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Coming theses from other universities

  • Searching for Synergy : Radiosensitization of 177Lu-DOTATATE Author: Sara Lundsten Link: Publication date: 2022-01-10 09:20

    Cancers presents a major health challenge, and there is a pressing need to develop new therapeutic strategies. Surgery, chemotherapy and radiation are the most commonly used treatments for cancer today. Radiation can be given as targeted radionuclide therapy (TRT), i.e., systemic administration of a radiolabeled cancer-targeting molecule. This is especially suitable for inoperable and disseminated tumors.

    177Lu-DOTATATE, a TRT directed against the somatostatin receptors (SSTRs), was recently approved for therapy of a subset of neuroendocrine tumors (NETs). Although it has prolonged the life of NET patients, complete remission is seldom achieved. Consequently, to increase the efficacy of the treatment, this thesis aimed to assess potential radiosensitizing strategies for 177Lu-DOTATATE. The two radiosensitization targets in focus were HSP90, a chaperone protein with numerous oncogenic client proteins, and p53, a central regulator of DNA damage.

    In papers I and II, we investigated the HSP90-inhibitor Onalespib, as a treatment for NETs, and as a potential radiosensitizer. The drugs were assessed in vitro and in vivo. We concluded that Onalespib reduced NET cell growth and acted synergistically with 177Lu-DOTATATE. Inhibition of EGFR, a HSP90 client protein, was suggested as a mediator of the observed synergy. Furthermore, the combination had a favorable toxicity profile. 

    In paper III, we assessed the novel stapled peptide VIP116, which inhibits the p53 repressors MDM2 and MDM4, as a potentiator of 177Lu-DOTATATE in wildtype p53 neuroblastoma cells. Combination therapy exhibited growth-inhibitory effects, with resulting additive or synergistic effects. The treatment-mediated effects on p53 signaling were characterized, revealing a possible involvement of V-myc myelocytomatosis viral oncogene homolog, neuroblastoma derived (MYCN), a prognostic marker for poor survival in neuroblastoma.

    In paper IV, we aimed to improve targeted delivery of VIP116, with the use of lipid bilayer disks (lipodisks). VIP116 was successfully loaded onto epidermal growth factor receptor (EGFR)-targeting lipodisks, leading to specific delivery and reduction of viability of EGFR expressing tumor cells. The study provided a proof-of-concept for utilizing lipodisks as a drug delivery system for p53-stabilizing peptides.

    In conclusion, we have investigated, and found, suitable candidates for potentiating 177Lu-DOTATATE therapy. We have addressed the feasibility of the treatments, toxicity and targeted delivery. Moreover, the work has explored the biology of TRT. This is an area in need of more attention, as more and more radionuclide-based therapies are entering clinicals trials and reaching approval.

  • On the structure and mechanical properties of in vitro salivary pellicles Author: Hannah Boyd Link: Publication date: 2022-01-10 07:53

    Salivary pellicles display exceptional hydration and lubrication performance. At present, there are still gaps in the understanding of how this is achieved. The aim of this thesis was therefore to increase our knowledge on the mechanisms underlying these properties and deepen the understanding of how they are related to the composition and structure of pellicles, with a focus on those formed under in vitro conditions. This has applications ranging from the development of artificial saliva and lubricating coatings for biomedical applications to methodological approaches for initial testing of oral healthcare products. For this, we also focused on developing suitable methodological approaches for these studies, centering on atomic force microscopy, quartz crystal microbalance with dissipation monitoring, ellipsometry and neutron reflectometry techniques, to investigate in vitro and model salivary pellicles.

    First, we confirmed a two-layer structure for in vitro salivary pellicles and showed that the outer layer is mainly composed by the oral mucin MUC5B, but that it also contains other salivary components that enhance swelling and hydration. In the presence of bulk saliva, the outer layer also contains a reversibly and loosely bound fraction. This fraction increases the adhesiveness of the pellicle but unexpectedly has no significant effect on its lubrication performance. We also investigated the effect of mechanical confinement on model salivary pellicles by means of Neutron Reflectometry, revealing that at a pressure of 1 bar they are already completely compressed and dehydrated. Finally, with the aim to advance towards better oral healthcare products, we investigated the effect of nonionic and amphoteric surfactants on salivary pellicles, showing that they have a gentler effect on pellicle structure than the commonly employed anionic surfactants.

