In the human body, the main function of the healthy thyroid gland is the regulation of the metabolism and hormone production. Included in the thyroid are organized structured and uniformly shaped follicles ranging from 50-500 μm in diameter. Pathologies lead to morphological changes of these follicles, affecting the density and size, but can also lead to an absence. In this study optical coherence tomography (OCT) was used to examine pathological thyroid tissue by extracting structural information of the follicles from image segmentation. However, OCT images usually include a high amount of speckle noise which affects the segmentation outcome. Due to that, the OCT images need to be improved. The aim of this thesis was to investigate the appropriate filtering methods to enhance the images and thus improve the segmentation outcome. The images of pathological thyroid tissues with a size of 0:5-1 cm where scanned by a spectral domain OCT system (Telesto II, Thorlabs GmbH, Germany) using a center wavelength of 1300nm. The obtained 2D and 3D images were saved as .oct file as well as implemented and visualized in a MATLAB graphical user interface (GUI) for further processing. For image improvement, four filtering enhancement methods were applied to the 2D images such as the enhanced resolution imaging (ERI), adaptive Wiener filter, discrete wavelet transform (DWT) and multi-frame wavelet transform (WT). The processed images were further converted to grayscale and binary images for intensity-based segmentation. The output of all methods were compared and evaluated using signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), enhanced number of looks (ENL), edge profiles and outcome of the segmented images. It was demonstrated that the complex DWT (cDWT) with a higher threshold and the multi-frame WT using the haar wavelet showed enhanced results over the other filtering methods. The computed SNR could be increased up to 52% and the ENL value up to 4802%, applying the multi-frame WT, while the CNR could be increased up to 106% for cDWT. The lowest obtained gradient was equal to an intensity decrease of -61% and -68% for multi-frame WT and cDWT, respectively. The filtering method could increase the smoothness of the image while the edge sharpness could be kept. The segmentation could detect both small and large follicles. ERI did not show any improvement in the segmentation but could enhance the structural detail of the image. Larger neighbourhoods of the adaptive Wiener filter showed a highly blurred image and led to merged follicles in the image segmentation. The wavelet filters DWT and multi-frame WT gave most satisfying results since high and low frequencies were divided into subbands, where individual information on vertical, horizontal and diagonal edges was stored. Applied cDWT had an even higher amount of subbands, so that more information on signal and speckle noise could be specified. Due to this fact, it was possible to achieve a decreased noise level while edge sharpness where maintained. Using a multi-frame image an increased SNR was obtained, as the intensity information stayed constant over the individual frames while the noise information changed. Wavelet based filtering showed higher improved results in comparison to the adaptive Wiener filter or the ERI in the 2D domain. By applying filtering methods in higher dimensions such as 3D or even 4D, better results in noise reduction are expected. Improved settings for the individual filtering methods as well as enhancement in segmentation are part of the future work.

Oncogenes and tumor suppressor genes play a key role in cancer induction and progression. They directly or indirectly regulate critical metabolic pathways, phosphatidylinositol-3 kinase pathway being frequently activated pathway in cancer. The catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), p110α, is the most frequently mutated kinase in human cancer, E542K, E545K, and H1047R mutations being the most common. Expression of hepatic E545K and H1047R p110α mutants in vivo shows marked and rapid increase in hepatic lipid and glycogen accumulation in mice with developmental (chronic) liver-specific deletion of p110α, which was not seen in mice when wildtype p110α is overexpressed. To investigate the logical pathways that could explain the lipid accumulation in mutant expressing mice, RNA sequencing from wildtype, knockout and mutated mouse livers was performed. Read alignment and count quantification was done using the Rsubread package and the statistical analyses are performed using the DeSeq2 package. Differentially expressed genes were identified with adjusted p-value of 0.05. Gene ontology analysis was performed on the differentially expressed genes using clusterProfiler, an R package to identify several key pathways which were upregulated and downregulated among the different sample groups. Signaling pathways related to cell cycle processes were mainly upregulated in the mutated samples when compared with the wildtype as well as knockout samples while signaling pathways related to many metabolic processes seem to be downregulated in mutated samples, even though these mutants showed upregulated metabolism by accumulation of lipids and glycogen physiologically. To confirm the results of gene expression data the results have to be cross validated with the gold standard quantitative Real Time Polymerase Chain Reaction.

