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Characterization of the anticancer effect of mebendazole and its interaction with standard cytotoxic drugs in patient tumor cells ex vivo and in an in vivo mouse model
No full textMebendazole (Mbz), a well‑known anthelminthic drug, has demonstrated anticancer properties in tumor models and patients, and is thus under consideration for repositioning into an anticancer drug. Mbz is directly cytotoxic in cell lines by various mechanisms and acts indirectly via immunomodulation. In the present study, the anticancer effects of Mbz, alone and in combination with cytotoxic drugs, were further characterized using primary cultures of patient tumor cells ex vivo and the murine colon cancer cell line, CT26, in vitro and in vivo. Patient‑derived tumor cells from acute myeloid leukemia (AML) and ovarian, colorectal and renal cancer were exposed to Mbz alone and, for solid tumors and the CT26 cell line, in combination with irinotecan, cisplatin or gemcitabine (patient cells only). Cytotoxicity was assessed using the fluorometric microculture cytotoxicity assay. In vivo, the antitumor effects of Mbz and irinotecan, alone and in combination, were evaluated in the BALB/c CT26 colon cancer mouse model by tumor growth measurements and flow cytometric analysis of tumor immune cell infiltration. In the patient cell samples, Mbz showed modest single‑agent cytotoxicity, with the AML samples being the most sensitive, and displayed enhanced effects when combined with cytotoxic drugs, particularly irinotecan. CT26 cells showed modest dose‑independent sensitivity to Mbz, which enhanced the effect of both cisplatin and irinotecan. In vivo, Mbz and irinotecan both inhibited tumor growth, but the combination did not significantly outperform Mbz alone. Flow cytometry of the resected mouse tumors indicated that Mbz promoted macrophage polarization from the M2 to M1 phenotype, suggesting that immune modulation may contribute to its anticancer effect. Mbz has features making it a candidate for repositioning into an anticancer drug and part of its effect may be mediated by macrophage modulation
Cost-efficient scenarios for reaching transportation climate targets
No full textWe explore cost-efficient scenarios for reaching climate targets for the transportation sectors in the EU and Sweden, covering both passenger and freight transport. Our focus is on the relative contributions to emissions reductions from electrification, biofuels and traffic reduction. Information about cost-efficient scenarios can serve as roadmaps to reach given targets. This is important not only for designing climate policies; it also has implications for traffic planning, biofuel production planning and the transformation of the vehicle manufacturing industry. Our results indicate that electrification is by far the most important factor for reaching the climate targets. With the recent EU vehicle regulations in place, it is possible to reach the climate targets at a moderate cost; with slow electrification, the long-run targets are virtually impossible to reach. Assuming that EU emission standards are binding, reaching the targets also requires considerable amounts of biofuel, especially in the short and medium term. Traffic reduction contributes only marginally to reduced emissions. Hence, other negative externalities from road traffic need to be handled by other policy measures; climate policy only makes a marginal contribution to reducing other traffic externalities.
