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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
281

Analysis of Human Appendiceal Peritoneal Carcinomatosis Samples Infected with Oncolytic Viruses

Zerhouni, Siham 11 December 2013 (has links)
Peritoneal carcinomatosis (PC), the intra-abdominal dissemination of malignancy, is equated with a 5-year survival of 15%, depending on the source. Appendiceal PC is a challenge to treat as cancer cells are embedded in copious amounts of mucin and are difficult to target. Oncolytic viruses (OVs) preferentially replicate and lyse cancer cells and present a targeted, novel strategy for PC. The hypothesis of this study is that appendiceal PC will show variable susceptibility to OVs and that protein expression in these tumours will predict OV replication efficiency. Human appendiceal PC infected ex-vivo with 4 different OVs displayed variable infectivity and replication by fluorescence microscopy and plaque assay. Immunohistochemistry analysis revealed differential expression of IRF3, pERK and TK in tumour compared to normal appendix. No correlation of protein expression with viral replication was observed. Personalizing OV therapy will be critical in the optimization of future care of patients treated with this modality.
282

Vztah sociální opory, zvládání stresu, depresivní symptomatiky a lokalizace kontroly u pacientů léčených peritoneální dialýzou a hemodialýzou / The Relationship of Social Support, Coping, Depressive Symptoms and Lokus of Control in Patients treated by Perioneal Dialysis and Hemodialysis

Bělešová, Sylvie January 2013 (has links)
Patients with chronic kidney failure, given that it is impossible to undergo transplantation, have to be treated by lifelong hemodialysis (HD) via extracorporeal circulation machine 3 times a week in hospital; or by peritoneal dialysis (PD) performed by patients at home. There were a number of studies comparing quality of life between HD and PD, but there have been fewer studies covering other psychological variables. The aim of this study was to examine whether HD and PD patients differ in social support, locus of control, coping and depressive symptoms. 143 HD patients (average age 65,56; 48,3 % men, 51,3 % women) and 48 PD patients (average age 63,79; 66,7 % men, 33,3 % women) were approached by random selection. Social Integration Survey (SIS) was applied to examine social support. Locus of control was depicted on visual analog scale. Coping strategies were mapped by a short version of COPE questionnaire - Brief COPE, which was translated to Czech language for this purpose. Beck's depression inventory (BDI - II) was used to evaluate incidence of depressive symptoms. Based on data statistical analysis there was no difference proved in social support, coping strategies, locus of control and depressive symptoms among HD and PD patients. Although HD and PD differ and cause diverse advantages and...
283

The Human Endometrium : Studies on Angiogenesis and Endometriosis

Moberg, Christian January 2017 (has links)
Angiogenesis is thought to play a pivotal role in the cycling endometrium. Coordinated by oestrogen and progesterone, endometrial blood vessel development is primarily mediated by vascular endothelial growth factor-A (VEGF-A), which promotes endothelial cell (EC) proliferation and protects ECs from induced apoptosis. Studying changes at transcript level in human endometrial endothelial cells (HEECs) in response to mitogenic and inhibitory stimuli is one way towards understanding the regulation of physiological endometrial angiogenesis. Endometriosis, the presence of endometrial-like tissue outside the uterine cavity, is a common gynaecological disorder in women of reproductive age, often causing pelvic pain and reduced fertility. Chronic inflammation in the peritoneal environment and defective endometrial protein expression are some of the contributors to the complex pathophysiology of endometriosis. The aim of this work was to study the changes in the transcriptome induced by VEGF-A and partial serum deprivation in primary HEECs, and to investigate biochemical factors associated with subfertility and chronic pelvic pain in endometriosis patients. Exposing primary HEECs to VEGF-A, and serum withdrawal was found to regulate transcripts associated with survival, migration, apoptosis and progression through the cell cycle, when assessed using microarray technology and bioinformatic tools. A subset of 88 transcripts was reciprocally regulated under the two experimental conditions; thus probably important in HEEC biology. Higher endometrial epithelial staining scores of oestrogen receptor-α and reduced staining of progesterone receptors were seen in subfertile endometriosis patients. Lower levels of the receptivity biomarker leukaemia inhibitory factor (LIF) and its receptor, as well as signs of dysregulated αB-crystallin expression and increased peritoneal fluid concentrations of interleukin (IL)-1α and IL-6 were associated with reduced pregnancy rates. Endometriosis patients with chronic pelvic pain had higher levels of vasoactive intestinal peptide (VIP) in eutopic endometria and in endometriotic lesions compared with patients without chronic pain. The presence of chronic pelvic pain was also associated with increased concentrations of VIP and IL-6 in peritoneal fluid. The present results may constitute a basis for further investigation of regulatory pathways in endometrial angiogenesis as well as for studies of endometrial receptivity and pain in women with endometriosis.
284

