Experimental oncology最新文献

Background: Inhibition of aerobic glycolysis of cancer cells is considered a promising therapeutic strategy for the treatment of neoplasms. Some inhibitors of energy metabolism can affect not only tumor cells but also the functional polarization of tumor-associated macrophages, which may either enhance the antitumor effect of such agents or impair their antitumor efficacy.

Aim: To investigate the effect of oxamate, a lactate dehydrogenase (LDH) inhibitor, on the polarization of peritoneal macrophages (PMP) in both intact mice and mice with transplanted Lewis lung carcinoma (LLC).

Materials and methods: The low-metastatic LLC variant, LLC/R9, was transplanted to female C57Bl/6 mice. Sodium oxamate was used as the test agent at concentrations of 0.02, 0.2, and 2 mg/ml. Macrophage polarization in tumor-bearing mice was estimated on day 23 after tumor transplantation by assessing nitric oxide (NO) production and arginase activity as functional indices of PMPs polarization.

Results: Oxamate can affect the functional polarization of PMPs in both intact mice and animals with transplanted LLC/R9. Oxamate in all studied concentrations changed the markers of PMPs polarization in intact mice (decreasing NO levels and activating arginase activity) that indicated the stimulation of M2 polarization. In tumor-bearing animals, stimulation of M2 polarization is observed at low concentrations of oxamate (0.02 mg/ml), but its high concentrations (2.0 mg/ml) causes M1 polarization, which is characterized by three-fold increase in the level of NO and a decrease in the level of arginase activity.

Conclusion: Oxamate, an inhibitor of LDH, can stimulate M2 polarization of peritoneal macrophages of mice bearing LLC in a dose-dependent manner.

R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of the National Academy of Science of Ukraine has been studying the mechanisms and specificities of individual radiation sensitivity (IRS) formation in professionals who work in the field of ionizing radiation, cancer patients and representatives of other population groups. Our data based on the use of G₂-test in in vitro irradiated blood lymphocytes in late G₂-period of cell cycle indicated an increased carcinogenic risk in professionals with high IRS. We suggest that the COVID-19 pandemic could make significant adjustments in the formation of IRS in professionals who have survived the disease and continue to work with ionizing radiation (IR). Increased systemic inflammatory activity, which persists for a long time in COVID-19 patients, in combination with low-dose range irradiation (professionals who continue to work with IR) and with local irradiation in the high-dose range (radiation therapy for cancer patients) may affect IRS. Repeated determination of IRS in professionals who have had COVID-19 infection, using chromosomal G₂-radiation sensitivity assay will answer the question: can SARS-CoV-2 coronavirus affect the IRS? The proposed hypothesis of the radiosensitivity evolution needs further experimental validation using a set of radiobiological indices to clarify the mechanism of IRS formation following COVID-19 infection. The detected changes (increase) of human IRS after COVID-19 must be taken into account for personalized planning of radiotherapy of COVID-19 cancer patients.

Aim: To study the correlation of pre-operative neutrophil to lymphocyte ratio (NLR) with pathological stage, Fuhrman grade, sarcomatoid differentiation, tumor necrosis and lymph node positivity and its prognostic role in non-metastatic renal cell carcinoma (non-mRCC).

Materials and methods: This retro-prospective, observational study was done at a tertiary care center in Mumbai, India. All patients with non-mRCC from July 2015 to April 2018 were included. Patients with co-existing systemic infection, prior immunotherapy, and long-term steroids were excluded. NLR closest to surgery, but within one month prior to surgery was used. Patients were stratified as NLR ≥ 3.0 or < 3. NLR was correlated with known prognostic factors by Pearson's correlation.

Results: 113 patients, aged 18-81 years (83 males and 30 females) were included. 75% had clear cell RCC. 62% had stage 1 disease. 58% patients had Fuhrman Grade 2. 10 patients had lymph node metastasis, 6 had sarcomatoid differentiation, 40 had tumor necrosis. The NLR was < 3 in 72 patients. Statistically significant correlation between NLR and tumor stage (p = 0.0054) as well as NLR and tumor necrosis (p = 0.0128) was shown.

Conclusions: NLR correlates significantly with higher T stage and tumor necrosis. NLR may be integrated with well-established prognostic markers to improve the accuracy of prognostic scores.

Aim: To assess the safety profile and efficacy of adjuvant radiation therapy and intermediate-dose interferon in comparison with intermediate-dose interferon alone in patients with synchronous and metachronous skin melanoma metastases in regional lymph nodes with unfavorable prognostic factors.

