Molecular and functional characterization of inflammation-induced cell state transitions in malignant-transformed melanocytes

Cellular phenotype plasticity is a hallmark of embryonic development in order to achieve cell type specification from precursor populations. The molecular mechanisms orchestrating phenotypic plasticity are of interest because they may also help to understand how its dysregulation contributes to disease development, in particular cancer. The neural crest is an embryonic cell population that is well known for its migratory capacity and phenotypic plasticity. Malignant melanoma, an aggressive type of skin cancer, is a neural crest-related malignancy originating from the pigment producing melanocytes in the epidermis. In the recent years, it became clear to the field of neural crest biologists that melanoma is an ideal model system to study basic principles of phenotype plasticity of the neural crest cell lineage. Melanoma cells are highly prone to phenotype switching and this is linked to the expression level of MITF (Microphthalmia-associated transcription factor), the master transcription factor of the melanocyte cell lineage that induces the expression of pigmentation-related genes among other effects. On this ba- sis, melanoma cell state transitions have been classified as a binary switch between a differentiated MITFhigh proliferative phenotype and a dedifferentiated MITFlow invasive phenotype. However, intermediate melanoma cell states, as well as the detailed molecular mechanisms concerting the transitions remain elusive. In this study we identified a novel nascent invasive cell state in melanoma. This pheno- type exhibits early inflammatory and early invasive signaling programs although keeping the differentiation signature. Expression of the cell surface 5'ectonucleotidase CD73 was revealed as a marker for nascent invasiveness and further increased upon full dedifferentiation. Interestingly, CD73 is not only known as a mesenchymal stem cell marker, but also involved in tumor immunosuppression and therefore emerges as a target for cancer immunotherapy. Computational and in vitro studies confirmed a critical cooperation of mitogenic growth factors and pro-inflammatory cytokines inducing CD73 expression. This was dependent on the MEK-ERK signaling cascade and coordinated by the transcription factor c-Jun, which critically bound to an intronic enhancer within the CD73 genomic locus. The findings reported in this thesis provide novel mechanistic insight into neural crest plasticity, melanoma cell state transitions and the regulation of a CD73-dependent immunosuppressive tumor microenvironment

Agonia do Eros e o narcisismo contemporâneo

Para Han, nem Eros escapa da sociedade do desempenho. O narcisismo confunde a noção do outro, da alteridade, e as noções que temos do amor. Esquecemos que o outro sempre será o outro. O dever da produtividade engana-nos de que é possível “consumir” até mesmo os matches do Tinder

Agonia do Eros e o narcisismo contemporâneo

Para Han, ni siquiera Eros escapa de la sociedad del desempeño. El narcisismo confunde la noción del otro, de la alteridad, y distorsiona las nociones que tenemos del amor. Olvidamos que el otro siempre será el otro. El deber de la productividad nos engaña con la posibilidad de “consumir” incluso matches de Tinder.For Han, not even Eros escapes from the performance society. Narcissism mixes the notion of the other and otherness, as well as the notions we have of love. We forget that the other will always be the other. The duty of productivity makes us think that even Tinder matches are “consumables”.Para Han, nem Eros escapa da sociedade do desempenho. O narcisismo confunde a noção do outro, da alteridade, e as noções que temos do amor. Esquecemos que o outro sempre será o outro. O dever da produtividade engana-nos de que é possível “consumir” até mesmo os matches do Tinder

Exploring the Most Visible German Websites on Melanoma Immunotherapy: A Web-Based Analysis

