Some peculiarities of motion of neutral and charged test particles in the field of a spherically symmetric charged object in General Relativity

We propose the method of investigation of radial motions for charged and neutral test particles in the Reissner-Nordstr\"{o}m field by means of mass potential. In this context we analyze special features of interaction of charges and their motions in General Relativity and construct the radial motion classification. For test particles and a central source with charges $q$ and $Q$, respectively, the conditions of attraction (when $qQ>0$) and repulsion (when $qQ<0$) are obtained. The conditions of motionless test particle states with respect to the central source are investigated and, in addition, stability conditions for such static equilibrium states are found. It is shown that stable states are possible only for the bound states of weakly charged particles in the field of a naked singularity. Frequencies of small oscillations of test particles near their equilibrium positions are also found.Comment: 15 pages, 9 figure

Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma

<div><p>Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-<i>sn</i>-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-<i>rac</i>-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless the antimetastatic effect was less effective in comparison with prophylactic DC vaccine.</p></div

CD4+ and CD8+ cell content in spleens of animals with Krebs-2 treated with prophylactic and therapeutic DC vaccines.

<p>A. w/t, non-treated mice with Krebs-2 injected with saline buffer, time of tumor development 19 days. B, C and D. Mice received prophylactic DC vaccines 1/LF, 1/LF/RNA and 1/lysate, respectively. E. w/t, non-treated mice with Krebs-2 injected with saline buffer, time of tumor development 11 days. F, G and H. Mice received therapeutic DC vaccines 2/LF, 2/LF/RNA and 2/lysate, respectively. CD4+ and CD8+ content at the point -7 days was measured just before DC vaccination and corresponded to baseline. Type of DC vaccine is presented as S/T/A—Scheme of the treatment 1 or 2/ Transfectant/ Antigen source. Blue line indicates CD4+ cells, red line—CD8+ cells. Arrows indicate the day of DC vaccination and the day of tumor transplantation. Data are presented as mean±S.E.M. All experimental points were run in triplicate.</p

Anti-tumour and anti-metastatic effects of DC vaccination under prophylactic and therapeutic schemes.

<p>A and B. Krebs-2 adenocarcinoma growth retardation after treatment with DC vaccines. w/t—non-treated mice with Krebs-2 injected with saline buffer. C and D. LLC tumor growth retardation and suppression of metastasis after treatment with DC vaccines. For A-D type of DC vaccine is presented as S/T/A—Scheme/ Transfectant/ Antigen source. w/t—non-treated mice with LLC injected with saline buffer. E. Suppression of B16 melanoma metastasis after treatment with DC vaccines. For E type of DC vaccine is presented as S-I/T/A—Scheme—Immunization number/ Transfectant/ Antigen source. w/t—non-treated mice with metastatic melanoma injected with saline buffer. Data were statistically analysed using one-way ANOVA with post hoc Fisher test. Data are presented as mean±S.E.M. <i>p</i> value <0.05 was considered to be statistically significant. Scheme 1: Healthy mice received i.v. DC vaccines according to presented S/T/A type. On day 7 after DC vaccination tumors were induced in mice by intramuscular injection of Krebs-2 cells (10⁵ cells/mouse) or LLC cells (6×10⁵ cells/mouse) into the femur muscle of right hindfoot. In the case of B16 model healthy mice received i.v. Dc vaccines according to presented S-I/T/A type: on day 7 before tumor transplantation (S-I: 1–1) and on day 14 and 7 before tumor transplantation (S-I:1–2). B16 was induced by transplantation of B16 cells (10⁵ cells/mouse) into lateral tail vein. Scheme 2. Tumors were induced in mice by intramuscular injection of Krebs-2 cells (10⁵ cells/mouse) or LLC cells (6×10⁵ cells/mouse) into the femur muscle of right hindfoot or intravenous inoculation of B16 cells (10⁵ cells/mouse) into lateral tail vein. On day 4 after tumor transplantation mice received i.v. Dc vaccines according to presented S/T/A or S-I/T/A type.</p

Box plots of Th2-specific cytokine content in the blood serum of mice with metastatic melanoma after prophylactic or therapeutic DC vaccination: (A) IL-4, (B) IL-10, (C) IL-5.

<p>Boxes represent 25^th, 50^th, and 75^th percentiles. Squares with line represent median. Whiskers represent minimum/maximum. w/t—non-treated mice with metastatic melanoma injected with saline buffer. Type of DC vaccine is indicated as S-I/T/A where S—scheme of the treatment 1 or 2, I—immunization number, T—transfectant, A—antigen source. Data were statistically analysed using one-way ANOVA with post hoc Fisher test. <i>p</i> value indicates a statistically reliable difference.</p

Relationships of growth factors, proinflammatory cytokines, and anti-inflammatory cytokines with long-term clinical results of autologous bone marrow mononuclear cell transplantation in STEMI

AIM

Experimental schedules of mouse treatments with DC vaccines.

