Jana Jurečeková

Most frequent molecular and immunohistochemical markers present in selected types of brain tumors

Tumors of brain tissue and meninges create a heterogeneous group with various biological behavior, therapy management and differing prognosis. Some of these do not require treatment, some can be cured by surgery and some are rapidly fatal despite treatment. Despite huge progress in tumor research, innovations in diagnostic tools and therapy, prognosis remains, in case of malignant tumor types, very serious. There has been an increased understanding of molecular abnormalities occurring in primary brain tumors. Genome-wide analyses of tumors have improved the knowledge in tumor biology. The aim of the research is to explain the oncogenesis features thus leading to the use of new therapeutic modalities in order to prolong survival rate of patients and at the same time providing satisfactory life quality. This article offers a short review of the basic genetic alterations present with some histological types of brain tumors.

The role of p21 3'UTR gene polymorphism in the risk of prostate cancer: A pilot study

The cell cycle regulator p21 plays an important role in regulating critical cell activities including cell cycle control, DNA repair and apoptosis. Consequently, it may affect the efficacy of the response to DNA damage and tumor development. The aim of our study was to evaluate the frequencies of the p21 C70T polymorphism, the association between this genetic variant and smoking status, and the serum prostate-specific antigen (PSA) levels and Gleason score in 118 prostate cancer patients and 130 males routinely screened for prostate cancer in the Slovak population. Blood samples were collected from all individuals for DNA isolation, used for subsequent genotyping assays via PCR-RFLP methods. Overall, we did not observe any significant association between this polymorphism and prostate cancer risk. An analysis of the association between the p21 genotypes and smoking was then conducted. Among smokers, CC and CT genotypes were associated with a non‑significant increased risk (OR=1.48; 95% CI, 0.80-2.76 and OR=1.15; 95% CI, 0.27‑4.77, respectively; p>0.05) in comparison to non-smokers with the CC genotype. Patients with a CT genotype and serum PSA levels≥10 ng/ml had an 84% decrease in prostate cancer risk (OR=0.16; 95% CI, 0.03-0.75; p<0.05) compared to cases with serum PSA levels <10 ng/ml and the CC genotype. No significant association was detected between Gleason score and prostate cancer risk. Based on these results, we concluded that the p21 C70T polymorphism is associated with decreased risk of prostate cancer in Slovak men. To confirm these findings, a systematic approach is required to identify sequence variants in this and other related genes, and subsequently, to test for an association between such variants, smoking status and tumor-specific clinicopathological characteristics in large samples.

Targeting of Bcl-2 family proteins for treatment of acute leukaemia

Many studies suggest that killing of tumour cell by commonly used therapies (chemotherapy, radiotherapy) is mediated primarily by induction of apoptosis. Therefore, resistance of tumour cells to therapy can be caused by a failure in the ability to initiate apoptosis. Defects in apoptosis signalling pathways are also one of the main features of cancer, and particularly acute leukaemia. Malignant cells constantly resist the effects of cellular stress (e.g. DNA damage, oncogene activation), which would cause death of normal cells through apoptosis. Dysregulation of apoptosis has therefore give rise to tumour growth, disease progression and resistance of malignant cells to chemotherapy. Structural analysis of Bcl-2 family proteins playing a key role in regulation of mitochondrial apoptosis together with studies of their biochemical functions have outlines strategies for generation of drugs, resulting in numerous novel chemical entities with potential to reverse resistance of malignant cells to apoptosis. The use of these therapeutic approaches may in the future represent a new way in cancer therapy with high potential to improve clinical outcome and prognosis of acute leukaemia patients.

Oxidative Damage and Bronchial Asthma

All organisms live in the environment that contains oxygen which is vital for all aerobic organisms, and reactive oxygen species (ROS) which are formed in cells as a consequence of aerobic metabolism. Moreover mitochondrial respiration (a base of energetic production in all eukaryotic organisms) is associated with an inevitable electron leak, resulting in a nonstop production of reactive oxygen species, such as superoxide anion radical, hydrogen peroxide and hydrogen radical. Universal nature of reactive oxygen species is underlined by the presence of one enzyme superoxide dismutase. This enzyme occurs in all aerobic organisms and it is responsible for dismutation of superoxide anions into oxygen and hydrogen peroxide. Genes involved in detoxification of reactive oxygen species are highly conserved among eukaryotes and their deficiency could be limit of several diseases and life span. Oxidative stress is a unique pathophysiological condition resulting from the disrupted balance between oxidants and antioxidants. Increased level of reactive oxygen species may cause oxidative damage of all biomolecules: nucleic acids, proteins, lipids, saccharides. A progressive grow of oxidative damage is the result of increasing production of reactive oxygen species or an insufficient antioxidant defence system and this damage may contribute to the origin and development of several diseases including bronchial asthma, but on the other hand oxidative damage can be the consequence of them as well (fig. 1).

