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Nina Schaller,1 Helge Krusemark,1 Esther Mende,1 Michael Weiß,1 Bianca Spanier,1 Otto Zelger,1 Jan Bischof,1 Bernhard Haller,2 Martin Halle,1,3,&ast; Monika Siegrist1,&ast; 1Department of Prevention and Sports Medicine, School of Medicine, University Hospital ‘rechts der Isar’, Technical University of Munich, Munich, Germany; 2Institute of AI and Informatics in Medicine, University Hospital ‘rechts der Isar’, Technical University of Munich, Munich, Germany; 3DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany&ast;These authors contributed equally to this workCorrespondence: Nina Schaller, Department of Prevention and Sports Medicine, School of Medicine, University Hospital ‘rechts der Isar’, Technical University of Munich, Georg-Brauchle-Ring 56, Munich, 80992, Germany, Tel +49 89 289 24441, Fax +49 89 289 24451, Email nina.schaller@mri.tum.dePurpose: Mobility is a crucial factor for independence and quality of life in old age. Nevertheless, many old people in retirement homes do not meet the physical activity recommendations. The aim of the Bestform-F – Best Function of Range of Motion feasibility study (bestform-F) was to evaluate the feasibility of implementing a machine-based multimodal exercise training program in older residents in retirement homes.Materials and Methods: The participants (n = 77) were recruited from two retirement homes and took part in a six-month multimodal exercise training program (2x/week, 45 minutes) on pneumatic strength training machines, a balance platform and bicycle ergometers. Feasibility criteria were recruitment number ≥ 35 participants within six months, dropout rate < 40% of participants within six months of exercise, and training adherence ≥ 50% of participants taking part in at least 50% of offered training sessions. Additionally, physical performance, fear of falling, cognitive function, and quality of life were assessed at baseline and after six months.Results: For the bestform-F study, 77 (85.6 ± 6.6 years; 78% women) out of 215 eligible residents from two senior residences were recruited. The dropout rate over six months was 10% (8/77 participants). The training adherence rate for the finishing participants was 77% (53/69 participants). In addition to the achieved feasibility criteria, significant improvements were recorded in the Chair Stand Test, Six-Minute Walk Test, and fear of falling after six months.Conclusion: All feasibility criteria have been fulfilled. The high number of recruited participants, the low dropout rate, and high adherence to the training program confirm the feasibility of a multimodal machine-based exercise training program offered to residents in retirement homes. The results provide a basis for a cluster-randomized controlled trial aimed at further investigating the efficacy of the bestform-F program.Keywords: machine-based exercise, seniors, sarcopenia, mobility, resistance training, balance

The transient responses of the energy budget and the hydrological cycle to CO2 and solar forcings of the same magnitude in a global climate model are quantified in this study. Idealized simulations are designed to test the assumption that the responses to forcings are linearly additive, i.e. whether the response to individual forcings can be added to estimate the responses to the combined forcing, and to understand the physical processes occurring as a response to a surface warming caused by CO2 or solar forcing increases of the same magnitude. For the global climate model considered, the responses of most variables of the energy budget and hydrological cycle, including surface temperature, do not add linearly. A separation of the response into a forcing and a feedback term shows that for precipitation, this non-linearity arises from the feedback term, i.e. from the non-linearity of the temperature response and the changes in the water cycle resulting from it. Further, changes in the energy budget show that less energy is available at the surface for global annual mean latent heat flux, and hence global annual mean precipitation, in simulations of transient CO2 concentration increase compared to simulations with an equivalent transient increase in the solar constant. On the other hand, lower tropospheric water vapor increase is similar between simulations with CO2 and solar forcing increase of the same magnitude. The response in precipitation is therefore more muted compared to the response in water vapor in CO2 forcing simulations, leading to a larger increase in residence time of water vapor in the atmosphere compared to solar forcing simulations. Finally, energy budget calculations show that poleward atmospheric energy transport increases more in solar forcing compared to equivalent CO2 forcing simulations, which is in line with the identified strong increase in large-scale precipitation in solar forcing scenarios. [ABSTRACT FROM AUTHOR]