<p>Vevs-karakterisering med høyoppløsning MAS MR spektroskopi</p><p>Høyoppløsning MAS er en MR spektroskopisk metode som gir høyt oppløste spekter av faste materialer. I dette doktorgradsarbeidet har høyoppløsning MAS blitt anvendt på forskjellige typer humant vev. Det primære målet var å etablere en metode for å studere biokjemiske egenskaper i vevsprøver, med hovedvekt på vev fra brystkreftpasienter.</p><p>Prøvepreparering før MAS analyser er enkelt sammenlignet med ekstraksjon. Vi har funnet at oppløsningen i spektrene, og dermed den oppnåelige biokjemiske informasjonen, er tilsvarende som i spekter fra ekstrakter av vevsprøver. En viktig fordel i forhold til ekstraksjons-metoder er at vevsprøven som studeres kan bevares slik at den kan vurderes ved andre metoder etterpå. Organer er gjerne satt sammen av forskjellige typer celler og vev og en slik heterogenitet vil ha betydning for den biokjemiske profilen, siden celler av forskjellig type kan ha forskjellig metabolisme. En del av prosjektet gikk ut på å optimalisere MR eksperimentene med hensyn på biokjemisk informasjon samtidig som at vevsprøven ble bevart for en patologisk undersøkelse. Lav temperatur under analysene ble funnet å være viktig for en slik bevaring av vevet. Vi oppnådde høyt oppløste spekter og har langt på vei kartlagt den kjemiske sammensetningen av intakte vevsprøver. Den metabolske profilen i brystkreftprøver viste en sammenheng med vevs-sammensetning bestemt ved patologi.</p><p>MR spekter av biologisk materiale kan inneholde hundrevis av topper, og flere av disse kan henge sammen med sykdomsprosesser i vevet. Ved sammenligning av enkelt-topper mot kliniske funn kan man miste viktig informasjon i spektrene som er ikke er synlig for det blotte øyet. Multivariate analyser gjør det mulig å undersøke hele spektrene mot kliniske kjennetegn. I denne avhandlingen har prisipalkomponent-analyse blitt brukt til å korrelere MAS spektrene med pasientenes diagnoser og andre kliniske funn.</p><p>En studie av livmorhalskreft omfattet vevsprøver fra åtte pasienter med livmorhalskreft og åtte kontroller. Prinsipalkomponent-analyse av MAS spektrene ga to klare grupperinger av de ulike spektrene i samsvar med prøvetype. Den kjemiske profilen bestemt med MAS har en sammenheng med de makroskopiske forandringene i kreftvev fra livmorhals.</p><p>Hjerneautopsier fra pasienter med en sjelden neurodegenerativ sykdom som rammer barn (neuronal ceroid lipofuscinosis) ble undersøk på samme måte mot autopsier fra personer uten kjent sykdom i nervesystemet. To former av sykdommen var inkludert i studien som omfattet totalt 24 biopsier, og den formen som bryter ut tidligst lot seg skille fra de to andre gruppene. Vevsprøver fra denne gruppen inneholdt svært lite eller ikke påviselige mengder NAA, som syntetiseres og lagres i nevroner. Dette korrelerer med tap av nevroner som er observert hos slike pasienter.</p><p>Den største studien inkluderte vevsprøver fra svulst og ikke-infiltrert vev (n=18) fra 85 brystkreftpasienter. MAS spekter fra disse prøvene ble undersøkt med hensyn på absolutt konsentrasjon av bestemte metabolitter og ved PCA med hensyn på sammenheng med flere kliniske parametere, som pasientens diagnose, svulstens størrelse og lymfeknutestatus hos pasienten. Det ble funnet flere trender til sammenhenger mellom MAS spekter og kliniske parametere. Det mest lovende resultatet med hensyn på fremtidig klinisk verdi var en mulig korrelasjon med lymfeknutestatus hos pasientgruppen med den vanligste formene for brystkreft.</p> / Paper III is a preprint of an article published in NMR in Biomedicine. http://www.interscience.wiley.com

