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The thesis discusses the methods of determination of tumor markers and their clinical importance in medical diagnostics. The theoretical part describes clinically important tumor markers and also the chemiluminescent immunoassay methods used for their determination. The practical part of the thesis describes the introduction of new chemiluminescent methods for the determination of tumor markers in routine operation, evaluates its basic analytical parameters and compares it with the existing immunoturbidimetric method. The practical part also presents results of monitoring of cancer patients with various tumors, which is performed by evaluation of the values of tumor markers. Comparison of our method with other methods within the context of System of external quality control is also documented.

Cities play a crucial role in sustainable energy system transformation. Urban energy systems account for 75% of global primary energy use, and 70% of global greenhouse gas (GHG) emissions (IEA, 2021). There is currently a large, untapped potential for reducing both energy demand and emissions by focusing measures on one of the largest consumers of energy: buildings. In North Macedonia, there is an estimated energy savings potential of 57% in the residential sector, and 29% in the public service sector (Apostolska et al., 2020). In the midst of the country’s ambitious targets of decreasing energy demand and GHG reductions, the city of Bitola is in the process of developing an action plan for a sustainable transition of the city. For this purpose, there is a need to investigate the current challenges in the energy system of the city and to evaluate potential future pathways to address these challenges, with a focus on the built environment. In this thesis, a city-scale urban building energy model (UBEM) of the city of Bitola was developed using the software City Energy Analyst (CEA). This involved modeling a total of 14 024 buildings in the city ranging from residential buildings to commercial and industrial facilities. Out of these 14 024 buildings, 10 792 were included in the analysis after excluding abandoned buildings which account for an estimated 25% of the total residential building stock. One Baseline scenario based on the current energy use in the built environment in the city, and four scenarios investigating building retrofit measures and alternative heating solutions were developed for the time period 2023-2040 which were then assessed based on three key performance indicators (KPIs). A 2% implementation rate was used for the measures included in the scenarios, resulting in a total of 34% of the buildings being included in the scenario assessment. The scenarios included in the analysis are Business-as-Usual (BAU), decentralized natural gas boilers (NGB), district heating (DH) and decentralized heat pumps (HP). The KPIs include the total primary energy demand, the total operational CO2 emissions, and the economic performance of the system, measured as a net present value (NPV). All scenarios were also evaluated with and without solar photovoltaic (PV). The results showed the BAU scenario to be the lowest performing scenario for all three KPIs, while the HP scenario showed to be the best-performing scenario regarding the reduction of energy demand and CO2 emissions, with a 99% reduction of CO2 emissions and a 65% lower energy demand than in the baseline year. However, this comes at a relatively high cost compared to the other scenarios. The DH and NGB scenarios performed moderately regarding demand and CO2 emission savings while performing better from an economic standpoint. All scenarios showed a low share of buildings on an individual level having a positive NPV, thus failing to reach a positive total NPV for the entire system. On the other hand, the sensitivity analysis demonstrated how a reduction of the capital expenditure (CAPEX) led to a positive NPV for all scenarios with PV, and for all scenarios