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Background: Ewing sarcoma (ES) cells exhibit extreme plasticity that contributes to the cell’s survival and recurrence. Although multiple studies reveal various signaling pathways mediated by the EWSR1/FLI1 fusion, the specific transcriptional control of tumor cell resistance to doxorubicin is unknown. Understanding the molecular hubs that contribute to this behavior provides a new perspective on valuable therapeutic options against tumor cells. Methods: Single-cell RNA sequencing and LC-MS/MS-based quantitative proteomics were used. Results: A goal of this study was to identify protein hubs that would help elucidate tumor resistance which prompted ES to relapse or metastasize. Several differentially expressed genes and proteins, including adhesion, cytoskeletal, and signaling molecules, were observed between embryonic fibroblasts and control and doxorubicin-treated tumor cell lines. While several cancer-associated genes/proteins exhibited similar expression across fibroblasts and non-treated cells, upregulation of some proteins belonging to metabolic, stress response, and growth pathway activation was uniquely observed in doxorubicin-treated sarcoma cells, respectively. The novel information on differentially expressed genes/proteins provides insights into the biology of ES cells, which could help elucidate mechanisms of their recurrence. Conclusions: Collectively, our results identify a novel role of cellular proteins in contributing to tumor cell resistance and escape from doxorubicin therapy and contributing to ES progression.

Ewing's sarcoma (ES) is a highly malignant tumor of children and adolescents that affects bones and soft tissues with the same frequency. The origins of ES are the subject to many discussions. Differential diagnosis is complicated and requires a full range of immunohistochemical and molecular genetic studies. The prognostic value for extraskeletal and bone ES under current chemotherapy protocols is unknown and requires further analysis. The purposes of this research were a comparative analysis of clinical characteristics, therapeutic approaches and outcomes of the disease in patients with extraskeletal and bone localizations of ES. Materials and methods used: a single-center retrospective cohort study was conducted, which included 330 patients (237 (71.8%) boys/93 (28.2%) girls) aged 0 to 18 y/o (median 11 [7; 14] y/o) with confirmed diagnosis of ES who received treatment in 2008-2022, of which 280 (84.85%) with primary bone localization (group of bone ES - BES), and 50 (15.15%) with soft tissue localization (group of extraskeletal ES - ESES). Comparative analysis of survival rates for primary tumor localization in the area of bones and soft tissues was performed. The median follow-up time for all patients was 35.5 [18.2; 68.5] months, 37.0 [18.0; 71.0] months with BES, and 29.5 [16.8; 65.5] months with ESES. All patients received treatment according to the protocols adopted at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov with the N.N. Blokhin Russian Cancer Research Center (Moscow, Russia): MMES-99, ES-2017. Overall survival (OS) was calculated with the Kaplan-Meier estimator. Results: the selected groups differed statistically significantly by gender (74% of boys in the BES group, and 60% of boys the ESES group, p=0.035) and age (10.5 [8; 15] years in the BES group, and 8.5 [4; 12] y/o in the ESES group, p=0.001). BES was diagnosed statistically significantly more often in older age groups than ESES (p=0.004). Compared with BES, in ESES the tumor was statistically significantly more often located in the region of the axial skeleton and visceral organs (24.0% vs. 56%, p<0.001). Disseminated form of the disease in the BES group was recorded in 110 (39.3%) patients, and in 15 (30.0%) in the ESES group. Authors did not find statistically significant differences in overall 5-year OS for localized forms of BES and ESES (79% and 78.5%, respectively), the median OS in these groups was not reached. The OS of patients with disseminated stages of BES and ESES was statistically significantly lower than in the group of localized forms. At the same time, the 5-year OS was 41.2% and 40.6%, the median OS was 46.9 and 28.4 months (p=0.001, respectively). Differences in 5-year progression-free survival (PFS) for localized forms were 71.6% for BES and 75.6% for ESES (p=0.001), for disseminated forms - 32.4% vs. 44.9% (p=0.036, respectively). In the disseminated stage of BES, progression/relapse was detected in 50% of cases after 21.1 months, and after 20.3 months for ESES. Conclusions: Authors have identified the following unfavorable prognostic factors. As for BES these were: older age, disease stage, primary tumor volume over 200 cm3 and length over 8 cm, radiation therapy in the treatment program or combined treatment. As for ESES, the unfavorable PFS factors were the stage of the disease, the volume of the primary tumor and the process dissemination. In this regard additional analysis of key genomic characteristics is required in order to further determine the risk group stratification and prognosis.

Introdaction.Ewing’s sarcoma of the pelvic bones in children and adolescents is a complex, poorly studied problem. This is explained by the rare occurrence of the tumor and its biological characteristics: aggressive course, a tendency to develop early hematogenous metastases and frequent relapses.The objective: analysis of the results of treatment of 72 children and adolescents with localized and disseminated Ewing sarcoma with primary lesions of the pelvic bones was carried out.Materials and methods.During the study, a retrospective and prospective analysis of the results of treatment of 72 children and adolescents with localized and disseminated Ewing sarcoma with primary lesions of the pelvic bones was carried out. The patients were divided into 3 clinical groups (Induction, High-dose chemotherapy, Polychemotherapy) depending on the treatment performed. The patients received treatment under the MMES-99 protocol.Results.The overall 1-year survival rate of all 72 patients included in the study was 86,1 %, 3-year – 50,0 %, 5-year – 42,5 % and 10-year – 39,3 %; disease-free survival rate – 66,6; 43,9; 41,9 % and 38,3 % respectively. Our analysis of overall survival did not reveal statistically significant differences between the High-dose chemotherapy and Polychemotherapy groups (p= 0,83). There were also no statistically significant differences in relapse-free survival (p= 0,68).Conclusion.Considering that the indicators of overall and relapse-free survival did not significantly differ when performing one or another type of consolidation (High-dose chemotherapy versus Polychemotherapy groups) in patients with a good antitumor effect achieved on induction, when choosing the type of consolidation, one should take into account the capabilities of the medical institution, the presence of experience and equipment for carrying out autologous transplantation, the desired total duration of therapy (with High-dose chemotherapy, it is significantly shorter), as well as the total cost of the program.

This article investigates the specific application of inhibitors in firefighting. The main emphasis is placed on the application of temperature-activated water jets (TAW). A generalized model of droplet motion in highly heated heat flows has been presented, taking into account not only the local heating of the droplet from heat flows, but also the integral, depending on the geometric and velocity characteristics of its motion.