The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model

2-Methoxyestradiol is one of the natural 17β-estradiol derivatives and a potential novel anticancer agent currently being under evaluation in advanced phases of clinical trials. However, the mechanism of anticancer action of 2-methoxyestradiol has not been yet fully established. In our previous studies we have demonstrated that 2-methoxyestradiol selectively induces the expression and nuclear translocation of neuronal nitric oxide synthase in osteosarcoma 143B cells. Heat shock proteins (Hsps) are factors involved in the regulation of expression and activity of nitric oxide synthases. Herein, we chose osteosarcoma cell lines differed in metastatic potential, metastatic 143B and highly metastatic MG63.2 cells, in order to further investigate the anticancer mechanism of 2-methoxyestradiol. The current study aimed to determine the role of major heat shock proteins, Hsp90 and Hsp70 in 2-methoxyestradiol-induced osteosarcoma cell death. We focused on the implication of Hsp90 and Hsp70 in control under expression of neuronal nitric oxide synthase, localization of the enzyme, and further generation of nitro-oxidative stress. To give the insight into the role of Hsp90 in regulation of anticancer efficacy of 2-methoxyestradiol, we used geldanamycin as a potent Hsp90 inhibitor. Herein, we evidenced that inhibition of Hsp90 controls the protein expression of 2-methoxyestradiol-induced neuronal nitric oxide synthase and inhibits enzyme nuclear translocation. We propose that decreased level of neuronal nitric oxide synthase protein after a combined treatment with 2-methoxyestradiol and geldanamycin is directly associated with the accompanying upregulation of Hsp70 and downregulation of Hsp90. This interaction resulted in abrogation of anticancer efficacy of 2-methoxyestradiol by geldanamycin

Unc119, a Novel Activator of Lck/Fyn, Is Essential for T Cell Activation

The first step in T cell receptor for antigen (TCR) signaling is the activation of the receptor-bound Src kinases, Lck and Fyn. The exact mechanism of this process is unknown. Here, we report that the novel Src homology (SH) 3/SH2 ligand–Uncoordinated 119 (Unc119) associates with CD3 and CD4, and activates Lck and Fyn. Unc119 overexpression increases Lck/Fyn activity in T cells. In Unc119-deficient T cells, Lck/Fyn activity is dramatically reduced with concomitant decrease in interleukin 2 production and cellular proliferation. Reconstitution of cells with Unc119 reverses the signaling and functional outcome. Thus, Unc119 is a receptor-associated activator of Src-type kinases. It provides a novel mechanism of signal generation in the TCR complex

Association between serum heat shock proteins and gamma-delta t cells—an outdated clue or a new direction in searching for an anticancer strategy? A short report

HSPs demonstrate a strong association with gamma-delta (γδ) T cells. Most of the studies regarding interactions between the parameters were conducted in the 1990s. Despite promising results, the concept of targeting γδ T cells by HSPs seems to be a forgotten direction due to potent non-peptidic phosphoantigens rather than HSPs have been found to be the essential stimulatory components for human γδ cells. Currently, with greater knowledge of lymphocyte diversity, and more accurate diagnostic methods, we decided to study the correlation once again in the neoplas-tic condition. Twenty-one children with newly diagnosed acute lymphoblastic leukaemia (ALL) were enrolled on the study. Serum HSP90 concentrations were evaluated by an enzyme-linked immunosorbent assay (ELISA), subsets of γδ T cells (CD3+ γδ, CD3+ γδ HLA/DR+, CD4+ γδ and CD8+ γδ) by flow cytometry. We have shown statistically relevant correlations between serum HSP90 and CD3+ HLA/DR+ γδ T cells in paediatric ALL at diagnosis (R = 0.53, p < 0.05), but not after induction chemotherapy. We also have demonstrated decreased levels of both serum HSP90 and CD3+ HLA/DR+ γδ T cells before treatment, which may indirectly indicate dose-dependent unknown interaction between the parameters. The results of our study may be a good introduction to research on the association between HSPs and CD3+ HLA/DR+ γδ T cells, which could be an interesting direction for the development of anti-cancer strategies, not just for childhood ALL

