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The transformation of societies and economies towards climate neutrality is a highly complex multi-sectoral and multi-level challenge. This paper examines the multi-level dimension of climate policy with particular reference to the European legal framework and the example of Germany. It analyses how regional and local governments are engaged and whether, in this regard, the existing arrangements of multi-level climate governance can be considered adequate and effective. In the light of the basic principles of federalism theory and in view of the – failed – German multi-level approaches to energy transition it is concluded, in particular, that federal climate governance must build not only on European and national objectives but also on regional and local climate targets and policy planning schemes as a means of both ensuring sufficient transformation efforts and preserving as much autonomy as possible for regional and local communities.

Abstract Pancreatic cancer has the worst prognosis among common tumors which is attributed to its aggressive phenotype, diagnosis at advanced, inoperable stages, and resistance to systemic therapy. Non-coding RNAs (ncRNAs) such as microRNAs, long non-coding RNAs, and circular RNAs have been established as important regulators of gene expression and their deregulation has been implicated in multiple diseases and foremost cancer. In the tumor microenvironment, non-coding RNAs can be distributed among cancer cells, stromal cells, and immune cells via small extracellular vesicles (sEVs), thereby facilitating intercellular communication and influencing major cancer hallmarks such as angiogenesis, evasion of the immune system, and metastatic dissemination. Furthermore, sEV-ncRNAs have shown promising potential as liquid biopsies with diagnostic and prognostic significance. In this review, we summarize the role of sEVs as carriers of ncRNAs and underlying molecular mechanisms in pancreatic cancer. Moreover, we review the potential of sEV-ncRNAs as biomarkers and highlight the suitability of sEVs as delivery vehicles for ncRNA-based cancer therapy.

The European Green Deal is a comprehensive initiative aimed at reshaping the functioning of the European Union towards sustainable development. While the immediate trigger for this initiative of the newly appointed European Commission under Ursula van Leyen was the need to address the challenges associated with climate change and to move towards carbon-free and circular economy – its goals seem to be much more ambitious: to put into practice the concept of sustainable development. Against the background of the concept of sustainability and its various ambiguities and interpretations, the article provides a brief description and analysis of the key pillars of the Green Deal, namely: the financial framework for promoting sustainability, the climate and energy strategy, and the strategy for industry and circular economy. It also presents and critically assesses the horizontal goals of the Green Deal i.e. improving involvement of the public into the decision-making and assuring equal opportunities for marginalised groups.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor entity, characterized by rapid disease progression, early metastatic dissemination, and late diagnosis at advanced tumor stages. Recently, we explored the clinical impact of several microRNAs (miR) associated with proliferation, epithelial-to-mesenchymal transition (EMT), and chemoresistance in tissue and blood serum specimens of PDAC patients. Here, we evaluated the potential of these miRs as diagnostic and prognostic biomarkers in PDAC in serum exosomes and their respective EpCAM-positive (epithelial cell adhesion molecule) subset. Expression analysis by RT-qRT-PCR (real-time quantitative reverse transcription polymerase chain reaction) revealed an overexpression of miR-200b and miR-200c in serum exosomes of PDAC patients as compared to healthy controls (p < 0.001; p = 0.024) and patients with chronic pancreatitis (p = 0.005; p = 0.19). Receiver operating characteristic (ROC) curve analysis showed that a biomarker panel consisting of miR-200b and miR-200c from total and EpCAM-positive serum exosomes enhanced the diagnostic accuracy of carbohydrate antigen 19-9 (CA.19-9) to 97% (p < 0.0001). Univariate survival analysis revealed a correlation between shorter overall survival (OS) and high expression of miR-200c in total serum exosomes (p = 0.038) and miR-200b in EpCAM-positive serum exosomes (p = 0.032), whereas EpCAM exosomal miR-200b was also indicative of shorter OS in the subgroup of patients treated with curative intent (p = 0.013). Multivariate survival analysis showed that miR-200b derived from EpCAM-positive serum exosomes might serve as an independent prognostic factor in PDAC (p = 0.044). Our findings indicate a potential role of exosomal miR-200 as diagnostic and prognostic liquid biopsy marker in PDAC and call for validation in a larger, multicenter setting.