Complicated Presence : The Unity of Being in Parmenides and Heidegger

The attempt to refer meaningful reality as a whole to a unifying ultimate principle - the quest for the unity of Being - was one of the basic tendencies of Western philosophy from its beginnings in ancient Greece up to Hegel's absolute idealism. However, the different trends of contemporary philosophy tend to regard such a speculative metaphysical quest for unity as obsolete. This study addresses this contemporary situation on the basis of the work of Martin Heidegger (1889-1976). Its methodological framework is Heidegger's phenomenological and hermeneutical approach to the history of philosophy. It seeks to understand, in terms of the metaphysical quest for unity, Heidegger's contrast between the first (Greek) beginning or "onset" (Anfang) of philosophy and another onset of thinking. This other onset is a possibility inherent in the contemporary situation in which, according to Heidegger, the metaphysical tradition has developed to its utmost limits and thereby come to an end. Part I is a detailed interpretation of the surviving fragments of the Poem of Parmenides of Elea (fl. c. 500 BC), an outstanding representative of the first philosophical beginning in Heidegger's sense. It is argued that the Poem is not a simple denial of apparent plurality and difference ("mortal acceptances," doxai) in favor of an extreme monism. Parmenides' point is rather to show in what sense the different instances of Being can be reduced to an absolute level of truth or evidence (aletheia), which is the unity of Being as such (to eon). What in prephilosophical human experience is accepted as being is referred to the source of its acceptability: intelligibility as such, the simple and undifferentiated presence to thinking that ultimately excludes unpresence and otherness. Part II interprets selected key texts from different stages in Heidegger's thinking in terms of the unity of Being. It argues that one aspect of Heidegger's sustained and gradually deepening philosophical quest was to think the unity of Being as singularity, as the instantaneous, context-specific, and differential unity of a temporally meaningful situation. In Being and Time (1927) Heidegger articulates the temporal situatedness of the human awareness of meaningful presence. His later work moves on to study the situational correlation between presence and the human awareness. Heidegger's "postmetaphysical" articulation seeks to show how presence becomes meaningful precisely as situated, in an event of differentiation from a multidimensional context of unpresence. In resigning itself to this irreducibly complicated and singular character of meaningful presence, philosophy also faces its own historically situated finitude. This resignation is an essential feature of Heidegger's "other onset" of thinking.

Turning the Kaleidoscope - (E)FL Educational Experience and Inquiry as Auto/biography