except BAU without PV. This indicates that subsidies provided by local or national stakeholders could result in a profitable investment. Two important conclusions can be drawn from the results: firstly, taking any action and implementing either of the HP, NGB and DH scenarios will be more beneficial than taking no action, and secondly, the sustainable development of the city needs to be led by the local municipality, as well as national stakeholders to enable a long-lasting transition. / Städer spelar en avgörande roll för omställningen till hållbara energisystem. Energisystem i städer står för 75% av den globala primära energianvändningen och 70% av de globala växthusgasutsläppen (IEA, 2021). För närvarande finns det en stor, outnyttjad potential för minskning av både energibehov och utsläpp genom att fokusera på åtgärder för en av de största energikonsumenterna: byggnader. I Nordmakedonien uppskattas det finnas potential för energibesparingar på 57% i bostadssektorn och 29% i offentlig sektor (Apostolska et al., 2020). I samband med landets ambitiösa mål om att minska energianvändning och växthusgasutsläpp genomgår staden Bitola för närvarande en process för att utveckla en handlingsplan för en hållbar omställning av staden. För detta ändamål krävs en undersökning av de aktuella utmaningarna i stadens energisystem och utvärdering av potentiella framtida riktningar för att möta dessa utmaningar, med fokus på den bebyggda miljön. I detta examensarbete utvecklades en modell i stadsskala av energianvändningen i byggnader för staden Bitola i Nordmakedonien med hjälp av programvaran City Energy Analyst (CEA). Modellen omfattade totalt 14 024 byggnader, från bostadshus till kommersiella och industriella fastigheter. Då 25% av stadens bostadsbyggnader uppskattas vara övergivna ingick totalt 10 792 byggnader i den slutgiltiga analysen. Ett basscenario som beskriver dagens energianvändning i byggnaderna, och fyra framtida scenarier, som omfattar energieffektiviseringsåtgärder och alternativa värmesystem, utvecklades för tidsperioden 2023-2040. En implementeringstakt om 2% av byggnadsbeståndet, vilket resulterade i att totalt 34% av byggnadsbeståndet inkluderades i scenarioanalysen. De fyra framtida scenarierna som ingick i analysen är Business-as-Usual (BAU), decentraliserade gasvärmepannor (NGB), fjärrvärme (DH) och decentraliserade värmepumpar (HP). Scenarierna bedömdes med hjälp av tre nyckeltal (KPI:er): den totala primärenergianvändningen, de totala operativa CO2 utsläppen och den ekonomiska prestandan, mätt som investeringens nu värde (NPV). Samtliga scenarier utvärderades med och utan implementering av solceller. Resultaten visade att scenariot BAU presterade sämst för alla tre KPI:er, medanHP-scenariot visade sig vara det bäst presterande scenariot för minskning avenergibehovet och CO2-utsläppen, med 99% minskning av CO2-utsläpp och 65%lägre energianvändning jämfört med basscenariot. Dock är detta förknippat medrelativt höga kostnader jämfört med de andra scenarierna. DH- och NGB-scenariotpresterade måttligt gällande besparing av energibehov och CO2-utsläpp, samtidigt somde presterade bättre ur ett ekonomiskt perspektiv. Alla scenarier resulterade i en lågandel av byggnader på individuell nivå med ett positivt NPV, vilket innebär att demisslyckas med att nå ett positivt totalt NPV för hela systemet. Å andra sidan visadekänslighetsanalysen att en minskning av investerings kostnaderna (CAPEX) ledde tillett positivt NPV för alla scenarier med solceller, och för alla scenarier utom BAU utan solceller. Detta indikerar att subventioner från lokala och nationella aktörer kan leda till en lönsam investering. Två viktiga slutsatser kan dras från dessa resultat: för det första, att vidta åtgärder och implementera något av HP-, NGB- eller DH-scenariot är mer fördelaktigt än att inte vidta några åtgärder, och för det andra, behöver den hållbara utvecklingen av staden ledas av den lokala kommunen samt nationella aktörer för att möjliggöra en långvarig omställning.

