of the inhibition of proteolysis. A similar induction of hsps and thermotolerance was seen with another proteasome inhibitor, clasto-lactacystin β-lactone, but not with an inhibitor of vacuolar proteases. Surprisingly, when the reversible inhibitor MG132 was removed, thermotolerance decreased rapidly, while synthesis of hsps continued to increase. In addition, exposure to MG132 and 37°C together had synergistic effects in promoting thermotolerance but did not increase hsp expression beyond that seen with either stimulus alone. Although thermotolerance did not correlate with hsp content, another thermoprotectant trehalose accumulated upon exposure of cells to MG132, and the cellular content of this disaccharide, unlike that of hsps, quickly decreased upon removal of MG132. Also, MG132 and 37°C had additive effects in causing trehalose accumulation. Thus, the resistance to heat induced by proteasome inhibitors is not just due to induction of hsps but also requires a short-lived metabolite, probably trehalose, which accumulates when proteolysis is reduced.     

Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children

Background

Variability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children.

Methods

Genotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (C_trough) and between 1 and 2 h after (C_post-dose) the administration of the next dose of drug. CD4⁺ T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r.

Results

MDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~ 50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV C_post-dose than homozygotes 1236TT (median C_post-dose = 3.04 μg/ml and 6.50 μg/ml, respectively; p = 0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36 weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes = − 0.50 log₁₀ copies/ml and − 2.08 log₁₀ copies/ml, respectively; p = 0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR.

Conclusions

Our results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4⁺ T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression.     

Characterisation of allergen-specific responses of IL-10-producing regulatory B cells (Br1) in Cow Milk Allergy

CD19+CD5+ regulatory B cells regulate immune responses by producing IL-10. IL-10-producing regulatory B cell (Br1) responses by allergen stimulation were investigated in human food allergy. Six milk allergy patients and eight milk-tolerant subjects were selected according to DBPCFC. PBMCs were stimulated by casein in vitro and stained for intracellular IL-10 and apoptosis. In response to allergen stimulation, Br1 decreased from 26.2 ± 18.3 to 15.5 ± 8.9% (p = 0.031, n = 6) in the milk allergy group and increased from 15.4 ± 9.0 to 23.7 ± 11.2% (p = 0.023, n = 8) in the milk-tolerant group. Apoptotic non-IL-10-producing regulatory B cells increased from 21.8 ± 9.3 to 38.0 ± 16.1% (p = 0.031, n = 6) in the milk allergy group and unchanged from 28.8 ± 13.8 to 28.0 ± 15.0% (p = 0.844, n = 8) in the milk-tolerant group. Br1 may be involved in the immune tolerance of food allergies by producing IL-10 and simultaneously undergoing apoptosis in humans. The exact roles for Br1 in immune tolerance needs to be further investigated.     

Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome

Cardiovascular manifestations in patients with Marfan syndrome (MFS) are related to aortic and valvular abnormalities. However, dilatation of the left ventricle (LV) can occur, even in the absence of aortic surgery or valvular abnormalities. We evaluated genetic characteristics of patients with MFS with LV dilatation. One hundred eighty-two patients fulfilling the MFS criteria, without valvular abnormalities or previous aortic surgery, with a complete FBN1 analysis, were studied. FBN1 mutations were identified in over 81% of patients. Twenty-nine patients (16%) demonstrated LV dilatation (LV end diastolic diameter corrected for age and body surface area > 112%). FBN1-positive patients carrying a non-missense mutation more often had LV dilatation than missense mutation carriers (14/74 versus 5/75; p < 0.05). Finally, FBN1-negative MFS patients significantly more often demonstrated LV dilatation than FBN1-positive patients (10/33 versus 19/149; p < 0.05). It is concluded that LV dilatation in MFS patients is more often seen in patients with a non-missense mutation and in those patients without an FBN1 mutation. Therefore physicians should be aware of the possibility of LV dilatation in these patients even in the absence of valvular pathology.     

