Eine blumistische Plauderei

Von Dr. E. Goeze

Das Rheingold : Vorabend zur Trilogie Der Ring des Nibelungen

von Richard Wagner. Durchges., mit den urspr. Fass. vergl., mit einer Einl. sowie den hauptsächlichst. Motiven und Notenbeisp. vers. von Edmund E. F. Kühn

Die Zukunft des Belgischen Congo : eine Untersuchung der Vorschläge der belgischen Regierung zur Congo-Reform

von E. D. Morel

Trading monopolies in West Africa : a protest against territorial concessions

by E. D. M.

Gottesdienst und Menschenadel : die sittliche Idee im Kampf um ihre Selbstbehauptung innerhalb der israelitisch-jüdischen und christlichen Religionsgeschichte

dargestellt von Edmund Mugler

The treatment of women and children in the Congo State : 1895 - 1904 ; an appeal to the women of the British Empire, and of the United States of America

by E. D. Morel

The Congo Slave State : a protest against the new African slavery ; and an appeal to the public of Great Britain, of the United States, and of the Continent of Europe

by Edmund D. Morel

The new African slavery; or, King Leopold's rule in Africa

by E. D. Morel

The Scandal of the Congo : Britain's duty

by E. D. Morel

Edmundi Castelli Lexicon hebraicum

ex ejus lexico heptaglotto seorsim typis descriptum adnotatis in margine vocum numeris ex Joannis Davidis Michaelis supplementis as lexica hebraica [[Elektronische Ressource]]

Role of activation of the protein tyrosine kinase, Src, in colorectal cancer chemoresistance

Advances in therapy for colorectal cancer have been hampered by development of resistance to chemotherapy. The Src family of protein tyrosine kinases has been associated with colorectal cancer development and progression. Activation of the prototypic member of the family, Src, occurs in advanced colorectal cancer and is associated with a worse outcome. This work tests the hypotheses that Src activation contributes to chemoresistance in some colon tumors and that this resistance can be overcome by use of Src inhibitors. The aims of the proposal were to (1) determine if constitutive Src activation is sufficient to induce oxaliplatin resistance; (2) evaluate the role of reactive oxygen species (ROS) in the activation of Src after oxaliplatin treatment; (3) determine the frequency of Src activation in liver metastases after oxaliplatin treatment; and (4) evaluate the safety, preliminary efficacy, and pharmacodynamics of the combination of dasatinib with oxaliplatin-based therapy in patients with metastatic colorectal cancer. ^ Using a panel of colon cancer cell lines and murine models, I demonstrate that administration of oxaliplatin, a commonly utilized chemotherapy for colorectal cancer, results in an increased activation of Src. The activation occurs acutely in some, but not all, colorectal carcinoma cell lines. Cell lines selected for oxaliplatin resistance are further increased in Src activity. Treatment of cell lines with dasatinib, a non-selective pharmacologic inhibitor of the Src family kinases synergistically killed some, but not all cell lines. Cell lines with the highest acute activation of Src after oxaliplatin administration were the most sensitive to the combination therapy. Previous work demonstrated that siRNA to Src increased sensitivity to oxaliplatin, suggesting that the effects of dasatinib are primarily due to its ability to inhibit Src in these cell lines. ^ To examine the mechanism underlying these results, I examined the effects of reactive oxygen species (ROS), as previous studies have demonstrated that platinum chemotherapeutics result in intracellular oxidative stress. I demonstrated that oxaliplatin-induced reactive oxygen species were higher in the cell lines with Src activation, relative to those in which Src was not activated. This oxaliplatin-induced Src activation was blocked by the administration of anti-oxidants, thereby demonstrating that synergistic killing between dasatinib and oxaliplatin was associated with the ability of the latter to generate ROS. ^ In a murine model of colorectal cancer metastasis to the liver, the combination of dasatinib and oxaliplatin was more effective in reducing tumor volume than either agent alone. However, when oxaliplatin resistant cell lines were treated with a combination of oxaliplatin and AZD0530, an inhibitor in the clinic with increased specificity for Src, no additional benefit was seen, although Src was activated by oxaliplatin and Src substrates were inhibited. The indolent growth of oxaliplatin-resistant cells, unlike the growth of oxaliplatin resistant tumors in patients, precludes definitive interpretation of these results. ^ To further explore Src activation in patients with oxaliplatin exposure and resistance, an immunohistochemistry analysis of tumor tissue from resected liver metastases of colorectal cancer was performed. Utilizing a tissue microarray, staining for phosphorylated Src and FAK demonstrated strong staining of tumor relative to stromal and normal liver. In patients recently exposed to oxaliplatin, there was increased FAK activation, supporting the clinical relevance of the prior preclinical studies. ^ To pursue the potential clinical benefit of the combination of Src inhibition with oxaliplatin, a phase IB clinical trial was completed. Thirty patients with refractory metastatic colorectal cancer were treated with a combination of 5-FU, oxaliplatin, an epidermal-growth factor receptor monoclonal antibody, and dasatinib. The recommended phase II dose of dasatinib was established, and toxicities were quantified. Pharmacodynamic studies demonstrated increased phosphorylation of the Src substrate paxillin after dasatinib therapy. Tumor biopsies were obtained and Src expression levels were quantitated. Clinical benefit was seen with the combination, including a response rate of 20% and disease control rate of 56%, prompting a larger clinical study. ^ In summary, although Src is constitutively activated in metastatic colorectal cancer, administration of oxaliplatin chemotherapy can further increase its activity, through a reactive oxygen species dependent manner. Inhibition of Src in combination with oxaliplatin provides additional benefit in vitro, in preclinical animal models, and in the clinic. Further study of Src inhibition in the clinic and identification of predictive biomarkers of response will be required to further advance this promising therapeutic target. ^

