First-Line Chemotherapy with Anthracycline and Taxane Combination in Metastatic Breast Cancer. Detection of bone metastases with TRACP 5b

Background: In Finland, breast cancer (BC) is the most common cancer among women, and prostate cancer (PC) that among men. At the metastatic stage both cancers remain essentially incurable. The goals of therapy include palliation of symptoms, improvement or maintenance of quality of life (QoL), delay of disease progression, and prolongation of survival. Balancing between efficacy and toxicity is the major challenge. With increasing costs of new treatments, appropriate use of resources is paramount. When new treatment regimes are introduced into clinical practice a comprehensive assessment of clinical benefit, adverse effects and cost is necessary. Both BC and PC show a predilection to metastasize to bone. Bone metastases cause significant morbidity impairing the patients´ QoL. Diagnosis of bone metastases relies mainly on radiological methods, which however lack optimal sensitivity and specificity. New tools are needed for detection and follow-up of bone metastases. Aims: Anthracyclines and taxanes are effective chemotherapeutic agents in the treatment of metastatic breast cancer (MBC) with different mechanisms of action. Therefore, evaluation of the combination of anthracyclines with taxanes was a justifiable approach in the treatment of MBC patients. We assessed the efficacy, toxicity, cost of treatment and QoL of BC patients treated with first-line chemotherapy for metastatic disease with the combination epirubicin and docetaxel. We also evaluated the diagnostic potential of tartrate-resistant acid phosphatase 5b (TRACP 5b) and carboxyterminal telopeptides of type I collagen (ICTP) in the diagnosis of bone metastases in BC and TRACP 5b in PC patients. Results: The combination of epirubicin and docetaxel was effective in this phase II study, but required individual dose adjustment to avoid neutropenic infections, and the use of growth factors to maintain a feasible dose level. The response rate was 54 % (95 % CI 37-71) and the median overall survival (OS) was 26 months. Of the patients, 87 % were treated for infections. The treatment of adverse events required additional use of health resources mainly due to neutropenic infections, thereby raising direct treatment costs by 20 %. Despite adverse events, the global QoL was not significantly compromised during the treatment. Clinically evident acute cardiac toxicity was not observed. The combination of serum TRACP 5b and ICTP was at least equally sensitive and specific in detection of of bone metastases as commonly used total alkaline phosphatise (tALP) in BC patients. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC patients. Conclusions: Treatment with epirubicin and docetaxel showed high efficacy in first-line chemotherapy of MBC. The relatively high incidence of neutropenic infections requiring hospitalization increased the treatment costs. Despite adverse events, the global QoL of the patients was not significantly compromised. The combination of TRACP 5b and ICTP showed similar activity as tALP in detecting bone metastases in MBC. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC.

Loss Modelling of Three-Level Inverters controlled with Space Vector Modulation Technique

The objective of this master’s thesis is to investigate the loss behavior of three-level ANPC inverter and compare it with conventional NPC inverter. The both inverters are controlled with mature space vector modulation strategy. In order to provide the comparison both accurate and detailed enough NPC and ANPC simulation models should be obtained. The similar control model of SVM is utilized for both NPC and ANPC inverter models. The principles of control algorithms, the structure and description of models are clarified. The power loss calculation model is based on practical calculation approaches with certain assumptions. The comparison between NPC and ANPC topologies is presented based on results obtained for each semiconductor device, their switching and conduction losses and efficiency of the inverters. Alternative switching states of ANPC topology allow distributing losses among the switches more evenly, than in NPC inverter. Obviously, the losses of a switching device depend on its position in the topology. Losses distribution among the components in ANPC topology allows reducing the stress on certain switches, thus losses are equally distributed among the semiconductors, however the efficiency of the inverters is the same. As a new contribution to earlier studies, the obtained models of SVM control, NPC and ANPC inverters have been built. Thus, this thesis can be used in further more complicated modelling of full-power converters for modern multi-megawatt wind energy conversion systems.