This thesis aims to investigate whether additive manufacturing is applicable in manufacturing the 1N thruster option that Bradford Ecaps offers. Therefore, the nozzle design is of particular interest as AM provides accessibilities to manufacturing complex structures. The current Ecaps 1N thruster has an operating thrust lifespan that exceeds the required lifespan commonly needed for the majority of customers. With AM, an increase in production throughput and optimization of nozzle design is possible. A candidate material, a platinum group metal, was picked for a future 1N thruster prototype concerning the limiting operating constraints. Computational fluid analysis was performed to investigate different contour nozzles to investigate the possibility of improving the performance of the Bradford ECAPS 1N thruster. AMATLAB code was developed to model the contour nozzles, and ANSYS Fluent was used for the computational analysis. Three different nozzle geometries were evaluated to investigate the overall performance of the expanding exhaust gas and thrust properties in vacuum conditions. Configuration 1. which had an extended nozzle was selected as a solution since it eliminatedthe interferences with the continuum. The Nasa CEA code was used to generate the fluid gas properties. No substantial performance gain was observed for the 1N thruster. This was found to be due to the boundary-dominated flow exhibited in the nozzle. A conical nozzle was found to work comparatively well. / Detta examensarbete syftar till att undersöka om additiv tillverkning (AM) är tillämplig vid tillverkning av Bradford Ecaps 1N raketmotor. Därför är munstycksdesignen av särskilt intresse eftersom AM ger möjlighet för tillverkning av komplexa strukturer. Den nuvarande Ecaps 1N-motorn har en livslängd som överstiger den livslängd som krävs för de flesta kunder. Med AM är ökning av produktionsgenomströmningen och optimering av munstycksdesign möjlig. Ett kandidatmaterial, en metall i platinagruppen, valdes ut för en framtida 1N prototyp med hänvisning till de begränsande driftsbegränsningarna. Beräkningsflödesanalys utfördes för att undersöka olika konturmunstycken för att undersöka möjligheten till att förbättra prestandan hos Bradford ECAPS 1N framdrivningssystem. En MATLAB-kod utvecklades för att modellera konturmunstyckena och ANSYS Fluent användes för beräkningsanalysen. Tre olika munstycksgeometrier utvärderades för att undersöka den totala prestandan hos de expanderande avgaserna och dragkraftsegenskaperna under vakuumförhållanden. Konfiguration 1. som hade ett förlängt munstycke valdes som en lösning eftersom detta eliminerade interferenserna med kontinuumet. Nasa CEA-koden användes för att generera fluidens gasegenskaper. Ingen betydande prestandaökning observerades för 1N motorn. Detta visade sig bero på det gränsskiktsdominerade flödet som uppvisades i munstycket. Ett koniskt munstycke visade sig fungera relativt bra.

Cancer is one of the major causes of morbidity in the world. Although the overall survival of cancer has been significantly improved by chemotherapy in the last three decades, the success of cancer chemotherapy is still severely limited by the lack of selectivity of anti-cancer drugs to malignant cells leading to dose-limiting toxicity and the resistance of cancer cells to the conventional anti-cancer drugs. Gene-directed enzyme prodrug therapy (GDEPT) was designed to direct the anti-cancer drugs to specifically target the cancer cells by using cancer specific promoter to drive the expression of enzyme which can convert prodrug into anti-cancer drug specifically in cancer cells. However, this strategy is hindered by the lack of strong cancer specific promoters to specifically express drug-converting enzymes in cancer cells. In consequence, there is not enough anti-cancer drug activated inside the cancer cells. The first part of this study was to employ NF-κB binding sites as a novel enhancer system to improve the promoter activity of carcinoembryonic antigen (CEA) and human telomerase reverse transcriptase (hTERT) for GDEPT. In this system, the basal CEA promoter sequences were placed downstream of the 4 or 8 NF-κB DNA binding sites linked in tandem (κB4 or κB8). The system was designed to serve two particular purposes: to exploit the high levels of intratumoural NF-kB expression and keep the relative tumour specificity of the CEA and hTERT promoters. The results demonstrated that κB enhancer systems increased the transcriptional activity of CEA and hTERT promoter without compromising its cancer specificity. The fidelity of the κB4-CEA enhancer-promoter system was therefore improved by the increased transcriptional contrast between the cancer and normal cells. Moreover, in comparison with CEA promoter alone, κB-CEA enhancer-promoter system expressed human thymidine phosphorylase (TP) protein at significantly higher levels which were comparable to those expressed by CMV promoter. The κBCEA- TP system transfected cells demonstrated significantly higher sensitivity to 5'-Deoxy-5-Fluorouridine (5'-DFUR), a prodrug of 5-fluorouracil (5-FU). The second part of this study was involved in using NF-κB inhibitor as a chemosensitizer to sentizise the anti-cancer drug-induced chemoresistance cells to anti-cancer drugs. The results derived from this study manifested that the anti-alcoholism drug, Disulfiram (DS), and anti-inflammatory drug, triptolide (PG490), markedly enhanced the cytotoxicity of several conventional anti-cancer drugs in colon, lung and breast cancer cell lines. PG490 induced caspase-dependent cell death accompanied by a significant decrease in Bcl-2 levels. PG490 induced the expression of p53 and down-regulated p21 expression. This study indicated that some clinically used non-cancerchemotherapeutic drugs may be developed as chemosensitizers for cancer chemotherapy

The bankruptcy problem involves the distribution of perfectly divisible goods. Particular attention is paid to the situations, where the amount of goods available is not enough to cover the demand. An example of real life situations that can be solved using various bankruptcy rules may be a division of a heritage or when a company goes bankrupt and its estates are sold to satisfy interested parties' claims. This paper introduces to the problem a linear structure of the participants, meaning that participants are now satisfied one after another in a preset order. It applies the equal awards (CEA) and the equal losses (CEL) solutions on the revised problem. Since their axiomatization is no longer valid, both solutions are extended and new characterizations are given in the thesis. The thesis contains a series of original proofs for both extended solutions and whole problem is examined in the setting of the well-known river sharing problem.

