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  • Public defence: 2019-12-06 13:00 Hörsal B, Unod T9, Umeå
    Holmgren, Klas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Permanent stoma after anterior resection for rectal cancer: prevalence and mechanisms2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    While sphincter-saving surgery constitutes standard treatment for rectal cancer, anterior resection still harbours a significant risk of a permanent stoma in the long run. Although anastomotic leakage plays a major role in this surgical dilemma, the exact mechanisms are not known, while surveys indicate a stoma-free outcome is essential for a majority of patients. To address this issue, the overall aim of the present thesis was to investigate the permanent stoma prevalence in patients undergoing anterior resection for rectal cancer in Sweden, and to identify plausible mechanisms that impede prospects of a stoma-free outcome.

    In a population-based cohort, chart review of patients who had anterior resection for rectal cancer in the Northern healthcare region in Sweden between 2007 and 2013 showed that 75 out of 316 (24%) patients ended up with a permanent stoma. Of 274 patients (87%) primarily defunctioned with a stoma, 229 underwent stoma closure, 21 (9%) of whom suffered major complications that required return to theatre or worse. A permanent stoma was shown to be more common among patients with anastomotic leakage and an advanced tumour stage.

    A registry-based method to estimate nationwide stoma outcome after anterior resection for rectal cancer was developed, using data from the Swedish Colorectal Cancer Registry and the National Patient Registry. With a chart-reviewed cohort as reference, stoma outcome was assessed with a positive predictive value of 85.1%, and a negative predictive value of 100.0%. In patients operated in Sweden between 2007 and 2013, the registry-based method determined that 942 out of 4768 (19.8%) had a permanent stoma, while stoma rates varied substantially between different healthcare regions.

    In a 1:1 matched case-control study of 82 patients who had curative resection for non-disseminated colorectal cancer, a subgroup analysis of 34 patients with rectal cancer displayed biomarker aberrations in serum measured preoperatively in those with anastomotic leakage. Compared to complication-free controls, 15 proteins related to inflammation were elevated, of which two (C-X-C motif chemokine 6, and C-C motif chemokine 11) remained significant after adjustment for multiple testing.

    Based on a cohort of 4529 patients who had anterior resection, tumour height served as a proxy to determine the extent of mesorectal excision, while long-term stoma outcome was classified using a previously validated registry-based method. Defunctioning stomas significantly decreased chances of a stoma-free outcome, especially in patients undergoing partial mesorectal excision; for these patients, faecal diversion was also least beneficial in terms of reducing anastomotic leakage.

    In conclusion, every fifth patient undergoing anterior resection for rectal cancer in Sweden eventually ends up with a permanent stoma. Although construction of a defunctioning stoma decreases the risk of symptomatic anastomotic leakage, subsequent takedown surgery carries a substantial risk of major complications, while chances of a long-term stoma-free outcome become significantly reduced. To facilitate selective use of faecal diversion, novel markers to identify high-risk anastomoses prior to surgery have been identified, but require validation in larger prospective settings. Anterior resection without a defunctioning stoma should be considered in appropriately informed patients for whom a stoma-free outcome is of importance. In particular, this holds true for patients eligible for partial mesorectal excision, where anastomotic dehiscence is less frequent and the advantageous effects of a defunctioning stoma are limited.

  • Public defence: 2019-12-11 09:00 N460
    Rebbling, Anders
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Application of fuel design to mitigate ash-related problemsduring combustion of biomass2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The energy supply of today is, through the use of fossil energy carriers,contributing to increased net emissions of greenhouse gases. This hasseveral negative effects on our environment and our climate. In order toreduce the impact of this, and possibly to reverse some of the effects, allrenewable energy sources must be used. Biomass is the renewable energycarrier that has the greatest potential to reduce net greenhouse gasemissions, but the transition from fossil fuels to biofuels is challenging.The combustion of biomass is associated with various technical andenvironmental problems such as slagging, corrosion, and emissions ofparticles, soot, or harmful chemical compounds. Most of these problemsare linked to ash chemical reactions involving alkali metals. Therefore, toreduce the risk of operational and environmental problems, it is importantto understand and control the ash transformation reactions involvingalkali metals.The research presented in this thesis has focused on the development oftools, such as models and indices, for predicting the behaviour of variousbiofuels during combustion, and on the development of the concept of fueldesign and implementation of the same during industrial combustion ofbiomass. The development of easy-to-use tools for predicting problematicash behaviour is crucial in order to make it possible to increase the use ofbiomass as an alternative to fossil fuels. The tools presented here are basedon theoretical and empirical knowledge and can be used to predictchallenges concerning the fuel ash composition and to propose relevantfuel design measures.The purpose of fuel design, as used here, is to broaden the fuel feedstockand to increase the usability of biomass in the global energy system. Thisis achieved through measures to change the ash chemical composition inorder to enhance beneficial properties, or reduce problematic properties,via the use of additives or blending of two or more different fuels.The present thesis extends the foundation of knowledge regarding fuel ashtransformation reactions and their implications for operational problemsthrough in-depth laboratory studies and analyses. Furthermore, thefeasibility of applying this extended knowledge in the medium and largescaleindustrial combustion of biomass is demonstrated and validated. More specifically, a slagging index has been developed using the results ofseveral years of combustion experiments. Fuel designs based on the indexwas demonstrated during normal operation in local and district heatingplants. Furthermore, a model was developed for predicting slaggingproblems that take into account both the chemical composition of the fueland the burner technology.Several studies have also been performed on different fuel designs basedon the same foundation as the index and the model. Additives to supply forexample calcium and sulphur, as well as the clay kaolin, have been used toreduce both technical and environmental problems.The conclusion is that fuel design, based on ash chemistry, is a possiblepath for increased fuel flexibility and a broader feedstock for bioenergy.

