EXPRESSION OF GENES INVOLVED IN P53 PATHWAY REGULATION IN NEUROBLASTOMA: A SHORT REVIEW.

The search for new prognostic and stratification genetic and epigenetic markers in neuroblastoma is an urgent problem in pediatric oncology. The review summarizes recent progress in studying the expression of genes involved in p53 pathway regulation in neuroblastoma. Several markers associated with recurrence risk and poor outcome are considered. Among them are MYCN amplification, high MDM2 and GSTP1 expression and homozygous mutant allele variant of GSTP1 gene A313G polymorphism. Prognostic criteria for neuroblastoma based on the analysis of miR-34a, miR-137, miR-380-5p, and miR-885-5p expression involved in regulating p53-mediated pathway are also considered. The authors' research data on the role of the above markers in regulation of this pathway in neuroblastoma are presented. The study of alterations in expression of microRNAs and genes involved in p53 pathway regulation will not only expand our understanding of the mechanisms of neuroblastoma pathogenesis but could substantiate new approaches for delineating risk groups and risk stratification of neuroblastoma patients as well as treatment optimization based on the genetic characteristics of the tumor.

Magnetically sensitive nanocomplex enhances antitumor efficacy of dendritic cell-based immunotherapy.

BACKGROUND: One of the major factors restricting in vivo efficacy of dendritic cells (DCs) based immunotherapy is the inefficient migration of these cells to the lymphoid tissue, wherein DCs activate antigen-specific T cells. A fundamentally new approach for the possibility of enhancing the antitumor effects of DC-based immunotherapy may be the use of magnetically sensitive nanocomplexes to increase the target delivery of DCs to the lymph nodes of the recipient. AIM: To study the antitumor and immunomodulatory effects of the DC-nanovaccine with magnetosensitive properties and its influence on the immunosuppressive tumor microenvironment in mice with sarcoma 37. MATERIALS AND METHODS: The antitumor, antimetastatic and immunomodulatory effects of DCs loaded with magnetic nanocomplex under magnetic field (MF) control in mice with sarcoma 37 have been investigated. RESULTS: Combined therapy contributed to a significant reduction in tumor volume and weight compared to the control group of mice and mice that received the DC vaccine without MF. Therapy with magnetically sensitive DC nanovaccine with and without the addition of the MF was accompanied by a significant down-regulation of the level of FoxP3, transforming growth factor ß, interleukin (IL)-10 and vascular endothelial growth factors, mRNA expression in tumor tissues. A significant increase in interferon-γ and IL-4 mRNA expression was found in mice treated with the magnetically sensitive DC nanovaccine under MF control. CONCLUSION: A significant increase in the antitumor efficacy of the DC vaccine can be achieved using magnetosensitive nanocarriers of tumor antigens under MF control.

Larval crowding results in hormesis-like effects on longevity in Drosophila: timing of eclosion as a model.

There is increasing evidence that stress during development can affect adult-life health status and longevity. In the present study, we examined life span (LS), fly weight, fecundity and expression levels of longevity-associated genes (Hsp70, InR, dSir2, dTOR and dFOXO) in adult Drosophila melanogaster flies reared in normal [low density (LD), ~ 300-400 eggs per jar] or crowded [high density (HD), more than 3000 eggs per jar] conditions by using the order (day) of emergence as an index of the developmental duration (HD1-5 groups). Developmental time showed a significant trend to increase while weight showed a significant trend to decrease with increasing the timing of emergence. In both males and females eclosed during first 2 days in HD conditions (HD1 and HD2 groups), both mean and maximum LSs were significantly increased in comparison to LD group. In males, mean LS was increased by 24.0% and 23.5% in HD1 and HD2 groups, respectively. In females, corresponding increments in mean LS were 23.8% (HD1 group) and 29.3% (HD2 group). In HD groups, a strong negative association with developmental time has been found for both male and female mean and male maximum LSs; no association with growth rate was observed for female maximum LS. The female reproductive activity (fecundity) tended to decrease with subsequent days of eclosion. In HD groups, the levels of expression of all studied longevity-associated genes tended to increase with the timing of eclosion in males; no differences were observed in females. On the basis of findings obtained, it can be assumed that the development in conditions of larval overpopulation (if not too extended) could trigger hormetic response thereby extending the longevity. Further studies are, however, needed to confirm this assumption.

Prevalence of two BRCA1 mutations, 5382insC and 300T > G, in ovarian cancer patients from Ukraine.

Ovarian cancer is the seventh most common cancer in women worldwide and the leading cause of gynecological malignant diseases-related deaths in women. The most significant risk factor for ovarian cancer is an inherited genetic mutation in one of two genes: breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2). The germline mutation c.5266dupC (also known as 5382insC or 5385insC) is the most common mutation among Slavic patients with breast and/or ovarian cancer. Missense mutation c.181T > G (also known as 300T > G or p.C61G) is regarded as the founder change in many Central European countries. We screened 306 ovarian cancer patients diagnosed at different ages by mutagenically separated polymerase chain reaction (PCR) and real-time PCR. A total of 25 BRCA1 mutations were detected (18 cases of 5382insC and 7 cases of 300 T > G). The frequency of the BRCA1 5382insC mutation is similar in breast and ovarian cancer patients from Ukraine, but the frequency of 300T > G was estimated in Ukraine at first time.

Prognostic significance of MDM2 gene expression in childhood neuroblastoma.

AIM: To investigate the association of MDM2 expression at the mRNA levels in neuroblastoma with clinical features and unfavorable disease factors to determine the possibility of it usage as a prognostic marker of neuroblastoma. MATERIALS AND METHODS: Total RNA and DNA were extracted from tumor tissue samples of total 91 neuroblastoma patients (mean age: 39.45 ± 4.81 months). MDM2 mRNA levels were detected with Q-PCR. TP53 gene deletion was detected with FISH method. MYCN amplification was detected with -Q-PCR analysis in fresh tumor samples and FISH in FFPE samples. RESULTS: We investigated the association of MDM2 mRNA expression with clinical outcome in neuroblastoma patients (n = 91). Kaplan - Meier curves showed a significant association of high MDM2 expression with poor event-free survival (p < 0.001). Clinical outcome of patients without MYCN amplification with low MDM2 expression was associated with better event-free survival than with high MDM2 expression (p < 0.001). Overexpression of MDM2 can be used as significant prognostic marker for patient stratification on risk groups and treatment optimization. CONCLUSION: Our results showed that the high expression of MDM2 at mRNA levels is an important factor of neuroblastoma prognosis. It may be a valuable additional molecular marker in guiding specific therapy in MYCN non-amplified NB patients without TP53 gene deletion.