Safe and Field Resilient Risk-Aware Path Planning with Dynamic Obstacle Avoidance in Unknown and Uncontrolled Environments
No full textThis PhD thesis advances robotic autonomy by developing novel path-planning and collision-avoidance solutions that enable resilient missions in complex, unstructured real-world environments. The primary contribution is D*+, a risk-aware path planner extending the D*-lite framework for ground and aerial robots. D*+ introduces a risk layer around occupied and unknown spaces, ensuring traversable paths with safety margins while operating on imperfect maps from real data. Its dynamic mapping supports adaptive replanning, enabling exploration missions in unknown environments, and is excellent for waypoint navigation. Real-world trials with a UAV and quadrupedal robot confirm its versatility across diverse scenarios. The second contribution is the Detect Track and Avoid Architecture (DTAA), which tackles dynamic obstacles using YOLO-based detection, Kalman filter state estimation, and a nonlinear model predictive controller (NMPC) for anticipatory avoidance maneuvers. DTAA effectively handles fast-moving objects while following D*+ paths; however, it is limited by a short predictive horizon and susceptible to local minima. To overcome these weaknesses, this thesis introduces A*+T, a distributed, time-dependent multi-agent path planner. Built on an A*framework, A*+T integrates D*+ 's risk layers and DTAA's dynamic obstacle handling, adding a temporal dimension to the planning process, enabling collision checks in time and space. The temporal dimension enables distributed autonomous robots to plan collision-free paths in shared spaces based on other robots' planned paths. Leveraging shared paths and predicted paths from DTAA, A*+T plans collision-free paths around the dynamic obstacles. Validated through simulations and real-world experiments, A*+T enhances mission readiness for multi-agent scenarios. Beyond these, the thesis integrates these modules into complete robotic systems, enhancing mission control for large-scale applications. Demonstrations include mining inspections (visual and gas detection) and search-and-rescue missions (locating humans/objects). These original advancements offer robust, practical solutions for robotic navigation, validated through extensive real-world testing, and contribute significantly to autonomous systems in high-stakes environments
Synchrotron X-ray diffraction for carbide evolution during tempering of laser powder bed fusion tool steel
No full textIn pursuit of enhancing the mechanical properties of laser powder bed fusion (L-PBF)-produced hot work tool steels, this study investigates the evolution of carbides from the as-built state to the quenched and tempered conditions of a modified H13 steel. The heat treatment involved austenitization and quenching, followed by tempering at two temperatures: 600 °C and 625 °C. To monitor microstructural changes over time, tempering durations of 10, 20, 40, 80, 120, 130, 140, 160, 200, and 240 min were applied at both temperatures. Subsequently, the samples underwent synchrotron radiation analysis, scanning electron microscopy (SEM), and hardness testing. The results revealed notable variations in carbide fractions, martensite tetragonality, and micro-strain depending on tempering time and temperature. Synchrotron X-ray diffraction (XRD) is shown to effectively track carbide evolution in L-PBF tool steels which provides guidance for optimizing post-process heat treatment
Implicit and explicit (in)justice on the route to Paris : an analysis of justice expressions in the Paris Agreement, EU-, and Swedish climate-forest policy mixes
No full textForests are central to climate change mitigation, and there is consensus that climate transition efforts must be just. However, the “just transition” concept often functions as a boundary object, leading to ambiguity in its implementation. Statements of commitment to just transitions therefore require scrutiny as to what a just transition is meant to entail, what kind of justice transition policies seek to ensure, and how these ambitions are envisioned to be realised in practice. Yet, it is precisely this that is missing in the current academic literature, especially in the forest sector context. This study addresses this gap by analysing implicit and explicit justice expressions in the Paris Agreement, and EU- and Swedish climate-forest policy mixes, thereby providing empirical insights on the ‘what’ and ‘how’ of just transitions in the forest sector. Using a newly developed framework that combines the policy mix concept with distributional, recognitional, and procedural justice dimensions, the analysis reveals shared narrow foci in just transition understanding, discrepancies between expressed just transition motivations, and inconsistent mechanisms for implementation across governance levels, thus risking stakeholder disengagement. The results call for explicit discussions in policy debate on how justice can be ensured in transition efforts in the forest sector across levels, regardless of the specific understanding of justice that is adhered to, and open societal debate on what a just transition ultimately ought to mean in a forest context. Furthermore, policy makers must take the step from ambiguous promises to concrete instruments to support forest stakeholders through the transition
