Vloga ciklooksigenaze-2 v malignem tkivu in možnosti uporabe njenih zaviralcev v zdravljenju raka

Cyclooxygenase-2 (COX 2), an inducible prostaglandin (PG) synthase, is elevated in many types of malignant and pre-malignant tissues. This enzyme is localized in neoplastic (epithelial) cells, microvascular endothelial cells, and stromal fibroblasts. Through the released PG it enhances carcinogenesis with increasing angiogenesis, inhibiting apoptosis, activating matrix metalloproteinases, suppressing of cell mediated antitumor immune response andprotection against damage by cytotoxic agents. Evidences from in vitro studies, studies on animal models as well as first clinical outcomes suggest that the inhibition of COX 2 may suppress carcinogenesis by affecting a numberof pathways: inhibiting angiogenesis, invasiveness of tumors and promoting apoptosis. References forecast that COX 2 inhibitors, mostly COX 2 selective inhibitors, may get a role in the therapy of cancer as an adjuvant therapy or as an co-chemotherapeutic agent. The purpose of the present articleis to summarize the most important facts about the role of COX 2 in themalignant tissue and discuss possible ways for potential therapeutic place of COX 2 inhibitors in clinical practice.Encim ciklooksigenaza-2 je inducibilna prostaglandinska sintaza. Njeno povečano izražanje so opisali v številnih premalignih in malignih tkivih. Preko povečanega sproščanja prostaglandinov pospešuje karcinogenezo, tako da pospeši tumorsko angiogenezo, zavira apoptozo, aktivira matriksne metaloproteinaze. Zavira tudi celično posredovan antitumorski imunski odgovor in ščiti pred poškodbami s citotoksičnimi učinkovinami. Cikloosigenaza-2 je lokalizirana v neoplastičnih epitelijskih celicah, endotelijskih celicah novonastalega tumorskega žilja, v fibroblastih in vnetnih celicah tumorske strome. Dokazi iz študij in vitro, raziskave na živalskih modelih ter prvi klinični rezultati kažejo, da zaviralci COX-2 lahko upočasnijo karcinogenezo zzaviranjem angiogeneze, zmanjšanjem invazivnosti tumorja in pospeševanje apoptoze tumorskih celic. Rezultati nakazujejo možno in zelo verjetno vlogo zaviralcev COX-2, predvsem selektivnih zaviralcev COX-2, v zdravljenju raka kot dodatna (adjuvantna) terapija, oz. so-kemoterapevtik, tako v primarni preventivi, zdravljenju kot tudi zaščiti pred ponovitvijo bolezni. Namen preglednega članka je predstaviti spoznanja o vlogi ciklooksigenaze-2 v malignem tkivu ter poiskati terapevtsko mesto zaviralcev COX-2 v klinični praksi

[Novi označevalec angiogeneze CD105 (endoglin): diagnostični, napovedni in terapevtski pomen]

Background. The well established notion that malignant tumours depend on angiogenesis to grow and metastasize focused the investigators interest on tumour vasculature into visualization and validation. Panendothelial markers (CD31, CD34, F8) and CD105 are differentially expressed in angiogenic and normal vessel endothelial cells. Since the former are excellent markers for the normal vasculature, CD105 (endoglin) is more suitable for identifying tumour angiogenesis. Endoglin is a transforming growth factor (TGF)- beta binding receptor, preferentially expressed on endothelial cells of angiogenic tissues, essential for angiogenesis and vascular development. Conclusions. Tumor microvessel density expressed by CD105 immunohistochemical staining in paraffin-embedded tissue section correlates significantly with tumour aggressiveness and prognosis in many solid tumours. Also, targeting of tumour neovasculature specific antigens offers the possibility of future therapeutic approaches.Izhodišča. Angiogeneza je ključna za napredovanje in metastaziranje malignih tumorjev, zato so številne raziskave usmerjene v prikaz in vrednotenje tumorskega žilja ter ugotavljanje povezanosti le-tega z napovedjo poteka bolezni. Panedotelijski označevalci (CD31, CD34 in F8) ter novejši označevalecCD105 so različno izraženi v endotelijskih celicah nastajajočih (predvsem tumorskih) žil in endotelijskih celicah normalnega žilja. Prvi so idealni označevalci normalnega žilja, CD105 (imenovan tudi endoglin) pa je primernejši za prikaz tumorske angiogeneze. Endoglin je receptor za tumorski rastni dejavnik (tumor growth factor-TGF) beta, ki ga najdemo na endotelijskihcelicah angiogenih tkiv. Potreben je pri aktivni angiogenezi v tumorju kot tudi pri razvoju žil pri zarodku. Zaključki. Gostota tumorskega žilja-prikazana z imunohistokemičnim označevanjem CD105 v tkivnih rezinah tumorja in izmerjena s histomorfometričnim metodami-je značilno povezana z agresivnostjo tumorja in napovedjo poteka bolezni pri številnih solidnih tumorjih. Učinkovanje na endoglin, ki je specifični antigen v tumorskem žilju,ima tudi velike terapevtske možnosti

