Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

Background The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. Methods A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. Results The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. Conclusions In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation.

Using resource discovery techniques to create a user friendly web presence

Implementing resource discovery techniques at the Museum of English Rural Life and Special Collections, University of Reading Using resource discovery techniques to create a user friendly web presence

Detecting fish aggregations from reef habitats mapped with high resolution side scan sonar imagery

As part of a multibeam and side scan sonar (SSS) benthic survey of the Marine Conservation District (MCD) south of St. Thomas, USVI and the seasonal closed areas in St. Croix—Lang Bank (LB) for red hind (Epinephelus guttatus) and the Mutton Snapper (MS) (Lutjanus analis) area—we extracted signals from water column targets that represent individual and aggregated fish over various benthic habitats encountered in the SSS imagery. The survey covered a total of 18 km2 throughout the federal jurisdiction fishery management areas. The complementary set of 28 habitat classification digital maps covered a total of 5,462.3 ha; MCDW (West) accounted for 45% of that area, and MCDE (East) 26%, LB 17%, and MS the remaining 13%. With the exception of MS, corals and gorgonians on consolidated habitats were significantly more abundant than submerged aquatic vegetation (SAV) on unconsolidated sediments or unconsolidated sediments. Continuous coral habitat was the most abundant consolidated habitat for both MCDW and MCDE (41% and 43% respectively). Consolidated habitats in LB and MS predominantly consisted of gorgonian plain habitat with 95% and 83% respectively. Coral limestone habitat was more abundant than coral patch habitat; it was found near the shelf break in MS, MCDW, and MCDE. Coral limestone and coral patch habitats only covered LB minimally. The high spatial resolution (0.15 m) of the acquired imagery allowed the detection of differing fish aggregation (FA) types. The largest FA densities were located at MCDW and MCDE over coral communities that occupy up to 70% of the bottom cover. Counts of unidentified swimming objects (USOs), likely representing individual fish, were similar among locations and occurred primarily over sand and shelf edge areas. Fish aggregation school sizes were significantly smaller at MS than the other three locations (MCDW, MCDE, and LB). This study shows the advantages of utilizing SSS in determining fish distributions and density.

Design, synthesis and characterization of sequence-specific DNA-cleaving metalloproteins

This thesis describes research pursued in two areas, both involving the design and synthesis of sequence specific DNA-cleaving proteins. The first involves the use of sequence-specific DNA-cleaving metalloproteins to probe the structure of a protein-DNA complex, and the second seeks to develop cleaving moieties capable of DNA cleavage through the generation of a non-diffusible oxidant under physiological conditions.

Chapter One provides a brief review of the literature concerning sequence-specific DNA-binding proteins. Chapter Two summarizes the results of affinity cleaving experiments using leucine zipper-basic region (bZip) DNA-binding proteins. Specifically, the NH_2-terminal locations of a dimer containing the DNA binding domain of the yeast transcriptional activator GCN4 were mapped on the binding sites 5'-CTGACTAAT-3' and 5'ATGACTCTT- 3' using affinity cleaving. Analysis of the DNA cleavage patterns from Fe•EDTA-GCN4(222-281) and (226-281) dimers reveals that the NH_2-termini are in the major groove nine to ten base pairs apart and symmetrically displaced four to five base pairs from the central C of the recognition site. These data are consistent with structural models put forward for this class of DNA binding proteins. The results of these experiments are evaluated in light of the recently published crystal structure for the GCN4-DNA complex. Preliminary investigations of affinity cleaving proteins based on the DNA-binding domains of the bZip proteins Jun and Fos are also described.

Chapter Three describes experiments demonstrating the simultaneous binding of GCN4(226-281) and 1-Methylimidazole-2-carboxamide-netropsin (2-ImN), a designed synthetic peptide which binds in the minor groove of DNA at 5'-TGACT-3' sites as an antiparallel, side-by-side dimer. Through the use of Fe•EDTA-GCN4(226-281) as a sequence-specific footprinting agent, it is shown that the dimeric protein GCN4(226-281) and the dimeric peptide 2- ImN can simultaneously occupy their common binding site in the major and minor grooves of DNA, respectively. The association constants for 2-ImN in the presence and in the absence of Fe•EDTA-GCN4(226-281) are found to be similar, suggesting that the binding of the two dimers is not cooperative.

