Procena zdravstvenog stanja i kvaliteta života beskućnika u Beogradu

Background/Aim. Homelessness is a problem with social, medical, economic, political and other implications. Despite a large number of studies, reports about health-related quality of life (HRQoL) of homeless persons remain sparse. There is a summary of consistent evidence that homeless people have higher prevalence of chronic disease (mental and somatic) than general population. The aim of this study was to assess HRQoL and depression in homeless persons in Belgrade, to describe their sociodemographic factors and health status (the presence of chronic mental and somatic diseases and addiction disorders) and analyse impact of sociodemographic factors and health status to HRQoL and depression of homeless persons. Methods. The study was conducted in the Shelter for Adult and Elderly Persons in Belgrade, from January 1 to January 31, 2012. A set of questionnaires used in survey included Serbian translation of SF-36 questionnaire, Serbian translation of Beck Depression Inventory-II (BDI-II) and sociodemographic questionnaire. Statistical analysis was performed by descriptive and analytic methods. Results. Our study sample consisted of 104 adult participants. The majority of them were male (74%) and the mean age in the sample was 48.2 ± 13.0 years. We have found that 35.6% participants had lifetime diagnosis of psychiatric disorder, most frequently depression (lifetime prevalence of 15.4% in the study group). The history of suicide attempts was registered in 28 (26.9%) participants. Lifetime illicit drugs use was reported by 12.5%, daily smoking by 82.7% and daily alcohol consumption by 8.7% of the participants. Most common somatic chronic diseases were cardiovascular while chronic lung diseases were the second most frequent. Single chronic disease was present in 33 (31.7%) of the participants and comorbidity of 2 chronic diseases was present in 20 of them. A statistically significant difference between participants' HRQoL SF-36 domain scores and norms of general population was found only for role physical domain (lower in homeless, p lt 0.001). ANOVA showed no statistically significant difference in SF-36 HRQoL domain and composite scores between different age groups, nor did marital status, education level, length of homelessness, alcohol use or smoking significantly affect the HRQoL. The mean BDI-II score in the studied population was 19.1 ± 11.6. Severe depression was registered in 20.2% of the participants, moderate in 23.1%, mild in 19.2% and minimal in 37.5%. A highly significant negative correlation was verified between BDI-II and all domains and composite scores of SF-36 (p lt 0.001). Conclusion. Measures for prevention of homelessness should include: foundation of national registry of homeless persons, development of systemic multisectorial cooperation and special psychosocial intervention strategies. In homeless population, health care measures should be focused on prevention and treatment of mental health disorders and chronic somatic diseases.Uvod/Cilj. Beskućništvo predstavlja problem sa širokim društvenim, zdravstvenim i ostalim implikacijama. Postoje brojni dokazi da beskućnici imaju višu prevalenciju hroničnih (mentalnih i somatskih) oboljenja u odnosu na opštu populaciju. Cilj rada je bio utvrđivanje kvaliteta života (KŽ) i depresivnosti kod beskućnika, socijalnodemografskog i zdravstvenog statusa u ovoj populaciji, te analiza faktora koji utiču na KŽ i depresivnost beskućnika. Metode. Istraživanje je sprovedeno u Centru za smeštaj odraslih i starih lica u Beogradu tokom januara 2012. godine. Korišćen je komplet upitnika: SF-36 za ispitivanje KŽ, Bekova skala depresije II (BDI-II) i sociodemografski upitnik. Analiza je obavljena metodama deskriptivne i analitičke statistike. Rezultati. Studija je obuhvatila 104 ispitanika. Većinu su činili muškarci (74%), a prosečna starost je iznosila 48,2 ± 13,0 godina. Kod 35,6% ispitanika utvrđena je dijagnoza psihijatrijske bolesti (najčešće depresije). Samoubistvo je pokušalo 28 (26,9%) ispitanika. U uzorku je bilo 82,7% pušača, a najčešće hronične somatske bolesti su bile kardiovaskularne bolesti. Komorbiditet više somatskih bolesti je bio prisutan kod trećine ispitanika. Fizička uloga je jedini domen KŽ koji je bio niži nego u opštoj populaciji (p lt 0,001). Depresija teškog stepena utvrđena je kod 20,2% ispitanika. Negativna korelacija postojala je između skorova BDI-II i svih skorova KŽ (p lt 0,001). Zaključak. Mere za prevenciju beskućništva bi trebalo da uključe formiranje nacionalnog registra beskućnika, razvoj sistemske međusektorske saradnje i primenu specijalnih psihosocijalnih interventnih strategija. Kod beskućnika zdravstveni sistem treba da bude fokusiran na prevenciju i lečenje mentalnih poremećaja i hroničnih somatskih oboljenja

