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BackgroundPeritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC.MethodsThis prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery.ResultsMedian follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms.ConclusionsAddition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy.

Human running features a spring-like interaction of body and ground, enabled by elastic tendons that store mechanical energy and facilitate muscle operating conditions to minimize the metabolic cost. By experimentally assessing the operating conditions of two important muscles for running, the soleus and vastus lateralis, we investigated physiological mechanisms of muscle work production and muscle force generation. We found that the soleus continuously shortened throughout the stance phase, operating as work generator under conditions that are considered optimal for work production: high force-length potential and high enthalpy efficiency. The vastus lateralis promoted tendon energy storage and contracted nearly isometrically close to optimal length, resulting in a high force-length-velocity potential beneficial for economical force generation. The favorable operating conditions of both muscles were a result of an effective length and velocity-decoupling of fascicles and muscle-tendon unit, mostly due to tendon compliance and, in the soleus, marginally by fascicle rotation.

Human tendons adapt to mechanical loading, yet there is little information on the effect of the temporal coordination of loading and recovery or the dose–response relationship. For this reason, we assigned adult men to either a control or intervention group. In the intervention group, the two legs were randomly assigned to one of five high-intensity Achilles tendon (AT) loading protocols (i.e., 90% maximum voluntary contraction and approximately 4.5 to 6.5% tendon strain) that were systematically modified in terms of loading frequency (i.e., sessions per week) and overall loading volume (i.e., total time under loading). Before, at mid-term (8 weeks) and after completion of the 16 weeks intervention, AT mechanical properties were determined using a combination of inverse dynamics and ultrasonography. The cross-sectional area (CSA) and length of the free AT were measured using magnetic resonance imaging pre- and post-intervention. The data analysis with a linear mixed model showed significant increases in muscle strength, rest length-normalized AT stiffness, and CSA of the free AT in the intervention group ( p  < 0.05), yet with no marked differences between protocols. No systematic effects were found considering the temporal coordination of loading and overall loading volume. In all protocols, the major changes in normalized AT stiffness occurred within the first 8 weeks and were mostly due to material rather than morphological changes. Our findings suggest that—in the range of 2.5–5 sessions per week and 180–300 s total high strain loading—the temporal coordination of loading and recovery and overall loading volume is rather secondary for tendon adaptation.

Urban expansion and densification pose a challenge to urban biodiversity. Rapid estimation of biodiversity could help urban planners balance development and conservation goals. While the Normalised Difference Vegetation Index (NDVI) has proven useful for predicting urban bird diversity, new products derived from remote sensing, such as vegetation volume, could provide more detailed descriptions of available habitat, potentially improving biodiversity predictions. We evaluated the effectiveness of NDVI and vegetation volume as predictors of urban bird diversity and local community composition for different buffers around 86 sampling points in Munich, Germany. Using linear models, we showed that a 100 m buffer best described bird diversity (highest R 2 ) for both NDVI and vegetation volume compared to the other buffers. Contrary to expectations, NDVI was better than vegetation volume in predicting bird diversity (mean R 2 NDVI = 0.47, mean R 2 vegetation volume 0.37). We found a shift in community composition from species associated with human-modified landscapes to those associated with forests along an urban greenness gradient. In contrast to diversity, we found that vegetation volume was slightly better at predicting community composition. Using NDVI to predict bird diversity across Munich, we demonstrated its potential for predicting city-wide bird diversity. We discuss how such predictive maps can be used for urban planning and conservation. As urbanisation continues to impact global biodiversity, refining ecological models for urban planning will be crucial to developing more biodiverse urban environments.

S100A8/S100A9 is a proinflammatory mediator released by myeloid cells during many acute and chronic inflammatory disorders. However, the precise mechanism of its release from the cytosolic compartment of neutrophils is unclear. Here, we show that E-selectin-induced rapid S100A8/S100A9 release during inflammation occurs in an NLRP3 inflammasome-dependent fashion. Mechanistically, E-selectin engagement triggers Bruton’s tyrosine kinase-dependent tyrosine phosphorylation of NLRP3. Concomitant potassium efflux via the voltage-gated potassium channel K V 1.3 mediates ASC oligomerization. This is followed by caspase 1 cleavage and downstream activation of pore-forming gasdermin D, enabling cytosolic release of S100A8/S100A9. Strikingly, E-selectin-mediated gasdermin D pore formation does not result in cell death but is a transient process involving activation of the ESCRT III membrane repair machinery. These data clarify molecular mechanisms of controlled S100A8/S100A9 release from neutrophils and identify the NLRP3/gasdermin D axis as a rapid and reversible activation system in neutrophils during inflammation. Neutrophils can release S100A8/S100A9 as an alarmin via gasdermin D pores. Here, the authors untangle the regulatory mechanisms driving this pathway and show that active repair processes make these pores transient, which can prevent the usual lytic cell death.

