Neuronal Polarity: Establishment and Maintenance

The term polarity in a biological context is used to describe an asymmetry in morphology and distribution of molecules. In neurons, their complex shape with typically one axon and several dendrites reflects this asymmetry. Although neurons assume many different shapes and sizes they always maintain these two domains, which are essential for neuronal function. In the most simple view, neurons use their axon to transmit signals over long distances due to its capacity to extend to enormous lengths. Dendrites, on the other hand, are shorter and receive and integrate signals from different locations. The selection of the site where the axon and dendrites initially emerge during embryonic development is a tightly regulated event, eventually important for the correct formation of neuronal circuits, and disturbances of these processes can have pathological consequences due to circuit malformation. An important question is which mechanisms neurons utilize to specify the sites where axonal and dendrite outgrowth occurs and how their identities are maintained during and after development. The formation of these functionally diverse domains is the result of polarized differences of membrane and protein delivery, mitochondria transport, actin dynamics and microtubule stability. However how and in which temporal order all those events which coordinate the selection and maintenance of axons and dendrites is still under investigation. This selection of articles shall highlight new findings, which help to unravel all molecular and cellular events important for neuronal polarity establishment and maintenance

Estimating the Potential of Radiomics Features and Radiomics Signature from Pretherapeutic PSMA-PET-CT Scans and Clinical Data for Prediction of Overall Survival When Treated with 177Lu-PSMA

Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PSMA-PET/CT) scans can facilitate diagnosis and treatment of prostate disease. Radiomics signature (RS) is widely used for the analysis of overall survival (OS) in cancer diseases. This study aims at investigating the role of radiomics features (RFs) and RS from pretherapeutic gallium-68 (68Ga)-PSMA-PET/CT findings and patient-specific clinical parameters to analyze overall survival of prostate cancer (PC) patients when treated with lutethium-177 (177Lu)-PSMA. A cohort of 83 patients with advanced PC was retrospectively analyzed. Average values of 73 RFs of 2070 malignant hotspots as well as 22 clinical parameters were analyzed for each patient. From the Cox proportional hazard model, the least absolute shrinkage and selection operator (LASSO) regularization method is used to select most relevant features (standardized uptake value (SUV)Min and kurtosis with the coefficients of 0.984 and −0.118, respectively) and to calculate the RS from the RFs. Kaplan–Meier (KM) estimator was used to analyze the potential of RFs and conventional clinical parameters, such as metabolic tumor volume (MTV) and standardized uptake value (SUV) for the prediction of survival. As a result, SUVMin, kurtosis, the calculated RS, SUVMean, as well as Hemoglobin (Hb)1, C-reactive protein (CRP)1, and ECOG1 (clinical parameters) achieved p-values less than 0.05, which suggest the potential of findings from 68Ga-PSMA-PET/CT scans as well as patient-specific clinical parameters for the prediction of OS for patients with advanced PC treated with 177Lu-PSMA therapy

Estimating the Potential of Radiomics Features and Radiomics Signature from Pretherapeutic PSMA-PET-CT Scans and Clinical Data for Prediction of Overall Survival When Treated with ¹⁷⁷Lu-PSMA

Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PSMA-PET/CT) scans can facilitate diagnosis and treatment of prostate disease. Radiomics signature (RS) is widely used for the analysis of overall survival (OS) in cancer diseases. This study aims at investigating the role of radiomics features (RFs) and RS from pretherapeutic gallium-68 (68Ga)-PSMA-PET/CT findings and patient-specific clinical parameters to analyze overall survival of prostate cancer (PC) patients when treated with lutethium-177 (177Lu)-PSMA. A cohort of 83 patients with advanced PC was retrospectively analyzed. Average values of 73 RFs of 2070 malignant hotspots as well as 22 clinical parameters were analyzed for each patient. From the Cox proportional hazard model, the least absolute shrinkage and selection operator (LASSO) regularization method is used to select most relevant features (standardized uptake value (SUV)Min and kurtosis with the coefficients of 0.984 and −0.118, respectively) and to calculate the RS from the RFs. Kaplan–Meier (KM) estimator was used to analyze the potential of RFs and conventional clinical parameters, such as metabolic tumor volume (MTV) and standardized uptake value (SUV) for the prediction of survival. As a result, SUVMin, kurtosis, the calculated RS, SUVMean, as well as Hemoglobin (Hb)1, C-reactive protein (CRP)1, and ECOG1 (clinical parameters) achieved p-values less than 0.05, which suggest the potential of findings from 68Ga-PSMA-PET/CT scans as well as patient-specific clinical parameters for the prediction of OS for patients with advanced PC treated with 177Lu-PSMA therapy

