Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-07T19:52:24Z No. of bitstreams: 1 janerochaduartecintra.pdf: 2932380 bytes, checksum: 42ad605d16a81a90bf6a3c42a06ea6b4 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-08T13:22:29Z (GMT) No. of bitstreams: 1 janerochaduartecintra.pdf: 2932380 bytes, checksum: 42ad605d16a81a90bf6a3c42a06ea6b4 (MD5) / Made available in DSpace on 2016-07-08T13:22:29Z (GMT). No. of bitstreams: 1 janerochaduartecintra.pdf: 2932380 bytes, checksum: 42ad605d16a81a90bf6a3c42a06ea6b4 (MD5) Previous issue date: 2012-03-23 / Objetivo: Analisar as taxas de sobrevida de cinco anos e os principais fatores associados ao perfil imunohistoquímico, em mulheres com câncer de mama. Métodos: A população foi composta a partir de coorte hospitalar formada por mulheres com diagnóstico de câncer de mama efetuado entre 2003 e 2005 (n=563) e atendidas em centro de referência em assistência oncológica de Juiz de Fora/MG. A data do diagnóstico histopatológico da doença foi considerada como início do tempo de sobrevida e a data do óbito pela doença foi considerada como o evento adverso. Foram censuradas as mulheres que permaneceram vivas até dezembro de 2010, data final do seguimento. Para aquelas que interromperam o seguimento, a data da censura foi referente ao último acompanhamento no registro médico. As curvas de sobrevida foram estimadas pelo método de Kaplan-Meier e o modelo de riscos proporcionais de Cox foi utilizado para a avaliação prognóstica. Resultados: A idade média das pacientes foi de 58,1 anos, sendo a maioria das pacientes (81,1%) da raça branca e pós-menopausa (66,8%). Os estádios clínicos predominantes foram o II (36,7%) e III (25,3%). Os subtipos mais frequentes foram os luminais A (n=295 casos – 52,4%) e os casos com perfil desconhecido (n=107 - 19%). A função de sobrevida específica para o câncer de mama, no período de cinco anos, foi de 79,9%. Entre as principais características associadas com uma melhor sobrevida não ajustada, na população de estudo, destacaram-se: subtipos imunohistoquímicos luminais (A e B) (p<0,0001), raça branca (p<0,0001), tamanho do tumor ≤ 2,0cm (p<0,0001), ausência de comprometimento linfonodal (p<0,0001), estádios mais precoces da doença (p<0,0001), realização de tratamento sistêmico (p=0,01) e uso de hormonioterapia (p<0,0001). Os principais fatores prognósticos associados à pior sobrevida foram: subtipos triplo negativo (p<0,001), HER2 superexpresso (p=0,01) e perfil imunohistoquímico desconhecido (p=0,01); raça não branca (p=0,02); doença avançada (estágio III e IV – p<0,001); tratamento sistêmico não realizado (p=0,009) e não utilização de quimioterapia de 1ª linha (p=0,09). Conclusão: Esta pesquisa possibilitou uma melhor caracterização do perfil imunohistoquímico e da sobrevida de pacientes com câncer de mama. / Purpose: Analyze the 5-year breast cancer specific-survival rate and according to the immunohistochemical profile of women diagnosed with breast cancer. Methods: The population was composed from a hospital-based cohort of all women diagnosed with breast cancer between 2003 and 2005 (n= 563), and treated at cancer care reference center in the city of Juiz de Fora/MG, Brazil. Survival time was counted from the date of the histopathological diagnosis and the date of death due to breast cancer was considered the adverse event. Women alive until December 2010, the final date of the follow-up, were censored. For those who interrupt treatment, censor date was the last follow-up in the medical records. Kaplan-Meier survival curves were estimated, and multivariate analysis was performed by the Cox proporciona hazard model. Results: Mean age was 58,05 years, and the majority were white skin color (81,1%) and postmenopausal (66,8%). Clinical Stages II (36,7%) and III (25,3%) predominated. The most common subtypes were luminal A (n= 295 cases – 52,4%) and cases with unknown profile (n= 107 – 19%) Breast cancer specific five-year survival rate was 79,93%. A better unadjusted survival was observed among women with disease diagnostic, immunohistochemical subtypes luminal A and B (p<0,0001), white skin color (p<0,0001), with tumor size ≤ 2.0cm (p<0,0001), without lymph node involvement (p<0,0001), in a less advanced disease stage (p<0,001), and of systemic treatment (p=0,01), and who used hormone therapy (p<0.0001). The main prognostic factors associated with poor survival were: subtypes triple negative (p<0.001), HER2 overexpression (p=0.01) and immunohistochemical profile unknown (p=0.01), no white race (p=0.02), advanced disease (stage III and IV – p<0.001), no realization of systemic treatment (p=0.009) and no use of first line chemotherapy (p=0.09). Conclusion: This research allowed identification of the profile and disease survival of breast cancer patients, according to imunohistochemical profile.

