Der Einfluß von Ovulationshemmern auf die Tumorbiologie und die Prognose des Mammakarzinoms Die Frage eines potentiellen Einflusses von Ovulationshemmern (OH) auf die Tumorbiologie und die Prognose des Mammakarzinoms stellt noch immer ein ungeklärtes Problem dar. Zur Untersuchung dieser Frage wurde eine Fall-Kontroll-Studie aufgelegt, die den Effekt der OH-Einnahme vor der Diagnose des Mammakarzinoms auf dessen Prognosefaktoren und den Verlauf der Erkrankung untersucht. Das mediane Follow-up belief sich auf 10 Jahre. Bei 471 Patientinnen wurde der Einfluß von OH auf konventionelle (Tumortyp, Grading, Tumorgröße, LK-Status, ER, PR) und molekularbiologische (PCNA, EGF-R, c-erbB-2, p53) Prognosefaktoren dargestellt. In Abhängigkeit von der Zeit seit der letzten Einnahme von OH konnten 2 Tumorentitäten charakterisiert werden. Bei OH-Einnahme bis zum Zeitpunkt der Diagnose fanden sich signifikant häufiger LK-positive (OR 2.14), schlecht differenzierte (OR 2.01) und stark proliferierende Tumoren (OR 2.13). Patientinnen mit langer Latenzperiode seit letzter OH-Einnahme zeigten signifikant häufiger ER-positive (OR 21.6-3.69) allerdings auch EGF-R-positive Tumoren (OR 1.73-2.0) mit moderater Proliferationsaktivität (OR 1.64-1.93). In multivaraiaten Überlebensanalysen hatten Patientinnen mit Langzeiteinnahme (mehr als 5 Jahre) und solche mit OH-Einnahme lange vor der Diagnose der Erkrankung (mehr als 96 Monate) ein signifikant besseres Überleben (HR 0.55, 95%CI 0.34-0.90; HR 0.49, 95%CI 0.26-0.92 respektive)als Patientinnen ohne OH-Einnahme. Dagegen hatte Patientinnen bei OH-Einnahme bis zur Diagnose oder Einnahme in den letzten beiden Jahren vor Diagnose ein signifikant schlechteres Überleben als solche ohne OH-Einnahme (HR 2.29, 95%CI 1.02-5.17; HR 3.80, 95%CI 1.45-9.97 respektive). Offenbar ist die OH-Einnahme während eines biologisch sensiblen Zeitraumes der Entwicklung des Mammakarzinomes von größerer Bedeutung als die Dauer der OH-Einnahme. Eine biologische Hypothese wird dargestellt. / Oral contraceptive use and breast cancer: Effect on tumorbiolgy and prognosis The question of whether oral contraceptive(OC) use before diagnosis has an effect on tumorbiology and prognosis of breast cancer remains a subject of discussion. Thus, a case-control study was conducted to investigate the effect of OC use on prognostic factors and the outcome of breast cancer patients. The median follow-up amounted to 10 years. In 471 breast cancer patients histomorphological (tumortype, grading, tumorsize, nodal status, ER, PR) and molecularbiological prognostic factors (PCNA, EGF-R, c-erbB-2, p53) and their association to OC use were studied. 297 (63%) patients were OC users, 113 were short-term users (less than 5 years) and 184 were long-term users. Dependend on the time since last OC use, two different biological tumor entities were characterised. In current users a significant increase in node-positive (OR 2.14) and poorly differentiated tumors (OR 2.01) and of tumors with a high proliferative fraction (OR 2.13) was observed. Past users with a long latency period had significantly more ER-positive (OR 2.16-3.69) but also EGF-R positive tumors (OR 1.73-2.0) with a moderate increase in proliferative activity (OR 1.64-1.93) compared to never users. In multivariate survival analyses long-term OC use (HR 0.55, 95%CI 0.34-0.90) and first OC use more than 96 months before diagnosis (HR 0.49, 95%CI 0.26-0.92) were associated with a significant improvement in survival, whereas current OC use ( HR 2.29, 95%CI 1.02-5.17) or last OC use during the last 2 years before diagnosis (HR 3.80, 95%CI 1.45-9.97) were related to a significant decrease in survival rates. OC use during a biologically sensitive time period seems to be more important than duration of use. A biological hypothesis is beeing suggested.