Introduction: High exercise adherence is a key factor for effective exercise programmes. However, little is known about predictors of exercise adherence to a multimodal machine-based training in older retirement home residents., Aims: To assess exercise adherence and potential predictors of adherence. Furthermore, to evaluate user acceptance of the multimodal training and the change in exercise self-efficacy., Methods: In this sub-analysis of the bestform-F study, a total of 77 retirement home residents ≥65 years (mean age: 85.6 ± 6.6 years, 77.9% female) participated in a 6-month machine-based resistance, coordination and endurance training. Attendance to the training was documented for each training session. To identify potential predictors a multiple linear regression model was fitted to the data. Analyzed predictors included age, sex, body mass index (BMI), physical function, exercise self-efficacy, and physical activity history. Different domains of user acceptance (e.g. safety aspects, infrastructure) and exercise self-efficacy were assessed by a questionnaire and the exercise self-efficacy scale (ESES), respectively., Results: Mean exercise adherence was 67.2% (median: 74.4%). The regression model (R 2  = 0.225, p = 0.033) revealed that the 6-minute walk test (6-MWT) at baseline significantly predicted exercise adherence (β: 0.074, 95% confidence interval (CI): 0.006-0.142, p = 0.033). Different user domains were rated at least as good by 83.9%-96.9% of participants, reflecting high acceptance. No statistically significant change was found for exercise self-efficacy over 6 months (mean change: 0.47 ± 3.08 points, p = 0.156)., Conclusion: Retirement home residents attended more than two thirds of offered training sessions and physical function at baseline was the key factor for predicting adherence. User acceptance of the training devices was highly rated. These findings indicate good potential for implementation of the exercise programme., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Background: Hepatocellular adenoma (HCA) is a rare liver tumour, which can have atypical morphological features such as cytological atypia, pseudoglandular architecture, and altered reticulin framework. Little is known about the genetic and epigenetic alterations of such HCAs and whether they show the alterations classically found in hepatocellular carcinoma (HCC) or in HCA without atypical morphology., Methods: We analysed five HCAs with atypical morphological features and one HCA with transition to HCC. Every tumour was subtyped by immunohistochemistry, sequenced by a targeted NGS panel, and analysed on a DNA methylation microarray., Results: Subtyping of the five HCAs with atypical features revealed two β-catenin mutated HCA (b-HCA), two β-catenin mutated inflammatory HCA (b-IHCA), and one sonic hedgehog activated HCA (shHCA). None of them showed mutations typically found in HCC, such as, e.g. TERT or TP53 mutations. The epigenomic pattern of HCAs with atypical morphological features clustered with reference data for HCAs without atypical morphological features but not with HCC. Similarly, phyloepigenetic trees using the DNA methylation data reproducibly showed that HCAs with morphological atypia are much more similar to nonmalignant samples than to malignant samples. Finally, atypical HCAs showed no relevant copy number variations (CNV)., Conclusion: In our series, mutational, DNA methylation, as well as CNV analyses, supported a relationship of atypical HCAs with nonatypical HCAs rather than with HCC. Therefore, in cases with difficult differential diagnosis between HCC and HCA, it might be advisable to perform targeted sequencing and/or combined methylation/copy number profiling., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Purpose: Occupational health programmes have been successfully implemented to improve body composition, physical fitness and cardiovascular risk. However, most programmes have been small and have not included long-term evaluation. Therefore, we evaluated a twelve-month life-style change programme in a German refinery., Methods: We offered a supervised six-week endurance exercise programme (2 × 90 min/week), starting after a two-day life-style seminar. After the active intervention and a half-day refresher seminar, employees were encouraged to continue exercising over one year on their own, with monthly supervised sessions to maintain adherence. Anthropometry, bicycle ergometry, cardio-metabolic risk profile, inflammatory parameters, and vascular function e.g. endothelial function was studied at baseline, after three and after twelve months., Results: Of 550 employees, n = 327 (age 40.8 ± 9.7 years, 88% males) participated in the study. Twelve-month intervention was associated with a reduced waist circumference (92.6 ± 12.2 to 90.8 ± 11.7 cm, 95% confidence interval for the mean change (CI): -2.5 to -1.1 cm) and a gain in maximal exercise capacity (202 ± 39.6 to 210 ± 38.9 Watt; 95% CI: + 5.1 to + 10.9 Watt). Metabolic and inflammatory parameters likewise HbA 1c and C-reactive protein improved in central tendency at a local 95% level of confidence. Vascular function e.g. Reactive-Hyperaemia-Index revealed a slight reduction, whereas no statistically robust changes in mean Cardio-Ankle-Vascular-Index and mean Ankle-Brachial-Index were observed., Conclusion: Health education added by a six-week supervised exercise programme was associated with minor long-term twelve-month improvements of body composition as well as physical fitness and a concomitant improvement of inflammatory state. These changes were, however, not clinically relevant and not accompanied by statistically robust improvements of vascular function., Trial Registration: ClinTrialsGov: NCT01919632; date of registration: August 9, 2013; retrospectively registered., (© 2023. The Author(s).)