Alzheimer's Disease: Definition, Molecular and Genetic Factors

Frequency of neurodegenerative diseases increase significantly with the age. One of the most frightening and devastating of all neurological disorders is the dementia that occurs in the elderly. Dementia is a common name for progressive degenerative brain syndromes which affect memory, thinking, behaviour and emotions. Dementia mainly affects older people, although there is a growing incidence of the cases that start before the age of 65. After age 65, the likelihood of developing dementia roughly doubles every five years. Dementia affects 1 – 6% of human population over 65 years and 10 – 20% over 80 years. In the present, average age is increasing and the number of people over 60 years increases as well. Although Ageing is a physiological process, however it seems to be linked with an increasing risk of origin and development of several diseases including neurodegenerative disorders. Dementia is characterised by the loss of or decline in memory and other cognitive abilities. It is caused by various diseases and conditions resulting in damaging brain cells. Different types of dementia (Alzheimer`s disease, vascular dementia or post-stroke dementia, mixed dementia, dementia with Lewy bodies, Parkinson`s disease, frontotemporal dementia, Creutzfeld-Jacob disease, normal pressure hydrocephalus) have been associated with distinct symptom patterns and distinguishing microscopic brain abnormalities. Alzheimers disease (AD) is the most common cause of dementia and this disease represents 60 – 80% of all dementia. Alzheimers disease is age-related disease and it is characterized by a range of changes in brain anatomy, biochemistry, genetic, and function. According to Alzheimer`s disease International in 2010, there were an estimated 35.6 million people with dementia worldwide. This means a 10 percent increase over previous global dementia prevalence reported in 2005 in The Lancet. Number of people with dementia will be increasing to 65.7 million by 2030 and 115.4 million by 2050. Hallmark abnormalities of Alzheimer`s disease are deposits of the protein fragment ┚-amyloid (plaques) and twisted strands of the protein tau (tangles). Protein oxidation and generation of protein aggregates may be caused by loss of cell function alike a decreased ability of old organisms to resist the physiological stresses and oxidative damage. The relationship between protein aggregation, oxidative damage and neurodegenerative

Association between interleukin-18 variants and prostate cancer in Slovak population.

Interleukin-18 (IL-18), pro-inflammatory cytokine, plays important role in antitumor immunity. Polymorphisms in the IL-18 gene may lead to its altered production/activity and such modulate susceptibility to prostate cancer. The aim of this study was to evaluate the relationship between the -607 and +105 polymorphisms in the IL-18 gene and the risk of prostate cancer development and progression in Slovak population. The study was performed using 425 patients with prostate cancer, 270 patients with benign prostatic hyperplasia (BHP) and 263 healthy male controls. The statistically significant association of the -607 AC genotype (OR = 2.24; p < 0.001), CC genotype (OR = 1.86; p = 0.006), as well as C allele (OR = 1.27; p = 0.033) with the higher risk of prostate cancer development was observed. No association of the IL-18 -607 polymorphism and BHP was detected. The subset analysis revealed the significant association of the -607 AC genotype (OR = 2.01; p = 0.008) with development of higher-grade carcinomas (Gleason score ≥7) and the strong association of the -607 AC genotype (OR = 3.11; p < 0.001), CC genotype (OR = 2.96; p < 0.001) as well as C allele (OR = 1.51; p = 0.003) with the higher risk of prostate cancer development in the group of patients with PSA < 10 ng/ml. The -607 AC genotype was also connected with significantly higher IL-18 plasma concentrations. No association between the IL-18 +105 polymorphism and prostate cancer was observed. The analysis of the distribution of the -607 and +105 haplotypes showed significant association of the - 607 C/ + 105 A and - 607 C/ + 105 C haplotypes with the risk of prostate cancer. This study found that the IL-18 -607 promoter polymorphism could contribute to prostate cancer development in Slovak population. Its presence was also associated with development of higher-grade carcinomas and therefore may influences the prognosis and aggressiveness of the disease.

The role of CYP17A1 in prostate cancer development: structure, function, mechanism of action, genetic variations and its inhibition

Androgens play an important role during the development of both normal prostate epithelium and prostate cancer and variants of genes involved in androgen metabolism may be related to an increased risk of prostate disease. Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a key regulatory enzyme in the steroidogenic pathway; it catalyses both 17α-hydroxylase and 17,20-lyase activities and is essential for the production of both androgens and glucocorticoids. In this review, we focus on the structure and enzymatic activity of CYP17A1 and the mechanism of modulation of CYP17A1 activities. We discuss the relationship between common genetic variations in CYP17A1 gene and prostate cancer risk and the main effects of these variations on the prediction of susceptibility and clinical outcomes of prostate cancer patients. The mechanism of action, the efficacy and the clinical potential of CYP17A1 inhibitors in prostate cancer are also summarized.