Analysis and forecast of foreign trade indicators of corn in Bosnia and Herzegovina

The aim of this paper is to present the application of quantitative methods in the analysis of foreign trade indicators of corn in Bosnia and Herzegovina. Subsequently, based on the analysis, the forecast of import and export parameters was created for the 2018-20 period which predicted that corn imports and exports would increase both in the natural and value form. Furthermore, it was established for the observed period that Serbia was the largest importer of this crop to Bosnia and Herzegovina, and that Turkey was a country to which the corn from Bosnia and Herzegovina was mostly exported. The research in this paper can serve the purpose of further planning and development of both the production and the markets of this crop and agriculture as a whole

Analysis and Forecast of Foreign Trade Indicators of Corn in Bosnia and Herzegovina

The aim of this paper is to present the application of quantitative methods in the analysis of foreign trade indicators of corn in Bosnia and Herzegovina. Subsequently, based on the analysis, the forecast of import and export parameters was created for the 2018-20 period which predicted that corn imports and exports would increase both in the natural and value form. Furthermore, it was established for the observed period that Serbia was the largest importer of this crop to Bosnia and Herzegovina, and that Turkey was a country to which the corn from Bosnia and Herzegovina was mostly exported. The research in this paper can serve the purpose of further planning and development of both the production and the markets of this crop and agriculture as a whole

Targeting αvβ3 and αvβ5 integrins inhibits pulmonary metastasis in an intratibial xenograft osteosarcoma mouse model

Osteosarcoma is an aggressive bone cancer that has a high propensity for metastasis to the lungs. Patients with metastatic disease face a very poor prognosis. Therefore, novel therapeutics, efficiently suppressing the metastatic process, are urgently needed. Integrins play a pivotal role in tumor cell adhesion, motility and metastasis. Here, we evaluated αvβ3 and αvβ5 integrin inhibition with cilengitide as a novel metastasis-suppressive therapeutic approach in osteosarcoma. Immunohistochemical analysis of αvβ3 and αvβ5 integrins expression in a tissue microarray of tumor specimens collected from osteosarcoma patients revealed that αvβ5 integrin is mainly found on tumor cells, whereas αvβ3 is predominantly expressed by stromal cells. In vitro functional assays demonstrated that cilengitide dose-dependently inhibited de novo adhesion, provoked detachment and inhibited migration of osteosarcoma cell lines. Cilengitide induced a decline in cell viability, blocked the cell cycle in the G1 phase and caused anoikis by activation of the Hippo pathway. In a xenograft orthotopic mouse model cilengitide minimally affected intratibial primary tumor growth but, importantly, suppressed pulmonary metastasis. The data demonstrate that targeting αvβ3 and αvβ5 integrins in osteosarcoma should be considered as a novel therapeutic option for patients with metastatic disease

