TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma.

Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference screen in a Burkitt lymphoma cell line model. We identified transformation/transcription domain-associated protein (TRRAP), a constituent of several histone acetyltransferase complexes, as a critical positive regulator of both mutp53 and wild-type p53 levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, whereas TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening, we identified a 109-amino-acid region in the N-terminal HEAT repeat region of TRRAP that was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small-molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDAC1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.

[User Interest in Digital Health Technologies to Enhance Physical Activity in Students and Staff of a University]. / Nutzerinteresse an mobilen digitalen Assistenzsystemen zur Förderung körperlicher Aktivität bei Studierenden und Mitarbeitern einer Universität.

INTRODUCTION: Though health-enhancing effects of physical activity are well documented, the majority of the population is unable to implement present recommendations into daily routine. Mobile health (mHealth) technologies might be able to increase the physical activity level. However, the interest of potential users is a mandatory basis for this. METHOD: We conducted an online-survey from 06-07/2015 by asking students and employees from the University of Potsdam for their activity level, interest in mHealth training support and other relevant parameters. RESULTS: 1 217 students and 485 employees (67.3% and 67.5% female, 26.0±4.9 and 42.7±11.7 years, respectively) participated in the survey. 70.1% of employees and 52.7% of students did not follow the recommendation for physical activity (3 times per week). 53.2% (students) and 44.2% (employees), independent of age, sex, BMI and level of education or professional qualification, indicated their interest in mHealth technology offering training support. CONCLUSION: Even in a younger population with higher education, most respondents reported an insufficient level of physical activity. About half of them indicated their interest in training support. Therefore, the use of personalized mHealth technology may be of increasing significance for a positive change of lifestyle.

Algorithm based on one monocular video delivers highly valid and reliable gait parameters.

Despite its paramount importance for manifold use cases (e.g., in the health care industry, sports, rehabilitation and fitness assessment), sufficiently valid and reliable gait parameter measurement is still limited to high-tech gait laboratories mostly. Here, we demonstrate the excellent validity and test-retest repeatability of a novel gait assessment system which is built upon modern convolutional neural networks to extract three-dimensional skeleton joints from monocular frontal-view videos of walking humans. The validity study is based on a comparison to the GAITRite pressure-sensitive walkway system. All measured gait parameters (gait speed, cadence, step length and step time) showed excellent concurrent validity for multiple walk trials at normal and fast gait speeds. The test-retest-repeatability is on the same level as the GAITRite system. In conclusion, we are convinced that our results can pave the way for cost, space and operationally effective gait analysis in broad mainstream applications. Most sensor-based systems are costly, must be operated by extensively trained personnel (e.g., motion capture systems) or-even if not quite as costly-still possess considerable complexity (e.g., wearable sensors). In contrast, a video sufficient for the assessment method presented here can be obtained by anyone, without much training, via a smartphone camera.

Scapular kinematics during unloaded and maximal loaded isokinetic concentric and eccentric shoulder flexion and extension movements.

Characterization of scapular kinematics under demanding load conditions might aid to distinguish between physiological and clinically relevant alterations. Previous investigations focused only on submaximal external load situations. How scapular movement changes with maximal load remains unclear. Therefore, the present study aimed to evaluate 3D scapular kinematics during unloaded and maximal loaded shoulder flexion and extension. Twelve asymptomatic individuals performed shoulder flexion and extension movements under unloaded and maximal concentric and eccentric loaded isokinetic conditions. 3D scapular kinematics assessed with a motion capture system was analyzed for 20° intervals of humeral positions from 20° to 120° flexion. Repeated measures ANOVAs were used to evaluate kinematic differences between load conditions for scapular position angles, scapulohumeral rhythm and scapular motion extent. Increased scapular upward rotation was seen during shoulder flexion and extension as well as decreased posterior tilt and external rotation during eccentric and concentric arm descents of maximal loaded compared to unloaded conditions. Load effects were further seen for the scapulohumeral rhythm with greater scapular involvement at lower humeral positions and increased scapular motion extent under maximal loaded shoulder movements. With maximal load applied to the arm physiological scapular movement pattern are induced that may imply both impingement sparing and causing mechanisms.

Descriptive Evaluation and Accuracy of a Mobile App to Assess Fall Risk in Seniors: Retrospective Case-Control Study.