This book is a study on learning, teaching/counselling, and research on the two. My quest has been to find a pedagogically-motivated way of researching learning and teaching interaction, and in particular counselling, in an autonomous language-learning environment. I have tried to develop a method that would make room for lived experience, meaning-making and narrating, because in my view these all characterise learning encounters between language learners and counsellors, and learners and their peers. Lived experience as a source of meaning, telling and co-telling becomes especially significant when we try to listen to the diverse personal and academic voices of the past as expressed in autobiographical narratives. I have aimed at researching various ALMS dialogues (Autonomous Learning Modules, University of Helsinki Language Centre English course and programme), and autobiographical narratives within them, in a way that shows respect for the participants, and that is relevant, reflective and, most importantly, self-reflexive. My interest has been in autobiographical telling in (E)FL [(English as a) foreign language], both in students first-person written texts on their language- learning histories and in the sharing of stories between learners and a counsellor. I have turned to narrative inquiry in my quest and have written the thesis as an experiential narrative. In particular, I have studied learners and counsellors in one and the same story, as characters in one narrative, in an attempt to avoid the impression that I am telling yet another separate, anecdotal story, retrospectively. Through narrative, I have shed light on the subjective dimensions of language learning and experience, and have come closer to understanding the emotional aspects of learning encounters. I have questioned and rejected a distanced and objective approach to describing learning and teaching/counselling. I have argued for a holistic and experiential approach to (E)FL encounters in which there is a need to see emotion and cognition as intertwined, and thus to appreciate learners and counsellors emotionally-charged experiences as integral to their identities. I have also argued for a way of describing such encounters as they are situated in history, time, autobiography, and the learning context. I have turned my gaze on various constellations of lived experience: the data was collected on various occasions and in various settings during one course and consists of videotaped group sessions, individual counselling sessions between students and their group counsellor, biographic narrative interviews with myself, open-ended personally-inspired reflection texts written by the students about their language-learning histories, and student logs and diaries. I do not consider data collection an unproblematic occasion, or innocent practice, and I defend the integrity of the research process. Research writing cannot be separated from narrative field work and analysing and interpreting the data. The foci in my work have turned to be the following: 1) describing ALMS encounters and specifying their narrative aspects; 2) reconceptualising learner and teacher autonomy in ALMS and in (E)FL; 2) developing (E)FL methodologically through a teacher-researcher s identity work; 4) research writing as a dialogical narrative process, and the thesis as an experiential narrative. Identity and writing as inquiry, and the deeply narrative and autobiographical nature of the (E)FL teaching/counselling/researching have come to the fore in this research. Research writing as a relational activity and its implications for situated ways of knowing and knowledge turned out to be important foci. I have also focussed on the context-bound and local teacher knowledge and ways of knowing about being a teacher, and I have argued for personal ways of knowing about, and learning and studying foreign languages. I discuss research as auto/biography: as a practising counsellor I use my own life and (E)FL experience to understand and interpret the stories of the research participants even though I was not involved in their course work. The supposedly static binaries of learner/teacher, and also learner autonomy/teacher autonomy, are thus brought into the discussion. I have highlighted the infinite variability and ever-changing nature of learning and teaching English, but the book is also of relevance to foreign language education in general.

Resistance Mechanisms of Non-Hodgkin Lymphomas against Rituximab Treatment

Rituximab, a monoclonal antibody against B-cell specific CD20 antigen, is used for the treatment of non-Hodgkin lymphomas (NHL) and chronic lymphatic leukemia. In combination with chemotherapeutics rituximab has remarkably improved the outcome of NHL patients, but a vast variation in the lengths of remissions remains and the outcome of individual patients is difficult to predict. This thesis has searched for an explanation for this by studying the effector mechanisms of rituximab and by comparing gene expression in lymphoma tissue samples of patients with long- and short-term survival. This work demonstrated that activation of complement (C) system is in vitro more efficient effector mechanism of rituximab than cellular mechanisms or apoptosis. Activation of the C system was also shown in vivo during rituximab treatment. However, intravenously administered rituximab could not enter the cerebrospinal fluid, and neither C activation nor removal of lymphoma cells was observed in central nervous system. In vitro cytotoxicity assays showed that rituximab-induced cell killing could be markedly improved with simultaneous neutralization of the C regulatory proteins CD46 (Membrane cofactor protein), CD55 (Decay-accelerating factor), and CD59 (protectin). In a retrospective study of follicular lymphoma (FL) patients, low lymphoma tissue mRNA expressions of CD59 and CD55 were associated with a good prognosis and in a progressive flow cytometry study high expression of CD20 relative to CD55 was correlated to a longer progression free survival. Gene expression profile analysis revealed that expression of certain often cell cycle, signal transduction or immune response related genes correlate with clinical outcome of FL patients. Emphasizing the role of tumor microenvironment the best differentiating genes Smad1 and EphA1 were demonstrated to be mainly expressed in the non-malignant cells of tumors. In conclusion, this thesis shows that activation of the C system is a clinically important effector mechanism of rituximab and that microenvironment factor in tumors and expression of C regulatory proteins affect markedly the efficacy of immunochemotherapy. This data can be used to identify more accurately the patients for whom immunochemotherapy is given. It may also be beneficial in development of rituximab-containing and other monoclonal antibody therapies against cancer.