Alteracije onkogena c-myc i c-erbB-2 u malignim tumorima jajnika

Introduction. According to clinical and epidemiological studies, ovarian cancer ranks fifth in cancer deaths among women. The causes of ovarian cancer remain largely unknown but various factors may increase the risk of developing it, such as age, family history of cancer, childbearing status etc. This cancer results from a succession of genetic alterations involving oncogenes and tumour suppressor genes, which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, c-erbB-2, c-Myc and K-ras, and of the tumour suppressor gene p53, have been frequently observed in a sporadic ovarian cancer. Objective. The aim of the present study was to analyze c-Myc and c-erbB-2 oncogene alterations, specifically amplification, as one of main mechanisms of their activation in ovarian cancers and to establish a possible association with the pathogenic process. Methods. DNA was isolated from 15 samples of malignant and 5 benign ovarian tumours, using proteinase K digestion, followed by phenol-chloroform isoamyl extraction and ethanol precipitation. C-Myc and c-erbB-2 amplification were detected by differential PCR. The level of gene copy increase was measured using the Scion image software. Results. The amplification of both c-Myc and c-erbB-2 was detected in 26.7% of ovarian epithelial carcinoma specimens. Only one tumour specimen concomitantly showed increased gene copy number for both studied genes. Interestingly, besides amplification, gene deletion was also detected (26.7% for c-erbB-2). Most of the ovarian carcinomas with alterations in c-Myc and c-erbB-2 belonged to advanced FIGO stages. Conclusion. The amplification of c-Myc and c-erbB-2 oncogenes in ovarian epithelial carcinomas is most probably a late event in the pathogenesis conferring these tumours a more aggressive biological behaviour. Similarly, gene deletions point to genomic instability in epithelial carcinomas in higher clinical stages as the result of clonal evolution and selection.Uvod. Kliničke i epidemiološke studije su pokazale da je kancer jajnika peti po redu uzročnik smrti žena. Iako postoje mnogi predisponirajući faktori, kao što su starosna dob, porodična istorija kancera, sterilnost, broj rođene dece i dr., tačni uzroci nastanka tumora jajnika još nisu poznati. Zna se, međutim, da je kancer jajnika rezultat akumulacije različitih genskih alteracija, od kojih su najznačajnije mutacije, odnosno povišena ekspresija određenih onkogena, kao što su c-myc, c-erbB-2 i K-ras, i tumor-supresorskih gena, od kojih je najvažniji p53. Cilj rada. Cilj istraživanja je bio da se ispitaju alteracije c-myc i c-erbB-2 (pre svega njihove amplifikacije), najčešćeg mehanizma aktivacije ovih onkogena, u epitelnim karcinomima jajnika, i utvrde njihove potencijalne uloge u patogenezi ovog tipa neoplazmi u našoj populaciji. Metode rada. DNK je izolovana iz 15 uzoraka malignih tumora i pet uzoraka benignih tumora jajnika. Amplifikacije onkogena c-myc i c-erbB-2 ustanovljavane su metodom diferencijalne reakcije lančanog umnožavanja DNK (engl. differential polymerase chain reaction - dPCR). Nivo amplifikacije određen je nakon denzitometrijskog merenja traka na gelu primenom programa Scion image. Rezultati. Amplifikacija i gena c-myc i c-erbB-2 otkrivena je u četiri uzorka (26,7%) epitelnog karcinoma jajnika. Jedan od ispitivanih uzoraka je imao simultanu amplifikaciju oba gena. Većina uzoraka bila je visokog stadijuma prema kriterijumima Međunarodne federacije za ginekologiju i akušerstvo (International Federation of Gynecology and Obstetrics - FIGO). Zanimljivo je da je pored amplifikacije nezavisno ustanovljena i delecija gena c-erbB-2 u 26,7% karcinoma. Svi karcinomi sa delecijama su takođe pripadali visokim kliničkim stadijumima. Zaključak. Amplifikovani onkogeni c-myc i c-erbB-2 su odlika kasnih stadijuma epitelnih maligniteta i verovatno jedan od razloga njihovog agresivnog biološkog ponašanja. Slično tome, i delecija gena erb obeležava uznapredovale stadijume bolesti i ukazuje na genomsku nestabilnost koja se javlja u epitelnim karcinomima kao rezultat evolucije i selekcije različitih tumorskih klonova