Chapter Four describes the synthesis and characterization of PBA-β-OH-His- Hin(139-190), a hybrid protein containing the DNA-binding domain of Hin recombinase and the putative iron-binding and oxygen-activating domain of the antitumor antibiotic bleomycin. This 54-residue protein, comprising residues 139-190 of Hin recombinase with the dipeptide pyrimidoblamic acid-β-hydroxy-L-histidine (PBA-β-OH-His) at the NH2 terminus, was synthesized by solid phase methods. PBA-β-OH-His-Hin(139- 190) binds specifically to DNA at four distinct Hin binding sites with affinities comparable to those of the unmodified Hin(139-190). In the presence of dithiothreitol (DTT), Fe•PB-β-OH-His-Hin(139-190) cleaves DNA with specificity remarkably similar to that of Fe•EDTA-Hin(139-190), although with lower efficiency. Analysis of the cleavage pattern suggests that DNA cleavage is mediated through a diffusible species, in contrast with cleavage by bleomycin, which occurs through a non-diffusible oxidant.

São muitos os remédios para os males dessa vida : análise de recursos terapêuticos a partir da doença crônica na infância

Esta tese discute cura e cuidado a partir da doença crônica infantil. Partimos da constatação de que a Biomedicina prioriza o diagnóstico, o conhecimento da doença e sua cura; a terapêutica fica habitualmente relegada à segundo plano. O impacto dos avanços tecnológicos nesta Medicina se faz notar nos atuais questionamentos sobre os limites da vida, da morte e da monstruosidade. Diante da doença grave, progressiva e incurável na infância a discussão destes limites se torna urgente. Ressaltamos o potencial, pouco explorado, de práticas e relações médico-sociais no tratamento de crianças com estas enfermidades bem como no cuidado de suas famílias. Valorizamos a busca de sentido, a percepção da doença pelo paciente, sua família e a equipe de saúde do hospital, a qualidade da relação médico-cliente (paciente-pais), a fé na cura e os grupos de ajuda mútua. Acreditamos na importância da construção contínua de um projeto possível para lidarmos com estas adversidades. Levantamos a perspectiva dos cuidados paliativos, num enfoque mais amplo para tratamento de qualquer paciente que não busque unicamente a cura da doença, mas também o acolhimento, o cuidado e a qualidade de vida daquele que sofre. A partir da pesquisa de campo visamos observar aproximações e distanciamentos entre a demanda da família e as possibilidades de oferta do serviço de saúde. Estas reflexões se baseiam na experiência profissional no Instituto Fernandes Figueira, hospital materno-infantil, público, terciário, da FIOCRUZ/Ministério da Saúde. Este trabalho se insere na linha de pesquisa desenvolvida no Instituto de Medicina Social que investiga práticas de saúde e racionalidades médicas, coordenada pela professora Madel T. Luz.

Procedures to prevent the occurrence of potentially dangerous situations during the operation of the Mackereth 1-metre mini or short sediment corer

During the 1950s and 1960s, F.J.H. Mackereth developed and published plans for a series of pneumatic samplers for lake sediments. Unfortunately, as the equipment was continually evolving during ensuing research, no user manuals, beyond the original publication, had been produced. Over the last few years there have been a few potentially very serious accidents with the 1-metre corer, which has prompted the authors to carry out a risk assessment. This highlighted two weaknesses in the design and its later developments. They can be corrected simply by checking for screw threads that may have been added to the exhaust port on the mini-corer, and by changing the operating procedure. An A4 nine-page user manual is now available from the authors. A small charge ( pound sterling 10 in 1998) will be made to cover handling costs and postage.

Site-Specific Isotopes in Small Organic Molecules

Stable isotope geochemistry is a valuable toolkit for addressing a broad range of problems in the geosciences. Recent technical advances provide information that was previously unattainable or provide unprecedented precision and accuracy. Two such techniques are site-specific stable isotope mass spectrometry and clumped isotope thermometry. In this thesis, I use site-specific isotope and clumped isotope data to explore natural gas development and carbonate reaction kinetics. In the first chapter, I develop an equilibrium thermodynamics model to calculate equilibrium constants for isotope exchange reactions in small organic molecules. This equilibrium data provides a framework for interpreting the more complex data in the later chapters. In the second chapter, I demonstrate a method for measuring site-specific carbon isotopes in propane using high-resolution gas source mass spectrometry. This method relies on the characteristic fragments created during electron ionization, in which I measure the relative isotopic enrichment of separate parts of the molecule. My technique will be applied to a range of organic compounds in the future. For the third chapter, I use this technique to explore diffusion, mixing, and other natural processes in natural gas basins. As time progresses and the mixture matures, different components like kerogen and oil contribute to the propane in a natural gas sample. Each component imparts a distinct fingerprint on the site-specific isotope distribution within propane that I can observe to understand the source composition and maturation of the basin. Finally, in Chapter Four, I study the reaction kinetics of clumped isotopes in aragonite. Despite its frequent use as a clumped isotope thermometer, the aragonite blocking temperature is not known. Using laboratory heating experiments, I determine that the aragonite clumped isotope thermometer has a blocking temperature of 50-100°C. I compare this result to natural samples from the San Juan Islands that exhibit a maximum clumped isotope temperature that matches this blocking temperature. This thesis presents a framework for measuring site-specific carbon isotopes in organic molecules and new constraints on aragonite reaction kinetics. This study represents the foundation of a future generation of geochemical tools for the study of complex geologic systems.

