Thioredoxin reductase as a target enzyme for electrophilic anticancer drugs

Induced production of reactive oxygen species (ROS) is a common attribute of most cancer cells. One strategy for cancer cells to maneuver the increased and potentially toxic levels of ROS is to induce the expression of cellular antioxidants and redox regulators, such as the thioredoxin (Trx) system. The Trx system consists of Trx and the NADPH-dependent thioredoxin reductase (TrxR protein/Txnrd1 gene). TrxR reduces Trx, which subsequently reduces disulfides in various proteins and supplies ribonucleotide reductase with electrons for DNA synthesis. Mammalian TrxRs have wide substrate specificity, also reducing other targets than Trx. Cytosolic Trx1 and TrxR1 are induced upon oxidative stress and both have proven to be overexpressed in many tumors. They are therefore proposed as potential targets for anticancer therapy. TrxR is a selenoprotein and contains selenium in the form of selenocysteine (Sec). The Sec residue is mostly de-protonated at physiological pH and is highly nucleophilic, thus being easily targeted by electrophilic drugs. The aim of this thesis was to address the role of TrxR1 as a potential drug target for anticancer therapy and evaluate its importance for side effects associated with the widely used anticancer drug cisplatin (cDDP). This thesis reports that RITA, a compound shown to induce p53 dependent cell-death by interacting and restoring p53 activity, caused inhibition of TrxR1. Cell culture experiments showed that RITA induced a 130 kDa covalently linked TrxR1-dimer, in a p53 dependent fashion. Furthermore, red wine, rich of polyphenols and flavonoids, was also shown to efficiently inhibit TrxR activity and to be highly toxic to various cancer cell lines. Transient TrxR1 knockdown in a lung carcinoma cell line lowered the TrxR activity by 90% and caused increased sensitivity towards menadione and 1-chloro-2,4- dinitrobenzene. TrxR1 knockdown cells were, however, more resistant towards cDDP. Depleting the glutathione (GSH) levels in knockdown cells had no effect on cell growth, suggesting that the remaining TrxR activity still was enough to sustain Trx function. Recent experiments in mice showed that normal replication of hepatocytes required either one functional copy of the Txnrd1 gene or a functional GSH system, agreeing with the previous interpretation. cDDP treatment is associated with side effects such as ototoxicity and nephrotoxicity. cDDP inhibits TrxR1 and cDDP-derivatized enzyme species have previously been shown to gain a pro-oxidant role in the cells. Data on cDDP-triggered nephrotoxicity in mice presented herein suggest that the degree of kidney damage is influenced by the TrxR status in both liver and kidney. Decreased TrxR activity in liver was associated with more renal damage, while high TrxR expression in kidney correlated with increased kidney toxicity. Pharmacokinetic studies on cDDP and oxaliplatin (Oxa) in guinea pig, showed that the cochlear uptake of cDDP was significantly higher than for Oxa, thus explaining why Oxa only rarely causes ototoxicity. Using a cancer cell line it was also shown that cDDP, but not Oxa, induced cell death which was dependent on calcium and superoxide levels and caused TrxR inhibition. In summary, this thesis shows that TrxR1 is an anticancer drug target that can have an important impact on the outcome of chemotherapy and its associated side effects

Современные взгляды на генетические семейства M. tuberculosis

М. tuberculosisМИКОБАКТЕРИИТУБЕРКУЛЕЗBEIJERINCKIACEAEBEIJERINCKIAАЛЬФА-ПРОТЕОБАКТЕРИ

Недифференцированная дисплазия соединительной ткани и малые аномалии сердца как предиктор развития нарушений ритма у пациентов с ишемической болезнью сердца

ОНТОГЕНЕЗМОРФОГЕНЕЗИШЕМИЧЕСКАЯ БОЛЕЗНЬ СЕРДЦ

Структурно-цитохимические особенности развивающихся почек крысят при антенатальном воздействии инкорпорированных радионуклидов

ГЛИКОПРОТЕИНЫПОЧКИРАДИОАКТИВНЫЕ ИЗОТОПЫРАДИОНУКЛИД

Kan reformen av CAP minska ekonomiska gap?