  • Public defence: 2019-12-12 13:00 Hörsal E, Umeå
    Dahlkvist, Mattias
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies.
    The politics of Islam, non-violence, and peace: the thought of Maulana Wahiduddin Khan in context2019Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This is a study of the multifaceted thought of Maulana Wahiduddin Khan (b.1925–), Indian writer, public intellectual, and Muslim religious leader. Khan has been a prolific writer since at least the 1970s and is also an ālim, a Muslim scholar learned in religion. His reputation is based on his public presentation of Islam, non-violence, and peace – a position he has defended in his monthly journal, al-Risāla (Eng. version: Spirit of Islam), a large number of published books and pamphlets, and recently also through use of the internet and social media. Furthermore, as a religious leader and debater Khan has been active as a commentator in Indian national media and through religious dialogue meetings, for which he has received national awards and honours. Khan’s religious thought may be summarised as a thorough attempt at presenting Islam, the Quran, and the example of the Prophet Muhammad as a systematic message of peace. Islam is described as a divine message calling for individual commitment and knowledge. Hence, Islam requires a setting of freedom, peace, and stability so that believers can choose its message without restriction. The Quran is regarded as highlighting non-violent patience as the most significant virtue and peace is both a divine quality as well as a requirement for salvation. The religious ideal of the Prophet Muhammad is not his political achievements. Instead, the Prophet’s message is understood as peaceful negotiation and success through turning conflict into friendship as the ultimate path to end hatred, violence, and persecution. The concept of jihad is seen as essential to this type of peace-building struggle; spreading Islam only through preaching, as well as overcoming the hurdles of the self and ego, for instance anger and violent impulses. By situating Khan’s thought in a context of historical and contemporary debate on the meaning of Islam, this study argues that he continues and develops the nineteenth century Indian Islamic Modernist tradition of presenting Islam, non-violence, and peace in relation to issues of the modern state and the minority situation of Indian Muslims. This type of religious position became nationally prominent from the 1920s during the Indian independence movement. In the contemporary Indian political and social situation however, Hindu nationalist and anti-Muslim rhetoric is being followed by large-scale violence. Khan’s thinking aims to dissociate the rhetorical connection between Islam and violence, while supporting the democratic, pluralist, and secular trappings of the state. The analysis of Khan’s thought considers Islamic Modernism and unmarked reform Sufi Islam, alongside the secularism, democratic liberalism, and reform socialism of the Indian constitution. However, these thematic and discursive structures of thought are formulated by Khan with regard to a certain historical situation, and address particular political and social issues. Studying the various connections between Khan’s thought, the ideological and religious debates, and the historical context of Indian and global society, the final analysis of this study takes on the theoretical issue of whether contemporary and globalised religion can be a force for the development of more democratic and peaceful societies.

  • Public defence: 2019-12-13 10:00 KB.E3.01 (Lilla hörsalen), Umeå
    Phal, Sereilakhena
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Development of electrochemical sensor and biosensor platforms: detection of therapeutic drugs and heavy metal ions2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Electrochemical sensors and biosensors combine the sensitivity of electroanalytical methods with the selectivity of a sensor or biosensor surface. The chemical or biochemical component (receptor) in the sensor recognizes an analyte and produces an electrical signal which is proportional to the analyte concentration. Some of these sensors are routinely used in clinical applications and are known for their simplicity, portability, cost-effective, and miniaturization. The glucose sensor used in the management of diabetes is a good example of such biosensors.

