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The aim of this study was to compare the warm-up effects of treadmill walking (TW) with a dynamic (DY) bodyweight warm-up on maximal aerobic exercise performance in children. Sixteen children (10.9 ± 1.5 vrs) were tested for peak oxygen uptake (VO2 peak) on 2 nonconsecutive days following different 6 min warm-up protocols. TW consisted of walking on a motor-driven treadmill at 2.2 mph and 0% grade whereas the DY warm-up consisted of 9 body weight movements including dynamic stretches, lunges, and jumps. Maximal heart rate was significantly higher following DY than TW (193.9 ± 6.2 vs. 191.6 ± 6.1 bpm, respectively; p = 0.008). VO2 peak (54.8 ± 9.6 vs. 51.8 ± 8.7 mL/kg/min; p = 0.09), maximal minute ventilation (68.9 ± 14.8 vs. 64.9 ± 9.4 L/min; p = 0.27), maximal respiratory exchange ratio (1.12 ± 0.1 vs. 1.11 ± 0.1; p = 0.85) and total exercise time (614.0 ± 77.1 vs. 605 ± 95.0 s; p = 0.55) did not differ significantly between DY and TM warm-ups, respectively. These findings indicate that the design of the warm-up protocol can influence the heart rate response to maximal aerobic exercise and has a tendency to influence VO2 peak. A DY warm-up could be a viable alternative to a TW warm-up prior to maximal exercise testing in children.

Carbon fiber reinforced polymer (CFRP) composites hybridized with hydrogen-doped NiTi wires can be used to design structures requiring high stiffness and high damping in the low frequency range, such as helicopter blades. The current work investigates aging and hydrogen-doping for high damping without hydrogen embrittlement. We establish a hydrogenation treatment that (i) results in a response that is repeatable in the martensitic phase and after exposure to composite processing temperatures and (ii) increases the loss factor in NiTi wires by nearly 470%. By embedding H-doped wires exhibiting the highest damping into the interlayers of a [0/±45]s carbon/epoxy laminate at a volume fraction of 0.1, the hybrid NiTi-CFRP composite loss factor increases by 170%. The measured dynamic properties were found to be close to micromechanical predictions based on the properties of the NiTi and CFRP.

Coevolutionary adaptation between humans and helminths has developed a finely tuned balance between host immunity and chronic parasitism due to immunoregulation. Given that these reciprocal forces drive selection, experimental models of helminth infection are ideally suited for discovering how host protective immune responses adapt to the unique tissue niches inhabited by these large metazoan parasites. This review highlights the key discoveries in the immunology of helminth infection made over the last decade, from innate lymphoid cells to the emerging importance of neuroimmune connections. A particular emphasis is placed on the emerging areas within helminth immunology where the most growth is possible, including the advent of genetic manipulation of parasites to study immunology and the use of engineered T cells for therapeutic options. Lastly,we cover the status of human challenge trials with helminths as treatment for autoimmune disease, which taken together, stand to keep the study of parasitic worms at the forefront of immunology for years to come.

SummaryGlobal health reports indicate that a vast majority of children and adolescents are not accumulating the recommended amount of moderate to vigorous physical activity (MVPA) daily. This decline in MVPA has coincided with troubling temporal trends in muscular fitness in modern day youth. Since a prerequisite level of muscular strength is needed to move proficiently, developmentally appropriate interventions that target neuromuscular deficits are needed to prepare girls and boys for ongoing participation in active play, exercise and sport activities. Instead of focusing exclusively on aerobic activities, the promotion of youth physical activity should recognize the shared importance of strength, skill and aerobic activities for all youth regardless of body size or physical prowess. In addition to enhancing muscular fitness and improving motor skill performance, regular participation in resistance training has been found to have a favorable influence on musculoskeletal strength, cardiometabolic function, body composition, and mental health in children and adolescents. A new mindset that recognizes the critical importance of strength-building activities early in life is needed before this generation of girls and boys becomes resistant to exercise interventions later in life.

The lack of antibodies with sufficient cancer selectivity is currently limiting the treatment of solid tumors by immunotherapies. Most current immunotherapeutic targets are tumor-associated antigens also found in healthy tissues. Such targets often do not display sufficient cancer selectivity to be used for potent antibody based immunotherapeutic treatments, such as chimeric antigen receptor (CAR) T cells. Many solid tumors, however, display aberrant glycosylation that results in the expression of tumor-associated carbohydrate antigens that are not present on healthy tissues. Targeting aberrantly glycosylated glycopeptide epitopes within existing or novel glycoprotein targets may provide the cancer selectivity needed for immunotherapy of solid tumours, but only a few such glycopeptide epitopes have been targeted. Here, we used O-glycoproteomics data from multiple cell lines to identify a glycopeptide epitope in CD44v6, a cancer-associated CD44 isoform, and through a glycopeptide immunization strategy developed a cancer-specific monoclonal antibody, 4C8. 4C8 selectively binds to Tn-glycosylated CD44v6 in a site-specific manner with low nanomolar affinity. 4C8 was shown to be highly cancer selective by immunohistochemistry of sections from multiple healthy and cancerous tissues. 4C8 CAR T cells demonstrated target-specific cytotoxicity in vitro and significant tumor regression, and increased survival in vivo. Importantly, 4C8 CAR T cells selectively killed target cells in a mixed organotypic skin cancer model without affecting healthy CD44v6+ keratinocytes, indicating tolerability and safety. Targeting aberrantly glycosylated glycopeptide epitopes may provide the cancer selectivity needed for solid tumour immunotherapy. Citation Format: Mikkel K.M. Aasted, Aaron C. Groen, John T. Keane, Sally Dabelsteen, Edwin Tan, Julia Schnabel, Fang Liu, Hyeon-Gyu S. Lewis, Constantine Theodoropulos, Avery D. Posey, Hans H. Wandall. Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrant O-glycosylated proteins. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5659.

CAR-T cells are a potent immunotherapy that redirect T cell specificity towards cell surface tumor-associated antigens. While this therapy has been effective in hematological malignancies, therapies against solid tumors not achieved the same efficacy due to a multitude of additional challenges, including a lack of tumor specific antigens and an immunosuppressive tumor microenvironment. One strategy to increase T cell potency is to use fourth generation CAR-T cells that also secrete an immunostimulatory factor, such as a cytokine. We have created CAR-T cells targeting Tn-MUC1 utilizing a scFv from the 5E5 antibody that also secrete interleukin-12 (IL-12), interleukin-18 (IL-18), and interleukin-23 (IL-23). These cytokine-secreting CAR-T cells have shown an increase in efficacy against multiple epithelial based tumors in impedance-based killing assays. In a xenograft model of human breast cancer, CAR-T cells secreting IL-12 and IL-23 were able to significantly delay tumor growth compared to non-transduced T cells, CAR-T cells alone, and CAR-T cells secreting IL-18. While these cells showed good efficacy in vivo, clinical translation is difficult due to concerns over cytokine storm due to the constitutive secretion of cytokines. To overcome this, we created a fusion protein utilizing an antibody specific to an invariant region found in majority of CAR molecules, including those utilized commercially available therapies and under pre-clinical development, fused to the three immunostimulatory cytokines. In impedance-based killing assays, antibody-cytokine fusions stimulated non-cytokine secreting CAR-T cells to completely clear the tumor at an E:T ratio in which the CAR-T cells incubated with only the antibody alone were unable to control the tumor growth. Interestingly, combination therapy of CAR-T cells and antibody-cytokine fusions outperformed CAR-T cells constitutively secreting the same cytokines in in vitro assays. This work highlights the use of a single reagent capable of increasing the efficacy of the majority of CAR-T cell therapies and may be an important contribution towards treating solid tumor malignancies with CAR-T cell therapies. Citation Format: John T. Keane, Avery D. Posey. PanCAR-specific antibody-cytokine fusion proteins. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4089.

CAR T cell therapies have made great strides in the clinic; however, multiple hurdles limit the efficacy of this approach for solid tumors. A new study has developed an optimized, dual-targeting CAR T cell that overcomes several of these challenges by enhancing T cell persistence and reducing therapy escape due to antigen loss.

Although evidence indicates that muscular fitness is foundational for ongoing participation in active play, exercise and sport, current national and international youth physical activity guidelines underplay the critical importance of strength-building activities during this developmental phase of life. In view of troubling trends in muscular fitness in today's youth, specific recommendations to address neuromuscular deficiencies are required. An understanding of the multidimensional development of youth physical inactivity and the importance of muscular fitness are needed to have the most significant impact on youth physical activity at the population level. The mounting evidence of the detrimental effects of physical inactivity on youth warrant a review of existing physical activity recommendations and guidelines. The proposed pediatric activity pyramid recognizes the shared importance of strength, skill, and aerobic activities required for the successful implementation of sustainable youth physical activity interventions.

Background and aimsLiver biomarkers and metabolic associated fatty liver disease (MAFLD) have been shown to be associated with cardiovascular disease (CVD). However, there is limited evidence on CVD subtypes [myocardial infarction (MI), ischemic stroke (IS), and intracerebral hemorrhage (ICH)], especially in the Chinese population. We examined these associations overall, by genetic predisposition to non-alcoholic fatty liver disease (NAFLD), and by lifestyle risk factors.Approach and resultsThis is a nested case-control study of CVD (10,298 cases and 5,388 controls) within the China Kadoorie Biobank. Cox regression was used to estimate adjusted hazard ratios (HRs) for CVD associated with liver biomarkers and MAFLD and by stratum of genetic risk and a combined high-risk lifestyle score. For liver enzymes, there were positive associations with MI and IS, but no associations with ICH or carotid plaque. There were positive associations of NAFLD with risks of MI, IS, and ICH (HR 1.43 [95% CI 1.30–1.57], 1.25 [1.16–1.35], and 1.12 [1.02–1.23]) as well as carotid plaque (odds ratio 2.36 [1.12–4.96]). The associations of NAFLD with CVD and carotid plaque were stronger among individuals with a high genetic risk (ICH: p-interaction < 0.05), while the associations with stroke were stronger among those with a favorable lifestyle (p-interaction < 0.05). The results for MAFLD mirrored those for NAFLD.ConclusionIn Chinese adults, liver biomarkers and MAFLD were associated with risk of CVD, with different magnitudes of associations by CVD subtypes. Genetic predisposition to NAFLD and lifestyle factors modified the associations of fatty liver with stroke.

We imagine that you want to be healthy; nobody likes to be ill because that often prevents us from doing the things we like to do. However, we often do not do everything in our power to keep ourselves healthy because modern life is designed to be comfortable. Consequently, we are moving and exercising less than ever, and even young people are suffering the effects of physical inactivity. In this article, we will explain why it is essential for you to move your body, to do so correctly, and to be physically active throughout your life. We will also dispel some myths about children and adolescents lifting weights. There are many things you can do in your daily life to be more physically active!

Neuromuscular training (NMT) facilitates the acquisition of new movement patterns that reduce ACL injury risk; however, the neural mechanisms underlying these changes are unknown.Determine the relationship between brain activation and biomechanical changes following NMT with biofeedback.Controlled Laboratory Study.Research laboratory.Final analyses included twenty high school female soccer athletes (15.7±0.95 years; 1.68±0.05 m; 59.91±5.62 kg).Ten participants completed 6 weeks of NMT augmented with real-time biofeedback (aNMT) to reduce knee injury risk movements, and 10 participants completed no training. aNMT was implemented with visual biofeedback that responded in real-time to injury-risk biomechanical variables. A drop vertical jump with 3D motion capture was used to assess injury risk neuromuscular changes before and after the six-week intervention. Pre to post brain activation changes were measured using functional magnetic resonance imaging (fMRI) during unilateral knee and multi-joint motor tasks.Following aNMT, sensory (precuneus), visual-spatial (lingual gyrus), and motor planning (pre-motor) brain activity increased for knee specific movement and sensorimotor cortex activity for multi-joint movement decreased. Knee abduction moment during landing also decreased (4.66±5.45 Nm; p=0.02; g=0.82) in the aNMT group with no change in the control group (p0.05). The training-induced increased brain activity for isolated knee movement was associated with decreases in knee abduction moment (r=.67, p=.036) and sensorimotor cortex activity for multi-joint movement (r=.87, p=.001). No significant change in brain activity was observed in the control group (p0.05).The relationship between neural changes observed across tasks and reduced knee abduction suggests that aNMT facilitates recruitment of sensory integration centers to support reduced injury risk mechanics and improve sensorimotor neural efficiency for multi-joint control. Further research is warranted to determine if this training related multimodal neuroplasticity enhances neuromuscular control during more complex sport-specific activities.