Анализ вероятностных моделей параметрических правил принятия решений функциональной диагностики

Рассмотрена задача статистического обоснования выбора вида математической модели измерительно-логических преобразований для процедуры функциональной диагностики с учетом ограниченности априорной информации о свойствах объекта диагностики. Построена и проанализирована информационная модель процедуры диагностики, которая учитывает требования плана диагностического эксперимента и вероятностные свойства математической модели этой процедуры.The problem of statistical justification of selecting the type of the mathematical model of measuring-logical transformations for the procedure of functional diagnostics taking into account limited aprioristic information on the properties of the object of diagnostics is considered. An information model of the procedure of diagnostics taking into account the requirements of the plan of diagnostics experiment and probabilistic properties of the mathematical model of this procedure is built and analyzed

Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma

Head and neck cancer is a common malignancy with approximately 600 000 new cases yearly. Disappointingly, the overall survival has not increased over the last decades. The concept of personalized medicine, i.e. to treat every patient with an individually planned treatment regime has gathered increased interest, but requires the establishment of novel biomarkers that can predict treatment response. The aim of this thesis is to propose novel predictive single markers or combinations of markers of response to radiation, cisplatin and cetuximab. The general methodology is to evaluate common differences of cell lines resistant to radiation, cisplatin or cetuximab compared to sensitive counterparts. In paper I, we analysed the expression of 14 proteins involved in growth control and/or apoptosis by western blot and related them to intrinsic radiosensitivity (IR) in nine cell lines. No factor had a significant correlation to IR on its own. A combination of EGFR, survivin, Bak, Smad4, and Hsp70 had the best correlation to IR (R=0.886, p=0.001). Additionally, we analysed the presence of p53 mutations in the cell lines. All cell lines had at least one missense, splice site or loss of transcript mutation. To be able to combine protein expression and presence of p53 mutations we created a system designated the number of negative points (NNP). With this system we could extract that expression of EGFR, survivin, and p53 missense or splice site mutations had the best correlation to IR (R=0.990, p<0.001). In paper II we conducted a gene expression microarray analysis of three cell lines, from which common deregulations in two cisplatin resistant cell lines was compared to a cisplatin sensitive cell line. From a bioinformatic approach of gene ontology and molecular network analysis, we defined a transcriptional profile of 20 genes. Finally, key findings were analysed in a larger panel of cell lines, where high MMP-7 expression correlated with higher cisplatin resistance. Paper III compared 4 cell lines with high IR to a radiosensitive equivalent. Using a similar bioinformatic approach as paper II, we established a transcriptional profile of 14 genes. Analysis in a larger panel of cell lines revealed that FN1 expression predicts higher IR. Paper IV establishes the cetuximab sensitivity of 35 cell lines of which 12 were resistant and five were sensitive to cetuximab. After whole genome gene copy number analysis of five cetuximab resistant and five cetuximab sensitive cell lines, and verification of key findings in a larger cell line panel, the results show that the amplification of the YAP1 gene is coupled to cetuximab resistance. In summary, this thesis proposes a number of novel markers of resistance to radiation, cisplatin, and cetuximab which could influence treatment choice in the future, following verifications in primary tumor material

On Predictive Factors of Treatment Response in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and yearly include 500 000 new cases worldwide. The outcomes for these patients have not been significantly improved over the last decades and the five year survival is still around 50 %. Establishing predictive markers of treatment response will have great impact on the clinical management of this disease. The aim of this thesis was to elucidate markers of intrinsic response to radiotherapy and cisplatin. Combining expression patterns of 14 proteins and identifying mutations in the p53 gene, we were able to incorporate both protein and genetic changes to create a predictive model termed Number of Negative Points (NNP). We used the NNP model to statistically calculate the combination of factors that had the best correlation to intrinsic radiosensitivity (IR). We established that a panel of three markers, epidermal growth factor receptor (EGFR), survivin and splice site/missence mutations of p53, had the best correlation to IR (R=0.990, p<0.0001). We also conducted gene expression analysis to investigate what genes and gene ontologies that are different between cell lines with varying IR. Furthermore, we wanted to identify key regulator genes with central positions of molecular networks, which were generated from the transcripts included in the deregulated gene ontologies. A transcriptional profile of 28 key regulator genes was generated. Immunoblot analysis supported deregulation at the protein level of three markers implicated from the transcriptional profile. We propose that these proteins, notch1, thrombospondin 1, and pai‐1 are predictive markers of IR. Finally, on a subset of cell lines with sensitivity or resistance to cisplatin, we performed gene expression analysis. Markers of intrinsic cisplatin sensitivity (ICS) such as gene ontologies and key regulators of molecular networks were proposed and five genes, APOE, CTNNB1, MMP7, MMP13, and THBS1 were selected for further analysis. Quantitative polymerase chain reaction (qPCR) analysis of these genes in 25 cell lines established that MMP7 (p=0.0013) and MMP13 (p=0.058) are possible predictive markers of ICS. The markers of IR and ICS presented here could, if confirmed in a clinical setting, guide clinicians in the choice of treatment and thus give a more individualized and effective therapy for patients with HNSCC

Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma

Head and neck cancer is a common malignancy with approximately 600 000 new cases yearly. Disappointingly, the overall survival has not increased over the last decades. The concept of personalized medicine, i.e. to treat every patient with an individually planned treatment regime has gathered increased interest, but requires the establishment of novel biomarkers that can predict treatment response. The aim of this thesis is to propose novel predictive single markers or combinations of markers of response to radiation, cisplatin and cetuximab. The general methodology is to evaluate common differences of cell lines resistant to radiation, cisplatin or cetuximab compared to sensitive counterparts. In paper I, we analysed the expression of 14 proteins involved in growth control and/or apoptosis by western blot and related them to intrinsic radiosensitivity (IR) in nine cell lines. No factor had a significant correlation to IR on its own. A combination of EGFR, survivin, Bak, Smad4, and Hsp70 had the best correlation to IR (R=0.886, p=0.001). Additionally, we analysed the presence of p53 mutations in the cell lines. All cell lines had at least one missense, splice site or loss of transcript mutation. To be able to combine protein expression and presence of p53 mutations we created a system designated the number of negative points (NNP). With this system we could extract that expression of EGFR, survivin, and p53 missense or splice site mutations had the best correlation to IR (R=0.990, p<0.001). In paper II we conducted a gene expression microarray analysis of three cell lines, from which common deregulations in two cisplatin resistant cell lines was compared to a cisplatin sensitive cell line. From a bioinformatic approach of gene ontology and molecular network analysis, we defined a transcriptional profile of 20 genes. Finally, key findings were analysed in a larger panel of cell lines, where high MMP-7 expression correlated with higher cisplatin resistance. Paper III compared 4 cell lines with high IR to a radiosensitive equivalent. Using a similar bioinformatic approach as paper II, we established a transcriptional profile of 14 genes. Analysis in a larger panel of cell lines revealed that FN1 expression predicts higher IR. Paper IV establishes the cetuximab sensitivity of 35 cell lines of which 12 were resistant and five were sensitive to cetuximab. After whole genome gene copy number analysis of five cetuximab resistant and five cetuximab sensitive cell lines, and verification of key findings in a larger cell line panel, the results show that the amplification of the YAP1 gene is coupled to cetuximab resistance. In summary, this thesis proposes a number of novel markers of resistance to radiation, cisplatin, and cetuximab which could influence treatment choice in the future, following verifications in primary tumor material

Kognitiva hjälpmedel i särskolan : - en kvalitativ intervjustudie ur specialpedagogers synvinkel

I vårt examensarbete har vi undersökt hur specialpedagoger betraktar kognitiva hjälpmedel samt hur dessa används och i vilken utsträckning. Studien är baserad på kvalitativa semistrukturerade intervjuer. Intervjuerna gjordes med tio specialpedagoger från tre olika särskolor. Svaren resulterade i fem huvudkategorier vilka sedan analyserades. Resultaten visar en positiv inställning till kognitiva hjälpmedel. Erfarenheter och behoven av kognitiva hjälpmedel styr användningen och utsträckningen av dessa. Slutsatsen visar att det finns många fördelar med kognitiva hjälpmedel och att även grundskolan kan ha användning av dessa i undervisningen

Studiemotivation ur ett elevperspektiv : - En intervjustudie med grundskoleelever i läs- och skrivsvårigheter/dyslexi

