Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their value for detection of adenomas and adenocarcinomas

Expression of Transcribed Ultraconserved Regions (T-UCRs) is often deregulated in cancer. The present study assesses the expression and methylation of three T-UCRs (Uc160, Uc283 and Uc346) in colorectal cancer (CRC) and explores the potential of T-UCR methylation in circulating DNA for the detection of adenomas and adenocarcinomas. Expression levels of Uc160, Uc283 and Uc346 were lower in neoplastic tissues from 64 CRC patients (statistically significant for Uc160, p<0.001), compared to non-malignant tissues, while methylation levels displayed the inverse pattern (p<0.001, p=0.001 and p=0.004 respectively). In colon cancer cell lines, overexpression of Uc160 and Uc346 led to increased proliferation and migration rates. Methylation levels of Uc160 in plasma of 50 CRC, 59 adenoma patients, 40 healthy subjects and 12 patients with colon inflammation or diverticulosis predicted the presence of CRC with 35% sensitivity and 89% specificity (p=0.016), while methylation levels of the combination of all three T-UCRs resulted in 45% sensitivity and 74.3% specificity (p=0.013). In conclusion, studied T-UCRs’ expression and methylation status are deregulated in CRC while Uc160 and Uc346 appear to have a complicated role in CRC progression. Moreover their methylation status appears a promising non-invasive screening test for CRC, provided that the sensitivity of the assay is improved

Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study

Objective. To assess the efficacy of rituximab (RTX) in SSc

Metabolite Cross-Feeding Enhances Virulence in a Model Polymicrobial Infection

Microbes within polymicrobial infections often display synergistic interactions resulting in enhanced pathogenesis; however, the molecular mechanisms governing these interactions are not well understood. Development of model systems that allow detailed mechanistic studies of polymicrobial synergy is a critical step towards a comprehensive understanding of these infections in vivo. In this study, we used a model polymicrobial infection including the opportunistic pathogen Aggregatibacter actinomycetemcomitans and the commensal Streptococcus gordonii to examine the importance of metabolite cross-feeding for establishing co-culture infections. Our results reveal that co-culture with S. gordonii enhances the pathogenesis of A. actinomycetemcomitans in a murine abscess model of infection. Interestingly, the ability of A. actinomycetemcomitans to utilize L-lactate as an energy source is essential for these co-culture benefits. Surprisingly, inactivation of L-lactate catabolism had no impact on mono-culture growth in vitro and in vivo suggesting that A. actinomycetemcomitans L-lactate catabolism is only critical for establishing co-culture infections. These results demonstrate that metabolite cross-feeding is critical for A. actinomycetemcomitans to persist in a polymicrobial infection with S. gordonii supporting the idea that the metabolic properties of commensal bacteria alter the course of pathogenesis in polymicrobial communities

Overexpression of phosphorylated p27(Kip1) at threonine 187 may predict outcome in aggressive B-cell lymphomas

Phosphorylation of p27<SUKip1</SU at threonine 187 (pThr187-p27<SUKip1</SU) occurs frequently in the development of human tumors, directing protein polyubiquitination and subsequent proteasomal degradation. We investigated the immunoexpression of p27<SUKip1</SU and pThr187-p27<SUKip1</SU in 126 B-cell lymphomas and their relation to proliferative activity and clinical parameters. Increased levels of p27<SUKip1</SU and pThr187-p27<SUKip1</SU were significantly correlated with indolent and aggressive lymphomas, respectively (p aEuroS < aEuroS0.001). pThr187-p27<SUKip1</SU expression showed a strong positive correlation with proliferation index in aggressive (p aEuroS== aEuroS0.01) and indolent (p aEuroS < aEuroS0.001) subgroups. Survival analysis revealed that pThr187-p27<SUKip1</SU was an unfavorable prognostic factor for disease-free (p aEuroS== aEuroS0.019) and overall survival (p aEuroS== aEuroS0.003) in aggressive lymphomas. Cox regression analysis demonstrated that the prognostic value of pThr187-p27<SUKip1</SU was independent of the international prognostic index (IPI) score, tumor stage, patient age, and serum lactate dehydrogenase (LDH) level. Overall, our results suggest that high levels of pThr187-p27<SUKip1</SU may predict a worse clinical outcome in patients with aggressive lymphomas.</

Altered trafficking of CD8(+) memory T cells after implantation of rapamycin-eluting stents in patients with coronary artery disease

Aim of this study was to investigate the effects of implantation of different coronary drug-eluting stents on trafficking of central (T-CM) or effector (T-EM) memory T cells in the coronary sinus of patients with coronary artery disease (CAD) undergoing percutaneous coronary revascularization. Thirty-two patients presenting with stable coronary disease and angiographically proven stenosis of left descending coronary artery were randomly assigned to treatment with rapamycin-eluting, paclitaxel-eluting or bare metal stents. Heparinized blood samples were obtained from the coronary sinus either before or 20 min after stent implantation. Mononuclear cells were stained with mAbs specific for CD3. CD4, CD8, CD45R0, and CD27 molecules. Analysis of surface phenotype was performed by four-color flow cytometry and data on both CD4(+) and CD8(+) T-CM and T-EM cells were expressed either as absolute cell numbers/muL of blood or as percentages relative to the corresponding total memory T cell populations in the individual patients. We found that the number of CD8(+) T-EM, as defined by CD3(+)CD45R0(+)CD8(+)CD27(-) phenotype, was significantly reduced in patients receiving a rapamycin-eluting stent as compared with basal values. Conversely, the number of CD8(+) T-CM (CD3(+)CD45R0(+)CD8(+)CD27(+)) was increased in the same treatment group after the revascularization procedure. No changes in the absolute number of CD4(+) and CD8(+) total (T-CM plus T-EM) memory T cells before and after the procedure were observred. These findings suggest that rapamycin eluted from medicated coronary stents rapidly induce a redistribution of memory CD8+ T lymphocyte subsets, with a significant decrease of T-EM and a corresponding increase of T-CM increase circulating within the coronary sinus. This anti-inflammatory effect could partially explain the reduction of coronary in-stent restenosis rate associated with the clinical use of this typed of device. (C) 2004 Published by Elsevier B.V