Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance.

Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models.

Investigation of business models of free zones and possible implications in South East Finland

Tutkielma tarkastelee vapaa alue konseptia osana yritysten kansainvälistä toimitusketjua. Tarkoituksena on löytää keinoja, millä tavoin vapaa alueen houkuttelevuutta voidaan lisätä yritysten näkökulmasta ja millaista liiketoimintaa yritysten on vapaa alueella mahdollista harjoittaa. Tutkielmassa etsitään tekijöitä, jotka vaikuttavat vapaa alueen menestykseen ja jotka voisivat olla sovellettavissa Kaakkois-Suomen ja Venäjän raja-alueelle ottaen huomioon vallitsevat olosuhteet ja lainsäädäntö rajoittavina tekijöinä. Menestystekijöitä ja liiketoimintamalleja haetaan tutkimalla ja analysoimalla lyhyesti muutamia olemassa olevia ja toimivia vapaa alueita. EU tullilain harmonisointi ja kansainvälisen kaupan vapautuminen vähentää vapaa alueen perinteistä merkitystä tullivapaana alueena. Sen sijaan vapaa alueet toimivat yhä enenevissä määrin logistisina keskuksina kansainvälisessä kaupassa ja tarjoavat palveluita, joiden avulla yritykset voivat parantaa logistista kilpailukykyään. Verkostoituminen, satelliitti-ratkaisut ja yhteistoiminta ovat keinoja, millä Kaakkois-Suomen alueen eri logistiikkapalvelujen tarjoajat voivat parantaa suorituskykyään ja joustavuutta kansainvälisessä toimitusketjussa.

Differential associations of personal and general just-world beliefs with the Five-Factor and HEXACO models of personality.

Recent literature evidences differential associations of personal and general just-world beliefs with constructs in the interpersonal domain. In line with this research, we examine the respective relationships of each just-world belief with the Five-Factor and the HEXACO models of personality in one representative sample of the working population of Switzerland and one sample of the general US population, respectively. One suppressor effect was observed in both samples: Neuroticism and emotionality was positively associated with general just-world belief, but only after controlling for personal just-world belief. In addition, agreeableness was positively and honesty-humility negatively associated with general just-world belief but unrelated to personal just-world belief. Conscientiousness was consistently unrelated to any of the just-world belief and extraversion and openness to experience revealed unstable coefficients across studies. We discuss these points in light of just-world theory and their implications for future research taking both dimensions into account.

Biotic interactions boost spatial models of species richness

Biotic interactions are known to affect the composition of species assemblages via several mechanisms, such as competition and facilitation. However, most spatial models of species richness do not explicitly consider inter-specific interactions. Here, we test whether incorporating biotic interactions into high-resolution models alters predictions of species richness as hypothesised. We included key biotic variables (cover of three dominant arctic-alpine plant species) into two methodologically divergent species richness modelling frameworks - stacked species distribution models (SSDM) and macroecological models (MEM) - for three ecologically and evolutionary distinct taxonomic groups (vascular plants, bryophytes and lichens). Predictions from models including biotic interactions were compared to the predictions of models based on climatic and abiotic data only. Including plant-plant interactions consistently and significantly lowered bias in species richness predictions and increased predictive power for independent evaluation data when compared to the conventional climatic and abiotic data based models. Improvements in predictions were constant irrespective of the modelling framework or taxonomic group used. The global biodiversity crisis necessitates accurate predictions of how changes in biotic and abiotic conditions will potentially affect species richness patterns. Here, we demonstrate that models of the spatial distribution of species richness can be improved by incorporating biotic interactions, and thus that these key predictor factors must be accounted for in biodiversity forecasts

The Business Models of Telecommunications Equipment Manufacturers. Case: Cisco Systems.