Syftet med studien var att undersöka och utvärdera kulturella verktyg och metoder som ingående komponenter i en strategi för ett ergonomiskt musicerande avseende främst stråkmusiker. Studien är metodologiskt genomförd som en fallstudie med semi-strukturerade kvalitativa intervjuer i kombination med observationer och tidigare insamlat datamaterial. Genom det kulturpsykologiska perspektivet kartläggs rytmik- och rörelsepedagogen Helle Axel-Nilssons kulturella verktygslåda. Axel-Nilsson är verksam vid Kungl. Musikhögskolan i Stockholm. Yttre (fysiska) påverkansfaktorer är kroppsliga besvär som uppstår av repetitiva rörelser, ensidiga och felaktiga ställningar i musicerandet. Med rätt metoder medvetandegörs vikten av dynamiken mellan spänning och avspänning. Inre (psykiska) påverkansfaktorer är en inre mental process, vi människor har möjlighet att förändra, hantera och påverka våra sinnen med tankens kraft. Mental närvaro bidrar till att upprätthålla en hållbar kropp. Det yttre och det inre samspelet bildar tillsammans en helhet och är beroende av varandra. För att vara en hållbar musiker och/eller pedagog är det viktigt att koppla samman den mentala närvaron med ergonomisk medvetenhet och att se hela kroppen som en helhet och inte som separata delar. Studiens övergripande resultat är att Axel-Nilsson kombinerar kunskaper från flera olika områden inom det yttre och det inre samt samspelet dem emellan i sin undervisning. Samspelet mellan det yttre och det inre utgör den pedagogiska metod Ki- kommunikation som Axel-Nilsson utformat och utövar. Hon arbetar med hela kroppens resurser och lyckas skapa en varierande undervisning med många sinnen aktiva. Genom att lära sig grunderna i hur man använder sin tyngdkraft i kroppens längd och rörelsemönster finner man sitt kroppsgehör för sitt kinistetiska sinne som tillsammans med mental närvaro ökar förutsättningarna för att upprätthålla en hållbar kropp. / The aim of the study was to examine and evaluate cultural tools and methods as components of ergonomic strategies for primarily string musicians. Methodologically, this thesis is conducted as a case study with semi-structured interviews in combination with observations and collected material. A cultural-psychological perspective has been employed to map out cultural tools used by Helle Alex-Nilsson, a teacher of music ergonomics at the Royal College of Music in Stockholm. External (physical) factors of influence are bodily discomfort from repetitive movements and bad ergonomics while playing music. With the correct methods and increased awareness of the causes of the problems, the teacher helps the students to understand the importance of dynamics between tension and relaxation. Internal (psychological) factors of influence are interpreted as an inner mental process. Human beings are dynamic and in possession of the power to control, change and influence our senses. Mental awareness contributes to sustain a solid body. The combination of the external and internal factors creates a bodily wholeness and one of the factors cannot function without the other, according to Axel-Nilsson. They contribute to an awareness of psychological factors within Ki-communication, a method that Axel-Nilsson has developed. The result of the study is that Axel-Nilsson uses various pedagogical tools and combines external and internal factors as a method called Ki-communication. By learning the basics of how to use gravity, body length and bodily movements, one can discover ones bodily “tonic” (as a musical metaphor used by Axel- Nilsson). By Ki-communication in combination with mental awareness and the kinaesthetic sense, the precondition to sustain a solid body increases.

Le traitement systémique adjuvant du cancer du sein infiltrant repose sur la chimiothérapie et l’hormonothérapie. Certains facteurs sont connus pour être pronostiques (âge, taille tumorale, statut ganglionnaire, grade tumoral, emboles vasculaires, statut des récepteurs hormonaux (RH) et de HER2) ou prédictifs de réponse aux traitements (RH et HER2) et influent sur nos décisions thérapeutiques. Cependant, certaines patientes récidivent malgré un traitement complet alors que d’autres vont recevoir un traitement qui aurait pu être évité de par leur bon pronostic « intrinsèque ». Nous avons cherché à identifier dans ce travail d’autres facteurs pronostiques et / ou prédictifs dans le cancer du sein infiltrant en situation néoadjuvante / adjuvante. Premièrement, nous montrons que le type histologique lobulaire, réputé pour être une histologie de cancer du sein de bon pronostic et peu chimiosensible, ne doit pas être un facteur décisionnel quant aux traitements systémiques. En situation adjuvante et concernant la chimiothérapie, la validité et l’utilité cliniques des tests génomiques nécessitent d’être évaluées spécifiquement dans ce sous-groupe. Ensuite, nous avons étudié la validité analytique, la validité clinique et l’utilité clinique de 2 classifications moléculaires des cancers du sein selon PAM50 et l’analyse immunohistochimique de biomarqueurs : récepteur œstrogène, HER2 et Ki67 avec un cut-off à 14%. Selon nos conclusions, il n’y a actuellement pas de données suffisamment robustes pour que ces 2 classifications modifient les décisions de traitement systémique. Nous avons mis en évidence un sous-groupe de tumeurs triples négatives exprimant le récepteur androgène et FOXA1 et se comportant comme des tumeurs luminales. Enfin, nous avons montré sur une large série néoadjuvante que la réponse histologique complète est un critère substitutif de survie pour les tumeurs RH négatifs / The adjuvant systemic treatment of invasive breast cancer is based on chemotherapy and endocrine therapy. Several prognostic factors (age, tumoral size, nodal status, tumoral grade, vascular embols, hormonal receptors (HR), HER2) and predictive factors of response to treatment (HR and HER2) are described and have an impact on our therapeutic decisions. However, recurrences are frequent after a complete treatment and patients could avoid such treatment because of the good “intrinsic” prognosis. In this work, we aimed to identify other prognostic and / or predictive factors for the invasive breast cancer in the neoadjuvant / adjuvant settings. Firstly, we showed that the lobular histology, considered as histology of good prognosis and low chemo sensitive, should not be a decisive factor regarding systemic therapy. In the adjuvant setting, regarding chemotherapy, clinical validity and utility of the genomic tests need to be specifically evaluated in this subgroup. Then, we studied analytical validity, clinical validity and clinical utility of 2 molecular classification of breast cancer: PAM50 and a panel of 3 biomarkers in immunohistochemistry (estrogen receptor, HER2 and Ki-67 with a cut-off of 14%). We concluded that the data were not strong enough and that the therapeutic decisions should not be influenced by these classifications. We identified a subgroup of triple negative breast cancer that express androgen receptor and FOXA1 and which behave like luminal tumors. At last, we showed in a large neoadjuvant population, that the pathological complete response is a surrogate marker of survival in RH negative tumors