Materials and methods: 96 patients with synchronous and metachronous skin melanoma metastases in regional lymph nodes (stage III according to American Joint Committee on Cancer) and unfavorable prognostic factors were randomized in 2 groups: one of them (n = 45) received regional radiation therapy 50-55 Gy and intermediate dose of α2b-interferon (RT + IFN) in adjuvant setting and another one (n = 51) intermediate dose of α2b-interferon alone (IFN).

Results: The most common adverse events in both groups were pyrexia and fatigue but grades 3-4 were observed more frequently in the RT + IFN group than in the IFN group (24.4 and 42.2% vs 11.8 and 27.5% respectively). 3-year recurrence-free survival was 78.5% in the RT + IFN group and 73.8% in the IFN group (p = 0.72), 3-year progression-free survival was 63.2% in the RT + IFN group comparing with 57.2% in the IFN group (p = 0.59) and 3-year overall survival was 77.1% and 66.7%, respectively (p = 0.29). Median of recurrence-free, progression-free and overall survival was not reached in any group.

Conclusions: Radiation therapy and intermediate-dose interferon in adjuvant setting tends to improve recurrence-free, progression-free and overall survival comparing with intermediate-dose interferon alone in patients with synchronous and metachronous skin melanoma metastases in regional lymph nodes and unfavorable prognostic factors but it needs further investigation in larger groups of patients.

Aim: To detect the frequency, diagnostic and prognostic significance of 11q23/MLL rearrangements and to determine the chromosomes that are most frequently involved in 11q23/MLL abnormalities in adult acute leukemia (AL).

Materials and methods: Cytogenetic investigations of bone marrow and/or peripheral blood cells from 140 patients with acute myeloid leukemia (AML) and 57 patients with acute lymphoblastic leukemia (ALL) were performed. The methods of conventional cytogenetics (GTG-banding) and fluorescence in situ hybridization were used.

Results: Chromosomal abnormalities in leukemia cells were found by conventional cytogenetic methods in 80 (57%) and 37 (65%) adult patients with AML and ALL, respectively. 11q23/MLL rearrangements were found in 7 (5%) and 8 (14%) patients with AML and ALL, respectively. Among them, 8 (53.4%) patients had translocations, 2 (13.3%) - had deletions and 5 (33.3%) patients had trisomies or tetrasomies of chromosome 11. With respect to the distribution of partner chromosomes involved in 11q23/MLL translocations chromosome 4 was found to participate in 3 (37.5%) cases of 11q23/MLL translocations, 9 - in 2 (25%) cases and chromosomes 10, 14 and non-identified chromosome were involved in 1 (12.5%) case each. Nine patients (60%), besides abnormal ones, had 9-86% normal metaphases in their karyotypes. Of 15 patients with 11q23/MLL rearrangements, 5 (33%) patients had only 11q23/MLL rearrangements, whereas other 10 (67%) - had additional cytogenetic abnormalities, besides 11q23/MLL rearrangements.

Conclusions: Chromosomal abnormalities of various kinds were found in 57% and 65% adult patients with AML and ALL, respectively. The frequency of 11q23/MLL rearrangements in patients with AML and ALL was 5% and 14%, respectively. Since AL patients with 11q23/MLL rearrangements are attributed to cytogenetic categories of AL with a poor or intermediate risk prognosis, cytogenetic methods should be included in the standard examination of AL patients for diagnosis, prognosis and selection of the optimal treatment strategy.

Background: Recently, bioactive ceramics based on hydroxyapatite (HAP) and tricalcium phosphate (TCP) have been preferred as implants in bone engineering.

Aim: To study bone regeneration under conditions of filling metaphyseal defects with the original HAP-TCP composition.

Materials and methods: The experiment was carried out on inbred rats, the observation period was 2, 4, 8 weeks. Morphological studies were carried out using light and electron microscopy.

Results: In the dynamics of observation at 2, 4 and 8 weeks, a gradual arrangement of osteoclasts and osteoblasts on the surface of HAP-TCP was recorded, which indicates its high biocompatibility with bone tissue. During the experiment, the processes of resorption of implants, mineralization, proliferation of cellular elements of collagen and osteogenesis (osteoblasts and osteoclasts) and the formation of mature bone tissue were recorded.

Conclusions: Experimental studies of plastic bone defects proved the presence of the osteoinductive and osteointegrative effect of HAP-TCP composition, which contributes to a more dynamic uncomplicated course of reparative osteogenesis.

Background: Recent studies have shown the potential of using different approaches for immunotherapy in cancer treatment. Macrophages (Mph) are one of the promising targets for immunotherapy.

Aim: To investigate changes in the functional activity of Mph in mice with Ehrlich carcinoma by nitric oxide (NO)/arginase (Arg), IRF4/IRF5 and STAT1/STAT6 ratios caused by administration of lectin from B. subtilis IMV-7724.