The extrapituitary prolactin promoter polymorphism is associated with rheumatoid arthritis and anti-CCP antibodies in Mexican population

Prolactin (PRL) is a hormone–cytokine that has been involved in autoimmunity due to its immunoregulatory and lymphoproliferative effects. It is produced by various extrapituitary sites including immune cells, under control of a superdistal promoter that contains a single nucleotide polymorphism − 1149 G/T previously associated with rheumatoid arthritis (RA) susceptibility in European population. The aim of this study was to investigate the association of the extrapituitary PRL − 1149 G/T promoter polymorphism with clinical parameters, clinical activity and disability indices in RA patients from Western Mexico and to analyze the PRL mRNA expression according to the PRL − 1149 G/T promoter polymorphism in total leucocytes from RA patients and controls. We conducted a case–control study that included 258 RA patients and 333 control subjects (CS). The DNA samples were genotyped using the PCR–RFLP method and the PRL mRNA expression was determined by quantitative real time PCR. PRL serum levels and antibodies to cyclic citrullinated peptides (anti-CCP) were measured with ELISA. We found significant differences in the genotype (p = 0.022) and allelic (p = 0.046) distribution of the polymorphism between RA patients and control subjects. According to the dominant genetic model, there is an association between the T allele (GT + TT genotypes) and decreased RA susceptibility in comparison to the G allele carriers (GG genotype) (OR 0.64, 95% CI 0.45–0.92; p = 0.011). The T allele carriers (GT + TT genotypes) had lower titers of anti-CCP antibodies in comparison to the G allele carriers (GG genotype) (median, 66 U/mL vs. 125 U/mL; p = 0.03). Furthermore, the GG homozygotes had higher PRL mRNA expression in comparison to the GT heterozygotes, and this latter with respect to the TT homozygotes, in both groups (RA: 1 > 0.72 > 0.19; CS: 1 > 0.54 > 0.28). However, PRL serum levels were similar in both groups. Our results suggest that the PRL − 1149 T allele is a genetic marker for decreased RA susceptibility and is associated with lower titers of anti-CCP antibodies in Mexican population. We also suggest influence of genotype upon PRL mRNA expression.     

No association between MTHFR C677T polymorphism and completed suicide

MTHFR C677T polymorphism (rs1801133) was associated with numerous psychiatric conditions but no prior study investigated whether it predisposes to completed suicide. We typed rs1801133 in 692 suicide victims and 3257 controls representative of a Polish adult population (the WOBASZ cohort). Although we had a power of 0.8 to detect (at alpha 0.05) an allelic OR = 1.19, we did not find significant difference among suicides vs. controls in the prevalence of the MTHFR 677T allele (OR = 1.02, p = 0.759) or the TT genotype (OR = 1.01, p = 0.926). Since among controls we found an association between TT and depression defined by Beck Depression Inventory (BDI, OR = 1.61, p = 0.049) we also compared suicides with controls without signs of depression (BDI ≤ 11) but found no association (OR = 1.0, p = 0.976). Analyses within suicides showed trends (not significant after Bonferroni correction) for correlations between the dose of the T allele and age at death among males and blood ethanol concentration among females, who committed suicide under the influence of alcohol. We conclude that MTHFR C677T polymorphism is not a risk factor for completed suicide. The sex-specific trends for correlations between rs1801133 and age at death, and blood ethanol concentration should be studied further.     

Neurohormonal and cytokine fluctuations following transcatheter closure for an atrial septal defect

Introduction

Inflammation and neurohormonal activation are considered to be involved in the development of earlier and/or later complications in congenital heart disease patients, even after a successful repair of the lesion. It is not yet clarified what is the role of the therapeutic interventions in the occurrence of such a response and how it could be associated with possible postoperative complications.

Aim

We sought to assess the inflammatory and neurohormonal response to transcatheter closure of secundum type atrial septal defects (ASD) over a six-month follow-up period. We also evaluated the association between the respective markers and catheterization data as well as echocardiographic measurements.

Methods

Plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), N-terminal-proatrial natriuretic peptide (NT-proANP) and N-terminal-probrain natriuretic peptide (NT-proBNP) were assessed and echocardiographic measurements were performed in twenty-eight patients with atrial septal defect prior to, and at the first, second and sixth months post transcatheter closure. Thirty-three age-matched healthy volunteers were also enrolled.

Results

IL-6 plasma levels, although higher preoperatively, [physical logarithm (ln) IL-6: 3.37 ± 0.66 vs 2.92 ± 0.44 pg/ml, p = 0.015], reached control levels postoperatively, at the end of the third month, whereas TNF-α and IL-10 were not influenced by the procedure. NT-proANP levels were elevated preoperatively compared to the control group (ln NT-proANP 3.78 ± 0.572 vs 3.48 ± 0.30, p = 0.031), with a further significant increase during the 1st month (ln NT-proANP 3.78 ± 0.572 vs 4.2 ± 0.42, p = 0.006), following the pattern of the left atrial volume enlargement, and remained high even 6 months after the procedure .On the other hand, the initially normal concentrations of NT-proBNP, after a transient significant increase during the first month postoperatively (ln NT-proBNP 3.56 ± 0.94 vs 4.58 ± 0.91, p < 0.0001) returned to the controls’ levels at the end of the third month. Preoperative concentrations of NT-proANP positively correlated with NT-proBNP concentrations and pulmonary to systemic flow ratio (Qp/Qs).