Tutkielman tavoitteena oli tarkastella telekommunikaatiolaitevalmistajien liiketoimintamalleja. Tutkielma jakaantuu teoreettiseen ja empiiriseen osaan. Teoreettinen osa keskittyy lähinnä liiketoimintamallin käsitteen määrittelyyn. Olemassa olevien määritelmien, sekä liiketoimintamallin käsitteeseen läheisesti liittyvien termien, pohjalta luotiin liiketoimintamallille uusi malli. Tutkielman empiirinen osa keskittyy case-yritys Cisco Systemsin liiketoimintamallin määrittelyyn ja kehityksen kuvaamiseen. Liiketoimintamallin kehitystä seurattiin kahden vuoden ajalta perehtymällä lähinnä yrityksen lehdistötiedotteisiin, artikkeleihin ja muuhun julkiseen materiaaliin. Ciscon lisäksi empiirisessä osassa tutkittiin kahdeksan muun laitevalmistajan liiketoimintamallien kehitystä. Empiirisen osan päätavoitteena oli selvittää, miten telekommunikaatiolaitevalmistajien liiketoimintamallit kehittyvät nyt ja tulevaisuudessa.

Mixed and Hybrid Models of Public Service Delivery

This symposium presents research from different contexts to improve our collective understanding of a variety of aspects of mixed forms of service delivery, be they mixed contracting at the level of the market (which is more common in the U.S.), or mixed management and ownership at the level of the firm (which is more common in Europe). The articles included in this special symposium examine the factors that give rise to mixed forms of service delivery (e.g., economic and fiscal stress, regulatory flexibility, geography, management) and how these factors impact their design and operation. Articles also explore the performance of mixed forms of service delivery relative to more conventional arrangements like contracted or direct service delivery. The articles contribute to a better theoretical and conceptual understanding of mixed/hybrid forms of services delivery.

Generative models of the human connectome.

The human connectome represents a network map of the brain's wiring diagram and the pattern into which its connections are organized is thought to play an important role in cognitive function. The generative rules that shape the topology of the human connectome remain incompletely understood. Earlier work in model organisms has suggested that wiring rules based on geometric relationships (distance) can account for many but likely not all topological features. Here we systematically explore a family of generative models of the human connectome that yield synthetic networks designed according to different wiring rules combining geometric and a broad range of topological factors. We find that a combination of geometric constraints with a homophilic attachment mechanism can create synthetic networks that closely match many topological characteristics of individual human connectomes, including features that were not included in the optimization of the generative model itself. We use these models to investigate a lifespan dataset and show that, with age, the model parameters undergo progressive changes, suggesting a rebalancing of the generative factors underlying the connectome across the lifespan.

Business Models of Packaging Machinery Manufacturers – Case Study

The goal of the study was to find a proper frame to understand business models and study business models of the chosen companies in packaging machinery manufacturing. Good practices and tips are searched from business models which have helped companies to success. Packaging industry’s future is also examined in front of different kinds of changes and the influence which they have on machinery manufacturer’s business models. In the theory part business models’ history and the best frame suitable for this study are presented. The chosen case companies have been discussed according to the frame, and they have been compared to each other to point out the differences. The good practices noticed in companies and according to information from other sources, new business model has been constructed including things that should be noticed while constructing a new business model. The information sources of this study where interviews, annual reports, companies presentations and web pages. The type of study was an interpretative case study.

In Vivo Longitudinal (1)H MRS Study of Transgenic Mouse Models of Prion Disease in the Hippocampus and Cerebellum at 14.1 T.

In vivo (1)H MR spectroscopy allows the non invasive characterization of brain metabolites and it has been used for studying brain metabolic changes in a wide range of neurodegenerative diseases. The prion diseases form a group of fatal neurodegenerative diseases, also described as transmissible spongiform encephalopathies. The mechanism by which prions elicit brain damage remains unclear and therefore different transgenic mouse models of prion disease were created. We performed an in vivo longitudinal (1)H MR spectroscopy study at 14.1 T with the aim to measure the neurochemical profile of Prnp -/- and PrPΔ32-121 mice in the hippocampus and cerebellum. Using high-field MR spectroscopy we were able to analyze in details the in vivo brain metabolites in Prnp -/- and PrPΔ32-121 mice. An increase of myo-inositol, glutamate and lactate concentrations with a decrease of N-acetylaspartate concentrations were observed providing additional information to the previous measurements.

Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice.

