Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC-202 blocks oncogenic hedgehog-GLI signaling and overcomes smoothened inhibitor resistance

Aberrant activation of Hedgehog (HH)/GLI signaling is causally involved in numerous human malignancies, including basal cell carcinoma (BCC) and medulloblastoma. HH pathway antagonists targeting smoothened (SMO), an essential effector of canonical HH/GLI signaling, show significant clinical success in BCC patients and have recently been approved for the treatment of advanced and metastatic BCC. However, rapid and frequent development of drug resistance to SMO inhibitors (SMOi) together with severe side effects caused by prolonged SMOi treatment call for alternative treatment strategies targeting HH/GLI signaling downstream of SMO. In this study, we report that 4SC-202, a novel clinically validated inhibitor of class I histone deacetylases (HDACs), efficiently blocks HH/GLI signaling. Notably, 4SC-202 treatment abrogates GLI activation and HH target gene expression in both SMOi-sensitive and -resistant cells. Mechanistically, we propose that the inhibition of HDACs 1/2/3 is crucial for targeting oncogenic HH/GLI signaling, and that class I HDAC inhibitors either in combination with SMOi or as second-line therapy may improve the treatment options for HH-associated malignancies with SMOi resistance

Awareness about the Relevance of Cascading Effects in Urban Critical Infrastructure Networks under Climate Change – a Participatory Impact Matrix Approach

Addressing climate change adaptation in urban areas is increasingly urgent. To achieve sustainable and climate-adapted fields of action requires fundamental transformations of supply chains and infrastructures such as transport and mobility, electricity and water supply, or telecommunication as well as an improved understanding of their interactions. Practical experiences show, that in general there is an increasing awareness about this, but for example emergency plans or crisis communication often falls short regarding the indirect impacts of climate change on potential infrastructural failures. Hence, there is also a growing need for applied research and systemic approaches to overcome the current prevailing isolated sectoral view of climate change impacts to gain a holistic understanding of the critical infrastructure networks. Against this background, the paper highlights the relevance of climate change impacts on critical infrastructures, infrastructure interdependencies and potential systemic cascading effects. The analysis uses a participatory approach that has been applied within a case-study for the metropolitan area of Hamburg, Germany. It is based on transdisciplinary research methods, connecting the realms of scientific knowledge about regional climate change with real-world experiences. A strong focus lies on the use of a specific impact matrix approach carried out with key stakeholders from different sectors to identify climate-related drivers causing the most severe failures and losses in the system – either directly in the same sector or indirectly due to breakdowns in other sectors. In sum, the case-study enables a first categorization of the role single key variables play in the infrastructure system. Furthermore, it introduces the topic of adaptation to climate change as a starting point for a better understanding and management of systemic risks in order to build and maintain resilient critical infrastructures and to make urban areas safe, resilient and sustainable

Selbstermächtigung und Selbstorganisation als Schlüssel für nachhaltige Lern- und Transformationsprozesse in der Region Römerland Carnuntum

The region Römerland Carnuntum (Lower Austria) is located between the metropolitan areas of Vienna andBratislava and benefits from dynamic demographic and economic development. However, these processes ofgrowth and rapid change are accompanied by specific challenges that are controversial and much-discussed within the region. The question comes up, how a high level of quality of life can be secured in the future and how a transformation towards sustainability can be initiated and established. Since traditional instruments of spatial planning, structural policy, and regional development increasingly show deficits in the face of such complex, multidimensional challenges, the region has set itself the goal of breaking new ground in cooperation, self-organisation, and self-empowerment, within the framework of which the actors in the region become self-organized, collaborative and long-term carriers of sustainable learning and transformation processes in the region. This article describes the structure of the project and highlights, in particular,challenges related to the committee 'Zukunftsrat Römerland Carnuntum', as a basis for self-empowerment, self-organisation and transformative learning as well as to the start-up phase of the transdisciplinary collaboration.First insights after almost one year of project runtime show, that therepresentative composition of the Zukunftsrat, and especially the random selection of citizens proved to be difficult. Nevertheless, the projekt benefits from outstanding commitment and a high willingness to participate on the part of the regional population

Consequences of the COVID-19 Pandemic and Governmental Containment Policies on the Detection and Therapy of Oral Malignant Lesions-A Retrospective, Multicenter Cohort Study from Germany

(1) Background: In response to the global COVID-19 pandemic, governmental measures have been undertaken. The impact of the crisis on the healthcare of patients with cancer is largely unexplored. This multicenter cohort study aimed to investigate a potential screening delay and its consequences in patients with oral cancer (OC) during the pandemic. (2) Material and Methods: Data of patients who were first diagnosed with OC during different periods were collected, especially in terms of OC incidence, tumor stage/entity and time to intervention. The periods lockdown (LD) (13 March-16 June 2020), post-lockdown (PLD) (17 June-1 November 2020), and the corresponding equivalents in 2018/19 were differentiated and compared. (3) Results: There was no obvious trend towards a higher incidence of OC or higher tumor stages, whereas a trend towards a shorter time to intervention during the LD2020 could be observed. Subgroup analyses revealed an increased incidence in OC within the PLD2020 in Mainz, which might be explained by the partial closure of dental practices in this federal state during LD. (4) Conclusions: While there was no overall higher incidence of OC, we found closure of practices during LD to possibly delay cancer diagnosis. Therefore, measures must be taken to identify patients at risk and to ensure basic healthcare, especially in the context of dental screening measures