INTRODUÇÃO: Para os pacientes portadores de transposição das grandes artérias que perderam a chance da cirurgia de Jatene nas primeiras semanas de vida, indica-se realizar o preparo ventricular através da bandagem do tronco pulmonar (BTP), objetivando causar aumento na massa miocárdica. Entretanto, com o tempo, a câmara hipertrofiada pode apresentar disfunção contrátil; portanto, é importante conhecer a qualidade do tecido preparado, uma vez que já se sabe que tanto os miocardiócitos (MCD) quanto as células do interstício e vasos (I/V) são capazes de proliferar após o período neonatal. Baseando-se no condicionamento físico de atletas e considerando-se que os músculos cardíaco e esquelético são ambos estriados, postula-se a hipótese de que o tipo de preparo ventricular possa influenciar nas características do miocárdio treinado. OBJETIVOS: Identificar o tipo de mecanismo adaptativo (hipertrofia/hiperplasia) envolvido no preparo rápido do ventrículo pulmonar submetido à sobrecarga de pressão por meio de BTP, através da análise dos MCD e células do I/V, verificando se existem diferenças em relação ao tipo de treinamento (contínuo x intermitente) em comparação com os controles. MÉTODOS: Foram estudados experimentalmente 21 cabritos após o período neonatal, divididos em três grupos (C = grupo controle, n = 7, sem procedimento cirúrgico; EC = grupo de estimulação contínua, n = 7, com bandagem progressiva e permanente do tronco pulmonar durante 96 horas; EI = grupo de estimulação intermitente, n = 7, com bandagem progressiva, 12 horas ao dia, totalizando 48 horas). Todos foram submetidos a estudo ecocardiográfico basal e aqueles dos grupos EC e EI a ecocardiogramas diários para verificar a aquisição de massa muscular do ventrículo direito (VD). Após o estudo, os animais foram sacrificados, os corações retirados e cortes histológicos do VD, ventrículo esquerdo (VE) e septo interventricular (S) fixados em formalina e processados para análise. Foram estudados a porcentagem de área de colágeno através do Picro-sirius, o diâmetro dos MCD e seus respectivos núcleos e o número de MCD e células do I/V marcadas com Ki-67. As células marcadas foram avaliadas por campo microscópico e por índice (número de células Ki-67+/2000 células). O nível de significância considerado foi de 0,05. RESULTADOS: Ambos os grupos estimulados apresentaram ganho significativo de massa muscular do VD (p < 0,05). Não houve aumento na porcentagem de colágeno do VD nos grupos treinados (p = 0,403). Considerando-se o VD, os grupos EC e EI apresentaram diâmetro dos MCD maior que o grupo controle (p < 0,001), ocorrendo o mesmo com os respectivos núcleos (EI x C: p < 0,001 e EC x C: p = 0,005). O número de MCD marcados com Ki-67 foi maior no VD dos grupos estimulados comparado com o VE (p = 0,009, índice de proliferação; p = 0,001, contagem por campo), bem como para as células do I/V (p < 0,001, contagem por campo e índice). CONCLUSÕES: Tanto hipertrofia quanto hiperplasia celular estão envolvidas na adaptação do ventrículo pulmonar submetido à sobrecarga sistólica através da BTP. Ambos os tipos de condicionamento (contínuo e intermitente) provocaram hipertrofia e hiperplasia dos MCD, induziram também à mitose das células do I/V, sem deposição de colágeno intersticial ao final do experimento. / INTRODUCTION: Rapid ventricular conditioning induced by pulmonary artery banding (PAB) has been indicated to those patients with transposition of the great arteries (TGA) who have lost the chance for arterial switch operation ? Jatene?s procedure ? aiming at induce myocardial mass increase. However, with time, hypertrophied chamber may exhibit contractile dysfunction, so that, it is important to assess quality of the prepared tissue, once it is of knowledge that both cardiomyocytes (CMC) and interstitial/vessel (I/V) cells are capable of proliferating after neonatal period. Based on fitness of athletes and considering that cardiac and skeletal muscles are both striated, there is the hypothesis that the type of ventricular prepare may influence the characteristics of the training myocardium. OBJECTIVES: Through CMC and I/V cells analysis, identifies the type of adaptive mechanism (hypertrophy/ hyperplasia) involved in rapid prepare of subpulmonary ventricle submitted to pressure overload by PAB, and verifies if there are differences in relation to the kind of training (continuous x intermittent), comparing them to the controls. METHODS: Twenty-one goats, beyond neonatal period, were experimentally studied. They were divided in three groups: C (control group, n = 7, with no surgical procedure); CS (continuous stimulation group, n = 7, with progressive and permanent PAB, during 96 hours); IS (intermittent stimulation group, n = 7, with progressive PAB, 12 hours/day, totalizing 48 hours). All the animals were submitted to basal echocardiograms and those from CS and IS groups to diary echocardiograms to verify right ventricular (RV) muscular mass acquisition. After the study, goats were killed, hearts excised and histological sections from RV, left ventricle (LV) and ventricular septum (VS) were formalin fixed and histologically processed. Collagen area fraction (through Picro-sirius red staining), CMC and respective nuclei diameter, and number of CMC and I/V cells Ki-67 positive were studied. Marked cells were analysed per high-power fields and by index (Ki-67 positive cells/2000 cells). The statistical significant level was set at 5%. RESULTS: Both stimulated groups presented significant RV muscular mass increase (p < 0.05). There were no augmentation in RV collagen area fraction in training groups (p = 0.403). Considering the RV, CS and IS groups showed an increase in CMC diameter compared to the control group (p < 0.01), occurring the same to respective nuclei (EI x C: p < 0.001 e EC x C: p = 0.005). Number of CMC marked with Ki-67 was greater in RV from stimulated groups in relation to LV (p = 0.009, proliferation index; p = 0.001, number/high-power fields); the same occurred to I/V cells (proliferation index and number/high-power fields: p < 0.001). CONCLUSIONS: Both cell hypertrophy and hyperplasia are involved in adaptation of the pulmonary ventricle submitted to pressure overload through PAB. Both types of conditioning (continuous and intermittent) caused CMC hypertrophy and hyperplasia, besides induced I/V cells mitosis, without interstitial collagen deposition at the end of experiment.

