To the Мemory of the Scientist, Teacher, Human: Dadicated to 65-th Аnniversary of Professor Anatolyj Fedosov

Висвітлено основні віхи життєвого шляху відомого вченого фізика професора А. В. Федосова.;The paper presents the career and scientific achievements of well-known physicist Professor Anatolyj Fedosov

Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy

Background: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. Patients and methods: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. Results: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. Conclusions: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.peer-reviewe

Corticosteroid Treatment Of Experimental Autoimmune Encephalomyelitis In The Lewis Rat Results in Loss of V Beta 8.2+ and Myelin Basic Protein-Reactive Cells from the Spinal Cord, with Increased Total T-Cell Apoptosis but Reduced Apoptosis of V Beta 8.2+

We have studied the effects of corticosteroid treatment on the numbers of lymphocytes obtained from the spinal cords of Lewis rats with acute experimental autoimmune encephalomyelitis (EAE) induced by inoculation with myelin basic protein (MBP) and adjuvants. Flow cytometric studies showed that treatment with dexamethasone (4 mg/kg) 8-12 h prior to study on day 14 after inoculation resulted in a reduction in the numbers of CD5+, TCR alpha beta + and V beta 8.2+ cells in the spinal cord. Limiting dilution analysis indicated that dexamethasone treatment 12 h prior to study on day 12 after inoculation reduced the frequencies of MBP-reactive and interleukin-2-responsive lymphocytes in the spinal cord to low levels, but reduced the frequency of concanavalin-A-responsive lymphocytes to a lesser extent. Using propidium iodide staining of nuclear chromatin we also studied lymphocyte apoptosis. Greater numbers of apoptotic cells were found in the cells extracted from the spinal cords of rats, examined on day 14, that had been treated 1-12 h previously with dexamethasone, than in saline-treated controls. This increased level of apoptosis was observed in the CD5+ and TCR alpha beta + cell populations. At 1-4 h after dexamethasone treatment there was a reduction in the selective apoptosis of V beta 8.2+ cells that normally occurs during spontaneous recovery from EAE. Therefore apoptosis of V beta 8.2+ cells cannot explain the reduction in the numbers of V beta 8.2+ cells and MBP-reactive cells in the CNS after dexamethasone treatment. By 8-12 h after dexamethasone treatment the selectivity of the apoptotic process was restored. These studies suggest that a reduction in the number of T-lymphocytes in the central nervous system contributes to the beneficial effects of corticosteroids in EAE

Apoptosis of Inflammatory Cells in Immune Control of the Nervous System: Role of Glia

Normal individuals have T lymphocytes capable of reacting to central nervous system (CNS) antigens such as myelin basic protein (MBP) (Martin et al., [1990]). In view of recent evidence indicating that T cells are much more cross-reactive than previously thought (Mason, [1998]), it is likely that these autoreactive T cells are often primed by exposure to cross-reacting environmental antigens. Indeed it has been shown that viral and bacterial peptides can activate myelin-reactive human T cells (Wucherpfennig and Strominger, [1995]; Hemmer et al., [1997]). Furthermore, normal healthy subjects experience surges of increased frequencies of circulating myelin-reactive T cells that might be driven by cross-reactive environmental antigens (Pender et al., [2000]). Such activated myelin-reactive T cells would be expected to enter the CNS in healthy individuals, because activated T cells of any specificity, including autoreactive T cells, enter the normal CNS parenchyma (Wekerle et al., [1986]; Hickey et al., [1991]). If CNS-reactive T cells survive in the CNS, they have the potential to attack the CNS, either directly or through the recruitment of other inflammatory cells, and thus lead to CNS damage such as demyelination. Therefore, the physiological control of autoreactive T cells in the CNS is likely to have an important role in preventing the development of autoimmune CNS disorders such as multiple sclerosis (MS) (Pender, [1998]). T-cell apoptosis in the CNS has been proposed to be an important mechanism for controlling autoimmune attacks on the CNS (Pender et al., [1992]; Schmied et al., [1993]). Although other mechanisms, such as immune deviation (Wenkel et al., [2000]), may possibly also contribute to the control of the immune response in the CNS, this review will focus on T-cell apoptosis in the CNS and the role of glia in this process

Activation-Induced Apoptosis of Autoreactive and Alloreactive T Lymphocytes in the Target Organ as a Major Mechanism of Tolerance