Submitted by Verena Bastos (verena@uefs.br) on 2015-09-21T14:21:13Z No. of bitstreams: 1 DISSERTA??O_Mariana Santos de Jesus_2013_v.FINAL.pdf: 2182580 bytes, checksum: 54eae6f08c950fc41cd0623949c61663 (MD5) / Made available in DSpace on 2015-09-21T14:21:13Z (GMT). No. of bitstreams: 1 DISSERTA??O_Mariana Santos de Jesus_2013_v.FINAL.pdf: 2182580 bytes, checksum: 54eae6f08c950fc41cd0623949c61663 (MD5) Previous issue date: 2013-03-25 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / The Brazilian semiarid region undergoes seasonal distribution of rainfall that is concentrated in short periods of the year, combined with shallow and stony soils with low organic matter content and ability to retain moisture. Given these limitations, has intensified in this region the use of cactus as a food source herd due to its high capacity to adapt to the climate of this region. This study evaluated for agronomic characteristics, chemical characteristics and chromosome 20 clones preselected by Oliveira 2010, forming part of the breeding program of cactus pear State University of Feira de Santana, in existence since December 2008. Two experiments were conducted. In the first containing palm girl (Nopalea cochenillifera & Salm Dyck) and the second with giant cactus (Opuntia ficus-indica Mill). The experimental design was randomized blocks with five replicates, the spacing was 0.5 x 1.0 m (x plant rows) and fertilization administered 30 t/ha-1 of manure. Data were submitted to ANOVA and Tukey test (p <0.01 and p <0.05). For agronomic characteristics, the tiny palm clones showed no significant differences between the observed means. For the giant cactus, clone 4:06 stood out compared to the other featuring the best averages for the number of cladodes per plant. In assessing chemical was observed on average 69.91% NDF, 13.09% ADF and 8.49% CP for Palm kid. For giant cactus values were 45.63% NDF, 18.20% ADF and 9.18% PB. Chromosome analysis revealed that the numbers ranged from 2n = 22 in the palm girl to 2n = 88 in the giant cactus, without occurrence of disploidias or aneupoidias plants analyzed. It was found that clones are very promising for breeding programs, and are recommended for cultivation in the region of Feira de Santana-BA. / O semi?rido brasileiro apresenta sazonalidade na distribui??o de chuvas que s?o concentradas em per?odos curtos do ano, aliados a solos pouco profundos e pedregosos com baixo teor de mat?ria org?nica e capacidade de reter umidade. Diante destas limita??es, tem-se intensificado nessa regi?o o uso da palma forrageira como fonte de alimento do rebanho devido a sua alta capacidade de adapta??o ao clima dessa regi?o. Este trabalho objetivou avaliar quanto ?s caracter?sticas agron?micas, bromatol?gicas e cromoss?micas 20 clones pr? selecionados por Oliveira (2010), que fazem parte do programa de melhoramento gen?tico da palma forrageira da universidade Estadual de Feira de Santana, existente desde Dezembro de 2008. Foram estabelecidos dois experimentos. No primeiro contendo palma mi?da (Nopalea cochenillifera Salm & Dyck) e o segundo com palma gigante (Opuntia f?cus-indica Mill). O delineamento experimental utilizado foi de blocos ao acaso com cinco parcelas, o espa?amento foi 0,5 x 1,0 m (plantas x fileiras) e a aduba??o administrada de 30 t/ha-1 de esterco bovino. Os dados foram submetidos ? an?lise de vari?ncia e teste de Scott-Knott (p<0,05). Para as caracter?sticas agron?micas, os clones de palma mi?da foram inferiores em rela??o ?s testemunhas IPA-sert?nia e IPA-mi?da para os caracteres CC, DC e AC. Para a palma gigante, o clone 04 destacou-se em rela??o aos demais diferindo estatisticamente quanto ao n?mero de clad?dios por planta. Na avalia??o bromatol?gica observou-se em m?dia 69,91% de FDN, 13,09% de FDA e 8,49% de PB para a palma mi?da. Para palma gigante os valores m?dios foram 45,63% FDN, 18,20% FDA e 9,18% PB. As an?lises cromoss?micas revelaram que os n?meros variaram de 2n=22 na palma mi?da a 2n=88 na palma gigante, sem ocorr?ncia de disploidias ou aneupoidias nas plantas analisadas. Verificou-se que os clones s?o bastante promissores para programas de melhoramento, e s?o recomend?veis para cultivo na regi?o de Feira de Santana-BA.