Einleitung: Nasenhöhlentumoren stellen mit bis zu 47 % die Hauptursache für Nasenausfluss beim Hund dar. Sie sind überwiegend maligne, zu 60 % Karzinome und zu 34 % Sarkome. Die mediane Überlebenszeit (MÜZ) liegt ohne Therapie bei etwa drei Monaten. Nach einer Bestrahlungstherapie beträgt sie etwa 8-20 Monate. Eine Therapie mit klassischen Chemotherapeutika oder eine Tumorablation über eine offen-chirurgische Rhinotomie führen nicht zu einer Verlängerung der Überlebenszeit. Durch ein neues Therapieverfahren, die endoskopisch interventionelle Zytoreduktion (EIZ), werden bei deutlich weniger Nebenwirkungen und Sitzungen in Allgemeinanästhesie ähnliche Überlebenszeiten erreicht wie durch eine Radiotherapie. Da es sich bei der EIZ um eine Zytoreduktion handelt, bei der die Nasenhöhlentumoren nicht mit Sicherheitsabstand im gesunden Gewebe entfernt werden können, stellt sich die Frage, ob die Überlebenszeit zusätzlich durch adjuvante Therapeutika verlängert werden kann. Als solche kommen beispielsweise Tyrosinkinase-Inhibitoren (TKI) und Cyclooxygenase-2 (COX-2)-Inhibitoren infrage, deren Zielstruktur-Expression besonders in kaninen nasalen Sarkomen noch unbekannt ist. Ziele der Untersuchungen: Ziel dieser Arbeit ist, anhand von Bioptaten von kaninen nasalen Karzinomen und Sarkomen eine immunhistochemische Charakterisierung durchzuführen. Hierzu wurden 10 Marker ausgewählt. Besonders im Fokus standen die Wachstumsfaktorrezeptoren vascular endothelial growth factor receptor-2 (VEGFR-2) und epidermal growth factor receptor (EGFR) sowie COX-2, die ersten beiden als Zielstrukturen von TKI und der letztere als Zielstruktur von COX-2-Inhibitoren. So soll eine Wirksamkeit dieser Medikamente bei kaninen nasalen Karzinomen und Sarkomen evaluiert werden. Weiterhin soll eine Korrelation zwischen der Expression von bestimmten Markern (p53, Ki-67, aktivierte Caspase-3, Survivin, E-Cadherin) mit den klinischen Daten zur Tumorkategorie und Überlebenszeit der Patienten untersucht werden. Außerdem soll als Grundlage für den Einsatz neuartiger Medikamente analysiert werden, ob EGFR, VEGFR-2 oder COX-2 in Karzinomen und Sarkomen unterschiedlich stark exprimiert werden. Tiere, Material und Methoden: Es wurden 19 Karzinome, sieben Sarkome und drei andere Tumorarten (ein malignes Melanom, zwei undifferenzierte maligne Tumoren unklarer Histogenese) retrospektiv immunhistochemisch auf die Expression von EGFR, VEGFR-2, COX-2, p53, Ki-67, aktivierter Caspase-3, Survivin, E-Cadherin, Zytokeratinen und Vimentin untersucht. Von drei Patienten wurden insgesamt vier Rezidivbioptate entnommen und ebenfalls immunhistochemisch untersucht. Beidseitige Nasenschleim-hautbioptate von neun gesunden Beagles dienten als Kontrollgruppe (genehmigungspflichtiger Tierversuch: TVV 02/18, Landesdirektion Sachsen). Alle Bioptate wurden während einer standardisierten Diagnostik mit computer-/ magnetresonanztomographischer Untersuchung - bei der auch ein Staging in vier Tumor-Kategorien (T1-T4) durchgeführt wurde - und Rhinoskopie zwischen Jan. 2015 und Dez. 2018 entnommen. Die immunhistochemische Untersuchung der in Formalin fixierten und in Paraffin eingebetteten Gewebeschnitte wurde mit der Avidin-Biotin-Komplex-Methode durchgeführt, nachdem die histopathologischen Diagnosen an Hämatoxylin-Eosin-gefärbten Schnitten gestellt wurden. Die immun-histochemischen Färbungen wurden entweder quantitativ oder semiquantitativ ausgewertet. Die Ergebnisse wurden auf Normalverteilung getestet und u.a. mit One-way Anova oder Kruskal-Wallis Test analysiert. Die MÜZ wurde mit der Kaplan Meier Methode berechnet und mit Log-Rank Test und Gehan-Breslow-Wilcoxon Test verglichen (Signifikanzniveau alpha = 5 %). Ergebnisse: 29 Hunde haben die Einschlusskriterien erfüllt. 14 Hunde wurden unmittelbar nach der Diagnostik euthanasiert; 15 Hunde wurden mit einer EIZ behandelt. Die MÜZ der Patienten in T1 (n = 3) nach EIZ betrug 1362 Tage und war signifikant länger als die MÜZ der Patienten in T2 (n = 1) mit 379 Tagen, in T3 (n = 8) mit 250 Tagen und in T4 (n = 1) mit 75 Tagen (p = 0,0062). Von den nasalen Karzinomen zeigten 68 % für EGFR, 100 % für VEGFR-2, 63 % für COX-2, 100 % für Survivin und 100 % für E-Cadherin eine immunhistochemisch positive Reaktion. Von den nasalen Sarkomen reagierten 100 % für VEGFR-2, 57 % für COX-2 und 86 % für Survivin positiv. Die Proteine EGFR und E-Cadherin werden ausschließlich von epithelialen Zellen exprimiert. Die Expression lag somit bei den vorliegenden Sarkomen bei 0 %. Unter den anderen Tumoren waren 33 % für EGFR, 100 % für VEGFR-2, 67 % für COX-2, 67 % für Survivin und 67 % für E-Cadherin positiv. Die mediane Expression von p53 lag bei 0,9 %, von Ki-67 bei 25 % und von aktivierter Caspase-3 bei 0,7 %. Die Unterschiede in der Expression von EGFR, VEGFR-2, COX-2, p53, Ki-67, aktivierter Caspase-3, Survivin und E-Cadherin zwischen den einzelnen histogenetischen Gruppen sowie zwischen den vier Tumor-Kategorien und in der MÜZ waren nicht signifikant. Eine Korrelation der VEGFR-2-Expression mit der MÜZ oder den T-Kategorien konnte nicht untersucht werden, da alle Tumoren der drei histogenetischen Gruppen VEGFR-2-positiv waren. 