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57. Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells

Author

Wiese M, Hamdan FH, Kubiak K, Diederichs C, Gielen GH, Nussbaumer G, Carcaboso AM, Hulleman E, Johnsen SA, and Kramm CM

Abstract

Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal (BET) protein BRD4, and leads to the reprogramming of the enhancer landscape contributing to the activation of DIPG super enhancer-driven oncogenes. The activity of the acetyltransferase CREB-binding protein (CBP) is enhanced by BRD4 and associated with acetylation of nucleosomes at super enhancers (SE). In addition, CBP contributes to transcriptional activation through its function as a scaffold and protein bridge. Monotherapy with either a CBP (ICG-001) or BET inhibitor (JQ1) led to the reduction of tumor-related characteristics. Interestingly, combined treatment induced strong cytotoxic effects in H3.3K27M-mutated DIPG cell lines. RNA sequencing and chromatin immunoprecipitation revealed that these effects were caused by the inactivation of DIPG SE-controlled tumor-related genes. However, single treatment with ICG-001 or JQ1, respectively, led to activation of a subgroup of detrimental super enhancers. Combinatorial treatment reversed the inadvertent activation of these super enhancers and rescued the effect of ICG-001 and JQ1 single treatment on enhancer-driven oncogenes in H3K27M-mutated DIPG, but not in H3 wild-type pedHGG cells. In conclusion, combinatorial treatment with CBP and BET inhibitors is highly efficient in H3K27M-mutant DIPG due to reversal of inadvertent activation of detrimental SE programs in comparison with monotherapy.

Published
2020

58. Halogenation‐Guided Chemical Screening Provides Insight into Tjipanazole Biosynthesis by the Cyanobacterium Fischerella ambigua

Author

Chilczuk, T., Schäberle, T.F., Vahdati, S., Mettal, U., El Omari, M., Enke, H., Wiese, M., König, G.M., Niedermeyer, T.H.J., and Publica

Abstract

Halogenated natural products (HNPs) show a wide range of interesting biological activities. Chemistry‐guided screening with a software tool dedicated to identifying halogenated compounds in HPLC‐MS data indicated the presence of several uncharacterised HNPs in an extract of the cyanobacterium Fischerella ambigua (Näg.) Gomont 108b. Three new natural products, tjipanazoles K, L, and M, were isolated from this strain together with the known tjipanazoles D and I. Taking into account the structures of all tjipanazole derivatives detected in this strain, reanalysis of the tjipanazole biosynthetic gene cluster allowed us to propose a biosynthetic pathway for the tjipanazoles. As the isolated tjipanazoles show structural similarity to arcyriaflavin A, an inhibitor of the clinically relevant multidrug‐transporter ABCG2 overexpressed by different cancer cell lines, the isolated compounds were tested for ABCG2 inhibitory activity. Only tjipanazole K showed appreciable transporter inhibition, whereas the compounds lacking the pyrrolo[3,4‐c] ring or featuring additional chloro substituents were found to be much less active.

Published
2020

84. Law of Property Casebook for Students

Author

Horn, JG, Knobel, IM, Wiese, M, Horn, JG, Knobel, IM, and Wiese, M

Subjects
Property--South Africa, Things (Law)--South Africa, Possession (Law)--South Africa
Abstract

This casebook provides undergraduate students with property law cases and materials accompanied by insightful and critical commentary. The layout and structure of case reports and legislation are discussed and explained, and students are provided with practical hints and advice regarding the reading of cases and legislation. One case is reproduced in full and used as an example of how cases should be read and analysed. Other cases are reproduced selectively to allow students to develop and exercise their skills in the reading and analysis of cases. The ninth edition (2021) was updated with case law up to December 2020. In view of financial considerations, the decision was made to produce this edition in English only. In some instances, cases which were discussed in some detail in the eighth edition of the Introduction to the Law of Property were not discussed again in the Casebook, since the idea is that these two books should be used together. We, therefore, approached the updating of the Introduction and the Casebook as one integrated project instead of two separate books. Under its new authorship, it was also decided to provide unofficial translations of the Afrikaans decisions to make some landmark/important law of property cases accessible to a greater number of students. These translations are in no way meant to be quoted in any official capacity. It was merely translated for the benefit and use of students. It was also decided to expand Part 6 and to include relevant legislation that is dealt with frequently in the law of property. The addition of this legislation would be specifically helpful to students when studying some aspects of the work.

