Derzeit erfolgt in Deutschland lediglich eine Erfassung anzeigepflichtiger Tierseuchen und meldepflichtiger Tierkrankheiten bei Equiden. Folglich besteht ein Bedarf an Informationen aus klinischen und post-mortem-Statistiken, um frühzeitig Hinweise auf Veränderungen im Erkrankungsspektrum dieser Tiere zu erhalten. Im Rahmen entsprechender Auswertungen ist es zudem möglich, Daten zu selten auftretenden Alterationen zu sammeln. Allerdings müssen bei der Interpretation der Ergebnisse Einflussfaktoren, die die Zusammensetzung des Untersuchungsgutes beeinflussen, berücksichtigt werden, da die ausgewerteten Fälle, insbesondere in retrospektiven Arbeiten, in der Regel nicht für eine bestimmte Population repräsentativ sind. Ziel dieser Arbeit war es daher, sich einen Überblick über die Hauptbefunde, welche in Equiden-Sektionen am Institut für Veterinär-Pathologie der Universität Leipzig und an der Tierärztlichen Hochschule Dresden zwischen 1890 und 2013 erhoben wurden, zu verschaffen. Darüber hinaus sollten Veränderungen im Krankheitsspektrum während des Untersuchungszeitraumes und epizootiologische Einflussfaktoren (Alter, Rasse, Geschlecht) untersucht sowie die Art und Prävalenz der haupt- und nebenbefundlich diagnostizierten Tumoren festgestellt werden. Anschließend sollten die getroffenen Beobachtungen unter Beachtung von zeitgeschichtlichen Aspekten und den Ergebnissen anderer Statistiken aus der Literatur interpretiert werden. Für die Statistik standen die Daten von 4743, zwischen 1890 und 2013 am Institut für Veterinär-Pathologie der Universität Leipzig bzw. an der Tierärztlichen Hochschule Dresden durchgeführten Equiden-Obduktionen zu Verfügung. Es erfolgte eine Erfassung der Angaben zu Monat und Jahr der Obduktion, Alter, Rasse, Geschlecht, Herkunftsort, weiterführenden Untersuchungen (Bakteriologie, Virologie, Toxikologie, Parasitologie, histologische Spezialfärbungen, Immunhistologie) und den erhobenen Befunden. Sofern vorhanden, wurden Informationen zur Anamnese und intra vitam festgestellten Diagnosen einbezogen. Nur in 79,6 %, 53,2 % bzw. 88,0 % der Fälle waren Angaben zu Alter, Rasse bzw. Geschlecht erhalten. Über den gesamten Untersuchungszeitraum betrachtet, waren die sezierten Equiden am häufigsten von einer Erkrankung der Verdauungsorgane (36,5 %), gefolgt von Alterationen der Atmungsorgane (10,5 %), des Nervensystems (9,6 %), der Kreislauforgane (8,4 %), des Stütz- und Bewegungsapparates (7,7 %) und generalisierten Veränderungen (7,4 %) als Hauptbefund betroffen. Weniger häufig traten Alterationen während der Trächtigkeit (5,2 %) oder im Bereich der großen Körperhöhlen (4,0 %), der Leber (3,1 %), des hämatopoetischen Systems (1,7 %), der Harnorgane und des Nabels (1,5 %), der Geschlechtsorgane (1,3 %), der Haut (0,9 %), des Endokriniums (0,2 %) sowie des Auges (0,0 %) auf. Unter dem Begriff „Sonstige Erkrankungen“ (2,0 %) wurden Fälle mit unklarer Genese, ohne Sektion oder Tiere mit ausgeprägter Autolyse und/oder Fäulnis zusammengefasst. Im Vergleich zum Beginn der Auswertungsperiode, nahm der Anteil der Veränderungen im Bereich des Verdauungstraktes, insbesondere infolge einer Reduktion der Fälle mit einer Quer- oder Längsachsendrehung bzw. der Tiere mit einer Obstipation (84/264 zwischen 1970 und 1989 diagnostiziert), im Verlauf der Jahrzehnte ab (1890-1899: 52,6 %; 1900-1909: 58,2 %; 2000-2009: 35,8 %; 2010-2013: 38,0 %). Demgegenüber traten in den 1990er Jahren die meisten Fälle mit dem Hauptbefund „Erkrankung des Nervensystems“, ausgelöst durch einen hohen Anteil an Equiden mit der Diagnose „Bornasche Krankheit“ (BD; 7,8 %), auf. Die Zunahme dieses Hauptbefundes unter den Obduktionstieren kann durch die deutsche Wiedervereinigung im Jahr 1990 und die damit verbundenen Änderungen im Bereich des Tierseuchenrechts erklärt werden. Seit 2000 ist der Anteil der Equiden mit dem Nachweis einer BD wieder rückläufig (2000-2009: 5,3 %; 2010-2013: 1,3 %). Im Vergleich zum gesamten Untersuchungszeitraum (1890-2013) fanden sich zudem zwischen 1990 und 2013 häufiger Alterationen während der Trächtigkeit (8,8 %) bzw. mehr Veränderungen im Bereich des Stütz- und Bewegungsapparates (10,4 %), der Haut (1,2 %) oder des Endokriniums (0,5 %). Während die Zunahme der Aborte am ehesten mit einer Änderung des Forschungsschwerpunktes des Institutes für Veterinär-Pathologie der Universität Leipzig erklärt werden kann, lässt sich mit hoher Wahrscheinlichkeit der Anstieg der Fälle mit Läsionen des Stütz- und Bewegungsapparates, zumindest teilweise, auf die wirtschaftlich bessere Situation der Gesamtbevölkerung zum Ende des Untersuchungszeitraumes, und einem damit verbundenen Rückgang an Pferdeschlachtungen, zurückführen. Des Weiteren nahm die Bedeutung von Veränderungen der Atmungsorgane, der großen Körperhöhlen oder von generalisierten Erkrankungen, welche häufig infolge einer bakteriellen Infektion auftreten, seit den 1950er Jahren im Sektionsgut ab. Für diese Entwicklung können Verbesserungen in der Therapie (u.a. der Einsatz von Antibiotika in der Tiermedizin) und der klinischen Diagnostik (z.B. bei der Diagnose der chronisch-obstruktiven Bronchitis oder „Recurrent Airway Obstruction“) sowie der Erfolg tierseuchenhygienischer Maßnahmen (u.a. Bekämpfung von Rotz, Druse und Tuberkulose) verantwortlich gemacht werden. Des Weiteren ergab die Auswertung, dass 