Production of [sigma]0 in [square root of s] = 91.2 GeV qq̄ events at LEP

This thesis presents a measurement of one of the three isospin states of the JP = 1[over] 2+ octet [sigma] baryons, the [sigma]0. In addition, the analysis yields the first differential cross-section measurement of the [sigma]0 hyperon in e+e-→ q[bar]q events. The unique particle identification capabilities of the DELPHI detector at LEP are used to obtain an increased efficiency by extending the standard [lambda]-finding algorithm.;The average number of [sigma]0\u27s produced per Z0 decay is calculated to beN([sigma]0)/Zsphad0=0.101 ± 0.008( stat) ± 0.014(syst) ± 0.007(extrap)\eqno(0.1) The measurement is about 30% above the prediction of the scJETSET model, but nevertheless is compatible with scJETSET within 2 [sigma]. Comparison with ARGUS results at √s = 10 GeV reveals similar levels of spin and strangeness suppression in hyperon production, within errors

The medical response to the Black Death

This paper discusses the medical response to the Black Death in both Europe and the Middle East. The Black Death was caused by a series of bacterial strands collectively known as Yersinia pestis. The Plague originated in the Mongolian Steppes. It was spread westward by the east-west trading system. Once it arrived in the Crimea in 1346, Italian merchants helped spread it throughout the Mediterranean. Medicine in Europe and the Middle East were centered on Galen’s theory of humors. There were many religious explanations for the Plague, but the main medical explanation was the spread of bad air, or miasma. Many preventative measures dealt with eliminating the miasma. The three main diagnostic methods used by physicians were astrology, uroscopy, and pulse-taking. Europeans realized the contagious nature of the disease, but many Muslims refuted the notion of contagion. Most cures for the Plague dealt with balancing body humors, such as bloodletting. Other cures included gold, rose water, and theriac. Even though the Plague killed many, it had beneficial effects on medicine, especially in Europe. Doctors began to question Galenic medicine, they relied more on observation, and they paid more attention to anatomy. There were also improvements in medical ethics, public health, and hospitals

Fortress defense in social aphids

Dissertação de mestrado em Evolução e Biologia Humanas, apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra.A idade à morte é um dos parâmetros a ser estimado pelo antropólogo forense, aquando da construção do perfil de um determinado indivíduo. O objectivo de tal análise é tentar estabelecer uma relação entre a idade cronológica e a idade biológica dos resquícios ósseos. São várias as metodologias utilizadas, sendo que a abordagem morfológica, se apresenta como mais recorrente, pois é, de certa forma, mais intuitiva. Contudo, os métodos microscópicos podem, em determinadas situações, revelar-se de extrema utilidade. A estimativa da idade em adultos baseia-se na observação da senescência intrínseca ao indivíduo. Este processo fisiológico tem bases celulares, logo não é de estranhar que a histologia tenha vindo a ser usada como ferramenta para aceder às microestruturas, que permitem estabelecer uma relação com a idade. O ponto fulcral deste projecto é testar a aplicabilidade da histomorfometria óssea na estimativa da idade, através do uso de metodologias práticas e de fácil execução. Esta investigação pretende, com base numa amostra forense de clavículas provenientes de 18 indivíduos, 10 do sexo feminino e 8 do sexo masculino, estabelecer uma relação entre a idade à morte e dois componentes histológicos, a percentagem de osso não remodelado e aérea cortical relativa. Os resultados obtidos foram altamente condicionados pelo número da amostra tendo um carácter preliminar. Não foi possível estabelecer uma relação entre a percentagem de osso não remodelado e a idade, devido a um conjunto de situações condicionantes. Em relação à área cortical relativa, foi possível observar que esta exibe uma tendência para diminuir em indivíduos mais velhos, já que segundo os resultados obtidos, as principais diferenças encontram-se nos dois extremos etários. Os indivíduos mais jovens apresentam uma área cortical relativa superior (63,66%) quando comparados aos indivíduos mais velhos (57,96%). Esta variável parece ser ainda influenciada pelo sexo, chegando mesmo a existir, no grupo etário dos 40 aos 49 anos, uma diferença de aproximadamente 16%. Sempre que possível, os resultados obtidos, ou a falta destes, foram analisados criticamente, sendo que o condicionamento da amostra revelou-se um grande impedimento ao presente estudo. Um balanço geral da metodologia usada, quer ao nível da preparação para a histologia, quer na análise microscópica e com recurso ao scâner. Esta última revelou-se de mais fácil aplicação, embora careça de resultados mais fidedignos. O desenvolvimento de investigações, que visem a aplicação da histologia na estimativa da idade, é um processo premente e basilar, dado existirem empiricamente menos estudos na área, comparativamente aos métodos morfológicos. Deste modo, pensa-se que apesar dos resultados obtidos, novos projectos poderão ser alcançados, com base na temática em estudo.Age at death is one of the key objectives that need to be estimated by the forensic anthropologist, when building the profile of an individual. The aim of this analysis is to establish a relationship between chronological age and the age observed in human skeletal remains. Several methods are used for this purpose, and the morphological approach seems to be the most recurrent, because somehow it is more intuitive. However, the microscopic methods can, under certain circumstances, be extremely useful. The age estimation in adults is based on the observation of the natural senescence, inherent to the individual. This physiological process has a cellular basis, so it is not unpredictable that histology has been used as a tool to access these microstructures, which ultimately may de related with age. The main goal of this project is to test the applicability of bone histomorphometry in the estimation of age at death, through the use of methods that are, at its core, practical and easy to perform. The current investigation is based on forensic samples of clavicles from 18 individuals (10 females and 8 males). It was intended to establish a relationship between age at death and two histological components, the percentage of unremodeled bone and the relative cortical area. The results were highly conditioned by the sample. Therefore emphasis is placed in the preliminary character of those. It was not possible to establish an association between the percentage of unremodeled bone and age at death, due to a set of circumstances that restricted all the analysis. Regarding the analysis of the cortical relative area, it was possible to verify that this component presents a downward trend in older individuals, since the main differences were found in extreme ages. Thereby younger individuals present a higher value of cortical area (63,66%) when compared with older individuals (57,96%). This variable seems to be sexrelated, since in the age group of 40 to 49 years, it was possible to verify about 16% of difference between sexes. Whenever possible, all the results, or the lack of them, were critically analyzed. It is important to state that the sample size was a major drawback to this study. Nevertheless it was still possible to come up with some hypotheses that may in theory explain the results. A general deliberation of the methodology used was performed both in terms of the preparation for histology as well as towards the analysis of the microstructures per se. The examination that used the scanner proved to be easier to implement, although it lacks of reliable results. The development of investigations concerning the application of histology in age at death estimation is an urgent and fundamental process, since there are empirically fewer studies in the area when compared to macroscopic approach. Thus, in spite of the results we think that a path was opened to the enlargement of future studies that use histology as a tool for age estimation in a Portuguese sample

The supporting-cell antigen: a receptor-like protein tyrosine phosphatase expressed in the sensory epithelia of the inner ear