Targeting EWS/FLI1 activity in ewing sarcoma

Ewing sarcoma (ES) is the second most frequent bone cancer in childhood. Clinically, ES appears as very aggressive osteolytic tumor with early tendency for development of metastasis. It belongs to the group of small-round-blue-cell tumors and is comprised of largely undifferentiated cells. The unique feature of this tumor is presence of the balanced t(11;22)(q24;q12) translocation in more than 85% of cases. This gene rearrangement results in the expression of a chimeric fusion protein where RNA binding domain of EWS is exchanged by the DNA binding domain of the ets transcription factor FLI1, thus generating a dysregulated transcription factor EWS/FLI1. More than 18 less represented alternative translocations involving EWS and other ets protein family members have been described since. Extensive evidence supports the fact that EWS/FLI1 is an essential oncogenic component of ES development. Its oncogenic activity is thought to be mediated through inappropriate regulation of target genes that are crucial for the fully malignant phenotype. Apart from having transforming and tumorigenic potential, even more important is that EWS/FLI1 appears to be necessary for tumor cell maintenance. For these reasons EWS/FLI1 represents an attractive target. However, it is widely accepted that transcription factors are ‘’undruggable’’, and EWS/FLI1 as intrinsically disordered protein is not prone to direct inhibition by a small molecule in the classical sense. No targeted agents have been routinely introduced into therapy of ES. Even though in the last few decades there has been considerable progress in both diagnosis as well as treatment of the localised disease, only 15% of patients with metastatic disease survive. Current treatment regimens of ES are not fully exploiting the fact that specific inhibition of signalling pathways is now possible. More specifically, it is not known whether specific pathway could affect the activity of EWS/FLI1. In this thesis, we characterized PHLDA1 as a novel direct target gene whose expression is repressed by EWS/FLI1. Moreover, the role of PHLDA1 in ES was addressed in this study. Using this gene and additional specific well-characterized target genes such as NROB1, NKX2.2, and CAV1, all activated by EWS/FLI1, as a read-out system, we established a screening system that is capable of detecting compounds targeting activity and/or expression of EWS/FLI1 either 6 directly or indirectly. This system is an important simplification of the previously applied gene expression based high-throughput screening, represents a more targeted approach than screenings based on survival or proliferation only, and is more robust than a screening approach based on a single-gene reporter assay. We screened a small-molecule compound library enriched for FDA-approved drugs for substances that modulated the expression of EWS/FLI1 target genes. Among a hit-list of 9 well known drugs such as camptothecin, fenretinide, etoposide and doxorubicin, we also identified the kinase inhibitor midostaurin (PKC412). Subsequent experiments demonstrated that midostaurin is able to induce apoptosis in a panel of 6 ES cell lines in vitro and can significantly suppress xenograft tumor growth in vivo. These results suggest that midostaurin might be a novel drug that is active against ES cells which might act by modulating the expression of EWS/FLI1 target genes. In the second part of this thesis, in order to identify molecular pathway(s) that may contribute to the transcriptional activity and oncogenic properties of EWS/FLI1, we used our well established screening approach and performed screening of a small library of 153 targeted inhibitors covering all major signaling pathways. We discovered PI3K inhibitors as potent modulators of EWS/FLI1 expression. This finding was confirmed in several ES cell lines and off target effects of the PI3K inhibitors was excluded by performing genetic loss of function experiments. Analysis of the EWS/FLI1 promoter region using various deletion constructs in reporter gene assays determined two 12bp minimal elements where transcription factor(s) under PI3K control is binding. Elucidating the direct link between PI3K and EWS/FLI1 is of importance, and identity of the responsible transcription factor(s) might provide novel therapeutic opportunities. Results presented in this thesis clearly demonstrate that screening approach here established can be used for both screening for compounds effective against ES as well as for screening targeted inhibitors leading to better understanding of the biology of ES. Together it should lead to development of novel therapeutic approaches for the treatment of ES

Plasma levels of miRNA-155 as a powerful diagnostic marker for dedifferentiated liposarcoma

Atypic lipomatous tumors (ALT) and dedifferentiated liposarcomas (DDLS) are closely related liposarcoma subtypes, often difficult to distinguish but they exhibit an entirely different clinical outcome. Recently discovered regulatory functions of miRNAs in liposarcoma progression prompted us to investigate miRNAs as potential diagnostic biomarkers in liposarcoma with a main focus on circulating miRNAs for fast and reliable differential diagnosis. Tumor and blood samples of 35 patients with lipomatous lesions collected between June 2011 and September 2014 were analyzed by qRT-PCR. They included 10 lipomas, 7 ALT, 5 DDLS and 13 myxoid liposarcomas (MLS). Ten samples of normal fat tissue and blood from 20 healthy volunteers were used as controls. A meta-analysis of public data on miRNA expression in liposarcoma revealed 9 miRNAs with potential diagnostic power. Out of these, miRNA-155 was found significantly elevated in the circulation of DDLS patients as compared to the plasma levels detected in all other liposarcoma subtypes and in healthy subjects. miRNA-155 levels in the plasma samples correlated significantly (r=0.41, p=0.02) with those in corresponding tumor extracts. This correlation was even more pronounced in an analysis of plasma and tumor extracts of malignant liposarcoma subtypes alone (r=0.51, p=0.02). Receiver operating characteristic analysis indicated that plasma miRNA-155 levels have a high diagnostic accuracy for distinguishing DDLS from healthy subjects (AUC=0.91, p=0.005) and from lipomas (AUC=0.86, p=0.02), MLS (AUC=0.92, p=0.006) and most importantly ALT (AUC=0.91, p=0.01) patients. In conclusion, this study identified miRNA-155 as a first blood biomarker for the differential diagnosis of DDLS