5,2 % der obduzierten Einhufer (248/4743) entweder haupt- (3,2 %) oder nebenbefundlich von 285 Tumoren betroffen waren. Bei 78,2 % (223/285) der Läsionen wurde die Diagnose histologisch bestätigt. Meist lag ein einzelner neoplastischer Prozess vor (n=221), vereinzelt fanden sich multiple Neoplasien (zwei unterschiedliche Tumoren pro Tier: n=19; drei Tumoren pro Tier: n=6; vier Tumoren pro Tier: n=2). Das mediane Alter der betroffenen Einhufer mit Altersangabe (n=219) lag bei 14 Jahren, wobei 87,9 % der Fälle älter als 6 Jahre alt waren. Deutlich ausgeprägte Schwankungen zeigten sich im Verlauf des Untersuchungszeitraumes in der Verteilung des Tumorvorkommens. Zwischen 1990 und 2013 wurden drei Viertel (214/285) aller im Untersuchungszeitraum festgestellten Neoplasien diagnostiziert, wobei sich die Läsionen mehrheitlich (180/214) nach 1999 zeigten. Das für die unterschiedlichen Zeitabschnitte der Auswertungsperiode ermittelte mediane Alter scheint bei dieser Entwicklung nicht im Vordergrund zu stehen. Die Läsionen (n=285) fanden sich meist im Bereich der großen Körperhöhlen (24,2 %), des Endokriniums (17,5 %), des hämatopoetischen Systems (14,7 %) und/oder der Haut (12,3 %). Dabei zeigten sich am häufigsten Lipome (23,2 %; n=66), Leukosen (12,6 %; n=36), maligne Melanome (8,4 %; n=24), Adenome der Hypophyse (6,3 %; n=18) und/oder Plattenepithelkarzinome (5,6 %; n=16). Zusammenfassend lässt sich feststellen, dass, in Übereinstimmung mit den Ergebnissen anderer Studien, Erkrankungen der Verdauungsorgane nach wie vor zu den häufigsten Abgangsursachen bei Equiden zählen. Die Prävalenz von Veränderungen des Nervensystems hingegen schwankt, in Abhängigkeit zum Vorkommen endemischer Erkrankungen, in verschiedenen Statistiken. Die Bedeutung der BD ist im eigenen Sektionsmaterial (Einzugsgebiet der Universität Leipzig und der Tierärztlichen Hochschule Dresden) seit 2000 rückläufig. Demgegenüber nimmt die Anzahl der diagnostizierten Tumoren in der vorliegenden Auswertung in den letzten Jahren (2000-2013) stark zu. Obwohl sich das Spektrum der diagnostizierten Tumorarten erweitert hat, zählen Neoplasien weiterhin zu den selten diagnostizierten Erkrankungen bei Einhufern.:I INHALTSVERZEICHNIS II ABKÜRZUNGSVERZEICHNIS 1 EINLEITUNG 2 LITERATURÜBERSICHT 2.1 Übersichts-Statistiken zu Equiden-Sektionen 2.1.1 Material und Methoden der Übersichts-Statistiken 2.1.2 Häufige Befunde in Übersichts-Statistiken 2.2 Klinische Übersichts-Statistiken zu Erkrankungen bei Equiden 2.3 Übersichts-Statistiken zu Tumoren bei Equiden 2.3.1 Sektionsstatistiken zu Tumoren bei Equiden 2.3.1.1 Methoden der Sektionsstatistiken 2.3.1.2 Häufig von Tumoren betroffene Organsysteme in Sektionsstatistiken 2.3.1.3 Häufige Tumorarten 2.3.2 Auswertungen von Biopsien bzw. Befunden aus klinischen Einrichtungen 2.3.2.1 Methoden der Tumor-Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.3.2.2 Häufig von Tumoren betroffene Organsysteme in Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.3.2.3 Übersicht der häufigsten Tumorarten in Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.4 Fazit aus der Literatur bezogen auf die initiale Fragestellung dieser Arbeit 3 MATERIAL UND METHODEN 3.1 Material 3.2 Methode 4 ERGEBNISSE 4.1 Auswertung der Hauptbefunde 4.1.1 Erkrankungen der Verdauungsorgane 4.1.2 Erkrankungen der Atmungsorgane 4.1.3 Erkrankungen des Nervensystems 4.1.4 Erkrankungen der Kreislauforgane 4.1.5 Erkrankungen des Stütz- und Bewegungsapparates 4.1.6 Generalisierte Erkrankungen 4.1.7 Pathologie der Trächtigkeit 4.1.8 Erkrankungen der großen Körperhöhlen 4.1.9 Erkrankungen der Leber 4.1.10 „Sonstige Erkrankungen“ 4.1.11 Erkrankungen des hämatopoetischen Systems 4.1.12 Erkrankungen der Harnorgane und des Nabels 4.1.13 Erkrankungen der Geschlechtsorgane 4.1.14 Erkrankungen der Haut 4.1.15 Erkrankungen des Endokriniums 4.1.16 Erkrankungen des Auges 4.2 Auswertung von Tumoren unter Berücksichtigung von Haupt- und Nebenbefunden 4.2.1 Häufigkeit und Klassifikation 4.2.2 Multiple Neoplasien 4.2.3 Häufigkeit benigner, semimaligner und maligner Tumoren 4.2.4 Metastasierende bzw. multizentrische Tumoren 5 DISKUSSION 5.1 Ziel der Arbeit 5.2 Kritische Beurteilung des Untersuchungsmaterials 5.3 Auswertung der Hauptbefunde 5.3.1 Erkrankungen der Verdauungsorgane 5.3.2 Erkrankungen der Atmungsorgane 5.3.3 Erkrankungen des Nervensystems 5.3.4 Erkrankungen der Kreislauforgane 5.3.5 Erkrankungen des Stütz- und Bewegungsapparates 5.3.6 Generalisierte Erkrankungen 5.3.7 Pathologie der Trächtigkeit 5.3.8 Erkrankungen der großen Körperhöhlen 5.3.9 Erkrankungen der Leber 5.3.10 „Sonstige Erkrankungen“ 5.3.11 Erkrankungen des hämatopoetischen Systems 5.3.12 Erkrankungen der Harnorgane und des Nabels 5.3.13 Erkrankungen der Geschlechtsorgane 5.3.14 Erkrankungen der Haut 5.3.15 Erkrankungen des Endokriniums 5.3.16 Erkrankungen des Auges 5.3.17 Fazit 96 5.4 Tumoren als Haupt- und Nebenbefund 5.4.1 Prävalenz von Tumoren bei Equiden 5.4.1.1 Prävalenz einzelner Tumorarten in klinischen Auswertungen 5.4.1.2 Prävalenz einzelner Tumorarten in Sektions- und Schlachthofstatistiken 5.4.2 Multiple Neoplasien 5.4.3 Metastasierende Tumoren 5.4.4 Fazit 6 ZUSAMMENFASSUNG 7 SUMMARY 8 LITERATUR 9 ANHANG 9.1 Klinische Übersichtsstatistiken zu dem Erkrankungskomplex „Kolik“ 9.2 Übersicht über die ausgewerteten Dokumente 