Background: Even though specific agents for the treatment of patients with pulmonary hypertension (PH) are available, in PH patients, physical capacity and quality of life (QoL) are often restricted and survival is reduced. Objectives: This study prospectively investigated the long-term effects of respiratory and exercise training in patients with severe chronic PH regarding safety, time to clinical worsening and survival. Methods: Fifty-eight consecutive patients with severe PH on stable disease-targeted medication received exercise and respiratory training in hospital for 3 weeks and continued at home. They were prospectively followed for 24 ± 12 months. Primary endpoints were time to clinical worsening and survival. Adverse events and changes in the 6-min walking test, QoL, WHO functional class and gas exchange were secondary endpoints and were evaluated at baseline and at weeks 3 and 15. Results: All patients tolerated the exercise training well without severe adverse events. In week 15, 6-min walking test results were significantly improved compared to baseline (by 84 ± 49 m, p < 0.001), as well as QoL scores, WHO functional class (from 2.9 ± 0.5 to 2.6 ± 0.6, p < 0.01), peak oxygen consumption (from 12.5 ± 3.0 to 14.6 ± 3.9 ml/min/kg, p < 0.001), heart rate at rest (from 75 ± 12 to 61 ± 18 beats/min, p < 0.001) and maximal workload (from 65 ± 21 to 80 ± 25 W, p < 0.001). Survival at 1 and 2 years was 100 and 95%, respectively. Fifteen events occurred during the follow-up. Conclusion: This study indicates that exercise and respiratory training as add-on to medical treatment may improve exercise capacity and QoL, and that they have a good long-term safety in the described setting. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Die vorliegende retrospektive Studie untersuchte die lokale Rezidiv- und Überlebensrate von Patienten mit Plattenepithelkarzinomen in Abhängigkeit vom Randstatus und Resektionsabstand der Tumorresektion sowie von der postoperativen Therapie. Dabei wurden Daten von 351 Patienten mit Plattenepithelkarzinomen des Oropharynx, Hypopharynx und Larynx ausgewertet, welche zwischen 2005 und 2009 reseziert wurden. Der gesundheitliche Zustand der Patienten wurde anschließend bis Dezember 2011 beobachtet. Im Ergebnis konnte kein Einfluss des Randstatus und des Resektionsabstandes auf die lokale Rezidivrate nachgewiesen werden. Beide Faktoren hatten jedoch einen signifikanten Einfluss auf die Letalitätsrate. Die postoperative Therapie zeigte einen positiven Einfluss auf die lokale Rezidivrate. Sie konnte aber die negativen Prognosefaktoren, die eine Indikation dieser Therapie darstellen, bezüglich der Letalitätsrate nicht ausgleichen. Weiterhin war ein positiver Einfluss der postoperativen Therapie auf das rezidivfreie Überleben (DFS-disease-free survival) sowohl uni- als auch multivariat nachweisbar. Die Gesamtüberlebensrate (OS-overall survival) wurde signifikant positiv durch einen geringeren Randstatus und einen zunehmenden Resektionsabstand (ASR Klassifikation) beeinflusst. Das krankheitsspezifische Überleben (DSS-disease-specific survival) sank bei Auftreten eines lokalen Rezidivs. Aus diesen Ergebnissen kann geschlussfolgert werden, dass eine postoperative Therapie zur Kontrolle lokaler Rezidive von hoher Bedeutung ist. Da lokale Rezidive die Überlebensrate signifikant senken, hat die postoperative Therapie indirekt einen positiven Effekt auf das Überleben. Des Weiteren zeigt sich bei Patienten mit freien Resektionsrändern die höchste Überlebensrate, wobei diese mit zunehmendem Abstand des Karzinoms vom Resektionsrand steigt.