Conclusions

Transcatheter closure could improve, on a mid- term basis, the inflammatory process but natriuretic peptides’ secretion continues in parallel with left atrial volume increase. Further follow up is required to determine the long-term progress of the inflammatory and neurohormonal response to the procedure.     

Genetic association of interleukin-10 promoter polymorphisms and susceptibility to diffuse large B-cell lymphoma: A meta-analysis

Published data on the association between interleukin-10 (IL-10) gene polymorphisms and diffuse large B-cell lymphoma (DLBCL) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed, focusing on four major IL-10 gene variants in the promoter region: –3575T/A, –1082A/G, –819C/T and –592C/A. We applied the false discovery rate (FDR) method to adjust for multiple testing. A significant association between IL-10 –3575T/A polymorphism and the risk of DLBCL was observed in the pooled 10 case–control studies (A vs. T: OR = 1.16, 95% CI = 1.08–1.25, P < 0.0001; AA + TA vs. TT: OR = 1.20, 95% CI = 1.08–1.33, P = 0.0009; AA vs. TA + TT: OR = 1.25, 95% CI = 1.09–1.44, P = 0.001). The results indicated that carriers of –1082G allele (–1082GG/GA genotypes) had a nearly 30% increased risk of DLBCL, as compared with carriers of –1082AA genotype (GG + GA vs. AA: OR = 1.30, 95% CI = 1.08–1.57, P = 0.005). When P-values were not adjusted for multiple testing, the risk was significantly decreased among people with –592AA genotype (AA vs. AC + CC: OR = 0.63, 95% CI = 0.43–0.94, P = 0.02), while carriers with –819TT genotype also modestly weakened the DLBCL susceptibility at a marginal level of significance (TT vs. CT + CC: OR = 0.59, 95% CI = 0.35–0.99, P = 0.05). However, these associations were not significant after correction for multiple testing. This meta-analysis suggests that IL-10 –3575A allele confers a greater risk to DLBCL susceptibility, while –1082A/G polymorphism also has significant association with DLBCL risk. These results may help to further clarify the malignancy-risk gene signature of DLBCL, and thus have prognostic and predictive value especially for early-stage DLBCL.     

Estrogen receptor expression and vessel density in the vagina wall in postmenopausal women with prolapse

After menopause, critically estrogen low levels result in modifications in vaginal wall. This cross-sectional study aims to determine whether there is a change in the number of vessels in the lamina propria of the vagina after menopause in parallel to the ER-alpha expression on the vaginal wall. Twelve women who underwent a genital surgery for genital prolapse up to grade II were selected. They were divided into two groups: a premenopausal group (PG) consisting of six women who were 18–40 years old with FSH levels =12 mIU/ml and regular cycles, and a menopausal group (MG) consisting of six women at least one year after menopause who were <65 years old with FSH levels =40 mIU/ml. Slides were stained for ER-alpha immunohistochemistry, and an endothelial cell marker CD3 was used to label vessels which were identified by using a system for morphometry. The number of vessels was significantly higher in the PG than in the MG both on the anterior wall (PG: 1.055 ± 145.8 vessels/mm², MG: 346.6 ± 209.9 vessels/mm², p < 0.0001) and on the posterior wall (PG: 1064 ± 303.3 vessels/mm², MG: 348.6 ± 167.3 vessels/mm², p = 0.0005). The ER-alpha score was significantly higher in the PG than the score for the MG on both the anterior and posterior walls (PG: 6.0 ± 0.52, MG: 2.5 ± 0.89, p = 0.007; PG: 5.8 ± 0.79, MG: 2.7 ± 0.95, p = 0.03, respectively). There was a positive correlation between the ER-alpha score and the vessel concentration on the anterior (r = 0.6656, p = 0.018) and posterior (r = 0.6738, p = 0.016) vaginal walls. Age was strongly negatively correlated with vessel concentration on the vaginal walls (respectively r = -0.9033, p < 0.0001, r = -0.7440, p = 0.0055). Therefore, postmenopausal women with genital prolapse have a smaller number of vessels on the vaginal wall compared to normoestrogenic controls with the same pathological condition. Hypoestrogenism and advancing age are factors that are associated to these changes.     