This essay is an analysis of the EU Common Agricultural Policy reform of 2003 and its impact on the economic growth and income distribution in African countries. In what follows we outline the most significant effects of the reform, and its purpose. A regression analysis using panel data is conducted to investigate the reform’s impact on economic growth in the examined countries. The effect on income distribution is analysed by testing the change in GINI-index, before and after the reform, with a Wilcoxon signed rank test. The result of the regression analysis indicates a significant increase in the economic growth rate explained by the CAP-reform. Testing the change in income distribution did not generate a significant result and therefore we cannot conclude that the reform has affected the income gap in the investigated countries

Treatment of Diabetes with Lifestyle Changes: Diet

The present chapter critically reviews scientific evidence on the impact of the diet and its components on the metabolic control, cardiovascular risk factors, and morbidity/mortality in diabetic patients. Three main topics are included in this chapter: (1) the effects of dietary treatment on body weight control in diabetic patients; (2) the optimal dietary composition in order to achieve blood glucose control and reduce other cardiovascular risk factors associated with type 2 diabetes; (3) the effects of lifestyle modifications and dietary changes on the risk to develop type 2 diabetes. The overall body of evidence seems to confirm the efficacy of current recommendations for diabetes management. However, although dietary strategies based on structured interventions are often successful, particularly in relation to body weight control, they are not easily applicable in clinical practice and, therefore, more feasible strategies should be identified. In addition, further intervention studies focused on the effects of lifestyle on hard endpoints in diabetic subjects are needed to definitively prove the role of diet in the prevention of both cardiovascular and microvascular complications in these patients over and above their impact on weight reduction

School Library Forum´s activity : - a case study from the viewpoint of the learning organization

10 years ago the School Library Forum´s core activity started; the development of model libraries. Since then, no comprehensive study of the School Library Forum has been made. How does the organization actually work and how do professionals perceive the changes of the organization? Against this background, the purpose of my essay is to examine the activity of the organization School Library Forum with a focus on organization and learning from the viewpoint of the learning organization. The following issues have been helpful to meet the purpose of the study: How do the business developer, the principals and the school librarians experience the collaboration on the school-libraries model-library activity? How does the collaboration contribute to learning within the organization according to the business developer, the principals and the school librarians? How do the business developer, the principals and the school librarians perceive the changes in the School Library Forum´s organization, seen from the perspective of the learning organization? By conducting five interviews with stakeholders in various positions within the organization, such as business developer, principals and school librarians, a deeper insight into how respondents perceive the business from the perspective of the learning organization is obtained. When the study is qualitative and the interview respondents are of a limited number there is no claim to generalize the perceptions to all workers involved in the organization. Results obtained in this study are that the organizational changes that have occurred are perceived as positive by principals and school librarians, while the business developer´s experience is more negative.