Temporär legalitet : Reglering av asyl genom bostad och utbildning i den svenska välfärdsstaten
No full textThis thesis examines the shift towards temporary protection for refugees in Sweden since 2016 and its implications for access to permanent residency and family reunification. Situated at the intersection of welfare law and critical border studies, the thesis conceptualises this shift and its implications in terms of ‘temporary legality’: a prevailing condition of asylum marked by legal conditionality and protracted deportability. Drawing on research on borders, racialisation, and neoliberal welfare reforms, it analyses how spatial, temporal, and racial dimensions converge in shaping this condition. The thesis examines residence-permit requirements tied to housing and education to show how such requirements function as internal borders that are negotiated across and within municipalities, revealing how migration law is enacted through welfare institutions. Methodologically, it adopts a socio-legal lens to trace migration law beyond the Migration Agency and the courts into welfare sites, foregrounding the municipality as a bordering space. The analysis draws on 31 interviews with welfare practitioners, local politicians, and civil society actors, complemented by policy documents, court cases, and press material. The analysis shows clearly that temporary legality produces a fluctuating space between legality and illegality, delegated to welfare practitioners to regulate. In such a space, municipal discretion, enacted through local policies and everyday practices, contests, cushions, or exacerbates migration law, generating locally differentiated status trajectories for individuals in need of protection. It is within such a condition, the thesis argues, that residence-permit requirements operate as internal borders, producing uneven and racialised access to welfare rights, family reunification, and permanent status. That is, by governing asylum through temporary legality, the Swedish state creates protracted forms of uncertainty and differentiates and dismantles the right to asylum
Mass Casualty Response in a Low-Resource Context : Challenges and Opportunities in Rwanda’s Mass Casualty Incident Response
No full textBackground In a mass casualty incident (MCI), sudden patient surges can overburden the health system and cause material and human resource limitations, as well as challenges in adapting systems and structures to the changed needs. This leads to an increased risk of avoidable patient morbidity and mortality. Low-resource countries bear the brunt of the global trauma and disaster burden, and, although not formally assessed, are more likely to be more frequently exposed to MCIs. The ability to adequately manage a sudden patient influx is called “surge capacity”, and can be measured using the 4S-Framework, which assesses the dimensions staff, stuff, systems, and space. However, current MCI research primarily originates from high-resource settings, with uncertain generalizability to low-resource settings. Objectives This thesis aimed to increase the understanding of MCI epidemiology in Rwanda, including at the incident level (event type, location, and timing) and at the patient level (injury patterns, patient outcomes, treatment provided) (studies I and IV). Secondly, this thesis aimed to assess the surge capacity to manage mass casualty incidents in Rwanda (studies II, III, and IV), and to develop a knowledge base for future surge capacity strengthening efforts. Materials and Methods This thesis employed multiple study designs and analysis methods. Study I was a pilot study for a new data collection method (the media review), based on a scoping review methodology using a database of news items. Study II was a qualitative study with semi-structured interviews with trauma care responders, which were analyzed using qualitative content analysis. Study III was a cross-sectional survey study of surge capacity perceptions with clinical department leaders at Rwanda’s leading trauma hospitals. Study IV was a retrospective study of routine prehospital data from emergency medical services (EMS). Studies I, III, and IV utilized descriptive statistics and parametric and non-parametric hypothesis tests for group comparisons. Study III additionally utilized analysis of one-way variance to assess intra-class correlation between respondents from the same hospital, and study IV utilized mixed-model analysis based on logistic and linear regression to evaluate the role of confounders in EMS MCI dispatch. Main results Studying MCIs and surge capacity in Rwanda is challenged by the lack of appropriate registers, the sudden onset of events, and resource limitations. In Rwanda, the media review demonstrated extensive reporting on the number of injured victims, on-site deaths, and the geographic location of the MCI, indicating that this method can be used as a complementary method to assess epidemiological patterns in MCIs in the absence of trauma registers. Rwanda has a high MCI exposure, with road-traffic accidents being the most frequent, but natural hazards appear to be on the rise. The majority of mass casualty incidents are small to moderately sized. MCIs are managed at all levels of the health system. Perceived surge capacity