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Coming dissertations at Uppsala university

  • Characterizing the spectrum of somatic alterations in canine and human cancers Author: Sharadha Sakthikumar Link: Publication date: 2020-01-30 12:35

    Cancers arise as a result of deleterious somatic alterations accumulating in the genome during the process of cell division. These alterations arise either via exposure to mutagens or due to errors occurring during DNA replication. In this thesis, a systematic exploration, from discovery to analyses of somatic alterations in three diverse cancers that affect dogs and humans, was undertaken.

    In Studies I and II, whole-exome sequencing of dogs affected by the cancers of osteosarcoma and hemangiosarcoma were done to delineate coding mutations that can contribute to their carcinogenesis. Besides, as these cancers mirror the corresponding human disease in clinical manifestation and histological features, a secondary objective was to confirm the molecular drivers found in the canines were also influencing factors in the human cancer(s).

    In the osteosarcoma investigations with three breeds, we found that tumors show a high frequency of somatic copy-number alterations, affecting key cancer genes. TP53 was the most frequently altered gene, akin to human osteosarcoma. The second most mutated gene, histone methyltransferase SETD2, has known epigenetic roles in multiple cancers but not in osteosarcoma. Our study highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine disease may serve as an excellent model for developing treatment strategies in both species.

    In the hemangiosarcoma study in golden retrievers, putative driver alterations were identified in the tumor suppressor TP53 and in genes involved in the cell cycle regulating PI3K pathway, including PIK3CA and PIK3R1. Furthermore, we find several somatic alterations between the dog hemangiosarcoma and human angiosarcoma overlap, indicating we can use the canine model to apprise the infrequently occurring human disease.

    In Study III, we implemented whole-genome sequencing methodologies to define both coding and non-coding alterations in the glioblastoma cancer genome. We find the coding somatic alterations recapitulate what has been previously seen for the cancer, including driver alterations in the genes of EGFR, PTEN, and TP53. Significantly though, using the concept of evolutionary constraint, we find an enrichment of non-coding mutations in regulatory regions, around GBM-implicated genes. The mutated regions include splice sites, promoters, and transcription factor binding sites, suggesting the importance of regulatory mutations for the pathogenesis of glioblastoma.

    Overall, the insights garnered from the above exome- and genome-wide surveys provide novel insights into unraveling some of the complexities associated with somatic genomic alterations in cancer genomes. It also convincingly underscores the benefits of using sequencing technologies to comprehend complex biological diseases.

  • Tissue Factor regulation, signaling and functions beyond coagulation with a focus on diabetes Author: Desirée Edén Link: Publication date: 2020-01-30 09:49

    Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein best known for initiating the coagulation cascade upon binding of its ligand FVIIa. Apart from its physiological role in coagulation, TF and TF/FVIIa signaling has proved to be involved in diseases such as diabetes, cancer and cardiovascular diseases. Biological functions coupled to TF/FVIIa signaling include diet-induced obesity, apoptosis, angiogenesis and migration.

    Aim: The aim of this thesis was to investigate the role of TF/FVIIa in cells of importance in diabetes, to further investigate the mechanism behind TF/FVIIa anti-apoptotic signaling in cancer cells and lastly to examine the regulation of TF expression in monocytes by micro RNAs (miRNA).

    Results: In paper I we found that TF/FVIIa signaling augments cytokine-induced beta cell death and impairs glucose stimulated insulin secretion from human pancreatic islets. In paper II the relevance of TF/FVIIa in isolated human primary adipocytes was investigated. Adipocytes are a target cell for insulin and diabetics typically have increased lipolysis and impaired glucose uptake. No evidence was found for a role of TF/FVIIa in lipolysis or glucose uptake in adipocytes. However, adipocytes were found to express TF and FVII. The FVII produced was sufficient to initiate coagulation in the adipocytes. In paper III an anti-apoptotic TF/FVIIa induced signaling pathway in prostate and breast cancer cells was investigated in depth. Previous research has shown that TF/FVIIa signaling results in transactivation of insulin-like growth factor 1 receptor (IGF-1R) leading to subsequent protection from apoptosis induced by TNF-related apoptosis inducing ligand (TRAIL). The current results propose a mechanism where IGF-1R transactivation by TF/FVIIa is dependent on integrin β1 (ITGβ1) signaling. TF/FVIIa/ ITGβ1 signaling was found to result in phosphorylation of src and subsequent phosphorylation of caveolin 1 (Cav1). Once phosphorylated, the inhibitory effect of Cav1 on IGF-1R is cancelled, resulting in IGF-1R activation. In paper IV the role of miRNA regulation of TF expression in monocytic cells was investigated. The miRNA miR-223-3p was identified to be differentially expressed in U937 cells undergoing differentiation to a more monocyte-like phenotype and an anti-parallel correlation between TF and miR-223-3p expression in monocytes was proved. Hence, miR-223-3p regulates the inducible expression of TF in monocytes.

    Conclusions: The work in this thesis furthers the knowledge of molecular mechanisms behind TF regulation and TF/FVIIa signaling and some functional consequences as well as their biological relevance in diabetes. 

  • Guiding Concepts : Essays on Normative Concepts, Knowledge, and Deliberation Author: Olle Risberg Link: Publication date: 2020-01-29 12:35

    This thesis addresses a range of questions about normativity, broadly understood. Recurring themes include (i) the idea of normative ‘action-guidance’, and the connection between normativity and motivational states, (ii) the possibility of normative knowledge and its role in deliberation, and (iii) the question of whether (and if so, how) normative concepts can themselves be evaluated.

    The first two papers, ‘The Entanglement Problem and Idealization in Moral Philosophy’ and ‘Weighting Surprise Parties: Some Problems for Schroeder’, critically examine various versions of the view that what we ought to do depends on some (actual or hypothetical) motivational states, such as desires. It is suggested that such views are, for different but interrelated reasons, extensionally inadequate.

    The third paper, ‘From Evolutionary Theory to Moral Skepticism, via Disagreement’ (co- authored with Folke Tersman), proposes that two arguments for moral skepticism can be combined in a mutually supportive way. A central role is played by the principle that a subject S knows that p only if S adherently believes that p, where this roughly means that S could not easily have failed to believe that p unless her epistemic position were worse or p were false. It is suggested that evolutionary considerations and facts about moral disagreement together indicate that moral beliefs violate this principle.

    The fourth paper, ‘Ethics and the Question of What to Do’, offers an account of the so- called ‘central deliberative question’ that is highlighted by several kinds of choice situations, including those that involve normative uncertainty and normative conflicts. It is proposed that this question is not best understood as the question of what one ought to do, not even in an ‘all things considered’ sense, but as the question of what to do. A meta-normative view that involves elements of both cognitivism and non-cognitivism is put forward as the best explanation of this fact.

    The fifth paper, ‘Meta-Skepticism’, develops a novel skeptical challenge to beliefs about the external world, the central idea being that even if beliefs about the external world can constitute knowledge, there are various other knowledge-like concepts that they cannot satisfy even if they are true. This raises the question of whether some of these concepts are epistemically more important than the others, and, in particular, the further question of how the relevant notion of ‘epistemic importance’ should be understood. Several answers to this question are considered and found wanting.