Nitrogen dioxide exposures among a selected group of residents of substandard housing in Houston, Texas

Nitrogen dioxide (NO$\sb2)$ levels in sixteen substandard houses located in Houston, Texas were examined. The classification of the houses as substandard was based on an assessment of structural integrity which would affect air exchange rates. In these homes, unvented gas space heaters were operated as the primary source of heat.^ The Ogawa passive sampling device was used to measure NO$\sb2$ concentrations over 24 to 48-hour periods during generally cold weather. A sampler was placed in the kitchen and bedroom of each house. The female head of household was asked to wear a monitor during area monitoring to assess her personal exposure. Outdoor levels of NO$\sb2$ were also measured.^ Mean (standard deviation) levels of kitchen, bedroom and personal exposures were 280 (125) ppb, 256 (155) ppb and 164 (102) ppb, respectively. Additional short-term ($<$24 hours) samples were measured in three houses. The mean level of NO$\sb2$ measured outdoors was 51 ppb over the course of the study.^ The measurements obtained with the Ogawa sampler were compared to those levels obtained using a reference method (chemiluminescence). Outdoor levels measured with the diffusion samplers were 48% higher.^ These results suggest that wintertime NO$\sb2$ levels within substandard houses using gas appliances for heating and cooking are extremely elevated. Further work is needed to investigate the prevalence of possible health effects associated with these exposures. ^

The cDNA cloning of murine HIP /L29 and the functional analysis of HIP/L29 domains

Human heparin/heparan sulfate interacting protein/L29 (HIP/L29) is a heparin/heparan sulfate (Hp/HS) binding protein found in many adult human tissues. Potential functions of this protein are promotion of embryo adhesion, modulation of blood coagulation, and control of cell growth. While these activities are diverse, the ability of human HIP/L29 to interact with Hp/HS at the cell surface may be a unifying mechanism of action since Hp/HS influences all of these processes. A murine ortholog has been identified that has 78.8% homology over the entire sequence and identity over the N-terminal 64 amino acids when compared to human HIP/L29. Northern, Western, and immunohistochemical analysis shows that murine HIP/L29 mRNA and protein are expressed in a tissue specific manner. Murine HIP/L29 is enriched in the membrane fraction of NmuMG cells where it is eluted with high salt, suggesting that it is a peripheral membrane protein. The ability of murine HIP/L29 to bind Hp is verified by studies using native and recombinant forms of murine HIP/L29. A synthetic peptide (HIP peptide-2) derived from the identical N-terminal region of HIP/L29 proteins was tested for the ability to bind Hp and support cell adhesion. This peptide was chosen because it conforms to a proposed consensus sequence for Hp/HS binding peptides. HIP peptide-2 binds Hp in a dose-dependent, saturable, and selective manner and supports Hp-dependent cell adhesion. However, a scrambled form of this peptide displayed similar activities indicating a lack of peptide sequence specificity required for activity. Lastly, an unbiased approach was used to identify sequences within human and mouse HIP/L29 proteins necessary for Hp/HS binding. A panel of recombinant proteins was made that collectively are deficient in every human HIP/L29 domain. The activities of these deletion mutants and recombinant murine HIP/L29 were compared to the activity of recombinant human HIP/L29 in a number of assays designed to look at differences in the ability to bind Hp/HS. These studies suggest that each domain within human HIP/L29 is important for binding to Hp/HS and divergences in the C-terminus of human and mouse HIP/L29 account for a decrease in murine HIP/L29 affinity for Hp/HS. It is apparent that multiple domains within human and mouse HIP/L29 contribute to the function of Hp/HS binding. The interaction of multiple HIP/L29 domains with Hp/HS will influence the biological activity of HIP/L29 proteins. ^

