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DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma
(2021)
Background: Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking. Methods: A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP). Results: We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma. Conclusions: These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy.
Die Rechtsgeschichte hat dem vormodernen Asyl lange Zeit einen bestenfalls marginalen Platz eingeräumt und es häufig als Hindernis auf dem Weg zum staatlichen Gewalt- und Justizmonopol bewertet oder den angeblichen "Missbrauch" des Asyls betont. Gleiches gilt cum grano salis für die allgemeine Geschichte, die wenige, eng begrenzte lokale Fallstudien beigesteuert hat, während umfassendere Darstellungen zur Geschichte der "Menschenrechte" oder zur historischen Kriminalitätsforschung das vormoderne Asylrecht weitgehend ignorieren. Erst in jüngster Zeit nahm die Zahl der Arbeiten zu, die sich intensiver mit der Geschichte des Asyls beschäftigen und neue Erkenntnisse sowie Forschungsperspektiven beitragen. ...
Lange hat die Forschung die zehn Kreise des Heiligen Römischen Reiches deutscher Nation vernachlässigt. Ließen diese sich doch kaum in das Modell der europäischen (National-)Staatsbildung einordnen. Die Reichskreise bildeten eine separate, spezifische verfassungsrechtliche Ebene zwischen der im Reich nur schwach ausgeprägten "Zentralgewalt", repräsentiert durch Kaiser und Reichstag, und den einzelnen Reichsständen. Unter letzteren billigte die ältere Forschung nur den größeren Territorien staatliche Qualitäten zu. Das Reich wurde dagegen als ein zu moderner Staatsbildung unfähiges "Monstrum" abgetan, das insbesondere in der Gesetzgebung sowie in der Außen-, Wirtschafts-, Ordnungs- und Sicherheitspolitik versagt habe. Erst die jüngere Forschung hat gezeigt, dass das Alte Reich als Ganzes und die Reichsmitglieder durchaus staatliche Funktionen ausübten, und zwar auch im Bereich der frühneuzeitlichen Ordnungs- bzw. Policeygesetzgebung. Die Normenproduktion der Reichskreise und kleineren Reichsstände ist allerdings noch kaum erschlossen, und moderne Editionen gerade umfangreicherer, exemplarischer Policeyordnungen fehlen völlig. Die hier vorzustellenden, von Wolfgang Wüst herausgegebenen drei Bände zur "guten Policey im Reichskreis" bilden folglich nicht nur eine wertvolle Ergänzung zu dem im Max-Planck-Institut für europäische Rechtsgeschichte entstandenen Repertorium der frühneuzeitlichen Policeyordnungen und den in diesem Kontext entstandenen Fallstudien, sondern sie verbinden mit den Themen "Reichskreise" und "Policeygesetzgebung" zwei wichtige Felder der Frühneuzeitforschung und eröffnen damit eine neue Perspektive auf die Gesetzgebungsgeschichte und die Entwicklung frühmoderner Staatlichkeit. ...
Konnte Michael Stolleis noch 1985 im Rechtshistorischen Journal beklagen, dass die Strafrechtsgeschichte ein blinder Fleck in der (rechts-)historischen Forschung sei, so ist seit etwa 1990 geradezu ein Boom der historischen Kriminalitätsforschung zu verzeichnen, der inzwischen auch die Rechtsgeschichte erfasst hat ...
Die vorliegende Münchner historische Dissertation untersucht am Beispiel der letzten Generation der Reichskammergerichtsassessoren die Wahrnehmung und Verarbeitung der Auflösung des Alten Reiches und die Bewältigung dieses epochalen Umbruchs durch die ehemaligen Richter bis in die Zeit des Deutschen Bundes hinein. Es geht folglich um Auflösung und Transfer eines Rechtssystems, das Mader am Beispiel der Bewältigungsstrategien der rund 20 Kammerrichter und ihrer Nachkarrieren detailliert rekonstruiert. Zwar fällt die Kritik des Verfassers an der "Untergangsorientierung" der Forschung zu einseitig und pauschal aus – denn diese hat das Funktionieren der Reichsverfassung auch in ihrer letzten Phase differenziert herausgearbeitet. Zutreffend ist jedoch, dass Fortwirkung, Kontinuität und Transfer des Alten Reiches, seines Rechts, seiner Institutionen und seiner Funktionsträger noch stärker erforscht werden sollten. ...