A bispecific antibody targeting IGF-IR and EGFR has tumor and metastasis suppressive activity in an orthotopic xenograft osteosarcoma mouse model

Osteosarcoma is a highly aggressive bone cancer and the second most frequent cause of cancer-associated death in childhood and adolescence. Pulmonary metastases account for the high mortality rate in osteosarcoma patients. Therefore, novel therapeutic approaches, efficiently restraining the metastatic disease, are mandatory for a significant improvement of the currently poor patients' survival. Although initial studies with antibodies targeting insulin-like growth factor receptor (IGF-IR) showed promising potential for the treatment of patients with bone and soft tissue sarcomas, phase II clinical trials revealed variable results, which implied activation of alternative signaling pathways leading to therapy resistance. Since a cross-talk between IGF-IR and the epidermal growth factor receptor (EGFR) has been demonstrated in several cancer types, co-targeting of these two receptors was considered in the present study as a valuable therapeutic strategy to overcome single-agent treatment resistance in osteosarcoma. The effects of IGF-IR and/or EGFR targeting by intraperitoneal administration of the monospecific IGF-IR antibody R1507 or the EGFR antibody Cetuximab or the bispecific IGF-IR/EGFR antibody XGFR* on primary tumor growth and pulmonary metastasis were investigated in an intratibial human xenograft osteosarcoma mouse model. In vitro functional assays demonstrated that targeting IGF-IR and EGFR didn't affect osteosarcoma cell viability, but inhibited ligand-activated intracellular signaling and cell migratory capacity. The blocking potential of ligand-induced signaling in vitro was similar for all antibodies, but, in vivo, only XGFR* treatment significantly inhibited intratibial primary tumor growth and pulmonary metastasis. The therapeutic response to XGFR* was associated with an infiltration of innate immune system effector cells into the tumor microenvironment. Taken together, our study highlights the bispecific anti-IGF-IR/EGFR antibody XGFR* as an innovative promising effective candidate for the treatment of metastatic osteosarcoma and provides the rationale for future clinical studies

Internet in The Function of Promotion of Bestiality: Profiling Zoophiles

The Internet is an inseparable part of contemporary man’s everyday life. The catalog of positive sides of this global information system, which encourage the development of creativity, is inexhaustible. Simultaneously, many negative aspects of the Internet in the context of breach of security, exposure to inappropriate content and promotion of bestiality exist. Therefore, in this paper we pay special attention to zoophilia, a specific disorder from the domain of paraphilia, which includes a sexual preference for animals with ethical and harmful consequences for health. According to the available data from the digital space, it is noted that this disorder affects a significant number of individuals. It is an very complex and sensitive disorder, which requires a multidisciplinary approach, including a psychopathological approach that would explore the symptoms, nature and factors (hereditary, organic and social) of pathological conditions and processes in these individuals. With tendency that this scientific paper represents an adequate reaction to make this disorder more visible, as part of preventive programs before the late manifestation, we applied methods: quantitative and qualitative content analysis, comparative analysis (reaction to zoophilia) and descriptive and analytical statistics. The goal is to recognize zoophilia as a disease and bestiality, that is, inhuman behavior, which requires an effective response from the social community

Involvement and Clinical Aspects of MicroRNA in Osteosarcoma

Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents, but its pathogenesis has been difficult to establish because of its well-known heterogeneous nature. OS has been associated with genetic and cytogenetic abnormalities, which include function-impairing mutations in tumor suppressors and the activation of oncogenes. OS tumorigenesis has been linked to alterations of several genes characterized by a high level of genetic instability and recurrent DNA amplifications and deletions. MicroRNAs (miRNAs), 18–25-nucleotide noncoding RNAs, are critical for various biological processes like differentiation, cell growth and cell death. Dysregulation of miRNA expression leads to phenotypic and genotypic changes in cells, which leads to cancer. Studies on miRNAs have initiated a significant effect in both diagnosis and treatment of cancer. This review focuses on the current knowledge of clinical applications of miRNAs for the better diagnosis and management of OS