Techno-Economic Feasibility of Novel On-Line Condition Monitoring Methods in Low Voltage Distribution Networks

The focus in this thesis is to study both technical and economical possibilities of novel on-line condition monitoring techniques in underground low voltage distribution cable networks. This thesis consists of literature study about fault progression mechanisms in modern low voltage cables, laboratory measurements to determine the base and restrictions of novel on-line condition monitoring methods, and economic evaluation, based on fault statistics and information gathered from Finnish distribution system operators. This thesis is closely related to master’s thesis “Channel Estimation and On-line Diagnosis of LV Distribution Cabling”, which focuses more on the actual condition monitoring methods and signal theory behind them.

People and the intertidal : human induced changes, biodiversity loss, livelihood implications and management in the Western Indian Ocean

Vad händer i tidvattenzonen? Var går gränsen mellan land och hav, vad händer i tidvattenzonen och vem ansvarar för detta? I västra Indiska oceanen (VIO) kan avståndet mellan den lägsta nivån för lågvattnet och den högsta nivån för högvattnet vara flera kilometer och nivåskillnaderna upp till 6 meter och detta skapar ett stort och föränderligt område. Syftet med min avhandling är att öka förståelsen för tidvattenzonen i tropiska och subtropiska västra Indiska oceanen. Sammanfattningsvis visar mina studier att det finns ett mycket stort värde i den komplexa tidvattenzonen, men också att det här området hotas från både land och hav, genom t.ex. överexploatering, erosion och föroreningar. Uttnyttjandet av tidvattenzonen är stort och min avhandling har visat att aktiviteter såsom fiske i form av plocking av musslor och andra ryggradslösa djur och hamnaktiviteter påverkar den biologiska mångfalden negativt, vilket leder till försämrad levnadsstandard för resursutnyttjande människor i regionen. För att förbättra situationen krävs det mer forskning, miljöövervakning och bättre förvaltning av tidvattenzonen. Experter i regionen har rangordnat förslag på förvaltningsstrategier som skulle kunna testas för att förbättra miljön och skapa ett mer hållbart nyttjande. Avhandlingen visar även att det är möjligt att använda fjärranalysteknik såsom satellitbildsanalys för att kvantifiera mängden sjögräsvegetation (i form av biomassa), vilket kan ha stor betydelse för att förbättra storskalig miljöövervakning av kustnära naturtyper (habitat). I avhandlingsarbetet har jag använt mig av ett multidisciplinärt tillvägagångssätt och använt metoder såsom ekologisk och biologisk provtagning, intervjuer, observationer, diskussionsgrupper, frågeformulär och fjärranalys. Resultaten presenterade i denna avhandling ger en ökad kunskap om tidvattenzonen i utvecklingsländerna inom VIO-regionen som kan användas för att initiera och fortsätta att utveckla hållbara förvaltningsstrategier av biologiska resurser.

The spindle assembly checkpoint as a drug target - Novel small-molecule inhibitors of Aurora kinases

Cell division (mitosis) is a fundamental process in the life cycle of a cell. Equal distribution of chromosomes between the daughter cells is essential for the viability and well-being of an organism: loss of fidelity of cell division is a contributing factor in human cancer and also gives rise to miscarriages and genetic birth defects. For maintaining the proper chromosome number, a cell must carefully monitor cell division in order to detect and correct mistakes before they are translated into chromosomal imbalance. For this purpose an evolutionarily conserved mechanism termed the spindle assembly checkpoint (SAC) has evolved. The SAC comprises a complex network of proteins that relay and amplify mitosis-regulating signals created by assemblages called kinetochores (KTs). Importantly, minor defects in SAC signaling can cause loss or gain of individual chromosomes (aneuploidy) which promotes tumorigenesis while complete failure of SAC results in cell death. The latter event has raised interest in discovery of low molecular weight (LMW) compounds targeting the SAC that could be developed into new anti-cancer therapeutics. In this study, we performed a cell-based, phenotypic high-throughput screen (HTS) to identify novel LMW compounds that inhibit SAC function and result in loss of cancer cell viability. Altogether, we screened 65 000 compounds and identified eight that forced the cells prematurely out of mitosis. The flavonoids fisetin and eupatorin, as well as the synthetic compounds termed SACi2 and SACi4, were characterized in more detail utilizing versatile cell-based and biochemical assays. To identify the molecular targets of these SAC-suppressing compounds, we investigated the conditions in which SAC activity became abrogated. Eupatorin, SACi2 and SACi4 preferentially abolished the tensionsensitive arm of the SAC, whereas fisetin lowered also the SAC activity evoked by lack of attachments between microtubules (MTs) and KTs. Consistent with the abrogation of SAC in response to low tension, our data indicate that all four compounds inhibited the activity of Aurora B kinase. This essential mitotic protein is required for correction of erratic MT-KT attachments, normal SAC signaling and execution of cytokinesis. Furthermore, eupatorin, SACi2 and SACi4 also inhibited Aurora A kinase that controls the centrosome maturation and separation and formation of the mitotic spindle apparatus. In line with the established profound mitotic roles of Aurora kinases, these small compounds perturbed SAC function, caused spindle abnormalities, such as multi- and monopolarity and fragmentation of centrosomes, and resulted in polyploidy due to defects in cytokinesis. Moreover, the compounds dramatically reduced viability of cancer cells. Taken together, using a cell-based HTS we were able to identify new LMW compounds targeting the SAC. We demonstrated for the first time a novel function for flavonoids as cellular inhibitors of Aurora kinases. Collectively, our data support the concept that loss of mitotic fidelity due to a non-functional SAC can reduce the viability of cancer cells, a phenomenon that may possess therapeutic value and fuel development of new anti-cancer drugs.