to manage low- to moderately sized mass casualty incidents is high in Rwanda. Trauma care responders attribute this to the wealth of real-life experience in MCI management and having a supportive team. The successful resolution of dilemmas during MCIs can lead to positive effects such as self-confidence, teambuilding, and personal or professional growth. Surge capacity is higher in tertiary “level 1” hospitals, located in urban areas. There are specific challenges in the Rwandan context, primarily resource and staff shortages, as well as limited EMS coverage in rural areas, that limit the generalizability of surge capacity paradigms from high-income countries. In formal assessment, surge capacity is limited in all 4S-domains metrics, including low levels of disaster plan uptake and limited awareness of existing plans. Formal surge capacity routines are also limited in the pre-hospital setting. Yet, Rwandan trauma care workers and emergency medical services utilize surge capacity strategies, including patient distribution to multiple facilities, on-site patient EMS treatment to reduce hospital referrals, and patient co-transportation. However, MCIs in rural areas are less likely to be managed by formal EMS. Viewed in the light of limited in-hospital surge capacity in rural areas, rural patients are likely at higher risk of poor outcomes in mass casualty incidents in Rwanda. Conclusions Despite limited formal disaster planning and routines, Rwanda appears to have developed a strong surge capacity to manage small- to moderately sized mass casualty incidents organically. However, there are limitations to surge capacity and areas for improvement in all 4S-domains, including staff, stuff, systems, and space, especially in rural areas. Trauma systems and emergency medical services need further development to ensure adequate surge capacity
4D Flow MRI Velocity and Turbulence Mapping in Mild Valvular Heart Disease
No full textBackground: Valvular heart disease (VHD) commonly leads to the development of turbulent blood flow. Turbulent kinetic energy (TKE), measured with 4D flow MRI, may be a complement to current metrics for early identification of VHD. Purpose: To investigate TKE as a marker of VHD in relation to flow velocity and cardiovascular geometry. Study Type: Retrospective observational cross-sectional. Population: Twenty controls and 106 subjects with VHDs, including mitral regurgitation, aortic regurgitation, pulmonary regurgitation, tricuspid regurgitation, and aortic stenosis. Field Strength/Sequences: Four-dimensional flow MRI using a spoiled gradient-echo phase-contrast sequence with asymmetric 4-point motion encoding at 1.5 or 3 T. Assessment: Time-resolved segmentations of the left and right ventricles (LV, RV), atria (LA, RA), and aorta were performed. Total and maximum TKE, maximum and average velocity, and diameters were evaluated in each. Correlations between TKE, velocity, and diameter were assessed, along with group differences between VHD subjects and controls. Statistical Tests: Student's t-test, Wilcoxon rank-sum test, chi-squared test, Pearson's correlation, two-way analysis of covariance. A p value &lt; 0.05 was considered significant. Results: Total and maximum TKE correlated significantly with maximum velocity (r = 0.45-0.76) and averaged velocity (r = 0.22-0.44) and less strongly with diameters for aorta, LV, LA, and RV (r = 0.18-0.37). Compared to controls, total and maximum aortic TKE were significantly higher in aortic stenosis (3.8 vs. 1.6 mJ; 291.7 vs. 133.7 J/m(3)). Maximum LV TKE was significantly elevated in aortic regurgitation (106.6 vs. 91.8 J/m(3)). Total TKE was significantly elevated in LA for mitral regurgitation (1.1 vs. 0.6 mJ), in RA for tricuspid regurgitation (1.6 vs. 0.7 mJ), and in RV for pulmonary regurgitation (1.7 vs. 1.0 mJ). Data Conclusion: TKE is elevated in mild VHD. When evaluated alongside velocity as a marker for VHD, TKE may be more discriminative. Consequently, it has potential to be a hemodynamic marker of early VHD conveying complementary information to velocity.Funding Agencies|Medical Faculty at Linkping University</p
Impact of MV reserve path operation on LV network hosting capacity
No full textThe hosting capacity of low-voltage (LV) networks is influenced by existing consumption and production in adjacent LV networks under the same medium-voltage (MV) network. Since LV transformers typically lack automatic on-load tap changers, both voltage and current limits require a joint assessment covering the MV network and all underlying LV networks. This paper introduces a methodology to include different MV operating conditions, like reserve operating paths, in the calculation of the hosting capacity for new production at LV networks. The MV voltage profile before the connection of new production, called the background voltage, is modelled to enable such analysis. The methodology is applied to an existing MV/LV network. The hosting capacity was lower, for the studied reserve operating paths, and the limitation was due to overvoltage issues. The proposed methodology is a valuable tool for distribution network planning. It was also shown that it is essential to use an accurate model of the background voltage for hosting capacity calculation of distribution networks.Funder: Skellefteå Kraft;Fulltext license: CC BY</p