<p>(A) Treatment of Krebs-2 and LLC tumors. Scheme 1 (prophylactic): Mice were injected with DC vaccines intravenously. A week later Krebs-2 or LLC cells were intramuscularly transplanted into mice. Mice with LLC and mice with Krebs-2 were sacrificed on days 19–20 and 20, respectively. Scheme 2 (therapeutic): Krebs-2 or LLC tumor cells were intramuscularly transplanted into the femur muscle of right hindfoot of mice, mice were treated with DC vaccines intravenously on day 4 and sacrificed on day 20. (B) Treatment of B16 tumors. Scheme 1 (prophylactic): Mice were intravenously injected with a DC vaccine once or twice with a one-week interval. A week after the last DC injection, B16 cells were inoculated intravenously into the mice. The mice were sacrificed on day 15. Scheme 2 (therapeutic): B16 cells were intravenously transplanted into mice, mice received one or two DC vaccines intravenously on day 4 or days 4 and 11, respectively. The mice were sacrificed on day 15.</p

The expression level of Tbet, GATA3, RORg, and Foxp3 in spleen cells of mice after DC vaccination (qPCR data).

<p>A. Prophylactic treatment scheme: healthy mice receiving DC vaccines 1-1/2D3/RNA and 1-2/2D3/RNA (1 and 2 immunization, respectively). B. Mice with metastatic melanoma receiving saline buffer. C. Therapeutic treatment scheme: mice with metastatic melanoma receiving DC vaccines 2-1/2D3/RNA and 2-2/2D3/RNA (1 and 2 immunization, respectively). Crossed square on Y axis displays the level of gene expression in healthy intact mice (baseline). Type of DC vaccine is indicated as S-I/T/A where S—scheme of the treatment 1 or 2, I—immunization number, T—transfectant, A—antigen source. Expression of the genes in group without treatment was measured on days 9 and 16 of tumor development. Expression of the genes in prophylactic and therapeutic groups was measured on day 5 after each immunization. Data represent the mean ± SD of three experiments performed in triplicate. Data were statistically analysed using one-way ANOVA with post hoc Fisher test.</p

Relationships of growth factors, proinflammatory cytokines, and anti-inflammatory cytokines with long-term clinical results of autologous bone marrow mononuclear cell transplantation in STEMI

<div><p>Aim</p><p>The aim of the study was to test the hypothesis suggesting that the pre-intervention levels of proinflammatory cytokines, anti-inflammatory cytokines, and angiogenic growth factors predict the long-term clinical results of autologous bone marrow-derived mononuclear cell (ABMMC) transplantation in patients with primary ST elevation myocardial infarction (STEMI).</p><p>Methods and results</p><p>From 2003 to 2006, a total of 62 patients with primary STEMI were enrolled in an open randomized study registered under the title ESTABOMA. Patients were randomized into two groups: group 1 included patients treated with percutaneous coronary intervention (PCI) and ABMMC transplantation (n = 28); group 2 comprised patients treated only with PCI (n = 34). Follow-up study was performed 7.96 ± 0.96 years after STEMI and involved physical examination, six-minute walk test, echocardiography, and determination of brain natriuretic peptide (BNP) levels. The total and cardiovascular mortality rates were higher in group 1 compared with group 2: 36% (n = 10) vs. 12% (n = 4) (p = 0.02) and 29% (n = 8) vs. 6% (n = 2) (p = 0.03), respectively. Lower levels of proinflammatory cytokines were observed in group 1 after PCI and ABMMC transplantation. Serum levels of FGF, VEGF, and IL-10, determined before PCI and ABMMC transplantation were prognostically significant long-term indicators of unfavorable course of CAD after STEMI.</p></div

siRNA-Mediated <i>Timp1</i> Silencing Inhibited the Inflammatory Phenotype during Acute Lung Injury

Acute lung injury is a complex cascade process that develops in response to various damaging factors, which can lead to acute respiratory distress syndrome. Within this study, based on bioinformatics reanalysis of available full-transcriptome data of acute lung injury induced in mice and humans by various factors, we selected a set of genes that could serve as good targets for suppressing inflammation in the lung tissue, evaluated their expression in the cells of different origins during LPS-induced inflammation, and chose the tissue inhibitor of metalloproteinase Timp1 as a promising target for suppressing inflammation. We designed an effective chemically modified anti-TIMP1 siRNA and showed that Timp1 silencing correlates with a decrease in the pro-inflammatory cytokine IL6 secretion in cultured macrophage cells and reduces the severity of LPS-induced acute lung injury in a mouse model