Die Hütte ist ein modernes Symbol für den Traum von einem ›alternativen‹ Leben. Sie verspricht denjenigen Vereinfachung und Entschleunigung, die die Freiheit besitzen, sich zu beschränken. Deshalb geben fiktionale Hütten Auskunft darüber, was eine Gesellschaft an sich selbst letztlich überflüssig findet. Darüber hinaus etabliert sich die Hütte im Rahmen der industriellen Revolution als Labor für Beziehungsweisen zwischen Menschen, aber auch zwischen Menschen und Nicht-Menschen. Ausgehend von den Paradigmen der Hütten-Imagination seit dem 19. Jahrhundert untersucht dieser Artikel drei Romane, die die Hütte nutzen, um experimentelle Kontaktszenen zu erkunden. Indem sie generische Konventionen an entscheidenden Stellen verschieben, können sie den zugleich kulturkritischen und sentimentalen Hüttentraum stören und in Frage stellen. Marlen Haushofers Die Wand, Laura Beattys Pollard und Céline Minards Le grand jeu produzieren vielmehr ein Wissen, dass seine epistemischen Bedingungen als epistemologische und kulturelle Inszenierung mitdenkt. / The cabin is a modern symbol for the dream of an ›alternative‹ life. It offers simplification and deceleration to those who are free to limit themselves. Fictional cabins therefore speak of the things a society deems actually superfluous. Moreover, during the industrial revolution cabins became a laboratory for ways of relating to humans and non-humans alike. Beginning with the paradigms of the history of cabin-imaginaries, this article reads three novels which use cabins to conduct experimental contact scenes. By displacing crucial generic conventions, the novels disrupt and challenge the equally sentimental cultural criticism of more typical cabin-dreams. Thus, Marlen Haushofer’s Die Wand, Laura Beatty’s Pollard und Céline Minard’s Le grand jeu produce knowledge that reflects its own conditions as the effect of an epistemological and cultural mise-en-scène.

Purpose: To enhance prognostic information of protein biomarkers for clear cell renal cell carcinomas (ccRCCs), we analyzed them within prognostic groups of ccRCC harboring different tumor characteristics of this clinically and molecularly heterogeneous tumor entity. Methods: Tissue microarrays from 145 patients with primary ccRCC were immunohistochemically analyzed for VHL (von Hippel-Lindau tumor suppressor), Ki67 (marker of proliferation 1), p53 (tumor protein p53), p21 (cyclin-dependent kinase inhibitor 1A), survivin (baculoviral IAP repeat containing 5), and UEA-1 (ulex europaeus agglutinin I) to assess microvessel-density. Results: When analyzing all patients, nuclear staining of Ki67 (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.04–1.12) and nuclear survivin (nS; HR 1.04, 95% CI 1.01–1.08) were significantly associated with disease-specific survival (DSS). In the cohort of patients with advanced localized or metastasized ccRCC, high staining of Ki67, p53 and nS predicted shorter DSS (Ki67: HR 1.07, 95% CI 1.02–1.11; p53: HR 1.05, 95% CI 1.01–1.09; nS: HR 1.08, 95% CI 1.02–1.14). In organ-confined ccRCC, patients with high p21-staining had a longer DSS (HR 0.96, 95% CI 0.92–0.99). In a multivariate model with stepwise backward elimination, tumor size and p21-staining showed a significant association with DSS in patients with "organ-confined" ccRCCs. The p21-staining increased the concordance index of tumor size from 0.75 to 0.78. In patients with "organ-confined" ccRCC, no disease-related deaths occurred in the group with p21-expression below the threshold of 32.5% p21-positive cells (log rank test: P=0.002). Conclusion: The prognostic information of the studied protein biomarkers depended on anatomic tumor stages, which displayed different acquired biological tumor characteristics. Analysis of prognostic factors within different clinical ccRCC groups could help to enhance their prognostic power. The p21-staining was an independent prognostic factor and increased prognostic accuracy in a predictive model in "organ-confined" ccRCC.

Ziel: Den Einfluss der Radikalität der Resektion eines Glioblastoma multiforme in Kombination mit einer adjuvanten Chemotherapie auf das Survival heraus zu arbeiten. Methoden: Zwischen 1997 und 2000 wurden 55 Patienten, die an einem primären Glioblastoma multiforme erkrankten, einer Tumorresektion unterzogen. Von den 55 Patienten waren 36 männlich und 19 weiblich. Im Mittel erkrankten die Patienten mit 56 Jahren. Tumorresektion und Radiatio wurden bei allen Patienten durchgeführt. 20 Patienten wurden darüber hinaus noch mit einer adjuvanten Chemotherapie behandelt. Ergebnisse: Die Patienten, die mit einer Chemotherapie behandelt wurden, zeigten ein signifikant längeres Überleben (85 versus 44 weeks). Und die Patienten mit einem postoperativen Resttumor profitierten am meisten von der adjuvanten Chemotherapie (75 versus 39 weeks). Zusammenfassung: Patienten, die mit einer adjuvanten Chemotherapie behandelt wurden zeigten ein signifikant längeres Überleben als die Patienten ohne diese Therapie. / Objective: To evaluate the influence of resection of a glioblastoma multiforme in combination with adjuvant chemotherapy regarding survival. Methods: From 1997 to 2000, 55 patients with primary glioblastoma multiforme underwent a tumor resection. Of the 55 patients 36 were male, 19 female, with an average age of 56 years. Tumor resection and radiatio were performed in all patients. 20 patients were treated additionally with chemotherapy. Results: Patients treated with chemotherapy displayed a significant longer survival (85 versus 44 weeks). And the patients with a residual postoperative tumor mass did benefit from adjuvant chemotherapy (75 versus 39 weeks). Conclusion: Patients treated with adjuvant chemotherapy had a significant longer survival then those without this therapy.