9.2.1 Tabellarische Übersicht 9.2.2 Bilddokumentation zu den erhaltenen Sektions-Journalen bzw. Sektions-Tagebüchern 9.3 Tabellen zur Auswertung der Tumoren im Sektionsgut 9.4 Überblick über Übersichts-Sektionsstatistiken zu Erkrankungen der Verdauungsorgane bei Equiden 10 DANKSAGUNG / Currently only notifiable diseases in Equidae are monitored in Germany. Therefore, information from clinical trials and post-mortem-examinations can be helpful to give early indications of changes in the spectrum of equine diseases. Furthermore, within those evaluations it is possible to collect data of rare illnesses. However, influencing factors, which affect the structure of the test material, must be considered when interpreting the results. Particularly in retrospective studies, the evaluated cases are not necessarily representative for a special population. The aim of this retrospective study was to get an overview of the main findings of 4743 equine autopsies, which were performed at the Institute of Pathology (Faculty of Veterinary Medicine, University of Leipzig respectively Dresden). In this context, changes in the spectrum of diseases during the investigated period and the influence of epizootiologic factors (age, race, sex) as well as the type and prevalence of tumours, detected as main or additional finding, were analysed. Moreover, the findings were evaluated in consideration of the actual animal health restrictions as well as historical and epidemiological aspects taking the scientific state-of-the art into account. The reports of 4743 Equidae, which were necropsied at the Institute of Pathology (Faculty of Veterinary Medicine, University of Leipzig respectively Dresden from 1890 to 1923) between 1890 and 2013, were available. The month and year of autopsy, age, race, sex, place of origin, further etiological examination procedures (e.g. parasitology, virology, microbiology, toxicology, histology, immunohistology) were taken into consideration. If applicable, information on anamnesis and diagnosis, which have been made intra vitam, was considered. Information on age, race respectively sex was available only in 79.6 %, 53.2 % respectively 88.0 % of the cases. During the investigation period, the necropsied Equidae were mostly affected by disorders (as a main finding) of the digestive tract (36.5 %), followed by alterations of the respiratory tract (10.5 %), the nervous system (9.6 %) or the cardiovascular system (8.4 %), locomotor system (7.7 %) and generalized changes (7.4 %). Less often abortions (5.2 %) or alterations in the area of the big body cavities (4.0 %), the liver (3.1 %), the haemopoietic system (1.7 %), the urinary organs or navel (1.5 %), the female and male genitalia (1.3 %), the skin (0.9 %), the endocrine system (0.2 %) or the eyes (0.0 %) appeared. The term “other diseases” (2.0 %) covers all cases with unknown origin, a distinct autolysis or animals without a necropsy. In comparison to the beginning of the investigation period, the amount of alterations of the alimentary canal, especially due to a reduction of cases with volvulus or torsion respectively animals with obstipation (84/264 diagnosed between 1970 and 1989), decreased over the decades (1890-1899: 52.6 %; 1900-1909: 58.2 %; 2000-2009: 35.8 %; 2010-2013: 38.0 %). In contrast most cases with the main finding ″disease of the nervous system″, characterised by a high percentage of Equidae with the diagnosis ″Borna Disease″ (BD, 7.8 %), arose during the 1990s. The increase of this main finding can be explained by the German reunification in 1990 and the related changes in animal health regulations. Since 2000 the percentage of Equidae with BD is declining again (2000-2009: 5.3 %; 2010-2013: 1.3 %). Compared to the whole investigation period (1890-2013) between 1990 and 2013 more alterations were found during pregnancy (8.8 %) respectively in the field of the musculosceletal system (10.4 %), the integument (1.2 %) or the endocrine system (0.5 %). The increase of abortions most likely can be explained by a change in the research priority of the Institute of Pathology of the Faculty of Veterinary Medicine (University of Leipzig) by the end of the observation period. Furthermore, the rise of cases with musculosceletal disorders is probably caused by the general improvement of the economic situation in Eastern Germany after the German reunification, coinciding with a reduction of equine slaughtering. In addition, a loss of importance in lesions of the respiratory organs, the big body cavities or generalized diseases, which often occur due to bacterial infections, can be observed in the investigated material since the 1950s. Improvements in treatment (among others the use of antibiotics in veterinary medicine) and in clinical diagnosis (e.g. in the diagnosis of the chronic obstructive pulmonary disease or ″recurrent airway obstruction″) as well as the success of animal health measures (e.g. eradication of glanders or tuberculosis) are responsible for this development. Moreover, the analysis showed that 5.2 % of the necropsied solipeds (248/4743) were affected as a main (3.2 %) or an additional finding by tumours (n=285). In 78.2 % of the lesions (223/285) the diagnosis ″neoplasia″ was confirmed histologically. Usually a single (n=221) tumour and occasionally multiple tumours (2 