41 results on '"Bossart M"'
Search Results
2. Psychische Belastung und deren Einflussfaktoren bei Überlebenden von malignen ovariellen Keimzell- oder Keimstrangstromatumoren : Eine Analyse der AGO-CORSETT-Datenbank
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Bossart, M., Plett, H., Krämer, B., Braicu, E., Czogalla, B., Klar, M., Singer, S., Mayr, D., Staebler, A., du Bois, A., Kommoss, S., Link, T., Burges, A., Heitz, F., Grube, M., Trillsch, F., Harter, P., Wimberger, Pauline, Buderath, P., and Hasenburg, A.
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Medizin - Abstract
Background: Sex cord–stromal tumors (SCST) and malignant ovarian germ cell tumors (MOGCT) are rare ovarian neoplasms that disproportionally affect young women. As prognosis is excellent throughout all stages, quality of life issues are important topics for long-term survivors. Aims: To investigate the prevalence of fertility-preserving therapy in patients with ovarian stromal tumors and germ cell tumors and to evaluate factors influencing anxiety, depression, quality of life, and sexuality. Materials and methods: The Current Ovarian geRm cell and SEx cord stromal Tumor Treatment strategies (CORSETT) study is an observational, multicenter, mixed retrospective/prospective cohort study of the “Arbeitsgemeinschaft für Gynäkologische Onkologie” (AGO) study group. Women who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete questionnaires (Hospital Anxiety and Depression Scale [HADS], Sexual Activity Questionnaire [SAQ], European Organisation for Research and Treatment of Cancer Core Quality of life Questionnaire [EORTC QLQ-C30]). This analysis focused on the value of fertility-preserving surgery and the relevance of factors influencing pain, anxiety, and depression on quality of life for survivors. Results: Of the 355 patients included, 152 women completed the questionnaires and thus were included in this analysis. In all, 85 (56%) had fertility-sparing surgery. Furthermore, 34% had significant levels of depression and anxiety. Women with fertility-conserving treatment had a higher probability for being sexually active and had less depression and anxiety. Pain was associated with the level of distress, irrespective of the time since diagnosis. Discussion: Fertility-sparing surgery should be offered to all SCST and MOGCT patients, when oncologically safe, in order to ensure the best possible quality of life for cancer survivors. Questionnaires evaluating depression, anxiety, pain, and sexuality should be routinely used during treatment and follow-up.
- Published
- 2023
3. Continuous-time echo state networks for predicting power system dynamics
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Roberts, C, Roberts, C, Lara, JD, Henriquez-Auba, R, Bossart, M, Anantharaman, R, Rackauckas, C, Hodge, BM, Callaway, DS, Roberts, C, Roberts, C, Lara, JD, Henriquez-Auba, R, Bossart, M, Anantharaman, R, Rackauckas, C, Hodge, BM, and Callaway, DS
- Abstract
With the growing penetration of converter-interfaced generation in power systems, the dynamical behavior of these systems is rapidly evolving. One of the challenges with converter-interfaced generation is the increased number of equations, as well as the required numerical timestep, involved in simulating these systems. Within this work, we explore the use of continuous-time echo state networks as a means to cheaply, and accurately, predict the dynamic response of power systems subject to a disturbance for varying system parameters. We show an application for predicting frequency dynamics following a loss of generation for varying penetrations of grid-following and grid-forming converters. We demonstrate that, after training on 20 solutions of the full-order system, we achieve a median nadir prediction error of 0.17 mHz with 95% of all nadir prediction errors within ±4 mHz. We conclude with some discussion on how this approach can be used for parameter sensitivity analysis and within optimization algorithms to rapidly predict the dynamical behavior of the system.
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- 2022
4. The need for accredited training in gynaecological oncology: a report from the European Network of Young Gynaecological Oncologists (ENYGO)
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Manchanda, R., Godfrey, M., Wong-Taylor, L. A., Halaska, M. J., Burnell, M., Grabowski, J. P., Gultekin, M., Haidopoulos, D., Zapardiel, I., Vranes, B., Kesic, V., Zola, P., Colombo, N., Verheijen, R., Bossart, M., and Piek, J.
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- 2013
- Full Text
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5. 876P The effect of surgical techniques on sexuality and global quality of life (Qol) in women with ovarian germ cell (OGCT) and sex cord stromal tumours (SCST): An analysis of the AGO-CORSETT database
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Hasenburg, A., primary, Plett, H., additional, Krämer, B., additional, Braicu, E., additional, Czogalla, B., additional, Bossart, M., additional, Singer, S., additional, Mayr, D., additional, Staebler, A., additional, du Bois, A., additional, Kommoss, S., additional, Link, T., additional, Burges, A., additional, Heitz, F., additional, Keul, J., additional, Trillsch, F., additional, Harter, P., additional, Wimberger, P., additional, Buderath, P., additional, and Klar, M., additional
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- 2020
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6. First-in-class positron emission tomography tracer for the glucagon receptor
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Velikyan, I., Haack, T., Bossart, M., Evers, A., Laitinen, I., Larsen, P., Plettenburg, O., Johansson, L., Pierrou, S., Wagner, M., and Eriksson, O.
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gallium 68 ,positron emission tomography ,Dual agonist ,Ga DO3A S02 GCG ,GLP-1 receptor ,autoradiography ,cAMP assay ,binding affinity ,rat ,receptor occupancy ,Ga DO3A S01 GCG ,isotope labeling ,phosphorus ,radiochemistry ,cysteine ,Original Research ,liver tissue ,dosimetry ,effective dose (radiation) ,adult ,Type 2 diabetes ,tracer ,peptide ,unclassified drug ,radiopharmaceutical agent ,female ,priority journal ,receptor affinity ,HEK293 cell line ,radioactivity ,retention time ,Radiology, Nuclear Medicine and Medical Imaging ,lcsh:Medical physics. Medical radiology. Nuclear medicine ,high performance liquid chromatography ,gene overexpression ,lcsh:R895-920 ,body weight ,male ,controlled study ,ddc:610 ,human ,radioisotope ,quality control ,glucagon like peptide 1 receptor agonist ,liver biopsy ,carboxy terminal sequence ,nonhuman ,gadoteridol ,exendin 4 ,animal model ,human cell ,GCG ,antidiabetic agent ,glucagon receptor ,Glucagon ,body weight loss ,human tissue ,internalization ,glucagon receptor agonist ,Radiologi och bildbehandling ,Dewey Decimal Classification::600 | Technik::610 | Medizin, Gesundheit ,Gcg ,Glp-1 Receptor ,Dual Agonist ,Type 2 Diabetes ,glucagon like peptide 1 - Abstract
The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement. Methods Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [68Ga]Ga-DO3A-S01-GCG and [68Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat. Results [68Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals. Conclusion [68Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans. Electronic supplementary material The online version of this article (10.1186/s13550-019-0482-0) contains supplementary material, which is available to authorized users.
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- 2019
7. LION-PAW – Lymphonodectomy (LNE) in Ovarian Neoplasm – Pleasure Ability of Women Prospektive Substudie der multizentrischen AGO LION Studie
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Hasenburg, A, additional, Sehouli, J, additional, Lampe, B, additional, Reuss, A, additional, Schmalfeldt, B, additional, Belau, A, additional, Bossart, M, additional, Mahner, S, additional, Hillemanns, P, additional, Petry, KU, additional, du Bois, A, additional, Herwig, U, additional, Hilpert, F, additional, Gropp-Meier, M, additional, Hanf, V, additional, Janni, W, additional, Schindelhauer, A, additional, Kimmig, R, additional, Greimel, E, additional, Wagner, U, additional, and Harter, P, additional
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- 2018
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8. Radiochemistry and Preclinical Evaluation of Two Novel Peptide Analogues Targeting Glucagon Receptor for AntiDiabetic Drug Development
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Velikyan, Irina, Bossart, M., Haack, T., Laitinen, I., Larsen, P., Plettenburg, O., Johansson, L., Pierrou, S., Wagner, M., Eriksson, Olof, Velikyan, Irina, Bossart, M., Haack, T., Laitinen, I., Larsen, P., Plettenburg, O., Johansson, L., Pierrou, S., Wagner, M., and Eriksson, Olof
- Published
- 2017
9. First-in-class PET tracer for the glucagon receptor
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Eriksson, Oskar, Bossart, M., Haack, T., Laitinen, I., Larsen, P., Plettenburg, O., Johansson, L., Pierrou, S., Wagner, M., Velikyan, Irina, Eriksson, Oskar, Bossart, M., Haack, T., Laitinen, I., Larsen, P., Plettenburg, O., Johansson, L., Pierrou, S., Wagner, M., and Velikyan, Irina
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- 2017
10. Die Therapie bei superinfiziertem genitalen Morbus Behçet – Colchicin als Alternative zur Cortisontherapie
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Hasanov, MF, primary, May, A, additional, Gitsch, G, additional, and Bossart, M, additional
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- 2016
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11. Bauchwandendometriose nach gynäkologischen Eingriffen: eine Fallserie
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Thornton, SA, primary, Maurer, S, additional, Woll, J, additional, Markfeld-Erol, F, additional, Prömpeler, HP, additional, and Bossart, M, additional
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- 2016
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12. Die Bedeutung von ZNF261 und der Lysin-spezifischen Demethylase LSD1 in der Androgenrezeptor-abhängigen und -unabhängigen Kanzerogenese
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Bossart, M, primary
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- 2016
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13. The work place educational: climate in gynecological oncology fellowships across Europe: the impact of accreditation
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Piek, J.M.J., Bossart, M., Boor, K., Halaska, M.J., Haidopoulos, D., Zapardiel, I., Grabowski, J.P., Kesic, V., Cibula, D., Colombo, N., Verheijen, RHM, Manchanda, R., Piek, J.M.J., Bossart, M., Boor, K., Halaska, M.J., Haidopoulos, D., Zapardiel, I., Grabowski, J.P., Kesic, V., Cibula, D., Colombo, N., Verheijen, RHM, and Manchanda, R.
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- 2015
14. The work place educational: climate in gynecological oncology fellowships across Europe: the impact of accreditation
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MS Gynaecologische Oncologie, Cancer, Piek, J.M.J., Bossart, M., Boor, K., Halaska, M.J., Haidopoulos, D., Zapardiel, I., Grabowski, J.P., Kesic, V., Cibula, D., Colombo, N., Verheijen, RHM, Manchanda, R., MS Gynaecologische Oncologie, Cancer, Piek, J.M.J., Bossart, M., Boor, K., Halaska, M.J., Haidopoulos, D., Zapardiel, I., Grabowski, J.P., Kesic, V., Cibula, D., Colombo, N., Verheijen, RHM, and Manchanda, R.
- Published
- 2015
15. The work place educational climate in gynecological oncology fellowships across Europe the impact of accreditation
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Piek, J, Bossart, M, Boor, K, Halaska, M, Haidopoulos, D, Zapardiel, I, Grabowski, J, Kesic, V, Cibula, D, Colombo, N, Verheijen, R, Manchanda, R, Manchanda, R., COLOMBO, NICOLETTA, Piek, J, Bossart, M, Boor, K, Halaska, M, Haidopoulos, D, Zapardiel, I, Grabowski, J, Kesic, V, Cibula, D, Colombo, N, Verheijen, R, Manchanda, R, Manchanda, R., and COLOMBO, NICOLETTA
- Abstract
Background: A good educational climate/environment in the workplace is essential for developing high-quality medical (sub) specialists. These data are lacking for gynecological oncology training. Objective: This study aims to evaluate the educational climate in gynecological oncology training throughout Europe and the factors affecting it. Methods: A Web-based anonymous survey sent to ENYGO (European Network of Young Gynecological Oncologists) members/trainees to assess gynecological oncology training. This included sociodemographic information, details regarding training posts, and a 50-item validated Dutch Residency Educational Climate Test (D-RECT) questionnaire with 11 subscales (1-5 Likert scale) to assess the educational climate. The chi(2) test was used for evaluating categorical variables, and the Mann-Whitney U (nonparametric) test was used for continuous variables between 2 independent groups. Cronbach alpha assessed the questionnaire reliability. Multivariable linear regression assessed the effect of variables on D-RECT outcome subscales. Results: One hundred nineteen gynecological oncological fellows responded. The D-RECT questionnaire was extremely reliable for assessing the educational environment in gynecological oncology (subscales' Cronbach alpha, 0.82-0.96). Overall, trainees do not seem to receive adequate/effective constructive feedback during training. The overall educational climate (supervision, coaching/assessment, feedback, teamwork, interconsultant relationships, formal education, role of the tutor, patient handover, and overall consultant's attitude) was significantly better (P = 0.001) in centers providing accredited training in comparison with centers without such accreditation. Multivariable regression indicated the main factors independently associated with a better educational climate were presence of an accredited training post and total years of training. Conclusions: This study emphasizes the need for better feedback mechanisms and
- Published
- 2015
16. Index-matched IWKB method for the measurement of spatially varying refractive index profiles within thin-film photovoltaics
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Pang, Y. T., primary, Bossart, M., additional, and Eisaman, M. D., additional
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- 2014
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17. The need for accredited training in gynaecological oncology: A report from the european network of young gynaecological oncologists (ENYGO)
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Manchanda, R, Godfrey, M, Wong Taylor, L, Halaska, M, Burnell, M, Grabowski, J, Gultekin, M, Haidopoulos, D, Zapardiel, I, Vranes, B, Kesic, V, Zola, P, Colombo, N, Verheijen, R, Bossart, M, Piek, J, Piek, J., COLOMBO, NICOLETTA, Manchanda, R, Godfrey, M, Wong Taylor, L, Halaska, M, Burnell, M, Grabowski, J, Gultekin, M, Haidopoulos, D, Zapardiel, I, Vranes, B, Kesic, V, Zola, P, Colombo, N, Verheijen, R, Bossart, M, Piek, J, Piek, J., and COLOMBO, NICOLETTA
- Abstract