Avaliação hidrodinâmica de uma válvula neurológica ajustável por acionamento mecânico / Hydrodynamic evaluation of an adjustable neurological valve by mechanical drive

Pinto, José Ricardo Camilo 13 December 2013 (has links)
A hidrocefalia é uma doença ocasionada pelo distúrbio na formação, circulação ou absorção do líquido cefalorraquidiano (líquor) que acarreta na elevação da pressão intracraniana. O tratamento mais usual para a disfunção é a derivação ventrículo-peritoneal (DVP) responsável pela drenagem do líquor do ventrículo até o abdômen do paciente, através do implante de um cateter ventricular, uma válvula neurológica e um cateter peritoneal. Desse modo, o presente estudo apresenta o conceito de uma nova válvula neurológica com um mecanismo inovador para alteração da pressão de funcionamento, com um menor custo produtivo e de possível aceitação pelo Sistema Único de Saúde (SUS). A norma ISO 7197 forneceu as diretrizes atendidas no desenvolvimento da válvula neurológica ajustável e as informações para a construção das bancadas de testes, utilizadas para a realização dos ensaios hidrodinâmicos no protótipo do dispositivo valvular. Foram pesquisados os biomateriais empregados na fabricação de válvulas neurológicas comerciais, para a proposição dos materiais necessários para a construção da válvula ajustável por acionamento mecânico proposta. O aparato utilizado nos testes hidrodinâmicos apresentou incertezas experimentais, que não comprometem os resultados e a avaliação do desempenho in vitro do dispositivo testado. O protótipo da válvula resistiu aos testes de vazamento e de refluxo de fluido. As pressões de abertura e de fechamento apresentaram-se adequadas para o início e a interrupção do escoamento na DVP. Também foi obtido o comportamento do diferencial de pressão, em função da vazão, para as quatro classes de funcionamento disponíveis no protótipo testado. A avaliação hidrodinâmica do protótipo da válvula ajustável por acionamento mecânico apresenta resultados satisfatórios no controle da drenagem de líquor, frente a todos os ensaios hidrodinâmicos realizados. / Hydrocephalus is a disease caused by disturbance in formation, circulation or absorption of cerebrospinal fluid (CSF) which causes high intracranial pressure. The most common treatment for the dysfunction is the ventricle-peritoneal shunt responsible for drainage of cerebrospinal fluid from the patient\'s ventricle to the abdomen, through the implant of a ventricular catheter, a neurological valve and a peritoneal catheter. Thus, the present study introduces the concept of a new valve with an innovative mechanism to change the working pressure, with a lower cost of production and possible acceptance by the Brazilian Health System. ISO 7197 provided the guidelines met in the development of adjustable neurological valve and the information for the construction of testing rigs, used for hydrodynamic testing on the valve device prototype. Biomaterials used in manufacturing commercial neurological valves have been researched for proposition of materials needed for the proposed adjustable neurological valve by mechanical drive. The apparatus used in hydrodynamic tests presented experimental uncertainties, which do not compromise the results and evaluation of in vitro performance of the device tested. The prototype of the valve withstood the leak and the fluid backflow testing. The opening and closing pressures were suitable for the beginning and the interruption of the flow in the ventricle-peritoneal shunt. It was also obtained the behavior of the pressure differential, due to the flow, for the four classes of operation available in the prototype tested. Hydrodynamic evaluation of the prototype of the adjustable valve by mechanical drive shows satisfactory results in the control of CSF drain, dealing with all hydrodynamic tests carried out.
285

Molecular characterization of rare thoraco-abdominal tumours / Caractérisation moléculaire des tumeurs thoraco-abdominales rares