Higher grade meningiomas tend to recur. We aimed to evaluate protein levels of vascular endothelial growth factor (VEGF)-A with the VEGF-receptors 1-3 and the co-receptors Neuropilin (NRP)-1 and -2 in WHO grade II and III meningiomas to elucidate the rationale for targeted treatments. We investigated 232 specimens of 147 patients suffering from cranial meningioma, including recurrent tumors. Immunohistochemistry for VEGF-A, VEGFR-1-3, and NRP-1/-2 was performed on tissue micro arrays. We applied a semiquantitative score (staining intensity x frequency). VEGF-A, VEGFR-1-3, and NRP-1 were heterogeneously expressed. NRP-2 was mainly absent. We demonstrated a significant increase of VEGF-A levels on tumor cells in WHO grade III meningiomas (p = 0.0098). We found a positive correlation between expression levels of VEGF-A and VEGFR-1 on tumor cells and vessels (p < 0.0001). In addition, there was a positive correlation of VEGF-A and VEGFR-3 expression on tumor vessels (p = 0.0034). VEGFR-2 expression was positively associated with progression-free survival (p = 0.0340). VEGF-A on tumor cells was negatively correlated with overall survival (p = 0.0084). The VEGF-A-driven system of tumor angiogenesis might still present a suitable target for adjuvant therapy in malignant meningioma disease. However, its role in malignant tumor progression may not be as crucial as expected. The value of comprehensive testing of the ligand and all receptors prior to administration of anti-angiogenic therapy needs to be evaluated in clinical trials.
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma
(2020)
Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas. Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29). Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy. Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
BRAF V600E mutations occur frequently in malignant melanoma, but are rare in most malignant glioma subtypes. Besides, more benign brain tumors such as ganglioglioma, dysembryoblastic neuroepithelial tumours and supratentorial pilocytic astrocytomas, only pleomorphic xanthoastrocytomas (50-78%) and epitheloid glioblastoma (50%) regularly exhibit BRAF mutations. In the present study, we report on three patients with recurrent malignant gliomas harbouring a BRAF V600E mutation. All patients presented with markedly disseminated leptomeningeal disease at recurrence and had progressed after radiotherapy and alkylating chemotherapy. Therefore, estimated life expectancy at recurrence was a few weeks. All three patients received dabrafenib as a single agent and all showed a complete or nearly complete response. Treatment is ongoing and patients are stable for 27 months, 7 months and 3 months, respectively. One patient showed a dramatic radiologic and clinical response after one week of treatment. We were able to generate an ex vivo tumor cell culture from CSF in one patient. Treatment of this cell culture with dabrafenib resulted in reduced cell density and inhibition of ERK phosphorylation in vitro. To date, this is the first series on adult patients with BRAF-mutated malignant glioma and leptomeningeal dissemination treated with dabrafenib monotherapy. All patients showed a dramatic response with one patient showing an ongoing response for more than two years.
Simple cells in primary visual cortex were famously found to respond to low-level image components such as edges. Sparse coding and independent component analysis (ICA) emerged as the standard computational models for simple cell coding because they linked their receptive fields to the statistics of visual stimuli. However, a salient feature of image statistics, occlusions of image components, is not considered by these models. Here we ask if occlusions have an effect on the predicted shapes of simple cell receptive fields. We use a comparative approach to answer this question and investigate two models for simple cells: a standard linear model and an occlusive model. For both models we simultaneously estimate optimal receptive fields, sparsity and stimulus noise. The two models are identical except for their component superposition assumption. We find the image encoding and receptive fields predicted by the models to differ significantly. While both models predict many Gabor-like fields, the occlusive model predicts a much sparser encoding and high percentages of ‘globular’ receptive fields. This relatively new center-surround type of simple cell response is observed since reverse correlation is used in experimental studies. While high percentages of ‘globular’ fields can be obtained using specific choices of sparsity and overcompleteness in linear sparse coding, no or only low proportions are reported in the vast majority of studies on linear models (including all ICA models). Likewise, for the here investigated linear model and optimal sparsity, only low proportions of ‘globular’ fields are observed. In comparison, the occlusive model robustly infers high proportions and can match the experimentally observed high proportions of ‘globular’ fields well. Our computational study, therefore, suggests that ‘globular’ fields may be evidence for an optimal encoding of visual occlusions in primary visual cortex.