Generation and deposition of A43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease

As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid- peptide (A) species, which are released from a C-terminal amyloid precursor protein fragment by -secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the A42 to A40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD. We now show that the very little A generated by PS1 L435F consists primarily of A43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of A43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found A43-containing plaques in brains of patients with this mutation. The aberrant generation of A43 by this particular mutant provides a direct objection against the presenilin hypothesis

Determinants of Dropout From Correctional Offender Treatment

Research indicates that approximately one third of offenders admitted to social-therapeutic correctional facilities in Germany fail to complete treatment and that treatment dropout is linked to higher recidivism in both sexual and violent offenders. The purpose of this study was to examine determinants of treatment dropout in a social-therapeutic correctional facility in Germany. The sample consisted of 205 incarcerated adult male offenders (49.8% sexual, 38.1% non-sexual violent) admitted to correctional treatment. Completers and dropouts were compared on variables pertaining to demographics, offense type, substance abuse, psychopathy, risk, and protective factors. Univariate analyses showed that treatment dropouts demonstrated significantly higher scores on measures of risk and psychopathy and lower scores on protective factors. Logistic regression analyses identified unemployment, non-sexual violent index offense, higher risk scores (HCR-20), and Facet 1 (interpersonal deficits) of the Psychopathy Checklist-Revised (PCL-R) as significant predictors of treatment dropout. Surprisingly, substance abuse disorder was a negative predictor of dropout. With the exception of substance abuse, the results support the notion that treatment dropouts represent a group of high-risk offenders with particular treatment needs. Practical implications and suggestions for further research are discussed

Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC-202 blocks oncogenic hedgehog-GLI signaling and overcomes smoothened inhibitor resistance

Aberrant activation of Hedgehog (HH)/GLI signaling is causally involved in numerous human malignancies, including basal cell carcinoma (BCC) and medulloblastoma. HH pathway antagonists targeting smoothened (SMO), an essential effector of canonical HH/GLI signaling, show significant clinical success in BCC patients and have recently been approved for the treatment of advanced and metastatic BCC. However, rapid and frequent development of drug resistance to SMO inhibitors (SMOi) together with severe side effects caused by prolonged SMOi treatment call for alternative treatment strategies targeting HH/GLI signaling downstream of SMO. In this study, we report that 4SC-202, a novel clinically validated inhibitor of class I histone deacetylases (HDACs), efficiently blocks HH/GLI signaling. Notably, 4SC-202 treatment abrogates GLI activation and HH target gene expression in both SMOi-sensitive and -resistant cells. Mechanistically, we propose that the inhibition of HDACs 1/2/3 is crucial for targeting oncogenic HH/GLI signaling, and that class I HDAC inhibitors either in combination with SMOi or as second-line therapy may improve the treatment options for HH-associated malignancies with SMOi resistance

Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function

Metzincin metalloproteases have major roles in intercellular communication by modulating the function of membrane proteins. One of the proteases is the a-disintegrin-and-metalloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer\u27s disease amyloid precursor protein. ADAM10 is also required for neuronal network functions in murine brain, but neuronal ADAM10 substrates are only partly known. With a proteomic analysis of Adam10-deficient neurons we identified 91, mostly novel ADAM10 substrate candidates, making ADAM10 a major protease for membrane proteins in the nervous system. Several novel substrates, including the neuronal cell adhesion protein NrCAM, are involved in brain development. Indeed, we detected mistargeted axons in the olfactory bulb of conditional ADAM10-/- mice, which correlate with reduced cleavage of NrCAM, NCAM and other ADAM10 substrates. In summary, the novel ADAM10 substrates provide a molecular basis for neuronal network dysfunctions in conditional ADAM10-/- mice and demonstrate a fundamental function of ADAM10 in the brain

Successive Cambia: A Developmental Oddity or an Adaptive Structure?

BackgroundSecondary growth by successive cambia is a rare phenomenon in woody plant species. Only few plant species, within different phylogenetic clades, have secondary growth by more than one vascular cambium. Often, these successive cambia are organised concentrically. In the mangrove genus Avicennia however, the successive cambia seem to have a more complex organisation. This study aimed (i) at understanding the development of successive cambia by giving a three-dimensional description of the hydraulic architecture of Avicennia and (ii) at unveiling the possible adaptive nature of growth by successive cambia through a study of the ecological distribution of plant species with concentric internal phloem.ResultsAvicennia had a complex network of non-cylindrical wood patches, the complexity of which increased with more stressful ecological conditions. As internal phloem has been suggested to play a role in water storage and embolism repair, the spatial organisation of Avicennia wood could provide advantages in the ecologically stressful conditions species of this mangrove genus are growing in. Furthermore, we could observe that 84.9% of the woody shrub and tree species with concentric internal phloem occurred in either dry or saline environments strengthening the hypothesis that successive cambia provide the necessary advantages for survival in harsh environmental conditions.ConclusionsSuccessive cambia are an ecologically important characteristic, which seems strongly related with water-limited environments