Leblay, Noémie 19 December 2018 (has links)
Les carcinoïdes pulmonaires, les carcinomes neuroendocriniens à grandes cellules (LCNEC) et les mésothéliomes malins sont des tumeurs thoraciques rares, dont l'incidence a augmenté au cours des dernières années. Le diagnostic de ces tumeurs est soumis à la variabilité inter-observateur et les opportunités thérapeutiques sont limitées. De grandes études génomiques visant à les caractériser au niveau moléculaire pourraient aider à mieux comprendre les mécanismes sous-jacents à leur développement et faciliter le diagnostic et le traitement de ces maladies. Mon projet de thèse visait à combler les lacunes dans la compréhension des carcinoïdes pulmonaires, des LCNEC et du mésothéliome péritonéal malin. À la suite des travaux entrepris au cours de ma thèse, nous avons constaté que (1) de la même manière que le mésothéliome pleural, les mésothéliomes péritonéaux sont également caractérisés par des mutations conduisant à la perte d'expression de BAP1, facteur de bon pronostic, (2) les patients atteints d’un LCNEC conservant une expression de RB1 présentent de meilleurs résultats lorsqu’ils sont traité avec une chimiothérapie du cancer du poumon non à petites cellules par rapport à une chimiothérapie du cancer du poumon à petites cellules, (3) les carcinoïdes pulmonaires peuvent être classés en trois groupes moléculaires pertinents sur le plan clinique, et (4) , l'identification de supra carcinoïdes confirme l'existence d'un lien moléculaire entre les néoplasmes neuroendocriniens pulmonaires de faible et de haut grade / Pulmonary carcinoids, large-cell neuroendocrine carcinomas (LCNEC), and malignant mesotheliomas are rare thoracic tumours, which incidence has been increasing over the past years. The diagnosis of these tumours is subjected to inter-observer variability and the therapeutic opportunities are limited. Large genomic studies to characterize them at a molecular level might help to better understand the mechanisms underlying their development, and to help the diagnosis and treatment of these diseases. My thesis project aimed to fill the gap in the understanding of pulmonary carcinoids, LCNEC, and malignant peritoneal mesothelioma. As result of the work undertaken during my thesis, we found that (1) similarly to pleural mesothelioma, peritoneal mesotheliomas are also characterised by mutations leading to the loss of expression of BAP1, which is a factor of good prognostic, (2) LCNEC patients with a remaining expression of RB1 have a better outcome when treated with non-small cell lung cancer chemotherapy in comparison to small-cell lung cancer chemotherapy, (3) pulmonary carcinoids can be classified in three clinically-relevant molecular groups, and (4), the identification of supra carcinoids supports a molecular link between the low and high-grade lung neuroendocrine neoplasms
286

Avalia??o da fun??o cognitiva em pacientes com insufici?ncia renal cr?nica em di?lise peritoneal

