An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.Alzheimer's disease ͉ extracellular signal-regulated kinase inhibitor ͉ paired helical filament ͉ tangles

Bendamustine is a novel cytostatic agent, with activity in nonHodgkin's lymphomas including B-chronic lymphocytic leukemia (B-CLL). The knowledge about its mode of action, however, is still limited. Here, we investigated the in vitro ability of bendamustine to induce apoptosis on freshly isolated peripheral lymphocytes in B-CLL and analyze the potential underlying mechanisms of action for inducing apoptosis. In CLL cells taken from 37 previously treated and untreated CLL patients, we investigated the influence of bendamustine alone, and in combination with fludarabine, on the induction of apoptosis and changes of Bcl-2 and Bax expression on mRNA and protein level using the RNase protection assay or flow cytometry, respectively. Apoptotic cells were determined with flow cytometry using the fluorescent DNA-binding agent 7-ADD. Using bendamustine alone in concentrations from 1 g/ml to 50 g/ml, a dose-and time-dependent manner of cytotoxicity from 30.4% to 94.8% after 48 h could be observed. The LD50 for untreated and pretreated CLL cells was 7.3 or 4.4 g/ml, respectively. The median apoptotic rate was similar in both groups. The combination of bendamustine with fludarabine led to a highly synergistic effect in inducing apoptosis, which was 150% higher than expected for bendamustine plus fludarabine. The level of the initial Bcl-2 and Bax protein and the m-RNA expression remained unchanged during the incubation with bendamustine. In conclusion, this study demonstrates for the first time the in vitro efficacy of bendamustine in inducing apoptosis in B-CLL cells alone and in combination with fludarabine.

CD30, a member of the tumor necrosis factor receptor (TNFR) family, is a characteristic cell surface receptor for activated T-cells and the malignant cells of Hodgkin's disease (HD), anaplastic large cell lymphoma (ALCL) and a few other non-Hodgkin's lymphomas. As an independent predictor of disease progression and poor prognosis, high serum levels of soluble CD30 (sCD30) have prognostic significance for patients with CD30-positive lymphomas and viral infections. Activation of CD30 by ligand binding or cross-linking with immobilized antibody leads to trimerization of the receptor, recruitment of signaling proteins and transducing of numerous effects. Due to the lack of an intrinsic enzymatic domain, signal transduction is exclusively mediated by the members of the TNFR-associated factor (TRAF) family and the various TRAF-binding proteins. CD30 signaling can induce several pathways including the activation of NFkappaB and the MAP kinases. CD30 mediated signal transduction is capable of promoting cell proliferation and cell survival as well as antiproliferative effects and cell death depending on cell type and co-stimulatory effects. Some data indicate the opposite signaling of CD30 in HD or ALCL cells, while other information point to pleiotropic signaling pathways in both malignancies. The pro and contra of this controversy is discussed in this review.

One of the major characteristics of anaplastic large cell lymphomas (ALCL) is the expression of the Ki-1/CD30 antigen. While the receptor mediates NF-kB-activation in Hodgkin's lymphomas, some data suggest the CD30-mediated apoptosis of other CD30-expressing cells. We were able to demonstrate that activation of CD30 leads to dierent eects regarding cell proliferation of the ALCL-derived cell lines Karpas 299 and JB6. Western and Northern blotting analysis revealed that CD30-induced growth inhibition of Karpas 299 cells correlated with a strong upregulation of the cell cycle inhibitor p21. We found a non activating point mutation at codon 273 in exon 8 of the p53 gene in Karpas 299 cells which indicates an p53-independent mechanism for induced p21 expression. Abundant p21 protein expression resulted in hypophosphorylation of the retinoblastoma protein (Rb) and inhibition of the proliferating cell nuclear antigen (PCNA). CD30-stimulated cells showed no indications of apoptotic cell death, like genomic DNA fragmentation or cleavage of the caspase-3 target protein poly (ADP-ribose) polymerase (PARP). Our results indicate that CD30 is able to mediate an p21-associated cell cycle arrest in ALCL with possible implications for prognosis and clinical treatment. Oncogene (2001) 20, 590 ± 598.

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