different tumours per animal: n=19; 3 different tumours per animal: n=6; 4 different tumours per animal: n=2) appeared. The median age of the affected solipeds with indication of age (n=219) was 14 years, whereas 87.9 % of the cases were older than 6 years. The appearance of tumours varied during the investigated period. Between 1990 and 2013 three quarters (214/285) of all diagnosed neoplasia were found, whereas most of them (180/214) are recorded after 1999. The median age, which was evaluated during the investigated period, is very likely not the only reason for this development. The lesions were mostly found in the region of the big body cavities (24.2 %), the endocrine (17.5 %) respectively the haematopoietic system (14.7 %) and/or the integuement (12.3 %). Mostly lipomas (23.2 %; n=66), leucosis (12.6 %; n=36), malignant melanomas (8.4 %; n=24), adenomas of the pituitary gland (6.3 %; n=18) and/or squamous cell carcinoma (5.6 %; n=16) occurred. In accordance with comparable studies, diseases of the digestive organs still are the most common cause of death in Equidae. The prevalence of alterations of the nervous system varies in different statistics, depending on the occurrence of endemic diseases. The importance of the BD in the own material (in the catchment area of the University of Leipzig and Dresden) has declined since 2000. Although, in this evaluation, the number and range of diagnosed tumours has increased considerably during the last years (2000-2013), neoplasia of solipeds rank among the rare diagnosed diseases of Equidae.:I INHALTSVERZEICHNIS II ABKÜRZUNGSVERZEICHNIS 1 EINLEITUNG 2 LITERATURÜBERSICHT 2.1 Übersichts-Statistiken zu Equiden-Sektionen 2.1.1 Material und Methoden der Übersichts-Statistiken 2.1.2 Häufige Befunde in Übersichts-Statistiken 2.2 Klinische Übersichts-Statistiken zu Erkrankungen bei Equiden 2.3 Übersichts-Statistiken zu Tumoren bei Equiden 2.3.1 Sektionsstatistiken zu Tumoren bei Equiden 2.3.1.1 Methoden der Sektionsstatistiken 2.3.1.2 Häufig von Tumoren betroffene Organsysteme in Sektionsstatistiken 2.3.1.3 Häufige Tumorarten 2.3.2 Auswertungen von Biopsien bzw. Befunden aus klinischen Einrichtungen 2.3.2.1 Methoden der Tumor-Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.3.2.2 Häufig von Tumoren betroffene Organsysteme in Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.3.2.3 Übersicht der häufigsten Tumorarten in Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.4 Fazit aus der Literatur bezogen auf die initiale Fragestellung dieser Arbeit 3 MATERIAL UND METHODEN 3.1 Material 3.2 Methode 4 ERGEBNISSE 4.1 Auswertung der Hauptbefunde 4.1.1 Erkrankungen der Verdauungsorgane 4.1.2 Erkrankungen der Atmungsorgane 4.1.3 Erkrankungen des Nervensystems 4.1.4 Erkrankungen der Kreislauforgane 4.1.5 Erkrankungen des Stütz- und Bewegungsapparates 4.1.6 Generalisierte Erkrankungen 4.1.7 Pathologie der Trächtigkeit 4.1.8 Erkrankungen der großen Körperhöhlen 4.1.9 Erkrankungen der Leber 4.1.10 „Sonstige Erkrankungen“ 4.1.11 Erkrankungen des hämatopoetischen Systems 4.1.12 Erkrankungen der Harnorgane und des Nabels 4.1.13 Erkrankungen der Geschlechtsorgane 4.1.14 Erkrankungen der Haut 4.1.15 Erkrankungen des Endokriniums 4.1.16 Erkrankungen des Auges 4.2 Auswertung von Tumoren unter Berücksichtigung von Haupt- und Nebenbefunden 4.2.1 Häufigkeit und Klassifikation 4.2.2 Multiple Neoplasien 4.2.3 Häufigkeit benigner, semimaligner und maligner Tumoren 4.2.4 Metastasierende bzw. multizentrische Tumoren 5 DISKUSSION 5.1 Ziel der Arbeit 5.2 Kritische Beurteilung des Untersuchungsmaterials 5.3 Auswertung der Hauptbefunde 5.3.1 Erkrankungen der Verdauungsorgane 5.3.2 Erkrankungen der Atmungsorgane 5.3.3 Erkrankungen des Nervensystems 5.3.4 Erkrankungen der Kreislauforgane 5.3.5 Erkrankungen des Stütz- und Bewegungsapparates 5.3.6 Generalisierte Erkrankungen 5.3.7 Pathologie der Trächtigkeit 5.3.8 Erkrankungen der großen Körperhöhlen 5.3.9 Erkrankungen der Leber 5.3.10 „Sonstige Erkrankungen“ 5.3.11 Erkrankungen des hämatopoetischen Systems 5.3.12 Erkrankungen der Harnorgane und des Nabels 5.3.13 Erkrankungen der Geschlechtsorgane 5.3.14 Erkrankungen der Haut 5.3.15 Erkrankungen des Endokriniums 5.3.16 Erkrankungen des Auges 5.3.17 Fazit 96 5.4 Tumoren als Haupt- und Nebenbefund 5.4.1 Prävalenz von Tumoren bei Equiden 5.4.1.1 Prävalenz einzelner Tumorarten in klinischen Auswertungen 5.4.1.2 Prävalenz einzelner Tumorarten in Sektions- und Schlachthofstatistiken 5.4.2 Multiple Neoplasien 5.4.3 Metastasierende Tumoren 5.4.4 Fazit 6 ZUSAMMENFASSUNG 7 SUMMARY 8 LITERATUR 9 ANHANG 9.1 Klinische Übersichtsstatistiken zu dem Erkrankungskomplex „Kolik“ 9.2 Übersicht über die ausgewerteten Dokumente 9.2.1 Tabellarische Übersicht 9.2.2 Bilddokumentation zu den erhaltenen Sektions-Journalen bzw. Sektions-Tagebüchern 9.3 Tabellen zur Auswertung der Tumoren im Sektionsgut 9.4 Überblick über Übersichts-Sektionsstatistiken zu Erkrankungen der Verdauungsorgane bei Equiden 10 DANKSAGUNG