The accurate assessment of the Achilles tendon cross-sectional area (CSA) is a crucial prerequisite to investigate tendon adaptation and to calculate the tendon Young׳s modulus. Besides magnetic resonance imaging (MRI), ultrasonography emerged as an alternative imaging technique. The purpose of the present study was to assess the objectivity and reliability of the ultrasound-based methodology and its validity with respect to the established MRI-based assessment. The Achilles tendon CSA from 17 healthy males was assessed by ultrasonography at the proximal, medial and distal position five times each on two separate days and three observers segmented the CSAs. For the validation, MRI-based CSA measurements were provided accordingly. The analysis of the ultrasound-based method revealed significant observer and day effects (p<0.05), despite high intra-class correlation coefficients for the three observers (>0.93) and both days (>0.89), respectively. The mean typical percentage error of both days was 7.1%. Comparing both methods, ultrasonography underestimated (19%) the CSA values obtained by MRI (p<0.05). Although the correlation coefficients of both methods were high in all three positions (>0.88), the respective absolute difference of in average 12mm2 and limits of agreement of up to +28mm2 and −2mm2 (~37% of the mean CSA) evidence considerable inconsistency. Besides the dependency of the CSA determination from the observer, the ultrasound method is not sensitive enough to detect physiological changes in tendon morphology of the magnitude that is reported by intervention studies. Furthermore, the validity analysis revealed a lack of agreement between both methods. Therefore, the ultrasound-based methodology cannot be recommended for an accurate Achilles tendon CSA determination in vivo.

Background High tendon strain leads to sub-rupture fatigue damage and net-catabolic signaling upon repetitive loading. While high levels of tendon strain occur in adolescent athletes at risk for tendinopathy, a direct association has not yet been established. Therefore, in this prospective longitudinal study, we examined the hypothesis that adolescent athletes who develop patellar tendon pain have shown increased levels of strain in advance. Methods In 44 adolescent athletes (12–17 years old), patellar tendon mechanical properties were measured using ultrasonography and inverse dynamics at four time points during a season. Fourteen athletes developed clinically relevant tendon pain (SYM; i.e., reduction of the VISA-P score of at least 13 points), while 23 remained asymptomatic (ASYM; VISA-P score of > 87 points). Seven cases did not fall into one of these categories and were excluded. Tendon mechanical properties of SYM in the session before the development of symptoms were compared to a randomly selected session in ASYM. Results Tendon strain was significantly higher in SYM compared to ASYM ( p  = 0.03). The risk ratio for developing symptoms was 2.3-fold higher in athletes with tendon strain ≥9% ( p  = 0.026). While there was no clear evidence for systematic differences of the force applied to the tendon or tendon stiffness between SYM and ASYM ( p  > 0.05), subgroup analysis indicated that tendon force increased prior to the development of symptoms only in SYM ( p  = 0.034). Discussio The study provides novel longitudinal evidence that high tendon strain could be an important risk factor for patellar tendinopathy in adolescent athletes. We suggest that inadequate adaptation of tendon stiffness to increases in muscle strength may occur if adolescent athletes are subject to mechanical loading which does not  provide effective tendon stimulation.

The gold standard to determine muscle morphological parameters is magnetic resonance imaging (MRI). To measure large muscles like the vastus lateralis (VL) in one sequence, scanners with a large field of view (FOV) and a high flux density are needed. However, large scanners are expensive and not always available. The purpose of the current study was to develop a marker-based approach to reconstruct the VL from several separate MRI sequences, acquired with a low-field MRI scanner. The VL muscle of 21 volunteers was marked at one-third and two-third of thigh length using fish oil capsules. Three consecutive MRI sequences (i.e. proximal, medial and distal part) of the thigh were captured between the markers and the muscle insertion and origin. After a manual segmentation of the VL the muscle was reconstructed using the developed approach. The muscle volume, maximal anatomical cross-sectional area and length were 715.1 ± 93.4 cm3, 34.0 ± 4.0 cm2 and 34.4 ± 2.2 cm respectively. The procedure showed an average error between 0.9% and 2.2% for the reconstructed muscle volume, the averaged RMSD between the cross-sectional areas of two overlapping sequences were between 0.80 ± 0.71 cm2 and 0.88 ± 0.78 cm2. The proposed approach provides an appropriate accuracy for muscle volume assessment, as the estimated error for muscle volume calculation was quite small. The reconstruction quality depends mainly on the proper marker attachment and identification, as well as the spatial resolution of the image sequences. We are confident that the presented method can be used in most investigations regarding muscle morphology.

The present study investigated the validity of a simplified muscle volume assessment that uses only the maximum anatomical cross-sectional area (ACSAmax), the muscle length (LM) and a muscle-specific shape factor for muscle volume calculation (Albracht et al., 2008, J Biomech 41, 2211–2218). The validation on the example of the triceps surae (TS) muscles was conducted in two steps. First LM, ACSAmax, muscle volume and shape factor were calculated from magnet resonance image muscle reconstructions of the soleus (SO), gastrocnemius medialis (GM) and lateralis (GL) of a group of untrained individuals (n=13), endurance (n=9) and strength trained (n=10) athletes. Though there were significant differences in the muscle dimensions, the shape factors were similar across groups and were in average 0.497±0.026, 0.596±0.030, and 0.556±0.041 for the SO, GM and GL respectively. In a second step, the shape factors were applied to an independent recreationally active group (n=21) to compare the muscle volume assessed by the simplified method to the results from whole muscle reconstructions. There were no significant differences between the volumes assessed by the two methods. In conclusion, assessing TS muscle volume on the basis of the reported shape factors is valid across populations and the root mean square differences to whole muscle reconstruction of 7.9%, 4.8% and 8.3% for SO, GM and GL show that the simplified method is sensitive enough to detect changes in muscle volume in the context of degeneration, atrophy or hypertrophy.