Background: Patients diagnosed with melanoma frequently search the internet for treatment information, including novel and complex immunotherapy. However, health literacy is limited among half of the German population, and no assessment of websites on melanoma treatment has been performed so far. Objective: The aim of this study was to identify and assess the most visible websites in German language on melanoma immunotherapy. Methods: In accordance with the common Web-based information-seeking behavior of patients with cancer, the first 20 hits on Google, Yahoo, and Bing were searched for combinations of German synonyms for “melanoma” and “immunotherapy” in July 2017. Websites that met our predefined eligibility criteria were considered for assessment. Three reviewers independently assessed their quality by using the established DISCERN tool and by checking the presence of quality certification. Usability and reliability were evaluated by the LIDA tool and understandability by the Patient Education Materials Assessment Tool (PEMAT). The Flesch Reading Ease Score (FRES) was calculated to estimate the readability. The ALEXA and SISTRIX tools were used to investigate the websites’ popularity and visibility. The interrater agreement was determined by calculating Cronbach alpha. Subgroup differences were identified by t test, U test, or one-way analysis of variance. Results: Of 480 hits, 45 single websites from 30 domains were assessed. Only 2 website domains displayed a German quality certification. The average assessment scores, mean (SD), were as follows: DISCERN, 48 (7.6); LIDA (usability), 40 (2.0); LIDA (reliability), 10 (1.6); PEMAT, 69% (16%); and FRES, 17 (14), indicating mediocre quality, good usability, and understandability but low reliability and an even very low readability of the included individual websites. SISTRIX scores ranged from 0 to 6872 and ALEXA scores ranged from 17 to 192,675, indicating heterogeneity of the visibility and popularity of German website domains providing information on melanoma immunotherapy. Conclusions: Optimization of the most accessible German websites on melanoma immunotherapy is desirable. Especially, simplification of the readability of information and further adaption to reliability criteria are required to support the education of patients with melanoma and laypersons, and to enhance transparency

How many species of mite-harvestmen (Opiliones, Cyphophthalmi) are there in Austria?

Der bodenbewohnende Milbenkanker Cyphophthalmus duricorius Joseph, 1868 (Fam. Sironidae) galt mehr als 60 Jahre lang als die einzige in Österreich vorkommende Art der Weberknecht-Unterordnung Cyphophthalmi. Neuere Aufsammlungen zeigen jedoch, dass mindestens zwei weitere Cyphophthalmi-Arten in Österreich existieren: 1) Siro cf. crassus Novak & Giribet, 2006 wurde an einer Lokalität in der SW Steiermark nahe der slowenischen Grenze gefunden und repräsentiert eine zweite Gattung von Sironiden in Österreich. 2) Ein weiterer, morphologisch distinkter Sironide („Sironidae gen. et sp. nov.?“) − derzeit noch unbeschrieben und taxonomisch nicht zugeordnet − stammt aus Böden im Grenzgebiet Steiermark-Kärnten. Obwohl bislang kein syntopes Vorkommen belegt ist, können alle drei Arten in einem kleinen Areal von wenigen Quadratkilometern gefunden werden.For the last 60 years, the mite-harvestman Cyphophthalmus duricorius Joseph, 1868, a soil-dwelling sironid, has been considered to be the only representative of the opilionid suborder Cyphophthalmi in Austria. However, novel data from recent collections confirm the presence of at least two further Austrian cyphophthalmid species. (1) Siro cf. crassus Novak & Giribet, 2006 occurs in at least one location in SW Styria near the Slovenian border and hence represents a member of a second genus of Austrian sironids. (2) A further morphologically distinct sironid (“Sironidae gen. et sp. nov.?”) – so far undescribed and systematically not placed in detail – was collected in the borderland between Styria and Carinthia. All three species can be found in a small area of a few square-kilometers; although no syntopic occurrence was recorded

Increased Volume and Function of Right Auditory Cortex as a Marker for Absolute Pitch