100 % der Karzinome zeigten eine Zytokeratin-Expression, 0 % eine Vimentin-Expression. Sarkome verhielten sich dazu konträr. In den anderen Tumoren konnten weder Zytokeratine noch Vimentin immunhistochemisch nachgewiesen werden. In den Rezidivbioptaten war ein Anstieg der COX-2 und aktivierte-Caspase-3-Expression zu beobachten, der aufgrund der geringen Fallzahl nicht statistisch untersucht werden konnte. Schlussfolgerungen: In der vorliegenden Studie wurden erstmalig kanine nasale Karzinome und Sarkome vergleichend immunhistochemisch untersucht. Weiterhin konnte erstmalig gezeigt werden, dass auch mesenchymale und andere Tumoren in vergleichbarer Häufigkeit wie Karzinome der Nase COX-2 exprimieren, wodurch ein Einsatz von COX-2-Inhibitoren nach einer Zytoreduktion bei Nasenhöhlentumoren allgemein von Nutzen sein könnte. Da alle Tumoren VEGFR-2 und die Mehrzahl der Karzinome (68 %) EGFR exprimierten, könnte eine adjuvante Therapie nach EIZ durch einen TKI mit VEGFR-2 oder EGFR als Zielstruktur einen positiven Einfluss auf die Überlebenszeit der erkrankten Hunde haben. Durch die Expression von E-Cadherin und Zytokeratinen in 100 % der Karzinome und 0 % der Sarkome sowie der Expression von Vimentin in 0 % der Karzinome und 100 % der Sarkome konnte die histopathologische Diagnose im Hinblick auf die Histogenese der Tumoren bestätigt werden. Auf der Grundlage der Ergebnisse der vorliegenden Studie sollte eine klinische Studie zur Anwendung von TKI und COX-2-Inhibitoren zur Untersuchung der klinischen Wirksamkeit und Sicherheit bei nasalen Tumoren von Hunden durchgeführt werden.:1 EINLEITUNG 1 2 LITERATURÜBERSICHT 2 2.1 Physiologie der Nasenhöhle 2 2.1.1 Anatomischer und histologischer Aufbau 2 2.1.2 Funktionen der Nasenhöhle und Nasenschleimhaut 3 2.2 Tumoren der Nase und der Nasennebenhöhlen 3 2.2.1 Prävalenz und Signalement von Hunden mit Nasentumoren 3 2.2.2 Biologisches Verhalten der Tumoren 3 2.3 Klinische Symptome 4 2.4 Diagnostik 5 2.4.1 Laboruntersuchungen 5 2.4.2 Bildgebende Verfahren 6 2.4.3 Rhinoskopie 9 2.4.4 Histopathologische Untersuchung 10 2.5 Therapieoptionen 10 2.5.1 Radiotherapie 10 2.5.2 Rhinotomie 11 2.5.3 Chemotherapie 11 2.5.4 Endoskopisch interventionelle Zytoreduktion (EIZ) 12 2.5.5 Tyrosinkinase-Inhibitoren 13 2.5.6 Antikörper gegen Rezeptortyrosinkinasen 15 2.5.7 Cyclooxigenase-Inhibitoren 16 2.6 Prognose 16 2.7 Zielantigene für die Immunhistochemie 17 2.7.1 Epidermal growth factor receptor (EGFR) 17 2.7.2 Vascular endothelial growth factor receptor-2 (VEGFR-2) 18 2.7.3 Cyclooxygenase-2 (COX-2) 18 2.7.4 p53 19 2.7.5 Ki-67 19 2.7.6 Aktivierte Caspase-3 20 2.7.7 Survivin 20 2.7.8 E-Cadherin 21 2.7.9 Zytokeratine 21 2.7.10 Vimentin 21 3 HUNDE, MATERIAL UND METHODEN 22 3.1 Patienten 22 3.2 Bioptate und Einschlusskriterien 23 3.3 Kontrolltiere 24 3.4 Immunhistochemische Untersuchungen 25 3.5 Auswertung der immunhistochemischen Reaktionen 28 3.6 Statistische Auswertung 29 4 ERGEBNISSE 31 4.1 Patienten 31 4.1.1 Signalement und Anamnese 31 4.1.2 Einteilung der Patienten in T-Kategorien 33 4.1.3 Histopathologische Befunde 34 4.1.4 Mediane Überlebenszeit nach endoskopisch interventioneller Zytoreduktion 34 4.1.5 Gesunde Kontrollgruppe 35 4.2 Ergebnisse der immunhistochemischen Untersuchungen 37 4.2.1 Kontrollen und Absorptionsreaktionen 37 4.2.2 Epidermal growth factor receptor (EGFR) 37 4.2.3 Vascular endothelial growth factor receptor-2 (VEGFR-2) 40 4.2.4 Cyclooxygenase-2 (COX-2) 42 4.2.5 p53 46 4.2.6 Ki-67 48 4.2.7 Aktivierte Caspase-3 50 4.2.8 Survivin 52 4.2.9 E-Cadherin 55 4.2.10 Zytokeratine 58 4.2.11 Vimentin 58 4.2.12 Bioptate von Tumorrezidiven 60 5 DISKUSSION 62 6 ZUSAMMENFASSUNG 84 7 SUMMARY 86 8 LITERATURVERZEICHNIS 88 9 ANHANG 105 9.1 Übersicht über die Hunde und Bioptate 105 9.2 Ergebnistabellen 107 9.3 Immunhistochemisches Reaktionsprotokoll 120 9.4 Ansatz der Lösungen und Puffer für die Immunhistochemie 122 9.5 Bezugsquellen für Geräte, Einmalartikel, Reagenzien und Chemikalien 123 9.6 Abbildungs- und Tabellenverzeichnis 125 / Introduction: Tumours of the nasal cavity are the main cause of nasal discharge in dogs (up to 47 %). They are almost always malignant, 60 % are carcinomas and 34 % are sarcomas. Without performing any treatment, the median survival time (MST) is about three months. After radiation therapy, the MST is about 8-20 months. A therapy with conventional chemotherapeutics or tumour ablation via open surgical rhinotomy does not prolong the survival time. A new treatment method, the endoscopic interventional cytoreduction (EIC), achieves survival