Background: Primary data on training experiences of European gynaecological oncology trainees are lacking. This study aims to evaluate trainee profile, satisfaction and factors affecting the training experience in gynaecological oncology in Europe. Patients and methods: A web-based anonymous survey sent to ENYGO members/trainees in July 2011. It included sociodemographic information and a 22-item (1-5 Likert scale) questionnaire evaluating training experience in gynaecological oncology. Chi-square tests were used for evaluating the independence of categorical variables and t-test (parametric)/Mann-Whitney (non-parametric) tests for differences between two independent groups on continuous data. Cluster analysis was used to identify groupings in multivariate data and Cronbachs-alpha for questionnaire reliability. A multivariable linear regression model was used to assess the effect of variables on training satisfaction. Results: One hundred and nineteen gynaecological-oncology trainees from 31 countries responded. The mean age was 37.4 (S.D, 5.3) years and 55.5 were in accredited training posts. Two clusters identified in the cohort (Calinski-Harabasz, CH 47.35) differed mainly by accredited training (P 0.003). The training-satisfaction score (TSS) had high reliability (Cronbachs alpha, 0.951) and was significantly associated with accredited posts (P < 0.0005), years of training (P 0.001) and salary (P 0.002). The TSS was independent of age (P 0.360), working hours (P 0.620), overtime-pay (P 0.318), annual leave (P 0.933), gender (P 0.545) and marital status (P 0.731). Accredited programme trainees scored significantly higher than others in 17 of 22 aspects of training. The areas of greater need included advanced laparoscopic/urological/colorectal surgery, radiation oncology, palliative-care, cancer genetics and research opportunities. Conclusions: Our data demonstrate the importance of accredited training and the need for harmonisation of gynaecological oncology trai
- Published
- 2013
18. Frühes Mammakarzinom – Lebensqualität nach Switch von Tamoxifen auf Exemestan
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Bossart, M., primary, Beussel, S., additional, Hadji, P., additional, and Hasenburg, A., additional
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- 2011
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19. ULTRASTRUCTURAL ANALYSES OF STONE HEART SYNDROME AT ONSET AND SIX DAYS LATER FOLLOWING TOTAL SUPPORT OF THE CIRCULATION WITH A PARTIAL ARTIFICIAL HEART OR LEFT VENTRICULAR ASSIST DEVICE (ALVAD)
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Sturm, J. T., Bossart, M. I., Holub, D. A., Milam, J. D., and Norman, J. C.
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cardiovascular system ,Articles - Abstract
Ischemic myocardial contracture developed in a 21-year-old man following aortic and mitral valve replacement. The patient's circulation was supported totally for 6 days with an abdominal left ventricular assist device (ALVAD). Cardiac allografting was then undertaken. Samples of myocardium taken at the original operation and 6 days later at transplantation were analyzed ultrastructurally. At the onset of ischemic cortracture, left ventricular abnormalities included hypercontraction of myofibrils, loss of normal A-band and Z-band patterns, mitochondrial swelling with fusion of cristae, interfibrillar edema and glycogen depletion. Capillaries demonstrated swelling of endothelial cells and basement membrane disruption. Six days later, ultrastructural morphology showed further degeneration. The myofibrils remained hypercontracted, but were more fragmented. Degenerative changes in mitochondria were more advanced and calcium deposition in cristae was present. No glycogen was seen. The right ventricular myocardium exhibited significantly fewer ultrastructural abnormalities. The principal right ventricular changes were endothelial swelling and basement membrane disruption. Glycogen granules were present. Ischemic contracture affects the left ventricle more than the right, and the morphology becomes more abnormal with time. To our knowledge, this is the first instance wherein morphologic progressions of the ultrastructural alterations of ischemic contracture have been documented.
- Published
- 1979
20. A method for enumeration ot T and B lymphocytes in tissues.
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Bastian, F O, primary, Middleditch, P R, additional, and Bossart, M I, additional
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- 1979
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21. The work place educational: climate in gynecological oncology fellowships across Europe: the impact of accreditation
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Jurgen M.J. Piek, Vesna Kesic, René H.M. Verheijen, Jacek P. Grabowski, Michael J. Halaska, Michaela Bossart, Klarke Boor, Ignacio Zapardiel, Dimitrios Haidopoulos, Nicoletta Colombo, David Cibula, Ranjit Manchanda, Piek, J, Bossart, M, Boor, K, Halaska, M, Haidopoulos, D, Zapardiel, I, Grabowski, J, Kesic, V, Cibula, D, Colombo, N, Verheijen, R, and Manchanda, R
- Subjects
Adult ,Male ,medicine.medical_specialty ,Medical psychology ,Students, Medical ,media_common.quotation_subject ,education ,Medical Oncology ,Coaching ,Likert scale ,Accreditation ,Cronbach's alpha ,Surveys and Questionnaires ,medicine ,Journal Article ,Humans ,gynecological oncology fellowships european network of young gynecological oncologists training education ,Fellowships and Scholarships ,TUTOR ,Workplace ,computer.programming_language ,media_common ,Medical education ,Teamwork ,business.industry ,Obstetrics and Gynecology ,Internship and Residency ,Test (assessment) ,Europe ,Oncology ,Gynecology ,Family medicine ,Education, Medical, Continuing ,Female ,business ,computer ,Follow-Up Studies - Abstract
BackgroundA good educational climate/environment in the workplace is essential for developing high-quality medical (sub)specialists. These data are lacking for gynecological oncology training.ObjectiveThis study aims to evaluate the educational climate in gynecological oncology training throughout Europe and the factors affecting it.MethodsA Web-based anonymous survey sent to ENYGO (European Network of Young Gynecological Oncologists) members/trainees to assess gynecological oncology training. This included sociodemographic information, details regarding training posts, and a 50-item validated Dutch Residency Educational Climate Test (D-RECT) questionnaire with 11 subscales (1–5 Likert scale) to assess the educational climate. The χ2 test was used for evaluating categorical variables, and the Mann-Whitney U (nonparametric) test was used for continuous variables between 2 independent groups. Cronbach α assessed the questionnaire reliability. Multivariable linear regression assessed the effect of variables on D-RECT outcome subscales.ResultsOne hundred nineteen gynecological oncological fellows responded. The D-RECT questionnaire was extremely reliable for assessing the educational environment in gynecological oncology (subscales’ Cronbach α, 0.82–0.96). Overall, trainees do not seem to receive adequate/effective constructive feedback during training. The overall educational climate (supervision, coaching/assessment, feedback, teamwork, interconsultant relationships, formal education, role of the tutor, patient handover, and overall consultant’s attitude) was significantly better (P = 0.001) in centers providing accredited training in comparison with centers without such accreditation. Multivariable regression indicated the main factors independently associated with a better educational climate were presence of an accredited training post and total years of training.ConclusionsThis study emphasizes the need for better feedback mechanisms and the importance of accreditation of centers for training in gynecological oncology to ensure training within higher quality clinical learning climates.