    This thesis deals with the development of electrochemical biosensor and sensor platforms for the detection of therapeutic drugs, demonstrated using methotrexate (MTX) which is the most common drug used for the treatment of cancer patients, and heavy metal ions (Pb2+ and Cd2+).

    The biosensor surfaces were generated by immobilization of antibody (anti-MTX) on chemically modified gold electrodes using different surface modification protocols. Self-assemble monolayer (SAM) using alkanethiol (cysteamine) or electrografting with diazonium salt (4- carboxybenzenediaonium tetrafluoroborate, 4-CBD) was used for surface modification. The surface modification was monitored and characterized using electrochemical immittance spectroscopy (EIS) and cyclic voltammetry (CV) along with other complementary technique such as X-ray photoelectron spectroscopy (XPS). The biosensing surfaces were used for the detection of MTX in an electrochemical flow cell (paper I) and in a batch system (paper II). The detection was based on non-faradaic electrochemical immittance spectroscopy (EIS) and singular value decomposition (SVD) for data evaluation. Both electrochemical biosensors provided the lowest limit of detection, LOD (at picomolar level) compared to earlier reports.

    The electrografting of 4-CBD on glassy carbon electrode (GCE) using CV and the parameters that influence the number of monolayers that can be grafted on the surface are demonstrated (paper III). The CVs obtained during grafting showed one or two reduction peaks, and this was found to be related to the number of monolayers deposited on the electrode. One can increase the number of monolayers by increasing the concentration of 4-CBD or decreasing the scan rate. The GCE, grafted using 4-CBD, was incorporated with Bi by an in situ electrodeposition of Bi3+ and used as an electrochemical sensor for detection of Pb2+ and Cd2+ using square wave anodic stripping voltammetry, SWASV (paper IV). The sensor resulted in LOD of 10 μg L-1 for Pb2+ and 25 μg L-1 for Cd2+. The applicability of the sensor was tested for detection of Pb2+ and Cd2+ in tap water and compared with ICP-OES. The results were comparable, demonstrating the potential of the sensor as an alternative to ICP-OES for the detection of metal ions in water samples.

  • Public defence: 2019-12-13 10:15 Hörsal S 213, Samhällsvetarhuset, Umeå
    Barnes, Philippa
    Umeå University, Faculty of Social Sciences, Department of Political Science.
    When processes collide: leadership, legitimacy and liberation in Palestine2019Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Palestinian national movement leadership has long been intertwined with thecontext of the national movement processes – liberation, peace and statebuilding. Over time, as these processes have not come to fruition, the numerousleadership groups have had to negotiate their relationships with these processesas both the groups and processes increasingly overlap, creating significantobservable points of tension within Palestinian politics. There are currentlymultiple levels of leadership across the national movement: two representativegoverning institutions – the Palestine Liberation Organisation and thePalestinian Authority; two dominant political movements – Fatah and Hamas;and numerous popular resistance initiatives such as the Boycott, Divestment andSanctions movement coalition that has different levels of endorsement (or lackof) by the other leaderships. This thesis seeks to map the Palestinian nationalliberation movement leadership, examining the inter-relations between themultiple leadership groups and internal (i.e. intra-Palestinian) legitimacies.Examining the internal legitimacies of the Palestinian leaderships results in anexpansion of how internal legitimacy can be conceptualised. For the historicalperiod (1958-2008) analysed, I found revolutionary, representative,oppositional, institutional, democratic and moral legitimacy types within thePalestinian case. Furthermore, these were all attributed to respective nationalmovement processes. Analysing the recent period (2016-2017) requires the useof a relational approach to further develop understandings of legitimacy. Thisapproach transforms legitimacy into a process of (de)legitimisation, whichinteracts with the national movement processes and helps us capture and analysethe complexities of the Palestinian case – that of concurrent, multiple andcontending perspectives. I found the continuation of the liberation and statebuilding processes as simultaneous bases of legitimisation to be a critical point oftension within the tandem legitimisation-delegitisimation process. Engaging arelational approach demonstrated the need for ongoing leadershipreconstruction. I conclude that, in order to negotiate the interactions andcontestations between the multiple and dynamic processes that underlielegitimacy, leaderships face an ultimatum of ‘reconstruct or delegitimise’. WherePalestinian leadership groups have stagnated and not engaged with a process ofreconstruction, we see processes of delegitimisation arising that can explain thecurrent leadership complexities within the Palestinian national movement.

