Significance of heterogeneous WNT and MAPK signaling in colorectal cancer

Constitutively active WNT signaling in colorectal cancers is hallmark and driver of malignant progression in these tumors. However, therapeutic targeting of WNT signaling is difficult due to anticipated side effects on WNT dependent normal tissue homeostasis. Using transcriptome, proteome and cell biology approaches, weidentified the transcription factor ADNP as a repressor of WNT signaling in colon cancer that can be induced pharmacologically by treatment with sub-narcotic doses of ketamine. Treatment results in significantly slowed tumor growth in pre-clinical xenograft models of colon cancer. Moreover, high ADNP expression in human colorectal cancers predicts improved disease outcome. Our findings indicate ADNP as a tumor suppressor and promising prognostic marker, and ketamine treatment with ADNP induction as a potential therapeutic approach that may add to current treatment protocols with benefits for colorectal cancer patients. Beside mutational WNT activation, about 40 % of colorectal cancers have mutations in KRAS with downstream activation of MAPK signaling that promotes tumor invasion and progression. We demonstrate that MAPK signaling shows strong intratumoral heterogeneity, and surprisingly remains regulated in colorectal cancer, irrespective of the tumors’ KRAS mutation status. Using primary colorectal cancer tissues,xenografts and MAPK reporter constructs, we show that tumor cells with high MAPK activity specifically reside at the leading tumor edge, cease to proliferate, undergo epithelial-mesenchymal transition (EMT), and express markers related to colon cancer stem cells. In KRAS mutant colon cancer cells, regulation of MAPK signaling is preserved through remaining wild-type RAS isoforms. Moreover, using a lineage tracing strategy, we provide evidence that high MAPK activity marks a progenitor cell compartment of growth fueling colon cancer cells in vivo. Our results imply that differential MAPK signaling balances EMT, cancer stem cell potential, and tumor growth in colorectal cancer. The positive crosstalk between WNT and MAPK signaling in colorectal cancer has strong implications for the development of combination therapies and a better understanding of the underlying mechanisms may lead to improved therapeutic strategies

Lightning current tests on radars and similar structures

A lightning stroke presents a real challenge due to its potential to cause irreversible damage on electronics. Future systems are packaged in composite shielding materials, which give little or no protection with respect to the electromagnetic fields caused by a nearby strike. A direct lightning stroke is even a higher threat for densely packed electronics in composite housings. Our objective is to determine an appropriate level of protection for a direct stroke. From the military standard MIL-STD-464A - Severe Strike, peak currents of the discharge between 50 and 200 kA, for the A pulse, 2 kA for the B pulse and 200 to 800 Amps for the C pulse are re-created in a closed environment. Experiments have been carried out using a test setup that could duplicate these three discharge components on structures representative for radar housing

Ultrafast processing of pixel detector data with machine learning frameworks

Modern photon science performed at high repetition rate free-electron laser (FEL) facilities and beyond relies on 2D pixel detectors operating at increasing frequencies (towards 100 kHz at LCLS-II) and producing rapidly increasing amounts of data (towards TB/s). This data must be rapidly stored for offline analysis and summarized in real time. While at LCLS all raw data has been stored, at LCLS-II this would lead to a prohibitive cost; instead, enabling real time processing of pixel detector raw data allows reducing the size and cost of online processing, offline processing and storage by orders of magnitude while preserving full photon information, by taking advantage of the compressibility of sparse data typical for LCLS-II applications. We investigated if recent developments in machine learning are useful in data processing for high speed pixel detectors and found that typical deep learning models and autoencoder architectures failed to yield useful noise reduction while preserving full photon information, presumably because of the very different statistics and feature sets between computer vision and radiation imaging. However, we redesigned in Tensorflow mathematically equivalent versions of the state-of-the-art, "classical" algorithms used at LCLS. The novel Tensorflow models resulted in elegant, compact and hardware agnostic code, gaining 1 to 2 orders of magnitude faster processing on an inexpensive consumer GPU, reducing by 3 orders of magnitude the projected cost of online analysis at LCLS-II. Computer vision a decade ago was dominated by hand-crafted filters; their structure inspired the deep learning revolution resulting in modern deep convolutional networks; similarly, our novel Tensorflow filters provide inspiration for designing future deep learning architectures for ultrafast and efficient processing and classification of pixel detector images at FEL facilities.Comment: 9 pages, 9 figure

Lightning current test on radar system

With the extended use of very sensitive electronic components, in modern systems, the danger represented by a lightning stroke becomes something not to be neglected. The Long Range Radar requires protection not only against direct strike, but also against the indirect effects. The formulation of the military standard MIL-STD-464A Severe Strike confirms this need. The peak currents of the discharges are between 50 and 200 kA, for the A pulse, 2 kA for the B pulse and 200 to 800 Amps for the C pulse. For a radar system placed high on a ship, the chosen approach is the fictitious Rolling Sphere Technique in order to confirm the protection offered by the design. Experiments have been carried out using a test setup that could duplicate the three discharge components

Lightning protection of ships in maritime and costal environment

An electromagnetic pulse due to a nearby lightning stroke generates a high intensity magnetic field. Thin metal layers as applied in composite structures cannot shield such a magnetic field. Electronic equipment inside such structures will suffer from high-induced voltages and damage and interference will occur. If a lightning stroke hits the composite structure directly the material will be damaged due to the heat generated in the composite material. A direct lightning stroke is even more complex. The current path for the fast transient and the long tail, with the largest portion of the energy, is different, and different protection measures have to be developed

A model for lightning in littoral areas

The littoral or coastal areas are different compared to the maritime or continental areas considering lightning. Only the last years some research about these areas has been carried out. The need for a model, regarding the lightning activity in these areas is much needed. And now, with the changes induced by the Global Warming, the thunderstorm models over these areas have and will continue to change. The continental areas are already investigated but the littoral area still needs attention. Because of the changeover between the maritime and continent, the littoral area has some atypical characteristics