2013, the DNA jubilee year

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Uticaj tumor supresorskih gena TP53 i PTEN na odgovor na različite načine lečenja raka dojke

Rak dojke (RD) je najčešći tip maligniteta i vodeći uzrok smrti od raka kod žena širom sveta. RD je izuzetno heterogena bolest i stoga su neophodni različiti modaliteti lečenja da bi se pokrile ove razlike. Cilj našeg istraživanja je bio da se ispita uticaj inaktivacije TP53 i PTEN tumor supresorskih gena (TSG) na odgovor RD na različite modalitete lečenja, kao i njihova moguća saradnja u tome, na postoperativnim uzorcima RD. Metode. Pacijentkinje su klasifikovane, na osnovu primenjene adjuvantne terapije, u četiri različite grupe: one koje su primale samo hormonsku terapiju (HT), hormonsku terapiju u kombinaciji sa hemoterapijom (HT/CHT), hormonsku terapiju u kombinaciji sa hemoterapijom i biološkom terapijom (HT/CHT/H) i druge sistemske terapije koje isključuju HT. Funkcionalna inaktivacija TP53 i PTEN TSG je proučavana analizom mutacionog statusa, gubitka heterozigotnosti (LOH) i metilacionog statusa. Rezultati. Naši rezultati su pokazali da je TP53 gen izmenjen kod 63 od 90 pacijenata (70%), dok je učestalost promena PTEN gena bila nešto niža, 54 od 90 (60%). Simultana inaktivacija je detektovana u 43 testirana uzorka (48%) sa značajnom povezanošću između dva analizirana TSG-a. Dalje, pokazali smo da status TP53 ima značajan uticaj na odgovor pacijenata na terapiju. Suprotno ovome, nismo pokazali značajnu asocijaciju između mutacionog statusa PTEN-a i različitih modaliteta lečenja. Međutim, utvrđena je značajna povezanost između primenjenih terapija i simultanih inaktivacija ova dva TSG-a (p = 0,00001). Zaključak. Pacijenti sa wtTP53 pokazuju značajno bolji terapijski odgovor bez obzira na vrstu terapije u poređenju sa nosiocima mutiranog TP53 gena.Introduction. Breast cancer (BC) is the most frequent type of malignancy and the leading cause of cancer related death among women worldwide. BC is exceptionally heterogeneous disease and therefore distinct treatment modalities are necessary to address these differences. The aim of our study was to investigate the impact of TP53 and PTEN tumor suppressor genes (TSGs) inactivation on BC response to different treatment modalities and their possible cooperation, on post-operative BC samples. Methods. Patients were classified, based on applied adjuvant therapy, into four distinct groups: those that received hormonal therapy (HT) only, hormonal therapy combined with chemotherapy (HT/CHT), hormonal therapy combined with chemo and biological therapy (HT/CHT/H), and other systemic therapies that exclude HT. Functional inactivation of TP53 and PTEN TSG’s were studied by mutation, loss of heterozygosity (LOH) and hypermethylation analysis. Results. Our results revealed that TP53 gene was altered in 63 out of 90 specimens (70%), while the frequency of PTEN alterations was slightly lower, 54 out of 90 (60%). Simultaneous inactivation was detected in 43 tested samples (48%) with significant association between two analyzed TSGs. Further, we found that TP53 status has significant influence on patients’ therapy response. Contrary to this, no significance was found between mutational status of PTEN and various treatment modalities. However, significant association was found between the type of applied therapy and simultaneous alterations of these two TSGs (p = 0.00001). Conclusion. Patients with wtTP53 show significantly better therapy response regardless of the type of therapy, compared to carriers of altered TPp53 gene

The spatial model of the classroom and its immediate surroundings: A variety of learning spaces

This paper looks into the spatial dispositions of the classroom and its immediate surroundings in elementary schools, with the goal of defining a broad learning space, in accordance with modern intentions in pedagogy. The starting assumption is that the learning space may offer versatility and a variety of options in the educational process. In the development of the spatial model two key contributing factors have been taken into account: the implications of the modern educational process and potential spatial characteristics. Various levels of spatial interrelationship are considered between the classroom and the adjacent classroom, the break-out space, communication area, social activity zones, and the outdoor classroom. Accordingly, by using the modelling method, a conceptual spatial model of the classroom and its immediate surroundings is defined such that it can receive specific applications in the design of elementary schools

Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer.

Breast cancer is the most commonly occurring malignancy and the leading cause of cancer-related death in women. Triple-negative breast cancer (TNBC) is the most aggressive subtype and is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival. The aim of this study was to investigate the PI3K/PTEN/Akt/mTOR pathway as one of the most frequently deregulated pathways in cancer. We aimed to explore the impact of PI3K and mTOR oncogenes as well as the PTEN tumor suppressor on TNBC clinical behavior, prognosis, and multidrug resistance (MDR), using immunohistochemistry and copy number analysis by quantitative real-time PCR. Our results revealed that loss of PTEN and high expression of PI3K and mTOR proteins are associated with poor outcome of TNBC patients. PTEN deletions appeared as a major cause of reduced or absent PTEN expression in TNBC. Importantly, homozygous deletions of PTEN (and not hemizygous deletions) are a potential molecular marker of metastasis formation and good predictors of TNBC outcome. In conclusion, we believe that concurrent examination of PTEN/PI3K/mTOR protein expression may be more useful in predicting TNBC clinical course than the analysis of single protein expression. Specifically, our results showed that PTEN-reduced/PI3K-high/mTOR-high expression constitutes a 'high risk' profile of TNBC

