KidsTUMove-A Holistic Program for Children with Chronic Diseases, Increasing Physical Activity and Mental Health.

The prevalence of chronic diseases in children and adolescents has risen alarmingly worldwide. Diseases such as asthma, diabetes, obesity, mental disorders, and congenital heart defects are increasingly affecting the lives of children and pose significant challenges for the healthcare system. Physical activity plays a crucial role in preventing and treating these diseases. Numerous studies have shown that regular exercise improves physical performance, increases well-being, and leads to better health in the long term. Specially tailored sports programs that meet the individual needs and abilities of the children and adolescents affected are particularly important. The KidsTUMove project addresses this by developing tailored exercise programs for children with chronic diseases' specific needs, medical conditions, and physical abilities. Therefore, it closes the gap in care provision and can thus sustainably improve the health prospects of these children and adolescents. KidsTUMove is positioned to make a significant impact on the lives of affected children across Europe. Promotion of such programs should therefore be an integral part of future health strategies.

Physical and Psychosocial Benefits of Sports Participation Among Children and Adolescents with Chronic Diseases: A Systematic Review.

BACKGROUND: This study aims to identify sports interventions for children and adolescents (CaA) with chronic diseases and evaluate their impact on physical, psychological, and social well-being. The findings of this study will contribute to our understanding of the potential benefits of sports interventions for CaA with chronic diseases and inform future interventions to promote their overall health and well-being. METHODS: A systematic review was conducted in eight databases. This systematic review followed PRISMA guidelines and utilized a comprehensive search strategy to identify studies on sport-based interventions for CaA with chronic diseases. The review included randomized controlled trials and observational studies that focused on physical and psychosocial outcomes. RESULTS: We screened 10,123 titles and abstracts, reviewed the full text of 622 records, and included 52 primary studies. A total of 2352 participants were assessed with an average of 45 ± 37 participants per study. Among the included studies involving CaA with chronic diseases with an age range from 3 to 18 years, 30% (n = 15) autism spectrum disorders, 21% (n = 11) cerebral palsy, 19% (n = 10) were attention deficit hyperactivity disorder, and 17% (n = 9) obesity. Other diseases included were cancer (n = 5), asthma (n = 1) and cystic fibrosis (n = 1). Interventions involved various sports and physical activities tailored to each chronic disease. The duration and frequency of interventions varied across studies. Most studies assessed physical outcomes, including motor performance and physical fitness measures. Psychosocial outcomes were also evaluated, focusing on behavioural problems, social competencies, and health-related quality of life. CONCLUSION: Overall, sport-based interventions effectively improved physical and psychosocial outcomes in CaA with chronic diseases. Interventions are generally safe, and participants adhere to the prescribed protocols favorably. Despite that, there is little evidence that interventions are being implemented. Future studies should include interventions tailored to meet the common issues experienced by CaA with chronic conditions, providing a comprehensive understanding of the impact of sports interventions on those affected. REGISTRATION: The methodology for this review was pre-determined and registered in the PROSPERO database (registration number: CRD42023397172).

Availability and adaption of exercise programs in pediatric oncology during the COVID-19 pandemic and beyond: a nationwide follow-up survey of providers in Germany.

Background: The COVID-19 pandemic has presented major challenges to clinical practice and delivery of care programs throughout all health care systems. Exercise programs, that are implemented in most centers for pediatric oncology in Germany, are a relatively new care program however with high clinical impact and health benefits. Objective: The impact and consequences of the pandemic on the delivery and availability of exercise programs in Germany for pediatric cancer patients and survivors are unknown. A national survey analyzed restrictions, challenges and novel approaches of exercise program delivery and scientific research. Method: A two-stage online survey was distributed to providers of exercise programs (acute clinics, non-clinical institutions, rehabilitation facilities) via the established Network ActiveOncoKids. Data was collected during the pandemic in 2022 and 2023 using a combination of open and closed questions. Results: In total, n = 27 (response rate: 82%) and n = 17 (response rate: 63%) providers participated in the first and second survey, respectively. Findings pointed out restrictions in 85% of all exercise programs in 2020 and 2021, with slight reductions in 2022. During pandemic, restrictions with major impact arose within exercise offers during follow-up and declined gradually. Whereas restrictions within the setting of acute therapy had medium or minor impact but persisted beyond. Delivery of provided exercise programs necessitated adaptions, including digital methods, supervised interventions from a distance and change of locations. Discussion: The findings highlight the adaptability, the demand and the potential of exercise programs in pediatric oncology. We assume that exercise professionals have used the pandemic-related challenges to review and modify existing concepts and made adaptations according to local conditions and novel tools for the provision of exercise programs. Nevertheless, a conspicuous lack of exercise-related care has become evident in certain patients and survivors. Further expansion of programs is imperative to address and accommodate all pertinent needs.

Effects of strength exercise interventions on activities of daily living, motor performance, and physical activity in children and adolescents with leukemia or non-Hodgkin lymphoma: Results from the randomized controlled ActiveADL Study.

Objectives: Pediatric patients with cancer experience impairments in muscle strength and physical activity (PA) that may reduce autonomy during hospitalization. To determine the effects of strength exercise interventions on the accomplishment of activities of daily living (ADLs), motor performance, and PA in children with leukemia or non-Hodgkin lymphoma, we randomly allocated patients (4-18 years) immediately after diagnosis into two exercise groups. Methods: The intervention group (IG; n = 21) received a specific strength training combined with a standard care exercise program, whereas the control group (CG; n = 20) was provided standard care exercise program without any targeted muscle strengthening. After the baseline visit, participants were followed-up three times until intensive treatment cessation. We assessed physical function limitations using the Activities Scale for Kids© (ASK) and Functional ADL Screen. Secondary outcomes were PA levels using accelerometer and motor performance as measured by MOON-test (motor performance in pediatric oncology-test). Results: In both groups, ADL accomplishment had significantly increased (p < 0.05). However, no significant between-group differences for ASK outcome were noted. Motor performance was reduced in all motor abilities. Conclusions: Both exercise interventions were effective to maintain ADLs and motor performance during intensive treatment. In comparison, regular strength exercise interventions in the course of therapy tended to be more beneficial with regards to muscular explosive and endurance strength.

Analysis of self-reported activities of daily living, motor performance and physical activity among children and adolescents with cancer: Baseline data from a randomised controlled trial assessed shortly after diagnosis of leukaemia or non-Hodgkin lymphoma.

OBJECTIVE: Cancer diagnosis, treatment side effects and physical inactivity can lead to reduced muscle strength. Patients undergoing acute treatment experience many burdens that can restrict their mobility and autonomy, leading to limited independence and loss of resources to cope with everyday tasks. In this work, we analyse the status quo and potential influencing factors for the accomplishment of activities of daily living (ADLs) shortly after cancer diagnosis. METHODS: We recruited participants ages 4-18 years diagnosed with acute leukaemia or non-Hodgkin lymphoma. For the baseline analysis, we assessed (1) physical function limitations using the Activities Scale for Kids©, (2) exercise-related ADLs simulated with the Functional ADL Screen, (3) motor performance using the Motor Performance in Paediatric Oncology test and (4) physical activity (PA) level measured using an accelerometer. RESULTS: We conducted the baseline assessment 19.2 ± 12.6 days post-diagnosis in 41 patients. All participants reported functional limitations in ADLs and PA. Motor performance was reduced for all abilities. Cumulative steroid dose was negatively correlated with hand grip strength (r = -0.50, p = 0.009). CONCLUSION: Shortly after diagnosis of paediatric cancer, patients experience various physical impairments that can be counteracted with regular, instructed exercise interventions.

Short-Term Consequences of Pediatric Anti-cancer Treatment Regarding Blood Pressure, Motor Performance, Physical Activity and Reintegration Into Sports Structures.

Background: Cardiovascular diseases in childhood cancer survivors are known late sequelae following treatment. Arterial stiffness, pulse wave velocity (PWV) and central systolic blood pressure (cSBP) are potential predictors to assess the status of cardiovascular health. Frequent inpatient stays and reduced physical activity (PA) during treatment can lead to noticeable impairments regarding motor skills and physical performance. The present study examined parameters of cardiovascular health, motor performance and the status of integration into sports structures shortly after cessation of treatment. Methods: A cross-sectional, monocentric study was conducted from April to June 2019. Participants (6-18 yrs, mixed cancer entities) during maintenance therapy and follow-up care were recruited. Peripheral and central systolic/diastolic blood pressure (pSBP, pDBP, cSBP) and PWV were assessed using the Mobil-O-Graph®. The MOON test (MOtor performance in pediatric ONcology) was used to scale motor performance. PA levels and status of integration into sports structures were assessed with a questionnaire referring to the KiGGS study. All measured data were compared to published reference values. Results: Forty participants (11.3 ± 3.8 years, 50% female) were recruited 1.6 ± 1.8 years post-treatment. PSBP (z-score: 0.87 ± 0.67, p = 0.003), pDBP (0.83 ± 1.94, p = 0.033) and cSBP (≥8 years: 0.60 ± 1.29, p = 0.011) were significantly increased compared to reference values. PWV was also elevated, but not significantly. Motor performance was reduced in almost all motor abilities. Thirty-six percent of the examined group did not participate in physical education at school to the full extent. Only 17% reported 1 hour of daily moderate-to-vigorous PA as recommended for children and adolescents by the World Health Organization. Half of the participants were active sports club members before treatment, but one third did not resume their former membership. Conclusion: Increased cardiovascular parameters and impaired motor performance shortly after cessation of treatment, physical inactivity, and low rates of integration into regular sports programs highlight the support needed. Young cancer patients should receive early support in coping with physical limitations preferably soon after diagnosis. Motor deficits could be reduced by applying targeted interventions. Furthermore, a regular sports therapy program during in- and outpatient care could increase engagement in PA to possibly counteract risk factors and improve cardiovascular health.

Transcriptome study and identification of potential marker genes related to the stable expression of recombinant proteins in CHO clones.

BACKGROUND: Chinese hamster ovary (CHO) cells have become the host of choice for the production of recombinant proteins, due to their capacity for correct protein folding, assembly, and posttranslational modifications. The most widely used system for recombinant proteins is the gene amplification procedure that uses the CHO-Dhfr expression system. However, CHO cells are known to have a very unstable karyotype. This is due to chromosome rearrangements that can arise from translocations and homologous recombination, especially when cells with the CHO-Dhfr expression system are treated with methotrexate hydrate. The present method used in the industry for testing clones for their long-term stability of recombinant protein production is empirical, and it involves their cultivation over extended periods of time prior to the selection of the most suitable clone for further bioprocess development. The aim of the present study was the identification of marker genes that can predict stable expression of recombinant genes in particular clones early in the development stage. RESULTS: The transcriptome profiles of CHO clones with stable and unstable recombinant protein production were investigated over 10-weeks of cultivation, using a DNA microarray. We identified 14 genes that were differentially expressed between the stable and unstable clones already at 2 weeks from the beginning of the cultivation. Their expression was validated by reverse-transcription quantitative real-time PCR (RT-qPCR). Furthermore, the k-nearest neighbour algorithm approach shows that the combination of the gene expression patterns of only five of these 14 genes is sufficient to predict stable recombinant protein production in clones in the early phases of cell-line development. CONCLUSIONS: The exact molecular mechanisms that cause unstable recombinant protein production are not fully understood. However, the expression profiles of some genes in clones with stable and unstable recombinant protein production allow prediction of such instability early in the cell-line development stage. We have thus developed a proof-of-concept for a novel approach to eliminate unstable clones in the CHO-Dhfr expression system, which saves time and labour-intensive work in cell-line development.

