"The Economic and Financial Crises in CEE and CIS: Gender Perspectives and Policy Choices"

This paper looks at the countries of Central and Eastern Europe (CEE) and the Commonwealth of Independent States (CIS), where economies have been most dramatically hit by the global crisis and its impact is likely to be most long-lasting, especially among poor and vulnerable groups. Using poverty as the main axis, it looks at aspects of economic and social development in countries at similar poverty levels to identify the degree of fiscal space in each, as well as the different policy choices made. The paper argues that despite such economic fundamentals as increasing external debt, worsening current account imbalances, and demands for a balanced budget, governments have policy choices to make about how to protect different groups, especially the most vulnerable-including women.Economic Crisis; Gender; Policy Response; Pro-poor Macro Policies; Gender; Policy Space; Central and Eastern Europe; Commonwealth of Independent States

Alergenski proteini u ribi

Riba predstavlja znatan deo ishrane ljudi u svetu. Pre svega, riba je značajan izvor proteina (15-24%) visoke biološke vrednosti, bogata je mineralima, vitaminima, a posebno esencijalnim masnim kiselinama za koje je dokazano da pogoduju u prevenciji mnogobrojnih oboljenja. Zbog velikog značaja polinezasićenih masnih kiselina n-3 klase, u Evropi su date i preporuke o optimalnom dnevnom unosu. Međutim, pored hranljivih svojstava koje ima, riba može biti i izvor različitih bioloških i hemijskih opasnosti. Od bioloških opasnosti posebno su značajni paraziti (Trematodae, Nematodae, Cestodae), bakterije (Salmonella spp, E. coli, Vibrio parahemolyticus, Vibrio vulnificus, Listeria monocytogenes, Clostridium botulinum, Staphyloccocus aureus), virusi (Norwalk virus, Entero virusi, Hepatitis A, Rotavirus) i biotoksini. Najznačajnije hemijske opasnosti su policiklična aromatična jedinjenja, histamin i teški metali (živa, olovo, kadmijum, arsen, gvožđe). Alergije usled konzumiranja pojedinih vrsta namirnica su u porastu poslednjih godina. Veliki pokret oko pravilnog načina ishrane je doveo do toga da ljudi sve češće konzumiraju ribu, proizvode od ribe kao i različite plodove mora. Pored različitih opasnosti koje mogu poticati iz ribe, posebni značaj poslednjih godina se daje ribi kao potencijalnom alergenu. Naime, veliki broj alergija koje se javljaju u svetu pripisuju se alergenima koji potiču iz mesa ribe, pre svega proteinima mesa ribe. Učestalost alergija koje se povezuju za unosom mesa ribe varira u Evropskim zemljama (Norveška 1,5%; 2,3% Turska, 2,3% Grčka; Švedska 1.2-3.2 %). Kao najznačajniji proteinski alergen iz mesa ribe navodi se parvalbumin (ß tip), koji je izolovan kod velikog broja vrsta. Smatra se da su šaran i bakalar najčešći izvori parvalbumina koji se dovodi u vezu sa različitim vidovima alergijskih reakcija. Potencijalni alergeni su takođe kolagen i želatin koji su izolovani iz kože i pojedinih organa riba. Takođe, značajan alergen iz plodova voda je i tropomiozin, arginin kinaza, aldolaza. Pored ovih alergena, značajni alergeni mogu da potiču iz ikre, pojedih vrsta kavijara, a opisani su slučajevi gde su alergijske reakcije povezane sa kolagenom koji se nalazi u ekstracelularnom matriksu proteina. Alergeni koji dovode do različitih alergijskih reakcija, pored proteina mesa ribe, mogu poticati i od gotovih proizvoda od ribe. Tu spadaju različiti panirani proizvodi od ribe koji sadrže celer, gluten i druge dodatke koji mogu biti potencijalni alergeni. Zbog značaja koji imaju na zdravlje ljude, tehnologija je omogućila različite metode za detekciju ovih alergena. Kao neke od njih navode se ELISA (Enzyme-linked immunosorbent assay), RAST (Radioallergosorbent test) i RIE (Rocket Immuno-electrophoresis). Koja će se metoda detekcije primeniti, prvenstveno zavisi od dostupnosti alergena i praga njegove detekcije. Industija mesa je razvojem tehnologije uvela pojedine tehnološke prosece koji imaju mogućnost inaktivacije pojedinih alergena, pre svega proteina mesa ribe. Visoke temperature koje se primenjuju u obradi mesa ribe mogu uticati na ove alergene, tako što će smanjiti alergeni potencijal, dok neki tehnološki postipci nemaju tu mogućnost

