Zugl.: Giessen, Universiẗat, Diss., 2008.

Zugl.: Giessen, Universiẗat, Diss., 2008.

Universiẗat, Diss.--Marburg, 1995.

Techn. Hochsch., Diss., 2002--Aachen.

Οι διαφορετικές θεραπευτικές προσεγγίσεις σε ασθενείς με καρκίνο (χειρουργική αποκατάσταση, ακτινοθεραπεία κ.λπ) μπορεί να έχουν επίδραση στην ποιότητα ζωής τους. Σκοπός. Σκοπός αυτής της μελέτης ήταν η διερεύνηση και καταγραφή, μέσω ερωτηματολογίων, της ποιότητας ζωής σε ασθενείς με καρκίνο, που υποβλήθηκαν σε ακτινοθεραπεία, και πως επηρεάζεται αυτή από τη χορήγηση διφωσφονικών ή ερυθροποιητίνης Ασθενείς-Μέθοδος. Τον πληθυσμό της έρευνας αποτέλεσαν 22 ασθενείς που νοσηλεύτηκαν στη Μονάδα Ακτινοθεραπευτικής Ογκολογίας στο Πανεπιστημιακό Νοσοκομείο του Pioυ από τον Οκτώβρη του 2007 μέχρι τον Ιούλιο του 2008. Οι ασθενείς έπασχαν από κάποια μορφή καρκίνου με μεταστάσεις και υποβλήθηκαν σε συνδυασμένη θεραπεία που περιλάμβανε ακτινοθεραπεία και χορήγηση διφωσφονικών ή ερυθροποιητίνης, ανάλογα με τις κλινικές ενδείξεις. Η συλλογή των δεδομένων έγινε με τη συμπλήρωση ερωτηματολογίων δημογραφικών στοιχείων και κλινικών χαρακτηριστικών. Η αξιολόγηση της κλινικής ανταπόκρισης ελάμβανε χώρα με την καταγραφή της κλίμακας πόνου (0-10), της ποιότητας ζωής (ερωτηματολόγιο EORTC-QΟL C30- κλίμακα φυσικής λειτουργικότητας, 0-100), και της φυσικής κατάστασης (ECOG κλίμακα 0-5). Αποτελέσματα: H σύγκριση των δεδομένων έδειξε ότι δεν υπήρχε στατιστικά σημαντική διαφορά στην καταγραφή του αισθήματος του πόνου και των παραμέτρων της ποιότητας ζωής των ασθενών με τη χορήγηση διφωσφωνικών ή ερυθροποιητίνης κατά τη διάρκεια του διαστήματος που υποβάλλονταν σε ακτινοθεραπεία. Συμπεράσματα: Η χορήγηση διφωσφωνικών ή ερυθροποιητίνης φαίνεται να μην μπορούν να επιφέρουν αλλαγές σε συγκεκριμένες διαστάσεις της ζωής και να έχουν επίδραση στην αναφερόμενη ποιότητα ζωής των ασθενών με καρκίνο. Η βελτίωση της ποιότητας ζωής αυτών των ασθενών αποτελεί μεγάλη πρόκληση για τους επαγγελματίες υγείας. / The different therapeutic approaches in patients with cancer (surgery, radiation, etc.) can affect their quality of life. Purpose: The purpose of this study was to evaluate and record, through questionnaires, the quality of life of patients with cancer undergoing radiation therapy, and how this is affected by treatment with bisphosphonates or erythropoietin Patients-Method. In this study, 22 patients were participated, admitted to the Radiation Oncology Unit at University Hospital of Rio from October 2007 until July 2008. Patients suffering from some form of cancer and metastases and underwent into combined treatment included radiation therapy and bisphosphonates or erythropoietin. All patients filled questionnaires about their demographic and clinical characteristics. The evaluation of clinical response took place by recording patients’ answers about pain scale (0-10), quality of life (QOL questionnaire EORTC-C30-scale physical functioning, 0-100), and physical condition (ECOG scale 0-5). Results: Elaboration of collected data showed no statistically significant difference in the recording feeling of pain and parameters of quality of life in patients treated with bisphosphonates or erythropoietin during the period of radiotherapy. Conclusions: Treatment with bisphosphonates or erythropoietin seems not to be able to make changes in specific parameters of life and to affect the reported quality of life of patients with cancer. Improving quality of life of these patients is a major challenge for health professionals.

All red blood cells, erythrocytes, originate in bone marrow. The process of their differentiation and maturation is called erythopoiesis and is regulated through hormone erythropoietin (EPO), which functions as a stimulatory factor for erythropoiesis. EPO is produced in kidney and its production is regulated by oxygen supplementation. EPO is transported to bone marrow via blood vessels. Chronic overproduction of erythrocytes leads to disease called polycythemia. Polycythemia may be diagnosed for example by measurement of haematocrit or haemoglobin concentration in blood. EPO level may or may not be increased. Patients suffering from polycythemia may or may not have any symptoms. It depends on manifestation level of the disease. The most common symptoms are higher blood pressure, headaches, dizziness, swelling and epistaxis. Recently, the most common treatment of polycythemia is phlebothomy. The aim of this master thesis is to unravel the role of a newly described mutation, which was found among members of one family suffering from polycythemia with increased EPO level. It is single substitution mutation -136 G > A in 5' UTR region of EPO gene. The clones of EPO producing cell lines bearing this mutation were prepared using CRISPR/Cas9 technology. Several experiments performed not only on those cell...