Understanding the in vitro dissolution rate of glasses with respect to future clinical applications

Glass is a unique material with a long history. Several glass products are used daily in our everyday life, often unnoticed. Glass can be found not only in obvious applications such as tableware, windows, and light bulbs, but also in tennis rackets, windmill turbine blades, optical devices, and medical implants. The glasses used at present as implants are inorganic silica-based melt-derived compositions mainly for hard-tissue repair as bone graft substitute in dentistry and orthopedics. The degree of glass reactivity desired varies according to implantation situation and it is vital that the ion release from any glasses used in medical applications is controlled. Understanding the in vitro dissolution rate of glasses provides a first approximation of their behavior in vivo. Specific studies concerning dissolution properties of bioactive glasses have been relatively scarce and mostly concentrated to static condition studies. The motivation behind this work was to develop a simple and accurate method for quantifying the in vitro dissolution rate of highly different types of glass compositions with interest for future clinical applications. By combining information from various experimental conditions, a better knowledge of glass dissolution and the suitability of different glasses for different medical applications can be obtained. Thus, two traditional and one novel approach were utilized in this thesis to study glass dissolution. The chemical durability of silicate glasses was tested in water and TRIS-buffered solution at static and dynamic conditions. The traditional in vitro testing with a TRISbuffered solution under static conditions works well with bioactive or with readily dissolving glasses, and it is easy to follow the ion dissolution reactions. However, in the buffered solution no marked differences between the more durable glasses were observed. The hydrolytic resistance of the glasses was studied using the standard procedure ISO 719. The relative scale given by the standard failed to provide any relevant information when bioactive glasses were studied. However, the clear differences in the hydrolytic resistance values imply that the method could be used as a rapid test to get an overall idea of the biodegradability of glasses. The standard method combined with the ion concentration and pH measurements gives a better estimate of the hydrolytic resistance because of the high silicon amount released from a glass. A sensitive on-line analysis method utilizing inductively coupled plasma optical emission spectrometer and a flow-through micro-volume pH electrode was developed to study the initial dissolution of biocompatible glasses. This approach was found suitable for compositions within a large range of chemical durability. With this approach, the initial dissolution of all ions could be measured simultaneously and quantitatively, which gave a good overall idea of the initial dissolution rates for the individual ions and the dissolution mechanism. These types of results with glass dissolution were presented for the first time during the course of writing this thesis. Based on the initial dissolution patterns obtained with the novel approach using TRIS, the experimental glasses could be divided into four distinct categories. The initial dissolution patterns of glasses correlated well with the anticipated bioactivity. Moreover, the normalized surface-specific mass loss rates and the different in vivo models and the actual in vivo data correlated well. The results suggest that this type of approach can be used for prescreening the suitability of novel glass compositions for future clinical applications. Furthermore, the results shed light on the possible bioactivity of glasses. An additional goal in this thesis was to gain insight into the phase changes occurring during various heat treatments of glasses with three selected compositions. Engineering-type T-T-T curves for glasses 1-98 and 13-93 were stablished. The information gained is essential in manufacturing amorphous porous implants or for drawing of continuous fibers of the glasses. Although both glasses can be hot worked to amorphous products at carefully controlled conditions, 1-98 showed one magnitude greater nucleation and crystal growth rate than 13-93. Thus, 13-93 is better suited than 1-98 for working processes which require long residence times at high temperatures. It was also shown that amorphous and partially crystalline porous implants can be sintered from bioactive glass S53P4. Surface crystallization of S53P4, forming Na2O∙CaO∙2SiO2, was observed to start at 650°C. The secondary crystals of Na2Ca4(PO4)2SiO4, reported for the first time in this thesis, were detected at higher temperatures, from 850°C to 1000°C. The crystal phases formed affected the dissolution behavior of the implants in simulated body fluid. This study opens up new possibilities for using S53P4 to manufacture various structures, while tailoring their bioactivity by controlling the proportions of the different phases. The results obtained in this thesis give valuable additional information and tools to the state of the art for designing glasses with respect to future clinical applications. With the knowledge gained we can identify different dissolution patters and use this information to improve the tuning of glass compositions. In addition, the novel online analysis approach provides an excellent opportunity to further enhance our knowledge of glass behavior in simulated body conditions.