<p>A 95-kDa protein was purified from normal human granulocytes. The protein reacted with a monoclonal antibody against CEACAM8. MALDI-Tof and MS/MS analyses revealed the protein to be a CGM6 gene product. Thus, the protein was proved to be identical to CEACAM8. </p><p>An ELISA for CEACAM8 was developed with detection range of 1-64μg/L. Data are presented on the levels of CEACAM8 in the blood of healthy individuals and patients undergoing surgery, as well as in patients with acute infection. The highly elevated levels of CEACAM8 in the blood of these patients were significantly correlated with the surface expression of CEACAM8 on neutrophils and the number of circulating neutrophils, which suggests that CEACAM8 could serve as a biological marker for granulocyte activitiy in vivo. </p><p>The cellular content of CEACAM8 in neutrophils was estimated to be 82.4 ± 8.9 ng/10⁶ cells. Subcellular localisation and mobilisation studies showed that the majority of CEACAM8 is present in the secondary granules of human neutrophils, with a small amount on the plasma membranes. Upon stimulation, CEACAM8 translocated to the plasma membranes from the secondary granules and was also released extracellularly (5.5 ± 0.7% of the total content of CEACAM8).</p><p>In eosinophils, the cellular content of CEACAM8 was estimated to be 73.8 ± 6.0 ng/10⁶ cells. In these cells, CEACAM8 is mainly stored in secretory vesicles. Upon activation, eosinophils released 5.1 ± 1.1% of the total content of CEACAM8. </p><p>Administration of granulocyte colony-stimulating factor (G-CSF) to healthy individuals resulted in an increased content of CEACAM8 in neutrophils on day 1, and decreased on day 4. However, the content of CEACAM8 in light membrane fractions was increased on day 4. The translocation of CEACAM8 observed <i>in vivo</i> after G-CSF administration is probably not directly related to this cytokine but to other cytokines such as TNF-a. </p>

A 95-kDa protein was purified from normal human granulocytes. The protein reacted with a monoclonal antibody against CEACAM8. MALDI-Tof and MS/MS analyses revealed the protein to be a CGM6 gene product. Thus, the protein was proved to be identical to CEACAM8. An ELISA for CEACAM8 was developed with detection range of 1-64μg/L. Data are presented on the levels of CEACAM8 in the blood of healthy individuals and patients undergoing surgery, as well as in patients with acute infection. The highly elevated levels of CEACAM8 in the blood of these patients were significantly correlated with the surface expression of CEACAM8 on neutrophils and the number of circulating neutrophils, which suggests that CEACAM8 could serve as a biological marker for granulocyte activitiy in vivo. The cellular content of CEACAM8 in neutrophils was estimated to be 82.4 ± 8.9 ng/106 cells. Subcellular localisation and mobilisation studies showed that the majority of CEACAM8 is present in the secondary granules of human neutrophils, with a small amount on the plasma membranes. Upon stimulation, CEACAM8 translocated to the plasma membranes from the secondary granules and was also released extracellularly (5.5 ± 0.7% of the total content of CEACAM8). In eosinophils, the cellular content of CEACAM8 was estimated to be 73.8 ± 6.0 ng/106 cells. In these cells, CEACAM8 is mainly stored in secretory vesicles. Upon activation, eosinophils released 5.1 ± 1.1% of the total content of CEACAM8. Administration of granulocyte colony-stimulating factor (G-CSF) to healthy individuals resulted in an increased content of CEACAM8 in neutrophils on day 1, and decreased on day 4. However, the content of CEACAM8 in light membrane fractions was increased on day 4. The translocation of CEACAM8 observed in vivo after G-CSF administration is probably not directly related to this cytokine but to other cytokines such as TNF-a.