Materials and methods: From the 2^nd day after Ehrlich carcinoma inoculation into female Balb/c mice, lectin from B. subtilis IMV B-7724 (0.02 mg/mouse) was administered for 10 days. The peritoneal Mph were isolated on days 14, 21, and 28 after tumor transplantation and their functional state (NO production, Arg activity and cytotoxic activity) was examined. The levels of mRNA expression of transcription factors STAT-1, STAT-6, IRF5, IRF4 were evaluated.

Results: In lectin-treated animals with Ehrlich carcinoma, the functional state of Mph (NO/Arg ratio, index of cytotoxic activity) was maintained at the level of intact mice exceeding the values in untreated animals with Ehrlich carcinoma at late terms of tumor growth (21, 28 days). Analysis of mRNA expression levels of transcription factors in these animals showed a significant increase (p < 0.05) in the ratio of STAT1/STAT6 on the day 21 and IRF5/IRF4 on day 28 of tumor growth compared to that in untreated mice.

Conclusions: Administration of lectin from B. subtilis IMV B-7724 to mice with Ehrlich carcinoma led to the prevalence of Mph exhibiting the functional properties of M1 type at late-term tumor growth. The transcription factors of the STAT and IRF signaling pathways are involved in the process of Mph polarization induced by lectin from B. subtilis IMV B-7724.

Collision synchronous tumors that are found at the same anatomical site are very rare. Their diagnostics, staging and treatment is very complicated. Here we present a clinical case of collision tumor in a single lymph node which consists of breast cancer and chronic lymphocytic leukemia/small lymphocytic lymphoma. The management of such cases is discussed.

Background: The infertile women have an increased risk of developing benign and malignant tumors, in particular, breast cancer. Most studies have examined the role of gene variants in the risk of developing breast cancer, but there is little evidence of genetic risk factors for benign tumors.

Aim: To assess the combined genetic risk of developing mastopathy in women with FSHR (rs6165, rs6166) and ESR1 (rs9340799, rs2234693) gene variants.

Materials and methods: The study included 87 infertile women (45 with concomitant fibrocystic mastopathy and 42 without mastopathy).

Results: For rs9340799 and rs2234693 variants of the ESR1 gene, we did not find any significant differences in the distribution of genotypes in infertile women with or without mastopathy. In patients with mastopathy, there was a reliable increase in the frequency of 307Ala/Ala and 680Ser/Ser genotypes of FSHR gene (χ² = 6.39, p = 0.012, OR = 4.49 (1.48-13.65)) as compared to patients without mastopathy. In the presence of 307Thr/Thr and 680Asn/Asn genotypes of the FSHR gene, a 4.88-fold reduction of mastopathy risk (χ² = 8.06, p = 0.005, OR = 0.21(0.07-0.59)) was observed. The frequency of the FSHR and the ESR1 genotypes combinations - 307Thr/Thr+680Asn/Asn+351AG+397TC was significantly decreased in patients with mastopathy.

Conclusions: Our study did not find an association of ESR1 gene variants with the risk of developing of mastopathy in infertile women although heterozygous variants of the ESR1 gene enhanced the "protective" effect of FSHR gene variants and reduced the risk of mastopathy.

Background: Expression of lipoprotein lipase (LPL) correlates with unmutated (UM) status of the variable region of the heavy chain of immunoglobulin (IGHV) genes, but the expression level of LPL in UM chronic lymphocytic leukemia (CLL) cases varies significantly.

Aim: To study the association of LPL expression with the genetic variants of the TP53 gene since both genes are involved in lipid metabolism.

Materials and methods: Expression of LPL mRNA was measured in peripheral blood mononuclears of 45 CLL patients with UM IGHV genes by real-time quantitative reverse transcription polymerase chain reaction. Mutational status of IGHV genes and TP53 genotyping (rs1042522, rs1642785, rs17883323, rs2909430, rs145153611, rs113530090, rs12947788, rs12951053, and rs17878362) were performed by polymerase chain reaction amplification followed by direct sequencing.

Results: Observed CLL patients were divided on groups with low (11.17 ± 2.66) and high (275.48 ± 39.37) LPL expression. In CLL patients with UM IGHV genes and low LPL expression we found an increased frequency of rs1042522 G (p = 0.0036), rs1642785 C (p = 0.0001), and rs17878362A2 alleles (p = 0.0091). The possible functional significance of these changes is discussed.

Conclusion: Some polymorphic variants of TP53 may be genetic modifiers for LPL expression level in CLL leukemic B-cells. Further research is required in a larger cohort to confirm these findings.