Bei der Replikation monotoner DNA - Sequenzen tritt theoretisch ein Vorgang auf, den wir als „Basenkonkurrenz“ bezeichnen: Da sich an jeder Replikations-Stelle mehrere Basenbausteine bewerben, aber immer nur einer benötigt wird, bewerben sich die übrig gebliebenen Bausteine an den jeweils nächsten Replikations - Positionen und erlangen wegen der fortwährenden Beschleunigung durch elektrostatische Anziehung immer größere kinetische Energien. Das führt dazu, dass an einer bestimmten Stelle der replizierenden monotonen Sequenz der eine Partner der Wasserstoffbrückenbindung ein hohes Energieniveau erreicht. Es wird berechnet, dass sich dadurch kurzzeitig eine sehr hohe Bindungsenergie zwischen den beiden Partnern der Wasserstoffbrückenbindung einstellt, wodurch der in dieser kurzen Zeitspanne wirkende DNA-Reparaturmechanismus unterdrückt wird. Die Auswirkungen der hohen Basenkonkurrenz – Energien werden berechnet (hohe Bindungsenergien der Wasserstoffbrückenbindungen, Tunnelvorgänge, irreparable Mutationen). Die Folgen dieser Erscheinung sind Tumorbildung, Alterung, Veränderung der DNA – Struktur, Beeinflussung der Evolution, worauf im Einzelnen eingegangen wird. Es zeigt sich, dass die negativen Auswirkungen der Basenkonkurrenz vorwiegend bei zu niedriger Viskosität des Zellplasmas auftreten.

<p>Prostate cancer is the second leading cause of cancer-related death among American men. Prostate tumor cells exhibit significant tropism for the bone and once metastasis occurs, survival rates fall significantly. Current treatment options are not curative and focus on symptom management. Immunotherapies are rapidly emerging as a possible therapeutic option for a variety of cancers including prostate cancer, however, variable patient response remains a concern. Chemotherapies, like cabozantinib, can have immune-priming effects which sensitize tumors to immunotherapies. Additionally, lower doses of chemotherapy can be used in this context which can reduce patient side effects. It was hypothesized that a combination of chemotherapy (cabozantinib) and immunotherapy (Interleukin-27 (IL-27)) could treat bone-metastatic prostate cancer and also exert pro-osteogenic effects. IL-27 is a multi-functional cytokine, which promotes immune cell recruitment to tumors, while also promoting bone repair. To test this hypothesis, <i>in vivo</i> experiments were performed where syngeneic C57BL/6J mice were implanted intratibially with TRAMP-C2ras-Luc cells able to form tumors in bone. Immunotherapy was administered in the form of intramuscular gene therapy, delivering plasmid DNA encoding a reporter gene (Lucia), or a therapeutic gene (IL-27). Ultrasound was used to aid gene delivery. Various gene delivery methods were tested and optimized through <i>in vivo</i> studies, with microbubbles in combination with ultrasound (sonoporation) emerging as the best method. Following immunotherapy, the animals received either cabozantinib or a vehicle control by oral gavage. Bioluminescence imaging was used to monitor tumor size over time. Combinatorial therapy inhibited tumor growth and improved survival. Further, RNA sequencing and cytokine arrays were used to investigate the mechanisms involved. Microcomputed tomography and differentiation assays indicated that the combination therapy improved bone health by improving osteoblast differentiation and inhibiting osteoclast differentiation. Our conclusion is that a chemo-immunotherapy approach such as the one examined in this work has potential to emerge as a novel therapeutic strategy for treating bone-metastatic prostate cancer. This approach should enable a significant reduction in chemotherapy-associated toxicity, improving sensitivity to immunotherapy, and simultaneously improving bone quality.</p>

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Carcinóides típicos são proliferações de células neuroendócrinas. Discute-se se são carcinomas ou adenomas, devido ao seu comportamento ambíguo. É imperativo conhecer seu potencial maligno para que se estabeleça o tratamento adequado. Os relatos de metástase exigem uma definição de quais são os critérios que podem ser utilizados para prever o fenômeno. Atualmente é utilizada a classificação proposta por Travis que estratifica os carcinóides em típicos e atípicos. Porém, todos os pacientes acometidos por carcinóide típico, pela classificação, são considerados como sendo de baixo risco para a ocorrência de metástase, o que torna a proposta insuficiente para se definir conduta terapêutica. O gênero, a idade, a localização central ou periférica, o diâmetro tumoral, e o estadiamento TNM, também já foram descritos como tendo correlação com malignidade em carcinóides. Busca-se descobrir outros critérios que possam ser utilizados para auxiliar na determinação do prognóstico, como os biomarcadores celulares e estromais. O estudo do comportamento celular através de marcadores correlacionados com o fenótipo maligno pode ser realizado utilizando-se a técnica de imunohistoquímica, assim como pelo estudo da matriz extracelular. A análise, para cada paciente, da interação destes fenômenos, permite melhor definição do verdadeiro risco de ocorrência de metástase. A exemplo de outras doenças, permite mesmo a confecção de índices de risco, ponderando-se a contribuição de cada um dos marcadores para a estratificação prognóstica. Com o objetivo de estudar a correlação entre variáveis clínicas (gênero, idade, dimensões e localização do tumor - central ou periférico -, margem de ressecção comprometida e estadiamento TNM) e biomarcadores teciduais, e o potencial metastático dos carcinóides típicos, procedeu-se à quantificação do nível de expressão imunohistoquímica