Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors

Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant-negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks

Processes, Roles and Their Interactions

Taking an interaction network oriented perspective in informatics raises the challenge to describe deterministic finite systems which take part in networks of nondeterministic interactions. The traditional approach to describe processes as stepwise executable activities which are not based on the ordinarily nondeterministic interaction shows strong centralization tendencies. As suggested in this article, viewing processes and their interactions as complementary can circumvent these centralization tendencies. The description of both, processes and their interactions is based on the same building blocks, namely finite input output automata (or transducers). Processes are viewed as finite systems that take part in multiple, ordinarily nondeterministic interactions. The interactions between processes are described as protocols. The effects of communication between processes as well as the necessary coordination of different interactions within a processes are both based on the restriction of the transition relation of product automata. The channel based outer coupling represents the causal relation between the output and the input of different systems. The coordination condition based inner coupling represents the causal relation between the input and output of a single system. All steps are illustrated with the example of a network of resource administration processes which is supposed to provide requesting user processes exclusive access to a single resource.Comment: In Proceedings IWIGP 2012, arXiv:1202.422

Efficient three-material PLIC interface positioning on unstructured polyhedral meshes

This paper introduces an efficient algorithm for the sequential positioning (or nested dissection) of two planar interfaces in an arbitrary polyhedron, such that, after each truncation, the respectively remaining polyhedron admits a prescribed volume. This task, among others, is frequently encountered in the numerical simulation of three-phase flows when resorting to the geometric Volume-of-Fluid method. For two-phase flows, the recent work of Kromer & Bothe (doi.org/10.1016/j.jcp.2021.110776) addresses the positioning of a single plane by combining an implicit bracketing of the sought position with up to third-order derivatives of the volume fraction. An analogous application of their highly efficient root-finding scheme to three-material configurations requires computing the volume of a twice truncated arbitrary polyhedron. The present manuscript achieves this by recursive application of the Gaussian divergence theorem in appropriate form, which allows to compute the volume as a sum of quantities associated to the faces of the original polyhedron. With a suitable choice of the coordinate origin, accounting for the sequential character of the truncation, the volume parametrization becomes co-moving with respect to the planes. This eliminates the necessity to establish topological connectivity and tetrahedron decomposition after each truncation. After a detailed mathematical description of the concept, we conduct a series of carefully designed numerical experiments to assess the performance in terms of polyhedron truncations. The high efficiency of the two-phase positioning persists for sequential application, thereby being robust with respect to input data and possible intersection topologies. In comparison to an existing decomposition-based approach, the number of truncations was reduced by up to an order of magnitude

Long non-coding RNAs as novel components in the TP53 pathway

C

Expression of the Neuroblastoma-Associated ALK-F1174L Activating Mutation During Embryogenesis Impairs the Differentiation of Neural Crest Progenitors in Sympathetic Ganglia

Neuroblastoma (NB) is an embryonal malignancy derived from the abnormal differentiation of the sympathetic nervous system. The Anaplastic Lymphoma Kinase (ALK) gene is frequently altered in NB, through copy number alterations and activating mutations, and represents a predisposition in NB-genesis when mutated. Our previously published data suggested that ALK activating mutations may impair the differentiation potential of neural crest (NC) progenitor cells. Here, we demonstrated that the expression of the endogenous ALK gene starts at E10.5 in the developing sympathetic ganglia (SG). To decipher the impact of deregulated ALK signaling during embryogenesis on the formation and differentiation of sympathetic neuroblasts, Sox10-Cre;LSL-ALK-F1174L embryos were produced to restrict the expression of the human ALK-F1174L transgene to migrating NC cells (NCCs). First, ALK-F1174L mediated an embryonic lethality at mid-gestation and an enlargement of SG with a disorganized architecture in Sox10-Cre;LSL-ALK-F1174L embryos at E10.5 and E11.5. Second, early sympathetic differentiation was severely impaired in Sox10-Cre;LSL-ALK-F1174L embryos. Indeed, their SG displayed a marked increase in the proportion of NCCs and a decrease of sympathetic neuroblasts at both embryonic stages. Third, neuronal and noradrenergic differentiations were blocked in Sox10-Cre;LSL-ALK-F1174L SG, as a reduced proportion of Phox2b+ sympathoblasts expressed βIII-tubulin and almost none were Tyrosine Hydroxylase (TH) positive. Finally, at E10.5, ALK-F1174L mediated an important increase in the proliferation of Phox2b+ progenitors, affecting the transient cell cycle exit observed in normal SG at this embryonic stage. Altogether, we report for the first time that the expression of the human ALK-F1174L mutation in NCCs during embryonic development profoundly disturbs early sympathetic progenitor differentiation, in addition to increasing their proliferation, both mechanisms being potential crucial events in NB oncogenesis

S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway

Peer reviewedPublisher PD

Evaluation of a Novel Rapid Test System for the Detection of Specific IgE to Hymenoptera Venoms

Background. The Allergy Lateral Flow Assay (ALFA) is a novel rapid assay for the detection of sIgE to allergens. The objective of this study is the evaluation of ALFA for the detection of sIgE to bee venom (BV) and wasp venom (WV) in insect venom allergic patients. Methods. Specific IgE to BV and WV was analyzed by ALFA, ALLERG-O-LIQ, and ImmunoCAP in 80 insect venom allergic patients and 60 control sera. Sensitivity and specificity of ALFA and correlation of ALFA and ImmunoCAP results were calculated. Results. The sensitivity/specificity of ALFA to the diagnosis was 100%/83% for BV and 82%/97% for WV. For insect venom allergic patients, the Spearman correlation coefficient for ALFA versus ImmunoCAP was 0.79 for BV and 0.80 for WV. However, significant differences in the negative control groups were observed. Conclusion. ALFA represents a simple, robust, and reliable tool for the rapid detection of sIgE to insect venoms