A completeness proof in full DDL

Dynamic doxastic logicians — not a large community — have trodden gingerly within the area of full DDL or, as with the present author, have not trodden at all. However, the latter, after having written up the final version of [6], realised that the proof given in that paper for two varieties of basic DDL can be extended to cover full DDL; in fact, the «full» proof is simpler than the «basic» one. The extended proof is outlined in Section 1–3. In Section 4, the relationship to AGM is considered. Section 5 puts the importance of the proof into perspective.This note — an extended abstract rather than a full-fledged paper — should be read as an appendix to [6]. Although some definitions are repeated here, many are not. Readers who require more detail are referred to [6], a copy of which they should have on hand

Improving NK cell-based immunotherapy of cancer by exploration of migration and inhibitory receptor-ligand interactions

The possibility to utilize the immune system as a mean to target malignantly transformed cells has emerged as a novel treatment modality during the last decades and is a field that is under rapid development. Natural Killer (NK) cells are immune cells with an intrinsic ability to recognize and lyse tumor-transformed cells. Their role in immune surveillance of cancer is well established and clinical studies have also highlighted their treatment potential. However, the efficacy has so far been suboptimal and means to further improve NK cell-based immunotherapy against cancer is under intensive investigation. This thesis mainly focuses on how to enhance NK cell treatment efficacy against acute myeloid leukemia (AML), a disease with poor prognosis that is in urgent need for novel and more efficacious treatment options. The potential to better home NK cells to the tumor environment is a highly appealing, but so far relatively unexplored approach to improve treatment efficacy for adoptive NK cell transfer. In Papers I and II, we have utilized a clinically approved mRNA transfection technique to explore how ex vivo expanded NK cells can be engineered to express the gain-of-function bone marrow (BM) homing receptor variant CXCR4R334X. We have shown that CXCR4R334X-expressing NK cells display an increased in vitro migration potential towards the ligand SDF-1 without compromising functionality in any other aspect. We have further highlighted the importance of the CXCR4-SDF-1 axis for in vivo BM homing using both CXCR4R334X mRNA transfected cells and CXCR4 knocked-out cells generated using the CRISPR/Cas9 technology. Finally, we showed that CXCR4R334X-expressing NK cells can be utilized to improve leukemia clearance in vivo, and furthermore have the potential to mediate a survival benefit in this context. Education is a complicated process in which NK cells are dynamically tuned by surrounding HLA class I molecules facilitating a strong effector response against target cells lacking such molecules. Members of the killer cell immunoglobulin-like receptor (KIR) family and the natural killer group 2 member A (NKG2A) receptor have previously been shown to mediate education. In paper III, we have shown for the first time that the LIR-1 receptor can mediate education in ex vivo expanded NK cells. We have identified an educated LIR-1-expressing NK cell subset that display an elevated degranulation capacity towards HLA class I deficient or low tumor targets and further showed that this subset also has a phenotype which resembles that of educated cells. In addition, we have displayed that the subset can be detuned after blockade with specific LIR-1 monoclonal antibodies in line with the rheostat model. Finally, we revealed that this subset has a potent ADCC capacity that even can overcome inhibitory signals from cognate HLA class I ligands. We have postulated that these traits make this subset highly attractive for NK cell-based immunotherapy and could be utilized in various cancer settings, including AML. Isocitrate dehydrogenase (IDH) 1 and 2 are frequently mutated in AML. IDH inhibitors (IDHi) have emerged as novel therapeutic agents. However, only a portion of the patients respond to treatment and the relapse rate is high. In paper IV, we have employed the TF- 1 AML cell line overexpressing the hotspot mutation IDH2R140Q as a model system to study the epigenetical and transcriptional landscape before and after treatment with an IDHi. We have shown that TF-1 IDH2R140Q cells display a hypermethylated DNA profile leading to differential gene expression, which can be further linked to a dysregulated transcriptional network involving myeloid-related transcription factors. We further displayed that this, at least in part, can be reversed upon treatment with the IDHi. Moreover, we showed that both TF-1 IDH2R140Q cells and primary AML cells carrying IDH mutations have hypermethylated HLA class I genes leading to HLA class I downregulation. This was associated with an increased sensitivity to NK cell-mediated responses against the IDH2R140Q mutated TF-1 cells compared to wild-type (WT) TF-1 cells. Lastly, we showed that HLA class I genes in IDH mutated primary AML cells of patients that did not respond to treatment with IDHi remained hypermethylated, indicating that this patient group may benefit from treatment based on adoptive NK cell infusions. Overall, this thesis provides evidence that NK cell migration can be modulated to redirect NK cells to bone marrow compartments for improved leukemia clearance. Furthermore, it includes a paper where the inhibitory receptor LIR-1 for the first time is shown to mediate education of ex vivo expanded NK cells, and identifies a unique subset of highly educated NK cells with a robust ADCC capacity that have the potential to be utilized against various cancer types including AML. Finally, the thesis includes a manuscript which shows that mutations in IDH can confer an increased NK cell sensitivity, and that IDH mutated AML patients resistant to treatment with IDHi constitute a subgroup of AML that may specifically benefit from NK cell-based immunotherapy. In conclusion, the thesis provides novel insights on how NK cells can be utilized to improve treatment for AML and potentially also other types of BM residing malignancies

A festival of facts

Consider yourself invited to a filmfestival — a festival of shorts. Regrettably it is a festival with a limitation: you will not be able actually to see the films. However, this limitation is offset by an unusual feature: the films to be shown are not only short but ultrashort — with one exception, each film consists of only a few frames. Instead of showing the films we shall be able to give a complete description of them