times similar to radiotherapy with considerably fewer sessions under general anaesthesia and fewer potential adverse events. As EIC is a cytoreduction procedure in which the intranasal tumours cannot be removed with safety margins in surrounding healthy tissue, the question arises whether survival could be prolonged by an additional application of adjuvant therapeutics. As such, for example, tyrosine kinase inhibitors (TKIs) and cyclooxygenase-2 (COX-2) inhibitors may be considered, whose target expression is still unknown, especially in canine nasal sarcomas. Aims of the study: One aim of this study is to perform an immunohistochemical characterisation on the basis of biopsy specimens from canine nasal carcinomas and sarcomas. For this purpose, 10 markers were selected. We particularly focused on the growth factor receptors vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) as well as COX-2, the first two being targets of TKIs and the latter one being the target of COX-2-inhibitors. Thus, a possible efficacy of these drugs in canine nasal carcinomas and sarcomas should be evaluated. Furthermore, a correlation between the expression of specific markers (p53, Ki-67, cleaved caspase-3, survivin, E-cadherin) with clinical data of the tumour stage and patient survival time should be investigated. Moreover, it will be analysed as a basis for the use of novel drugs whether EGFR, VEGFR-2 or COX-2 are differentially expressed in carcinomas and sarcomas. Animals, Material and Methods: A total of 19 carcinomas, seven sarcomas and three other tumour types (one malignant melanoma, two undifferentiated malignant tumorus of unclear histogenesis) were retrospectively examined by immunohistochemistry for the expression of EGFR, VEGFR-2, COX-2, p53, Ki-67, cleaved caspase-3, survivin, E-cadherin, cytokeratins and vimentin. A total of four biopsies from recurrent tumours were obtained from three patients and also examined by immunohistochemistry. Bilateral nasal mucosal samples from nine healthy beagles served as a control group (animal experiment requiring approval: TVV 02/18, Directorate of the Federal State of Saxony, Germany). All biopsy specimens were collected during a standardised diagnostic procedure with computer /magnetic resonance tomography, which also included a staging into four tumour stages (T1-T4) and rhinoscopy between Jan 2015 and Dec 2018. The immunohistochemical examination of tissue sections fixed in formalin and embedded in paraffin was performed using the avidin-biotin complex method after histopathological diagnoses had been made on haematoxylin-eosin stained sections. The immunohistochemically stained sections were evaluated either quantitatively or semiquantitatively. Results were tested for normal distribution and analysed by the one-way anova or Kruskal-Wallis test, among others. MST was calculated using the Kaplan Meier method and compared with the log-rank test and Gehan-Breslow-Wilcoxon test (significance level alpha = 5 %). Results: A total of 29 dogs met the inclusion criteria. A total of 14 dogs were euthanised immediately after diagnosis; 15 dogs were treated with an EIC. The MST of patients in T1 (n = 3) after EIC was 1362 days and was significantly longer than the MST of those patients in T2 (n = 1) at 379 days, T3 (n = 8) at 250 days and T4 (n = 1) at 75 days (p = 0.0062). Of the nasal carcinomas, 68 % were immunohistochemically positive for EGFR, 100 % for VEGFR-2, 63 % for COX-2, 100 % for survivin and 100 % for E-cadherin. Of the nasal sarcomas, 100 % reacted positively for VEGFR-2, 57 % for COX-2 and 86 % for survivin. The proteins EGFR and E-cadherin were expressed exclusively by epithelial cells and, therefore, the expression was 0 % in the present sarcomas. Amongst the other tumours, 33 % were positive for EGFR, 100 % for VEGFR-2, 67 % for COX-2, 67 % for survivin and 67 % for E-cadherin. The median expression of p53 was 0.9 %, that of Ki-67 25 % and that of cleaved caspase-3 0.7 %. Differences in expression of EGFR, VEGFR-2, COX-2, p53, Ki-67, cleaved caspase-3, survivin and E-cadherin among the histogenetic groups, the four tumour stages and in MST were not significant. However, a correlation of VEGFR-2 expression with MST or the tumour stages could not be investigated because all tumours in the three histogenetic groups were VEGFR-2 positive. A total of 100 % of carcinomas showed cytokeratin expression, and 0 % showed vimentin expression. Sarcomas behaved in a contrary manner. In the other tumours, neither cytokeratins nor vimentin could be detected by immunohistochemistry. An increase in COX-2 and cleaved caspase-3 expression was observed in the recurrent tumour biopsies, which could not be statistically investigated due to the small number of cases. Conclusions: In the present study, canine nasal carcinomas and sarcomas were investigated comparatively