  • Studies of ankle fractures : classification, epidemiology, complications and results Author: Hans Juto Link: Publication date: 2022-01-07 06:00

    The ankle fracture is one of the most common fractures in adult patients and is a heterogeneous group of fractures. From the fully stable fracture on the most distal part of thefibula to severely unstable and even dislocated ankles. Patients with ankle fractures often report a good result after treatment, but a small group have persistent problems.The purpose of the dissertation is to investigate classification, epidemiology, complications, and results in order to improve knowledge and management of ankle fractures.This dissertation is mainly based on data from the Swedish Fracture Register (SFR).

    In Study I the accuracy of the AO/OTA classification, version 2007, of ankle fractures in the SFR was examined. Entry of data into the SFR is mainly performed by the attending doctors at the accident and emergency departments, often with varying experience of fracture classification. Classification of fractures can in some cases bedifficult even for experienced orthopaedic surgeons. This is because the fractures to be categorized can be seen being on a spectrum and there will always be cases which is on the border between different categories. We created a reference group that classified several randomly selected ankle fractures from the SFR based on X-rays from treatingorthopedic departments. The assessment that was then agreed upon was considered to be the gold standard classification and could in turn be compared to the classification found in the SFR. The agreement between the classification in the SFR and the classification of the reference group was 88% for AO/OTA type level and 74% for AO/OTAgroup level. This corresponded to a kappa value of 0.77 and 0.66 respectively. The findings were equivalent to or higher than in previous studies.

    In study II the aim was to examine the incidence of ankle fractures in Norrbotten county, as well as the relationship between AO/OTA-classes of ankle fractures with age, gender and low-energy trauma. Ankle fractures are increasing in an ageing population but are not generally seen as a fragility fracture. All ankle fractures treated at a hospital in the county were retrospectively identified, X-rays were inspected and classified, and the medical record reviewed. The study found 1,756 ankle fractures corresponding to an incidence of 179 per 100,000 person-years. Females had an increasing incidence with age while among males the incidence was more evenly distributed. The type B fractures showed a slightly higher proportion of low-energy trauma and increased substantially with age. In contrast were the A21-subgroup and type C ankle fractures which had a lower mean age and proportion of women.

    Study III investigated the association between the incidence of venous thromboembolic event (VTE) and the use of low-molecular-weight heparin (LMWH) prophylaxis following an ankle fracture, as well as factors affecting the risk of VTE. VTE is a well-known complication after ankle fracture and especially after ankle fracture surgery. The use of LMWH prophylaxis is debated. Data on ankle fracture treatment from the Swedish Fracture Register was linked to data for VTE diagnosis and LMWH prescription from the Swedish National Patient Register and the Swedish Prescribed Drug Register. Cases of diagnosed VTE were identified among 222 of 14,954 ankle fractures. Orthopaedic departments with higher-than-average use of LMWH prophylaxis among non-operatively treated ankle fractures had a lower incidence of VTE (OR 0.60, 95% CI, 0.39-0.92). Among patients treated operatively at departments with guidelines for routine use of LMWH prophylaxis there was an incidence of VTE of 1.6%, compared to 2,7% at departments without routine use of LMWH prophylaxis (OR 0.56, 95% CI, 0.37-0.86). During the first two weeks following injury, there was only one case of VTE in 5,332 patients with prescribed LMWH, compared to 39 cases of VTE among 9,622 patients without prescription.

    Study IV examined the variations in the length of sick leave in ankle fracture patients. Even though most patients with an ankle fracture report a satisfactory outcome there are still a number of patients with persistent pain and functional impairment. The aim of the study was to analyse how treatment, different types of ankle fracture and patients-related factors were associated with the length of sick leave by combining data from the SFR and Swedish Social Insurance Agency (SSIA). Fifty-three per cent of patients registered with an ankle fracture in the SFR had a period of paid sick leave from the SSIA. There was an association between the length of the sick leave and the severity of the fracture. A correlation was also seen between the length of the sick leave and a worse patient-reported outcome.