The cAMP response element modulator (CREM) regulates TH2 mediated inflammation

A characteristic feature of allergic diseases is the appearance of a subset of CD4+ cells known as TH2 cells, which is controlled by transcriptional and epigenetic mechanisms. We aimed to analyze the role of CREM, a known transcriptional activator of T cells, with regard to TH2 responses and allergic diseases in men and mice. Here we demonstrate that T cells of asthmatic children and PBMCs of adults with atopy express lower mRNA levels of the transcription factor CREM compared to cells from healthy controls. CREM deficiency in murine T cells results in enhanced TH2 effector cytokines in vitro and in vivo and CREM-/- mice demonstrate stronger airway hyperresponsiveness in an OVA-induced asthma model. Mechanistically, both direct CREM binding to the IL-4 and IL-13 promoter as well as a decreased IL-2 dependent STAT5 activation suppress the TH2 response. Accordingly, mice selectively overexpressing CREMα in T cells display decreased TH2 type cytokines in vivo and in vitro, and are protected in an asthma model. Thus, we provide evidence that CREM is a negative regulator of the TH2 response and determines the outcome of allergic asthma

La laïcité en question

Cet ouvrage inscrit la réflexion sur la laïcité dans la longue durée de l’histoire française et allemande, tout en croisant les approches disciplinaires, afin d’éclairer respectivement chacun des deux modèles dans sa spécificité. Les contributeurs (historiens, philosophes, théologiens, juristes, sociologues, germanistes) s’y écartent de conceptions philosophico-idéologiques de la laïcité et se placent sur le terrain de l’histoire et du droit pour se mettre à distance de partis pris militants qui biaisent la réflexion sur un sujet si brûlant. Si le mot laïcité n’a pas d’équivalent en allemand, cela ne veut pas dire cependant que les réalités françaises et allemandes en la matière ne soient pas comparables. Divers éléments entrent en ligne de compte pour ce faire : outre le critère de neutralité réciproque du politique et du religieux, le respect de la liberté religieuse dans ses diverses facettes, la séparation des Églises et de l’État sous ses différentes formes, le statut juridique accordé aux sociétés religieuses, la mise en oeuvre du droit à l’incroyance. L’ouvrage, organisé selon une structure à la fois chronologique et thématique comporte, outre l’introduction, quatre parties où alternent analyses générales et études de cas : la laïcité dans l’histoire ; questions juridiques et politiques ; modèles allemand et français à l’épreuve de l’islam ; l’école face à la religion et à la transmission des valeurs en Allemagne et en France

mHTT Seeding Activity:A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease

Self-propagating, amyloidogenic mutant huntingtin (mHTT) aggregates may drive progression of Huntington's disease (HD). Here, we report the development of a FRET-based mHTT aggregate seeding (FRASE) assay that enables the quantification of mHTT seeding activity (HSA) in complex biosamples from HD patients and disease models. Application of the FRASE assay revealed HSA in brain homogenates of presymptomatic HD transgenic and knockin mice and its progressive increase with phenotypic changes, suggesting that HSA quantitatively tracks disease progression. Biochemical investigations of mouse brain homogenates demonstrated that small, rather than large, mHTT structures are responsible for the HSA measured in FRASE assays. Finally, we assessed the neurotoxicity of mHTT seeds in an inducible Drosophila model transgenic for HTTex1. We found a strong correlation between the HSA measured in adult neurons and the increased mortality of transgenic HD flies, indicating that FRASE assays detect disease-relevant, neurotoxic, mHTT structures with severe phenotypic consequences in vivo. Ast et al. present the development of a FRET-based aggregate seeding (FRASE) assay that facilitates the detection and quantification of mHTT seeding activity (HSA) in complex biosamples. They show that HSA is detectable in brains of presymptomatic Huntington's disease (HD) mice and correlates with disease progression and neurotoxicity in HD transgenic flies

Malignant Melanoma S3-Guideline "Diagnosis, Therapy and Follow-up of Melanoma"

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years