Transcriptomic variation between different Chinese hamster ovary cell lines.

OBJECTIVES: To identify transcription markers that uniquely determine specific Chinese hamster ovary (CHO) cell lines and can be used for the identification of cell lines in the process of biopharmaceutical cell-line development. RESULTS: Five CHO cell lines with different origins were extensively characterised at the transcriptomic level and the results were compared to their karyotype characterisation. The analysed cell lines differ in their karyotype but, due to the genome instability observed during parental and recombinant cell-line establishment, karyotyping is not the preferred method for accurate identification of the various CHO cell lines. Marker genes unique to a specific cell line were identified by microarrays, and their expression was validated by reverse-transcription quantitative real-time PCR. The analysed cell lines can be differentiated by the presence/absence of detectable marker gene expression. Additionally, the similarity of the transcriptional profiles is dependent on cell-line history but independent of the manipulation steps involved in the recombinant cell-line development process. CONCLUSIONS: Certain transcripts can be used as markers for the identification of a CHO cell line undergoing recombinant development and thus represent a powerful tool for ensuring the maintenance of high quality standards.

Reduction in C-terminal amidated species of recombinant monoclonal antibodies by genetic modification of CHO cells.

BACKGROUND: During development of recombinant monoclonal antibodies in Chinese hamster ovary (CHO) cells, C-terminal amidated species are observed. C-terminal amidation is catalysed by peptidylglycine α-amidating monooxygenase (PAM), an enzyme known to be expressed in CHO cells. The significant variations between clones during clone selection, and the relatively high content of amidated species (up to 15%) in comparison to reference material (4%), led us to develop a cell line with reduced production of C-terminal amidated monoclonal antibodies using genetic manipulation. RESULTS: Initial target validation was performed using the RNA interference approach against PAM, which resulted in a CHO cell line with C-terminal amidation decreased to 3%. Due to the transient effects of small-interfering RNAs, and possible stability problems using short-hairpin RNAs, we knocked-down the PAM gene using zinc finger nucleases. Plasmid DNA and mRNA for zinc finger nucleases were used to generate a PAM knock-out, which resulted in two CHO cell lines with C-terminal amidation decreased to 6%, in CHO Der2 and CHO Der3 cells. CONCLUSION: Two genetically modified cell lines were generated using a zinc finger nuclease approach to decrease C-terminal amidation on recombinant monoclonal antibodies. These two cell lines now represent a pool from which the candidate clone with the highest comparability to the reference molecule can be selected, for production of high-quality and safe therapeutics.

Heterogeneity in the cysteine protease inhibitor clitocypin gene family.

Clitocypin from the basidiomycete Clitocybe nebularis is the first fungal protein cysteine protease inhibitor to be characterised in detail, yet no information on its molecular genetics is available. Owing to its unique characteristics, it was assigned as the only member of a new family of cysteine protease inhibitors in the MEROPS inhibitor classification. Here we describe the full-length sequence of the clitocypin gene. A BLAST search confirmed its lack of significant sequence similarity to any other gene. The gene is composed of four exons and three short introns and belongs to a small family of closely related genes with more than 90% identity. Sequence variability is evenly distributed in introns and exons and deduced amino acid substitutions are distributed throughout the protein sequence. Basidiocarps collected at two distant locations were examined and the level of heterogeneity found in one basidiocarp is similar to that between the two. Sequencing of the ribosomal DNA spacers from the two basidiocarps confirmed that the heterogeneity observed in the clitocypin gene is not due to evolutionary divergence of the two specimens caused by geographic separation. Clitocypin is expressed in different parts of the basidiocarp and in cultured mycelia in a manner suggesting regulation by developmental and/or environmental factors.