<p>A global mapping of early stage medical technology companies has been implemented. The companies have emerging products within neurology and have undergone an evaluation by clinicians concerning the ability to provide clinical value for Swedish health care. The evaluation process has been executed by discussion with neurologists and neurosurgeons in combination with a literature survey. To limit the evaluation process, areas of stroke, traumatic brain injury, Parkinson’s disease, multiple sclerosis and epilepsy were chosen.</p><p>Some companies turn up to develop more requested products than others. Medfield Diagnostics AB, with their microwave screening product could in the future address the need for fast, accurate and accessible diagnosis of stroke and head trauma. The NBS system from Nexstim Ltd. has potential to provide clinical value by the ability of the products TMS technology to navigate in the brain. Elminda Ltd. product built of an evidence based rehabilitation platform could enhance recovery of patients with neurological disorders on an individual basis. BrainsGate Ltd. product to deliver drugs over the blood brain barrier provides totally new treatment options and NeuroSonix Ltd. ultrasound based product could assist the surgeon and decrease damageable embolic debris. Neurolife non-invasive solutions innovative device, which non-invasively measured the intracranial pressure, would be a totally new way to monitor patients.</p><p>A symposium was organized and three top ranked companies with stroke care products were invited to present their technology for Swedish clinicians in Stockholm. Participating companies were Nexstim Ltd., Elminda Ltd. and Medfield Diagnostics AB, who were all well received and considered to have interesting technologies with ability to provide clinical value.</p>

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Vevs-karakterisering med høyoppløsning MAS MR spektroskopi Høyoppløsning MAS er en MR spektroskopisk metode som gir høyt oppløste spekter av faste materialer. I dette doktorgradsarbeidet har høyoppløsning MAS blitt anvendt på forskjellige typer humant vev. Det primære målet var å etablere en metode for å studere biokjemiske egenskaper i vevsprøver, med hovedvekt på vev fra brystkreftpasienter. Prøvepreparering før MAS analyser er enkelt sammenlignet med ekstraksjon. Vi har funnet at oppløsningen i spektrene, og dermed den oppnåelige biokjemiske informasjonen, er tilsvarende som i spekter fra ekstrakter av vevsprøver. En viktig fordel i forhold til ekstraksjons-metoder er at vevsprøven som studeres kan bevares slik at den kan vurderes ved andre metoder etterpå. Organer er gjerne satt sammen av forskjellige typer celler og vev og en slik heterogenitet vil ha betydning for den biokjemiske profilen, siden celler av forskjellig type kan ha forskjellig metabolisme. En del av prosjektet gikk ut på å optimalisere MR eksperimentene med hensyn på biokjemisk informasjon samtidig som at vevsprøven ble bevart for en patologisk undersøkelse. Lav temperatur under analysene ble funnet å være viktig for en slik bevaring av vevet. Vi oppnådde høyt oppløste spekter og har langt på vei kartlagt den kjemiske sammensetningen av intakte vevsprøver. Den metabolske profilen i brystkreftprøver viste en sammenheng med vevs-sammensetning bestemt ved patologi. MR spekter av biologisk materiale kan inneholde hundrevis av topper, og flere av disse kan henge sammen med sykdomsprosesser i vevet. Ved sammenligning av enkelt-topper mot kliniske funn kan man miste viktig informasjon i spektrene som er ikke er synlig for det blotte øyet. Multivariate analyser gjør det mulig å undersøke