Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients.

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

Genetic Variant Screening of DNA Repair Genes in Myelodysplastic Syndrome Identifies a Novel Mutation in the XRCC2 Gene.

BACKGROUND: We aimed to detect single nucleotide polymorphisms (SNPs) and mutations in DNA repair genes and their possible association with myelodysplastic syndrome (MDS). METHODS: Targeted enrichment resequencing of 84 DNA repair genes was initially performed on a screening cohort of MDS patients. Real-time polymerase chain reaction was used for genotyping selected SNPs in the validation cohort of patients. RESULTS: A heterozygous frameshift mutation in the XRCC2 gene was identified. It leads to the formation of a truncated non-functional protein and decreased XRCC2 expression level. Decreased expression levels of all DNA repair genes functionally connected with mutated XRCC2 were also present. Moreover, a synonymous substitution in the PRKDC gene and 2 missense mutations in the SMUG1 and XRCC1 genes were also found. In the screening cohort, 6 candidate SNPs were associated with the tendency to develop MDS: rs4135113 (TDG, p = 0.03), rs12917 (MGMT, p = 0.003), rs2230641 (CCNH, p = 0.01), rs2228529 and rs2228526 (ERCC6, p = 0.04 and p = 0.03), and rs1799977 (MLH1, p = 0.04). In the validation cohort, only a polymorphism in MLH1 was significantly associated with development of MDS in patients with poor cytogenetics (p = 0.0004). CONCLUSION: Our study demonstrates that genetic variants are present in DNA repair genes of MDS patients and may be associated with susceptibility to MDS.

[PCSK9 inhibitors - new possibilities in the treatment of hypercholesterolemia: For which patients will be indicated?Czech atherosclerosis society statement]. / PCSK9 inhibitory - nové moznosti v lécbe hypercholesterolemie: U koho budou indikovány?Stanovisko Ceské spolecnosti pro aterosklerózu.

First line drug for the treatment of hypercholesterolemia are statins, which reduce LDL-cholesterol up to 50 %; such reduction is sufficient for most patients to achieve the target values. The exceptions are patients with familial hypercholesterolemia and patients with statin intolerance. To achieve target LDL-cholesterol in these two groups of patients will be possible with new drugs - PCSK9 inhibitors, which decrease LDL-cholesterol by an additional 50-60 %. The first two PCSK9 inhibitors (alirocumab and evolocumab) already had been approved for clinical use by European regulatory authorities. The primary indication for combination statin with PCSK9 inhibitor should be undoubtedly patients with a confirmed diagnosis of familial hypercholesterolemia, who are treated in the Czech Republic primarily in specialized centers of MedPed project. Furthermore, this treatment should be available for other patients at very high risk of cardiovascular diseases, who cannot achieve target LDL-cholesterol (eg. for statins intolerance).

[Hyperlipoproteinemia in children]. / Hyperlipoproteinemie u detí.

Hyperlipoproteinemia (HLP) is one of the most common metabolic disorder in childhood. We assume that 20 % of children have a disorder of the lipid metabolism. Some HLP are very common in the population, and moderate, and some are very rare, but are very severe. These may occur secondary to pathological conditions, or are formed on the basis of the primary monogenic or polygenic disorders of lipid metabolism. The detection of children with HLP in the Czech Republic is either random, or more often by selective screening of children with familial history of cardiovascular disease, provided by general pediatric practitioners for children and adolescents. Treatment in childhood is primarily dietetic, some of them, especially children with familial hypercholesterolemia are treated from 8-10 years pharmacologically.Key words: diagnosis - hyperlipoproteinemia - children - treatment.

[Familial hypercholesterolemia - past and present. My experiences and findings in our group of patients with familial hypercholesterolemia]. / Familiární hypercholesterolemie vcera a dnes. Vlastní zkusenosti a nálezy u naseho souboru nemocných s familiární hypercholesterolemií

Currently, the familial hypercholesterolemia (FH) rises the interest. The reason is that this genetic disorder is targeted by newly emerged and highly effective hypolipidemic agents, PCSK-9 inhibitors, lomitapid and mipomersen. Present paper discusses 2 patient study groups, before 50 years and nowadays. Although direct statistical analysis is impossible some changes in clinical features of FH might be found over the course of the time. In fact, the basic FH characteristic has not changed dramatically. Severe isolated hypercholesterolemia with total cholesterol 9-10 mmol/l, LDL-cholesterol 7-8 mmol/l and normal values of triglycerides dominates in laboratory analysis. Interestingly, the values of triglycerides increase and almost reach the pathological range in comparison to the values from the period 50 years ago. The values of HDL-cholesterol are normal. Manifestation of CHD in male patients over 40 years of age and in female patients over 50 years of age is not exceptional (rarely occur cases of myocardial infarction in third decade of age). Typical clinical manifestation of FH is xanthomatosis. The early detection and aggressive treatment in FH patients cause that xanthoma tendinosum, xanthelesma and arcus lipoides are less frequent as decades ago. Obesity, diabetes mellitus (DM) and hypertension do not belong to typical clinical sign of FH.