The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells

Background: Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Methods: Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. Results: HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Conclusion: Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.<br

Small-scale (flash) flood early warning in the light of operational requirements: opportunities and limits with regard to user demands, driving data, and hydrologic modeling techniques

In recent years, the Free State of Saxony (Eastern Germany) was repeatedly hit by both extensive riverine flooding, as well as flash flood events, emerging foremost from convective heavy rainfall. Especially after a couple of small-scale, yet disastrous events in 2010, preconditions, drivers, and methods for deriving flash flood related early warning products are investigated. This is to clarify the feasibility and the limits of envisaged early warning procedures for small catchments, hit by flashy heavy rain events. Early warning about potentially flash flood prone situations (i.e., with a suitable lead time with regard to required reaction-time needs of the stakeholders involved in flood risk management) needs to take into account not only hydrological, but also meteorological, as well as communication issues. Therefore, we propose a threefold methodology to identify potential benefits and limitations in a real-world warning/reaction context. First, the user demands (with respect to desired/required warning products, preparation times, etc.) are investigated. Second, focusing on small catchments of some hundred square kilometers, two quantitative precipitation forecasts are verified. Third, considering the user needs, as well as the input parameter uncertainty (i.e., foremost emerging from an uncertain QPF), a feasible, yet robust hydrological modeling approach is proposed on the basis of pilot studies, employing deterministic, data-driven, and simple scoring methods

Lattice permutations and Poisson-Dirichlet distribution of cycle lengths

We study random spatial permutations on Z^3 where each jump x -> \pi(x) is penalized by a factor exp(-T ||x-\pi(x)||^2). The system is known to exhibit a phase transition for low enough T where macroscopic cycles appear. We observe that the lengths of such cycles are distributed according to Poisson-Dirichlet. This can be explained heuristically using a stochastic coagulation-fragmentation process for long cycles, which is supported by numerical data.Comment: 18 pages, 14 figure

Repeatability and reproducibility of cerebral 23Na imaging in healthy subjects

Abstract Background Initial reports of 23Na magnetic resonance imaging (MRI) date back to the 1970s. However, methodological challenges of the technique hampered its widespread adoption for many years. Recent technical developments have overcome some of these limitations and have led to more optimal conditions for 23Na-MR imaging. In order to serve as a reliable tool for the assessment of clinical stroke or brain tumor patients, we investigated the repeatability and reproducibility of cerebral sodium (23Na) imaging in healthy subjects. Methods In this prospective, IRB approved study 12 consecutive healthy volunteers (8 female, age 31 ± 8.3) underwent three cerebral 23Na-MRI examinations at 3.0 T (TimTrio, Siemens Healthineers) distributed between two separate visits with an 8 day interval. For each scan a T1w MP-RAGE sequence for anatomical referencing and a 3D-density-adapted, radial GRE-sequence for 23Na-imaging were acquired using a dual-tuned (23Na/1H) head-coil. On 1 day, these scans were repeated consecutively; on the other day, the scans were performed once. 23Na-sequences were reconstructed according to the MP-RAGE sequence, allowing direct cross-referencing of ROIs. Circular ROIs were placed in predetermined anatomic regions: gray and white matter (GM, WM), head of the caudate nucleus (HCN), pons, and cerebellum. External 23Na-reference phantoms were used to calculate the tissue sodium content. Results Excellent correlation was found between repeated measurements on the same day (r2 = 0.94), as well as on a different day (r2 = 0.86). No significant differences were found based on laterality other than in the HCN (63.1 vs. 58.7 mmol/kg WW on the right (p = 0.01)). Pronounced inter-individual differences were identified in all anatomic regions. Moderate to good correlation (0.310 to 0.701) was found between the readers. Conclusion Our study has shown that intra-individual 23Na-concentrations in healthy subjects do not significantly differ after repeated scans on the same day and a pre-set time interval. This confirms the repeatability and reproducibility of cerebral 23Na-imaging. However, with manual ROI placement in predetermined anatomic landmarks, fluctuations in 23Na-concentrations can be observed

Three-Dimensional In Vivo Imaging of the Murine Liver: A Micro-Computed Tomography-Based Anatomical Study

Various murine models are currently used to study acute and chronic pathological processes of the liver, and the efficacy of novel therapeutic regimens. The increasing availability of high-resolution small animal imaging modalities presents researchers with the opportunity to precisely identify and describe pathological processes of the liver. To meet the demands, the objective of this study was to provide a three-dimensional illustration of the macroscopic anatomical location of the murine liver lobes and hepatic vessels using small animal imaging modalities. We analysed micro-CT images of the murine liver by integrating additional information from the published literature to develop comprehensive illustrations of the macroscopic anatomical features of the murine liver and hepatic vasculature. As a result, we provide updated three-dimensional illustrations of the macroscopic anatomy of the murine liver and hepatic vessels using micro-CT. The information presented here provides researchers working in the field of experimental liver disease with a comprehensive, easily accessable overview of the macroscopic anatomy of the murine liver

Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOS &lt;sup&gt;SMARCB1-&lt;/sup&gt; , which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS &lt;sup&gt;SMARCB1-&lt;/sup&gt; show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOS &lt;sup&gt;Smarcb1-&lt;/sup&gt; . In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOS &lt;sup&gt;SMARCB1-&lt;/sup&gt; within the TME

WHO-EORTC classification for cutaneous lymphomas

Primary cutaneous lymphomas are currently classified by the European Organization for Research and Treatment of Cancer (EORTC) classification or the World Health Organization (WHO) classification, but both systems have shortcomings. In particular, differences in the classification of cutaneous T-cell lymphomas other than mycosis fungoides, S\uc3\ua9zary syndrome, and the group of primary cutaneous CD30+lymphoproliferative disorders and the classification and terminology of different types of cutaneous B-cell lymphomas have resulted in considerable debate and confusion. During recent consensus meetings representatives of both systems reached agreement on a new classification, which is now called the WHO-EORTC classification. In this paper we describe the characteristic features of the different primary cutaneous lymphomas and other hematologic neoplasms frequently presenting in the skin, and discuss differences with the previous classification schemes. In addition, the relative frequency and survival data of 1905 patients with primary cutaneous lymphomas derived from Dutch and Austrian registries for primary cutaneous lymphomas are presented to illustrate the clinical significance of this new classification