BACKGROUND: Fall-risk assessment is complex. Based on current scientific evidence, a multifactorial approach, including the analysis of physical performance, gait parameters, and both extrinsic and intrinsic risk factors, is highly recommended. A smartphone-based app was designed to assess the individual risk of falling with a score that combines multiple fall-risk factors into one comprehensive metric using the previously listed determinants. OBJECTIVE: This study provides a descriptive evaluation of the designed fall-risk score as well as an analysis of the app's discriminative ability based on real-world data. METHODS: Anonymous data from 242 seniors was analyzed retrospectively. Data was collected between June 2018 and May 2019 using the fall-risk assessment app. First, we provided a descriptive statistical analysis of the underlying dataset. Subsequently, multiple learning models (Logistic Regression, Gaussian Naive Bayes, Gradient Boosting, Support Vector Classification, and Random Forest Regression) were trained on the dataset to obtain optimal decision boundaries. The receiver operating curve with its corresponding area under the curve (AUC) and sensitivity were the primary performance metrics utilized to assess the fall-risk score's ability to discriminate fallers from nonfallers. For the sake of completeness, specificity, precision, and overall accuracy were also provided for each model. RESULTS: Out of 242 participants with a mean age of 84.6 years old (SD 6.7), 139 (57.4%) reported no previous falls (nonfaller), while 103 (42.5%) reported a previous fall (faller). The average fall risk was 29.5 points (SD 12.4). The performance metrics for the Logistic Regression Model were AUC=0.9, sensitivity=100%, specificity=52%, and accuracy=73%. The performance metrics for the Gaussian Naive Bayes Model were AUC=0.9, sensitivity=100%, specificity=52%, and accuracy=73%. The performance metrics for the Gradient Boosting Model were AUC=0.85, sensitivity=88%, specificity=62%, and accuracy=73%. The performance metrics for the Support Vector Classification Model were AUC=0.84, sensitivity=88%, specificity=67%, and accuracy=76%. The performance metrics for the Random Forest Model were AUC=0.84, sensitivity=88%, specificity=57%, and accuracy=70%. CONCLUSIONS: Descriptive statistics for the dataset were provided as comparison and reference values. The fall-risk score exhibited a high discriminative ability to distinguish fallers from nonfallers, irrespective of the learning model evaluated. The models had an average AUC of 0.86, an average sensitivity of 93%, and an average specificity of 58%. Average overall accuracy was 73%. Thus, the fall-risk app has the potential to support caretakers in easily conducting a valid fall-risk assessment. The fall-risk score's prospective accuracy will be further validated in a prospective trial.

Reliability and validity of the Kinect V2 for the assessment of lower extremity rehabilitation exercises.

BACKGROUND: Besides its initial use as a video gaming system the Kinect might also be suitable to capture human movements in the clinical context. However, the system's reliability and validity to capture rehabilitation exercises is unclear. RESEARCH QUESTION: The purpose of this study was to evaluate the test-retest reliability of lower extremity kinematics during squat, hip abduction and lunge exercises captured by the Kinect and to evaluate the agreement to a reference 3D camera-based motion system. METHODS: Twenty-one healthy individuals performed five repetitions of each lower limb exercise on two different days. Movements were simultaneously assessed by the Kinect and the reference 3D motion system. Joint angles and positions of the lower limb were calculated for sagittal and frontal plane. For the inter-session reliability and the agreement between the two systems standard error of measurement (SEM), bias with limits of agreement (LoA) and Pearson Correlation Coefficient (r) were calculated. RESULTS: Parameters indicated varying reliability for the assessed joint angles and positions and decreasing reliability with increasing task complexity. Across all exercises, measurement deviations were shown especially for small movement amplitudes. Variability was acceptable for joint angles and positions during the squat, partially acceptable during the hip abduction and predominately inacceptable during the lunge. The agreement between systems was characterized by systematic errors. Overestimations by the Kinect were apparent for hip flexion during the squat and hip abduction/adduction during the hip abduction exercise as well as for the knee positions during the lunge. Knee and hip flexion during hip abduction and lunge were underestimated by the Kinect. SIGNIFICANCE: The Kinect system can reliably assess lower limb joint angles and positions during simple exercises. The validity of the system is however restricted. An application in the field of early orthopedic rehabilitation without further development of post-processing techniques seems so far limited.

The Effectiveness of Telerehabilitation as a Supplement to Rehabilitation in Patients After Total Knee or Hip Replacement: Randomized Controlled Trial.

