Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology—a strategy that is based on perturbing primary... Show morePrecision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology—a strategy that is based on perturbing primary tumor cells from cancer patients—could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC. Show less
We present results from a systematic interdisciplinary study on (pre-)historic rural settlement and landscape development in an upland region of northern Bavaria, Germany. The archaeological and... Show moreWe present results from a systematic interdisciplinary study on (pre-)historic rural settlement and landscape development in an upland region of northern Bavaria, Germany. The archaeological and geoarchaeological investigations—supported by radiocarbon dating, optically stimulated luminescence dating, and palaeoecological analysis—were performed to (i) identify so far unknown prehistoric rural settlement sites, (ii) determine site-specific soil erosion from colluvial deposits, and (iii) assess the composition of woodland from on- and offsite charcoal finds. The earliest indicators of human activities from the Younger Neolithic (late 5th to early 4th millennium B.C.E.) come from colluvial deposits. Our investigations, for the first time, show Middle to Late Bronze Age (ca. 1400–800 B.C.E.), permanent rural settlement in a German central upland region, with a peak in the Late Bronze Age. Due to the varying thicknesses of Bronze Age colluvial deposits, we assume land use practices to have triggered soil erosion. From the spectrum of wood species, Maloideae, ash, and birch are regarded as successional indicators after fire clearance in that period. Settlement continued until the 5th century B.C.E. After a hiatus of 500 years, it re-flourished in the Late Roman and Migration periods (mid-3rd–5th century C.E.) and went on in the Medieval period. Show less
The aging brain undergoes several anatomical changes that can be measured with Magnetic Resonance Imaging (MRI). Early studies using lower field strengths have assessed changes in tissue properties... Show moreThe aging brain undergoes several anatomical changes that can be measured with Magnetic Resonance Imaging (MRI). Early studies using lower field strengths have assessed changes in tissue properties mainly qualitatively, using T 1 T1 - or T ∗ 2 T2∗ - weighted images to provide image contrast. With the development of higher field strengths (7 T and above) and more advanced MRI contrasts, quantitative measures can be acquired even of small subcortical structures. This study investigates volumetric, spatial, and quantitative MRI parameter changes associated with healthy aging in a range of subcortical nuclei, including the basal ganglia, red nucleus, and the periaqueductal grey. The results show that aging has a heterogenous effects across regions. Across the subcortical areas an increase of T 1 T1 values is observed, most likely indicating a loss of myelin. Only for a number of areas, a decrease of T ∗ 2 T2∗ and increase of QSM is found, indicating an increase of iron. Aging also results in a location shift for a number of structures indicating the need for visualization of the anatomy of individual brains. Show less
Kothieringer, K.; Lambers, K.; Seregély, T.; Schäfer, A. 2014
This paper describes the results of initial archaeological and geoarchaeological fieldwork in the Northern Franconian Jura between the cities of Bayreuth and Bamberg. Our research aims at the... Show moreThis paper describes the results of initial archaeological and geoarchaeological fieldwork in the Northern Franconian Jura between the cities of Bayreuth and Bamberg. Our research aims at the reconstruction of settlement patterns and strategies of land use during the Metal Ages (Bronze Age and Iron Age) in the catchment area of the river Weismain. The project is designed as a case study for research into the settlement and landscape history of a rural region of the Central German Uplands during the last two millennia before our era. Show less