Studiens syfte är att, utifrån ett elevperspektiv, nå fördjupad kunskap och ökad förståelse om studiemotivation hos elever i läs- och skrivsvårigheter/dyslexi. I denna studie är motivation det centrala med fokus på elevers studiemotivation. Elevers motivation till det egna skolarbetet kan vara högst varierande. I studien ställs även motivation i relation till elever i läs- och skrivsvårigheter/dyslexi. I dag finns begränsad forskning utifrån ett elevperspektiv och vi eftersträvar med denna studie att kunna bidra med ytterligare kunskap om hur elever beskriver motivation som en del i det egna lärandet. Genom semistrukturerade intervjuer fick åtta stycken mellanstadieelever i läs- och skrivsvårigheter eller dyslexi, möjlighet att berätta om sina egna erfarenheter och upplevelser av sin undervisning och lärmiljö. Studiens resultat visar att flera faktorer påverkar elevernas studiemotivation, vilka framförallt kan kopplas till lärarens roll och undervisningens utformning. Resultatet visar också att relationer, både mellan lärare och elev men också elever emellan, påverkar studiemotivation positivt och negativt. Det förekommer olika drivkrafter som eleverna använder sig av för att motiveras i skolarbetet, drivkrafterna visar sig genom prestationsmål och lärandemål. Studiens slutsats är att lärmiljön i allra högsta grad påverkar elevernas studiemotivation. Till stor del påverkas studiemotivationen av undervisningens utformning, vilket innebär att läraren får en betydande roll

Gas flow observer for a Scania Diesel Engine with VGT and EGR

Today’s diesel engines are complex with systems like VGT and EGR to be able to fulfil the stricter emission legislations and the demands on the fuel consumption. Controlling a system like this demands a sophisticated control system. Furthermore, the authorities demand on self diagnosis requires an equal sophisticated diagnosis system. These systems require good knowledge about the signals present in the system and how they affect each other. One way to achieve this is to have a good model of the system and based on this calculate an observer. The observer is then used to estimate signals used for control and diagnosis. Advantages with an observer instead of using just sensors are that the sensor signals often are noisy and need to be filtered before they can be used. This causes time delay which further complicates the control and diagnosis systems. Other advantages are that sensors are expensive and that some engine quantities are hard to measure. In this Master’s thesis a model of a Scania diesel engine is developed and an observer is calculated. Due to the non-linearities in the model the observer is based on a constant gain extended Kalman filter

Att vara eller inte vara - en hälsocoach : En kvalitativ studie om hur yrkesrollen som hälsocoach bidrar till att forma den personliga identiteten och förhållningssättet till hälsa

Syfte: Syftet med studien var att undersöka hur lärandet av yrkesrollen som hälsocoach bidrar till att forma den personliga identiteten. Syftet var även att undersöka hur denna lärprocess skulle kunna påverka hälsocoachernas individuella hälsa, genom beskrivningar av deras personliga förhållningssätt till hälsa. Metod: Föreliggande studie har haft en kvalitativ metodansats där datainsamlingen har skett genom sex semistrukturerade intervjuer med yrkesverksamma hälsocoacher. Studien hade en hermeneutisk epistemologisk ansats, och utgick vidare från ett abduktivt arbetssätt. Det empiriska materialet sammanställdes till olika teman och analyserades sedan utifrån det teoretiska ramverket. Resultat: Resultatet visade att deltagarna identifierar sig med yrkesrollen som hälsocoach, och att det kan vara svårt att bortse från rollen som hälsocoach även i privata sammanhang. Genom sociala interaktioner med kunder och kollegor har hälsocoacherna lärt sig vad yrket kräver och har utvecklats i sin yrkesroll genom att anamma särskilda egenskaper och färdigheter som anses viktiga för yrkesrollen. Genom att utvecklas i yrkesrollen som hälsocoach har intervjupersonerna fått ökad kunskap inom hälsoområdet och vidare fått en mer balanserad syn på hälsa. Hälsocoacherna anser att det finns yttre förväntningar på hur de bör vara och agera, men upplever inga negativa konsekvenser av detta. Slutsats: Lärprocessen som sker inom yrkesrollen har format hälsocoacherna på så sätt att särskilda egenskaper utvecklats och yrkesrollen har blivit en stor del av den personliga identiteten. Den ökade kunskapen och utvecklingen i yrkesrollen har bidragit till att hälsocoacherna har förändrat sitt sätt att tolka, tillämpa och förstå hälsoinformation. Detta har i sin tur resulterat i ett mer balanserat förhållningssätt till hälsa, vilket i sin tur kan ha positiva hälsoeffekter.Aim: The purpose of this study was to examine how the learning of the professional role as health coach contributes to shape the personal identity. The aim was also to investigate how this learning process could affect the health coaches' individual well-being, through their descriptions of personal approach to health. Method: The present study had a qualitative methodological approach, where data collection occurred through six semi-structured interviews with professional health coaches. The empirical data were compiled into themes and then analyzed through the theoretical framework. Results: The results shows that learning, in terms of interactions with customers and colleagues, and the adoption of particular characteristics and skills, may influence the personal identity of health coaches. Through learning, the individuals identified themselves, even in private settings, with the professional role. Due to learning, the health coaches have a more balanced approach to diet, exercise, and individual health. Conclusion: The learning process that takes place within the professional role has shaped the health coaches in such ways that special characteristics has developed and the professional role has become a big part of their personal identity. Furthermore, the results also shows that learning may influence the way of interpreting, applying, and understanding health information. Even their personal approach to health has changed for more balanced, which in turn may have positive health effects

