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Leisegang, Matthias ; Fork, Christian ; Josipovic, Ivana ; Richter, Florian Martin ; Preussner, Jens ; Hu, Jiong ; Miller, Matthew J. ; Epah, Jeremy ; Hofmann, Patrick ; Günther, Stefan ; Moll, Franziska ; Valasarajan, Chanil ; Heidler, Juliana ; Ponomareva, Yuliya ; Freiman, Thomas Michael ; Mägdefessel, Lars ; Plate, Karl ; Mittelbronn, Michel Guy André ; Uchida, Shizuka ; Künne, Carsten Tobias ; Stellos, Konstantinos ; Schermuly, Ralph T. ; Weißmann, Norbert ; Devraj, Kavi ; Wittig, Ilka ; Boon, Reinier ; Dimmeler, Stefanie ; Pullamsetti, Soni Savai ; Looso, Mario ; Miller, Francis J. ; Brandes, Ralf
Background: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs.
Methods: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression.
Results: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding.
Conclusion: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function.
Wenger-Alakmeh, Katharina Johanna ; Richter, Christian ; Burger, Michael Christian ; Urban, Hans ; Kaulfuß, Stefan ; Harter, Patrick Nikolaus ; Sreeramulu, Sridhar ; Schwalbe, Harald ; Steinbach, Joachim Peter ; Hattingen, Elke ; Bähr, Roy Oliver ; Pilatus, Ulrich
Simple Summary: Targeted therapies are of growing interest to physicians in cancer treatment. These drugs target specific genes and proteins involved in the growth and survival of cancer cells. Brain tumor therapy is complicated by the fact that not all drugs can penetrate the blood brain barrier and reach their target. We explored the non-invasive method, Magnetic Resonance Spectroscopy, for monitoring drug penetration and its effects in live animals bearing brain tumors. We were able to show the presence of the investigated drug in mouse brains and its on-target activity.
Abstract: Background: BAY1436032 is a fluorine-containing inhibitor of the R132X-mutant isocitrate dehydrogenase (mIDH1). It inhibits the mIDH1-mediated production of 2-hydroxyglutarate (2-HG) in glioma cells. We investigated brain penetration of BAY1436032 and its effects using 1H/19F-Magnetic Resonance Spectroscopy (MRS). Methods: 19F-Nuclear Magnetic Resonance (NMR) Spectroscopy was conducted on serum samples from patients treated with BAY1436032 (NCT02746081 trial) in order to analyze 19F spectroscopic signal patterns and concentration-time dynamics of protein-bound inhibitor to facilitate their identification in vivo MRS experiments. Hereafter, 30 mice were implanted with three glioma cell lines (LNT-229, LNT-229 IDH1-R132H, GL261). Mice bearing the IDH-mutated glioma cells received 5 days of treatment with BAY1436032 between baseline and follow-up 1H/19F-MRS scan. All other animals underwent a single scan after BAY1436032 administration. Mouse brains were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Results: Evaluation of 1H-MRS data showed a decrease in 2-HG/total creatinine (tCr) ratios from the baseline to post-treatment scans in the mIDH1 murine model. Whole brain concentration of BAY1436032, as determined by 19F-MRS, was similar to total brain tissue concentration determined by Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), with a signal loss due to protein binding. Intratumoral drug concentration, as determined by LC-MS/MS, was not statistically different in models with or without R132X-mutant IDH1 expression. Conclusions: Non-invasive monitoring of mIDH1 inhibition by BAY1436032 in mIDH1 gliomas is feasible.
Comprehensive analysis of tumour sub-volumes for radiomic risk modelling in locally advanced HNSCC
(2020)
Leger, Stefan ; Zwanenburg, Alex ; Leger, Karoline ; Lohaus, Fabian ; Linge, Annett ; Schreiber, Andreas ; Kalinauskaite, Goda ; Tinhofer, Inge ; Guberina, Nika ; Guberina, Maja ; Balermpas, Panagiotis ; Müller-von der Grün, Jens ; Ganswindt, Ute ; Belka, Claus ; Peeken, Jan Caspar ; Combs, Stephanie E. ; Boeke, Simon ; Zips, Daniel ; Richter, Christian ; Krause, Mechthild ; Baumann, Michael ; Troost, Esther Gera Cornelia ; Löck, Steffen
Simple Summary: Radiomic risk models are usually based on imaging features, which are extracted from the entire gross tumour volume (GTV entire ). This approach does not explicitly consider the complex biological structure of the tumours. Therefore, in this retrospective study, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma who were treated with primary radio-chemotherapy. The GTV entire was cropped by different margins to define the rim and corresponding core sub-volumes of the tumour. Furthermore, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. As a result, the models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed an improved performance compared to models based on the corresponding tumour core. This indicates that the consideration of tumour sub-volumes may help to improve radiomic risk models.