- Published
- 2015
22. The need for accredited training in gynaecological oncology: a report from the European Network of Young Gynaecological Oncologists (ENYGO)
- Author
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Boris Vranes, Nicoletta Colombo, Jurgen M.J. Piek, Paolo Zola, René H.M. Verheijen, Michaela Bossart, Ranjit Manchanda, Michael J. Halaska, Dimitrios Haidopoulos, Matthew Burnell, M. Godfrey, Vesna Kesic, L. A. Wong-Taylor, Jacek P. Grabowski, Murat Gultekin, Ignacio Zapardiel, Manchanda, R, Godfrey, M, Wong Taylor, L, Halaska, M, Burnell, M, Grabowski, J, Gultekin, M, Haidopoulos, D, Zapardiel, I, Vranes, B, Kesic, V, Zola, P, Colombo, N, Verheijen, R, Bossart, M, and Piek, J
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Adult ,Male ,medicine.medical_specialty ,Palliative care ,Accredited programme ,education ,Medical Oncology ,Likert scale ,ENYGO ,Cronbach's alpha ,Neoplasms ,Surveys and Questionnaires ,medicine ,Training ,Humans ,Accreditation ,Gynecology ,Questionnaire ,business.industry ,Palliative Care ,Hematology ,ESGO ,Colorectal surgery ,Europe ,Gynaecological oncology ,Oncology ,Family medicine ,Cohort ,Workforce ,Neoplasm ,Marital status ,Education, Medical, Continuing ,Female ,business ,Human - Abstract
Background: Primary data on training experiences of European gynaecological oncology trainees are lacking. This study aims to evaluate trainee profile, satisfaction and factors affecting the training experience in gynaecological oncology in Europe. Patients and methods: A web-based anonymous survey sent to ENYGO members/trainees in July 2011. It included sociodemographic information and a 22-item (1-5 Likert scale) questionnaire evaluating training experience in gynaecological oncology. Chi-square tests were used for evaluating the independence of categorical variables and t-test (parametric)/Mann-Whitney (non-parametric) tests for differences between two independent groups on continuous data. Cluster analysis was used to identify groupings in multivariate data and Cronbachs-alpha for questionnaire reliability. A multivariable linear regression model was used to assess the effect of variables on training satisfaction. Results: One hundred and nineteen gynaecological-oncology trainees from 31 countries responded. The mean age was 37.4 (S.D, 5.3) years and 55.5 were in accredited training posts. Two clusters identified in the cohort (Calinski-Harabasz, CH 47.35) differed mainly by accredited training (P 0.003). The training-satisfaction score (TSS) had high reliability (Cronbachs alpha, 0.951) and was significantly associated with accredited posts (P < 0.0005), years of training (P 0.001) and salary (P 0.002). The TSS was independent of age (P 0.360), working hours (P 0.620), overtime-pay (P 0.318), annual leave (P 0.933), gender (P 0.545) and marital status (P 0.731). Accredited programme trainees scored significantly higher than others in 17 of 22 aspects of training. The areas of greater need included advanced laparoscopic/urological/colorectal surgery, radiation oncology, palliative-care, cancer genetics and research opportunities. Conclusions: Our data demonstrate the importance of accredited training and the need for harmonisation of gynaecological oncology training within Europe. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
- Published
- 2012
23. Imaging of the Glucose-Dependent Insulinotropic Polypeptide Receptor Using a Novel Radiolabeled Peptide Rationally Designed Based on Endogenous GIP and Synthetic Exendin-4 Sequences.
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Velikyan I, Bossart M, Haack T, Laitinen I, Estrada S, Johansson L, Pierrou S, Wagner M, and Eriksson O
- Abstract
Imaging and radiotherapy targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) could potentially benefit the management of neuroendocrine neoplasms (NENs), complementing clinically established radiopharmaceuticals. The aim of this study was to evaluate a GIPR-targeting positron emission tomography (PET) radioligand with receptor-specific binding, fast blood clearance, and low liver background uptake. The peptide DOTA-bioconjugate, C803-GIP, was developed based on the sequence of the endogenous GIP(1-30) and synthetic exendin-4 peptides with selective amino acid mutations to combine their specificity for the GIPR and in vivo stability, respectively. The
68 Ga-labeled bioconjugate was evaluated in vitro in terms of binding affinity, specificity, and internalization in HEK293 cells transfected with the human GIPR, GLP1, or GCG receptors and in sections of human insulinoma and NENs. In vivo binding specificity, biodistribution, and tissue background were investigated in mice bearing huGIPR-HEK293 xenografts and in a pig. Ex vivo organ distribution, pharmacokinetics, and dosimetry were studied in normal rats. [68 Ga]Ga-C803-GIP was stable and demonstrated a high affinity to the huGIPR-HEK293 cells. Binding specificity was demonstrated in vitro in frozen sections of NENs and huGIPR-HEK293 cells. No specific uptake was observed in the negative controls of huGLP1R and huGCGR cells. A novel rationally designed PET radioligand, [68 Ga]Ga-C803-GIP, demonstrated promising binding characteristics and specificity towards the GIPR.- Published
- 2022
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24. Gender-related differences in career development among gynecologic oncology surgeons in Europe. European Network of Young Gynecologic Oncologists' Survey based data.
