Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes.

Human MSCs may respond to TLR ligation, and recent research has suggested that many tissues contain tissue-specific MSCs, possibly located in periendothelial and perivascular regions. At present, the functional consequences of these findings are unclear. We hypothesized that tissue-specific MSCs could play an instructional role during early phases of bacterial challenge. To investigate this hypothesis further, we set up a coculture system of glandular MSCs and peripheral blood neutrophils so that we could analyze the cellular interactions of these cells in response to LPS challenge. We found that stimulation with bacterial endotoxin induced chemokine receptor expression and mobility of MSCs. Activated MSCs secreted large amounts of inflammatory cytokines and recruited neutrophils in an IL-8- and MIF-dependent manner. Recruited and activated neutrophils showed a prolonged lifespan, an increased expression of inflammatory chemokines, and an enhanced responsiveness toward subsequent challenge with LPS. Our findings demonstrate a complex, functional interaction between tissue-resident MSCs and peripheral blood neutrophils upon bacterial challenge and suggest a role for MSCs in the early phases of pathogen challenge, when classical immune cells have not been recruited yet.

Manual segmentation of computed tomography (CT) datasets was performed for robot-assisted endoscope movement during functional endoscopic sinus surgery (FESS). Segmented 3D models are needed for the robots' workspace definition. A total of 50 preselected CT datasets were each segmented in 150-200 coronal slices with 24 landmarks being set. Three different colors for segmentation represent diverse risk areas. Extension and volumetric measurements were performed. Three-dimensional reconstruction was generated after segmentation. Manual segmentation took 8-10 h for each CT dataset. The mean volumes were: right maxillary sinus 17.4 cm(3), left side 17.9 cm(3), right frontal sinus 4.2 cm(3), left side 4.0 cm(3), total frontal sinuses 7.9 cm(3), sphenoid sinus right side 5.3 cm(3), left side 5.5 cm(3), total sphenoid sinus volume 11.2 cm(3). Our manually segmented 3D-models present the patient's individual anatomy with a special focus on structures in danger according to the diverse colored risk areas. For safe robot assistance, the high-accuracy models represent an average of the population for anatomical variations, extension and volumetric measurements. They can be used as a database for automatic model-based segmentation. None of the segmentation methods so far described provide risk segmentation. The robot's maximum distance to the segmented border can be adjusted according to the differently colored areas.

Recent years have witnessed the groundbreaking success of immune checkpoint blockage (ICB) in metastasized malignant melanoma. However, biomarkers predicting the response to ICB are still urgently needed. In the present study, we investigated CTLA4 promoter methylation (mCTLA4) in 470 malignant melanoma patients from The Cancer Genome Atlas (non-ICB cohort) and in 50 individuals with metastasized malignant melanomas under PD-1/CTLA-4-targeted immunotherapy (ICB cohort). mCTLA4 levels were quantified using the Infinium HumanMethylation450 BeadChip (non-ICB cohort) and methylation-specific quantitative real-time PCR in DNA formalin-fixed and paraffin-embedded tissues (ICB cohort). Methylation levels were associated with molecular and clinicopathological variables and analyzed with respect to response (irRECIST) and overall survival. CTLA-4 mRNA and mCTLA4 showed a significant inverse correlation (non-ICB cohort: Spearman's ρ = -0.416, P < 0.001). In ICB-treated melanoma patients, low mCTLA4 was further strongly correlated with response to therapy (P = 0.009, ANOVA) and overall survival (hazard ratio = 2.06 [95% CI: 1.29-3.29], P = 0.003). Our data strongly support the assumption that mCTLA4 predicts response to both anti-PD-1 and anti-CTLA-4 targeted ICB in melanoma and provides paramount information for the selection of patients likely to respond to ICB.

The functional role of short-, medium- and long-latency responses for the maintenance of upright posture was investigated in twenty healthy subjects standing on a platform which could be rotated in pitch around the subject's ankle joints. Tilting the platform toe-up evokes a stretch reflex in the triceps surae muscle (TS, latency 55-65 ms) and at higher speeds and amplitudes of platform displacement a medium-latency response (latency 108-123 ms). Both responses functionally destabilize posture, since they enforce the induced backward displacement of the body. Compensation of body displacement in this situation is achieved by a long-latency EMG response in the anterior tibial muscle (TA 130-145 ms). Platform movement toe-down elicits a rather small medium-latency response in TA (103-118 ms), but no short-latency response. A late compensatory response occurs in the triceps surae muscle (latency 139-170 ms). The mean latency of the late antagonistic EMG response was significantly shorter than that of a voluntary movement triggered by a somatosensory stimulus. Integrals of rectified EMG responses from the two muscles were linearly related to the amplitude and to a smaller degree to the velocity of platform displacement. The slope of this function (gain) varied depending on the direction of ankle displacement and the functional importance of the subsequent EMG responses. Destabilizing short- and medium-latency responses of the stretched muscle had a lower gain relative to amplitude than the late stabilizing response of the antagonist. This functionally adaptive modulation of gain was not seen in relation to the rate of platform displacement.