Modal logic and philosophy

Modal logic is one of philosophy’s many children. As a mature adult it has moved out of the parental home and is nowadays straying far from its parent. But the ties are still there: philosophy is important to modal logic, modal logic is important for philosophy. Or, at least, this is a thesis we try to defend in this chapter. Limitations of space have ruled out any attempt at writing a survey of all the work going on in our field—a book would be needed for that. Instead, we have tried to select material that is of interest in its own right or exemplifies noteworthy features in interesting ways. Here are some themes that have guided us throughout the writing: • The back-and-forth between philosophy and modal logic. There has been a good deal of give-and-take in the past. Carnap tried to use his modal logic to throw light on old philosophical questions, thereby inspiring others to continue his work and still others to criticise it. He certainly provoked Quine, who in his turn provided—and continues to provide—a healthy challenge to modal logicians. And Kripke’s and David Lewis’s philosophies are connected, in interesting ways, with their modal logic. Analytic philosophy would have been a lot different without modal logic! • The interpretation problem. The problem of providing a certain modal logic with an intuitive interpretation should not be conflated with the problem of providing a formal system with a model-theoretic semantics. An intuitively appealing model-theoretic semantics may be an important step towards solving the interpretation problem, but only a step. One may compare this situation with that in probability theory, where definitions of concepts like ‘outcome space’ and ‘random variable’ are orthogonal to questions about “interpretations” of the concept of probability. • The value of formalisation. Modal logic sets standards of precision, which are a challenge to—and sometimes a model for—philosophy. Classical philosophical questions can be sharpened and seen from a new perspective when formulated in a framework of modal logic. On the other hand, representing old questions in a formal garb has its dangers, such as simplification and distortion. • Why modal logic rather than classical (first or higher order) logic? The idioms of modal logic—today there are many!—seem better to correspond to human ways of thinking than ordinary extensional logic. (Cf. Chomsky’s conjecture that the NP + VP pattern is wired into the human brain.) In his An Essay in Modal Logic (1951) von Wright distinguished between four kinds of modalities: alethic (modes of truth: necessity, possibility and impossibility), epistemic (modes of being known: known to be true, known to be false, undecided), deontic (modes of obligation: obligatory, permitted, forbidden) and existential (modes of existence: universality, existence, emptiness). The existential modalities are not usually counted as modalities, but the other three categories are exemplified in three sections into which this chapter is divided. Section 1 is devoted to alethic modal logic and reviews some main themes at the heart of philosophical modal logic. Sections 2 and 3 deal with topics in epistemic logic and deontic logic, respectively, and are meant to illustrate two different uses that modal logic or indeed any logic can have: it may be applied to already existing (non-logical) theory, or it can be used to develop new theory

- Det händer aldrig mig - En kartläggning av kuratorsarbetet med smittspårningssamtalet

Denna uppsats grundas i ett uppdrag från en enhetschef inom kvinnosjukvården. Uppsatsen syftar till att samla in och systematisera den erfarenhet och kunskap som finns i arbetet med smittspårningssamtalet hos kuratorer på olika valda enheter inom Sahlgrenska Universitetssjukhus. Studien syftade till att beskriva en enhetlig metod för smittspårningssamtalet. Vi utgick från dessa frågeställningar för att uppnå syftet: • Hur ser smittspårningssamtalets struktur och innehåll ut? • Vilka strategier och samtalstekniker använder sig kuratorerna av för att skapa en arbetsallians i smittspårningsarbetet? Uppsatsen är en kvalitativ studie där vi intervjuat åtta kuratorer som är verksamma inom olika enheter inom Sahlgrenskas Universitetssjukhus samt öppenvårdsmottagningen Sesam. För att analysera empirin använde vi oss av de teoretiska perspektiven; Bernler & Johnssons teori för psykosocialt arbete, Motiverande Intervju och Petitt & Olsons begrepp sammanhangsmarkering. Spridningen av klamydia, den vanligaste rapporterade sexuellt överförbara infektionen, har ökat markant de senaste åren. Denna spridning bidrar till det stora och allvarliga infertilitetsproblem som finns i dagens samhälle. Av studien framgår att kuratorernas huvuduppgift i smittspårningssamtalet är att hindra spridningen av klamydia. För att detta skall ske på mest gynnsamt vis krävs en arbetsallians där kurator och patient tillsammans utreder vilka som kan ha blivit smittade. Kuratorerna poängterar att ett mål med samtalen även syftar till är att patienten skall känna sig sedd och minska personens känsla av skuld och skam. Kuratorerna förmedlar att det är viktigt att de finns till för patienten och lyssnar på dennes livssituation. Studien syftar till att vara en kvalitetssäkring och möjlighet till utvärdering och utveckling av kuratorernas arbetsmetod i smittspårningssamtalet

"5 Days in August" – How London Local Authorities used Twitter during the 2011 riots

© IFIP International Federation for Information Processing 2012This study examines effects of microblogging communications during emergency events based on the case of the summer 2011 riots in London. During five days in August 2011, parts of London and other major cities in England suffered from extensive public disorders, violence and even loss of human lives. We collected and analysed the tweets posted by the official accounts maintained by 28 London local government authorities. Those authorities used Twitter for a variety of purposes such as preventing rumours, providing official information, promoting legal actions against offenders and organising post-riot community engagement activities. The study shows how the immediacy and communicative power of microblogging can have a significant effect at the response and recovery stages of emergency events