Victor Klemperer im Kreise seiner Geschwister: Rebell und Hoffnungsträger

'Der Aufsatz zu den Geschwisterbeziehungen des deutsch-jüdischen Romanistikprofessors Victor Klemperer (1881-1960) baut auf der Untersuchung seiner Autobiographie Curriculum Vitae und der Tagebücher der Jahre 1918-1933 auf. Es geht dabei um die Frage, welche Lebensbereiche mit welchen Mitteln von seinen Geschwistern beeinflusst und geprägt wurden, und zwar in der langen Zeitspanne von der Geburt bis weit in seine professorale Amtszeit an der Technischen Hochschule Dresden hinein. Darüber hinaus wird erörtert, welche Strategien Klemperer entwickelte, um seine individuellen Vorstellungen gegenüber der Einwirkung seiner Geschwister durchzusetzen und seine eigenen Interessen zu wahren. Letztlich zielt die Fallstudie also darauf ab, die subjektive Wahrnehmung geschwisterlicher Einflussnahme zu erkennen. Dabei ist zum einen zu berücksichtigen, dass Klemperer der jüngste Nachkomme in einer Großfamilie war, zum anderen ist seine soziale Stellung innerhalb des aufstiegsorientierten deutsch-jüdischen Bildungsbürgertums zu berücksichtigen. Festzuhalten bleibt, dass vor allem die beiden ältesten Brüder versuchten, auf die zentralen Lebensbereiche - vor allem Partnerwahl und Werdegang - Einfluss zu nehmen; dies geschah hauptsächlich über den Weg der finanziellen Zuwendung an den lange Zeit mittellosen Privatdozenten. Victor versuchte diesen Einflüssen zunächst zu entkommen, was immer wieder in Spannungen und Konflikten mit seiner Familie mündete. Erst im fortgeschrittenen Alter gelang es ihm, seine Herkunftsfamilie im Wesentlichen zu akzeptieren.' (Autorenreferat)'Based on his autobiography Curriculum Vitae as well as his diaries of the years 1918-1933, this essay addresses the question of sibling influence in the life of Victor Klemperer (1881-1960), Judaeo-German professor of Romance language and literature at the Dresden Institute of Technology. The case study focuses on the problem on which areas of Klemperer's life his sisters and especially his brothers had an impact and by which means they tried to achieve their ends. Moreover, it addresses the question which strategies Klemperer devised in order to defend his interests and make his way in life despite his siblings. For this examination has been essential, first, to reflect upon the fact that Victor was the youngest of all brothers and sisters in his family, and secondly, to consider his social position within the ambitious Judaeo-German bourgeoisie of the Weimar era. To conclude, Klemperer was above all influenced by his two eldest brothers, who tried to impose their will on their youngest brother in regard to such pivotal issues as the choice of his marriage partner and professional career. They did so in particular by giving him money for his maintenance during his extended unpaid lectureship in literature. For a long time, Klemperer tried to resist this exertion of influence, thus causing repeated trouble and tensions between the siblings. It was not until his mature years that he was capable of reconciling himself with his family.' (author's abstract

Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours

The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metasasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate reduction in primary subcutaneous tumour growth. Overall, this study demonstrates the potential for Nk4 gene therapy of metastatic tumours, when delivered by AAV or non-viral methods

AAV2-mediated in vivo immune gene therapy of solid tumours

Abstract Background Many strategies have been adopted to unleash the potential of gene therapy for cancer, involving a wide range of therapeutic genes delivered by various methods. Immune therapy has become one of the major strategies adopted for cancer gene therapy and seeks to stimulate the immune system to target tumour antigens. In this study, the feasibility of AAV2 mediated immunotherapy of growing tumours was examined, in isolation and combined with anti-angiogenic therapy. Methods Immune-competent Balb/C or C57 mice bearing subcutaneous JBS fibrosarcoma or Lewis Lung Carcinoma (LLC) tumour xenografts respectively were treated by intra-tumoural administration of AAV2 vector encoding the immune up-regulating cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and the co-stimulatory molecule B7-1 to subcutaneous tumours, either alone or in combination with intra-muscular (IM) delivery of AAV2 vector encoding Nk4 14 days prior to tumour induction. Tumour growth and survival was monitored for all animals. Cured animals were re-challenged with tumourigenic doses of the original tumour type. In vivo cytotoxicity assays were used to investigate establishment of cell-mediated responses in treated animals. Results AAV2-mediated GM-CSF, B7-1 treatment resulted in a significant reduction in tumour growth and an increase in survival in both tumour models. Cured animals were resistant to re-challenge, and induction of T cell mediated anti-tumour responses were demonstrated. Adoptive transfer of splenocytes to naïve animals prevented tumour establishment. Systemic production of Nk4 induced by intra-muscular (IM) delivery of Nk4 significantly reduced subcutaneous tumour growth. However, combination of Nk4 treatment with GM-CSF, B7-1 therapy reduced the efficacy of the immune therapy. Conclusions Overall, this study demonstrates the potential for in vivo AAV2 mediated immune gene therapy, and provides data on the inter-relationship between tumour vasculature and immune cell recruitment