While obesity impairs health-related quality of life (HRQOL), lifestyle interventions targeting weight reduction have been effective in improving HRQOL. Therefore, we hypothesised that a meal replacement-based lifestyle intervention, which has been shown to successfully reduce weight, would also improve HRQOL more effectively than a lifestyle intervention alone. In the international, multicenter, randomised-controlled ACOORH-trial (Almased-Concept-against- Overweight-and-Obesity-and-Related-Health-Risk), overweight or obese participants with elevated risk for metabolic syndrome (n = 463) were randomised into two groups. Both groups received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement for 6 months. HRQOL was estimated at baseline, after 3 and 12 months, using the SF-36 questionnaire, and all datasets providing HRQOL data (n = 263) were included in this predefined subanalysis. Stronger improvements in the physical component summary (PCS) were observed in the intervention compared to the control group, peaking after 3 months (estimated treatment difference 2.7 [1.2; 4.2]; p < 0.0001), but also in the long-term. Multiple regression analysis demonstrated that insulin levels and the achieved weight loss were associated with the mental component summary (MCS) after 12 months (p < 0.05). Thus, meal replacement-based lifestyle intervention is not only effective in weight reduction but, concomitantly, in enhancing HRQOL.

Lifestyle interventions including meal replacement are suitable for prevention and treatment of obesity and type-2-diabetes. Since leptin is involved in weight regulation, we hypothesised that a meal replacement-based lifestyle intervention would reduce leptin levels more effectively than lifestyle intervention alone. In the international, multicentre, randomised-controlled ACOORH-trial (Almased-Concept-against-Overweight-and-Obesity-and-Related- Health-Risk), overweight or obese participants with metabolic syndrome criteria (n = 463) were randomised into two groups and received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement. Data were collected at baseline, after 1, 3, 6, and 12 months. All datasets providing leptin data (n = 427) were included in this predefined subanalysis. Serum leptin levels significantly correlated with sex, body mass index, weight, and fat mass at baseline (p < 0.0001). Stronger leptin reduction has been observed in the intervention compared to the control group with the lowest levels after 1 month of intervention (estimated treatment difference −3.4 µg/L [1.4; 5.4] for females; −2.2 µg/L [1.2; 3.3] for males; p < 0.001 each) and was predictive for stronger reduction of body weight and fat mass (p < 0.001 each) over 12 months. Strongest weight loss was observed after 6 months (−5.9 ± 5.1 kg in females of the intervention group vs. −2.9 ± 4.9 kg in the control group (p < 0.0001); −6.8 ± 5.3 kg vs. −4.1 ± 4.4 kg (p = 0.003) in males) and in those participants with combined leptin and insulin decrease. A meal replacement-based lifestyle intervention effectively reduces leptin which is predictive for long-term weight loss.