Allergen-specific B cell subset responses in cow’s milk allergy of late eczematous reactions in atopic dermatitis

B cells have regulatory functions in immune responses. Antigen-specific responses of B cell subsets by allergen stimulation ex vivo were examined in milk allergy of late eczematous reactions. Eight milk allergy subjects and 13 milk tolerant subjects were selected by DBPCFC. PBMCs were stimulated by casein ex vivo and stained for B cell subsets using monoclonal antibodies. CD19+ B cells unchanged from 8.7 ± 3.8% to 8.0 ± 5.1% (p = 0.504, n = 8) in the milk allergy group and decreased in the milk tolerant group from 8.5 ± 3.2% to 5.0 ± 1.6% (p = 0.001, n = 13). The fraction of apoptotic B cells in B cells significantly decreased 4.4 ± 3.1% to 1.3 ± 0.4% (p = 0.027, n = 4) in the allergy group and insignificantly increased from 2.8 ± 0.6% to 5.4 ± 2.6% (p = 0.059, n = 6) in the milk tolerant group. CD5+ regulatory B1 cell% in B cells decreased in milk allergy subjects from 36.2 ± 5.0% to 31.0 ± 5.7% (p = 0.010) and unchanged in milk tolerant subjects from 41.6 ± 10.2% to 43.8 ± 10.0% (p = 0.413). IL-10 producing CD19+CD5+ regulatory B cell% in CD19+CD5+ regulatory B cells significantly decreased from 24.9 ± 6.5% to 13.8 ± 5.6% (p = 0.002, n = 5) by casein stimulation in milk allergy group and unchanged from 44.8 ± 11.3% to 43.9 ± 10.0% (p = 0.297, n = 5) in the milk tolerant group. B cell subset responses to IL-4 and IL-5 were also similar in both groups. B cell subset changes seemed to have diagnostic value. Exact immunologic roles of regulatory CD5+ B1 cells need further investigation.     

Cloning and expression analysis of novel Aux/IAA family genes in Gossypium hirsutum

The associations between polymorphisms of prostate stem cell antigen (PSCA-rs2294008C > T and -rs2976392G > A) and gastric cancer (GC) risk for Eastern Asians have been commonly studied, but the results were conflicting. The aim of the present study was to further assess the associations by the method of meta-analysis. The databases of Medline, Embase and CNKI (up to May 25th, 2011) were retrieved to identify eligible case-control studies. Odds ratio (OR) and 95% confidence interval (95%CI) were used to present the strength of the associations. In total, eight case-control studies in seven articles with 16792 individuals (9738 cases of GC and 7054 controls) were included in this meta-analysis. Through quantitative analyses, we found that T allele of rs2294008C > T and A allele of rs2976392G > A were significantly associated with increased GC risk [rs2294008C > T: OR (95%CI) = 1.31 (1.22-1.42), P_z-test < 0.001, P_{heterogeneity} = 0.166 for TT vs. C carriers; rs2976392G > A: OR (95%CI) = 1.36(1.24-1.50), P_z-test = 0.015, P_{heterogeneity} = 0.111 for AA vs. G carriers]. The results of subgroup analyses (according to histopathology, countries and sources of controls) indicated that T allele of rs2294008C > T and A allele rs2976392G > A were associated with increased risk of both intestinal- and diffuse-type GC, and associated with increased risk of GC for Chinese, Japanese, Koreans, PCC and HCC/PHCC. Furthermore, T allele of rs2294008C > T was also associated with increased risk of cardia and non-cardia GC, and associated with increased risk of GC for males and females. Besides those, this meta-analysis also indicated that the interactions between T allele of rs2294008C > T and A allele of rs2976392G > A was associated with increased risk of GC (A-T vs. G-T: OR = 1.16, 95%CI = 1.06-1.27, P_z-test = 0.001, P_{heterogeneity} = 0.835). Although modest limitations and potential bias cannot be eliminated, this meta-analysis suggests that PSCA -rs2294008C > T and -rs2976392G > A are potential factors of GC development for Eastern Asians, and future work may incorporate these findings and evaluate these variants as potential markers for screening and early diagnosis of GC.