Avec quatorze anticorps utilisés en oncologie, les anticorps monoclonaux ont enfin une place de choix dans l'arsenal thérapeutique anticancéreux. Cependant, l'un des modes d'action les plus importants de ces molécules, la cytotoxicité à médiation cellulaire dépendante des anticorps (ADCC), souffre de plusieurs limites en raison de la nécessité d'une interaction optimale avec le Fc&#947;RIIIA. L'équipe du Dr. Daniel Baty a conçu de nouveaux formats d'anticorps bispécifiques basés sur l'utilisation de domaine unique d'anticorps de lamas (sdAb) et capables de contourner la plupart de ces limites. Des banques de phages issus de lamas immunisés ont permis de sélectionner deux sdAbs (d'affinités différentes) dirigés contre le Fc&#947;RIIIA exprimé par des cellules NK et les macrophages, ainsi qu'un sdAb dirigé contre l'antigène tumoral carcino-embryonnaire (ACE). En utilisant les domaines CH1 et Ck d'IgG1 humaine comme motif d'hétérodimérisation et les sdabs anti-ACE et anti-Fc&#947;RIII précédemment sélectionnés, nous avons développé des formats innovants d'anticorps bispécifiques Fab-like nommés bsFabs. Ces molécules sont faciles à produire, très stables et peuvent déclencher la lyse des cellules tumorales par les cellules NK humaines à des concentrations de l'ordre du picomolaire. Elles ne se lient pas au récepteur inhibiteur Fc&#947;RIIB, n'entrent pas en compétition avec des IgG sériques pour la liaison aux récepteurs, et leur activité cytotoxique est indépendante de la glycosylation du Fc et du polymorphisme du Fc&#947;RIIIA. / With fourteen antibodies used in oncology, monoclonal antibodies finally have a place in the therapeutic arsenal against cancer. However one of the modes of action of the most important of these molecules, cell-mediated cytotoxicity antibody-dependent (ADCC), suffers from several limitations due to the need for optimal interaction with the Fc&#947;RIIIA. Daniel Baty's team has developed new formats of bispecific antibodies based on the use of single domain llama antibodies (SdAb) that are capable of circumventing most of the these limitations. Phage libraries from immunized llamas were used to select two sdAbs directed against the Fc&#947;RIIIA expressed by NK cells and macrophages (with different affinities for Fc&#947;RIII), as well as one SdAb directed against the tumor antigen carcinoembryonic (CEA). Using CH1 and Ck domains of human IgG1 as a motif for heterodimerization and sdabs previously selected, we have developed innovative anti-CEA and anti-Fc&#947;RIII formats of bispecific antibodies Fab-like named bsFabs. These molecules are easy to produce, very stable and can trigger tumor cell lysis by human NK cells at picomolar concentrations. They do not bind Fc&#947;RIIB inhibitory receptor, do not compete with serum IgG and their cytotoxic activity is independent of Fc&#947;RIIIA polymorphism. In addition, they slow tumor growth in mouse model. In terms of pharmacokinetics, although bsFabs have a reasonable tumor retention, one of the limitations of these formats is size, which leads to rapid renal elimination. Such findings led us to consider the creation of new antibody formats to both increase tumor retention and secondly the half-life of antibodies in the body.