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Nikolova T, Bossart M, Kacperczyk-Bartnik J, Razumova Z, Strojna A, Bizzarri N, Pletnev A, Gómez-Hidalgo NR, Theofanakis C, Lanner M, Selcuk I, Shushkevich A, Anca CR, Nikolova N, Concin N, and Zalewski K
- Abstract
Introduction: Gender-related differences in career development are well known issues in various professions. An international survey on gender-related differences was performed among young gynecologic oncology surgeons in Europe to identify potential gender inequalities in career development., Material and Methods: A survey on demographics, clinical and academic working environment, family/parenting, career development, salary and leadership was sent to all members of the European Network of Young Gynecologic Oncologists (ENYGO), which is a network within the European Society of Gynecologic Oncology (ESGO). Gynecologic oncology surgeons and obstetricians/gynecologists who actively work in this field in Europe were included in the study., Results: Responses were analyzed from 192 gynecologic oncology surgeons of whom 65.1% (125/192) were female (median age 37, IQR: 34 - 42) and 34.9% (67/192) were male (median age 38, IQR: 36 - 41). Male reported to perform a median of 15 and female a median of 10 operations per month (p = . 007). Among female, 24.8% had a leadership position vs. 44.8% among male, crude OR = 2.46, 95% CI 1.31-4.62, p< .01. When stratifying for age under 41 and having children, 36.7% of male and 5.6% of female had a leadership position, adjusted OR 10.8, 95% CI 3.28-35.64, p <.001. A significantly higher proportion of female compared to male believed they earned less than their gender counterparts at the same clinical position and with same qualifications (30.4% vs. 2.5%, p< .001). There was not a statistically significant gender difference in the academic qualification PhD degree or professorship ( p = .92 and p = .64, respectively). In the previous year, male published more peer-reviewed articles than female (median 3 vs. median 2; p = .017)., Conclusion: This first comprehensive survey on gender-differences in gynecologic oncology in Europe revealed that there are gender gaps concerning several aspects during the critical time of career development in the young generation of gynecologic oncology surgeons. These gender gaps are particularly reflected by a lower rate of female leadership positions. ENYGO and ESGO are dedicated to work on solution to overcome the identified obstacles and to support closing gender gaps., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nikolova, Bossart, Kacperczyk-Bartnik, Razumova, Strojna, Bizzarri, Pletnev, Gómez-Hidalgo, Theofanakis, Lanner, Selcuk, Shushkevich, Anca, Nikolova, Concin and Zalewski.)
- Published
- 2022
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25. Glucagonlike Peptide-1 Receptor Imaging in Individuals with Type 2 Diabetes.
- Author
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Eriksson O, Velikyan I, Haack T, Bossart M, Laitinen I, Larsen PJ, Berglund JE, Antoni G, Johansson L, Pierrou S, Tillner J, and Wagner M
- Subjects
- Gallium Radioisotopes, Humans, Peptides chemistry, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography methods, Reproducibility of Results, Diabetes Mellitus, Type 2 diagnostic imaging, Glucagon-Like Peptide-1 Receptor metabolism
- Abstract
The glucagonlike peptide-1 receptor (GLP1R) is a gut hormone receptor, intricately linked to regulation of blood glucose homeostasis via several mechanisms. It is an established and emergent drug target in metabolic disease. The PET radioligand
68 Ga-DO3A-VS-exendin4 (68 Ga-exendin4) has the potential to enable longitudinal studies of GLP1R in the human pancreas. Methods:68 Ga-exendin4 PET/CT examinations were performed on overweight-to-obese individuals with type 2 diabetes ( n = 13) as part of a larger target engagement study (NCT03350191). A scanning protocol was developed to optimize reproducibility (target amount of 0.5 MBq/kg [corresponding to peptide amount of <0.2 µg/kg], blood sampling, and tracer stability assessment). The pancreas and abdominal organs were segmented, and binding was correlated with clinical parameters. Results: Uptake of68 Ga-exendin4 in the pancreas, but not in other abdominal tissues, was high but variable between individuals. There was no evidence of self-blocking of GLP1R by the tracer in this protocol, despite the high potency of exendin4. The results showed that a full dynamic scan can be simplified to a short static scan, potentially increasing throughput and reducing patient discomfort. The68 Ga-exendin4 concentration in the pancreas (i.e., GLP1R density) correlated inversely with the age of the individual and tended to correlate positively with body mass index. However, the total GLP1R content in the pancreas did not. Conclusion: In summary, we present an optimized and simplified68 Ga-exendin4 scanning protocol to enable reproducible imaging of GLP1R in the pancreas.68 Ga-exendin4 PET may enable quantification of longitudinal changes in pancreatic GLP1R during the development of type 2 diabetes, as well as target engagement studies of novel glucagonlike peptide-1 agonists., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2022
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26. Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist.
- Author
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Bossart M, Wagner M, Elvert R, Evers A, Hübschle T, Kloeckener T, Lorenz K, Moessinger C, Eriksson O, Velikyan I, Pierrou S, Johansson L, Dietert G, Dietz-Baum Y, Kissner T, Nowotny I, Einig C, Jan C, Rharbaoui F, Gassenhuber J, Prochnow HP, Agueusop I, Porksen N, Smith WB, Nitsche A, and Konkar A
- Subjects
- Animals, Gastric Inhibitory Polypeptide, Glucagon-Like Peptide 1, Humans, Peptides pharmacology, Glucagon-Like Peptide-1 Receptor agonists, Glycemic Control, Incretins pharmacology, Receptors, Gastrointestinal Hormone agonists, Receptors, Glucagon agonists, Weight Loss drug effects
- Abstract
Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism., Competing Interests: Declaration of interests M.B., M.W., R.E., A.E., T.H., T. Kloeckener, K.L., C.M., G.D., Y.D.-B., T. Kissner, I.N., C.E., C.J., F.R., J.G., H.-P.P., I.A., N.P., A.N., and A.K. were employees of Sanofi when the studies were conducted and may hold shares and/or stock options in the company. M.B., M.W., A.E., and K.L. are inventors on the patent application WO2018100135 containing SAR441255. O.E. and S.P. are employees of Antaros Medical AB, which received payment for the practical conduct of the PET study. Otherwise, they declare no competing interests. L.J. is co-founder, co-owner, and employee of Antaros Medical AB, which received payment for the practical conduct of the PET study. Otherwise, L.J. declares no competing interests. I.V. is an employee of Uppsala University Hospital, which received payment for the practical conduct of the PET study. I.V. declares no competing interests. W.B.S. was the principal investigator of the study conducted at the MDNOCCR Alliance for Multispecialty Research (AMR)/DBA NOCCR (New Orleans Center for Clinical Research), Knoxville, Tennessee, and received payment for the practical conduct of the study. No payment was received for the preparation of this manuscript. No other potential conflicts of interest relevant to this article were reported., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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27. Imaging of the Glucagon Receptor in Subjects with Type 2 Diabetes.