  • Public defence: 2019-12-17 13:00 N450, Umeå
    Wang, Jianfeng
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Enhanced block sparse signal recovery and bayesian hierarchical models with applications2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is carried out within two projects ‘Statistical modelling and intelligentdata sampling in Magnetic resonance imaging (MRI) and positron-emission tomography(PET) measurements for cancer therapy assessment’ and ‘WindCoE -Nordic Wind Energy Center’ during my PhD study. It mainly focuses on applicationsof Bayesian hierarchical models (BHMs) and theoretical developments ofcompressive sensing (CS). Under the first project, Paper I improves the quantityestimation of MRI parametric imaging by utilizing inherent dependent structure inthe image through BHMs; Paper III constructs a theoretically unbiased and asymptoticallynormal estimator of sparsity of a sparsified MR image by using a BHM;Paper IV extends block sparsity estimation from real-valued signal recovery tocomplex-valued signal recovery. It also demonstrates the importance of accuratelyestimating the block sparsity through a sensitivity analysis; Paper V proposes anew measure, i.e. q-ratio block constrained minimal singular value, of measurementmatrix for block sparse signal recovery. An algorithm for computing thisnew measure is also presented. In the second project, Paper II estimates the uncertaintyof Weather Research and Forecasting (WRF) model’s daily-mean 2-metertemperature in a cold region by using a BHM. It is a computationally cheaper andfaster alternative to traditional ensemble approach. In summary, this thesis makessignificant contributions in improving and optimizing the estimation proceduresof parameters of interest in MRI and WRF in practice, and developing the novelestimators and measure under the framework of CS in theory.

  • Public defence: 2019-12-18 13:00 E04, Umeå
    Mallikarjuna, Pramod
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå university.
    The role of transforming growth factor‐β signaling and hypoxia‐inducible factors in renal cell carcinoma2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Renal cell carcinoma (RCC) is the cancer of the kidneys; about 1100 patients with RCC are diagnosed in Sweden each year. RCC can be classified into several subtypes, clear cell renal cell carcinoma (ccRCC) is most common accounting to about 70% of all RCCs, and also the most lethal; papillary renal cell carcinoma (pRCC) accounts to about 10%‐15%, while chromophobe renal cell carcinoma (chRCC) accounts to about 5% of all RCCs. There is a need to study the distinguishing features of RCC subtypes to design treatment. Von Hippel‐Lindau tumor suppressor gene (VHL) is often inactivated in ccRCC, unlike in pRCC or chRCC. Transforming growth factor‐β (TGF‐β) is a cytokine involved in various biological processes such as differentiation, proliferation, apoptosis, migration, andepithelial‐mesenchymal transition. TGF‐β exerts its functions through canonical (Smad‐dependent) and non‐canonical (Smadindependent) signaling pathways. In the first study, we have shown that both canonical and non‐canonical TGF‐β signaling pathways are associated with ccRCC tumor progression. VHL is known to have a dampening effect on TGF‐β signaling in RCC. However, the effects of pVHL status on the TGF‐β signaling pathway in ccRCC and non-ccRCC has not yet been studied in detail. In the second study, we have investigated the effects of the TGF‐β signaling pathway in the presence or absence of pVHL in ccRCC and non‐ccRCC. We show that, in ccRCC, VHL has an inhibiting effect exclusively on canonical TGF‐β signaling, and has no effect on non‐canonical TGF‐β signaling via ALK5‐ICD. In non‐ccRCC, TGF‐β signaling did not have an effect on tumor progression. Further, we demonstrate that VHL, through its ubiquitin ligases activity ubiquitinates ALK5 in a K48 dependent manner and subjects it to proteasomal degradation. During the normoxic conditions, VHL is implicated in ubiquitination and proteasomal degradation of Hypoxia‐inducible factors (HIFs). In hypoxic conditions or when the loss of VHL occurs, HIFs accumulates in the cytoplasm and enters the nucleus to initiate angiogenesis, cell proliferation, and tumor progression. In the third study, we have explored a potential synergistic cross‐talk between TGF‐β signaling and hypoxia in ccRCC. We demonstrate a correlation between TGF‐β signaling components and HIF‐1α/2α in ccRCC. We have also shown that TGF‐β signaling enhances the expression of HIF‐1α/2α and their target genes even under normoxic conditions, dependent on the kinase activity of ALK5 and dictated by the status of VHL. We present novel data that the synergistic crosstalk between hypoxia and TGF‐β is orchestrated through interactions between ALK5 and HIF‐1α/2α. HIF‐3α is only limited studied, compared with HIF‐1α and HIF‐2α. In the fourth study, we have analyzed the roles of HIF‐3α in ccRCC and pRCC and show that HIF‐3α is associated with advanced stage and metastasized tumors. We also found that HIF‐3α is associated with TRAF6, a crucial component of non‐canonical TGF‐β signaling.