The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma

The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy±surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P=0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P=0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value

EFFECT OF POLYPHOSPHATES ON THE ACTIVITY OF AMINE OXIDASES

The interaction between polyphosphates and polyamines was investigated by P-31-NMR spectroscopy and by amine oxidase activity measurements. An apparent competition between negatively charged polyphosphates (ATP, ADP, AMP, tripolyphosphate and pyrophosphate) and positively charged polyamine, for the active site of bovine serum and soybean seedling amine oxidases, was observed by activity measurements. This behavior was explained by formation of polyamine-polyphosphate complexes and the stability constants of these complexes were calculated by P-31 NMR. However, at a given concentration of polyphosphate, the amine oxidase activity was found higher than that expected on the basis of the free amine concentration calculated according to the NMR stability constant, This fact, and the different extent of inhibition of the spermidine oxidase activity of soybean seedling and of bovine serum amine oxidases observed in the presence of a given polyphosphate, suggest that amine oxidases may be active also on the polyamine-polyphosphate complexes. This hypothesis was supported by the strong dependence of the k(cat)/K-m of bovine serum amine oxidase on ionic strength, indicating an electrostatic interaction between the charged amine and the active site, while no effect of ionic strength on k(cat)/K-m was observed in the presence of ATP. A kinetic model of this behavior was found to fit the experimental data

Mechanisms of regulatory T-cell suppression – a diverse arsenal for a moving target

Naturally-occurring regulatory T cells (Tregs) are emerging as key regulators of immune responses to self-tissues and infectious agents. Insight has been gained into the cell types and the cellular events that are regulated by Tregs. Indeed, Tregs have been implicated in the control of initial activation events, proliferation, differentiation and effector function. However, the mechanisms by which Tregs disable their cellular targets are not well understood. Here we review recent advances in the identification of distinct mechanisms of Treg action and of signals that enable cellular targets to escape regulation. Roles for inhibitory cytokines, cytotoxic molecules, modulators of cAMP and cytokine competition have all been demonstrated. The growing number of inhibitory mechanisms ascribed to Tregs suggests that Tregs take a multi-pronged approach to immune regulation. It is likely that the relative importance of each inhibitory mechanism is context dependent and modulated by the inflammatory milieu and the magnitude of the immune response. In addition, the target cell may be differentially susceptible or resistant to distinct Treg mechanisms depending on their activation or functional status at the time of the Treg encounter. Understanding when and where each suppressive tool is most effective will help to fine tune therapeutic strategies to promote or constrain specific arms of Treg suppression

Selenium, nickel, and calcium levels in cancerous and non-cancerous prostate tissue samples and their relation with some parameters

In the present study, tissue samples of patients with cancerous and non-cancerous prostate were analyzed for their Se, Ni, and Ca contents. Possible relationship between Se, Ni, and Ca concentrations and some parameters including preoperative prostate-specific antigen (PSA) levels, histopathological neurovascular invasion, extra-capsular extension, seminal vesicle invasion, positive surgical margins, PSA relapse after radical prostatectomy, and total Gleason scores were obtained. Inductively coupled plasma (ICP) optical emission spectrometry and ICP-mass spectrometry instruments were used for the determination of analytes interested. All the system parameters in digestion and measurement steps were optimized to obtain efficient digestion and sensitive measurements. There was no statistically meaningful difference observed in the concentration of selenium in cancerous and benign prostatic tissues (p = 0.347) while nickel levels in cancerous tissues were observed as significantly lower than benign tissues (p < 0.001). In addition, calcium concentration in cancerous tissue samples were found to be statistically lower than those in benign tissues (p < 0.001) with mean values of 657 and 1,431 mg/kg, respectively

CUORE-0 detector: Design, construction and operation

The CUORE experiment will search for neutrinoless double-beta decay of 130Te with an array of 988 TeO2 bolometers arranged in 19 towers. CUORE-0, the first tower assembled according to the CUORE procedures, was built and commissioned at Laboratori Nazionali del Gran Sasso, and took data from March 2013 to March 2015. In this paper we describe the design, construction and operation of the CUORE-0 experiment, with an emphasis on the improvements made over a predecessor experiment, Cuoricino. In particular, we demonstrate with CUORE-0 data that the design goals of CUORE are within reach