Imaging of the Inner Zone of Blast Furnaces Using MuonRadiography: The BLEMAB Project

The aim of the BLEMAB project (BLast furnace stack density Estimation through online Muons ABsorption measurements) is the application of muon radiography techniques, to image a blast furnace’s inner zone. In particular, the goal of the study is to characterize the geometry and size of the so-called “cohesive zone”, i.e., the spatial region where the slowly downward-moving material begins to soften and melt, which plays such an important role in the performance of the blast furnace itself. Thanks to the high penetration power of natural cosmic-ray muon radiation, muon transmission radiography could be an appropriate non invasive methodology for the imaging of large high-density structures such as a blast furnace, whose linear dimensions can be up to a few tens of meters. A state-of-the-art muon tracking system is currently in development and will be installed at a blast furnace on the ArcelorMittal site in Bremen (Germany), where it will collect data for a period of various months. In this paper, the status of the project and the expectations based on preliminary simulations are presented and briefly discussed

The BLEMAB European project: Muon radiography as an imaging tool in the industrial field

The European project called BLEMAB (BLast furnace stack density Estimation through on-line Muons ABsorption measurements), provides for the application of the muon radiography technique in the industrial environment. The project represents a non-invasive way of monitoring a blast furnace and in particular aims to study the geometric and density development of the so-called “cohesive zone”, which is important for the performance of the blast furnace itself. The installation of the detectors is expected in 2022 at the ArcelorMittal site in Bremen (Germany). This paper describes the status of the project, the experimental setup and the first results obtained with preliminary simulations. © 2022 Societa Italiana di Fisica. All rights reserved

Transient inhibition of the JAK/STAT pathway prevents B-ALL development in genetically predisposed mice

Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/− mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/− versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/− B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development.C. Cobaleda and C. Vicente-Dueñas labs are members of the EU COST Action LEGEND (CA16223). Research in C. Vicente-Dueñas group has been funded by Instituto de Salud Carlos III through the project " PI17/00167 and by a “Miguel Servet Grant” [CPII19/00024 - AES 2017-2020; co-funded by European Regional Development Fund (ERDF)/European Social Fund (ESF) "A way to make Europe"/"Investing in your future"]. J.J. Yang and K.E. Nichols receive funding from the American Lebanese Syrian Associated Charities (ALSAC) and R01CA241452 from the NCI. Research in ISG group is partially supported by FEDER and by SAF2015-64420-R MINECO/FEDER, UE, RTI2018-093314-B-I00 MCIU/AEI/FEDER, UE, 9659122185-122185-4-21 MCIU/AEI/FEDER, UE, by Junta de Castilla y León (UIC-017, CSI001U16, CSI234P18, and CSI144P20). M. Ramírez-Orellana and I. Sánchez-García have been supported by the Fundacion Unoentrecienmil (CUNINA project). C. Cobaleda, M. Ramírez-Orellana, and I. Sánchez-García have been supported by the Fundación Científica de la Asociación Española contra el Cáncer (PRYCO211305SANC). A. Casado-García (CSI067-18) and M. Isidro-Hernández (CSI021-19) are supported by FSE-Conserjería de Educación de la Junta de Castilla y León 2019 and 2020 (ESF, European Social Fund) fellowship, respectively. J. Raboso-Gallego is supported by a scholarship from University of Salamanca co-financed by Banco Santander and ESF. S. Alemán-Arteaga is supported by an Ayuda para Contratos predoctorales para la formación de doctores (PRE2019-088887)

European consensus statement on phenotypes of pustular psoriasis

Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co-incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments, and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [1-5], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials. The European Rare and Severe Psoriasis Expert Network (ERASPEN) was founded to define consensus criteria for diagnosis, deeply phenotype large groups of PP patients, analyse the genetics and pathophysiology and prepare for prospective clinical trials. This work reviews historical aspects of these conditions, new genetic findings and presents our initial considerations on the phenotypes of PP and a consensus classification of clinical phenotypes that will be used as a baseline for further, prospective studies of PP. Generalized Pustular Psoriasis (GPP) is defined as primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques). GPP can occur with or without systemic inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (> 3 months) condition. Acrodermatitis continua of Hallopeau (ACH) is characterized by primary, persistent (> 3 months), sterile, macroscopically visible pustules affecting the nail apparatus. Palmoplantar pustulosis (PPP) has primary, persistent (> 3 months), sterile, macroscopically visible pustules on palms and/or soles and can occur with or without PV