The influence of ultrafine-grained structure on the mechanical properties and biocompatibility of austenitic stainless steels.

In this study, equal-channel angular pressing (ECAP) of austenitic 316L and Cr-Ni-Ti stainless steels was carried out. Effect of ECAP at 400°C on the evolution of the microstructure, mechanical properties, and biocompatibility of these steels was investigated. The biocompatibility of samples with the ultrafine grain structure obtained in the ECAP process did not deteriorate in comparison with an austenitic 316L stainless steel in coarse-grained state. However, this treatment enhances the multipotent mesenchymal stromal/stem cell proliferation by 26% for 316L steel and by 17% for Cr-Ni-Ti stainless steel in comparison with coarse-grained counterparts. At the same time, ECAP contributes to a significant improvement in performance and weight reduction of medical devices, which is especially important for the creation of implanted prostheses for replacement of skeletal defects, due to significant increase in specific strength of steels. The strength properties of austenitic stainless steels were remarkably improved due to the grain refinement and deformation twinning resulted from ECAP at 400°C. After ECAP, the yield strength of 316L and Cr-Ni-Ti stainless steels increased by 4.2 and 2.9 times up to 950 and 900 MPa, and the fatigue limit by 2 and 1.7 times up to 500 and 475 MPa, respectively, comparing to coarse-grained counterparts.

Immunological monitoring for prediction of clinical response to antitumor vaccine therapy.

Immunotherapy has shown promising results in a variety of cancers, including melanoma. However, the responses to therapy are usually heterogeneous, and understanding the factors affecting clinical outcome is still not achieved. Here, we show that immunological monitoring of the vaccine therapy for melanoma patients may help to predict the clinical course of the disease. We studied cytokine profile of cellular Th1 (IL-2, IL-12, IFN-γ) and humoral Th2 (IL-4, IL-10) immune response, vascular endothelial growth factor (VEGFA), transforming growth factor-ß 2 (TGF-ß 2), S100 protein (S100A1B and S100BB), adhesion molecule CD44 and serum cytokines ß2-microglobulin to analyze different peripheral blood mononuclear cell subpopuations of patients treated with dendritic vaccines and/or cyclophosphamide in melanoma patients in the course of adjuvant treatment. The obtained data indicate predominance of cellular immunity in the first adjuvant group of patients with durable time to progression and shift to humoral with low cellular immunity in patients with short-term period to progression (increased levels of IL-4 and IL- 10). Beta-2 microglobulin was differentially expressed in adjuvant subgroups: its higher levels correlated with shorter progression-free survival and the total follow-up time. Immunoregulatory index was overall higher in patients with disease progression compared to the group of patients with no signs of disease progression.

The "cavitary" type of angiogenesis by gastric cancer. Morphological characteristics and prognostic value.

UNLABELLED: The "cavitary" type of angiogenesis in patients with gastric cancer (GC) is described for the first time. MATERIAL AND METHODS: The samples of tumour and adjacent gastric mucosa (GM) in 73 patients with GC who had undergone radical surgery were being studied. The sections were stained with hematoxylin and eosin (H&E) and immunohistochemically (IGH) using antibodies to CD34. RESULTS: А new type of vessel formation consists of the appearance of cavitary structures (CS) in tumours and the adjacent GM, which are then lined by endothelial cells and merged into the blood vessels of the organ. We believe that the CS can be formed by means: 1) of the abruption of layers of epithelial cells (both normal and tumoral) from their underlying foundation and their desquamation into the lumen of the "obliterated" gastric glands (GG); 2) of the dilatation of the GG and thinning of their walls; 3) of the formation of "cavity" directly in the lamina propria of GM or in the tumoral stroma. It was noted that only the presence of multiple "cavitary" vessels (CV) of type-1 had been associated with the decrease of 3-year overall survival (OR=15,0, 95%CI=2,96-76,31) and relapse-free survival (OR=14,93, 95%CI=4,34-51,38). We also observed the improvement of the long-term outcomes in patients with GC having received antibacterial therapy (AT) before surgery that can be associated with its influence on the formation of CV type-1. CONCLUSION: The described new type of angiogenesis is of great clinical importance.

Trans-, cis-, and dihydro-resveratrol: a comparative study.

BACKGROUND: Recent studies showed that moderate consumption of red or white wines increased the chances of breast cancer, while similar consumption of red wines, rich in trans-resveratrol (trans-R), decreased the rate of prostate cancer. This prompted us to explore the role of various forms of R in cancer proliferation. RESULTS: Trans-R was found to be the most potent antiproliferative agent. Cis-R demonstrated somewhat less potency compared to trans-R. Unlike cis-R and trans-R, dihydro-R exhibits moderate proliferative effect on androgen-independent prostate cancer cell lines PC-3 and DU-145 at picomolar concentrations. At higher concentrations, dihydro-R caused proliferation inhibition, similar to cis-R and trans-R. The proliferative effect of dihydro-R at low concentrations can be reversed by trans-R which acts as a partial antagonist in the presence of dihydro-R. Mixtures of dihydro-R and trans-R demonstrated complex non-monotonic cross-modulation activity patterns. CONCLUSIONS: Dihydro-R exhibits proliferative effects in androgen-independent prostate cancer cells at picomolar and nanomolar concentrations. While the exact mechanism of these effects requires further evaluation, our preliminary results point to hormone receptor modulation activity. We also observed strong cross modulation between trans-R and dihydro-R at sub-picomolar concentrations. The role of dihydro-R in cancer proliferation related to moderate consumption of red wine remains an open question because dihydro-R has a very complex activity pattern in the presence of trans-R.