Costa, Caroline Reinhardt Correa 29 March 2011 (has links)
Made available in DSpace on 2015-04-14T13:35:12Z (GMT). No. of bitstreams: 1 431165.pdf: 850340 bytes, checksum: a2e688c3555bab8a8fa5c9cdf12fa3d4 (MD5) Previous issue date: 2011-03-29 / Introdu??o: A doen?a renal cr?nica ? um grave problema de sa?de p?blica no pa?s. D?ficit cognitivo ? comum em pacientes com insufici?ncia renal cr?nica terminal e depress?o ? uma condi??o prevalente na doen?a renal cr?nica terminal. Objetivo: avaliar a fun??o cognitiva de pacientes com insufici?ncia renal cr?nica submetidos ? di?lise peritoneal no Hospital S?o Lucas da PUC e Hospital Benefic?ncia Portuguesa de Pelotas. Materiais e M?todos: Estudo transversal controlado. Foram inclu?dos pacientes em tratamento para doen?a renal cr?nica terminal, em di?lise peritoneal h? pelo menos tr?s meses, com idade acima de 18 anos, e pontua??o no Mini Exame do Estado Mental acima de 18. Foram exclu?dos pacientes com dem?ncia pr?via conhecida, hist?ria de acidente vascular cerebral, doen?a aguda, e hospitalizado com dificuldades de aprendizagem conhecidas. O grupo controle incluiu parentes saud?veis de pacientes em Di?lise Peritoneal (DP) e Hemodi?lise (HD), mesma idade e n?vel s?cio-educativo. Todos os participantes foram submetidos a uma ?nica aplica??o de testes psicom?tricos no momento da consulta cl?nica ou agendados. Os testes utilizados foram a Escala de Intelig?ncia Wechsler para Adultos (WAIS-III), o Invent?rio de Depress?o Beck (BDI) e o Mini-Exame do Estado Mental (MEEM). Participaram 60 indiv?duos, 30 pacientes em DP e 30 indiv?duos saud?veis. Resultados: Os grupos n?o foram diferentes quanto a escores do MEEM (DP 25,9+5,4, Controle 26,8+3,3, p=0,462) e do WAIS-III, com exce??o do ?ndice da velocidade de processamento (DP 90 +19,6, controle 99 + 14,3, p=0,039). Os pacientes em DP apresentaram o escore BDI significativamente maior que os controles (DP=14, IIQ=6-23; Controle=9, IIQ=4-13; p=0,010). Ajustando os dados para presen?a de depress?o e atividade laboral, verificou-se que o ?ndice de velocidade de processamento dos pacientes foi 12,7 pontos menor que nos controles. Conclus?o: O ?ndice de velocidade de processamento da escala WAIS-III foi menor nos pacientes em DP do que nos controles. Os demais aspectos da fun??o cognitiva de pacientes em DP n?o foram diferentes de controles com mesma idade e n?vel s?cio-econ?mico-educacional
287

Implementation of and Electrical Bioimpedance Measurement System for Renal Function Monitoring

Pérez-Vázquez Losada, Sonia January 2008 (has links)
Peritoneal Dialysis is a treatment for patients suffering from renal failure thatallows out-patient care. This means that the patient only needs to visit the hospital forconsultation and not for treatment, increasing considerably the comfort of the patient,while reducing remarkably the cost per patient.In order to increase the level of medical supervision obtained with the periodicvisits to the clinic, televisit has been put into practice in some hospitals. But thesetelevisits are based on indirect and qualitative indicators of renal failure, and thereforethey are just valid for detection of situations near limit cases, such as well over-hydratedor dehydrated.Electrical Bioimpedance Measurements have been proved to constitute anappropriate method for assessment of body composition, and therefore they can providewith direct indicators of body fluid distribution. Such ability of EBI technology allowsthe detection of body fluid unbalance caused by renal dysfunction, and therefore,nephrology televisits would benefit tremendously from EBI measurements.This project is based on the AD5933 Impedance Network Analyzer of AnalogDevices, and the main task is to develop a software application that controls theevaluation board in which it is implemented, and allows the storage of the EBImeasurements in EDF+ files that will facilitate the management of medical data whenapplied to televisit. These files are uploaded to XML format in order to be sent to aremote server, where a software application will have been implemented for medicalconsultation. / Uppsatsnivå: D
288

Psychological distress, health-related quality of life and marital relationship among Chinese renal patients receiving continuous ambulatory peritoneal dialysis in Hong Kong.