by immunohistochemistry for the first time. Again, it was shown for the first time that mesenchymal and other tumours also express COX-2 at comparable frequencies to carcinomas of the nose, suggesting that the use of COX-2 inhibitors after cytoreduction may be of general benefit in nasal cavity tumours. As all tumours expressed VEGFR-2 and the majority of carcinomas (68 %) expressed EGFR, the adjuvant therapy after EIC by a TKI targeting VEGFR-2 or EGFR could have a beneficial effect on the survival of diseased dogs. The expression of E-cadherin and cytokeratins in 100 % of the carcinomas and 0 % of the sarcomas as well as the expression of vimentin in 0 % of the carcinomas and 100 % of the sarcomas confirmed the histopathological diagnosis with regard to the histogenesis of the tumours. Based on these results of the present study, a clinical trial should be performed on the use of TKIs and COX-2 inhibitors to investigate the clinical efficacy and safety of canine nasal tumours.:1 EINLEITUNG 1 2 LITERATURÜBERSICHT 2 2.1 Physiologie der Nasenhöhle 2 2.1.1 Anatomischer und histologischer Aufbau 2 2.1.2 Funktionen der Nasenhöhle und Nasenschleimhaut 3 2.2 Tumoren der Nase und der Nasennebenhöhlen 3 2.2.1 Prävalenz und Signalement von Hunden mit Nasentumoren 3 2.2.2 Biologisches Verhalten der Tumoren 3 2.3 Klinische Symptome 4 2.4 Diagnostik 5 2.4.1 Laboruntersuchungen 5 2.4.2 Bildgebende Verfahren 6 2.4.3 Rhinoskopie 9 2.4.4 Histopathologische Untersuchung 10 2.5 Therapieoptionen 10 2.5.1 Radiotherapie 10 2.5.2 Rhinotomie 11 2.5.3 Chemotherapie 11 2.5.4 Endoskopisch interventionelle Zytoreduktion (EIZ) 12 2.5.5 Tyrosinkinase-Inhibitoren 13 2.5.6 Antikörper gegen Rezeptortyrosinkinasen 15 2.5.7 Cyclooxigenase-Inhibitoren 16 2.6 Prognose 16 2.7 Zielantigene für die Immunhistochemie 17 2.7.1 Epidermal growth factor receptor (EGFR) 17 2.7.2 Vascular endothelial growth factor receptor-2 (VEGFR-2) 18 2.7.3 Cyclooxygenase-2 (COX-2) 18 2.7.4 p53 19 2.7.5 Ki-67 19 2.7.6 Aktivierte Caspase-3 20 2.7.7 Survivin 20 2.7.8 E-Cadherin 21 2.7.9 Zytokeratine 21 2.7.10 Vimentin 21 3 HUNDE, MATERIAL UND METHODEN 22 3.1 Patienten 22 3.2 Bioptate und Einschlusskriterien 23 3.3 Kontrolltiere 24 3.4 Immunhistochemische Untersuchungen 25 3.5 Auswertung der immunhistochemischen Reaktionen 28 3.6 Statistische Auswertung 29 4 ERGEBNISSE 31 4.1 Patienten 31 4.1.1 Signalement und Anamnese 31 4.1.2 Einteilung der Patienten in T-Kategorien 33 4.1.3 Histopathologische Befunde 34 4.1.4 Mediane Überlebenszeit nach endoskopisch interventioneller Zytoreduktion 34 4.1.5 Gesunde Kontrollgruppe 35 4.2 Ergebnisse der immunhistochemischen Untersuchungen 37 4.2.1 Kontrollen und Absorptionsreaktionen 37 4.2.2 Epidermal growth factor receptor (EGFR) 37 4.2.3 Vascular endothelial growth factor receptor-2 (VEGFR-2) 40 4.2.4 Cyclooxygenase-2 (COX-2) 42 4.2.5 p53 46 4.2.6 Ki-67 48 4.2.7 Aktivierte Caspase-3 50 4.2.8 Survivin 52 4.2.9 E-Cadherin 55 4.2.10 Zytokeratine 58 4.2.11 Vimentin 58 4.2.12 Bioptate von Tumorrezidiven 60 5 DISKUSSION 62 6 ZUSAMMENFASSUNG 84 7 SUMMARY 86 8 LITERATURVERZEICHNIS 88 9 ANHANG 105 9.1 Übersicht über die Hunde und Bioptate 105 9.2 Ergebnistabellen 107 9.3 Immunhistochemisches Reaktionsprotokoll 120 9.4 Ansatz der Lösungen und Puffer für die Immunhistochemie 122 9.5 Bezugsquellen für Geräte, Einmalartikel, Reagenzien und Chemikalien 123 9.6 Abbildungs- und Tabellenverzeichnis 125

The purpose of this thesis is to examine idiomatic structures with ki in the ki-wo [transitive verb] and ki-ga [intransitive verb] constructions. It is argued that for Japanese language learners, it is crucial to be able to understand and produce ki idioms, because they are frequently used in everyday speech. There are often misconceptions regarding ki in the West for those who are fans of Japanese culture due to the influence of martial arts and anime, which paint ki as a spiritual energy that can be controlled and developed. However, upon examining the above mentioned idiomatic structures with ki, it is clear that ki can be expressed as both controllable by the subject of ki (transitive), as well as a thing that acts of its own accord and is spontaneous (intransitive). This thesis somewhat corroborates the studies of W. M. Jacobson, Zoe Pei Sui Luk , and Yoshihiko Ikegami by arguing that intransitive constructions are often used in Japanese, and examining both transitive and intransitive expressions with ki is significant to understanding the meanings produced in ki expressions. It is hoped that analyzing 37 transitive and intransitive idiomatic structures with ki will help Japanese language learners not only understand the syntactic and semantic aspects of transitivity in the Japanese language, but also to help these L2 learners conceptualize the abstract noun ki, which can be defined in so many different ways in a dictionary.

