The importance of IκBNS and Ca²+ signaling in DLBCL development

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disorder of mature B-lymphocytes presenting with 40% of novel lymphoma cases worldwide the most common subtype of adult Non-Hodgkin lymphoma. DLBCL is characterised by a high degree of heterogeneity regarding clinical, pathologic and molecular genetic issues. Gene expression profiling revealed distinct molecular DLBCL subtypes resembling germinal centre B-cells (GCB DLBCL) and activated B-cells (ABC DLBCL). Despite advances in therapy, the 3-year progression free survival rates of GCB and ABC DLBCL upon immunochemotherapy are still at 74% and 40%, respectively. Consequently, there is an obvious need for identifying new molecular targets and biomarkers serving as starting points to develop new, more efficient therapeutic strategies especially of the adverse ABC DLBCL subtype. In the present study we were able to demonstrate that IκBNS is constitutively expressed in ABC DLBCL cell lines and human biopsies, whereas IκBNS expression is absent in GCB DLBCL. We noticed that two IκBNS isoforms were detectable, the described p35 and a second larger IκBNS isoform exhibiting an additional N-terminal unstructured portion. Silencing of IκBNS led to a reduced growth of ABC DLBCL cell lines, suggesting an oncogenic function of IκBNS. Promoter studies suggested that IκBNS expression is under the control of NF-κB and NFAT signalling. Interestingly, we detected constitutive activation of NFAT in DLBCL cell lines, which was necessary to drive the expression of IκBNS in ABC DLBCL. Calcineurin inhibitors, which decrease the activity of NFAT proteins, did not only impair the expression of IκBNS, but also induced cell death in multiple ABC DLBCL cell lines. The expression of the pro-survival cytokines IL-6/-10 was markedly reduced by calcineurin inhibition, which might at least partially explain their toxicity in ABC DLBCL cell lines. With the help of phosphoproteomics, we identified several new calcineurin substrates in ABC DLBCL, including CD79, suggesting a more central role of calcineurin in tumorigenesis. Taken together, these results provide first insights into the essential function of IκBNS in the development of ABC DLBCL. Furthermore, we suggest IκBNS as a promising biomarker to discriminate ABC from GCB DLBCL. Finally, we propose that calcineurin inhibitors could have therapeutic potential for the treatment of aggressive ABC DLBCL

Biodiversity and structure of spider communities along a metal pollution gradient

The objective of the study was to determine whether long-term metal pollution affects communities of epigeal spiders (Aranea), studied at three taxonomic levels: species, genera, and families. Biodiversity was defined by three indices: the Hierarchical Richness Index (HRI), Margalef index (DM) and Pielou evenness index (J). In different ways the indices describe taxa richness and the distribution of individuals among taxa. The dominance pattern of the communities was described with four measures: number of dominant species at a site, percentage of dominant species at a site, average dominant species abundance at a site, and the share of the most numerous species (Alopecosa cuneata) at a site. Spiders were collected along a metal pollution gradient in southern Poland, extending ca. 33 km from zinc and lead smelter to an uncontaminated area. The zinc concentration in soil was used as the pollution index.The study revealed a significant effect of metal pollution on spider biodiversity as described by HRI for species (p = 0.039), genera (p = 0.0041) and families (p = 0.0147), and by DM for genera (p = 0.0259) and families (p = 0.0028). HRI correlated negatively with pollution level, while DM correlated positively. This means that although broadly described HRI diversity decreased with increasing pollution level, species richness increased with increasing contamination. Mesophilic meadows were generally richer. Pielou (J) did not show any significant correlations. There were a few evidences for the intermediate disturbance hypothesis: certain indices reached their highest values at moderate pollution levels rather than at the cleanest or most polluted sites

Do fiscal rules matter? A survey on recent evidence

Fiscal rules are argued to be important for sound and sustainable fiscal policies and have been increasingly adopted over the last 20 years. However, as increased fiscal pressure and fiscal risks urge countries to address the public debt legacy left by recent economic crises, fiscal rules come under greater scrutiny. To inform the debate on fiscal frameworks, this paper presents a comprehensive survey of the empirical literature on the impact of fiscal rules. In particular, we discuss the recent empirical literature that investigates the impact of fiscal rules on various elements related to fiscal performance and beyond. Our survey finds that fiscal rules are associated with improved fiscal performance as approximated by improved budget balances, lower debt and lower public spending volatility. Furthermore, empirical research finds that fiscal rules are related to more accurate budget forecasts and improved sovereign bond ratings. From a macroeconomic perspective, well-designed fiscal rules do not principally undermine public investment and do not increase pro-cyclicality in fiscal-policy making. These results, however, also depend on the broader economic and institutional context. Moreover, there is emerging literature that links fiscal rules to broader outcomes, such as income distribution and political polarisation. We discuss methodological challenges related to identification and point to avenues for future research

Échantillonner des populations rares

L’échantillonnage de populations dont il est impossible de connaître a priori les contours avec précision constitue un défit majeur en sciences sociales. Certaines solutions ont néanmoins été proposées pour tenter de produire des données fiables dans ce type de cas. Parmi les procédures d’échantillonnage alternatives, c’est indubitablement la méthode du Respondant Driven Sampling (RDS) – «  échantillonnage guidé par les répondants » –, apparue à la fin des années 1990 qui a connu la plus forte audience. L’ambition de cet article sera de présenter les points forts et les faiblesses de cette procédure, à travers un retour sur expérience dans le cadre d’une recherche sur des «  musicien‑ne‑s ordinaires » suisses romand‑e‑s. Il s’agira premièrement de présenter l’outillage théorique, méthodologique et statistique qui structure cette procédure d’échantillonnage. Dans un deuxième temps, on montrera comment le RDS permet de construire des données originales et de qualité par rapport à d’autres procédures plus souvent utilisées – notamment l’enquête «  en ligne » – pour des recherches sur des populations «  rares ». Enfin, on reviendra sur les limites de l’échantillon recruté, du point de vue de la structuration du réseau complet des collaborations musicales sur une année de référence.Sampling populations without clear administrative boundaries is a major issue in social sciences. Some solutions have, however, been proposed in order to gather reliable data on this kind of populations. The Respondant Driven Sampling (RDS) undoubtedly figures as the most widespread of alternative sampling techniques. The main goal of this article is to discuss the strengths and the weaknesses of this procedure through our field work experience on Swiss “ordinary musicians.” The theoretical, methodological and statistical tools involved in this kind of procedure will be presented first. Secondly, the article turns to discuss the originality and robustness of data gathered by the RDS method as compared with other more common procedure (like online surveys) in research on “rare” but not necessarily “hard to reach” populations. Finally, the article evaluates the limits of the sample by analysing the structuration of the whole network of musical collaborations

Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a major therapeutic challenge. DLBCL can be classified into at least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad anti-tumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and JAK kinases. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL