@article{BuschBuschScholzetal.2016, author = {Busch, Albert and Busch, Martin and Scholz, Claus-J{\"u}rgen and Kellersmann, Richard and Otto, Christoph and Chernogubova, Ekaterina and Maegdefessel, Lars and Zernecke, Alma and Lorenz, Udo}, title = {Aneurysm miRNA Signature Differs, Depending on Disease Localization and Morphology}, series = {International Journal of Molecular Science}, volume = {17}, journal = {International Journal of Molecular Science}, number = {1}, issn = {International Journal of Molecular Science}, doi = {10.3390/ijms17010081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146422}, pages = {81}, year = {2016}, abstract = {Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.}, language = {en} } @article{BuschHoffjanBergmannetal.2016, author = {Busch, Albert and Hoffjan, Sabine and Bergmann, Frauke and Hartung, Birgit and Jung, Helena and Hanel, Daniela and Tzschach, Andeas and Kadar, Janos and von Kodolitsch, Yskert and Germer, Christoph-Thomas and Trobisch, Heiner and Strasser, Erwin and Wildenauer, Ren{\´e}}, title = {Vascular type Ehlers-Danlos syndrome is associated with platelet dysfunction and low vitamin D serum concentration}, series = {Orphanet Journal of Rare Diseases}, volume = {11}, journal = {Orphanet Journal of Rare Diseases}, number = {111}, doi = {10.1186/s13023-016-0491-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147757}, year = {2016}, abstract = {Background The vascular type represents a very rare, yet the clinically most fatal entity of Ehlers-Danlos syndrome (EDS). Patients are often admitted due to arterial bleedings and the friable tissue and the altered coagulation contribute to the challenge in treatment strategies. Until now there is little information about clotting characteristics that might influence hemostasis decisively and eventually worsen emergency situations. Results 22 vascular type EDS patients were studied for hemoglobin, platelet volume and count, Quick and activated partial thromboplastin time, fibrinogen, factor XIII, von Willebrand disease, vitamin D and platelet aggregation by modern standard laboratory methods. Results show a high prevalence of over 50 \% for platelet aggregation disorders in vascular type EDS patients, especially for collagen and epinephrine induced tests, whereas the plasmatic cascade did not show any alterations. Additionally, more than half of the tested subjects showed low vitamin D serum levels, which might additionally affect vascular wall integrity. Conclusion The presented data underline the importance of detailed laboratory screening methods in vascular type EDS patients in order to allow for targeted application of platelet-interacting substances that might be of decisive benefit in the emergency setting.}, language = {en} } @phdthesis{Busch2011, author = {Busch, Albert Franz Jakob}, title = {Pr{\"a}lamin A und Progerie - verursachende Mutanten im Kontext nukle{\"a}rer Transportprozesse, der Kernlaminaintegrit{\"a}t und CaaX - Prozessierung}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71662}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Zur Charakterisierung nukle{\"a}rer Proteinexportvorg{\"a}nge wurde in dieser Arbeit zum ersten Mal ein System heterodimerisierender Fusionsproteine auf Basis des kommerziell verf{\"u}gbaren ARGENT™ Regulated Heterodimerization Kit 2.0 von ARIAD verwendet. Die Expressionsvektoren wurden so ver{\"a}ndert, dass ein CRM1 - vermittelter Proteinexport {\"u}ber die Zellkernh{\"u}lle mittels Fluoreszenzmikroskopie in HeLa - Zellen und humanen Fibroblasten live oder nach Fixation dargestellt werden konnte. Der Export folgte in HeLa - zellen einer exponentiellen Kinetik, FN/C - Bestimmungen zwischen Wildtyp - und RD (Restriktive Dermopathie) - Fibroblasten ergaben keinen Unterschied im Proteinexport. Eine Inhibition der initialen CaaX - Prozessierung von trunkiertem Pr{\"a}lamin A (head/rod) durch Mevinolin ergab keine signifikante Akkumulationsver{\"a}nderung des trunkierten Pr{\"a}lamins im Zellkern. Erg{\"a}nzende subzellul{\"a}re Lokalisationsstudien unter Zuhilfenahme ausgew{\"a}hlter CaaX - Mutanten, um die gezeigte Unabh{\"a}ngigkeit der CaaX - Prozessierung zu verifizieren, stehen noch aus. FRAP - Untersuchungen in HeLa - Zellen zeigten f{\"u}r die episomal exprimierten trunkierten Fusionsproteine DsRed - Pr{\"a}lamin A Δ50 und DsRed - Pr{\"a}lamin A Δ90 keinen Unterschied in der lateralen Mobilit{\"a}t. Gegen{\"u}ber dem Wildtyp - DsRed - Pr{\"a}lamin A ist die Beweglichkeit jedoch signifikant reduziert. Bei der Applikation von thermischem Stress (37°C - 51°C) auf Pr{\"a}lamin A, Pr{\"a}lamin A Δ50 oder Pr{\"a}lamin A Δ90 exprimierende HeLa - Zellen, konnte keine Ver{\"a}nderung hinsichtlich der subzellul{\"a}ren Verteilung des zus{\"a}tzlich koexprimierten Markerproteins GFP - ß - Galaktosidase im Sinne nukle{\"a}ren Schrankenst{\"o}rung festgestellt werden. Somit scheint die Kernh{\"u}lle trotz der zu Zellkerndysmorphien und KPK - Fehllokalisationen f{\"u}hrenden Pr{\"a}lamin A - Mutanten hinsichtlich ihrer Schrankenfunktion intakt zu bleiben.