January 2007 (has links)
Luk, Pik Shan Yvonne. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 134-146). / Abstracts in English and Chinese ; some text in appendix also in Chinese. / Abstract (English version) --- p.ii-iii / Abstract (Chinese version) --- p.iv / Acknowledgement --- p.v / List of Table --- p.vi / Appendices --- p.vii / Chapter 1 --- Introduction --- p.1-5 / Chapter 2 --- Literature Review / Introduction --- p.6-7 / Psychological Distress --- p.7-13 / Health-related Quality of Life --- p.13-25 / Marital Relationship --- p.26-31 / Summary --- p.31-34 / Chapter 3 --- Aims & Methodology / Aims & Objectives --- p.35-37 / Operational Definition --- p.37-38 / Research Design --- p.38-39 / Setting & Sample --- p.39-40 / Instrument / Psychological Distress --- p.41-43 / Health-related Quality of Life --- p.43.44 / Marital Relationship --- p.44-46 / Demographic Data --- p.47 / Data Collection Procedure --- p.4748 / Ethical Consideration --- p.48-50 / Data Analysis --- p.50-51 / Pilot Study --- p.51-52 / Chapter 4 --- Findings / Introduction --- p.53-54 / Sociodemographic Characteristics --- p.54-56 / Psychological Distress --- p.57-58 / Health-related Quality of Life --- p.59-61 / Marital Relationship --- p.62-65 / Normality of the Outcome Variables --- p.65-66 / Relationships between the Study Outcomes and Sociodemographic Data --- p.66-68 / "Relationships between Anxiety, Depression, Health-Related Quality of Life and Marital Relationship" --- p.68-76 / Summary --- p.16-78 / Chapter 5 --- Discussion / Introduction --- p.79 / Socio-demographic and Clinical Characteristics of CAPD patients --- p.79-84 / Psychological Distress of CAPD Patients --- p.84-85 / Components of Psychological Distress: Anxiety --- p.85-86 / Components of Psychological Distress: Depression --- p.86-88 / Gender differences of the Levels of Anxiety and Depression among CAPD Patients --- p.88-89 / Cultural Difference of Anxiety and Depression among CAPD Patients --- p.89-90 / Health-related Quality of Life among CAPD Patients / Health-related Quality of Life of CAPD Patients Affected by Renal Symptoms --- p.90-91 / Health-related Quality of Life of CAPD Patients Affected by the effects of Kidney Disease --- p.91-93 / Health-related Quality of Life of CAPD Patients Affected by the burden of / Having Kidney Disease --- p.93-94 / Health-related Quality of Life of CAPD Patients Affected by the General Physical Health --- p.94-96 / Health-related Quality of Life of CAPD Patients Affected by the General Mental Health --- p.96-97 / Gender differences of the Levels of Health-related Quality of Life among CAPD Patients --- p.97-98 / Cultural Difference of Health-related Quality of Life among CAPD Patients --- p.98-99 / Sexual Issues and Marital Relationship of CAPD Patients / Sexual Issues of CA PD Patients --- p.100-102 / CAPD Patients' Perception of the Marital Relationship --- p.102-104 / Gender Differences in Perception of the Marital Relationship among CAPD Patients --- p.104 / Cultural Difference in Perception of the Marital Relationship among CAPD Patients --- p.105-106 / "Relationships between Participants' Characteristics and Psychological Distress," / HRQoL and Marital Relationship / "Relationships of Income with Anxiety, Depression and General Mental Health" --- p.107-108 / Relationship between Duration of Receiving Dialysis and Health-related Quality of Life --- p.108-109 / Relationship between Occupational Status and General Mental Health --- p.199.110 / "Relationships among Anxiety, Depression, HRQoL and Marital Relationship" / The Relationship between Anxiety and Depression --- p.110-111 / "The Relationship between Anxiety, Depression and HRQoL" --- p.112 / "The Relationship between Anxiety, Depression and Marital Relationship" --- p.112-113 / The Relationships among Domains of Health-related Quality of Life --- p.113-114 / The Relationship between Health-related Quality of Life and Marital Relationship --- p.114-115 / Predictors of Health-related Quality of Life among CAPD Patients / Anxiety and Depression as Predictors of Health-related Quality of Life --- p.116-118 / Marital Relationship as Predictors of Health-related Quality of Life --- p.118-119 / Summary --- p.119-121 / Chapter 6 --- Conclusion / Limitations / Validity of Participants' Responses --- p.122-123 / Generalization of the Study's Findings --- p.123-124 / Psychometric Property of the Chinese Version of KDQOL-36 --- p.124-125 / The Sexual Items ofKDQOL-SF --- p.125 / Appropriateness of Using HADS and Multiple Correlations --- p.126 / Implications of the Study Findings / Implications for nursing knowledge --- p.126-128 / Implications on the Nursing Practice --- p.128-130 / Recommendations for Further Research --- p.130-132 / Conclusion --- p.132-133 / Chapter 7 --- Reference --- p.134-146 / Chapter 8 --- Appendix --- p.147-179
289

Radioimmunothérapie préciblée de la carcinose péritonéale par chimie bioorthogonale / Peritoneal carcinosis radioimmunotherapy by bioorthogonal chemistry

