@article{BeykanDamEberleinetal.2016,
  author    = {Beykan, Seval and Dam, Jan S. and Eberlein, Uta and Kaufmann, Jens and Kj{\ae}rgaard, Benedict and J{\o}dal, Lars and Bouterfa, Hakim and Bejot, Romain and Lassmann, Michael and Jensen, Svend Borup},
  title     = {\(^{177}\)Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model},
  series = {EJNMMI Research},
  volume    = {6},
  journal   = {EJNMMI Research},
  number    = {50},
  doi       = {10.1186/s13550-016-0204-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146888},
  year      = {2016},
  abstract  = {Background \(^{177}\)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of \(^{177}\)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications. Results \(^{177}\)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 \% in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 \% of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq \(^{177}\)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels. Conclusions The \(^{177}\)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.},
  language  = {en}
}
@phdthesis{Klammert2006,
  author    = {Klammert, Uwe},
  title     = {Evaluation einer neuen BMP-2 Mutante mit antagonistischer Aktivit{\"a}t - Eine in vivo Studie in Ratten -},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-21052},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2006},
  abstract  = {Bone Morphogenetic Proteins sind in eine Vielzahl von physiologischen Wachstums-und Entwicklungsvorg{\"a}ngen involviert und an verschiedenen unphysiologischen bzw. pathologischen Prozessen insbesondere im Bereich des Skelettsystems beteiligt. Ein gezielter Eingriff in die BMP-Signalkaskade k{\"o}nnte denkbare therapeutische Ans{\"a}tze liefern. In der vorliegenden experimentellen Arbeit wurde die Wirksamkeit eines neuartigen Antagonisten am BMP-Rezeptor, der BMP-2-Doppelmutante A34D/D53A, in vivo evaluiert. Hierzu diente ein heterotopes Implantationsmodell (Skelettmuskulatur) sowie ein orthotopes Defektmodell (Kalottentrepanationsdefekt) bei Ratten. F{\"u}r die eingesetzten Proteine wurde equines EXKK als Tr{\"a}ger- und Freisetzungssystem verwendet. Im heterotopen Implantatlager diente zugesetztes BMP-2 in einer gut evaluierten Dosis als zu unterdr{\"u}ckender osteogener Stimulus. Im orthotopen Defektmodell (Defekt nicht kritischer Gr{\"o}ße) sollte der Einfluss auf die physiologischerweise ablaufende kn{\"o}cherne Defektregeneration ohne weiteren Zusatz von Morphogenen untersucht werden. Bez{\"u}glich der heterotopen Implantation konnte eine signifikante, dosisabh{\"a}ngige Hemmung der BMP-2-induzierten Osteoneogenese festgestellt werden. Bei dem orthotopen Implantationsmodell war keine Beeinflussung der physiologischen kn{\"o}chernen Defektregeneration zu verzeichnen. Die Inhibierung eines einzelnen definierten osteogenen Reizes durch BMP-Rezeptorantagonismus konnte somit gut in vivo belegt werden. Im Rahmen der komplexeren physiologischen orthotopen Knochenregeneration mit vermutlich einer Vielzahl beteiligter Wachstumsfaktoren scheint hingegen die Hemmung eines m{\"o}glichen Teilaspektes der Osteogenese keine ausschlaggebende Rolle zu spielen.},
  language  = {de}
}
@article{KlammertMuellerHellmannetal.2015,
  author    = {Klammert, Uwe and M{\"u}ller, Thomas D. and Hellmann, Tina V. and Wuerzler, Kristian K. and Kotzsch, Alexander and Schliermann, Anna and Schmitz, Werner and Kuebler, Alexander C. and Sebald, Walter and Nickel, Joachim},
  title     = {GDF-5 can act as a context-dependent BMP-2 antagonist},
  series = {BMC Biology},
  volume    = {13},
  journal   = {BMC Biology},
  number    = {77},
  doi       = {10.1186/s12915-015-0183-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125550},
  year      = {2015},
  abstract  = {Background Bone morphogenetic protein (BMP)-2 and growth and differentiation factor (GDF)-5 are two related transforming growth factor (TGF)-β family members with important functions in embryonic development and tissue homeostasis. BMP-2 is best known for its osteoinductive properties whereas GDF-5—as evident from its alternative name, cartilage derived morphogenetic protein 1—plays an important role in the formation of cartilage. In spite of these differences both factors signal by binding to the same subset of BMP receptors, raising the question how these different functionalities are generated. The largest difference in receptor binding is observed in the interaction with the type I receptor BMPR-IA. GDF-5, in contrast to BMP-2, shows preferential binding to the isoform BMPR-IB, which is abrogated by a single amino acid (A57R) substitution. The resulting variant, GDF-5 R57A, represents a "BMP-2 mimic" with respect to BMP receptor binding. In this study we thus wanted to analyze whether the two growth factors can induce distinct signals via an identically composed receptor. Results Unexpectedly and dependent on the cellular context, GDF-5 R57A showed clear differences in its activity compared to BMP-2. In ATDC-5 cells, both ligands induced alkaline phosphatase (ALP) expression with similar potency. But in C2C12 cells, the BMP-2 mimic GDF-5 R57A (and also wild-type GDF-5) clearly antagonized BMP-2-mediated ALP expression, despite signaling in both cell lines occurring solely via BMPR-IA. The BMP-2- antagonizing properties of GDF-5 and GDF-5 R57A could also be observed in vivo when implanting BMP-2 and either one of the two GDF-5 ligands simultaneously at heterotopic sites. Conclusions Although comparison of the crystal structures of the GDF-5 R57A:BMPR-IAEC- and BMP-2:BMPR-IAEC complex revealed small ligand-specific differences, these cannot account for the different signaling characteristics because the complexes seem identical in both differently reacting cell lines. We thus predict an additional component, most likely a not yet identified GDF-5-specific co-receptor, which alters the output of the signaling complexes. Hence the presence or absence of this component then switches GDF-5′s signaling capabilities to act either similar to BMP-2 or as a BMP-2 antagonist. These findings might shed new light on the role of GDF-5, e.g., in cartilage maintenance and/or limb development in that it might act as an inhibitor of signaling events initiated by other BMPs.},
  language  = {en}
}
@article{PerkovicAgarwalFiorettoetal.2016,
  author    = {Perkovic, Vlado and Agarwal, Rajiv and Fioretto, Paola and Hemmelgarn, Brenda R. and Levin, Adeera and Thomas, Merlin C. and Wanner, Christoph and Kasiske, Bertram L. and Wheeler, David C. and Groop, Per-Henrik},
  title     = {Management of patients with diabetes and CKD: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) controversies conference},
  series = {Kidney International},
  volume    = {90},
  journal   = {Kidney International},
  number    = {6},
  doi       = {10.1016/j.kint.2016.09.010},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186599},
  pages     = {1175-1183},
  year      = {2016},
  abstract  = {The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.},
  language  = {en}
}