Physical properties and neutron texture measuerments of deep-sea carbonates of DSDP Holes 62-463 and 62-465A

In weakly indurated, nannofossil-rich, deep-sea carbonates compressional wave velocity is up to twice as fast parallel to bedding than normal to it. It has been suggested that this anisotropy is due to alignment of calcite c-axes perpendicular to the shields of coccoliths and shield deposition parallel to bedding. This hypothesis was tested by measuring the preferred orientation (fabric) of calcite c-axes in acoustic anisotropic, calcareous DSDP sediment samples by X-ray goniometry, and it was found that the maximum c-axis concentrations are by far too low to explain the anisotropies. The X-ray method is subject to a number of uncertainties due to preparatory and technical shortcomings in weakly indurated rocks. The most serious weaknesses are: sample preparation, volume of measured sample (fraction of a mm3), beam defocusing and background intensity corrections, combination of incomplete pole figures, and necessity of recalculation of the c-axis orientations from other crystallographic directions. Goniometry using thermal neutrons overcomes most of these difficulties, but it is time consuming. We test the interferences made about velocity anisotropy by X-ray studies about the concentration of c-axes in deep-sea carbonates by employing neutron texture goniometry to eight DSDP samples comprising mostly nannofossil material. Fabric and sonic velocity were determined directly on the core specimens, thus from the same rock volume and requiring no preparation. The c-axis orientation is obtained directly from the [0006] calcite diffraction peak without corrections. The fabrics are clearly defined, but weak (1.1 to 1.86 times uniform) with the maximum about normal to bedding. They have crudely orthorhombic symmetry, but are not axisymmetric around the bedding normal. The observed c-axis intensities, although higher than determined by the X-ray method on other samples, are by far too low to explain the observed acoustic anisotropies.

U-Pb (zircon) geochronologic analyses for rocks of the Transantarctic Mountains (Table 4.3-1)

The Byrd Glacier discontinuity us a major boundary crossing the Ross Orogen, with crystalline rocks to the north and primarily sedimentary rocks to the south. Most models for the tectonic development of the Ross Orogen in the central Transantarctic Mountains consits of two-dimensional transects across the belt, but do not adress the major longitudinal contrast at Byrd Glacier. This paper presents a tectonic model centering on the Byrd Glacier discontinuity. Rifting in the Neoproterozoic producede a crustal promontory in the craton margin to the north of Byrd Glacier. Oblique convergence of the terrane (Beardmore microcontinent) during the latest Neroproterozoic and Early Cambrian was accompanied by subduction along the craton margin of East Antarctica. New data presented herein in the support of this hypothesis are U-Pb dates of 545.7 ± 6.8 Ma and 531.0 ± 7.5 Ma on plutonic rocks from the Britannia Range, subduction stepped out, and Byrd Glacier. After docking of the terrane, subduction stepped out, and Byrd Group was deposited during the Atdabanian-Botomian across the inner margin of the terrane. Beginning in the upper Botomian, reactivation of the sutured boundaries of the terrane resulted in an outpouring of clastic sediment and folding and faulting of the Byrd Group.