BACKGROUND: Telerehabilitation can contribute to the maintenance of successful rehabilitation regardless of location and time. The aim of this study was to investigate a specific three-month interactive telerehabilitation routine regarding its effectiveness in assisting patients with physical functionality and with returning to work compared to typical aftercare. OBJECTIVE: The aim of the study was to investigate a specific three-month interactive telerehabilitation with regard to effectiveness in functioning and return to work compared to usual aftercare. METHODS: From August 2016 to December 2017, 111 patients (mean 54.9 years old; SD 6.8; 54.3% female) with hip or knee replacement were enrolled in the randomized controlled trial. At discharge from inpatient rehabilitation and after three months, their distance in the 6-minute walk test was assessed as the primary endpoint. Other functional parameters, including health related quality of life, pain, and time to return to work, were secondary endpoints. RESULTS: Patients in the intervention group performed telerehabilitation for an average of 55.0 minutes (SD 9.2) per week. Adherence was high, at over 75%, until the 7th week of the three-month intervention phase. Almost all the patients and therapists used the communication options. Both the intervention group (average difference 88.3 m; SD 57.7; P=.95) and the control group (average difference 79.6 m; SD 48.7; P=.95) increased their distance in the 6-minute-walk-test. Improvements in other functional parameters, as well as in quality of life and pain, were achieved in both groups. The higher proportion of working patients in the intervention group (64.6%; P=.01) versus the control group (46.2%) is of note. CONCLUSIONS: The effect of the investigated telerehabilitation therapy in patients following knee or hip replacement was equivalent to the usual aftercare in terms of functional testing, quality of life, and pain. Since a significantly higher return-to-work rate could be achieved, this therapy might be a promising supplement to established aftercare. TRIAL REGISTRATION: German Clinical Trials Register DRKS00010009; https://www.drks.de/drks_web/navigate.do? navigationId=trial.HTML&TRIAL_ID=DRKS00010009.

Drug-perturbation-based stratification of blood cancer.

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.

Integrative genomic and transcriptomic analysis of leiomyosarcoma.

Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of "BRCAness", including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies.

Reproducibility of scapular muscle activity in isokinetic shoulder flexion and extension.

Repetitive overhead movements have been identified as a main risk factor to develop shoulder complaints with scapular muscle activity being altered. Reliable assessment of muscle activity is essential to differentiate between symptomatic and asymptomatic individuals. Therefore, the present study aimed to investigate the intra- and inter-session reliability of scapular muscle activity during maximal isokinetic shoulder flexion and extension. Eleven asymptomatic adults performed maximum effort isokinetic shoulder flexion and extension (concentric and eccentric at 60°/s) in a test-retest design. Muscle activity of the upper and lower trapezius and serratus anterior was assessed by sEMG. Root Mean Square was calculated for whole ROM and single movement phases of absolute and normalized muscle activity. Absolute (Bland-Altman analysis (Bias, LoA), Minimal detectable change (MDC)) and relative reliability parameters (Intraclass correlation coefficient (ICC), coefficient of variation (CV)/test-retest variability (TRV)) were utilized for the evaluation of reproducibility. Intra-session reliability revealed ICCs between 0.56 and 0.98, averaged CVs of 18% and average MDCs of 81mV. Inter-session reliability resulted in ICCs between 0.13 and 0.93, averaged TRVs of 21%, average MDCs of 15% and systematic and random error between -8±60% and 12±36%. Scapular muscle activity assessed in overhead movements can be measured reliably under maximum load conditions, though variability is dependent on the movement phase. Measurement variability does not exceed magnitudes of altered scapular muscle activities as reported in previous studies. Therefore, maximum load application is a promising approach for the evaluation of changes in scapular control related to pathologies.

User Interest in Digital Health Technologies to Encourage Physical Activity: Results of a Survey in Students and Staff of a German University.