das proteínas p53, Ki-67 e Bcl-2, mensurou-se as fibras colágenas e elásticas e a densidade de microvasos no estroma tumoral, e coletaram-se dados dos prontuários. Metástases linfonodais ocorreram em 9 dos 55 pacientes, e à distância em 6 (2 para o fígado, 1 para osso, 1 para pulmão, 1 para tireóide e 1 para gordura mediastinal). Dois doentes tiveram metástase linfonodal e hematogênica concomitantes. À análise estatística univariada, os 5 biomarcadores (p53, Ki-67 e densidade de microvasos elevados, Bcl-2 e densidade de fibras estromais reduzidos) e o gênero masculino foram relacionados à maior ocorrência de metástase. A faixa etária elevada apresentou tendência a relacionar-se com o fenômeno. À análise multivariada por regressão logística, a densidade de microvasos foi o único fator independentemente relacionado ao fenômeno. O aumento da população estudada poderia, talvez, implicar os outros marcadores como variáveis associadas ao fenômeno, mesmo à análise multivariada por regressão logística. Estabelecendo-se as correlações, à análise univariada, entre cada marcador, faixa etária e gênero com o fenômeno metastático, foi composto um painel utilizando-se a razão de riscos. Ponderou-se o odds ratio e propôs-se um modelo de índice com valores numéricos diretamente proporcionais ao risco de ocorrência de metástase, que apesar de não ter validade externa ao estudo, pode ser desenvolvido por meio do aumento da população estudada e pela adição de novos marcadores. A aplicação de um índice na prática clínica auxilia a determinação do prognóstico de um dado indivíduo. Conclui-se que há correlação entre os níveis de expressão dos 5 marcadores e do gênero com o potencial metastático. E que é possível o desenvolvimento de um índice numérico que se relacione com o risco de ocorrer metástase. / Typical carcinoid tumors are neuroendocrine cell\'s proliferations. If they are carcinomas or adenomas is still under discussion, due to their ambiguous behavior. It is imperative to define their malignant potential, intending to establish the adequate treatment. Metastasis reports demand a definition of which are the criteria that can be used to foresee the phenomenon. Nowadays it is used the classification proposed by Travis who stratifies the carcinoid tumors in typical and atypical. However, all typical carcinoid tumors, by this classification, are considered as being of low risk for metastatic spread, what turns insufficient this proposal to define therapeutic approach for all patients. Gender, age, the central or peripheral location, tumoral diameter and TNM stage, also have already been described as predictors of malignancy in carcinoid tumors. It looks for discovering other criteria that can be used to assist in the determination of the prognosis, like cellular and stromal biomarkers. The study of the cellular behavior based on biomarkers related to the malignant phenotype can be carried out using the immunohistochemical technique, as well as by the study of the extra cellular matrix. The analysis, for each patient, of the interaction between these phenomena, allows better definition of real metastasis risk. Like in otherillness, it allows an index risk construction, pondering the contribution of each biomarker for the prognostic bedding. In spite to study the correlation between clinical features (gender, age, diameter and tumor localization - central or peripheral -, residual neoplasm in operative margins and TNM stage), iomarkers and the malignant potential of typical carcinoids, it was proceeded to the quantification of the immunohistochemical expression level of the proteins p53, ki-67 and Bcl-2, it was also measured the collagens fibers and elastic and microvessels density in tumoral stoma, and it was collected data from the medical charters. Nodal metastasis has been diagnosed in 9 of 55 patients, and haematogenic in 6 (liver: 2, bone:1, lung: 1, thyroid: 1, pericardial fat: 1). In 2 patients it was diagnosed both nodal and haematogenic metastasis. Univariate statistical analysis showed that all the 5 biomarkers (over expression of p53, Ki-67 and microvessels density and under expression of Bcl-2 and matrix fibers) and male gender are related to increased risk for metastasis. Age (older patients) was borderline only related to metastatic increased risk. Under multivariate analysis by multiple steps logistic regression, only microvessel density was independently related to metastasis. Perhaps, if it has been studied in a larger group of patients, other biomarkers could be implied in multivariate analysis in the equation for increased risk for metastatic disease. Based on univariate analysis for defining correlation between each biomarker, age group and gender with the metastatic phenomenon, it was composed a panel using the odds ratio for each factor. It was proposed a practical model (to be developed by future research) for a numeric risk index directly proportional to the metastatic risk. The application of an index in the clinical practice assists the determination of the prognosis for each patient. It was concluded that there is a correlation between the expression levels of the 5 studied biomarkers and gender with the metastatic potential, and that is possible the development of a practical numeric risk index related to the metastatic risk.