}, subject = {Progeria infantilum}, language = {de} } @phdthesis{Busch2021, author = {Busch, Albert Franz Jakob}, title = {Modification of angiogenesis to abrogate abdominal aortic aneurysm growth}, doi = {10.25972/OPUS-24135}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241356}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Introduction: Abdominal aortic aneurysm (AAA) is a pathological saccular enlargement most often of the infrarenal aorta. Eventual rupture is fatal, making preemptive surgical therapy upon a diameter threshold of >50mm the treatment of choice. The pathophysiology, especially the initial trigger aortic remodeling is still largely unknown. However, some characteristic features involved in aneurysm growth have been established, such as medial angiogenesis, low-grade inflammation, vascular smooth muscle cell (VSMC) phenotype switch, extracellular remodeling, altered hemodynamics and an eventual humoral immune answer. Currently, no medical treatment options are available. RNA therapeutics and drug repurposing offer new possibilities to overcome this shortage. Using such to target angiogenesis in the aneurysm wall and investigate their potential mechanisms is the aim of this thesis. Material and Methods: We test our hypothesis by targeting the long non-coding RNA H19 and re-use the anti-cancer drug Lenvatinib in two murine inducible AAA models and one preclinical large animal model in the LDLR-/- pig. Furthermore, a H19-/- mouse is included to verify the results. AAA and control samples from a human biobank along with a primary human cell culture are used to verify results ex vivo by qPCR, WesternBlot, live cell imaging, histo- and immunohistochemistry along with gene array analysis, RNA knockdown, pull-down- and promotor assays. Results: H19 is significantly upregulated in AAA mice models and its knockdown limited aneurysm growth. It is well known that H19 interacts with several transcription factors. We found that cytoplasmic interaction between H19 and hypoxia-inducible factor 1-alpha (HIF1α) increased apoptosis in cultured SMCs associated with sequential p53 stabilization. In contrast, the knockdown of H19 was associated with markedly decreased apoptotic cell rates. Our data underline that HIF1α was essential in mediating the pro-apoptotic effects of H19. Secondly, Lenvatinib was applied both systemically and locally by endovascular means in mice with an established AAA. The drug significantly halted aneurysm growth and array analysis revealed myosin heavy chain 11 (MYH11) as the most differentially regulated target. This was shown to be up regulated after Lenvatinib treatment of primary AAA smooth muscle cells suggesting a salvage mechanism to obtain a contractile phenotype based on gene expression and immunohistochemistry. The same results were shown upon a local endovascular Lenvatinib-coated balloon angioplasty in the established aneurysmatic lesion of a novel atherosclerotic LDLR-/- Yucatan minipig model. Decreased phosphorylation of extracellular-signal regulated kinases 1-2 (ERK1-2) is the downstream effect of Lenvatinib-specific blockage of the vascular endothelial growth factor receptor (VEGFR2). Conclusion: Taking into account the heterogeneity of the disease, inhibition of VSMC phenotype switch, extracellular remodeling and angiogenesis seem promising targets in some if not all AAA patients. Together with surveillance and surgical therapy, these new non-invasive treatment strategies would allow for a more personalized approach to treat this disease.}, subject = {Aortenaneurysma}, language = {en} } @article{BuschTschernitzThurneretal.2013, author = {Busch, Albert and Tschernitz, Sebastian and Thurner, Anette and Kellersmann, Richard and Lorenz, Udo}, title = {Fatal Paraneoplastic Embolisms in Both Circulations in a Patient with Poorly Differentiated Neuroendocrine Tumour}, series = {Case Reports in Vascular Medicine}, journal = {Case Reports in Vascular Medicine}, doi = {10.1155/2013/739427}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97335}, year = {2013}, abstract = {Arterial embolism with lower limb ischemia is a rare manifestation of paraneoplastic hypercoagulability in cancer patients. We report a unique case of fatal thromboembolism involving both circulations associated with a poorly differentiated neuroendocrine tumor of the lung with rapid progress despite high doses of unfractioned heparin and review the current literature on anticoagulative regimen in tumour patients.}, language = {en} } @article{BuschLorenzTiurbeetal.2013, author = {Busch, Albert and Lorenz, Udo and Tiurbe, George Christian and B{\"u}hler, Christoph and Kellersmann, Richard}, title = {Femoral vein obturator bypass revascularization in groin infectious bleeding: two case reports and review of the literature}, series = {Journal of Medical Case Reports}, journal = {Journal of Medical Case Reports}, doi = {10.1186/1752-1947-7-75}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-95901}, year = {2013}, abstract = {Introduction Groin infections resulting in arterial bleeding due to bacterial vessel destruction are a severe challenge in vascular surgery. Patients with them most often present as emergencies and therefore need individualized reconstruction solutions. Case presentation Case 1 is a 67-year-old man with infectious bleeding after an autologous reconstruction of the femoral bifurcation with greater saphenous vein due to infection of a bovine pericard patch after thrombendarterectomy. Case 2 is a 35-year-old male drug addict and had severe femoral bleeding and infection after repeated intravenous and intra-arterial substance abuse. Both patients were treated with an autologous obturator bypass of the superficial femoral vein. We review the current literature and highlight our therapeutic concept of this clinical entity. Conclusions Treatment should include systemic antibiotic medication, surgical control of the infectious site, revascularization and soft tissue repair. An extra-anatomical obturator bypass with autologous superficial femoral vein should be considered as the safest revascularization procedure in infections caused by highly pathogenic bacteria.}, language = {en} }