5-azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity.

Epigenetic 5-azacitidine (AZA) therapy of high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) represents a promising, albeit not fully understood, approach. Hematopoietic transcription factor PU.1 is dynamically regulated by upstream regulatory element (URE), whose deletion causes downregulation of PU.1 leading to AML in mouse. In this study a significant group of the high-risk MDS patients, as well as MDS cell lines, displayed downregulation of PU.1 expression within CD34+ cells, which was associated with DNA methylation of the URE. AZA treatment in vitro significantly demethylated URE, leading to upregulation of PU.1 followed by derepression of its transcriptional targets and onset of myeloid differentiation. Addition of colony-stimulating factors (CSFs; granulocyte-CSF, granulocyte-macrophage-CSF and macrophage-CSF) modulated AZA-mediated effects on reprogramming of histone modifications at the URE and cell differentiation outcome. Our data collectively support the importance of modifying the URE chromatin structure as a regulatory mechanism of AZA-mediated activation of PU.1 and induction of the myeloid program in MDS.

[Pancreatic cancer--association with diabetes mellitus and smoking]. / Pankreatický karcinom--vztah k diabetes mellitus a kourení.

INTRODUCTION: Pancreatic cancer is a disease with rather poor prognosis. This can be explained, among other reasons, by unusually aggressive course of the tumour growth and, in the majority of cases, late, and thus further treatment limiting, diagnosis. In addition, no effective screening programme for pancreatic cancer is available and thus identification of risk factors associated with the development of pancreatic cancer represents a possible approach to diagnosing early stages of the disease. Smoking represents a general and diabetes mellitus a specific risk factor for pancreatic cancer. The aim of our prospective study in pancreatic cancer patients was to identify patients with diabetes mellitus and divide these into smokers and non-smokers--in association with the diagnosis of pancreatic carcinoma. MATERIALS AND METHODS: We included 83 patients, 50 men and 33 women, with pancreatic cancer who were divided into 3 groups--non-smokers with diabetes mellitus, smokers and smokers with diabetes mellitus; the mean age was 64.2 years in male and 59.8 years in female patients. Pancreatic cancer was confirmed histomorphologically from pancreatic biopsies or a histology of pancreatic tissue obtained during a surgery. RESULTS: Pancreatic cancer was diagnosed after 3 or more years in patients with diabetes mellitus, the majority of diagnoses in smokers were made within the first year from the first dyspeptic symptoms. We found that the proportion of patients with subsequent diagnosis of pancreatic cancer increased with the number of cigarettes smoked per day (33.3% up to 10 cigarettes per day and 66.5% over 10 cigarettes per day). The highest incidence of pancreatic cancer, in 42 persons (50.6%), was associated with concurrent diabetes and smoking. CONCLUSION: Pancreatic cancer was identified in 24% of patients with diabetes mellitus, 25.3% of smokers with no diabetes and in more than 50% of smokers with diabetes mellitus. We assume that smoking is an independent risk factor for pancreatic cancer induction and it importantly increases the risk of pancreatic cancer in patients with diabetes mellitus.

[Pathologic gastroesophageal reflux in patients with bronchial asthma]. / Patologický gastroezofageální reflux u pacientu s astmatem bronchiale.

Gastrooesophageal reflux (GER) and asthma bronchiale are frequent diseases. Asthma affects some 3-10% of adults. Gastrooesophageal reflux is present in some 45-89% asthmatic patients. Symptoms of GER are not only gastrooesophageal, and recently increased attention is focused on extraoesophageal symptoms where in particular the relationship of GER and asthma or chronic cough is investigated. At our clinic we implemented a pilot study with the objective to monitor the presence of pathological GER in patients with asthma and to assess whether antireflux therapy will influence the respiratory complaints of the patients. The group was formed by 14 patients selected at random with different severity of asthma and different symptoms of GER. The patients had a baseline examination evaluating the presence of GER (24-hour pH metry) and pulmonary function (FEV1). In case of a pathological GER the patients were treated by antireflux therapy and then check-up examinations were made. It was found that after treatment of GER in patients with asthma in particular subjective symptoms improved such as cough and pyrosis which leads to a substantial improvement of the quality of life. On the other hand reflux treatment did not exert a basic effect on pulmonary functions and it was not possible to reduce the medication of asthma.

[Importance of assessment of Helicobacter pylori antigen in faeces]. / Prínos stanovení antigenu Helicobacter pylori ve stolici.

Diagnostic methods for the detection of Helicobacter pylori (H.P.) can be divided into invasive and non-invasive ones. Among non-invasive methods we can include now also detection of H.P. antigen in faeces. The objective of our study was to evaluate the sensitivity ans specificity of the test when monitoring the eradication therapy, as compared with another non-invasive test and to test the method in common clincal practice. H.P. positivity was based on the result of the histological examination and CLO test. Repeatedly samples of faeces were collected to detect H.P. antigen in faeces before the onset of and after eradication treatment. For detection of H.P antigen the commercial Premier Platinum HpSa set was used which was developed on the principle of enzyme immunoanalysis. From the assembled data the sensitivity value (87.1%) and specificity values (88.5%) was calculated. The test correlates well with the results of the CLO test, histological examination and the breath test and is thus a suitable method for the detection of H.P. positive subjects as well as for checking the success of eradication treatment of H.P.