No description available.

Proteins and their interactions are fundamental to cellular life. Disruption of protein-protein, protein-RNA, or protein-DNA interactions can lead to disease, by affecting the function of protein complexes or by affecting gene regulation. A better understanding of these interactions on the molecular level gives rise to new methods to predict protein interaction, and is critical for the rational design of new therapeutic agents that disrupt disease-causing interactions. This thesis consists of three parts that focus on various aspects of protein interactions and their prediction in the context of disease. In the first part of this thesis, we classify interfaces of protein-protein interactions. We do so by systematically computing all binding sites between protein domains in protein complex structures solved by X-ray crystallography. The result is SCOPPI, the Structural Classification of Protein Protein Interfaces. Clustering and classification of geometrically similar interfaces reveals interesting examples comprising viral mimicry of human interface binding sites, gene fusion events, conservation of interface residues, and diversity of interface localisations. We then develop a novel method to predict protein interactions which is based on these structural interface templates from SCOPPI. The method is applied in three use cases covering osteoclast differentiation, which is relevant for osteoporosis, the microtubule-associated network in meiosis, and proteins found deregulated in pancreatic cancer. As a result, we are able to reconstruct many interactions known to the expert molecular biologist, and predict novel high confidence interactions backed up by structural or experimental evidence. These predictions can facilitate the generation of hypotheses, and provide knowledge on binding sites of promising disease-relevant candidates for targeted drug development. In the second part, we present a novel algorithm to search for protein binding sites in RNA sequences. The algorithm combines RNA structure prediction with sequence motif scanning and evolutionary conservation to identify binding sites on candidate messenger RNAs. It is used to search for binding sites of the PTBP1 protein, an important regulator of glucose secretion in the pancreatic beta cell. First, applied to a benchmark set of mRNAs known to be regulated by PTBP1, the algorithm successfully finds significant binding sites in all benchmark mRNAs. Second, collaborators carried out a screen to identify changes in the proteome of beta cells upon glucose stimulation while inhibiting gene expression. Analysing this set of post-transcriptionally controlled candidate mRNAs for PTBP1 binding, the algorithm produced a ranked list of 11 high confident potential PTBP1 binding sites. Experimental validation of predicted targets is ongoing. Overall, identifying targets of PTBP1 and hence regulators of insulin secretion may contribute to the treatment of diabetes by providing novel protein drug targets or by aiding in the design of novel RNA-binding therapeutics. The third part of this thesis deals with gene regulation in disease. One of the great challenges in medicine is to correlate genotypic data, such as gene expression measurements, and other covariates, such as age or gender, to a variety of phenotypic data from the patient. Here, we address the problem of survival prediction based on microarray data in cancer patients. To this end, a computational approach was devised to find genes in human cancer tissue samples whose expression is predictive for the survival outcome of the patient. The central idea of the approach is the incorporation of background knowledge information in form of a network, and the use of an algorithm similar to Google s PageRank. Applied to pancreas cancer, it identifies a set of eight genes that allows to predict whether a patient has a poor or good prognosis. The approach shows an accuracy comparable to studies that were performed in breast cancer or lymphatic malignancies. Yet, no such study was done for pancreatic cancer. Regulatory networks contain information of transcription factors that bind to DNA in order to regulate genes. We find that including background knowledge in form of such regulatory networks gives highest improvement on prediction accuracy compared to including protein interaction or co-expression networks. Currently, our collaborators test the eight identified genes for their predictive power for survival in an independent group of 150 patients. Under a therapeutic perspective, reliable survival prediction greatly improves the correct choice of therapy. Whereas the live expectancy of some patients might benefit from extensive therapy such as surgery and chemotherapy, for other patients this may only be a burden. Instead, for this group, a less aggressive or different treatment could result in better quality of the remaining lifetime. Conclusively, this thesis contributes novel analytical tools that provide insight into disease-relevant interactions of proteins. Furthermore, this thesis work contributes a novel algorithm to deal with noisy microarray measurements, which allows to considerably improve prediction of survival of cancer patients from gene expression data.

No description available.

No description available.