Caminhos contemporâneos Cortázar e outros destruidores de bússolas

A presente tese se ocupa de uma vertente da literatura e do cinema contemporâneos, especialmente do escritor Julio Cortázar e do cineasta David Lynch, que: busca um novo tratamento para a realidade, não esconde os artifícios discursivos das obras, joga com estratégias ilusionistas e antiilusionistas, debate a própria ficção por meio de recursos metaficcionais, que se utiliza da metáfora do teatro como espaço diferenciado e como palco de ilusões e que trabalha com a questão do fantástico (ou absurdo). Grande parte do trabalho é dedicada ao estudo da obra do escritor argentino Julio Cortázar. Estudo esse que se constrói a partir das correspondências entre as produções ficcionais e teóricas de Cortázar, além de suas próprias entrevistas. Cortázar é nosso foco principal e dele, acreditamos, brotou um veio dos mais significativos na narrativa contemporânea, que estabelece novos modos de se lidar com a representação e com as referências. É devido a esses aspectos, apontados anteriormente, que estabelecemos relações com outros autores, inclusive do cinema, como é o caso de David Lynch

Meu nome não é ninguém: narrativa sobre excluídos na Literatura Brasileira Contemporânea: Cidade de Deus e Meu nome não é Johnny

O tema da exclusão social sempre esteve presente na Literatura Brasileira, porém, na virada do século XX para o XXI, ele ganha ainda mais relevo, através de narrativas realistas, chocantes, exacerbadas de violência e até anomia, que enfatizam a imagem dos excluídos. Cidade de Deus (Paulo Lins: 1997) e Meu nome não é Johnny (Guilherme Fiuza: 2004) focalizam a exclusão dos envolvidos com o narcotráfico. A despeito das diferenças entre as duas narrativas, os seus protagonistas entram em ação a partir da marginalidade; ganham autonomia, no cenário urbano, através da criminalidade, e se tornam ameaçadoramente visíveis, depois de uma histórica invisibilidade. O estudo das complexidades concernentes ao tratamento ficcional do tema se distribuiu, nessa dissertação, em três capítulos. No primeiro capítulo, as obras foram estudadas individualmente, em função da organização dos relatos no espaço narrativo. O segundo capítulo abordou a correlação entre geografia cultural e teoria da literatura, em suas considerações sobre a proeminência da categoria do espaço para o trabalho narratológico. Nessa perspectiva interdisciplinar, foram analisadas as paisagens ficcionais de ambos os romances e, em seguida, articulou-se o roteiro ficcional de cada romance com o pensamento de Foucault sobre os lugares heterotópicos. No terceiro capítulo, intertextualizando o binômio disciplinar geografia cultural e literatura com a filosofia, retroagiu-se aos filósofos idealistas alemães que teorizaram sobre o trágico e intuíram que a tragicidade não se manifesta apenas na tragédia, mas também em obras que lidam com a experiência do irrepresentável, da representação negativa e, em termos estéticos, do sublime. Conjugando as idéias de Hölderlin sobre o vislumbre do divino, de Schopenhauer sobre a metafísica da música, e de Nietzsche sobre a correlação entre o apolíneo e o dionisíaco, tragédia e música, chegou-se à conclusão de que ambas as narrativas incorporam produtivamente ao projeto ficcional duas metáforas absolutas (Hans Blumenberg) que dizem respeito à exclusão/inclusão: a cidade e o hipocorístico (Johnny), dois espaços um material, outro alegórico interativos, em ambos os romances. Em Meu nome não é Johnny, o percurso simbólico do protagonista o leva do sofrimento à redenção social e à inclusão (grandemente graças à atividade musical); em Cidade de Deus, a brutalização progressiva das relações humanas leva à erradicação de qualquer manifestação da sensibilidade, a uma cidade sem música e à permanência da exclusão