hele spektrene mot kliniske kjennetegn. I denne avhandlingen har prisipalkomponent-analyse blitt brukt til å korrelere MAS spektrene med pasientenes diagnoser og andre kliniske funn. En studie av livmorhalskreft omfattet vevsprøver fra åtte pasienter med livmorhalskreft og åtte kontroller. Prinsipalkomponent-analyse av MAS spektrene ga to klare grupperinger av de ulike spektrene i samsvar med prøvetype. Den kjemiske profilen bestemt med MAS har en sammenheng med de makroskopiske forandringene i kreftvev fra livmorhals. Hjerneautopsier fra pasienter med en sjelden neurodegenerativ sykdom som rammer barn (neuronal ceroid lipofuscinosis) ble undersøk på samme måte mot autopsier fra personer uten kjent sykdom i nervesystemet. To former av sykdommen var inkludert i studien som omfattet totalt 24 biopsier, og den formen som bryter ut tidligst lot seg skille fra de to andre gruppene. Vevsprøver fra denne gruppen inneholdt svært lite eller ikke påviselige mengder NAA, som syntetiseres og lagres i nevroner. Dette korrelerer med tap av nevroner som er observert hos slike pasienter. Den største studien inkluderte vevsprøver fra svulst og ikke-infiltrert vev (n=18) fra 85 brystkreftpasienter. MAS spekter fra disse prøvene ble undersøkt med hensyn på absolutt konsentrasjon av bestemte metabolitter og ved PCA med hensyn på sammenheng med flere kliniske parametere, som pasientens diagnose, svulstens størrelse og lymfeknutestatus hos pasienten. Det ble funnet flere trender til sammenhenger mellom MAS spekter og kliniske parametere. Det mest lovende resultatet med hensyn på fremtidig klinisk verdi var en mulig korrelasjon med lymfeknutestatus hos pasientgruppen med den vanligste formene for brystkreft. / Paper III is a preprint of an article published in NMR in Biomedicine. http://www.interscience.wiley.com

Cervical cancer is the second most common cancer in women worldwide. Persistent infection by an oncogenic type of human papillomavirus (HPV) is a necessary but not sufficient cause and there is also a genetic component. This thesis aims to identify host genetic risk factors for cervical cancer based on the hypothesis that susceptibility is affected by genetic variation in the immune response towards HPV infection. Paper I analyzed allergy in sons and cervical cancer in their mothers, and revealed an inverse association between cervical cancer and allergy across generations. Mothers of allergic sons have a lower incidence of cervical cancer, supporting the importance of immunogenetic factors. Paper II investigated the HPV type in 1079 women diagnosed 1965-1993. All women were from families with at least two affected. It appeared that HPV 16 was becoming less common with time. There was no evidence that related women were prone to infection by the same type, indicating that the immunogenetic factors act in a general, rather than an HPV type specific, manner. Paper III and IV analysed the association of candidate genes with susceptibility to cervical cancer in 1306 women with cervical cancer in situ and 288 unrelated controls. Paper III showed the association of variation in the two immune response genes chemokine receptor 2 (CCR-2) and interleukin 4 receptor (IL-4R) with cervical cancer. In paper IV variation at several loci in the MHC region was studied and the importance of the HLA class II locus DQB1 emphasized. This thesis work supports the contribution of genes of the immune system to cervical cancer susceptibility. The genetic risk factors so far identified account for only a part of the genetic susceptibility, which implies that other yet undiscovered variants of importance remain to be identified.