Rondon, Aurelie 11 December 2018 (has links)
La radioimmunothérapie (RIT) est une stratégie théranostique associant la spécificité de reconnaissance d’anticorps monoclonaux (AcMs) (ou de formes dérivées) vis-à-vis des antigènes tumoraux et les propriétés des radionucléides (imagerie/thérapie). L’efficacité de la RIT est cependant limitée sur les tumeurs solides à cause de la lente diffusion des AcMs et de leur longue demi-vie plasmatique. Les approches de radioimmunothérapie préciblée (PRIT), qui dissocient l’injection des AcMs de celle des radioligands constituent des alternatives pertinentes envisagées pour diminuer l’hématotoxicité et améliorer l’efficacité thérapeutique de la RIT classique. Nous avons ainsi travaillé sur une stratégie de PRIT utilisant la chimie bioorthogonale par interaction entre un trans-cyclooctène (TCO) et une tétrazine (TZ), à la fois pour l’imagerie et pour la thérapie de la carcinose péritonéale (CP) d’origine colorectale (modèle A431-CEA-Luc/ AcM 35A7). Dans un premier temps nous avons évalué à la fois in vitro et in vivo dans le modèle de CP ainsi que dans un modèle sous-cutané de cancer colorectal (modèle HT29/ AcM Ts29.2) l’effet des modifications apportées aux AcMs. Nous avons ainsi montré que les modifications d’AcMs influencent l’interaction entre les TCO et la TZ, sans pour autant altérer leur immunoréactivité. L’ajout d’espaceurs PEGylés (polyéthylène glycol) entre les AcMs et les TCO induit une diminution significative de l’interaction TCO/TZ. De plus, nous avons montré que les TCO sont sujets à l’isomérisation en cis-cyclooctènes, inactifs vis-à-vis de la TZ, et que la PEGylation aggrave ce phénomène. Ces études ont ainsi montré à la fois que les AcMs-TCO ne contenant pas d’espaceur PEGylé étaient les plus favorables pour le préciblage mais également, qu’il était primordial de contrôler le taux d’isomérisation des TCO avant greffage aux AcMs pour ne pas altérer l’interaction vis-à-vis des TZ. Dans un second temps nous avons effectué avec succès la preuve de concept de l’imagerie SPECT de la CP par préciblage entre l’AcM 35A7-TCO et la TZ-PEG4-DOTA-177Lu (i.e. TZ-1). Un ciblage spécifique des tumeurs péritonéales a ainsi été obtenu, avec un très bon contraste. L’étude de PRIT effectuée avec cette même sonde TZ-1 a cependant échoué à mettre en évidence une amélioration des médianes de survie ou un ralentissement de la croissance tumorale, nous amenant ainsi à reconsidérer la structure de la TZ-1. Trois autres TZ (i.e. TZ-2-4) ont donc été évaluées par la suite, en biodistribution, afin de déterminer la meilleure pour la PRIT de la CP. Ainsi, la TZ-3, qui comporte un espaceur PEGylé plus long que la TZ-1, s’est avérée être la plus favorable dans ce type de stratégie et sera prochainement utilisée pour une nouvelle étude de thérapie. En conclusion, ces travaux de thèse ont permis de démontrer la faisabilité du concept de préciblage par chimie bioorthogonale utilisant l’interaction TCO/TZ pour l’imagerie de tumeurs disséminées dans la cavité péritonéale. Cette stratégie reste néanmoins compliquée à mettre en place du fait de l’instabilité des TCO et des problèmes de réactivité de certaines sondes TZ et nécessite encore de nombreuses optimisations avant de pouvoir envisager une application thérapeutique. / Radioimmunotherapy (RIT) consists to combine the specificity of monoclonal antibodies (mAbs), or mAbs derived structures, towards tumor antigens with the imaging/therapy properties of radionuclides, representing thus a theranostic strategy. RIT efficiency in solid tumors is limited due to both mAbs slow diffusion and long blood clearance. Pretargeted radioimmunotherapy (PRIT) appears as an alternative to circumvent hematotoxicity and improve therapeutic efficacy. We have thus worked on PRIT based on bioorthogonal click chemistry relying on the interaction between trans-cyclooctene (TCO) and tetrazine (TZ). Application of this strategy was made for imaging and therapy of peritoneal carcinomatosis (PC) from colorectal origin (A431-CEA-Luc model/ 35A7 mAb). We have first assessed the influence of mAbs modifications, in vitro and in vivo experiments made on both PC model and subcutaneous colorectal cancer (HT29 model/ Ts29.2 mAb). We thus demonstrated that mAbs modifications influence the interaction between TCO and TZ without decreasing their antigen binding capacities. Indeed, addition of PEGylated (polyethylene glycol) linkers between mAbs and TCO induced a significant decrease of TCO/TZ interaction. In addition, we also demonstrated that TCO moieties undergo severe isomerization to cis-cyclooctene (CCO) moieties which are unreactive towards TZ. Addition of PEG linkers also increased the isomerization rate of TCO to CCO. Our results highlighted that a non PEGylated mAb should represent the best structure for PRIT to avoid isomerization and consequently to control the ratio of CCO before mAbs coupling to maximize TCO/TZ interaction. In disseminated PC, we have made for the first time the proof of concept of SPECT imaging between 35A7-TCO and TZ-PEG4-DOTA-177Lu (i.e. TZ-1). We indeed obtained a specific signal corresponding to PC tumors with a very good contrast. However, a PRIT experiment using TZ-1 did not allow observing neither improvement of median survivals nor tumor growth slow down. Those disappointing results led to reconsider the TZ-1 structure and evaluate three new TZ (i.e. TZ-2-4). The TZ-3, bearing a longer PEG linker than TZ-1, appears as the most appropriate for PRIT studies and will soon be considered for a new therapy experiment. In conclusion, we demonstrated the possibility to do pretargeted imaging of peritoneal disseminated tumors using bioorthogonal click chemistry with TCO/TZ interaction. Nevertheless, this strategy is quite complicated to do due to both TCO isomerization and reactivity of radiolabelled TZ probes. Further optimizations will be mandatory before therapy can be transferred to clinic.
290

