TRPS1 maintains luminal progenitors in the mammary gland by repressing SRF/MRTF activity.

The transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and is critical during puberty and pregnancy. Its function in the resting state remains however unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy adult mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. Using transcriptomic approaches, flow cytometry and functional assays, we show that TRPS1 activity is essential to maintain a functional luminal progenitor compartment. This requires the repression of both YAP/TAZ and SRF/MRTF activities. TRPS1 represses SRF/MRTF activity indirectly by modulating RhoA activity. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors intrinsically linked to mechanotransduction in the mammary gland. It may also provide new insights into the oncogenic functions of TRPS1 as luminal progenitors are likely the cells of origin of many breast cancers.

A Novel Anthropomorphic Phantom Composed of Tissue-Equivalent Materials for Use in Experimental Radiotherapy: Design, Dosimetry and Biological Pilot Study.

The production of anthropomorphic phantoms generated from tissue-equivalent materials is challenging but offers an excellent copy of the typical environment encountered in typical patients. High-quality dosimetry measurements and the correlation of the measured dose with the biological effects elicited by it are a prerequisite in preparation of clinical trials with novel radiotherapy approaches. We designed and produced a partial upper arm phantom from tissue-equivalent materials for use in experimental high-dose-rate radiotherapy. The phantom was compared to original patient data using density values and Hounsfield units obtained from CT scans. Dose simulations were conducted for broad-beam irradiation and microbeam radiotherapy (MRT) and compared to values measured in a synchrotron radiation experiment. Finally, we validated the phantom in a pilot experiment with human primary melanoma cells.

Development and characterization of modular mouse phantoms for end-to-end testing and training in radiobiology experiments.

Objective. In radiation oncology, experiments are often carried out using mice as a model forin vivoresearch studies. Due to recent technological advances in the development of high-precision small-animal irradiation facilities, the importance of quality assurance for both dosimetry and imaging is increasing. Additive manufacturing (AM) offers the possibility to produce complex models from a three-dimensional data set and to build cost-effective phantoms that can easily be adapted to different purposes. The aim of this work was therefore to develop detailed anatomical mouse models for quality assurance and end-to-end testing of small-animal irradiation and imaging by means of AM.Approach. Two mouse phantom concepts were designed, constructed, and examined for this purpose. The first model includes cavities corresponding to the most important organs. The final solid model was constructed using AM in two separate parts that can be attached with a plug connection after filling these cavities with tissue-equivalent mixtures. Moreover, different radiation dosimeters can be placed in the lower part of the model. For the second concept, AM was used for building modules like the phantom outer shell and bones, so that different mixtures can be used as a filling, without modifying the phantom structure.Main results.CT as well as Micro-CT scans of both concepts showed an excellent quality and adequate image contrast, with material attenuation properties close to those of mouse tissues, apart from the current bone surrogates. Radiation dose measurements with radiochromic films were, with some exceptions in areas with larges bone volumes, in agreement with calculations within less than ±4%.Significance. AM shows great potential for the development of mouse models that are inexpensive, easy to adapt, and accurate, thus enabling their use for quality assurance in small-animal radiotherapy and imaging. The introduction of such 3D-printable mouse phantoms in the workflow could also significantly reduce the use of living animals for optimization and testing of new imaging and irradiation protocols.

A new digital measurement system for assessing the lip in patients with cleft lip and palate (CLP).

Objective: In order to better and more objectively assess and compare the aesthetics of the lip, we offer an inovative, digital measurement method. Patients and method: Patients were divided into 2 groups:a) patients with unilateral CLP andb) patients with bilateral CLP.Based on standardised photos from 3 different directions, lip symmetry and aesthetics were assessed. A new digital measurement system was used, which was integrated into a proven clinical programme. Different symmetry indices were compared with a non-cleft control group. In addition, the function was investigated and a standardised questionnaire was used. Results: In total, 92 patients with operated CLP could be recruitetd and showed significant residual asymmetry compared to the control group with 49 patients. The results were more symmetrical in group b) than in group a). In contrast, scar width and scar aesthetics as well as orofacial function were better in group a). The preoperative cleft width showed a positive correlation with the postoperative scar width and scar aesthetics. Socioeconomic factors were not related to surgical outcome. Satisfaction of affected children and parents correlated with objectively assessed scar aesthetics and function. There was no correlation between satisfaction and symmetry or cleft width or scar width. Conclusion: The presented measurement system can be used excellently and effectively in clinical routine, especially for the inexperienced examiner, for fast and yet detailed, objective recording of findings. The measurement results can be analyzed comparatively and interpreted predictively for diagnostics, planning and therapy.

The Microbeam Insert at the White Beam Beamline P61A at the Synchrotron PETRA III/DESY: A New Tool for High Dose Rate Irradiation Research.

High dose rate radiotherapies such as FLASH and microbeam radiotherapy (MRT) both have developed to the stage of first veterinary studies within the last decade. With the development of a new research tool for high dose rate radiotherapy at the end station P61A of the synchrotron beamline P61 on the DESY campus in Hamburg, we increased the research capacity in this field to speed up the translation of the radiotherapy techniques which are still experimental, from bench to bedside. At P61, dose rates of several hundred Gy/s can be delivered. Compared to dedicated biomedical beamlines, the beam width available for MRT experiments is a very restrictive factor. We developed two model systems specifically to suit these specific technical parameters and tested them in a first set of experiments.