Normal individuals have mature T lymphocytes that are capable of reacting to self-antigens and can be activated by cross-reacting environmental antigens. The mechanism that maintains immune tolerance and prevents these activated autoreactive T cells from causing autoimmune disease is unclear. We have previously hypothesized that activation-induced apoptosis of previously activated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance. Here I review the current evidence to support this hypothesis. It is proposed that when activated autoreactive T cells enter the target organ, they are reactivated mainly by non-professional antigen-presenting cells (APC) and deleted by activation-induced apoptosis through the Fas (CD95) pathway before producing significant target organ damage. This apoptosis occurs because the reactivated T cells do not receive sufficient costimulation from the non-professional APC to up-regulate their expression of Bcl-2-related anti-apoptotic proteins, which inhibit the CD95 pro-apoptotic pathway. This is in contrast to the situation in peripheral lymphoid organs, where reactivation of T cells by professional APC results in sufficient costimulation-induced up-regulation of Bcl-2-related proteins to inhibit the CD95 pathway and allow T cell proliferation and survival as memory T cells. Activation-induced apoptosis of alloreactive T cells in allografts can similarly account for spontaneous allograft acceptance, as occurs after MHC-mismatched liver transplantation

PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomised, double-blind study

BACKGROUND: This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. METHODS: Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2 ) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. RESULTS: The risk ratio for ORR was 0.940 (95% CI: 0.842–1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80–1.25. ORR was 62.5% (95% CI: 57.2–67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3–71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. CONCLUSION: When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT0198967

Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke

Increasing evidences show that immune response affects the reparative mechanisms in injured brain. Recently, we have demonstrated that CD4+T cells serve as negative modulators in neurogenesis after stroke, but the mechanistic detail remains unclear. Glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR), a multifaceted regulator of immunity belonging to the TNF receptor superfamily, is expressed on activated CD4+T cells. Herein, we show, by using a murine model of cortical infarction, that GITR triggering on CD4+T cells increases poststroke inflammation and decreases the number of neural stem/progenitor cells induced by ischemia (iNSPCs). CD4+GITR+T cells were preferentially accumulated at the postischemic cortex, and mice treated with GITR-stimulating antibody augmented poststroke inflammatory responses with enhanced apoptosis of iNSPCs. In contrast, blocking the GITR–GITR ligand (GITRL) interaction by GITR–Fc fusion protein abrogated inflammation and suppressed apoptosis of iNSPCs. Moreover, GITR-stimulated T cells caused apoptosis of the iNSPCs, and administration of GITR-stimulated T cells to poststroke severe combined immunodeficient mice significantly reduced iNSPC number compared with that of non-stimulated T cells. These observations indicate that among the CD4+T cells, GITR+CD4+T cells are major deteriorating modulators of poststroke neurogenesis. This suggests that blockade of the GITR–GITRL interaction may be a novel immune-based therapy in stroke

Functional Role of Kallikrein 6 in Regulating Immune Cell Survival

Kallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur.Using murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice.KLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis

Learning and teaching support kit «History of Ukrainian Statehood and Culture»

Дана навчальна дисципліна є теоретичною та практичною основою сукупності знань та вмінь, оскільки є однією з головних складових гуманітарної загальноосвітньої підготовки фахівців із вищою освітою для усіх спеціальностей. Метою викладання дисципліни є поглиблення наукових знань з історії виникнення і розвитку українського народу, його державності, суспільно-політичних і національно-культурних процесів, які відбуваються в Україні, формування свідомих громадян нашої держави.This academic discipline is the theoretical and practical basis of the body of knowledge and skills, since it is one of the main components of the general education of specialists in Human Sciences for all specialties. The purpose of teaching the discipline is to highlight the specificities of the struggle for Ukrainian statehood at various stages of the historical and political development of society. In this connection, it considers the cultural and historical process of the Ukrainian people from ancient times until the present time

Learning and teaching support kit «History of Ukrainian Statehood and Culture»

Дана навчальна дисципліна є теоретичною та практичною основою сукупності знань та вмінь, оскільки є однією з головних складових гуманітарної загальноосвітньої підготовки фахівців із вищою освітою для усіх спеціальностей. Метою викладання дисципліни є поглиблення наукових знань з історії виникнення і розвитку українського народу, його державності, суспільно-політичних і національно-культурних процесів, які відбуваються в Україні, формування свідомих громадян нашої держави.This academic discipline is the theoretical and practical basis of the body of knowledge and skills, since it is one of the main components of the general education of specialists in Human Sciences for all specialties. The purpose of teaching the discipline is to highlight the specificities of the struggle for Ukrainian statehood at various stages of the historical and political development of society. In this connection, it considers the cultural and historical process of the Ukrainian people from ancient times until the present time