Aus der Studie und den Ergebnissen können wertvolle Impulse abgeleitet werden. Es darf nicht aus den Augen verloren werden, dass junge Menschen mit traumatisierenden Erfahrungen spezifische Perspektiven (Kenny, Dooley, & Fitzgerald, 2016) und Bedenken in Bezug auf die Vertrauenswürdigkeit von KI (Grasser, 2020) haben können. Demzufolge ist wichtig, die subjektive Sicherheit sowie andere Einflussgrößen auf die Nutzung von KI und E-Health Angeboten zu kennen und in Betracht zu ziehen. Ferner zeigen Studien, dass E-Health Literacy (E-Health-Kompetenz) bei minderjährigen Geflüchteten eher gering ist (Bergmann, Nilsson, Dahlberg, Jaensson, & Wångdahl, 2021) und Forschung zur Erhöhung des Uptake von qualitativ hochwertigen Angeboten dringend benötigt wird. Die Integration der Zielgruppe kann jedoch nur dann gelingen, wenn die E-Health-Apps als wichtig erkannt werden und bei ihrer Umsetzung darauf geachtet wird, dass sie praktikabel sind. [Aus: Zusammenfassung]

Respiratory tract diseases are of the most common infectious diseases among both children and adult population all over the world. Viruses are the most frequent cause of respiratory diseases. In healthy immunocompetent individuals respiratory infection proceeds mostly without major complications. Immunocompromissed hosts, for example patients after transplatation, are more susceptible to infection and even common infection may be life threatening for them. Human polyomaviruses KI (KIPyV) and WU (WUPyV) and human bocavirus (HBoV) are most frequently detected in the respiratory tract of patients with acute respiratory tract infection primarily in children and in immunosuppressed patients. However, clear causative link between presence of these viruses and the respiratory disease has not been established. In this retrospective study were tested by quantitative real-time PCR 822 (745 from adults and 77 from children) respiratory samples from 380 immunocompromissed patients included 326 adults and 54 children. Viruses were also detected in the 84 peripheral blood samples. The most frequently detected virus was HBoV (6,32 % positive pacients), followed by KIPyV (5,79 % positive pacients) and WUPyV (0, 53 % positive patients). Only HBoV was detected in blood samples. The study confirmed the presence of KI...

Objetivos do Estudo: O aumento do crescimento de melanoma foi avaliado em camundongos expostos a hipóxia intermitente. As proteínas que caracterizam a agressividade do tumor ainda não foram investigadas. O estudo teve como objetivo verificar se a hipóxia intermitente simulada pela apneia do sono afeta marcadores de melanoma na progressão tumoral. Desenho: Estudo prospectivo controlado em animais. Senário: Hospital Universitário. Participantes: Doze camundongos C57BL/6. Intervenções: Camundongos foram expostos a hipóxia intermitente ou simulada. Durante 8 horas por dia, o grupo hipóxia foi submetido a um total de 480 ciclos de 30 segundos de hipóxia progressiva SpO2 nadir de 8 ± 1%, seguidos por 30 segundos de normóxia. Um milhão de células de melanoma B16F10 foi injetado por via subcutânea. No dia 14, após a eutanásia, os tumores foram removidos, fixados e corados. Médias e resultados: coloração imunohistoquímica de Ki-67, PCNA, S100-B, HMB-45, Melan-A, TGF, Caspase-1 e HIF-1α foi quantificada por dois observadores que utilizaram captura digital e processamento em três lâminas de cada animal para cada marcador. O tamanho e o peso dos tumores foram semelhantes nas experiências de hipóxia e simulada. A percentagem da mediana [25-75 quartis] de área positiva corada para Ki-67 foi de 23% [15-28] no grupo hipóxia e 0,3% [0,2-1,1] no grupo controle (P = 0,02); para PCNA, as percentagens foram 31% [25-38] e 7% [5-18], respectivamente (P = 0,009). As diferenças entre os grupos para os marcadores restantes não foram significativas. Conclusões: Os marcadores da transcrição do RNA ribossomal e da síntese de DNA são mais expressos em tumores de camundongos expostos a hipóxia intermitente do que em controles, indicando que a apneia do sono pode levar a uma maior agressividade do tumor. / Study Objectives: Increased melanoma growth has been reported in mice exposed to intermittent hypoxia. Proteins that characterize tumor aggressiveness have not been investigated. The study aims to verify whether intermittent hypoxia mimicking sleep apnea affects markers of melanoma tumor progression. Design: Prospective controlled animal study. Settings: University hospital. Participants: Twelve C57bl/6 mice. Interventions: Mice were exposed to intermittent or sham hypoxia. During 8 hours per day, the hypoxia group was submitted to a total of 480 cycles of 30 seconds of progressive hypoxia to a nadir FIO2 of 8±1%, followed by 30 seconds of normoxia. One million B16F10 melanoma cells were injected subcutaneously. On the 14th day, after euthanasia, tumors were removed, fixed and stained. Measurements and Results: Immunohistochemistry staining for Ki-67, PCNA, S100-B, HMB-45, Melan-A, TGFβ, Caspase-1 and HIF-1α was quantified by two observers using digital capture and processing in three slides from each animal for each marker. The size and weight of the tumors were similar in hypoxia and simulated experiments. Median [25-75 quartiles] percentage of positive area stained for Ki-67 was 23% [15-28] in the hypoxia group and 0.3% [0.2-1.1] the control group (P=0.02); for PCNA, the percentages were 31% [25-38] e 7% [5-18], respectively (P=0.009). The differences between the groups for the remaining markers were not significant. Conclusions: Markers of ribosomal RNA transcription and of DNA synthesis are more expressed in tumors of mice exposed to intermittent hypoxia than of controls, indicating that sleep apnea can lead to greater tumor aggressiveness.

Previous research on the relationship between spatial memory and adult hippocampal neurogenesis has been controversial. In the present study, neurogenesis was compared between two natural populations of the same species that differ in their reliance on spatial memory to cache and retrieve stored food. Western red squirrels store food in a single site whereas eastern red squirrels store food in multiple sites. Neurogenesis was assessed using endogenous markers of the number of proliferating cells (Ki-67) and the number of immature neurons (DCX), and neuronal recruitment was determined by measuring the area of the dentate gyrus of the hippocampus. The number of proliferating cells, immature neurons and neuronal recruitment were enhanced in the eastern compared to the western red squirrels, reflecting the food storing strategies used by the squirrels. This suggests that there is a positive correlation between adult hippocampal neurogenesis and spatial learning and memory.