Cytotoxic Activity of Peripheral Blood Mononuclear Leukocytes, Activated by Interleukin-2/ß-Cyclodextrin Nanocomposition against Androgen Receptor-Negative Prostate Cancers.

Nanocomposition comprised of interleukin-2 in suboptimal noneffective concentration and ß-cyclodextrin was studied in vitro. This preparation as well as interleukin-2 in optimal concentration was shown to increase natural killer activity to K-562 cells and cytotoxicity of activated peripheral blood mononuclear cells (PBMCs) against PC-3 and DU 145 cells. At the same time ß-cyclodextrin or interleukin-2 in equimolar concentrations did not influence the spontaneous killer activity of PBMC. This combination of cyclodextrin + interleukin-2 led to the decrease of interleukin-2 effective concentration by an order. This phenomenon could be explained by cyclodextrins ability to promote the formation of nanoparticles with drugs, which results in enhancing their water solubility and bioavailability. Besides, interleukine-2/ß-cyclodextrin nanocomposition as opposed to interleukin-2 alone led to increasing the number of not only lymphocytes, but also macrophages contained in activated PBMC population. Application of low concentration of interleukin-2 allowing for good clinical efficiency may significantly mitigate the side effects of the drug and enable to develop adoption of immunotherapy for patients with androgen-resistant prostate cancer.

Dihydro-resveratrol--a potent dietary polyphenol.

Dihydro-resveratrol (dihydro-R), a prominent polyphenol component of red wine, has a profound proliferative effect on hormone-sensitive tumor cell lines such as breast cancer cell line MCF7. We found a significant increase in MCF7 tumor cells growth rates in the presence of picomolar concentrations of this compound. The proliferative effect of dihydro-R was not observed in cell lines that do not express hormone receptors (MDA-MB-231, BT-474, and К-562).

Is it necessary to deplete the lymphokine activated killers' populations of CD4+CD25+ lymphocytes? Regulatory Foxp3-positive T cells within lymphokine activated killers.

LAKs are used in cancer therapy. A common argument against LAK therapy is the probability of the activation of Tregs by IL-2 alongside with NK cells. In order to evaluate negative impact of Tregs, contents of Foxp3(+)CD4(+)CD25(+) Tregs and their influence on LAKs' cytotoxic activity in the samples of healthy volunteers' PBMCs cultured with or without IL-2 were determined. A marked increase in the proportion of the CD4(+)CD25(+) T cells in the most of the PBMCs cultured with IL-2 was evident. Surprisingly, the contents of Foxp3(+)CD4(+)CD25(+) Tregs showed variable response to IL-2 in blood samples of different people. Their proportions increased, remained on the same level or even decreased compared to PBMCs cultured without exogenous IL-2. Different methods of Treg isolation were compared regarding the purities of the resulting T-cell populations and their enrichment in the Foxp3-expressing Tregs, as well as their viability. Neither of the kits applied provided any enrichment in Foxp3-level in the purified cells compared to the CD4(+)CD25(+) T cells gated on applying flow-cytometric cell analysis in the non-separated LAKs. Moreover, the addition of the purified supposedly Tregs to LAKs never inhibited their cytotoxic reactions, even then they were added in great non-physiological excess. In some of the blood samples, there have been detected another non-identified type of the Foxp3-expressing cells, which lacked CD25, as well as CD4. They may be a new type of regulatory cells, which has not been described before.

Ricin at Subpicomole Concentrations Induce Cytolytic Activity and Stimulate Lymphokine Secretion by Human Peripheral Blood Mononuclear Cells.

Human PBMCs were stimulated by ricin at very low concentrations (10(-14) M and lower) for 48 h at 37 degrees C. Cytolytic activity to K562 cell line and lymphokine secretion were been measured. PBMCs possessed the highest cytotoxicity (63 +/- 2.8% and 64 +/- 3.1%, respectively) to K562 cell line in the presence of 10(-15) M or 10(-16) M ricin. The high secretion of IL-1beta (2000 pg/ml), IL-2 (1300 pg/ml) and TNF-alpha (2200 pg/ml) was detected in the presence of 10(-15) M ricin. The mechanisms of the target cell death induced by PBMCs after co-incubation with various lectins: 10(-8) M phytohemagglutinin, 10(-8) M concanavalin A and ricin at 10(-15) M or 10(-16) M concentrations were compared. Internucleosomal DNA fragmentation characteristic of apoptotic mechanisms of the target cell death in all cases were observed, and the maximum of DNA fragmentation was registered in the presence of 10(-15) M ricin.

Purification and Partial Characterization of a 14 kDa Protein Enhancing Mitogen-Stimulated Proliferation of Human Peripheral Blood Mononuclear Cells.

Cytotoxicity of plasma free platelets or peripheral blood mononuclear cells (PBMCs) upon stimulation with Ca-ionophore A23187 at various (10(-9) - 10(-6) M) concentrations has been studied on human erythroid leukaemia cell line (K562). A 14 kDa protein, which did not display any cytotoxic activity to K562 cells, but stimulate PBMC proliferation has been isolated from the supernatant of plasma free platelets stimulated by 10(-7) M Ca-ionophore. The protein displayed a very slight mitogenic effect on PBMCs, but it enhanced proliferative response of PBMC stimulated by concanavalin A at suboptimal concentrations. The p14 N-terminal sequence ((1)VLERTXA(7)-) is identical to the region 99-103 residues of the human MHC class II antigen DQ-beta chain. Also, we identified this 14 kDa protein in the supernatant of PBMCs stimulated by 10(-7) M Ca-ionophore. Its N-terminal sequence (VLERTXA-) is identical to the one of p14 from the stimulated plasma-free platelet supernatant.