Abstract: Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTVentire). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTVentire was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTVentire achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend (p = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models.
López, Cristina ; Kleinheinz, Kortine ; Aukema, Sietse M. ; Rohde, Marius ; Bernhart, Stephan H. ; Hübschmann, Daniel ; Wagener, Rabea ; Toprak, Umut H. ; Raimondi, Francesco ; Kreuz, Markus ; Waszak, Sebastian Martin ; Huang, Zhiqin ; Sieverling, Lina ; Paramasivam, Nagarajan ; Seufert, Julian ; Sungalee, Stephanie ; Russell, Robert B. ; Bausinger, Julia ; Kretzmer, Helene ; Ammerpohl, Ole ; Bergmann, Anke K. ; Binder, Hans ; Borkhardt, Arndt ; Brors, Benedikt ; Claviez, Alexander ; Doose, Gero ; Feuerbach, Lars ; Haake, Andrea ; Hansmann, Martin-Leo ; Höll, Jessica ; Hummel, Michael ; Korbel, Jan Oliver ; Lawerenz, Chris ; Lenze, Dido ; Radlwimmer, Bernhard ; Richter, Julia ; Rosenstiel, Philip ; Rosenwald, Andreas ; Schilhabel, Markus B. ; Stein, Harald ; Stilgenbauer, Stephan ; Stadler, Peter F. ; Szczepanowski, Monika ; Weniger, Marc Andrèe ; Zapatka, Marc ; Eils, Roland ; Lichter, Peter ; Löffler, Markus ; Möller, Peter ; Trümper, Lorenz ; Klapper, Wolfram ; Hoffmann, Steve ; Küppers, Ralf ; Burkhardt, Birgit ; Schlesner, Matthias ; Siebert, Reiner
Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.
Ablikim, Medina ; Achasov, Mikhail N. ; Ahmed, Samer ; Albrecht, Malte ; Amoroso, Antonio ; An, Fenfen ; An, Qi ; Bai, Jingzhi ; Bai, Y. ; Bakina, Olga ; Baldini Ferroli, Rinaldo ; Ban, Yong ; Bennett, D.W. ; Bennett, Jake V. ; Berger, Niklaus ; Bertani, Monica ; Bettoni, Diego ; Bian, J.M. ; Bianchi, Fabrizio ; Boger, E. ; Boyko, Igor R. ; Briere, Roy A. ; Cai, H. ; Cai, Xiao ; Cakir, O. ; Calcaterra, Alessandro ; Cao, G.F. ; Çetin, Serkant Ali ; Chai, J. ; Chang, Jinfan ; Chelkov, Gueorgui A. ; Chen, G. ; Chen, Hesheng ; Chen, J.C. ; Chen, M.L. ; Chen, P.L. ; Chen, S.J. ; Chen, X.R. ; Chen, Yuanbo ; Chu, X.K. ; Cibinetto, Gianluigi ; Dai, Hongliang ; Dai, J.P. ; Dbeyssi, Alaa ; Dedovich, Dmitri V. ; Deng, Ziyan ; Denig, Achim ; Denysenko, Igor ; Destefanis, Marco Giovanni Maria ; De Mori, Francesca ; Ding, Y. ; Dong, C. ; Dong, J. ; Dong, Liaoyuan ; Dong, Mingyi ; Dou, Z.L. ; Du, Shuxian ; Duan, P.F. ; Fang, J. ; Fang, Shuangshi ; Fang, Y. ; Farinelli, Riccardo ; Fava, Luciano ; Fegan, S. ; Feldbauer, Florian ; Felici, Giulietto ; Feng, C.Q. ; Fioravanti, Elisa ; Fritsch, Miriam ; Fu, Chengdong ; Gao, Q. ; Gao, X.L. ; Gao, Y. ; Gao, Y.G. ; Gao, Z. ; Garillon, B. ; Garzia, I. ; Goetzen, Klaus ; Gong, L. ; Gong, Wenxuan ; Gradl, Wolfgang ; Greco, M. ; Gu, Minhao ; Gu, Y.T. ; Guo, Aiqiang ; Guo, R.P. ; Guo, Yuping ; Haddadi, Z. ; Han, S. ; Hao, Xiqing ; Harris, F.A. ; He, K.L. ; He, X.Q. ; Heinsius, Fritz-Herbert ; Held, T. ; Heng, Yuekun ; Holtmann, Tobias ; Hou, Zhilong ; Hu, Haiming ; Hu, T. ; Hu, Y. ; Huang, G.S. ; Huang, J.S. ; Huang, Xingtao ; Huang, X.Z. ; Huang, Z.L. ; Hussain, Tahir ; Ikegami Andersson, Walter ; Ji, Quan ; Ji, Qingping ; Ji, X.B. ; Ji, X.L. ; Jiang, Xiaoshan ; Jiang, X.Y. ; Jiao, J.B. ; Jiao, Z. ; Jin, D.P. ; Jin, Shan ; Jin, Y. ; Johansson, Tord ; Julin, A. ; Kalantar-Nayestanaki, Nasser ; Kang, Xiaolin ; Kang, X.S. ; Kavatsyuk, Myroslav O. ; Ke, Bai-Cian ; Khan, T. ; Khoukaz, Alfons ; Kiese, P. ; Kliemt, Ralf ; Koch, Leonard ; Kolcu, Onur Bugra ; Kopf, Bertram ; Kornicer, M. ; Kuemmel, M. ; Küßner, Meike ; Kuhlmann, M. ; Kupsc, Andrzej ; Kühn, Wolfgang ; Lange, Jens Sören ; Lara, M. ; Larin, Paul ; Lavezzi, Lia ; Leithoff, H. ; Leng, C. ; Li, C. ; Li, Cheng ; Li, D.M. ; Li, F. ; Li, F.Y. ; Li, G. ; Li, Haibo ; Li, H.J. ; Li, J.C. ; Li, Jin ; Li, K.J. ; Li, Kang ; Li, Ke ; Li, Lei ; Li, P.L. ; Li, P.R. ; Li, Q.Y. ; Li, Weidong ; Li, Weiguo ; Li, X.L. ; Li, X.N. ; Li, X.Q. ; Li, Z.B. ; Liang, H. ; Liang, Y.F. ; Liang, Y.T. ; Liao, G.R. ; Lin, D.X. ; Liu, B. ; Liu, B.J. ; Liu, C.X. ; Liu, D. ; Liu, F.H. ; Liu, Fang ; Liu, Feng ; Liu, H.B. ; Liu, H.M. ; Liu, Huanhuan ; Liu, Huihui ; Liu, J.B. ; Liu, J.Y. ; Liu, K. ; Liu, K.Y. ; Liu, Ke ; Liu, L.D. ; Liu, P.L. ; Liu, Q. ; Liu, S.B. ; Liu, X. ; Liu, Y.B. ; Liu, Zhen-An ; Liu, Zhiqing ; Long, Y.F. ; Lou, Xinchou ; Lu, H.J. ; Lu, Junguang ; Lu, Y. ; Lu, Yunpeng ; Luo, Chenglin ; Luo, M.X. ; Luo, X.L. ; Lyu, Xiao-Rui ; Ma, Fengcai ; Ma, H.L. ; Ma, Lianliang ; Ma, M.M. ; Ma, Qiumei ; Ma, T. ; Ma, X.N. ; Ma, Xiaoyan ; Ma, Y.M. ; Maas, Frank E. ; Maggiora, Marco ; Malik, Qadeer Afzal ; Mao, Yajun ; Mao, Zepu ; Marcello, Simonetta ; Meng, Z.X. ; Messchendorp, Johannes Gerhardus ; Mezzadri, Giulio ; Min, J. ; Min, T.J. ; Mitchell, Ryan Edward ; Mo, Xiaohu ; Mo, Y.J. ; Morales Morales, C. ; Muchnoi, Nikolai Yu. ; Muramatsu, H. ; Mustafa, A. ; Nefedov, Yury ; Nerling, Frank ; Nikolaev, Ivan Borisovich ; Ning, Z. ; Nisar, Shabana ; Niu, S.L. ; Niu, X.Y. ; Olsen, Stephen L. ; Ouyang, Qun ; Pacetti, Simone ; Pan, Y. ; Papenbrock, Michael ; Patteri, P. ; Pelizäus, Marc ; Pellegrino, Jacopo ; Peng, H.P. ; Peters, Klaus ; Pettersson, J. ; Ping, J.L. ; Ping, R.G. ; Pitka, A. ; Poling, Ronald ; Prasad, Vindhyawasini ; Qi, H.R. ; Qi, Ming ; Qian, S. ; Qiao, Congfeng ; Qin, N. ; Qin, X.S. ; Qin, Zhonghua ; Qiu, Jinfa ; Rashid, K.H. ; Redmer, Christoph Florian ; Richter, Matthias ; Ripka, M. ; Da Rocha Rolo, Manuel Dionisio ; Rong, Gang ; Rosner, Christoph ; Sarantsev, Andrei V. ; Savrié, M. ; Schnier, Claudius ; Schönning, Karin ; Shan, W. ; Shao, M. ; Shen, C.P. ; Shen, P.X. ; Shen, X.Y. ; Sheng, H.Y. ; Song, J.J. ; Song, W.M. ; Song, X.Y. ; Sosio, Stefano ; Sowa, C. ; Spataro, Stefano ; Sun, Gongxing ; Sun, J.F. ; Sun, L. ; Sun, S.S. ; Sun, X.H. ; Sun, Y.J. ; Sun, Y.K. ; Sun, Y.Z. ; Sun, Z.J. ; Sun, Z.T. ; Tang, C.J. ; Tang, G.Y. ; Tang, X. ; Tapan, I. ; Tiemens, M. ; Tsednee, B. ; Uman, Ismail ; Varner, G.S. ; Wang, B. ; Wang, B.L. ; Wang, D. ; Wang, D.Y. ; Wang, Dan ; Wang, K. ; Wang, L.L. ; Wang, L.S. ; Wang, M. ; Wang, Meng ; Wang, P. ; Wang, P.L. ; Wang, W.P. ; Wang, X.F. ; Wang, Y. ; Wang, Y.D. ; Wang, Y.F. ; Wang, Y.Q. ; Wang, Z. ; Wang, Z.G. ; Wang, Z.Y. ; Wang, Zongyuan ; Weber, T. ; Wei, D.H. ; Weidenkaff, P. ; Wen, Shuopin ; Wiedner, Ulrich ; Wolke, Magnus ; Wu, Linghui ; Wu, L.J. ; Wu, Z. ; Xia, L. ; Xia, Y. ; Xiao, D. ; Xiao, H. ; Xiao, Y.J. ; Xiao, Zhenjun ; Xie, Y.G. ; Xie, Y.H. ; Xiong, X.A. ; Xiu, Q.L. ; Xu, Guofa ; Xu, J.J. ; Xu, L. ; Xu, Q.J. ; Xu, Q.N. ; 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Zhu, Y.S. ; Zhu, Zian ; Zhuang, J. ; Zou, B.S. ; Zou, Jiaheng
Using a data sample of e+e− collision data corresponding to an integrated luminosity of 2.93 fb−1 collected with the BESIII detector at a center-of-mass energy of s=3.773GeV, we search for the singly Cabibbo-suppressed decays D0→π0π0π0, π0π0η, π0ηη and ηηη using the double tag method. The absolute branching fractions are measured to be B(D0→π0π0π0)=(2.0±0.4±0.3)×10−4, B(D0→π0π0η)=(3.8±1.1±0.7)×10−4 and B(D0→π0ηη)=(7.3±1.6±1.5)×10−4 with the statistical significances of 4.8σ, 3.8σ and 5.5σ, respectively, where the first uncertainties are statistical and the second ones systematic. No significant signal of D0→ηηη is found, and the upper limit on its decay branching fraction is set to be B(D0→ηηη)<1.3×10−4 at the 90% confidence level.