Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin's lymphoma

Classical Hodgkin's lymphoma (cHL), although originating from B-cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted now a high-throughput pharmacological screening based on more than 28,000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote re-expression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of two of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the anti-leukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked re-expression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibody-mediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell Non-Hodgkin's lymphoma-tailored small compound inhibitors Ibrutinib and Idelalisib. In essence, we report here a conceptually novel, re-differentiation-based treatment strategy for cHL

DRIFT: incorporating an eco-social system network and time series approach into environmental flow assessments

DRIFT (Downstream Response to Imposed Flow Transformation) is an interactive, ecological-social process and software package to assist with environmental flow assessments and river management decision-making. It was originally developed in the 1990s and has subsequently evolved and been applied in over 50 studies in Africa, South America, Asia and Europe. Early versions provided predicted ecological responses over time to specific flow changes, while the latest version provides responses to flow and non-flow drivers as seasonal time series. here, an ecosystem or eco-social network is built for the river, with links between driver and responder indicators, and relationships created for each link. the network and relationships are developed and entered into the software by specialists based on available data and their knowledge. A range of scenarios is explored through the predicted indicator time series, discipline and site level ecological integrity, and social well-being. while DRIFT models vary in complexity, they are all based on relatively simple fundamental principles and arithmetic. Sequential averaging and summation through the system network is used to calculate an indicator’s response to different drivers for successive seasons over time, while the discipline and site level summaries are found using weighted summation of indicator results and individual discipline results, respectively. Information from different specialist areas is therefore processed in the same way, thereby enabling coherent integration across disciplines

Attaining low uncertainties in measurements with RF signal generators and analyzers

In this paper, practical investigations of level accuracy and uncertainties using a Rohde & Schwarz signal generator (R&S SMB-B140) and spectrum analyzer (R&S FSV40) are performed up to 30GHz. We show that it is possible to measure frequency responses of DUTs with uncertainties below ±0.05dB up to 30 GHz instead of ±0.5...1.5dB using auto settings, standard setup, or relying on datasheets. The level linearity of instruments with integrated step attenuators is shown to be improved to ±0.03dB instead of ±0.3...1dB by using a special “hybrid” procedure. Furthermore, it is shown how computer aided measurements procedures should be programmed with these instruments to attain low deviations between measurements

A versatile, automated, cost-effective testing platform for hands-on UHF RFID measurements

In this paper, we present cost-effective techniques to assess UHF RFID performance for real world applications. This includes a positioner, made from roof battens and stepper motors, which can position a tag in 3-D space. It can be used for a variety of measurements, e.g., tag RSSI or phase patterns or influence of distance to materials and other tags. We also present a 1-D positioner from similar materials to lift a reader antenna to show reflections from ground and perform limited motion measurements. For the measurements themselves, we use a commercial off-the-shelf R420 Impinj reader, which we control via LLRP commands, implemented in Python. To verify the communication link between reader and tag, we use a low-cost SDR based on an RTL2832U chip. We also built clamps and adapters from hardware store materials to connect a tag to RF equipment to read the communication and test external antennas. For bulk detection performance testing, we built a frame with RF neutral layers with attached tags

Profiling the Enthusiastic, Neutral, and Sceptical Users of Conditionally Automated Cars in 17 Countries: A Questionnaire Study

The L3Pilot project tested SAE Level 3 (L3) conditionally automated driving functions addressing driving and travel behavior, impacts on safety, efficiency, environment and socio-economics, and user acceptance. To investigate individual variance in acceptance of conditionally automated cars, an online survey was performed among 18,631 respondents from 17 countries evaluating differences in age, gender, knowledge about the functionality of conditionally automated cars, awareness, information consumption behavior, and expected benefits of conditionally automated cars. Respondents were divided into Enthusiasts, Neutrals, and Sceptics differing in a high, moderate, and low acceptance of conditionally automated cars, respectively. Enthusiasts, Neutrals, and Sceptics differed most with regard to the expected benefits in the productive use of travel time, comfort, and safety of conditionally automated cars. Enthusiasts were male, younger, more knowledgeable about conditionally automated cars, more aware of automated cars, and more likely to receive information about automated cars from different sources, expecting improvements in the productive use of travel time, comfort, and safety due to conditionally automated cars. All groups were most knowledgeable about the lane keeping behavior of conditionally automated cars and least knowledgeable about the operation of conditionally automated cars in dedicated operational design domains. The results indicate that the communication and marketing of automated cars should create a realistic image of the capabilities and limitations of conditionally automated cars where user education programs should be harmonized to calibrate expectations and educate the public

Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations

This article addresses the opposing roles of NF-κB in cancer therapy and highlights the context-dependent nature of cancer pathways. Using a cross-species approach, comparing human and mouse model systems, and extrapolating the data to a patient cohort, Jing et al. identify oncogenic networks in which chemotherapy-activated NF-κB signaling no longer mediates resistance, but promotes senescence and contributes to the outcome of cancer therapy. It is related to the article by Chien et al