Chronic liver inflammation causes continuous liver damage with progressive liver fibrosis and cirrhosis, which may eventually lead to hepatocellular carcinoma (HCC). Whereas the 10-year incidence for HCC in patients with cirrhosis is approximately 20%, many of these patients remain tumor free for their entire lives. Clarifying the mechanisms that define the various outcomes of chronic liver inflammation is a key aspect in HCC research. In addition to a wide variety of contributing factors, microRNAs (miRNAs) have also been shown to be engaged in promoting liver cancer. Therefore, we wanted to characterize miRNAs that are involved in the development of HCC, and we designed a longitudinal study with formalin-fixed and paraffin-embedded liver biopsy samples from several pathology institutes from Switzerland. We examined the miRNA expression by nCounterNanostring technology in matched nontumoral liver tissue from patients developing HCC (n = 23) before and after HCC formation in the same patient. Patients with cirrhosis (n = 26) remaining tumor free within a similar time frame served as a control cohort. Comparison of the two cohorts revealed that liver tissue from patients developing HCC displayed a down-regulation of miR-579-3p as an early step in HCC development, which was further confirmed in a validation cohort. Correlation with messenger RNA expression profiles further revealed that miR-579-3p directly attenuated phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) expression and consequently protein kinase B (AKT) and phosphorylated AKT. In vitro experiments and the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology confirmed that miR-579-3p controlled cell proliferation and cell migration of liver cancer cell lines. Conclusion: Liver tissues from patients developing HCC revealed changes in miRNA expression. miR-579-3p was identified as a novel tumor suppressor regulating phosphoinositide 3-kinase-AKT signaling at the early stages of HCC development., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: As formula diets have demonstrated to be effective in reducing weight, we hypothesised that in patients with overweight or obesity and accompanied cardiovascular risk factors, combining a liquid formula diet with a lifestyle intervention is superior in reducing weight and improving cardiovascular risk factors than lifestyle intervention alone., Methods: In this multicenter RCT 463 participants with overweight or obesity (BMI: 27-35 kg/m²; at least one additional co-morbidity of the metabolic syndrome) were randomised (1:2) into either a control group with lifestyle intervention only (CON, n = 155) or a lifestyle intervention group including a liquid meal replacement (INT, n = 308). Both groups used telemonitoring devices (scales and pedometers), received information on healthy diet and were instructed to increase physical activity. Telemonitoring devices automatically transferred data into a personalised online portal and acquired data were discussed. INT obtained a liquid meal replacement substituting three meals/day (~1200 kcal) within the first week. During weeks 2-4, participants replaced two meals/day and during weeks 5-26 only one meal/day was substituted (1300-1500 kcal/day). Follow-up was conducted after 52 weeks. Intention-to-treat analyses were performed. Primary outcome was weight change. Secondary outcomes comprised changes in cardiometabolic risk factors including body composition and laboratory parameters., Results: From the starting cohort 360 (78%, INT: n = 244; CON: n = 116) and 317 (68%, INT: n = 216; CON: n = 101) participants completed the 26-weeks intervention phase and the 52-weeks follow-up. The estimated treatment difference (ETD) between both groups was -3.2 kg [-4.0; -2.5] (P < 0.001) after 12 weeks and -1.8 kg [-2.8; -0.8] (P < 0.001) after 52 weeks., Conclusions: A low-intensity lifestyle intervention combined with a liquid meal replacement is superior regarding weight reduction and improvement of cardiovascular risk factors than lifestyle intervention alone.

An epithelial to mesenchymal transition (EMT) is an embryonic dedifferentiation program which is aberrantly activated in cancer cells to acquire cellular plasticity. This plasticity increases the ability of breast cancer cells to invade into surrounding tissue, to seed metastasis at distant sites and to resist to chemotherapy. In this study, we have observed a higher expression of interferon-related factors in basal-like and claudin-low subtypes of breast cancer in patients, known to be associated with EMT. Notably, Irf1 exerts essential functions during the EMT process, yet it is also required for the maintenance of an epithelial differentiation status of mammary gland epithelial cells: RNAi-mediated ablation of Irf1 in mammary epithelial cells results in the expression of mesenchymal factors and Smad transcriptional activity. Conversely, ablation of Irf1 during TGFβ-induced EMT prevents a mesenchymal transition and stabilizes the expression of E-cadherin. In the basal-like murine breast cancer cell line 4T1, RNAi-mediated ablation of Irf1 reduces colony formation and cell migration in vitro and shedding of circulating tumor cells and metastasis formation in vivo. This context-dependent dual role of Irf1 in the regulation of epithelial-mesenchymal plasticity provides important new insights into the functional contribution and therapeutic potential of interferon-regulated factors in breast cancer.

Introduction: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. It has distinct molecular features and primarily affects the KIT and PDGFRA genes., Objective: We wanted to assess the molecular profile of 68 GIST patients who were sequenced consecutively between 2014 and 2019 at our institute of pathology., Methods: Our cohort comprised 60 primary and 8 metastatic GIST patients; 43 and 57% of the cases, respectively, were analyzed by Sanger sequencing or next-generation sequencing (NGS)., Results: Of the 60 primary GIST patients, 47 (78%) showed a KIT mutation; 2 cases showed a double KIT mutation, and 1 of these was a therapy-naive GIST. Nine (15%) patients harbored a PDGFRA mutation, 2 (3%) had a BRAF mutation, 1 (2%) had a PIK3CA mutation, and 1 (2%) did not show any mutation. One BRAF and the PIK3CA mutation have not been described in GIST before. All metastatic GIST harbored exclusively KIT mutations., Conclusion: A retrospective analysis of GIST sequenced at our institute revealed incidences of KIT and PDGFRA mutations comparable to those in other cohorts from Europe. Interestingly, we found 2 previously undescribed mutations in the BRAF and PIK3CA genes as well as 1 treatment-naive case with a double KIT mutation in exon 11., (© 2020 S. Karger AG, Basel.)