TY - THES A1 - Heinrich, Tilman T1 - Siliciumorganische Wirkstoffe : Synthese und pharmakologische Eigenschaften siliciumhaltiger Muscarin-, Dopamin- und alpha1-Rezeptor-Antagonisten sowie Ca2+-Kanal-Blocker T1 - synthesis and pharmacological characterization of silicon-containing muscarinic antagonists, dopamine receptor antagonists, Ca2+ channel blockers, and alpha1-adrenoceptor antagonists N2 - Im Rahmen der vorliegenden Arbeit wurden neuartige siliciumhaltige Muscarinrezeptor-Antagonisten, Dopaminrezeptor-Antagonisten, Ca2+-Kanal-Blocker sowie alpha1-Rezeptor-Antagonisten synthetisiert, welche Sila-Analoga (C/Si-Austausch) bekannter organischer Pharmaka darstellen. Die C/Si-Analoga wurden pharmakologisch charakterisiert und damit Beiträge zur Thematik der C/Si-Bioisosterie geleistet. N2 - In this work novel silicon-containing muscarinic antagonists, dopamine receptor antagonists, Ca2+ channel blockers, and alpha1-adrenoceptor antagonists – representing sila-analogues (C/Si replacement) of known organic drugs – were synthesized and pharmacologically characterized (studies on C/Si bioisosterism). KW - Muscarinrezeptor KW - Dopaminrezeptor KW - Alpha-1-Rezeptor KW - Antagonist KW - Calciumantagonist KW - Siliciumorganische Verbindungen KW - Pharmakologie KW - Bioisosterie KW - Silicium KW - siliciumorganisch KW - Bioisosterie KW - Rezeptor-Antagonisten KW - silicon KW - organosilicon KW - bioisosterism KW - receptor antagonists Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-11106 ER - TY - THES A1 - Heinrich, Tilman T1 - Validierung der Zellzyklusdiagnostik bei Ataxia telangiectasia T1 - Exclusion/confirmation of Ataxia telangiectasia via cell cycle analysis N2 - Im Rahmen der vorliegenden Arbeit wurde die Methode der durchflusszytometrischen Zellzyklusanalyse von Lymphozyten bei Patienten mit der klinischen Verdachtsdiagnose Ataxia telangiectasia beschrieben. Hierzu wurden die Daten von 327 Patienten ausgewertet. In 82 Fällen ergab sich eine Bestätigung der Verdachtsdiagnose, in 225 Fällen konnte das Vorliegen dieser Erkrankung ausgeschlossen werden, bei den übrigen untersuchten Fällen ergab die Zellzyklusanalyse Auffälligkeiten hinsichtlich des Proliferationsverhaltens der untersuchten Zellen und/oder ihrer Strahlensensitivität, die eine eindeutige Zuordnung zu einer der beiden Gruppen (AT-postiv/AT-negativ) zunächst nicht gestatteten. Diese Auffälligkeiten lassen sich teils auf technische Probleme (geronnenes Blut, langer Zeitraum zwischen Blutentnahme und Analyse), teils auf biologische Besonderheiten (bestehende Begleiterkrankungen wie Leukämie, Lymphom) zurückführen. Die durchflusszytometrische Zellzyklusanalyse von Lymphozyten ergibt als diagnostisch relevante Parameter den Anteil der nicht-proliferierenden Zellen (G0,G1) sowie den Anteil der in der G2-Phase des 1. Zellzyklus verbleibenden Zellen bezogen auf die Wachstumsfraktion (G2/GF). Der Anteil der nicht-proliferierenden Zellen (G0,G1) ist ein Maß für die Stimulierbarkeit der Lymphozyten. Diese Stimulierbarkeit ist bei Zellen von AT-Patienten häufig vermindert, d.h. das Ausmaß der Mitogenantwort gibt ebenso einen Hinweis auf das Vorliegen der Erkrankung AT wie die Strahlensensitivität der Zellen. Letztere wird durch den zweiten der oben angeführten Parameter (G2/GF) repräsentiert. Der für die Erkrankung AT charakteristische Funktionsverlust des ATM-Proteins, welches im unbeeinträchtigten Zustand für die Kontrolle der Reparatur von strahleninduzierten DNA-Schädigungen verantwortlich ist, führt typischerweise zu einer Erhöhung des Anteils von Zellen in der G2-Phase, nachdem diese Zellen ionisierender Strahlung ausgesetzt waren. Die zweidimensionale Auftragung dieser Parameter (G0,G1 gegen G2/GF) erlaubt in der Regel bereits eine guten Abgrenzung der Gruppe der AT-positiven gegen die AT-negativen Fälle. Die Berücksichtigung eines weiteren Parameters, nämlich des AFP-Wertes, gestattet darüberhinaus in mehreren Fällen die Zuordnung der oben erwähnten, zunächst unklaren Fälle zu einer dieser Gruppen. Die durchflusszytometrische Zellzyklusanalyse von bestrahlten