RSK1 promotes murine breast cancer growth and metastasis

Introduction. Triple-negative breast cancer (TNBC), representing over 15% of all breast cancers, has a poorerprognosis than other subtypes. There is no effective targeted treatment available for the TNBC sufferers. Ribosomal S6 kinases (RSKs) have been previously proposed as drug targets for TNBC based on observations that 85% of these tumors express activated RSKs.Materials and methods. Herein we examined an involvement of RSK1 (p90 ribosomal S6 kinase 1) in a regulation of TNBC growth and metastatic spread in an animal model, which closely imitates human disease. Micewere inoculated into mammary fat pad with 4T1 cells or their RSK1-depleted variant. We examined tumorgrowth and formation of pulmonary metastasis. Boyden chamber, wound healing and soft agarose assays wereperformed to evaluate cells invasion, migration and anchorage-independent growth.Results. We found that RSK1 promoted tumor growth and metastasis in vivo. After 35 days all animals inoculatedwith control cells developed tumors while in the group injected with RSK1-negative cells, there were 75%tumor-bearing mice. Average tumor mass was estimated as 1.16 g and 0.37 g for RSK1-positive vs. -negativesamples, respectively (p < 0.0001). Quantification of the macroscopic pulmonary metastases indicated that micewith RSK1-negative tumors developed approximately 85% less metastatic foci on the lung surface (p < 0.001).This has been supported by in vitro data presenting that RSK1 promoted anchorage-independent cell growthand migration. Moreover, RSK1 knock-down corresponded with decreased expression of cell cycle regulatingproteins, i.e. cyclin D3, CDK6 and CDK4.Conclusions. We provide evidence that RSK1 supports tumor growth and metastatic spread in vivo as well asin vitro migration and survival in non-adherent conditions. Further studies of RSK1 involvement in TNBC progression may substantiate our findings, laying the foundations for development of anti-RSK1-based therapeuticstrategies in the management of patients with TNBC

On the β-detection efficiency of a combined Si and plastic stack detector for DESPEC

A Geant4 simulation has been carried out in order to determine the B-detection efficiency of a rare isotope beam implantation setup, for decay spectroscopy experiments, comprising a number of Double Sided Silicon Strip Detectors (DSSSDs) and two plastic scintillation detectors placed upstream and downstream. The absolute efficiency for the emitted B-particle detection from radioactive fragments implanted in the DSSSDs using fast-timing plastic-scintillator detector, is calculated. The detection efficiency of the setup has been studied with two different distances between the Si layers and plastics. The requirement for the thickness of the Si detector layers and its implication on the B-detection effciency has been investigated for 1 mm and 300 um thickness of Si layers. The combined efficiency of DSSSD and plastic detectors were also simulated for two different thicknesses of the DSSSD

beta-decay study of Cu-77

A beta-decay study of Cu-77 has been performed at the ISOLDE mass separator with the aim to deduce its beta-decay properties and to obtain spectroscopic information on Zn-77. Neutron-rich copper isotopes were produced by means of proton- or neutron-induced fission reactions on U-238. After the production, Cu-77 was selectively laser ionized, mass separated and sent to different detection systems where beta-gamma and beta-n coincidence data were collected. We report on the deduced half-live, decay scheme, and possible spin assignment of 77Cu

Health promotion intervention for people with early-stage dementia: A quasi-experimental study

Introduction: With the limited advancements in medical treatment, there is a growing need for supporting people with early‐stage dementia adjust to their diagnosis and improve their quality of life. This study aimed to investigate the effects of a 12‐week health promotion course for people with early‐stage dementia. Methods: Quasi‐experimental, single group, pretest‐posttest design. A total of 108 persons with dementia participated in this study, and for each participant, a carer was interviewed. The 12‐week health promotion intervention consisted of 2‐hr sessions at weekly intervals. Outcome measures were cognition, measured by Mini‐Mental State Examination, personal, and instrumental activities of daily living (P‐ADL and I‐ADL), measured by Lawton and Brody's Physical Self‐Maintenance Scale and Instrumental Activities of Daily Living Scale, self‐rated health, measured by the European Quality of life Visual Analogue Scale, depressive symptoms, measured by the Cornell Scale for Depression in Dementia, and neuropsychiatric symptoms, measured by The Neuropsychiatric Inventory. Assessments were conducted at baseline and at follow‐up 1–2 months postintervention. Results: The results demonstrate a small but statistically significant improvement in depressive symptoms (p = .015) and in self‐rated health (p = .031). The results also demonstrated a small statistically significant decline in the participants’ I‐ADL (p = .007). The participants’ cognitive function, P‐ADL, and neuropsychiatric symptoms were stable during the 4‐month follow‐up. Conclusion: This study demonstrates promising results with regard to the benefit of attending a 12‐week health promotion intervention in promoting health and well‐being in people with early‐stage dementia. With the majority of participants with early‐stage dementia living at home without any healthcare services in a vulnerable stage of the condition, this study makes an important contribution to highlighting the need for, and benefit of, educational approaches for this population.publishedVersio

Core-coupled states and split proton-neutron quasi-particle multiplets in 122-126Ag

Neutron-rich silver isotopes were populated in the fragmentation of a 136Xe beam and the relativistic fission of 238U. The fragments were mass analyzed with the GSI Fragment separator and subsequently implanted into a passive stopper. Isomeric transitions were detected by 105 HPGe detectors. Eight isomeric states were observed in 122-126Ag nuclei. The level schemes of 122,123,125Ag were revised and extended with isomeric transitions being observed for the first time. The excited states in the odd-mass silver isotopes are interpreted as core-coupled states. The isomeric states in the even-mass silver isotopes are discussed in the framework of the proton-neutron split multiplets. The results of shell-model calculations, performed for the most neutron-rich silver nuclei are compared to the experimental data