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Eriksson O, Velikyan I, Haack T, Bossart M, Laitinen I, Larsen PJ, Berglund JE, Antoni G, Johansson L, Pierrou S, Tillner J, and Wagner M
- Subjects
- Adult, Body Weight, Female, Gallium Radioisotopes, Humans, Kidney metabolism, Male, Positron Emission Tomography Computed Tomography, Radiometry, Tissue Distribution, Diabetes Mellitus, Type 2 diagnostic imaging, Diabetes Mellitus, Type 2 metabolism, Receptors, Glucagon metabolism
- Abstract
Despite the importance of the glucagon receptor (GCGR) in disease and in pharmaceutical drug development, there is a lack of specific and sensitive biomarkers of its activation in humans. The PET radioligand
68 Ga-DO3A-VS-Tuna-2 (68 Ga-Tuna-2) was developed to yield a noninvasive imaging marker for GCGR target distribution and drug target engagement in humans. Methods: The biodistribution and dosimetry of68 Ga-Tuna-2 was assessed by PET/CT in 13 individuals with type 2 diabetes as part of a clinical study assessing the occupancy of the dual GCGR/glucagon like peptide-1 receptor agonist SAR425899. Binding of68 Ga-Tuna-2 in liver and reference tissues was evaluated and correlated to biometrics (e.g., weight or body mass index) or other biomarkers (e.g., plasma glucagon levels). Results:68 Ga-Tuna-2 binding was seen primarily in the liver, which is in line with the strong expression of GCGR on hepatocytes. The kidneys demonstrated high excretion-related retention, whereas all other tissue demonstrated rapid washout. The SUV55 min (SUV during the last 10-min time frame, 50-60 min after administration) uptake endpoint was sensitive to endogenous levels of glucagon.68 Ga-Tuna-2 exhibited a safe dosimetry profile and no adverse events after intravenous administration. Conclusion:68 Ga-Tuna-2 can be used for safe and accurate assessment of the GCGR in human. It may serve as an important tool in understanding the in vivo pharmacology of novel drugs engaging the GCGR., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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28. Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography.
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Eriksson O, Velikyan I, Haack T, Bossart M, Evers A, Lorenz K, Laitinen I, Larsen PJ, Plettenburg O, Johansson L, Pierrou S, and Wagner M
- Subjects
- Animals, Female, Humans, Hypoglycemic Agents, Male, Radiochemistry, Rats, Signal Transduction physiology, Gastric Inhibitory Polypeptide metabolism, Glucose metabolism, Positron-Emission Tomography methods, Receptors, Gastrointestinal Hormone metabolism
- Abstract
Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with
68 Ga. The resulting PET tracer [68 Ga]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [68 Ga]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [68 Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [68 Ga]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [68 Ga]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [68 Ga]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy., (© 2021 by the American Diabetes Association.)- Published
- 2021
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29. Automated GMP-Compliant Production of [ 68 Ga]Ga-DO3A-Tuna-2 for PET Microdosing Studies of the Glucagon Receptor in Humans.
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Wagner M, Doverfjord JG, Tillner J, Antoni G, Haack T, Bossart M, Laitinen I, Johansson L, Pierrou S, Eriksson O, and Velikyan I
- Abstract
Introduction : [
68 Ga]Ga-DO3A-VS-Cys40 -Tuna-2 (previously published as [68 Ga]Ga-DO3A-VS-Cys40 -S01-GCG) has shown high-affinity specific binding to the glucagon receptor (GCGR) in vitro and in vivo in rats and non-human primates in our previous studies, confirming the suitability of the tracer for drug development applications in humans. The manufacturing process of [68 Ga]Ga-DO3A-VS-Cys40 -Tuna-2 was automated for clinical use to meet the radiation safety and good manufacturing practice (GMP) requirements. Methods: The automated synthesis platform (Modular-Lab PharmTrace, Eckert & Ziegler, Eurotope, Germany), disposable cassettes for68 Ga-labeling, and pharmaceutical-grade68 Ge/68 Ga generator (GalliaPharm® ) used in the study were purchased from Eckert & Ziegler. The parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration, and pH, as well as product purification step, were investigated and optimized. Process optimization was conducted with regard to product quality and quantity, as well as process reproducibility. The active pharmaceutical ingredient starting material DO3A-VS-Cys40 -Tuna-2 (GMP-grade) was provided by Sanofi Aventis. Results: The reproducible and GMP-compliant automated production of [68 Ga]Ga-DO3A-VS-Cys40 -Tuna-2 with on-line documentation was developed. The non-decay-corrected radiochemical yield was 45.2 ± 2.5% ( n = 3, process validation) at the end of the synthesis with a labeling synthesis duration of 38 min and a quality controlincluding release procedure of 20 min. The radiochemical purity of the product was 98.9 ± 0.6% ( n = 17) with the total amount of the peptide in the preparation of 48 ± 2 µg ( n = 3, process validation). Radionuclidic purity, sterility, endotoxin content, residual solvent content, and sterile filter integrity tests met the acceptance criteria. The product was stable at ambient temperature for at least 2 h. Conclusion: The fully automated GMP-compliant manufacturing process was developed and thoroughly validated. The resulting [68 Ga]Ga-DO3A-VS-Cys40 -Tuna-2 was used in a clinical study for accurate quantification of GCGR occupancy by a dual anti-diabetic drug in vivo in humans.- Published
- 2020
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30. Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates.
- Author
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Eriksson O, Velikyan I, Haack T, Bossart M, Evers A, Laitinen I, Larsen PJ, Plettenburg O, Takano A, Halldin C, Antoni G, Johansson L, Pierrou S, and Wagner M
- Subjects
- Animals, Female, Glucagon-Like Peptide-1 Receptor metabolism, Humans, Ligands, Liver diagnostic imaging, Liver metabolism, Macaca fascicularis, Male, Peptides metabolism, Positron Emission Tomography Computed Tomography, Protein Binding, Radiometry, Rats, Rats, Sprague-Dawley, Reproducibility of Results, Spleen diagnostic imaging, Biomarkers metabolism, Receptors, Glucagon metabolism
- Abstract
The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [
68 Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [68 Ga]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 µg/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [68 Ga]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [68 Ga]Ga-DO3A-S01-GCG binding in liver. [68 Ga]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2 µg/kg. In vivo Kd for [68 Ga]Ga-DO3A-S01-GCG corresponded to 0.7 µg/kg, which indicates high potency. The test-retest reproducibility for [68 Ga]Ga-DO3A-S01-GCG binding in liver was 5.7 ± 7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5 ± 9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [68 Ga]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [68 Ga]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.- Published
- 2019
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31. First-in-class positron emission tomography tracer for the glucagon receptor.