Carcinóides típicos são proliferações de células neuroendócrinas. Discute-se se são carcinomas ou adenomas, devido ao seu comportamento ambíguo. É imperativo conhecer seu potencial maligno para que se estabeleça o tratamento adequado. Os relatos de metástase exigem uma definição de quais são os critérios que podem ser utilizados para prever o fenômeno. Atualmente é utilizada a classificação proposta por Travis que estratifica os carcinóides em típicos e atípicos. Porém, todos os pacientes acometidos por carcinóide típico, pela classificação, são considerados como sendo de baixo risco para a ocorrência de metástase, o que torna a proposta insuficiente para se definir conduta terapêutica. O gênero, a idade, a localização central ou periférica, o diâmetro tumoral, e o estadiamento TNM, também já foram descritos como tendo correlação com malignidade em carcinóides. Busca-se descobrir outros critérios que possam ser utilizados para auxiliar na determinação do prognóstico, como os biomarcadores celulares e estromais. O estudo do comportamento celular através de marcadores correlacionados com o fenótipo maligno pode ser realizado utilizando-se a técnica de imunohistoquímica, assim como pelo estudo da matriz extracelular. A análise, para cada paciente, da interação destes fenômenos, permite melhor definição do verdadeiro risco de ocorrência de metástase. A exemplo de outras doenças, permite mesmo a confecção de índices de risco, ponderando-se a contribuição de cada um dos marcadores para a estratificação prognóstica. Com o objetivo de estudar a correlação entre variáveis clínicas (gênero, idade, dimensões e localização do tumor - central ou periférico -, margem de ressecção comprometida e estadiamento TNM) e biomarcadores teciduais, e o potencial metastático dos carcinóides típicos, procedeu-se à quantificação do nível de expressão imunohistoquímica das proteínas p53, Ki-67 e Bcl-2, mensurou-se as fibras colágenas e elásticas e a densidade de microvasos no estroma tumoral, e coletaram-se dados dos prontuários. Metástases linfonodais ocorreram em 9 dos 55 pacientes, e à distância em 6 (2 para o fígado, 1 para osso, 1 para pulmão, 1 para tireóide e 1 para gordura mediastinal). Dois doentes tiveram metástase linfonodal e hematogênica concomitantes. À análise estatística univariada, os 5 biomarcadores (p53, Ki-67 e densidade de microvasos elevados, Bcl-2 e densidade de fibras estromais reduzidos) e o gênero masculino foram relacionados à maior ocorrência de metástase. A faixa etária elevada apresentou tendência a relacionar-se com o fenômeno. À análise multivariada por regressão logística, a densidade de microvasos foi o único fator independentemente relacionado ao fenômeno. O aumento da população estudada poderia, talvez, implicar os outros marcadores como variáveis associadas ao fenômeno, mesmo à análise multivariada por regressão logística. Estabelecendo-se as correlações, à análise univariada, entre cada marcador, faixa etária e gênero com o fenômeno metastático, foi composto um painel utilizando-se a razão de riscos. Ponderou-se o odds ratio e propôs-se um modelo de índice com valores numéricos diretamente proporcionais ao risco de ocorrência de metástase, que apesar de não ter validade externa ao estudo, pode ser desenvolvido por meio do aumento da população estudada e pela adição de novos marcadores. A aplicação de um índice na prática clínica auxilia a determinação do prognóstico de um dado indivíduo. Conclui-se que há correlação entre os níveis de expressão dos 5 marcadores e do gênero com o potencial metastático. E que é possível o desenvolvimento de um índice numérico que se relacione com o risco de ocorrer metástase. / Typical carcinoid tumors are neuroendocrine cell\'s proliferations. If they are carcinomas or adenomas is still under discussion, due to their ambiguous behavior. It is imperative to define their malignant potential, intending to establish the adequate treatment. Metastasis reports demand a definition of which are the criteria that can be used to foresee the phenomenon. Nowadays it is used the classification proposed by Travis who stratifies the carcinoid tumors in typical and atypical. However, all typical carcinoid tumors, by this classification, are considered as being of low risk for metastatic spread, what turns insufficient this proposal to define therapeutic approach for all patients. Gender, age, the central or peripheral location, tumoral diameter and TNM stage, also have already been described as predictors of malignancy in carcinoid tumors. It looks for discovering other criteria that can be used to assist in the determination of the prognosis, like cellular and stromal biomarkers. The study of the cellular behavior based on biomarkers related to the malignant phenotype can be carried out using the immunohistochemical technique, as well as by the study of the extra cellular matrix. The analysis, for each patient, of the interaction between these phenomena, allows better definition of real metastasis risk. Like in otherillness, it allows an index risk construction, pondering the contribution of each biomarker for the prognostic bedding. In spite to study the correlation between clinical features (gender, age, diameter and tumor localization - central or peripheral -, residual neoplasm in operative margins and TNM stage), iomarkers and the malignant potential of typical carcinoids, it was proceeded to the quantification of the immunohistochemical expression level of the proteins p53, ki-67 and Bcl-2, it was also measured the collagens fibers and elastic and microvessels density in tumoral stoma, and it was collected data from the medical charters. Nodal metastasis has been diagnosed in 9 of 55 patients, and haematogenic in 6 (liver: 2, bone:1, lung: 1, thyroid: 1, pericardial fat: 1). In 2 patients it was diagnosed both nodal and haematogenic metastasis. Univariate statistical analysis showed that all the 5 biomarkers (over expression of p53, Ki-67 and microvessels density and under expression of Bcl-2 and matrix fibers) and male gender are related to increased risk for metastasis. Age (older patients) was borderline only related to metastatic increased risk. Under multivariate analysis by multiple steps logistic regression, only microvessel density was independently related to metastasis. Perhaps, if it has been studied in a larger group of patients, other biomarkers could be implied in multivariate analysis in the equation for increased risk for metastatic disease. Based on univariate analysis for defining correlation between each biomarker, age group and gender with the metastatic phenomenon, it was composed a panel using the odds ratio for each factor. It was proposed a practical model (to be developed by future research) for a numeric risk index directly proportional to the metastatic risk. The application of an index in the clinical practice assists the determination of the prognosis for each patient. It was concluded that there is a correlation between the expression levels of the 5 studied biomarkers and gender with the metastatic potential, and that is possible the development of a practical numeric risk index related to the metastatic risk.

