The Role of Gender-specific Cytokine Pathways as Drug Targets and Gender- specific Biomarkers in Personalized Cancer Therapy.

The definition of personalized treatments in tumor disease could lead to an improvement of the therapeutic success rate. Therefore, biomarkers are urgently required in order to select the patients that could benefit from adjuvant therapies in the initial phase of the disease and to better define and treat the clinical/therapeutic subgroups in the advanced pathological phases. Disregulation of cytokine physiological network is directly involved in the genesis and progression of tumors. Cytokines are of central importance in the regulation of immune system, but they are rarely released singly: each cytokine is able to induce the production of many other factors leading to a network in which they cooperate with other cell regulators such as hormones and neuropeptides. For these reasons the research must be directed to the evaluation of the interrelationships between the different cytokines and their respective pathways, as well as their contribution to the disease aetiology and progression in order to identify real and effective drug targets and biomarkers. The T CD4+ helper cells (Th) have various subpopulations, among which Th1, Th2, Th3, Th9 and Th17, respectively produce cytokines. It has become clear that disorders within the interactions of the network of these cytokines can produce neoplastic diseases. Furthermore, studies focusing on gender have shown that the homeostasis of the immune system is controlled by pathways of cytokines that are different between sexes and defined for this reason "genderspecifics". Therefore, this perspective article aims to highlight the significance of these cytokine pathways in order to identify new clinical strategies and personalized therapy in neoplastic diseases.

Autoregulation of XTcf-4 depends on a Lef/Tcf site on the XTcf-4 promoter.

The restricted expression of XTcf-4 in the anterior midbrain is regulated via an active wnt/beta-catenin pathway (Kunz et al.,2004, Dev Biol 273:390-401). The molecular mechanism of this autoregulatory loop, however, remained elusive. Here we show that the activity of a 1,775 bp promoter fragment containing a consensus Lef/Tcf binding site at position -1,437 to -1,428 is upregulated by activating transcription factors of the Lef/Tcf family. Furthermore, chromatin immunoprecipitation revealed that endogenous beta-catenin is bound to the Lef/Tcf site on the promoter. Thus, regulation of XTcf-4 by canonical wnt-signaling is directly controlled by binding to and activating a consensus Lef/Tcf binding site within its own promoter.

Dynamic colonization of Helicobacter pylori in human gastric mucosa.

OBJECTIVE: To investigate the dynamic behaviour of Helicobacter pylori in the colonization of the human gastric mucosa in patients previously treated for H. pylori infection. MATERIAL AND METHODS: Twenty-one dyspeptic patients were included in the study. Biopsies from each individual were taken and analysed for H. pylori detection using cultural, molecular and ultrastructural methods. RESULTS: Through culture, H. pylori was isolated in 7 out of 21 patients and the detection of the minimum inhibitory concentration (MIC) against drugs commonly used in H. pylori therapy revealed a susceptibility panel in which only one strain was multidrug resistant. By studying the expression of the H. pylori glmM constitutive gene, viable H. pylori cells were detected in 19 out of 21 analysed biopsies. In these positive cases, the expression of the Quorum-Sensing related gene, luxS, was always detected. The analysis of glmM and luxS sequences confirmed the H. pylori identity. Scanning electron microscopy (SEM) analysis of biopsies from patients harbouring culturable bacteria showed a prevalent "S-shape" H. pylori morphotype co-existent with coccoid aggregated bacteria embedded in an abundant matrix; while samples from patients shown as H. pylori-positive only through the molecular method showed clustered coccoid bacteria arranged in a microbial biofilm. CONCLUSIONS: In the present work we describe a new scenario in H. pylori mucosa colonization suggesting, in infection recalcitrance, the planning of more efficacious protocols in order also to identify camouflaged and protected clustered bacteria, taking into account this serious microbial problem in medicine in the recommendation of therapeutic regimens.