- Author
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Velikyan I, Haack T, Bossart M, Evers A, Laitinen I, Larsen P, Plettenburg O, Johansson L, Pierrou S, Wagner M, and Eriksson O
- Abstract
The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement., Methods: Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [
68 Ga]Ga-DO3A-S01-GCG and [68 Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat., Results: [68 Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68 Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals., Conclusion: [68 Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans.- Published
- 2019
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32. Team Players or Opponents: Coadministration of Selective Glucagon and GLP-1 Receptor Agonists in Obese Diabetic Monkeys.
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Elvert R, Bossart M, Herling AW, Weiss T, Zhang B, Kannt A, Wagner M, Haack T, Evers A, Dudda A, Keil S, Lorenz M, Lorenz K, Riz M, Hennerici W, and Larsen PJ
- Subjects
- Animals, Bariatric Surgery, Blood Glucose metabolism, Diabetes Mellitus metabolism, Diabetes Mellitus, Type 2 surgery, Drug Therapy, Combination, Energy Metabolism drug effects, Macaca fascicularis, Mice, Obesity surgery, Blood Glucose drug effects, Body Weight drug effects, Diabetes Mellitus, Type 2 metabolism, Eating drug effects, Glucagon-Like Peptide-1 Receptor agonists, Obesity metabolism, Receptors, Glucagon agonists
- Abstract
We assessed the therapeutic contribution of the individual components of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonists alone and in combination upon energy homeostasis and glycemic control in diet-induced obese, diabetic nonhuman primates. The pharmacological active dose ranges of selective agonists were established through a dose-finding study, followed by a 6-week chronic study. Repeated subcutaneous administration of a selective GCGR agonist (30 µg/kg once daily) did not affect food intake or body weight, whereas the selective GLP-1R agonist (3 µg/kg once daily) alone decreased energy intake by 18% and body weight by 3.8% ± 0.9%. Combination of both agonists reduced significantly cumulative food intake by 27% and body weight by 6.6% ± 0.9%. Fasting plasma glucose (FPG) was improved by GLP-1R agonist (baseline vs end of study, 176.7 ± 34.0 vs 115.9 ± 16.1 mg/dL). In contrast, groups exposed to GCGR agonist experienced nonsignificant elevations of FPG. More accurate assessment of therapeutic interventions on glucose homeostasis was tested by an IV glucose tolerance test. Glucose excursion was significantly elevated by chronic GCGR agonist administration, whereas it was significantly decreased in GLP-1R agonist-treated monkeys. In the combination group, a nonsignificant increase of glucose excursion was seen, concomitantly with significantly increased insulin secretion. We conclude that chronic glucagon agonism does not affect energy homeostasis in nonhuman primates. In combination with GLP-1R agonism, glucagon agonism synergistically enhances negative energy balance with resulting larger body weight loss. However, adding GCGR to GLP-1R agonism diminishes glycemic control in diabetic monkeys. Therefore, long-term therapeutic implications of using GLP-1R/GCGR coagonists for weight management in diabetes warrants further scrutiny.
- Published
- 2018
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33. Compliance, analgesic use and side-effect protection within a German cohort of the TEAM trial.
- Author
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Bossart M, Becker M, Hadji P, Kieback DG, and Hasenburg A
- Subjects
- Androstadienes administration & dosage, Antineoplastic Agents, Hormonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Disease-Free Survival, Drug Interactions, Female, Fractures, Bone chemically induced, Humans, Middle Aged, Retrospective Studies, Tamoxifen administration & dosage, Tamoxifen adverse effects, Analgesics administration & dosage, Androstadienes adverse effects, Antineoplastic Agents, Hormonal adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Medication Adherence
- Abstract
Background: Compliance is an essential aspect for the success of any medical intervention. Adverse events (AEs) contribute significantly to non-compliance with endocrine treatment. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial compared five years of adjuvant exemestane therapy with the sequence of tamoxifen followed by exemestane., Patients and Methods: A retrospective analysis of the German cohort of TEAM was conducted to determine the effects of prior tamoxifen on the tolerability profile of exemestane in both treatment arms., Results: Fracture incidence was significantly higher during the first 30 months of exemestane versus the 30 months of exemestane following tamoxifen for 2-3 years; however, the incidence of AEs was not significantly different. With regard to compliance, the use of analgesics did not influence overall or disease-free survival (DFS) nor the incidence of distant recurrence in both treatment groups., Conclusion: Tamoxifen has a boneprotective effect when applied before exemestane treatment. Intake of analgesics (or pain medication) does not influence compliance or treatment outcome.
- Published
- 2012
34. Studies on the synthesis of apoptolidin A. 1. Synthesis of the C(1)-C(11) fragment.
- Author
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Handa M, Scheidt KA, Bossart M, Zheng N, and Roush WR
- Subjects
- Alkynes chemical synthesis, Alkynes chemistry, Macrolides chemistry, Molecular Structure, Propanols chemical synthesis, Propanols chemistry, Pyrones chemistry, Thioglycosides chemical synthesis, Thioglycosides chemistry, Carbon chemistry, Macrolides chemical synthesis, Pyrones chemical synthesis
- Abstract
A synthesis of the C(1)-C(11) fragment of apoptolidin A has been accomplished by a convergent route involving the stereoselective glycosidation of 9 and the Suzuki cross-coupling reaction of bromodienoate 7 and the vinylborane generated via chemoselective hydroboration of diyne 6 with diisopinocampheylborane.
- Published
- 2008
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35. Stereoselective radical aryl migration from silicon to carbon.
- Author
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Amrein S, Bossart M, Vasella T, and Studer A
- Subjects
- Alcohols chemical synthesis, Alkylation, Carbon, Stereoisomerism, Alcohols chemistry, Ethers chemistry, Phenols chemistry, Silicon chemistry
- Abstract
Highly diastereoselective radical 1,5 phenyl migration reactions from silicon in diarylsilyl ethers to various C-centered radicals to form the corresponding 3-phenylated alcohols are described. Functionalized aryl groups can also be transferred. The effect of the variation of the attacking radical on the aryl transfer reaction is discussed. Best results are obtained for the phenyl migration to nucleophilic secondary alkyl radicals, where high yields (up to 81%) and high selectivities (up to 95% ds) have been obtained. The mechanism of the process is discussed and a model to explain the stereochemical outcome of the reaction is presented. Finally, stereoselective 1,4 aryl migration reactions from Si to C, including a new method for the alpha-arylation of esters, are presented.
- Published
- 2000
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36. Calcification in chronically-implanted blood pumps: experimental results and review of the literature.
