Identification of dynamic driver sets controlling phenotypical landscapes.

Controlling phenotypical landscapes is of vital interest to modern biology. This task becomes highly demanding because cellular decisions involve complex networks engaging in crosstalk interactions. Previous work on control theory indicates that small sets of compounds can control single phenotypes. However, a dynamic approach is missing to determine the drivers of the whole network dynamics. By analyzing 35 biologically motivated Boolean networks, we developed a method to identify small sets of compounds sufficient to decide on the entire phenotypical landscape. These compounds do not strictly prefer highly related compounds and show a smaller impact on the stability of the attractor landscape. The dynamic driver sets include many intervention targets and cellular reprogramming drivers in human networks. Finally, by using a new comprehensive model of colorectal cancer, we provide a complete workflow on how to implement our approach to shift from in silico to in vitro guided experiments.

Digitalization of adverse event management in oncology to improve treatment outcome-A prospective study protocol.

The occurrence of adverse events frequently accompanies tumor treatments. Side effects should be detected and treated as soon as possible to maintain the best possible treatment outcome. Besides the standard reporting system Common Terminology Criteria for Adverse Events (CTCAE), physicians have recognized the potential of patient-reporting systems. These are based on a more subjective description of current patient reporting symptoms. Patient-reported symptoms are essential to define the impact of a given treatment on the quality of life and the patient's wellbeing. They also act against an underreporting of side effects which are paramount to define the actual value of a treatment for the individual patient. Here, we present a study protocol for a clinical trial that assesses the potential of a smartphone application for CTCAE conform symptom reporting and tracking that is adjusted to the standard clinical reporting system rather than symptom oriented descriptive trial tools. The presented study will be implemented in two parts, both lasting over six months. The first part will assess the feasibility of the application with 30 patients non-randomly divided into three equally-sized age groups (<55years, 55-75years, >75years). In the second part 36 other patients will be randomly assigned to two groups, one reporting using the smartphone and one not. This prospective second part will compare the impact of smartphone reported adverse events regarding applied therapy doses and quality of life to those of patients receiving standard care. We aim for early detection and treatment of adverse events in oncological treatment to improve patients' safety and outcomes. For this purpose, we will capture frequent adverse events of chemotherapies, immunotherapies, or other targeted therapies with our smartphone application. The presented trial is registered at the U.S. National Library of Medicine ClinicalTrials.gov (NCT04493450) on July 30, 2020.

Switch-like behavior enables Wnt11 concentration specific response during dorso-ventral axis formation in Xenopus laevis.

Wnt signaling plays a role in diverse processes such as cell proliferation, differentiation, migration or cell polarity. Dysfunction of Wnt signaling is associated with human diseases and aging. Wnts can activate several interacting intracellular signaling pathways, in particular the so called canonical and non-canonical pathways. The canonical Wnt response leads to a stabilization of cytoplasmic ß-catenin whereas non-canonical Wnt signaling can result in the activation of calcium-calmodulin dependent kinase II (CamKII). Earlier data revealed that those signaling pathways can inhibit each other in a concentration dependent manner. During Xenopus laevis dorsal axis formation, Wnt11 has been shown to activate both, ß-catenin signaling as well as CamKII activity. In line, Wnt11 is required for dorsal as well as ventral cell fates. Here, we show that the concentration dependent mutual inhibition of CamKII and ß-catenin signaling is sufficient to obtain a switch-like behavior as opposed to a graded response. We present a model that faithfully recapitulates the activity of Wnt11 during dorso-ventral axis formation in Xenopus laevis on the basis of the Wnt switch behavior.

Measurement of the number of molecules of a single mRNA species in a complex mRNA preparation.

The normalization of data obtained from hybridization experiments with DNA chips to determine mRNA expression and concentration (gene expression profiling) is an unsolved problem. Furthermore, slight changes in mRNA expression or small numbers of mRNA molecules which may be relevant to disease cannot be detected so far. We have designed a method to calculate the number of molecules of a single mRNA species in a complex mRNA preparation. The basic concept is the transformation of a quantitative problem into a qualitative problem. Individual molecules pertaining to the same molecular species (IMPSMS) are transformed to a mixture of new different molecular species (DMS) and amplified. We propose two implementations of the method. The first procedure is based on a method for cloning tagged nucleic acid molecules onto the surface of micro-beads. It should be possible to transform and determine up to 10(6) IMPSMS into new DMS. The second strategy uses multimeric linkers, a method frequently used in DNA computing to assemble random DNA. The second strategy should be easier to implement but is limited to a few hundred IMPSMS.