CFD Modelling of Direct Contact Condensation in Suppression Pools by Applying Condensation Models of Separated Flow

The condensation rate has to be high in the safety pressure suppression pool systems of Boiling Water Reactors (BWR) in order to fulfill their safety function. The phenomena due to such a high direct contact condensation (DCC) rate turn out to be very challenging to be analysed either with experiments or numerical simulations. In this thesis, the suppression pool experiments carried out in the POOLEX facility of Lappeenranta University of Technology were simulated. Two different condensation modes were modelled by using the 2-phase CFD codes NEPTUNE CFD and TransAT. The DCC models applied were the typical ones to be used for separated flows in channels, and their applicability to the rapidly condensing flow in the condensation pool context had not been tested earlier. A low Reynolds number case was the first to be simulated. The POOLEX experiment STB-31 was operated near the conditions between the ’quasi-steady oscillatory interface condensation’ mode and the ’condensation within the blowdown pipe’ mode. The condensation models of Lakehal et al. and Coste & Lavi´eville predicted the condensation rate quite accurately, while the other tested ones overestimated it. It was possible to get the direct phase change solution to settle near to the measured values, but a very high resolution of calculation grid was needed. Secondly, a high Reynolds number case corresponding to the ’chugging’ mode was simulated. The POOLEX experiment STB-28 was chosen, because various standard and highspeed video samples of bubbles were recorded during it. In order to extract numerical information from the video material, a pattern recognition procedure was programmed. The bubble size distributions and the frequencies of chugging were calculated with this procedure. With the statistical data of the bubble sizes and temporal data of the bubble/jet appearance, it was possible to compare the condensation rates between the experiment and the CFD simulations. In the chugging simulations, a spherically curvilinear calculation grid at the blowdown pipe exit improved the convergence and decreased the required cell count. The compressible flow solver with complete steam-tables was beneficial for the numerical success of the simulations. The Hughes-Duffey model and, to some extent, the Coste & Lavi´eville model produced realistic chugging behavior. The initial level of the steam/water interface was an important factor to determine the initiation of the chugging. If the interface was initialized with a water level high enough inside the blowdown pipe, the vigorous penetration of a water plug into the pool created a turbulent wake which invoked the chugging that was self-sustaining. A 3D simulation with a suitable DCC model produced qualitatively very realistic shapes of the chugging bubbles and jets. The comparative FFT analysis of the bubble size data and the pool bottom pressure data gave useful information to distinguish the eigenmodes of chugging, bubbling, and pool structure oscillations.

Thermal comfort in reduced models of broilers' houses, under different types of roofing materials

The research was developed to evaluate the use of different types of roofing materials regularly used in poultry houses. Measurements of thermal comfort were made through the use of techniques such as the Black Globe and Humidity Index (BGHI), the Thermal Heat Load (THL) and Enthalpy (H). Conducted in the State University of Goiás, during the months of April and May, 2011, the experiment was composed of five different treatments: AC - Asbestos cement tiles, BA -Bamboo tiles, BAP - Bamboo tiles painted in white, FB -Vegetable fiber tiles and bitumen, FBP -Vegetable fiber tiles and bitumen painted in white. The experiment consisted in 15 repetitions, which were considered the different days of measurements taken. Throughout the studied period, the time of the day considered the least comfortable was the one observed at 2:00pm, and the coverage of vegetable fiber and bitumen showed the highest value of BGHI (84.1) when compared to other types of coverage, characterizing a situation of lower thermal comfort, and no difference was found for THL and H on treatments in the studied region.

Evaluation of roof slope and exposure with different roofing materials in reduced models of animal production facilities in spring and summer

The present study was conducted at the Department of Rural Engineering and the Department of Animal Morphology and Physiology of FCAV/Unesp, Jaboticabal, SP, Brazil. The objective was to verify the influence of roof slope, exposure and roofing material on the internal temperature of reduced models of animal production facilities. For the development of the research, 48 reduced and dissemble models with dimensions 1.00 × 1.00 × 0.50 m were used. The roof was shed-type, and the models faced to the North or South directions, with 24 models for each side of exposure. Ceramic, galvanized-steel and fibro tiles were used to build the roofs. Slopes varied between 20, 30, 40 and 50% for the ceramic tile and 10, 30, 40 and 50% for the other two. Inside the models, temperature readings were performed at every hour, for 12 months. The results were evaluated in a general linear model in a nested 3 × 4 × 2 factorial arrangement, in which the effects of roofing material and exposure were nested on the factor Slope. Means were compared by the Tukey test at 5% of probability. After analyzing the data, we observed that with the increase in the slope and exposure to the South, there was a drop in the internal temperature within the model at the geographic coordinates of Jaboticabal city (SP/Brazil).