Levels of serum fibronectin as a biomarker in gastric cancer patients: Correlation with clinical diagnosis and outcome

Fibronectin is an important component of the extracellular matrix and serves a role in the pathogenesis of multiple malignancies. The expression of fibronectin also affects the outcome for patients with cancer. The objective of the present study was to determine the clinical significance of the serum fibronectin levels in patients with gastric cancer. A total of 63 patients with a pathologically confirmed diagnosis of gastric cancer were enrolled into the present study. Serum fibronectin concentrations were determined by the solid-phase sandwich enzyme-linked immunosorbent assay method. Age and sex matched healthy controls (n=30) were included in the analysis. The median age at diagnosis was 62 years (range 28–82 years). The baseline serum fibronectin levels of the patients with gastric cancer were significantly higher compared with those in the control group (median values, 606, vs. 193 ng/ml; P<0.001). The known clinical variables, including the age of the patient, gender, site of lesion, histology, histological grade, stage of disease and serum tumor markers, including lactate dehydrogenase, carcinoembryonic antigen and cancer antigen 19.9, were not found to be correlated with serum fibronectin concentrations (P>0.05). In addition, no correlation was observed in serum fibronectin level and response to chemotherapy (P=0.12). Serum fibronectin concentration demonstrated no prognostic role on survival (P=0.43). In conclusion, the serum levels of fibronectin may have a good diagnostic marker in patients with gastric cancer. However, its predictive and prognostic values remain to be elucidated

Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system

Abstract Background Amyloid beta peptide (Aβ) is the main component of extraneuronal senile plaques typical of Alzheimer’s disease (AD) brains. Although Aβ is produced by normal neurons, it is shown to accumulate in large amounts within neuronal lysosomes in AD. We have recently shown that under normal conditions the majority of Aβ is localized extralysosomally, while oxidative stress significantly increases intralysosomal Aβ content through activation of macroautophagy. It is also suggested that impaired Aβ secretion and resulting intraneuronal increase of Aβ can contribute to AD pathology. However, it is not clear how Aβ is distributed inside normal neurons, and how this distribution is effected when Aβ secretion is inhibited. Methods Using retinoic acid differentiated neuroblastoma cells and neonatal rat cortical neurons, we studied intracellular distribution of Aβ by double immunofluorescence microscopy for Aβ40 or Aβ42 and different organelle markers. In addition, we analysed the effect of tetanus toxin-induced exocytosis inhibition on the intracellular distribution of Aβ. Results Under normal conditions, Aβ was found in the small cytoplasmic granules in both neurites and perikarya. Only minor portion of Aβ was colocalized with trans-Golgi network, Golgi-derived vesicles, early and late endosomes, lysosomes, and synaptic vesicles, while the majority of Aβ granules were not colocalized with any of these structures. Furthermore, treatment of cells with tetanus toxin significantly increased the amount of intracellular Aβ in both perikarya and neurites. Finally, we found that tetanus toxin increased the levels of intralysosomal Aβ although the majority of Aβ still remained extralysosomally. Conclusion Our results indicate that most Aβ is not localized to Golgi-related structures, endosomes, lysosomes secretory vesicles or other organelles, while the suppression of Aβ secretion increases intracellular intra- and extralysosomal Aβ.</p