Background: Transplantation of marrow stromal cells (MSC) has been shown to improve heart perfusion and cardiac function after ischemia. Erythropoietin (EPO) is capable of inducing angiogenesis and inhibiting cell apoptosis. The aim of this study was to investigate the effect of EPO on the therapeutic potency of MSC transplantation in a rat model of myocardial infarction. Methods: MSC viability was detected by MTT andflow cytometry following culture in serum-free medium for 24 h with or without EPO. Release of vascular endothelial growth factor (VEGF) by MSC incubated with different doses of EPO was assayed using ELISA. Immediately after coronary ligation, autologous MSC (3 × 10 6 cells) were injected into the ischemic myocardium (MSC and MSC-EPO groups). EPO (3,000 U/kg body weight) was injected daily for 3 consecutive days starting 1 day prior to ligation. The same EPO dose was also injected for consecutive 3 days starting 15 days after surgery (EPO and MSC-EPO groups). Control animals were injected saline solution for the same time period. Cardiac function was assessed by echocardiography 2 and 21 days after surgery, respectively. Western blot and immunohistological assessments were performed to examine the effects of treatments. Results: In vitro, EPO inhibited MSC apoptosis induced by serum-free medium and increased vascular endothelial growth factor (VEGF) release by MSC. In vivo, cardiac infarct size was significantly smaller, cardiac function significantly improved, and capillary density obviously higher in the MSC and EPO groups than in the control group. Combined treatment with EPO infusion and MSC transplantation demonstrated a further decrease in infarct size, a further improvement in cardiac function, and a further increase in capillary density compared with MSC or EPO alone. Furthermore, a higher ratio of phosphorylated Akt to total Akt was measured by Western blot; Bcl-2 was upregulated and Bax was downregulated by immunohistochemistry in the MSC-EPO group compared to the other three groups. Conclusion: Transplantation of MSC combined with EPO infusion is superior to MSC monotherapy for angiogenesis and cardiac function recovery.

We postulated that combining erythropoietin (EPO) infusion with bone marrow mesenchymal stem cells (MSC) delivery may give better prognosis in a rat infarcted heart. Acute myocardial infarction (MI) model was developed by coronary artery ligation. Animals were grouped (n = 18) to receive intramyocardial injection of 30 μl saline solution without cells (EPO and control groups) or with 3 × 106 MSC from transgenic green fluorescent protein (GFP)+ male mice (MSC and MSC-EPO groups). The animals received either 5000 U/kg body weight EPO (EPO and MSC-EPO groups) or saline solution (MSC and control groups) for 7 days after MI. Cardiac functions were measured by echocardiography and cardiac tissue was harvested for immunohistological studies 3 weeks after surgery. We observed regeneration of MSC in and around the infarcted myocardium in MSC and MSC-EPO groups. Capillary density was markedly enhanced with significantly smaller infarct size and reduced fibrotic area in MSC-EPO group as compared with other three groups. A smaller left ventricular (LV) diastolic dimension and a higher LV fractional shortening were observed in MSC-EPO group than in other three groups. Transplantation of MSC combined with cytokine EPO is superior to either of the monotherapy approach for angiomyogenesis and cardiac function recovery.

The DNA- binding complex Hypoxia-inducible factor 1 (HIF-1), a heterodimeric basic helix-loop-helix (bHLH) transcription factor, is involved in the regulation of gene expression by oxygen, a prime target being the human erythropoietin (EPO) gene. In this study, the human HIF-1α subunit was expressed in a baculovirus system. To simplify purification, a polyhistidine tag was attached to the C terminus to facilitate the fusion protein to be specifically adsorbed to a Talon metal affinity resin. Expression studies revealed that this overexpressed HIF-1α was found in soluble, nuclear, and insoluble cell extracts. Electrophoretic mobility shift assays (EMSA) demonstrated that the fusion protein heterodimerize with the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT), and bound to a probe spanning nucleotides 1 to 18 (W18) of the human erythropoietin gene enhancer that confers hypoxic induction. This study also demonstrates that the presence of 7 mM hemin or different cobalt concentrations (50 mM; 100 mM; and 200 mM) results in no obvious effect on the solubility or expression level of HIF-1a in insect cells. Similarly, coexpression of ARNT and HIF-1α in Sf9 cells did not increase solubility of the recombinant HIF-1α protein. Gel shift assays demonstrated that the Talon-purified recombinant HIF-1α and ARNT proteins could bind the W18 DNA probe only when reconstituted in the presence of a heat-sensitive factor(s) found in soluble and nuclear extracts of Sf9 cells as well as in rabbit reticulocyte lysate. Interestingly, reconstitution of DNA binding activity was only possible when using HIF-1α purified under native conditions. When using HIF-1α purified under denaturing conditions and refolded, DNA-binding activity was absent.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19369号 / 医博第4046号 / 新制||医||1012(附属図書館) / 32383 / 新制||医||1012 / 京都大学大学院医学研究科医学専攻 / (主査)教授 宮本 享, 教授 柳田 素子, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM