Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model

Background: The expression levels of the clotting initiator protein Tissue Factor (TF) correlate with vessel density and the histological malignancy grade of glioma patients. Increased procoagulant tonus in high grade tumors (glioblastomas) also indicates a potential role for TF in progression of this disease, and suggests that anticoagulants could be used as adjuvants for its treatment. Objectives: We hypothesized that blocking of TF activity with the tick anticoagulant Ixolaris might interfere with glioblastoma progression. Methods and results: TF was identified in U87-MG cells by flow-cytometric and functional assays (extrinsic tenase). In addition, flow-cytometric analysis demonstrated the exposure of phosphatidylserine in the surface of U87-MG cells, which supported the assembly of intrinsic tenase (FIXa/FVIIIa/FX) and prothrombinase (FVa/FXa/prothrombin) complexes, accounting for the production of FXa and thrombin, respectively. Ixolaris effectively blocked the in vitro TF-dependent procoagulant activity of the U87-MG human glioblastoma cell line and attenuated multimolecular coagulation complexes assembly. Notably, Ixolaris inhibited the in vivo tumorigenic potential of U87-MG cells in nude mice, without observable bleeding. This inhibitory effect of Ixolaris on tumor growth was associated with downregulation of VEGF and reduced tumor vascularization. Conclusion: Our results suggest that Ixolaris might be a promising agent for anti-tumor therapy in humans.

New Relativistic Atomic Natural Orbital Basis Sets for Lanthanide Atoms with Applications to the Ce Diatom and LuF3

New basis sets of the atomic natural orbital (ANO) type have been developed for the lanthanide atoms La-Lu. The ANOs have been obtained from the average density matrix of the ground and lowest excited states of the atom, the positive ions, and the atom in an electric field. Scalar relativistic effects are included through the use of a Douglas-Kroll-Hess Hamiltonian. Multiconfigurational wave functions have been used with dynamic correlation included using second-order perturbation theory (CASSCF/CASPT2). The basis sets are applied in calculations of ionization energies and some excitation energies. Computed ionization energies have an accuracy better than 0.1 eV in most cases. Two molecular applications are inluded as illustration: the cerium diatom and the LuF3 molecule. In both cases it is shown that 4f orbitals are not involved in the chemical bond in contrast to an earlier claim for the latter molecule.

Expression of human papillomavirus type 16 E7 oncoprotein alters keratinocytes expression profile in response to tumor necrosis factor-alpha

Acute expression of E7 oncogene from human papillomavirus (HPV) 16 or HPV18 is sufficient to overcome tumor necrosis factor (TNF)-alpha cytostatic effect on primary human keratinocytes. In the present study, we investigated the molecular basis of E7-induced TNF resistance through a comparative analysis of the effect of this cytokine on the proliferation and global gene expression of normal and E7-expressing keratinocytes. Using E7 functional mutants, we show that E7-induced TNF resistance correlates with its ability to mediate pRb degradation and cell transformation. On the other hand, this effect does not depend on E7 sequences required to override DNA damage-induced cell cycle arrest or extend keratinocyte life span. Furthermore, we identified a group of 66 genes whose expression pattern differs between normal and E7-expressing cells upon cytokine treatment. These genes are mainly involved in cell cycle regulation suggesting that their altered expression may contribute to sustained cell proliferation even in the presence of a cytostatic stimulus. Differential expression of TCN1 (transcobalamin I), IFI44 (Interferon-induced protein 44), HMGB2 (high-mobility group box 2) and FUS [Fusion (involved in t(12; 16) in malignant liposarcoma)] among other genes were further confirmed by western-blot and/or real-time polymerase chain reaction. Moreover, FUS upregulation was detected in HPV-positive cervical high-grade squamous intraepithelial lesions when compared with normal cervical tissue. Further evaluation of the role of such genes in TNF resistance and HPVassociated disease development is warranted.

Crystal and molecular structures of three 2-sulphur-substituted cyclohexanones studied by X-ray crystallography and by ab initio molecular orbital calculations

The conformational features of three 2-sulphur-substituted cyclohexanone derivatives, which differ in the number of sulphur-bound oxygen atoms, i.e. zero (I), one (II) and two (III), were investigated by single crystal X-ray crystallography and geometry optimized structures determined using Hartree-Fock method. In each of (I)-(III) an intramolecular S center dot center dot center dot O(carbonyl) interaction is found with the magnitude correlated with the oxidation state of the sulphur atom, i.e. 2.838(3) angstrom in (I) to 2.924(2) angstrom in (II) to 3.0973(18) angstrom in (III). There is an inverse relationship between the strength of this interaction and the magnitude of the carbonyl bond. The supramolecular aggregation patterns are primarily determined by C-H center dot center dot center dot O contacts and are similarly influenced by the number of oxygen atoms in the molecular structures. Thus, a supramolecular chain is found in the crystal structure of (I). With an additional oxygen atom available to participate in C-H center dot center dot center dot O interactions, as in (II), a two-dimensional array is found. Finally, a three-dimensional network is found for (III). Despite there being differences in conformations between the experimental structures and those calculated in the gas-phase, the S center dot center dot center dot O interactions persist. The presence of intermolecular C-H center dot center dot center dot O interactions involving the cyclohexanone-carbonyl group in the solid-state, disrupts the stabilising intramolecular C-H center dot center dot center dot O interaction in the energetically-favoured conformation. (I): C(12)H(13)NO(3)S, triclinic space group P (1) over bar with a = 5.392(3) angstrom b = 10.731(6) angstrom, c = 11.075(6) angstrom, alpha = 113.424(4)degrees, beta = 94.167(9)degrees, gamma = 98.444(6)degrees, V = 575.5(6) angstrom(3), Z = 2, R(1) = 0.052; (II): C(12)H(13)NO(4)S, monoclinic P2(1)/n, a = 7.3506(15) angstrom, b = 6.7814(14) angstrom, c = 23.479(5) angstrom, beta = 92.94(3)degrees, V = 1168.8(4) angstrom(3), Z = 4, R(1) = 0.046; (III): C(12)H(13)NO(5)S, monoclinic P2(1)/c, a = 5.5491(11) angstrom, b = 24.146(3) angstrom, c = 11.124(3) angstrom, beta = 114.590(10)degrees, V = 1355.3(5) angstrom(3), Z = 4, R(1) = 0.051.

Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes

AIMS/HYPOTHESIS: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease. METHODS: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used. RESULTS: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality. CONCLUSIONS/INTERPRETATIONS: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.

Polimorfismos dos genes do citocromo P450, da glutationa S-transferase e do supressor de tumor TP53 em populações sul-americanas e em pacientes com doença pulmonar obstrutiva crônica e câncer de pulmão

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Aplicação de sensoriamento remoto orbital no mapeamento de unidades vulcano-sedimentar no Platô da Ramada, Vila Nova do Sul, RS

Os produtos de sensoriamento remoto gerados pelos novos sensores orbitais, aliados ao desenvolvimento de sistemas computacionais e de técnicas de processamento de imagens possibilitam a manipulação numérica das imagens, visando o realce de informações de interesse para a interpretação visual ou automática. O uso dessas técnicas traz boas perspectivas no mapeamento geológico básico, pois possibilita uma visão sinóptica de amplas áreas e a integração de dados litológicos e estruturais de várias fontes. Este trabalho selecionou as imagens do sensor ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer) devido as características de suas resoluções espectral e espacial, como as mais promissoras para identificação dos diferentes litotipos da área do Platô da Ramada, em especial as unidades vulcânicas e hipabissais relacionadas e sedimentares subjacentes. O Platô da Ramada, região de Vila Nova do Sul (RS) constitui uma feição geomorfológica de destaque na área, facilmente identificável nas imagens orbitais, sendo formado por uma seqüência vulcânica caracterizada por depósitos efusivos e piroclásticos, de composição dominantemente ácida. Representa uma fração significativa do magmatismo alcalino sódico neoproterozóico no Escudo Sul-rio-grandense e marca um dos ciclos vulcânicos do período pós-colisional do Ciclo Brasiliano Este estudo testou e avaliou diversos processamentos das imagens multiespectrais para diferenciação litológica, a identificação de alvos e a definição de morfoestruturas da área do Platô da Ramada. A integração de dados geológicos existentes com os produtos obtidos neste estudo possibilitou novas informações anexadas ao mapa geológico utilizado como verdade terrestre. O processamento utilizando a técnica de Transformação por Componentes Principais Seletivas proporcionou os melhores resultados realçando diferenças espectrais existentes entre as rochas vulcânicas e hipabissais e as rochas sedimentares. A partir dessa técnica, selecionou-se as imagens CP2 dos pares das bandas 4-5 (R), 3-4 (G) e 8-9 (B) na geração de uma composição colorida. Esta imagem permitiu a diferenciação espectral entre as rochas vulcânicas do Platô da Ramada e as rochas sedimentares do Grupo Maricá, bem como a individualização, no Grupo Maricá, de duas subunidades, levando-se em conta a densidade de intrusões de diques riolíticos ao norte da área. Identificou-se, ainda, um corpo diorítico com forma elíptica na borda SW do Platô da Ramada, não registrado anteriormente.

Monitoramento de temperaturas noturnas da superfície terrestre no estado do Rio Grande do Sul com uso do sensor orbital AVHRR/NOAA

A temperatura da superfície terrestre (TST), além da ação determinante sobre o crescimento e o desenvolvimento das plantas, influencia também muitos processos físicos, químicos e biológicos, tendo significativa relevância científica em um vasto campo das atividades de pesquisa e gerenciamento dos recursos naturais. O objetivo geral deste estudo foi verificar a adequação do uso de sensores orbitais AVHRR/3 NOAA (National Oceanic and Atmospheric Administration) classe POES (Polar Operational Environmental Satellites) para mapeamento de temperaturas da superfície terrestre no Rio Grande do Sul, visando sua implementação em programas operacionais de monitoramento agrometeorológico. No estudo realizado no período de junho a setembro de 2002, foram utilizadas 11 imagens noturnas e 20 imagens diurnas, captadas na estação de recepção de imagens NOAA pertencente ao Centro Estadual de Pesquisas em Sensoriamento Remoto e Meteorologia (CEPSRM). Após processamento, as imagens foram utilizadas para a determinação da temperatura de brilho da banda 4 e 5 da TST através dos métodos de Becker e Li (1990), Kerr et al. (1992) e Sobrino et al. (1993). A TST obtida a partir das imagens foi comparada aos dados de temperatura do ar obtidos em 13 estações meteorológicas de superfície Os resultados mostraram que os sensores orbitais AVHRR/3 são adequados para o mapeamento noturno de temperaturas da superfície terrestre no Rio Grande do Sul. O método de Sobrino et al. (1993) é o mais adequado entre os métodos testados para a estimativa das temperaturas noturnas no Estado, embora ainda seja necessário um aprofundamento teórico em relação aos efeitos atmosféricos sobre regiões localizadas em baixas latitudes. Também a temperatura estimada por sensores remotos pode ser utilizada para estimar a temperatura do ar nos locais avaliados, sendo que ainda deve ser testada a extrapolação para outros locais.

Teoria do Orbital Molecular (TOM)

O material aborda a Teoria do Orbital Molecular (TOM), ressaltando o conceito de energia e probabilidade. O objetivo é propiciar a compreensão da teoria através da visualização das ligações dos orbitais.