Capable Production Process

This master thesis is about capability analysis performed at Bosch Rexroth in Mellansel. The aim is to analyse the manufacturing process and to find where they are capable or not, by process observations and looking at the measured data over a period of time. The capability analysis is a statistical method, looking at both measured values of a produced part, as well as measurement distributions. It is used to find variation and predict future behaviour of the process. It is found that capability is a useful tool, and can be used to give manufacturing processes an index to measure the stability. The capability process is made in two steps. First the measuring tools are looked at, and if the tool is considered so that an operator can affect the process, then operator variation is as well looked at. When the measuring tool is capable the process data is analysed, to find or create a capable process. It was found that capability analysis is a powerful tool in order to give its production process a measurable value. The capability indices will provide answers if the process is stable or not, and it can be seen changes in stability over time. When working with capability easy method need to be establish in order to be able to fast provide the capability indices. It was also found that small changes in randomness of data can affect the result of the capability significantly, and cautions when data is not normal distributed when transforming data if needed.I detta examensarbete är en kapabilitetsanalys genomförd hos Bosch Rexroth i Mellansel. Målet var att analysera deras tillverkningsprocess och hitta vart de är kapabel eller inte, genom att titta på processen och mätdata över en tidsperiod. En kapabilitetsprocess är en statisk metod, där man tittar på både mätvärden för producerade delar och fördelningar på mätdatat. Det används för att hitta variationer och för att kunna förutspå framtida händelser för en process. Kapabilitet är ett användbart verktyg och kan användas för att ge processen ett mätbart index för stabiliteten i processen. Kapabilitetsprocessen är genomfört i två steg. Först ses mätdonet över och om man antar att en operatör kan påverka mätutrustningen görs en operatörs variation för mätutrustningen. När mätutrustningen är kapabel analyseras insamlat mätdatat, för att se om processen är kapabel eller inte, då processen var icke kapabel utfördes en utvärdering på varför och hur de kan bli kapabel. Slutsatsen blev att kapabilitet är ett användbart verktyg för att kunna ge sin produktions process ett mätbart värde. Kapabilitetsindex kan ge svar på om process är stabil eller inte, man kan även se ändringar över en period av tid. Vid användning av kapabilitet är det viktigt att ha enkla arbetsmetoder för att snabbt kunna ge svar på processens kapabilitetindex, då små ändraringar på mätdatat kan ge märkbara ändringar på kapabiliteten. En viss aktsamhet behöver finnas då slumpvariationer på mätdatat uppstår och när en datainsamling inte är normalfördelat och eventuellt behöver transformeras

Capable Production Process

This master thesis is about capability analysis performed at Bosch Rexroth in Mellansel. The aim is to analyse the manufacturing process and to find where they are capable or not, by process observations and looking at the measured data over a period of time. The capability analysis is a statistical method, looking at both measured values of a produced part, as well as measurement distributions. It is used to find variation and predict future behaviour of the process. It is found that capability is a useful tool, and can be used to give manufacturing processes an index to measure the stability. The capability process is made in two steps. First the measuring tools are looked at, and if the tool is considered so that an operator can affect the process, then operator variation is as well looked at. When the measuring tool is capable the process data is analysed, to find or create a capable process. It was found that capability analysis is a powerful tool in order to give its production process a measurable value. The capability indices will provide answers if the process is stable or not, and it can be seen changes in stability over time. When working with capability easy method need to be establish in order to be able to fast provide the capability indices. It was also found that small changes in randomness of data can affect the result of the capability significantly, and cautions when data is not normal distributed when transforming data if needed.I detta examensarbete är en kapabilitetsanalys genomförd hos Bosch Rexroth i Mellansel. Målet var att analysera deras tillverkningsprocess och hitta vart de är kapabel eller inte, genom att titta på processen och mätdata över en tidsperiod. En kapabilitetsprocess är en statisk metod, där man tittar på både mätvärden för producerade delar och fördelningar på mätdatat. Det används för att hitta variationer och för att kunna förutspå framtida händelser för en process. Kapabilitet är ett användbart verktyg och kan användas för att ge processen ett mätbart index för stabiliteten i processen. Kapabilitetsprocessen är genomfört i två steg. Först ses mätdonet över och om man antar att en operatör kan påverka mätutrustningen görs en operatörs variation för mätutrustningen. När mätutrustningen är kapabel analyseras insamlat mätdatat, för att se om processen är kapabel eller inte, då processen var icke kapabel utfördes en utvärdering på varför och hur de kan bli kapabel. Slutsatsen blev att kapabilitet är ett användbart verktyg för att kunna ge sin produktions process ett mätbart värde. Kapabilitetsindex kan ge svar på om process är stabil eller inte, man kan även se ändringar över en period av tid. Vid användning av kapabilitet är det viktigt att ha enkla arbetsmetoder för att snabbt kunna ge svar på processens kapabilitetindex, då små ändraringar på mätdatat kan ge märkbara ändringar på kapabiliteten. En viss aktsamhet behöver finnas då slumpvariationer på mätdatat uppstår och när en datainsamling inte är normalfördelat och eventuellt behöver transformeras