BACKGROUND: Although the benefits for health of physical activity (PA) are well documented, the majority of the population is unable to implement present recommendations into daily routine. Mobile health (mHealth) apps could help increase the level of PA. However, this is contingent on the interest of potential users. OBJECTIVE: The aim of this study was the explorative, nuanced determination of the interest in mHealth apps with respect to PA among students and staff of a university. METHODS: We conducted a Web-based survey from June to July 2015 in which students and employees from the University of Potsdam were asked about their activity level, interest in mHealth fitness apps, chronic diseases, and sociodemographic parameters. RESULTS: A total of 1217 students (67.30%, 819/1217; female; 26.0 years [SD 4.9]) and 485 employees (67.5%, 327/485; female; 42.7 years [SD 11.7]) participated in the survey. The recommendation for PA (3 times per week) was not met by 70.1% (340/485) of employees and 52.67% (641/1217) of students. Within these groups, 53.2% (341/641 students) and 44.2% (150/340 employees)-independent of age, sex, body mass index (BMI), and level of education or professional qualification-indicated an interest in mHealth fitness apps. CONCLUSIONS: Even in a younger, highly educated population, the majority of respondents reported an insufficient level of PA. About half of them indicated their interest in training support. This suggests that the use of personalized mobile fitness apps may become increasingly significant for a positive change of lifestyle.

Effectiveness of an interactive telerehabilitation system with home-based exercise training in patients after total hip or knee replacement: study protocol for a multicenter, superiority, no-blinded randomized controlled trial.

BACKGROUND: Total hip or knee replacement is one of the most frequently performed surgical procedures. Physical rehabilitation following total hip or knee replacement is an essential part of the therapy to improve functional outcomes and quality of life. After discharge from inpatient rehabilitation, a subsequent postoperative exercise therapy is needed to maintain functional mobility. Telerehabilitation may be a potential innovative treatment approach. We aim to investigate the superiority of an interactive telerehabilitation intervention for patients after total hip or knee replacement, in comparison to usual care, regarding physical performance, functional mobility, quality of life and pain. METHODS/DESIGN: This is an open, randomized controlled, multicenter superiority study with two prospective arms. One hundred and ten eligible and consenting participants with total knee or hip replacement will be recruited at admission to subsequent inpatient rehabilitation. After comprehensive, 3-week, inpatient rehabilitation, the intervention group performs a 3-month, interactive, home-based exercise training with a telerehabilitation system. For this purpose, the physiotherapist creates an individual training plan out of 38 different strength and balance exercises which were implemented in the system. Data about the quality and frequency of training are transmitted to the physiotherapist for further adjustment. Communication between patient and physiotherapist is possible with the system. The control group receives voluntary, usual aftercare programs. Baseline assessments are investigated after discharge from rehabilitation; final assessments 3 months later. The primary outcome is the difference in improvement between intervention and control group in 6-minute walk distance after 3 months. Secondary outcomes include differences in the Timed Up and Go Test, the Five-Times-Sit-to-Stand Test, the Stair Ascend Test, the Short-Form 36, the Western Ontario and McMaster Universities Osteoarthritis Index, the International Physical Activity Questionnaire, and postural control as well as gait and kinematic parameters of the lower limbs. Baseline-adjusted analysis of covariance models will be used to test for group differences in the primary and secondary endpoints. DISCUSSION: We expect the intervention group to benefit from the interactive, home-based exercise training in many respects represented by the study endpoints. If successful, this approach could be used to enhance the access to aftercare programs, especially in structurally weak areas. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), ID: DRKS00010009 . Registered on 11 May 2016.

Creating functional engineered variants of the single-module non-ribosomal peptide synthetase IndC by T domain exchange.

Non-ribosomal peptide synthetases (NRPSs) are enzymes that catalyze ribosome-independent production of small peptides, most of which are bioactive. NRPSs act as peptide assembly lines where individual, often interconnected modules each incorporate a specific amino acid into the nascent chain. The modules themselves consist of several domains that function in the activation, modification and condensation of the substrate. NRPSs are evidently modular, yet experimental proof of the ability to engineer desired permutations of domains and modules is still sought. Here, we use a synthetic-biology approach to create a small library of engineered NRPSs, in which the domain responsible for carrying the activated amino acid (T domain) is exchanged with natural or synthetic T domains. As a model system, we employ the single-module NRPS IndC from Photorhabdus luminescens that produces the blue pigment indigoidine. As chassis we use Escherichia coli. We demonstrate that heterologous T domain exchange is possible, even for T domains derived from different organisms. Interestingly, substitution of the native T domain with a synthetic one enhanced indigoidine production. Moreover, we show that selection of appropriate inter-domain linker regions is critical for functionality. Taken together, our results extend the engineering avenues for NRPSs, as they point out the possibility of combining domain sequences coming from different pathways, organisms or from conservation criteria. Moreover, our data suggest that NRPSs can be rationally engineered to control the level of production of the corresponding peptides. This could have important implications for industrial and medical applications.