Asociación entre polimorfismos genéticos de la interleucina 6 y el asma bronquial en niños

INTRODUCTION The genetic background of bronchial asthma is complex, and it is likely that multiple genes contribute to its development both directly and through gene-gene interactions. Cytokines contribute to different aspects of asthma, as they determine the type, severity and outcomes of asthma pathogenesis. Allergic asthmatics undergoing an asthmatic attack exhibit significantly higher levels of pro-inflammatory cytokines, such as interleukins and chemokines. In recent years, cytokines and their receptors have been shown to be highly polymorphic, and this prompted us to investigate interleukin 6 promoter polymorphisms at position -174G/C (rs1800795) and at -572G/C (rs1800796) in relation to asthma in children. METHODS Interleukin 6 promoter polymorphisms were analyzed in bronchial asthma patients and healthy children using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS We observed a significant association between polymorphism at -174G/C and bronchial asthma (OR=3.4, 95% CI: 2.045-5.638, P<.001). Higher associations between polymorphism at IL-6 -174G/C and bronchial asthma were observed in atopic patients (OR=4.1, 95% CI: 2.308-7.280, P<8.10-7). CONCLUSIONS Interleukin 6 polymorphism is associated with bronchial asthma, particularly its atopic phenotype. Expression and secretion of interleukins in asthmatic patients may be affected by genetic polymorphisms, and could have a disease-modifying effect in the asthmatic airway and modify the therapeutic response.

Oxidative Changes and Possible Effects of Polymorphism of Antioxidant Enzymes in Neurodegenerative Disease

Frequency of neurodegenerative diseases increase significantly with the age. In the present, average age is increasing and the number of people over 60 years increases as well. Ageing is a physiological process; however it seems to be linked with an increasing risk of origin and development of several diseases including neurodegenerative disorders such as Alzheimers disease, Parkinson’s disease, and Huntington’s disease. Exact mechanisms of ageing are still unclear but experimental evidences support a hypothesis that ageing changes are consequen‐ ces of increasing oxidative damage of organs, tissues, cells and all biomolecules. Oxidative damage is elevated when production of reactive oxygen species is increased compared to the physiological condition or a defence ability of organism against attacks of reactive oxygen species is decreased. Oxidation of specific proteins could play a key role in age associated damage. A relationship between protein aggregation, oxidative stress and neurodegeneration remains unclear although neurodegenerative diseases are connected with an origin of protein deposits. It assumes that protein oxidation and generation of protein aggregates generate a base for a loss of cell function and a reduced ability aged organisms to resist to physiological stress. Accumulation of modified proteins, disturbance of ion homeostasis, lipid and DNA modifications, and impairment of energy production are some of the crucial mechanisms linking ageing to neurodegeneration. In addition mitochondrial dysfunction plays a key role in neurology. Damage of mitochondrial electron transport may be an important factor in the pathogenesis of neurodegenerative diseases, such as Alzheimers, Parkinsons, and Hunting‐ tons diseases.

Bcl-2 Family Proteins in Development and Treatment of Malignant Diseases

Bcl-2 Family Proteins in Development and Treatment of Malignant Diseases Proteins of Bcl-2 family are key regulators of mitochondrial pathway of apoptosis. Deregulation of apoptosis disrupts the complex and delicate balance between cell proliferation, survival and death and plays an important role in the development of malignant diseases. In addition to uncontrolled proliferation, alterations in apoptotic proteins are frequently associated with resistance of malignant cells to chemotherapy, leading to ineffective treatment with chemotherapy that primarily acts by apoptosis initiation. Despite the progress in combinatory and biologic therapy, response rates for treatment of different malignant diseases are not high enough. Therefore, new anti-cancer agents that selectively kill tumour cells and spare normal tissues are still urgently needed. Progress in biochemistry and cell biology leading to detailed dissection of cell signalling pathways allows development of new therapeutic strategies targeting different proteins involved in malignant transformation and uncontrolled proliferation of malignant cells. Emerging knowledge on molecular mechanisms of apoptosis deregulation in cancer development has revealed Bcl-2 family proteins as potential targets for drugs discovery. Structural analysis of these proteins together with studies of apoptosis mechanisms have outlined strategies for generation of new drugs, resulting in numerous novel chemical entities with mechanism-based activity. Many of the most logical targets for promoting apoptosis of malignant cells are technically challenging, involving often disruption of protein interactions or changes in gene expression, as opposed to traditional pharmaceutical approach that predominantly attacks enzymes. Understanding of the core components of the apoptotic machinery at the molecular and structural levels may lead to new era in cancer therapy where the intrinsic and acquired resistance of malignant cells to apoptosis can be pharmacologically reversed, reinstating natural pathways of cell suicide.