Background: Metastatic melanoma remains a life-threatening disease because most tumours develop resistance in response to conventional treatment. Even though targeted drugs represent promising therapeutics, the clinical outcome remains poor, with high relapse rates coinciding with pronounced metastatic outgrowth. Therefore, successful therapy is still challenging, and alternative treatment options are demanded as first or second line therapy to overcome acquired resistance. In this context, cell death induction by the tumour-selective death ligand TRAIL (Tumour necrosis factor-Related Apoptosis-Inducing Ligand) might serve as an alternative single or co-treatment option. Unfortunately, melanoma cells were shown to stay largely resistant against conventional TRAIL treatment and the first-generation TRAIL-based therapeutics failed in clinical trials due to the limited therapeutic activity in patients. To overcome this therapeutic limitation, a second-generation hexavalent TRAIL receptor agonist IZI1551 has been developed showing increased bioactivity thereby enhancing the cytotoxic effects on cancer cells. Questions and Hypothesis. We hypothesized that cells that do not receive the full but only a sublethal drug-dose may not only be responsible for drug resistance but may also confer tumour relapse and metastatic outgrowth. By switching the signal transduction from pro-apoptotic to anti-apoptotic and pro-survival, these cells may foster an aggressive phenotype with enhanced proliferation and migration. Therefore, an in depth understanding of the underlying mechanisms of emerging drug resistance that may additionally trigger secondary metastasis formation is required to identify new therapeutic targets and alternative treatment options. Methodology. Melanoma cell lines were conditioned to the TRAIL receptor agonist IZI1551 and the expression of members of the anti-apoptotic NFκB and MAPK pathways as well as of the TRAIL receptor-driven apoptotic pathway were investigated by semi-quantitative Western-blot analysis. Protein expression/activation data of parental IZI1551-sensitive versus conditioned IZI1551-resistant melanoma cells were implemented into a network topology derived from literature. A Dynamic Bayesian Network (DBN) model was combined with a sophisticated regularisation strategy resulting in sparse and context-sensitive networks to identify cell line-specific deregulations within the signalling network. Predictions of the model were confirmed by siRNA-mediated knock down. Enhanced proliferation and migration of resistant-cells were investigated by proliferation, clonogenic, and scratch assays. Following the 2D studies, migration and invasion were monitored by confocal microscopy in 3D migration/invasion assays and 3D spheroids models. Expression of pro-metastatic cell adhesion molecules was evaluated by flow cytometry. In order to identify potential regulators of the aggressive phenotype, quantitative transcriptome analysis (RNA-seq) was performed. The therapeutic outcome of the new identified treatment options with IZI1551 alone or in combination with Smac mimetics or bortezomib was evaluated by cell death detection ELISA. Results. In this thesis, IZI1551 was shown to induce pronounced apoptotic cell death in melanoma cells compared to mutation specific targeted kinase inhibitors, as being used in the clinic. Comparing IZI1551-sensitive to IZI1551-resistant melanoma cells, the DBN model accurately predicted activation of NFκB in concert with upregulation of the anti-apoptotic protein XIAP to be the key mediator of IZI1551 resistance. Moreover, XIAP was identified to serve as a potential biomarker for TRAIL responsiveness. According to these findings, human melanoma cell lines were re-sensitised to TRAIL in vitro by co-application of the IAP antagonists Smac mimetics as well as bortezomib, a proteasome inhibitor currently used in cancer treatment. In addition, by triggering survival instead of apoptotic signalling pathways, resistant cells caused an aggressive phenotype with enhanced proliferation and migration/invasion into 3D collagen matrices, coinciding with upregulation of the cell adhesion molecules MelCAM and αVβ3 integrin, which are known to promote tumour progression and metastasis. Combining in silico studies of RNA-seq and protein expression data, YAP, an intracellular transducer of mechanical stimuli, and its upstream regulator FAK, a component of the focal adhesion complex, were identified as key promoters of proliferation and migration. Conclusions. Identification of new biomolecular markers or targets combining experimental and computational approaches is a promising avenue to assess the effects of drug combinations and to identify responders to selected combination therapies. In this thesis, IZI1551 was identified as an alternative treatment option for metastatic melanoma. Our data also suggest that XIAP expression may serve as a potential predictive marker for the sensitivity of tumour cells to TRAIL-induced apoptosis. Above this, we demonstrated that three alternative treatment options with IZI1551 in combination with Smac mimetics, bortezomib or FAK inhibitors may represent a promising approach for the treatment of TRAIL-resistant melanomas and to prevent undesired metastatic outgrowth.