The quality control theory of aging

The quality control (QC) theory of aging is based on the concept that aging is the result of a reduction in QC of cellular systems designed to maintain lifelong homeostasis. Four QC systems associated with aging are 1) inadequate protein processing in a distressed endoplasmic reticulum (ER); 2) histone deacetylase (HDAC) processing of genomic histones and gene silencing; 3) suppressed AMPK nutrient sensing with inefficient energy utilization and excessive fat accumulation; and 4) beta-adrenergic receptor (BAR) signaling and environmental and emotional stress. Reprogramming these systems to maintain efficiency and prevent aging would be a rational strategy for increased lifespan and improved health. The QC theory can be tested with a pharmacological approach using three well-known and safe, FDA-approved drugs: 1) phenyl butyric acid, a chemical chaperone that enhances ER function and is also an HDAC inhibitor, 2) metformin, which activates AMPK and is used to treat type 2 diabetes, and 3) propranolol, a beta blocker which inhibits BAR signaling and is used to treat hypertension and anxiety. A critical aspect of the QC theory, then, is that aging is associated with multiple cellular systems that can be targeted with drug combinations more effectively than with single drugs. But more importantly, these drug combinations will effectively prevent, delay, or reverse chronic diseases of aging that impose such a tremendous health burden on our society

Impact of Histone Deacetylase Inhibitors SAHA and MS-275 on DNA Repair Pathways in Human Mesenchymal Stem Cells

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Pyrrole-Based Hydroxamates and 2-Aminoanilides: Histone Deacetylase Inhibition and Cellular Activities

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Clinical experience with the novel histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in patients with relapsed lymphoma

Preclinical studies indicate that vorinostat (suberoylanilide hydroxamic acid or SAHA) inhibits histone deacetylase (HDAC) activity, increases acetylated histones H2a, H2b, H3, and H4, and thereby induces differentiation and apoptosis in a variety of tumour cell lines, including murine erythroleukaemia, human bladder transitional cell carcinoma, and human breast adenocarcinoma. On the basis of these favourable preclinical findings, vorinostat has been selected as a candidate for clinical development with the potential to treat patients with selected malignances, including Hodgkin's disease and non-Hodgkin's lymphomas. Phase I clinical trials in patients with haematological malignances and solid tumours showed that both intravenous (i.v.) and oral formulations of vorinostat are well tolerated, can inhibit HDAC activity in peripheral blood mononuclear cells and tumour tissue biopsies, and produce objective tumour regression and symptomatic improvement with little clinical toxicity. The dose-limiting toxicities (DLT) of i.v. vorinostat were primarily haematologic and were rapidly reversible within 4–5 days of therapy cessation. In contrast, the DLT for oral vorinostat were primarily non-haematologic (including dehydration, anorexia, diarrhoea, fatigue) and were also rapidly reversible, usually within 3 days. Further research is warranted to optimise the dosing schedule for vorinostat, particularly with respect to dose, timing of administration, and duration of therapy, and to fully delineate the mechanism(s) of antitumour effect of vorinostat in various types of malignances. Several phase II studies are currently ongoing in patients with haematological malignances and solid tumours

Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery

Histone deacetylase 8 (HDAC8) is an enzyme involved in deacetylating the amino groups of terminal lysine residues, thereby repressing the transcription of various genes including tumor suppressor gene. The over expression of HDAC8 was observed in many cancers and thus inhibition of this enzyme has emerged as an efficient cancer therapeutic strategy. In an effort to facilitate the future discovery of HDAC8 inhibitors, we developed two pharmacophore models containing six and five pharmacophoric features, respectively, using the representative structures from two molecular dynamic (MD) simulations performed in Gromacs 4.0.5 package. Various analyses of trajectories obtained from MD simulations have displayed the changes upon inhibitor binding. Thus utilization of the dynamically-responded protein structures in pharmacophore development has the added advantage of considering the conformational flexibility of protein. The MD trajectories were clustered based on single-linkage method and representative structures were taken to be used in the pharmacophore model development. Active site complimenting structure-based pharmacophore models were developed using Discovery Studio 2.5 program and validated using a dataset of known HDAC8 inhibitors. Virtual screening of chemical database coupled with drug-like filter has identified drug-like hit compounds that match the pharmacophore models. Molecular docking of these hits reduced the false positives and identified two potential compounds to be used in future HDAC8 inhibitor design

Expression Pattern of Long Non-Coding RNA Growth Arrest-Specific 5 in the Remission Induction Therapy in Childhood Acute Lymphoblastic Leukemia

Background: Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing GAS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. Methods: GAS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 ofremission induction therapy using RT-qPCR methodology. Results: Our results have shown interindividual differences in GAS5 expression at all time points. For each ALL patient, GAS5 expression was higher on day 15 in comparison to its level at diagnosis (p<0.0005). On day 33, the level of GAS5 expression decreased in comparison with day 15 (p<0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per mL of peripheral blood had a higherGAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). Conclusions: Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents