Search

IntroductionAlthough checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy.MethodsTYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352).ResultsTwenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1–2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro.DiscussionThis study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed.

IntroductionAngiopoetin-2 (Ang-2) is a key mediator of tumour angiogenesis. When upregulated it is associated with tumour progression and poor prognosis. Anti-vascular endothelial growth factor (VEGF) therapy has been widely used in the treatment of metastatic colorectal cancer (mCRC). The potential benefit of combined inhibition of Ang-2 and VEGF-A in previously untreated patients with mCRC was evaluated in the phase II McCAVE study (NCT02141295), assessing vanucizumab versus bevacizumab (VEGF-A inhibitor), both in combination with mFOLFOX-6 (modified folinic acid [leucovorin], fluorouracil and oxaliplatin) chemotherapy. To date, there are no known predictors of outcome of anti-angiogenic treatment in patients with mCRC. In this exploratory analysis, we investigate potential predictive biomarkers in baseline samples from McCAVE participants.MethodsTumour tissue samples underwent immunohistochemistry staining for different biomarkers, including Ang-2. Biomarker densities were scored on the tissue images using dedicated machine learning algorithms. Ang-2 levels were additionally assessed in plasma. Patients were stratified by KRAS mutation status determined using next generation sequencing. Median progression-free survival (PFS) for each treatment group by biomarker and KRAS mutation was estimated using Kaplan–Meier plots. PFS hazard ratios (and 95% confidence intervals) were compared using Cox regression.ResultsOverall low tissue baseline levels of Ang-2 were associated with longer PFS, especially in patients with wild-type KRAS status. In addition, our analysis identified a new subgroup of patients with KRAS wild-type mCRC and high levels of Ang-2 in whom vanucizumab/mFOLFOX-6 prolonged PFS significantly (log-rank p=0.01) by ~5.5 months versus bevacizumab/mFOLFOX-6. Similar findings were seen in plasma samples.DiscussionThis analysis demonstrates that additional Ang-2 inhibition provided by vanucizumab shows a greater effect than single VEGF-A inhibition in this subpopulation. These data suggest that Ang-2 may be both a prognostic biomarker in mCRC and a predictive biomarker for vanucizumab in KRAS wild-type mCRC. Thus, this evidence can potentially support the establishment of more tailored treatment approaches for patients with mCRC.

Vanucizumab is a novel bispecific antibody inhibiting vascular endothelial growth factor (VEGF-A) and angiopoietin-2 (Ang-2) that demonstrated safety and anti-tumor activity in part I of a phase I study of 42 patients with advanced solid tumors. Part II evaluated the pharmacodynamic effects of vanucizumab 30 or 15 mg/kg every 2 weeks in 32 patients. Serial plasma samples, paired tumor, and skin-wound-healing biopsies were taken over 29 days to evaluate angiogenic markers. Vanucizumab was associated with marked post-infusion reductions in circulating unbound VEGF-A and Ang-2. By day 29, tumor samples revealed mean reductions in density of microvessels (−32.2%), proliferating vessels (−47.9%) and Ang-2 positive vessels (−62.5%). Skin biopsies showed a mean reduction in density of microvessels (−49.0%) and proliferating vessels (−25.7%). Gene expression profiling of tumor samples implied recruitment and potential activation of lymphocytes. Biopsies were safely conducted. Vanucizumab demonstrated a consistent biological effect on vascular-related biomarkers, confirming proof of concept. Skin-wound-healing biopsies were a valuable surrogate for studying angiogenesis-related mechanisms.

Abstract Background Ideally, monoclonal antibodies provide selective treatment by targeting the tumour, without affecting normal tissues. Therefore, antibody imaging is of interest, preferably in early stages of drug development. However, the imaging signal consists of specific, as well as non-specific, uptake. The aim of this study was to assess specific, target-mediated uptake in normal tissues, with immuno-PET in a phase I dose escalation study, using the anti-CD44 antibody RG7356 as example. Results Data from thirteen patients with CD44-expressing solid tumours included in an imaging sub-study of a phase I dose escalation clinical trial using the anti-CD44 antibody RG7356 was analysed. 89Zirconium-labelled RG7356 (1 mg; 37 MBq) was administered after a variable dose of unlabelled RG7356 (0 to 675 mg). Tracer uptake in normal tissues (liver, spleen, kidney, lung, bone marrow, brain and blood pool) was used to calculate the area under the time antibody concentration curve (AUC) and expressed as tissue-to-blood AUC ratios. Within the dose range of 1 to 450 mg, tissue-to-blood AUC ratios decreased from 10.6 to 0.75 ± 0.16 for the spleen, 7.5 to 0.86 ± 0.18 for the liver, 3.6 to 0.48 ± 0.13 for the bone marrow, 0.69 to 0.26 ± 0.1 for the lung and 1.29 to 0.56 ± 0.14 for the kidney, indicating dose-dependent uptake. In all patients receiving ≥ 450 mg (n = 7), tumour uptake of the antibody was observed. Conclusions This study demonstrates how immuno-PET in a dose escalation study provides a non-invasive technique to quantify dose-dependent uptake in normal tissues, indicating specific, target-mediated uptake.

Abstract This study examined the impact of sport-specific cognitive training (CT) on executive functions (EFs) in youth soccer players. Thirty-one athletes (13–15 years) participated, 13 in the intervention group (IG) and 18 in the control group (CG). The IG underwent an 8-week soccer-focused CT program, while the CG maintained regular training. The assessments included working memory, inhibition, and cognitive flexibility tasks. The results revealed no significant improvements in EFs in the IG compared to those in the CG. Both groups showed enhanced cognitive flexibility, possibly due to general cognitive development or learning effects. The study suggested that an 8-week sport-specific CT may not enhance EFs in young soccer players, potentially due to a ceiling effect in highly skilled athletes. These findings should be considered when designing cognitive training programs for athletes, and future research could explore the optimal duration of such programs.

The study investigates relative age effects (RAE) in German youth soccer (Youth Bundesliga A: January 2004 to December 2005 and B: January 2006 to December 2007; highest league in German youth soccer) and its persistence in third-division players. Data from the 2022–2023 season (120 teams, 3,174 players) were analyzed using chi-square tests. Significant RAE was found in the A-series (p

IntroductionExecutive functions (EFs) are relevant for game performance in soccer and have been investigated in previous research. However, emotions are a well-known performance factor in sport competitions, which may affect performance by means of EFs. The diagnostic of EFs has mainly been performed disregarding the potential impact of emotional states. Thus, we aimed to initially analyze interaction between emotional states and EFs in two studies with male youth elite soccer players.MethodsIn the first study, 105 players (Mage = 14.97) completed computerized tasks assessing inhibition, cognitive flexibility and working memory. In the second study, 92 players (Mage = 15.17) performed adapted and validated tests of inhibition (n = 45) or cognitive flexibility (n = 47) in a soccer-specific setting (SoccerBot360). Emotional and affective states were assessed using the German Sport Emotion Questionnaire and self-assessment manikins.ResultsFor the computerized tasks, results showed a significant negative correlation between switch costs accuracy and tension, r = 0.28, indicating lower error rates with higher levels of tension. In contrast, in the SoccerBot360 we found significant positive correlations for response time and tension (no-switch: r = 0.38; switch: r = 0.39) representing prolonged response times related to tension. Further, for soccer-specific inhibition, positive emotions were significantly positively correlated with response time (congruent: r = 0.32; incongruent: r = 0.32). Subsequent regression analyses also demonstrate that valence and arousal effectively explain variance in cognitive performance parameters under neutral conditions.DiscussionAccordingly, the ambiguity of the results suggests high variability in EF performance, affective and emotional states as well as a potentially moderating influence of other variables such as context and task difficulty. Thus, future cognitive diagnostic research should integrate assessments of emotional and affective states as these may contribute to situational fluctuations in EF performance.

Cognitive training primarily aims to improve executive functions (EFs). It has become a popular research topic, as previous studies have provided preliminary evidence that EFs relate to sports performance. However, whether a domain-generic cognitive training intervention can improve EFs in high-performance athletes is still unclear. The present randomized controlled study aimed to examine the effects of an eight-week (5 min/day, 5 days/week) smartphone-based domain-generic cognitive training intervention (i.e., the smartphone game “Fruit Ninja”) on EFs in youth soccer athletes (N = 33; intervention: n = 15, passive control: n = 18; German youth soccer academy). We assessed working memory (3-back task), inhibition (Flanker & Go/NoGo task), and cognitive flexibility (number-letter task) in a pre-post design with computerized tasks. The results showed no significant time x group differences attributable to the cognitive training between the intervention group and the control group, except for a response time variable of the Go/NoGo task. These preliminary results do not suggest an application of CT as a smartphone-based game to improve EFs performance in soccer players. However, more research is needed to establish the efficacy of domain-specific interventions in high-level team sport athletes.

Cognitive diagnostics, especially the measurement of executive functions (EFs) in the context of sports and talent diagnostics, is a popular research topic. However, research is lacking on how self-reports are sufficient to examine the EFs of youth athletes for performance diagnostics. Thus, the current study aims to evaluate the relationships between neuropsychological tasks (3-back task, cued Go/NoGo task, flanker task, and number-letter task) and a self-report for examining EFs (BRIEF-SB). Furthermore, it should be investigated whether it is possible to predict the outcome of EF tasks using a self-report inventory. Therefore, 68 young professional soccer players (Mage = 14.26 ± 1.35 years) from a national youth academy were included in the study. The weak-to-moderate correlations (r = 0.000, p = 0.999 to r = −0.442, p < 0.01) and the results of sensitivity analysis (0.125 to 0.538) do not support using a self-report of EFs for cognitive performance diagnostics. The inventory is only suitable for identifying executive dysfunctions in athletes recovering from head injuries or concussions.

Exercise modes can be categorized based on the skills required (open vs. closed skills), which implicates various demands on cognitive skills, especially executive functions (EFs). Thus, their practice may have varying effects on EFs. There is a lack of detailed analysis of cognitive requirements and suitable classification of sports. It is hypothesized that the amount and type of cognitive requirements of sports lead to small effect sizes when comparing open-skill exercising (OSE) and closed-skill exercising (CSE) athletes. The current meta-analysis evaluates the variances in EFs skills caused by particular sport modes. Four research databases (Web of Science, PubMed, ScienceDirect, PsychINFO) were searched for cross-sectional studies in which the authors compare the performance in EF tasks of OSE and CSE athletes. Risk of bias assessment was conducted using funnel plots and two reviewer selection process (overall and subgroup analysis; low risk of publication and selection bias). A total of 19 studies were included, revealing an overall effect size of Hedge’s g = 0.174 (p = 0.157), favoring OSE for the development of EFs. The subgroup analysis revealed the effects for the subdomains of EFs (cognitive flexibility: Hedge’s g = 0.210 > inhibitory control: Hedge’s g = 0.191 > working memory: Hedge’s g = 0.138; p > 0.05), which could be characterized as low to moderate. The hypothesis that studies with the smallest effect sizes compare sport modes with similar cognitive demands was rejected. The paper discusses the differentiation of sports into OSE and CSE and presents new approaches for their categorization.

Visual anticipation is essential for performance in sports. This review provides information on the differences between stimulus presentations and motor responses in eye-tracking studies and considers virtual reality (VR), a new possibility to present stimuli. A systematic literature search on PubMed, ScienceDirect, IEEE Xplore, and SURF was conducted. The number of studies examining the influence of stimulus presentation (in situ, video) is deficient but still sufficient to describe differences in gaze behavior. The seven reviewed studies indicate that stimulus presentations can cause differences in gaze behavior. Further research should focus on displaying game situations via VR. The advantages of a scientific approach using VR are experimental control and repeatability. In addition, game situations could be standardized and movement responses could be included in the analysis.

In this research article, a novel endoscopic system, which is suited to perform a digital inspection of the aircraft wing fuel tanks, is introduced. The aim of this work is to specifically design and develop an assisting system, called `Eeloscope’, to allow accessing and diving through an aircraft kerosene tank in a minimally invasive matter. Currently, mechanics often suffer from the harsh working environment and the arduous maintenance duties within the tank. To address such challenges and derive a tailored solution, an adapted Design Thinking (DT) process is applied. The resulting system enables a fully digital inspection and generation of 3-dimensional structural inspection data. Consequently, devices such as the Eeloscope will facilitate a more efficient and continuous inspection of fuel tanks to increase the transparency regarding the condition of hardly accessible aircraft structures and provide a work relief for mechanics at the same time.

Athletes in a particular sport have specific cognitive skills acquired due to regular confrontation with sport-specific requirements. Studies show that the particular type of sport carried out and fostered by general physical activity impacts executive functions (EFs) such as inhibition, working memory, and cognitive flexibility. There are inconsistent results on the connections between domain-specific cognitive skills and executive functions. This study aimed to evaluate the relations between EFs and domain-specific cognitive skills in climbing. Due to that, we examined the executive functions (neuropsychological tests) and domain-specific cognitive skills (climbing-specific test: a preview of the route vs. climbed moves; climbed moves vs. recognition of moves) of 19 climbers (10 novices, 9 experts, grades 5 to 6a vs. 6c+ to 7b). The inter-subject effects analysis shows that novices and experts in sport climbing do not differ in executive functions in this particular case. Concerning domain-specific cognitive skills, there are differences between experts and novices. Experts show a significantly higher level in planning performance or route idea (p < 0.001) as well as in memorizing of climbed moves (p = 0.004). There are no relations between executive functions and domain-specific cognitive skills in climbers.

In this study, the response of fiber Bragg gratings (FBGs) embedded in cast aluminum parts under thermal and mechanical load were investigated. Several types of FBGs in different types of fibers were used in order to verify general applicability. To monitor a temperature-induced strain, an embedded regenerated FBG (RFBG) in a cast part was placed in a climatic chamber and heated up to 120 ∘C within several cycles. The results show good agreement with a theoretical model, which consists of a shrink-fit model and temperature-dependent material parameters. Several cast parts with different types of FBGs were machined into tensile test specimens and tensile tests were executed. For the tensile tests, a cyclic procedure was chosen, which allowed us to distinguish between the elastic and plastic deformation of the specimen. An analytical model, which described the elastic part of the tensile test, was introduced and showed good agreement with the measurements. Embedded FBGs - integrated during the casting process - showed under all mechanical and thermal load conditions no hysteresis, a reproducible sensor response, and a high reliable operation, which is very important to create metallic smart structures and packaged fiber optic sensors for harsh environments.

Current testing methods are capable of measuring strain near the surface on structural parts, for example by using strain gauges. However, stress peaks often occur within the material and can only be approximated. An alternative strain measurement incorporates fibre-optical strain sensors (Fiber Bragg Gratings, FBG) which are able to determine strains within the material. The principle has already been verified by using embedded FBGs in tensile specimens. The transition area between fibre and aluminium, however, is not yet properly investigated. Therefore, strains in tensile specimens containing FBGs were measured by neutron diffraction in gauge volumes of two different sizes around the Bragg grating. As a result, it is possible to identify and decouple elastic and plastic strains affecting the FBGs and to transfer the findings into a fully descriptive FE-model of the strain transition area.We thus accomplished closing the gap between the external load and internal straining obtained from cast-in FBG and generating valuable information about the mechanisms within the strain transition area.It was found that the porosity within the casting has a significant impact on the stiffness of the tensile specimen, the generation of excess microscopic tensions and thus the formation of permanent plastic strains, which are well recognized by the FBG. The knowledge that FBG as internal strain sensors function just as well as common external strain sensors will now allow for the application of FBG in actual structural parts and measurements under real load conditions. In the future, applications for long-term monitoring of cast parts will also be enabled and are currently under development.

In recent years, the observation of the behaviour of components during the production process and over their life cycle is of increasing importance. Structural health monitoring, for example of carbon composites, is state-of-the-art research. The usage of Fibre Bragg Gratings (FBGs) in this field is of major advantage. Another possible area of application is in foundries. The internal state of melts during the solidification process is of particular interest. By using embedded FBGs, temperature and stress can be monitored during the process. In this work, FBGs were embedded in aluminium alloys in order to observe the occurring strain. Two different FBG positions were chosen in the mould in order to compare its dependence. It was shown that FBGs can withstand the solidification process, although a compression in the range of one percent was measured, which is in agreement with the literature value. Furthermore, different lengths of the gratings were applied, and it was shown that shorter gratings result in more accurate measurements. The obtained results prove that FBGs are applicable as sensors for temperatures up to 740 °C.