Recent research has emphasized the need to professionally manage campsites for long-term use, particularly in light of rising visitation to natural protected areas worldwide. Camping regulations vary considerably along the length of any long-distance trail due to the many land types and management agencies involved. Large proportions of long-distance trails have at-large camping policies, resulting in camping problems associated with visitor-chosen or developed campsites. Several long-term monitoring studies in areas with at-large camping policies indicate the expansion and proliferation of individual campsites, and growth of overall camping related impacts, to be a substantial managerial concern. This research evaluates the relative influence of environmental and topographic factors, both collected in the field and modeled in GIS using high-resolution topography (LiDAR) data, on areal measures of campsite impact utilizing Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression for factor selection and Ordinary Least Squares (OLS) for regressions. Chosen variables in regressions explained 64% of the variation in campsite size and 61% of the variation in the area of vegetation loss on a campsite. Results indicate four variables managers can utilize to enhance the sustainability of campsites: use level, overnight site type, and terrain characteristics relating to slope and topographic roughness. Results support indirect management methods that rely on the design and location of campsites and trails and not the effectiveness of enforcement or restricting visitor freedom. In the face of rising use, techniques and concepts presented aid in identifying or creating ecologically sustainable campsites. / Master of Science

The purpose of this study was to identify barriers that contribute to a disparity in utilization across different segments of an urban trail. To achieve this aim, subjective ratings of trail characteristics for high-use areas (western sections of the trail) were compared to subjective ratings of lower-use areas (eastern sections of the trail). These ratings were compared between those who reported primarily traveling the western, high-use sections vs. those who primarily travel the eastern, low-use sections. Data were collected through self-report and a cross-sectional analysis based on sections of primary use. Ratings for each trail characteristic from an online survey were compared for different trail segments as a function of these groups. Comparisons were conducted through ANOVA and showed that perceptions of trail characteristics varied strongly as a function of which sections of the trail were used most by the respondents. Users of the high-traffic, western sections held significantly more negative views of the eastern sections. In contrast, users of the low-traffic, eastern sections held similar views of the eastern and western sections. Objective measurements of trail characteristics were conducted on all six segments of trail to compare to user perceptions. A trail count and researcher evaluation/audit of all trail characteristics provided data for comparison. A descriptive analysis of the differences between trail user perceptions and objective measures was reported. The trail count and survey results showed similar patterns of usage. The western sections exhibited the highest number of trail users representing 80% of the people on the trail. The central sections contained 14% and the eastern sections 6%. Mode of travel observed was 94% walking or running and 6% cycling. In addition, these numbers are similar to those of the earlier, pilot study (TEMBA, 2011). Given the similarities between the online survey, and both the objective trail count for usage and the earlier TEMBA study, it is hoped that the online sample is representative of the population of regular trail users. A comparison of subjective and objective ratings revealed different patterns of agreement depending on east vs. west group membership. Overall, west users are misinformed about crime and amenities on the east side but are in general agreement on other characteristics. This suggests that their concerns about trail continuity, directional clarity, and loop options may be warranted. Overall, east users showed general agreement with objective measures on the west side except for exposure to traffic, which they rated more poorly than objective measures. / text

The Ballad of Sam Bass is an original. play based on the life of Sam Bass the outlaw. Cowboys camped on the Chisholm trail are entertained by a stranger who sings a song about Sam Bass. Bass was a good-hearted individual who was seduced by his vices, drinking and gambling, and fell into the life of an outlaw. He was successful in eluding the law until he was betrayed by one of his own men, Jim Murphy. In the course of his song, the stranger reveals himself to be Frank Jackson, the only surviving member of Bass's gang. Jackson had talked Bass out of killing Murphy when Bass became suspicious. Creating the song serves as a catharsis for Jackson's guilt.