Lymphozyten kann daher als Screening-Methode bei der Untersuchung von Patienten mit der Verdachtsdiagnose Ataxia telangiectasia als ein dem CSA überlegenes Verfahren angesehen werden. Die Kombination dreier Parameter: 1) Anteil der nicht-proliferierenden Zellen (G0,G1), 2) Anteil der in der G2-Phase des 1. Zellzyklus verbleibenden Zellen bezogen auf die Wachstumsfraktion (G2/GF) und 3) AFP-Wert erlaubt hierbei im Rahmen der AT-Diagnostik in >93% der Fälle eine eindeutige Zuordnung zur Gruppe der AT-negativen bzw. AT-positiven Fälle. N2 - Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder with increased radiosensitivity and cancer susceptibility. The responsible gene (ATM) consists of 66 exons and a coding region of 9171 bp which precludes direct sequencing as a screening assay for confirmation or exclusion of the clinical suspicion of AT. Peripheral blood mononuclear cells of 327 patients refered for the exclusion of AT were exposed to ionizing radiation (IR) and incubated for 72 h in the presence of PHA. Using bivariate BrdU-Hoechst/Ethidium bromide flowcytometry, the following cell cycle parameters were ascertained: (1) proportion of non-proliferating (G0,G1) cells as a measure of mitogen response, (2) proportion of first cycle G2-phase cells relative to the growth fraction (G2/GF) as a measure of radiosensitivity. >93% of the cases could be unequivocally assigned either to the AT-negative or the AT-positive group of patients. Combination of cell cycle data with serum AFP concentrations led to the exclusion of AT in nearly all of the uncertain cases. We conclude that cell cycle testing complemented by serum AFP measurements fulfills the criteria as a rapid and economical screening procedure in the differential diagnosis of juvenile ataxias. KW - Ataxia telangiectasia KW - Zellzyklus KW - ATM KW - Durchflusszytometrie KW - Radiosensitivität KW - childhood ataxia KW - ataxia telangiectasia KW - cell cycle KW - flowcytometry KW - radiosensivitity Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-14654 ER - TY - JOUR A1 - Rhiem, Kerstin A1 - Engel, Christoph A1 - Graeser, Monika A1 - Zachariae, Silke A1 - Kast, Karin A1 - Kiechle, Marion A1 - Ditsch, Nina A1 - Janni, Wolfgang A1 - Mundhenke, Christoph A1 - Golatta, Michael A1 - Varga, Dominic A1 - Preisler-Adams, Sabine A1 - Heinrich, Tilman A1 - Bick, Ulrich A1 - Gadzicki, Dorothea A1 - Briest, Susanne A1 - Meindl, Alfons A1 - Schmutzler, Rita K. T1 - The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study JF - Breast Cancer Research N2 - Introduction: While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations. Methods: A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status. Results: The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families. Conclusions: Contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy. KW - contralateral breast cancer KW - BRCA1/2 negative KW - BRCA1 positive KW - BRCA2 positive Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135715 VL - 14 IS - 6 ER - TY - JOUR A1 - Sepahi, Ilnaz A1 - Faust, Ulrike A1 - Sturm, Marc A1 - Bosse, Kristin A1 - Kehrer, Martin A1 - Heinrich, Tilman A1 - Grundman-Hauser, Kathrin A1 - Bauer, Peter A1 - Ossowski, Stephan A1 - Susak, Hana A1 - Varon, Raymonda A1 - Schröck, Evelin A1 - Niederacher, Dieter A1 - Auber, Bernd A1 - Sutter, Christian A1 - Arnold, Norbert A1 - Hahnen, Eric A1 - Dworniczak, Bernd A1 - Wang-Gorke, Shan A1 - Gehrig, Andrea A1 - Weber, Bernhard H. F. A1 - Engel, Christoph A1 - Lemke, Johannes R. A1 - Hartkopf, Andreas A1 - Huu Phuc, Nguyen A1 - Riess, Olaf A1 - Schroeder, Christopher T1 - Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women JF - BMC Cancer N2 - Background Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. Conclusions To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results. KW - breast cancer KW - age at onset KW - DNA-repair genes KW - next-generation-sequencing KW - panel sequencing KW - extreme phenotypes KW - hereditary breast and ovarian cancer KW - BRCA1 KW - DNA-repair Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237676 VL - 19 ER -