Analysis of risk factors in patients with severe chronic kidney disease. The role of atorvastatin.

Holmberg, Benny January 2013 (has links)
Background and aim: There had been no randomized end-point studies with statins for patients with severe renal failure. The purpose of this prospective, open, randomized, controlled study was to investigate whether atorvastatin (10 mg/day) would alter cardiovascular end-points and the overall mortality rate of patients with chronic kidney disease stage 4 or 5 (creatinine clearance</30 ml/min) and to influence risk factors. Material & Methods: This was an open, prospective, randomized study. A total of 143 patients were included: 73 were controls and 70 were prescribed 10 mg/day of atorvastatin. As efficacy variables, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride levels were determined at the start of the study and at 1, 3, 6, 12, 18, 24, 30 and 36 months. The primary end-points were all cause of mortality, non-lethal acute myocardial infarction, and coronary artery intervention. Various risk factors were studied. In the 97 patients on haemodialysis inter dialysis weight gain (IDWG) was calculated as ultrafiltration in kg/body weight in kg given in percentage of the weight. The burden of IDWG was analyzed. Results: In the atorvastatin group, total cholesterol and low-density lipoprotein cholesterol were significantly reduced, the latter by 35% at 1 month and then sustained. Atorvastatin was withdrawn in 23% of patients due to unacceptable side effects, most frequent complaints being gastrointestinal discomfort and headache. Primary end-points occurred in 74% of the subjects. There was no difference in cardiovascular endpoint and survival between the control and atorvastatin groups. The 5-year end-point-free survival rate from study entry was 20%. There was no evidence of more benefit of atorvastatin for patients with diabetes mellitus and chronic kidney disease versus the other patients; instead plasma fibrinogen increased. The IDWG was significantly larger in patients who suffered from end-points due to cardiovascular reasons, cardiac reasons, congestive heart failure, aortic aneurysm, and intracerebral bleeding. Conclusion: These data showed that in contrast to other patient groups, patients with severe chronic kidney disease 4 and 5, including those with diabetes mellitus, seem to have no benefit from 10mg/day of atorvastatin. Instead we found a high IDWG to be an important risk factor that should be prevented. There was no evident connection between atorvastatin medication and IDWG.

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