TITLE: Ancient trails in the area of the Otava River AUTHOR: Michal Pitín DEPARTMENT: History and History Didactics Department SUPERVISOR: prof. PhDr. Petr Charvát, DrSc. ABSTRACT: The diploma thesis focuses on one of the modern science called stibology which concentrates on the human past and human's relation to the landscape and its settlement and mainly passing trails through the landscape. The aim of this work is to study settlement and possible passing of the communications through the landscape in the area of the Otava River since the Celtic settlement, but mainly at the Early and the High Middle Ages. The work focuses on realisation of the stibologic knowledge in the area of the town Strakonice at the period of the Early Middle Ages. It also shows that the theme of the old trails is missed out of education and its possible usage in the subject called The Heritage Education in School Education Programmes. The work also includes analysis of the cartographic materials and their information about trails passing the landscape. The work is completed by the picture supplement from the area of the Otava River and cartographic materials. KEYWORDS: trail, way, settlement, area of the Otava River

TNF-related apoptosis-inducing ligand (TRAIL) is a member of TNF family expressed mainly by hematopoietic cells. TRAIL brought significant attention mainly for its ability to trigger apoptosis in a number of cancer cells. In addition to apoptosis, TRAIL can induce several other signaling pathways such as activation of MAP kinases or canonical NF-B signaling. Human TRAIL can bind to five receptors but only two of them (death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5) can trigger TRAIL-mediated apoptotic and non-apoptotic signaling in target cells. Both receptors are ubiquitously expressed on normal and cancer cells, but the relative contribution of DR4 and DR5 to TRAIL-induced signaling is not well known. Using DR4/DR5-specific variants of TRAIL, we examined how individual receptor contributes to the induction of apoptosis and NF-B, JNK, p38, ERK1/2 and TAK1 signaling pathways in selected colorectal cells. We found that in DLD-1 cells, apoptosis and activation of JNKs are mainly mediated by DR4-selective ligand. In TRAIL-resistant HT-29 cells, we show that though DISC formation and activation of caspase-8 proceeds mainly via DR4-specific signaling, activation of NF-B pathway is mainly triggered by DR5 selective ligand. In other cells and analyzed signaling pathways both receptor-specific ligands triggered very...

Title: The project of educational cycling trails in Protected Landscape Area of Eagle mountains  Objective The aim of this work is to create prject of three cycling trails, with three degrees of difficulty in eagle mountains area. The trails will be shown in information brochure with photos and information about this area. The brochure will be available in tourist information centre and online on some web page. Methods Analyzes of existing trails in this area, searching for information about interesting places, history and geografical points. Consulting and verifying this information with people from Eagle mountains PLA (Protected Landscepe Area) organization and interviewing locals about this area. Verifying trails by group of cyclists. Results The result of this thesis is a brochure with three bicycle educational trails in eagle mountains. The brochure contains maps, photos, cultural stops and other informatin about this area. Key words: Eagle mountains, educational trail, bicycling Powered by TCPDF (www.tcpdf.org)

Title: The project of educational cycling trails in Protected Landscape Area of Eagle mountains Objective The aim of this work is to create prject of three cycling trails, with three degrees of difficulty in eagle mountains area. The trails will be shown in information brochure with photos and information about this area. The brochure will be available in tourist information centre and on ČD (Czech railways ) and CHKO (www.chko.cz) web pages for free download. Methods Analyzes of existing trails in this area, searching for information about interesting places, history and geografical points. Consulting and verifying this information with people from Eagle mountains PLA (Protected Landscepe Area) organization and interviewing locals about this area. Verifying trails by group of cyclists. Results The result is a brochure with three bicycle educational tracks in eagle mountains. The brochure contains maps, photos, cultural stops and other informatin about this area. Key words: Eagle mountains, bicycle track, protected area, bicysle trail, Educational trail

Intervention into the public space / hoax -  Forged tourist signs in the  fields (obora = game preserve/park) Holedná(Brno Jundrov - Bystrc). Against standard practices, the trail is marked off any existing paths, through fences, signs are extremely frequent Work bordering with political art. The trail was handed over to  Mayor Onderka at the occassion of his birthday.

This thesis studies the diffusion of architectural types and the rise of regionally distinct typologies in the Willamette Valley's settlement period (1840-1865) in Oregon. Using Geographic Information Systems (GIS) to analyze the dispersion of architectural types within the Willamette Valley revealed trends amongst the extant settlement architecture samples. Brownsville, Oregon, was identified to have a locally-specific architectural subtype, the closer study of which enabled deeper investigation of the development of architectural landscapes during the Willamette Valley's settlement period. Field and archival research revealed that the appearance of an architectural subtype, at least in Brownsville, was not directly connected to a shared provenance of settlers but rather came about through a number of regionally-specific circumstances, especially an active local carpenter community.