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Coming dissertations at MedFak

  • Functional communication and non-linguistic factors in severe aphasia : Associations and assessment Author: Camilla Olsson Link: Publication date: 2021-10-01 09:35

    Severe post-stroke aphasia implies impairment of the ability to speak and write, and impairments of language comprehension, severely restricting the communication of the individual. Intervention in severe aphasia often entails aiming for access to meaningful social interaction and participation, in spite of the linguistic impairments. This demands knowledge about the non-linguistic factors that influence the communication of people with severe aphasia (PWSA). Assessment in PWSA is a challenge due to the linguistic impairments, thus the issue of measurement is intertwined with the study of non-linguistic factors in PWSA.

    The overall aim of this thesis was to explore the relationship between functional communication, language and three non-linguistic factors; executive function, self-efficacy, and resilience, in PWSA. An additional aim was to investigate the assessment of these non-linguistic factors in PWSA.

    Studies I and IV were quantitative studies investigating the relations of functional communication and language to executive function (study I), and to self-efficacy and resilience (study IV). In study II, two methods for measuring executive functions were compared; standardised neuropsychological screening and informant reports. Study III was a qualitative study exploring the informants’ understanding of the questionnaire used for informant reports in study II.

    The results demonstrated that there is large variation in executive function and functional communication in PWSA, especially in the nonverbal subgroup. In this subgroup, there is an association between executive functions and functional communication. It is important that PWSA are given thorough evaluation of their abilities, and that the impact of executive dysfunction is considered in communication intervention.

    Focusing on assessment of executive functions in PWSA, results of study II and III demonstrated that informant reports of executive function do not measure the same construct as, and cannot be used as a substitute for, standardised neuropsychological tests. The quantitative results of informant reports should be interpreted with caution, since it is uncertain whether the responses represent executive functions. The use of informant reports does not solve the problem of aphasia being a confounding factor in assessment of executive function.

    Study IV indicated that assessment of self-efficacy and resilience is, with proper adaptation, possible in a majority of PWSA. PWSA seem to have decreased self-efficacy and self-rated resilience compared to general populations. No clear associations with severity of language impairment or functional communication were found, but this issue needs further exploration. 

  • Tumor-stroma interactions in hepatocellular carcinoma Author: Nataša Pavlović Link: Publication date: 2021-09-28 11:52

    Hepatocellular carcinoma (HCC), a highly deadly primary liver cancer with a rising global incidence and limited therapeutic options, is characterized by a vicious cross-talk between the tumor and its surrounding hepatic stroma. The stromal environment, consisting of hepatic stellate cells (HSC), endothelial cells, resident and infiltrating macrophages and other immune cells, platelets and extracellular matrix (ECM) components, actively contributes to creating an ideal niche for tumor proliferation and invasiveness. For instance, by secreting copious amounts of growth factors and ECM proteins, activated HSC directly stimulate tumor proliferation and promote fibrosis, neo-angiogenesis, inflammation and immunosuppression. In turn, tumor cell-derived factors induce the activated HSC phenotype, while also shaping other stromal components to benefit carcinogenesis. Infiltrating platelets are also known to have detrimental effects within a tumor microenvironment, and have been widely linked to stellate cell activation, inflammation and tumorigenesis in HCC. Another important hallmark of HCC development is endoplasmic reticulum (ER)-stress, a condition during which misfolded and unfolded proteins accumulate in the ER lumen and trigger a cellular survival strategy known as the unfolded protein response (UPR). Key mediators of the UPR have been shown to promote different facets of HCC progression, including tumor cell survival, fibrosis and inflammation. In the present studies, a chemically induced HCC mouse model, along with several 2D and 3D in vitro approaches, was used to study the role of tumor-stroma interactions in HCC development in order to identify new potential therapeutic targets that could benefit patients with liver cancer. It was thereby found that activated platelets promote disease progression by stimulating tumor growth, fibrosis and by altering the hepatic immune response. Additionally, the IRE1α-mediated UPR signaling branch was shown to play a key role in promoting hepatocarcinogenesis, fibrosis and in fueling the vicious cross-talk between stellate cells and tumor cells. Therefore, as stromal biology plays a key role in potentiating HCC progression, the malicious tumor-stroma interactions that shape the hepatic microenvironment also offer potential therapeutic targets for the treatment of liver cancer, thereby encouraging further research in the field.

  • Role of TGFβ-induced hyaluronan-CD44 signaling in cancer progression Author: Constantinos Kolliopoulos Link: Publication date: 2021-09-27 09:55

    Hyaluronan, a prevalent glycosaminoglycan of the extracellular space often accumulates in pathological conditions, such as chronic inflammation, infection, and cancer. Hyaluronan synthase HAS2 has been responsible for the synthesis and deposition of hyaluronan in a variety of tumors. We have shown that HAS2 was required for efficient transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition (EMT), a developmental program which is commandeered by cancer cells to increase their migratory and invasive capacity. In study I, our findings show that long non-coding RNA Has2as has a key role in TGFβ- and Has2-induced breast cancer EMT, migration and acquisition of stemness.

    Hyaluronan conveys its signaling properties via binding to its cell surface receptor CD44, a well-established stem cell marker in a plethora of tumors. CD44 exerts its signaling properties by interacting with components of the actin cytoskeleton machinery, and by acting as a co-receptor for other receptor tyrosine or threonine kinases impacting their signaling properties. Furthermore, CD44 is subjected to proteolytic cleavage, which eventually liberates the cytoplasmic tail (CD44-ICD). CD44-ICD translocates to the nucleus and alters gene expression. In study II, our findings support that TRAF4/6 mediates pro-tumorigenic effects of CD44, and suggests that inhibitors of CD44 signaling via TRAF4/6 and RAC1 may be beneficial in the treatment of tumor patients.

    Glioblastoma (GBM) multiforme remains one of the most aggressive and lethal types of brain tumors worldwide with a poor prognosis. In study III, we have initiated studies to elucidate the CD44-dependent molecular mechanisms in GBM progression by knocking out (KO) CD44 by employing CRISPR/Cas9 gene editing in glioma U251MG cells.

    Aberrant hyaluronan levels are also found during infectious diseases. In study V, we show that in a cohort study of dengue patients, high levels of circulating Dengue Nonstructural Protein 1 (NS1) correlate with high levels of serum hyaluronan. Moreover, we propose that hyaluronan can serve as a prognostic marker for the onset of warning signs during the course of dengue viral infection. Mechanistically, NS1 treatment-induced hyaluronan production contributing to increased vascular permeability.

    In study IV, we have identified a bifurcating loop during TGFβ signaling, whereby transcriptional induction of NUAK1 serves as a negative checkpoint and NUAK2 induction positively contributes to signaling and terminal differentiation responses to TGFβ activity.

    In summary, the current thesis provides mechanistic insights into the roles of TGFβ-induced hyaluronan-CD44 interactions in cancer progression.