Role of macrophages in the antitumor action of the recombinant probiotic Subalin

Course administration of the recombinant probiotic subalin was shown to significantly potentiate the cytotoxic action of macrophages from healthy and tumor-bearing mice against mastocytoma P-815 cells and syngeneic target cells of lung sarcoma of Lewis. Carrageenan, an inhibitor of macrophage activity, significantly cut down the antimetastaic effect of subalin. The crucial role of macrophages in the mechanism of this function of the drug is discussed.     

The luminol-amplified chemiluminescence of neutrophils and monocytes in patients with gastric cancer after intraoperative radiotherapy using radiosensitizer sanazole

The effect of electron-beam intraoperative radiotherapy (IORT) with radiosensitizer sanazole (drug AK-2123) on the functional activity of neutrophils and monocytes in patients with gastric cancer was studied with the use of luminol-amplified chemiluminescence. Sanazole was administered intravenously in a dose of 1.2 g/m2, 30 min before IORT. After resection of the tumor a single dose of 10 Gy was given to the field of regional lymph collectors and the bed of the removed tumor applying a small-size betatron MIB-6E. Cells were separated and chemiluminescence was estimated on the 1-st day before and on the 3-d day and 2-d week after IORT with sanazole. Insignificant effect on the zymosan- or phorbol-12 -myristate-13-acetate (PMA)-stimulated chemiluminescence was observed in this group, although there was found a considerable increase of chemiluminescence of neutrophils in response to zymosan and PMA in 5 from 8 patients, and chemiluminescence of monocytes--in 3 from 8 patients. Correlation between individual indices of zymosan- and PMA-stimulated chemiluminescence of neutrophils before IORT with sanazole was not high, r = 0.71, but it increased significantly to r = 0.91 on the 3-d day and to r = 0.96 on 2-d week after treatment. Correlation between individual indices of stimulated chemiluminescence of monocytes before IORT with sanazole was r = 0.90, and increased to r = 0.99 on the 3-d day and to r = 0.96 on the 2-d week after treatment. So, it is indicative of a correcting effect of the combined treatment including IORT with sanazole administration on the functional activity of neutrophils and monocytes, and the absence of functional disturbances of these cells.     

The immunomodulator thymalin in the experimental chemotherapy of tumors

Experiments on inbred and noninbred mice showed thymalin to potentiate the therapeutic effect of cytostatic drugs. Thymalin treatment was followed by inhibition of tumor growth and dissemination, increase in the animal's life span and amelioration of antitumor drug-induced immunodepression.     

The oxidative metabolism of the blood neutrophilic granulocytes in precancer and cancer of the stomach]

The results of investigation of blood polymorphonuclear leukocytes oxidative metabolism by nitroblue tetrazolium (NBT) test and luminol-dependent chemiluminescence in patients with gastric precancer and cancer are presented. Chemiluminescence was increased in the patients of both groups as compared with control. Disturbances in oxidative metabolism of neutrophils was detectable by NBT test when functional test was used.     

The distribution pattern of ERα expression,ESR1 genetic variation and expression of growth factor receptors: association with breast cancer prognosis in Russian patients treated with adjuvant tamoxifen

Identification of additional biomarkers associated with ER genomic and nongenomic pathways could be very useful to distinguish patients who will benefit from tamoxifen treatment. The aim of this study was to analyze the prognostic significance of the distribution pattern of ERα expression, ESR1 gene single-nucleotide polymorphisms and expression levels of growth factor receptors in Russian hormone receptor-positive breast cancer patients treated with adjuvant tamoxifen. Formalin-fixed paraffin-embedded tumor tissue samples from 97 patients were examined for the distribution pattern of ERα expression, as well as for EGFR and TGF-βR1 expression by immunohistochemistry. Genotypes for ESR1 +30T>C (rs2077647) and ESR1 2014G>A (rs2228480) were analyzed using a TaqMan assay. Progression-free survival (PFS) was used as an endpoint for the survival analyses. We found that patients with the heterogeneous distribution of ERα expression had poor prognosis on tamoxifen treatment (P = 0.021). We identified a high EGFR expression in patients who developed distant metastasis or recurrence during tamoxifen treatment (a tamoxifen-resistant group—TR) in contrast to the distant metastasis-free patients (a tamoxifen-sensitive group—TS) (80.0 vs. 41.9 %, respectively, P = 0.009). Carriers of the ESR12014A mutant allele were more prevalent among the TR patients compared to the TS patients (26.3 vs. 8.0 %, respectively, P = 0.009). EGFR expression and the distribution pattern of ERα expression were associated with the response to tamoxifen by both univariate and multivariate logistic regression analyses. The presence of these markers either alone or in combination was correlated with the worse PFS for all patients. Analysis of the distribution pattern of ERα expression and the EGFR status in tumor tissue may be valuable for patient selection for tamoxifen adjuvant therapy.     