- Author
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Turner SA, Bossart MI, Milam JD, Fuqua JM Jr, Igo SR, McGee MG, and Frazier OH
- Abstract
Blood compatibility is a major objective in the development of long-term, implantable circulatory assist (left ventricular assist devices) and replacement (total artificial heart) devices. An important problem in experimental studies in animals has been the propensity for calcification to occur at the blood/material interface. Presented is a summary of our experience (27 studies) with blood pump calcification and a review of the current literature regarding this complication.
- Published
- 1982
37. ULTRASTRUCTURAL ANALYSES OF STONE HEART SYNDROME AT ONSET AND SIX DAYS LATER FOLLOWING TOTAL SUPPORT OF THE CIRCULATION WITH A PARTIAL ARTIFICIAL HEART OR LEFT VENTRICULAR ASSIST DEVICE (ALVAD).
- Author
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Sturm JT, Bossart MI, Holub DA, Milam JD, and Norman JC
- Abstract
Ischemic myocardial contracture developed in a 21-year-old man following aortic and mitral valve replacement. The patient's circulation was supported totally for 6 days with an abdominal left ventricular assist device (ALVAD). Cardiac allografting was then undertaken. Samples of myocardium taken at the original operation and 6 days later at transplantation were analyzed ultrastructurally. At the onset of ischemic cortracture, left ventricular abnormalities included hypercontraction of myofibrils, loss of normal A-band and Z-band patterns, mitochondrial swelling with fusion of cristae, interfibrillar edema and glycogen depletion. Capillaries demonstrated swelling of endothelial cells and basement membrane disruption. Six days later, ultrastructural morphology showed further degeneration. The myofibrils remained hypercontracted, but were more fragmented. Degenerative changes in mitochondria were more advanced and calcium deposition in cristae was present. No glycogen was seen. The right ventricular myocardium exhibited significantly fewer ultrastructural abnormalities. The principal right ventricular changes were endothelial swelling and basement membrane disruption. Glycogen granules were present. Ischemic contracture affects the left ventricle more than the right, and the morphology becomes more abnormal with time. To our knowledge, this is the first instance wherein morphologic progressions of the ultrastructural alterations of ischemic contracture have been documented.
- Published
- 1979
38. Restrictive cardiomyopathy with kappa light chain deposits in myocardium as a complication of multiple myeloma. Histochemical and electron microscopic observations.
- Author
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McAllister HA Jr, Seger J, Bossart M, and Ferrans VJ
- Subjects
- Aged, Aged, 80 and over, Amyloidosis metabolism, Amyloidosis pathology, Cardiomyopathy, Restrictive pathology, Female, Humans, Multiple Myeloma complications, Multiple Myeloma ultrastructure, Myocardium ultrastructure, Cardiomyopathy, Restrictive metabolism, Immunoglobulin kappa-Chains analysis, Multiple Myeloma analysis, Myocardium analysis
- Abstract
kappa Light chain deposits occurring in myocardium as a complication of multiple myeloma were identified ultrastructurally and immunohistochemically in a right ventricular endomyocardial biopsy specimen from a patient who presented with clinical and hemodynamic findings of restrictive cardiomyopathy. These deposits were not evident on routine histopathologic examination; they were Congo red-negative and gave a positive immunoperoxidase reaction for kappa light chains and a negative reaction for lambda chains. They consisted of amorphous, electron-dense granules that formed discontinuous layers adjacent to the plasma membranes of cardiac myocytes, arteriolar endothelial and smooth-muscle cells, and neural elements. These observations underscore the need for critical study of endomyocardial biopsy specimens, using electron microscopy and immunohistochemical reagents, for the precise identification of protein components in tissue deposits in patients suspected of having cardiac amyloidosis or related disorders.
- Published
- 1988
39. Persistent atrial paralysis: Case report with light microscopy and ultrastructural analyses.
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Turner SA, Bossart MI, Klima T, Leachman RD, Cooley DA, and Norman JC
- Abstract
Persistent atrial paralysis in a patient with complete heart block and mild mitral insufficiency is presented. Left atrial specimens obtained during implantation of a permanent cardiac pulse generator showed evidence of hypertrophy and fibrosis; subcellular degenerative changes ranged from near normal to irreversible, thus suggesting that atrial paralysis may be due to the replacement of normal atrial muscle with nonfunctional fibrous tissue.
- Published
- 1980
40. Rare primary sarcomas of the heart.
- Author
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Klima T, Milam JD, Bossart MI, and Cooley DA
- Subjects
- Adult, Cell Nucleus ultrastructure, Cytoplasm ultrastructure, Female, Fibrosarcoma pathology, Fibrosarcoma ultrastructure, Heart Neoplasms ultrastructure, Humans, Leiomyosarcoma pathology, Leiomyosarcoma ultrastructure, Male, Microscopy, Electron, Retrospective Studies, Sarcoma ultrastructure, Heart Neoplasms pathology, Sarcoma pathology
- Abstract
Three patients with primary malignant cardiac neoplasms are described. All tumors were intracavitary myxomatous masses of the left atrium. Preoperative clinical diagnostic techniques did not indicate malignancy, but suggested mitral stenosis, cor triatriatum, and cardiac myxoma. Grossly, the tumors were sessile rather than pedunculated, and they invaded the underlying structures. Microscopically, although the tumors resembled benign cardiac myxomas, they exhibited mitotic activity and areas of necroses. Ultrastructural examination revealed a spectrum of differentiated mesenchymal cells that lacked the maturation features of cardiac myxoma cells. These gross, microscopic, and ultrastructural features, which suggested the tumors' malignant potential, should help in the early recognition and management of similar tumors.
- Published
- 1986
41. Chloroquine-induced cardiomyopathy.
- Author
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McAllister HA Jr, Ferrans VJ, Hall RJ, Strickman NE, and Bossart MI
- Subjects
- Adult, Aged, Cardiomegaly pathology, Chloroquine adverse effects, Female, Humans, Microscopy, Electron, Muscles pathology, Myocardium pathology, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Cardiomegaly chemically induced, Chloroquine analogs & derivatives, Lupus Erythematosus, Systemic drug therapy
- Abstract
Biventricular hypertrophy and failure developed in two patients during treatment of systemic lupus erythematosus with chloroquine phosphate. In both patients, morphologic analysis of the myocardium, obtained by a right ventricular endomyocardial biopsy in one patient and at autopsy in the other, revealed accumulations of electron-dense concentric and parallel lamellae and curvilinear bodies within cardiac myocytes. These deposits were similar to those reported in chloroquine-induced skeletal myopathy and were considered to represent evidence of chloroquine-induced cardiotoxicity rather than a cardiovascular manifestation of the underlying disease. Clinical awareness and an endomyocardial biopsy specimen are necessary for the appropriate diagnosis of chloroquine-induced cardiomyopathy.
- Published
- 1987
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