Absolute pitch (AP) perception is the auditory ability to effortlessly recognize the pitch of any given tone without external reference. To study the neural substrates of this rare phenomenon, we developed a novel behavioral test, which excludes memory-based interval recognition and permits quantification of AP proficiency independently of relative pitch cues. AP- and non-AP-possessing musicians were studied with morphological and functional magnetic resonance imaging (fMRI) and magnetoencephalography. Gray matter volume of the right Heschl's gyrus (HG) was highly correlated with AP proficiency. Right-hemispheric auditory evoked fields were increased in the AP group. fMRI revealed an AP-dependent network of right planum temporale, secondary somatosensory, and premotor cortices, as well as left-hemispheric "Broca's” area. We propose the right HG as an anatomical marker of AP and suggest that a right-hemispheric network mediates AP "perception,” whereas pitch "labeling” takes place in the left hemispher

Primary motor cortex activation and lateralization in patients with tumors of the central region

AbstractHemispheric lateralization is a frequently encountered phenomenon of cortical function. It describes the functional specialization of a region on one side of the brain for a given task. It is well characterized in motor and sensory, as well as language systems and becomes more and more known for various cognitive domains. While in the adult healthy brain hemispheric lateralization is mostly set, pathological processes may lead to cortical reorganization. In these cases neuroplasticity of the corresponding region in the non-dominant hemisphere seems to play an important role. In a previous study we investigated language associated regions in right-handed patients with frontal and temporal tumors of the left hemisphere. We observed a marked change of language lateralization in these patients towards the non-dominant hemisphere as measured by functional MRI (Partovi et al., 2012).In the present study we evaluated activation and lateralization of cortical motor areas in patients with tumors of the central region. BOLD fMRI was performed during unilateral voluntary movements of the contralesional hand in 87 patients. Individual correlations of measured BOLD-signals with the model hemodynamic reference function were determined on a ROI basis in single subjects and compared to those of 16 healthy volunteers. In volunteers the strongest activation is usually found in the M1 hand representation contralateral to the movement, while a weaker homotopic co-activation is observed in ipsilateral M1 (Stippich et al., 2007a). In the patient group our results show significant changes of motor activations, ranging from a reduction of M1 lateralization to equalization of M1 activations or even inversion of M1 lateralization during contralesional movements. This study corroborates in a large patient group the idea that lesions affecting M1 may lead to functional reorganization of cortical motor systems and in particular equalize hemispheric lateralization. However, it is not yet clear whether these changes are only an epiphenomenon or indeed reflect an attempt of recovery of brain function

Common miRNA patterns of Alzheimer’s disease and Parkinson’s disease and their putative impact on commensal gut microbiota

With the rise of Next-Generation-Sequencing (NGS) methods, Micro-RNAs (miRNAs) have achieved an important position in the research landscape and have been found to present valuable diagnostic tools in various diseases such as multiple sclerosis or lung cancer. There is also emerging evidence that miRNAs play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) or Parkinson’s disease (PD). Apparently, these diseases come along with changes in miRNA expression patterns which led to attempts from researchers to use these small RNA species from several body fluids for a better diagnosis and in order to observe disease progression. Additionally, it became evident that microbial commensals might play an important role for pathology development and were shown to have a significantly different composition in patients suffering from neurodegeneration compared with healthy controls. As it could recently be shown that secreted miRNAs are able to enter microbial organisms, it is conceivable that the host’s miRNA might affect the gut microbial ecosystem. As such, miRNAs may inherit a central role in shaping the “diseased microbiome” and thereby mutually act on the characteristics of these neurodegenerative diseases. We have therefore 1) compiled a list of miRNAs known to be associated with AD and/or PD, 2) performed an in silico target screen for binding sites of these miRNA on human gut metagenome sequences and 3) evaluated the hit list for interesting matches potentially relevant to the etiology of AD and or PD. The examination of protein identifiers connected to bacterial secretion system, lipopolysaccharide biosynthesis and biofilm formation revealed an overlap of 37 bacterial proteins that were targeted by human miRNAs. The identified links of miRNAs to the biological processes of bacteria connected to AD and PD have yet to be validated via in vivo experiments. However, our results show a promising new approach for understanding aspects of these neurodegenerative diseases in light of the regulation of the microbiome