After noise- or drug-induced hair-cell loss, the sensory epithelia of the avian inner ear can regenerate new hair cells. Few molecular markers are available for the supporting-cell precursors of the hair cells that regenerate, and little is known about the signaling mechanisms underlying this regenerative response. Hybridoma methodology was used to obtain a monoclonal antibody (mAb) that stains the apical surface of supporting cells in the sensory epithelia of the inner ear. The mAb recognizes the supporting-cell antigen (SCA), a protein that is also found on the apical surfaces of retinal Müller cells, renal tubule cells, and intestinal brush border cells. Expression screening and molecular cloning reveal that the SCA is a novel receptor-like protein tyrosine phosphatase (RPTP), sharing similarity with human density-enhanced phosphatase, an RPTP thought to have a role in the density-dependent arrest of cell growth. In response to hair-cell damage induced by noise in vivo or hair-cell loss caused by ototoxic drug treatment in vitro, some supporting cells show a dramatic decrease in SCA expression levels on their apical surface. This decrease occurs before supporting cells are known to first enter S-phase after trauma, indicating that it may be a primary rather than a secondary response to injury. These results indicate that the SCA is a signaling molecule that may influence the potential of nonsensory supporting cells to either proliferate or differentiate into hair cell

L’opera d'arte cinematografica come trattato teologico-mistagogico.: Tra Tarkovskij e Balthasar

The aim of the present study is to probe the theological possibilities of film, whether therefore the technical and specific language reserved for film can bear the weight of mystagogy, the weight of the theological treatise. In order to analyse the language of film from the point of view of its theological possibilities, we will make use of a concrete test that could be called ‘comparative’. We must make use of this principle by analysing the works of authors so different from each other, so distant and yet so bound by mutual influences as Hans Urs von Balthasar and Andrej Tarkovskij.Celem niniejszego studium jest zbadanie teologicznych możliwości filmu: czy zatem techniczny i specyficzny język zarezerwowany dla filmu może udźwignąć ciężar mistagogii, ciężar traktatu teologicznego. Aby przeanalizować język filmu z punktu widzenia jego teologicznych możliwości, posłużymy się konkretnym testem, który można nazwać „komparatystycznym”. Będziemy korzystać z tej zasady, analizując dzieła autorów tak różnych od siebie, tak odległych, a jednak tak związanych wzajemnymi wpływami, jak Hans Urs von Balthasar i Andrej Tarkowski.Celem niniejszego studium jest zbadanie teologicznych możliwości filmu: czy zatem techniczny i specyficzny język zarezerwowany dla filmu może udźwignąć ciężar mistagogii, ciężar traktatu teologicznego. Aby przeanalizować język filmu z punktu widzenia jego teologicznych możliwości, posłużymy się konkretnym testem, który można nazwać „komparatystycznym”. Będziemy korzystać z tej zasady, analizując dzieła autorów tak różnych od siebie, tak odległych, a jednak tak związanych wzajemnymi wpływami, jak Hans Urs von Balthasar i Andrej Tarkowski

α5β1 integrin mediates pulmonary epithelial cyst formation

BACKGROUND: Formation of the epithelial cyst involves the establishment of apical-basolateral polarity through a series of cellular interactions that are in part mediated by the extracellular matrix (ECM). We report that in a three-dimensional multi-cellular self-assembly model of lung development, α5 integrin regulates epithelial cyst formation through organization of soluble fibronectin matrix into insoluble fibrils through a process called fibrillogenesis. RESULTS: Dissociated murine embryonic lung cells self-assemble into three-dimensional pulmonary bodies that are dependent on α5β1 integrin mediated fibrillogenesis for cell-cell mediated self-assembly: compaction and epithelial cyst formation. Knockdown of α5 integrin resulted in a significant increase in another mediator of fibrillogenesis, αV integrin. Compensatory increased expression of another mediator of fibrillogenesis, αV integrin, was not sufficient to normalize epithelial cyst formation. Loss of α5 integrin-mediated fibrillogenesis perturbed the ability of clustered epithelial cells to establish clear polarity, loss of epithelial cell pyramidal shape, and disrupted apical F-actin-rich deposition. Lack of rich central epithelial localization of F-actin cytoskeleton and Podocalyxin suggests that loss of α5 integrin-mediated fibrillogenesis interferes with the normal cytoskeleton organization that facilitates epithelial cysts polarization. CONCLUSIONS: We conclude that lung epithelial cyst formation in development is mediated in part by α5β1 integrin dependent fibrillogenesi