Effect of phenolic-rich plant materials on protein and lipid oxidation reactions

The antioxidant activity of natural plant materials rich in phenolic compounds is being widely investigated for protection of food products sensitive to oxidative reactions. In this thesis plant materials rich in phenolic compounds were studied as possible antioxidants to prevent protein and lipid oxidation reactions in different food matrixes such as pork meat patties and corn oil-in water emulsions. Loss of anthocyanins was also measured during oxidation in corn oil-in-water emulsions. In addition, the impact of plant phenolics on amino acid level was studied using tryptophan as a model compound to elucidate their role in preventing the formation of tryptophan oxidation products. A high-performance liquid chromatography (HPLC) method with ultraviolet and fluorescence detection (UV-FL) was developed that enabled fast investigation of formation of tryptophan derived oxidation products. Byproducts of oilseed processes such as rapeseed (Brassica rapa L.), camelina (Camelina sativa) and soy meal (Glycine max L.) as well as Scots pine bark (Pinus sylvestris) and several reference compounds were shown to act as antioxidants toward both protein and lipid oxidation in cooked pork meat patties. In meat, the antioxidant activity of camelina, rapeseed and soy meal were more pronounced when used in combination with a commercial rosemary extract (Rosmarinus officinalis). Berry phenolics such as black currant (Ribes nigrum) anthocyanins and raspberry (Rubus idaeus) ellagitannins showed potent antioxidant activity in corn oil-in-water emulsions toward lipid oxidation with and without β-lactoglobulin. The antioxidant effect was more pronounced in the presence of β-lactoglobulin. The berry phenolics also inhibited the oxidation of tryptophan and cysteine side chains of β-lactoglobulin. The results show that the amino acid side chains were oxidized prior the propagation of lipid oxidation, thereby inhibiting fatty acid scission. In addition, the concentration and color of black currant anthocyanins decreased during the oxidation. Oxidation of tryptophan was investigated in two different oxidation models with hydrogen peroxide (H2O2) and hexanal/FeCl2. Oxidation of tryptophan in both models resulted in oxidation products such as 3a-hydroxypyrroloindole-2-carboxylic acid, dioxindolylalanine, 5-hydroxy-tryptophan, kynurenine, N-formylkynurenine and β-oxindolylalanine. However, formation of tryptamine was only observed in tryptophan oxidized in the presence of H2O2. Pine bark phenolics, black currant anthocyanins, camelina meal phenolics as well as cranberry proanthocyanidins (Vaccinium oxycoccus) provided the best antioxidant effect toward tryptophan and its oxidation products when oxidized with H2O2. The tryptophan modifications formed upon hexanal/FeCl2 treatment were efficiently inhibited by camelina meal followed by rapeseed and soy meal. In contrast, phenolics from raspberry, black currant, and rowanberry (Sorbus aucuparia) acted as weak prooxidants. This thesis contributes to elucidating the effects of natural phenolic compounds as potential antioxidants in order to control and prevent protein and lipid oxidation reactions. Understanding the relationship between phenolic compounds and proteins as well as lipids could lead to the development of new, effective, and multifunctional antioxidant strategies that could be used in food, cosmetic and pharmaceutical applications.

HPLC analysis of plant sterol oxidation products

Increased interest in the cholesterol-lowering effect of plant sterols has led to development of plant sterol-enriched foods. When products are enriched, the safety of the added components must be evaluated. In the case of plant sterols, oxidation is the reaction of main concern. In vitro studies have indicated that cholesterol oxides may have harmful effects. Due their structural similarity, plant sterol oxidation products may have similar health implications. This study concentrated on developing high-performance liquid chromatography (HPLC) methods that enable the investigation of formation of both primary and secondary oxidation products and thus can be used for oxidation mechanism studies of plant sterols. The applicability of the methods for following the oxidation reactions of plant sterols was evaluated by using oxidized stigmasterol and sterol mixture as model samples. An HPLC method with ultraviolet and fluorescence detection (HPLC-UV-FL) was developed. It allowed the specific detection of hydroperoxides with FL detection after post-column reagent addition. The formation of primary and secondary oxidation products and amount of unoxidized sterol could be followed by using UV detection. With the HPLC-UV-FL method, separation between oxides was essential and oxides of only one plant sterol could be quantified in one run. Quantification with UV can lead to inaccuracy of the results since the number of double bonds had effect on the UV absorbance. In the case of liquid chromatography-mass spectrometry (LC-MS), separation of oxides with different functionalities was important because some oxides of the same sterol have similar molecular weight and moreover epimers have similar fragmentation behaviour. On the other hand, coelution of different plant sterol oxides with the same functional group was acceptable since they differ in molecular weights. Results revealed that all studied plant sterols and cholesterol seem to have similar fragmentation behaviour, with only relative ion abundances being slightly different. The major advantage of MS detection coupled with LC separation is the capability to analyse totally or partly coeluting analytes if these have different molecular weights. The HPLC-UV-FL and LC-MS methods were demonstrated to be suitable for studying the photo-oxidation and thermo-oxidation reactions of plant sterols. The HPLC-UV-FL method was able to show different formation rates of hydroperoxides during photo-oxidation. The method also confirmed that plant sterols have similar photo-oxidation behaviour to cholesterol. When thermo-oxidation of plant sterols was investigated by HPLC-UV-FL and LC-MS, the results revealed that the formation and decomposition of individual hydroperoxides and secondary oxidation products could be studied. The methods used revealed that all of the plant sterols had similar thermo-oxidation behaviour when compared with each other, and the predominant reactions and oxidation rates were temperature dependent. Overall, these findings showed that with these LC methods the oxidation mechanisms of plant sterols can be examined in detail, including the formation and degradation of individual hydroperoxides and secondary oxidation products, with less sample pretreatment and without derivatization.

Prognostic importance of the tumour microenvironment in follicular lymphoma patients treated with immunochemotherapy

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma. It is an indolent and clinically heterogeneous disease, which is generally considered incurable. Currently, immunochemotherapy has significantly improved the outcome of FL patients. This is based on the combination of rituximab, a monoclonal anti-CD20 antibody, with chemotherapy, and is used at present as a standard first-line therapy in FL. Thus far, however, patients have been selected for treatment based on clinical risk factors and indices that were developed before the rituximab era. Therefore, there is a growing need to understand the molecular mechanisms underlying the disease, which would not only provide information to predict survival in the rituximab era, but also enable the design of more targeted therapeutic strategies. In this study, our aim was to identify genes predicting the outcome in FL patients treated with immunochemotherapy. Thus, we performed a cDNA microarray with 24 FL patients. When gene expression differences from diagnostic tumour samples were related to the clinical outcome, we identified novel genes with a prognostic impact on survival. The expression of selected genes was further characterized with quantitative PCR and immunohistochemistry (IHC). Interestingly, the prognostic influence of these genes was often associated with their expression in non-malignant cells instead of tumour cells. Based on the observed gene expression patterns, we analyzed the abundance and prognostic value of non-malignant immune cells in 95-98 FL patients treated with immunochemotherapy. We observed that a high content of tumour-associated macrophages was a marker of a favourable prognosis. In contrast, the accumulation of mast cells correlated with a poor outcome and was further associated with tumour vascularity. Increased microvessel density also correlated with an inferior outcome. In addition, we used the same microarray data with a systems biology approach to identify signalling pathways or groups of genes capable of separating patients with favourable or adverse outcomes. Among the transcripts, there were many genes associated with signal transducers and activators of the transcription (STAT5a) pathway. When IHC was used as validation, STAT5a expression was mostly observed in T-cells and follicular dendritic cells, and expression was found to predict a favourable outcome. In cell cultures, rituximab was observed to induce the expression of STAT5a-associated interleukins in human lymphoma cell lines, which might provide a possible link for the cross-talk between rituximab-induced FL cells and their microenvironment. In conclusion, we have demonstrated that the microenvironment has a prognostic role in FL patients treated with immunochemotherapy. The results also address the importance of re-evaluating the prognostic markers in the rituximab era of lymphoma therapies.