Published
2021

91. Erstmaliger Nachweis einer knöchernen Mittellinienbegrenzung (Crista vertebralis mediana posterior) und Darstellung ihrer Bedeutung bei der operativen Behandlung des sequestrierten lumbalen Bandscheibenvorfalls – eine anatomische Studie

Author

Teske, W, Bastians, P, Zirke, S, von Schulze-Pellengahr, C, Lahner, M, and Wiese, M

Subjects
chirurgische Anatomie Wirbelsäule, ddc: 610, 610 Medical sciences, Medicine, Nucleus pulposus Sequester
Abstract

Fragestellung: Klinisch relevant ist bei der operativen Ausräumung von großen Sequestern einseitiger lumbalen Bandscheibenprolaps die Risikoabschätzung, inwieweit bei der vorwiegend mikroskopisch gestützten Manipulation des Sequesters im Rahmen der Extraktion dieser zur kontralateralen[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2019)

Published
2019
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97. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Author

Hauser, M.A., Allingham, R.R., Aung, T., Heide, C.J. Van Der, Taylor, K.D., Rotter, J.I., Wang, S.J., Bonnemaijer, P.W.M., Williams, S.E., Abdullahi, S.M., Abu-Amero, K.K., Anderson, M.G., Akafo, S., Alhassan, M.B., Asimadu, I., Ayyagari, R., Bakayoko, S., Nyamsi, P.B., Bowden, D.W., Bromley, W.C., Budenz, D.L., Carmichael, T.R., Challa, P., Chen, Yi, Chuka-Okosa, C.M., Bailey, J.N., Costa, V.P., Cruz, Dario, DuBiner, H., Ervin, J.F., Feldman, R.M., Flamme-Wiese, M., Gaasterland, D.E., Garnai, S.J., Girkin, C.A., Guirou, N., Guo, X., Haines, J.L., Hammond, C.J., Herndon, L., Hoffmann, T.J., Hulette, C.M., Hydara, A., Igo, R.P., Jr., Jorgenson, E., Kabwe, J., Kilangalanga, N.J., Kizor-Akaraiwe, N., Kuchtey, R.W., Lamari, H., Li, Z, Liebmann, J.M., Liu, Y, Loos, R.J., Melo, M.B., Moroi, S.E., Msosa, J.M., Mullins, R.F., Nadkarni, G., Napo, A., Ng, M.C., Nunes, H.F., Obeng-Nyarkoh, E., Okeke, A., Okeke, S., Olaniyi, O., Olawoye, O., Oliveira, M.B., Pasquale, L.R., Perez-Grossmann, R.A., Pericak-Vance, M.A., Qin, X., Ramsay, M., Resnikoff, S., Richards, J.E., Schimiti, R.B., Sim, K.S., Sponsel, W.E., Svidnicki, P.V., Thiadens, A., Uche, N.J., Duijn, C.M. van, Vasconcellos, J.P.C. de, Wiggs, J.L., Zangwill, L.M., Risch, N., Milea, D., Ashaye, A., Klaver, C.C.W., Weinreb, R.N., Koch, A.E., Fingert, J.H., Khor, C.C., Hauser, M.A., Allingham, R.R., Aung, T., Heide, C.J. Van Der, Taylor, K.D., Rotter, J.I., Wang, S.J., Bonnemaijer, P.W.M., Williams, S.E., Abdullahi, S.M., Abu-Amero, K.K., Anderson, M.G., Akafo, S., Alhassan, M.B., Asimadu, I., Ayyagari, R., Bakayoko, S., Nyamsi, P.B., Bowden, D.W., Bromley, W.C., Budenz, D.L., Carmichael, T.R., Challa, P., Chen, Yi, Chuka-Okosa, C.M., Bailey, J.N., Costa, V.P., Cruz, Dario, DuBiner, H., Ervin, J.F., Feldman, R.M., Flamme-Wiese, M., Gaasterland, D.E., Garnai, S.J., Girkin, C.A., Guirou, N., Guo, X., Haines, J.L., Hammond, C.J., Herndon, L., Hoffmann, T.J., Hulette, C.M., Hydara, A., Igo, R.P., Jr., Jorgenson, E., Kabwe, J., Kilangalanga, N.J., Kizor-Akaraiwe, N., Kuchtey, R.W., Lamari, H., Li, Z, Liebmann, J.M., Liu, Y, Loos, R.J., Melo, M.B., Moroi, S.E., Msosa, J.M., Mullins, R.F., Nadkarni, G., Napo, A., Ng, M.C., Nunes, H.F., Obeng-Nyarkoh, E., Okeke, A., Okeke, S., Olaniyi, O., Olawoye, O., Oliveira, M.B., Pasquale, L.R., Perez-Grossmann, R.A., Pericak-Vance, M.A., Qin, X., Ramsay, M., Resnikoff, S., Richards, J.E., Schimiti, R.B., Sim, K.S., Sponsel, W.E., Svidnicki, P.V., Thiadens, A., Uche, N.J., Duijn, C.M. van, Vasconcellos, J.P.C. de, Wiggs, J.L., Zangwill, L.M., Risch, N., Milea, D., Ashaye, A., Klaver, C.C.W., Weinreb, R.N., Koch, A.E., Fingert, J.H., and Khor, C.C.

Abstract

Item does not contain fulltext, Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 x 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. Th

Published
2019

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