DFMA Aspects in the Design of a Transfer Line for Off-line Ion Sources

In this thesis, the DFMA is presented and used for the purpose of having a design for a vertical transfer line that can be easily manufactured and assembled. The design of the transfer line, the major components and drawings are presented. The ease of assembly, the costs of manufacturing and differences between the use of steel structure and aluminum are compared. The ALARA principle is followed to minimize the risk of radiation exposure by the means of locating the test ion sources outside the radioactive area.

The Effects of Anesthetic Induced Loss of Consciousness on Quantitative Electroen Cephalogram, and Bispectral and Spectral Entropy Indices. Studies on Healthy Male

Changes in the electroencephalography (EEG) signal have been used to study the effects of anesthetic agents on the brain function. Several commercial EEG based anesthesia depth monitors have been developed to measure the level of the hypnotic component of anesthesia. Specific anesthetic related changes can be seen in the EEG, but still it remains difficult to determine whether the subject is consciousness or not during anesthesia. EEG reactivity to external stimuli may be seen in unconsciousness subjects, in anesthesia or even in coma. Changes in regional cerebral blood flow, which can be measured with positron emission tomography (PET), can be used as a surrogate for changes in neuronal activity. The aim of this study was to investigate the effects of dexmedetomidine, propofol, sevoflurane and xenon on the EEG and the behavior of two commercial anesthesia depth monitors, Bispectral Index (BIS) and Entropy. Slowly escalating drug concentrations were used with dexmedetomidine, propofol and sevoflurane. EEG reactivity at clinically determined similar level of consciousness was studied and the performance of BIS and Entropy in differentiating consciousness form unconsciousness was evaluated. Changes in brain activity during emergence from dexmedetomidine and propofol induced unconsciousness were studied using PET imaging. Additionally, the effects of normobaric hyperoxia, induced during denitrogenation prior to xenon anesthesia induction, on the EEG were studied. Dexmedetomidine and propofol caused increases in the low frequency, high amplitude (delta 0.5-4 Hz and theta 4.1-8 Hz) EEG activity during stepwise increased drug concentrations from the awake state to unconsciousness. With sevoflurane, an increase in delta activity was also seen, and an increase in alpha- slow beta (8.1-15 Hz) band power was seen in both propofol and sevoflurane. EEG reactivity to a verbal command in the unconsciousness state was best retained with propofol, and almost disappeared with sevoflurane. The ability of BIS and Entropy to differentiate consciousness from unconsciousness was poor. At the emergence from dexmedetomidine and propofol induced unconsciousness, activation was detected in deep brain structures, but not within the cortex. In xenon anesthesia, EEG band powers increased in delta, theta and alpha (8-12Hz) frequencies. In steady state xenon anesthesia, BIS and Entropy indices were low and these monitors seemed to work well in xenon anesthesia. Normobaric hyperoxia alone did not cause changes in the EEG. All of these results are based on studies in healthy volunteers and their application to clinical practice should be considered carefully.