Decreased luminol-dependent chemiluminescence response of neutrophils to recombinant human tumour necrosis factor in patients with gastric cancer

Summary Production of reactive oxygen species by neutrophils was analysed by a chemiluminometric method in the presence of luminol in ten healthy donors, eight patients with gastric cancer and ten patients with gastric precancer. The neutrophil chemiluminominescence response to recombinant tumour necrosis factor (rTNF) was almost five times lower in the gastric patients when compared with healthy donors and precancer patients. The chemiluminescence response to zymosan was decreased only in the gastric cancer patients with chemiluminescence index activation (C _TNF) <1. The observed changes of neutrophil functions are thought to result in a decrease of neutrophil cytotoxic activity in gastric cancer patients.     

Impact of estrogen receptor α on the tamoxifen response and prognosis in luminal-A-like and luminal-B-like breast cancer

Clinical and Experimental Medicine - The luminal-A-like and luminal-B-like breast cancer groups have distinct biological features that lead to differences in the treatment response and clinical...     

Potentialities of aberrantly methylated circulating DNA for diagnostics and post-treatment follow-up of lung cancer patients

To date, aberrant DNA methylation has been shown to be one of the most common and early causes of malignant cell transformation and tumors of different localizations, including lung cancer. Cancer cell-specific methylated DNA has been found in the blood of cancer patients, indicating that cell-free DNA circulating in the blood (cirDNA) is a convenient tumor-associated DNA marker that can be used as a minimally invasive diagnostic test. In the current study, we investigated the methylation status in blood samples of 32 healthy donors and 60 lung cancer patients before and after treatment with neoadjuvant chemotherapy followed by total tumor resection. Using quantitative methylation-specific PCR, we found that the index of methylation (IM), calculated as IM = 100 × [copy number of methylated/(copy number of methylated + unmethylated gene)], for the RASSF1A and RARB2 genes in the cirDNA isolated from blood plasma and cell-surface-bound cirDNA was elevated 2- to 3-fold in lung cancer patients compared with healthy donors. Random forest classification tree model based on these variables combined (RARB2 and RASSF1A IM in both plasma and cell-surface-bound cirDNA) lead to NSCLC patients’ and healthy subjects’ differentiation with 87% sensitivity and 75% specificity. An association of increased IM values with an advanced stage of non-small-cell lung cancer was found for RARB2 but not for RASSF1A. Chemotherapy and total tumor resection resulted in a significant decrease in the IM for RARB2 and RASSF1A, in both cirDNA fractions, comparable to the IM level of healthy subjects. Importantly, a rise in the IM for RARB2 was detected in patients within the follow-up period, which manifested in disease relapse at 9 months, confirmed with instrumental and pathologic methods. Our data indicate that quantitative analysis of the methylation status of the RARB2 and RASSF1A tumor suppressor genes in both cirDNA fractions is a useful tool for lung cancer diagnostics, evaluation of cancer treatment efficiency and post-treatment monitoring.     

Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation

Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history-negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed calculations showing that the homozygous carriers of rare recessive cancer predisposing alleles are unlikely to report a family history of the disease. We further revealed that the c.2515_2519delAAGTT homozygous mutation in a Holliday junction resolvase, GEN1, was overrepresented in women with bilateral breast cancer (BC) as compared to healthy controls [11/360 (3.1 %) vs. 18/1305 (1.4 %); odds ratio (OR) = 2.25 (1.02–4.75); p = 0.031], although this trend was not maintained in unilateral BC patients [23/1851 (1.2 %)]. Noticeably, presence of biallelic c.2515_2519delAAGTT mutation was associated with the absence of BC in mother both in bilateral and unilateral BC cases [7/239 (3.0 %) vs. 0/41 (0 %) and 21/1,558 (1.3 %) vs. 0/215 (0 %), respectively; Mantel–Haenszel p = 0.041]. Thus, this study suggests that identification of dominant and recessive cancer predisposing genes may require distinct study groups.