The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune response. The IRF5 gene has received considerable attention since it was shown to be associated with two autoimmune diseases; systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The aim of this thesis was to examine if IRF5 is associated with other autoimmune diseases and to investigate the role of the genetic variation of IRF5. In the first study a set of common polymorphisms in IRF5 were analyzed for their association with two subgroup of inflammatory bowel disease (IBD); Crohn´s diseases (CD) and ulcerative colitis (UC). A strong signal of association of IRF5 with IBD was found. The most strongly associated polymorphism is a 5 base pair (bp) insertion-deletion (indel) in the promoter region of the IRF5 gene. The association was detected within both UC and CD, and appeared to be stronger in UC. In the second study we investigated the association of IRF5 with multiple sclerosis (MS). A similar set of polymorphisms as in the IBD study were genotyped in a cohort of MS patients and controls. The same polymorphisms that were associated with IBD were also found to be associated with MS. In the third study, we performed a comprehensive investigation of the IRF5 gene to detect most of the polymorphisms in the gene, and to determine to what extent they account for the association signals obtained from the gene. IRF5 was sequenced and 34 new polymorphisms were identified. Twenty seven of these, and 20 previously known SNPs in IRF5 were genotyped in an SLE case-control cohort. We found that only two polymorphisms, the 5bp indel and a SNP downstream of IRF5, account for the association signal from all the remaining markers in the IRF5 gene, and that these two polymorphisms are independently associated with SLE. Interestingly, in our studies on IBD and MS, we only observed the signal from the 5bp indel polymorphism as a risk factor for IBDs. In the fourth study the two independent risk alleles in IRF5, were tested for their association with primary Sjögren´s syndrome (pSS). In this study we also included one SNP in the STAT4 gene, since STAT4 had recently been shown to be associated with SLE. Both risk factors in IRF5 and STAT4 were found to be associated with pSS. The regulation of expression of IRF5 was also investigated in the first three studies. We observed allele-specific differences in protein binding as well as increased binding of the transcription factor SP1 to the 5bp risk allele. We also detected increased expression of the IRF5 mRNA from a promoter containing the risk allele. Taken together, the results of our studies suggest a general function for IRF5 as a regulator of the autoimmune response, where the 5bp indel is associated with IBD, MS, SLE and pSS. The additionally polymorphisms, which account for the remaining association signal obtained with SLE and pSS, may contribute to the disease manifestations that are specific for rheumatic diseases. Our studies add to the evidence that there are genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

This thesis presents the non-invasive use of diffuse reflectance spectroscopy (DRS) to provide information about the biochemical composition of living tissue. During DRS measurements, the incident, visible light is partially absorbed by chromophores but also scattered in the tissue before being remitted. Human skin and heart, the main tissue objects in this thesis, are dependent on a sufficient inflow of oxygenized blood, and outflow of metabolic byproducts. This process could be monitored by DRS using the spectral fingerprints of the most important tissue chromophores, oxyhemoglobin and deoxyhemoglobin. The Beer-Lambert law was used to produce models for the DRS and has thus been a foundation for the analyses throughout this work. Decomposition into the different chromophores was performed using least square fitting and tabulated data for chromophore absorptivity. These techniques were used to study skin tissue erythema induced by a provocation of an applied heat load on EMLA-treated skin. The absorbance differences, attributed to changes in the hemoglobin concentrations, were examined and found to be related to, foremost, an increase in oxyhemoglobin. To estimate UV-induced border zones between provoked and nonprovoked tissue a modified Beer-Lambert model, approximating the scattering effects, was used. An increase of chromophore content of more than two standard deviations above mean indicated responsive tissue. The analysis revealed an edge with a rather diffuse border, contradictory to the irradiation pattern. Measuring in the operating theater, on the heart, it was necessary to calculate absolute chromophore values in order to assess the state of the myocardium. Therefore, a light transport model accounting for the optical properties, and a calibrated probe, was adopted and used. The absolute values and fractions of the chromophores could then be compared between sites and individuals, despite any difference of the optical properties in the tissue. A hyperspectral imaging system was developed to visualize the spatial distribution of chromophores related to UV-provocations. A modified Beer-Lambert approximation was used including the chromophores and a baseline as an approximate scattering effect. The increase in chromophore content was estimated and evaluated over 336 hours. In conclusion, advancing from a restricted Beer-Lambert model, into a model estimating the tissue optical properties, chromophore estimation algorithms have been refined progressively. This has allowed advancement from relative chromophore analysis to absolute values, enabling precise comparisons and good prediction of physiological conditions.