TP53 and c-myc Co-alterations: A hallmark of oral cancer progression

Background: Head and neck squamous cell carcinoma, including oral cancer, is the sixth most common cancer worldwide. Despite advances in surgery and treatment, the 5-year survival rate has not improved significantly. Therefore, reliable molecular markers for oral cancer progression are badly needed. Methods: We conducted a copy number analysis to estimate amplification status of c-myc, cycD1 and EGFR oncogenes, mutational PCR-SSCP analysis to determine activation of H-ras oncogene and inactivation of TP53 tumour suppressor gene and methylation specific PCR analysis to evaluate hypermethylation of p16 and MGMT genes. Results: c-myc oncogene was amplified in 56.7%, cycDI in 20% and EGFR in 16.7% of Oral Squamous Cell Carcinoma (OSCC) cases while H-ras was activated in 33.3% of samples. Amplification of c-myc was significantly associated with the tumour grade 2. Interestingly, EGFR and H-ras alterations were mutually exclusive. p16 and MGMT were inactivated by hypermethylation in 30% and 13.3% of cases. Co-alteration of cycDI and p16 were not observed in any of the analyzed samples. TP53 was inactivated in 56.7% of samples and was significantly associated with progression of OSCC, grade 2 and stage 2. Moreover, TP53 and c-myc oncogene were simultaneously altered in grade 2 OSCC. Conclusions: The most promising marker of OSCC progression remains the TP53 tumour suppressor, which is the most frequently mutated gene in oral cancers. Since there is synergism between TP53 and c-myc, it seems that co-alteration of these two genes could be also a good marker of OSCC progression from grade1 to grade 2 tumours.Uvod: Skvamocelularni karcinomi glave i vrata (HNSCC) uključujući i skvamocelularni karcinom usne duplje (OSCC) ubrajaju se u šest najčešćih tipova humanih maligniteta. Uprkos značajnim napredcima u hirurškom i terapijskom tretmanu, stopa petogodišnjeg preživljavanja kod ovog tipa maligniteta nije značajnije popravljena. Upravo zato, definisanje pouzdanih molekularnih markera progresije kod OSSC predstavlja apsolutni prioritetet. Metode: Amplifikacioni status c-myc, cycD1 i EGFR gena određen je pomoću eseja za detekciju broja genskih kopija, aktivacija H-ras onkogena i inaktivacija TP53 tumor supresora određena je PCR-SSCP mutacionom analizom, a hipermetilacija promotora p16 i MGMT gena je ispitana metil specifičnim PCR-om (MSP). Rezultati: Amplifikacija c-myc onkogena detektovana je kod 56,7%, cycD1 onkogena kod 20%, a EGFR onkogena kod 16,7% analiziranih oralnih skvamocelularnih carcinoma. Istovremeno, mutaciona aktivacija H-ras onkogena detektovana je kod 33,3% ispitanih uzoraka. Amplifikovani c-myc, statistički značajno korelira sa gradusom 2 OSCC. Posebno intrigantan je bio nalaz po kom se onkogene aktivacije u EGFR i H-ras genu međusobno isključuju. Hipermetilacija promotora p16 gena detektovana je kod 30%, a MGMT kod 13,3% analiziranih uzoraka. Ko-alteracije cycDI i p16 gena nisu zapažene ni u jednom od analiziranih uzoraka. Inaktivacija TP53 gena detektovana je kod 56,7% uzoraka i utvrđeno je da statistički značajno korelira sa gradusom 2 i statusom 2 OSCC. Pored ovoga, utvrđeno je da statistički značajan broj uzoraka gradusa 2, sa aktiviranim TP53 genom ima istovremeno aktiviran i c-myc onkogen. Zaključak: TP53, najčešće mutirani gen u oralnim karcinomima, ostaje za sada i najpouzdaniji marker progresije kod OSCC. Obzirom na detektovani sinergizam između TP53 i c-myc gena, možemo reći da su istovremene promene u ova dva gena još pouzdaniji pokazatelj progresije OSSC iz gradusa 1 u gradus 2.Projekat ministarstva br. III 41031 i br. ON17304

The spatial model of the classroom and its immediate surroundings: A variety of learning spaces

This paper looks into the spatial dispositions of the classroom and its immediate surroundings in elementary schools, with the goal of defining a broad learning space, in accordance with modern intentions in pedagogy. The starting assumption is that the learning space may offer versatility and a variety of options in the educational process. In the development of the spatial model two key contributing factors have been taken into account: the implications of the modern educational process and potential spatial characteristics. Various levels of spatial interrelationship are considered between the classroom and the adjacent classroom, the break-out space, communication area, social activity zones, and the outdoor classroom. Accordingly, by using the modelling method, a conceptual spatial model of the classroom and its immediate surroundings is defined such that it can receive specific applications in the design of elementary schools

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SUSTAINABILITY OF POST-SOCIALIST URBAN DESIGN TREATMENT OF PUBLIC OPEN SPACES IN MULTI-FAMILY HOUSING AREAS: CASE STUDY OF NIS, SERBIA

This research focuses on the treatment of public open spaces (POS) in multi-family housing areas in post-socialist Central and Eastern European (CEE) countries. The aim is to evaluate their quality and sustainability and to identify all important impact factors influencing their properties. A case study was conducted on a representative sample of four multi-family housing sites in Nis, Serbia. Determining the interconnection between urban planning parameters and the realized quality of POS is one of the primary objectives that could lead to forming recommendations for future multi-family housing development, including more usable and sustainable POS in the current social and economic context. The models for improvement of POS quality and sustainability are defined as a research result