<p>  </p> <p>The phosphatases of regenerating liver are a subfamily of protein tyrosine phosphatases that consist of PRL1, PRL2 and PRL3. The overexpression of PRLs promote cell proliferation, migration and invasion and contribute to tumorigenesis and metastasis to aggravate survival outcome. Although there is increasing interest in understanding the implication of these phosphatases in tumor development, currently, limited knowledge is available about their mechanism of action and the efficacy of PRL inhibition in <em>in vivo</em> tumor models, the tumor extrinsic role of PRLs that allow them to impact tumor development, as well as <em>in vivo</em> physiological function of PRLs that could implicate them in diseases other than cancer. The work presented here aims to address these limitations.</p> <p><br></p>

Increasing time trends in the recorded incidence of childhood cancer have been reported in many different settings. The extent to which these trends reflect real changes in incidence, rather than improvements in methods for diagnosis and registration, is controversial. Using data from the National Registry of Childhood Tumours (NRCT), this thesis investigates time trends in cancer diagnosed under age 15 in residents of Britain during 1966-2005 (54650 cases), and considers potential sources of artefact in detail. Several different methods are used to estimate completeness of NRCT registration. The history of methods for diagnosis and registration of childhood cancers in Britain is described, and predictions are made for effects on recorded incidence. For each of the 12 main diagnostic groups, Poisson regression is used to fit continuous time trends and ‘step’ models to the annual age-sex-standardised rates by year of birth and year of diagnosis. Age-specific rates by period, and quinquennial standardised rates for diagnostic subgroups, are shown graphically. For three broad groups (leukaemia, CNS tumours and other cancer), geographical variation is compared by period of diagnosis. The results of these analyses are discussed in relation to the predicted artefacts. The evidence for a positive association between affluence and recorded incidence of childhood leukaemia is briefly reviewed. A special form of diagnostic artefact, the ‘fatal infection’ hypothesis, is proposed as an explanation of both this association and the leukaemia time trend. This hypothesis is examined in a novel test based on clinical data. The recorded incidence of childhood cancer in Britain increased in each of 12 diagnostic groups during 1966-2005 (from 0.5% per year for bone cancer to 2.5% for hepatic cancer, with 0.7% for leukaemia). Evidence presented here suggests that these increases are probably artefacts of diagnosis and registration. The potential implications for epidemiological studies of childhood cancer should be considered.

Human cancers exhibit the common phenotype of elevated glycolytic metabolism, which causes acidification of the tissue microenvironment and may facilitate tumour invasion. In this thesis, we use mathematical models to address a series of open problems underlying the glycolytic tumour phenotype and its attendant acidity. We first explore tissue-scale consequences of metabolically-derived acid. Incorporating more biological detail into a canonical model of acidity at the tumour-host interface, we extend the range of tumour behaviours captured by the modelling framework. We then carry out an asymptotic travelling wave analysis to express invasive tumour properties in terms of fundamental parameters, and find that interstitial gaps between an advancing tumour and retreating healthy tissue, characteristic of aggressive invasion and comprising a controversial feature of the original model, are less significant under our generalised formulation. Subsequently, we evaluate a potential role of lactate---historically assumed to be a passive byproduct of glycolytic metabolism---in a perfusion-dependent metabolic symbiosis that was recently proposed as a beneficial tumour behaviour. Upon developing a minimal model of dual glucose-lactate consumption in vivo and employing a multidimensional sensitivity analysis, we find that symbiosis may not be straightforwardly beneficial for our model tumour. Moreover, new in vitro experiments, carried out by an experimental collaborator, place U87 glioblastoma tumours in a weakly symbiotic parameter regime despite their clinical malignancy. These results suggest that intratumoural metabolic cooperation is unlikely to be an important role for lactate. Finally, we examine the complex pH regulation system that governs expulsion of metabolically derived acid loads across tumour cell membranes. This system differs from the healthy system by expression of only a few key proteins, yet its dynamics are non-intuitive in the crowded and poorly perfused in vivo environment. We systematically develop a model of tumour pH regulation, beginning with a single-cell scenario and progressing to a spheroid, within a Bayesian framework that incorporates information from in vitro data contributed by a second experimental collaborator. We predict that a net effect of pH regulation is a straightforward transmembrane pH gradient, but also that existing treatments are unable to disrupt the system strongly enough to cause tumour cell death. Taken together, our models help to elucidate previously unresolved features of glycolytic tumour metabolism, and illustrate the utility of a combined mathematical, statistical, and experimental approach for testing biological hypotheses. Opportunities for further investigation are discussed.

The aim of the work described in this thesis was to explore the synthesis of glycosidase inhibitors and to evaluate their potential as anti-cancer agents. Glycosidases catalyze the fission of glycosidic bonds and are involved in vital biological functions. With regard to their potential for anti-cancer therapy, two glycosidases were identified: α-N-acetyl-galactosaminidase and β-N-acetyl-hexosaminidase. The former has been implicated in causing immunosuppression in advanced cancer patients by negating the effect of the macrophage activating factor (MAF), while the latter is secreted by invading cancer cells and hence associated with metastasis formation. The synthetic focus was on generating piperidine and azetidine iminosugars, carbohydrate mimetics with their endocylic oxygen replaced by nitrogen. Their structural similarity to carbohydrates make iminosugars excellent inhibitors of glycosidases. Following synthesis of a pipecolic amide, its previously reported potent β-N-acetyl-hexosaminidase inhibition was confirmed. This data, along with inhibition profiles of several pyrrolidines, allowed the generation of a molecular model for predicting activity of β-N-acetyl-hexosaminidase inhibitors. The model was used to select azetidines in the D/L-ribo and D-lyxo configuration as suitable candidates to be explored in novel chemical space, leading to the first synthesis of a fully unprotected 3-hydroxy-2-carboxy-azetidine. The potent α-N-acetyl-galactosamindase inhibitor 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) was successfully derivatised via N-alkylation. Important structural discoveries with regard to glycosylation of vitamin D₃-binding protein, the precursor of MAF, were made using MALDI mass-spectrometry. By comparing the enzymatic and cellular inhibition of N-alkylated derivatives of DGJNAc and a pyrrolidine the following generalization on iminosugar biodistribution was found: N-butylation promotes uptake into the cell/organelles, while hydrophilic side-chains restrict cellular access. An in vitro assay evaluating cancer cell invasion was devised and β-N-acetyl-hexoamindase inhibitors were shown to retard cell migration, including with the highly metastatic breast cancer cell line MDA-MB-231. Additive effects where found when the iminosugar was combined with a protease inhibitor, suggesting potential for future combination therapy.