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Aim: To investigate the relationship between off-target binding of the amyloid tracer [ 18 F]florbetaben (FBB) in the skull and skull density., Methods: Forty-three consecutive patients were included retrospectively (age 70.2±7.5y, 42% females, 65% amyloid-positive). For each patient, CT skull density (in Hounsfield units) and (late) FBB uptake in the skull were obtained using an individual skull mask generated by warping the skull tissue probability map provided by the statistical parametric mapping software package (version SPM12) to the native patient space. Skull FBB uptake (mean of the 10% hottest voxels) was scaled to the individual median FBB uptake in the pons. The association between skull FBB uptake and skull density was tested by correlation analyses. Univariate analysis of variance (ANOVA) of skull FBB uptake with dichotomized skull density (low: ≤ median, high), sex (female, male) and amyloid-status (positive, negative) as between-subjects factors was used to assess the impact of sex and amyloid status., Results: There was a significant inverse correlation between skull FBB uptake and skull density (Pearson correlation coefficient -0.518, p < 0.001; Spearman rho -0.321, p = 0.036). The ANOVA confirmed the bone density effect on the FBB uptake in the skull (p = 0.019). In addition, sex (p = 0.012) and density*sex interaction (p = 0.016) had a significant impact. Skull FBB uptake was significantly higher in females with low skull density than for all other combinations of sex and skull density. Amyloid status did not reach statistical significance (p = 0.092)., Conclusion: Off-target binding of FBB in the skull is inversely associated with skull density. The relationship is mainly driven by females. Amyloid status does not have a major impact on skull FBB binding., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Plasma cell differentiation is a tightly regulated process that requires appropriate T cell helps to reach the induction threshold. To further understand mechanisms by which T cell inputs regulate B cell fate decision, we investigate the minimal IL-2 stimulation for triggering human plasma cell differentiation in vitro. Here we show that the timed repression of BACH2 through IL-2-mediated ERK/ELK1 signalling pathway directs plasma cell lineage commitment. Enforced BACH2 repression in activated B cells unlocks the plasma cell transcriptional program and induces their differentiation into immunoglobulin M-secreting cells. RNA-seq and ChIP-seq results further identify BACH2 target genes involved in this process. An active regulatory region within the BACH2 super-enhancer, under ELK1 control and differentially regulated upon B-cell activation and cellular divisions, helps integrate IL-2 signal. Our study thus provides insights into the temporal regulation of BACH2 and its targets for controlling the differentiation of human naive B cells.

Unlabelled: Liver damage in humans is induced by various insults including alcohol abuse, hepatitis B/C virus infection, autoimmune or metabolic disorders and, when persistent, leads to development of liver fibrosis. Because the nuclear factor-κB (NF-κB) system is activated in response to several of these stresses, we hypothesized that NF-κB activation in hepatocytes may contribute to fibrosis development. To activate the NF-κB signaling pathway in a time- and cell-type-specific manner in the liver, we crossed transgenic mice carrying the tetracycline-responsive transactivator under the control of the liver activator protein promotor with transgenic mice carrying a constitutively active form of the Ikbkb gene (IKK2 protein [CAIKK2]). Double-transgenic mice displayed doxycycline-regulated CAIKK2 expression in hepatocytes. Removal of doxycycline at birth led to activation of NF-κB signaling, moderate liver damage, recruitment of inflammatory cells, hepatocyte proliferation, and ultimately to spontaneous liver fibrosis development. Microarray analysis revealed prominent up-regulation of chemokines and chemokine receptors and this induction was rapidly reversed after switching off the CAIKK2 expression. Turning off the transgene expression for 3 weeks reversed stellate cell activation but did not diminish liver fibrosis. The elimination of macrophages by clodronate-liposomes attenuated NF-κB-induced liver fibrosis in a liver-injury-independent manner., Conclusion: Our results revealed that hepatic activation of IKK/NF-κB is sufficient to induce liver fibrosis by way of macrophage-mediated chronic inflammation. Therefore, agents controlling the hepatic NF-κB system represent attractive therapeutic tools to prevent fibrosis development in multiple chronic liver diseases., (Copyright © 2012 American Association for the Study of Liver Diseases.)

The Ewing family of tumors (EFT) is an important group of pediatric malignancies with a guarded prognosis. Little is known about the heterogeneity of EFT cells, and the cellular origin of EFT is disputed. We now add evidence that EFT are heterogeneous by showing that EFT cells from spheres growing in serum-free medium are markedly more tumorigenic than adherently growing EFT cells. Furthermore, EFT cells strongly expressing CD57 (HNK-1), a surface marker for migrating and proliferating neural crest cells, are more tumorigenic than cells with low expression of CD57, possibly mediated in part by enhanced adhesion and invasion. We contribute to the controversy about the cellular origin of EFT by clonal analysis, showing that EFT cells can differentiate similar to neural crest cells. These data increase our knowledge about the pathogenesis and heterogeneity of EFT.