Neural underpinnings of preferential pain learning and the modulatory role of fear.

Due to its unique biological relevance, pain-related learning might differ from learning from other aversive experiences. This functional magnetic resonance imaging study compared neural mechanisms underlying the acquisition and extinction of different threats in healthy humans. We investigated whether cue-pain associations are acquired faster and extinguished slower than cue associations with an equally unpleasant tone. Additionally, we studied the modulatory role of stimulus-related fear. Therefore, we used a differential conditioning paradigm, in which somatic heat pain stimuli and unpleasantness-matched auditory stimuli served as US. Our results show stronger acquisition learning for pain- than tone-predicting cues, which was augmented in participants with relatively higher levels of fear of pain. These behavioral findings were paralleled by activation of brain regions implicated in threat processing (insula, amygdala) and personal significance (ventromedial prefrontal cortex). By contrast, extinction learning seemed to be less dependent on the threat value of the US, both on the behavioral and neural levels. Amygdala activity, however, scaled with pain-related fear during extinction learning. Our findings on faster and stronger (i.e. "preferential") pain learning and the role of fear of pain are consistent with the biological relevance of pain and may be relevant to the development or maintenance of chronic pain.

Intraoperative contrast-enhanced ultrasound has an outcome-relevant impact on surgery of primary and metastatic liver lesions.

PURPOSE: Complete resection of the affected tissue remains the best curative treatment option for liver-derived tumors and colorectal liver metastases. In addition to preoperative cross-sectional imaging, contrast-enhanced intraoperative ultrasound (CE-IOUS) plays a crucial role in the detection and localization of all liver lesions. However, its exact role is unclear. This study was designed to evaluate the clinical and oncological impact of using CE-IOUS in the surgical treatment of these diseases. MATERIALS AND METHODS: Over the three-year study period, 206 patients with primary liver tumors and hepatic metastases were enrolled in this prospective, monocentric study to evaluate the impact of CE-IOUS in liver surgery. Secondary outcomes included comparing the sensitivity and specificity of CE-IOUS with existing preoperative imaging modalities and identifying preoperative parameters that could predict a strategic impact of CE-IOUS. In addition, the oncological significance of CE-IOUS was evaluated using a case-cohort design with a minimum follow-up of 18 months. RESULTS: CE-IOUS findings led to a change in surgical strategy in 34% of cases (n=70/206). The accuracy in cases with a major change could be confirmed histopathologically in 71.4% of cases (n=25/35). The impact could not be predicted using parameters assumed to be clinically relevant. An oncological benefit of a CE-IOUS adapted surgical approach was demonstrated in patients suffering from HCC and colorectal liver metastases. CONCLUSION: CE-IOUS may significantly increase R0 resection rates and should therefore be used routinely as an additional staging method, especially in complex liver surgery.

Dancing the Nanopore limbo - Nanopore metagenomics from small DNA quantities for bacterial genome reconstruction.

BACKGROUND: While genome-resolved metagenomics has revolutionized our understanding of microbial and genetic diversity in environmental samples, assemblies of short-reads often result in incomplete and/or highly fragmented metagenome-assembled genomes (MAGs), hampering in-depth genomics. Although Nanopore sequencing has increasingly been used in microbial metagenomics as long reads greatly improve the assembly quality of MAGs, the recommended DNA quantity usually exceeds the recoverable amount of DNA of environmental samples. Here, we evaluated lower-than-recommended DNA quantities for Nanopore library preparation by determining sequencing quality, community composition, assembly quality and recovery of MAGs. RESULTS: We generated 27 Nanopore metagenomes using the commercially available ZYMO mock community and varied the amount of input DNA from 1000 ng (the recommended minimum) down to 1 ng in eight steps. The quality of the generated reads remained stable across all input levels. The read mapping accuracy, which reflects how well the reads match a known reference genome, was consistently high across all libraries. The relative abundance of the species in the metagenomes was stable down to input levels of 50 ng. High-quality MAGs (> 95% completeness, ≤ 5% contamination) could be recovered from metagenomes down to 35 ng of input material. When combined with publicly available Illumina reads for the mock community, Nanopore reads from input quantities as low as 1 ng improved the quality of hybrid assemblies. CONCLUSION: Our results show that the recommended DNA amount for Nanopore library preparation can be substantially reduced without any adverse effects to genome recovery and still bolster hybrid assemblies when combined with short-read data. We posit that the results presented herein will enable studies to improve genome recovery from low-biomass environments, enhancing microbiome understanding.

Chromatic aberration correction employing reinforcement learning.

In fluorescence microscopy a multitude of labels are used that bind to different structures of biological samples. These often require excitation at different wavelengths and lead to different emission wavelengths. The presence of different wavelengths can induce chromatic aberrations, both in the optical system and induced by the sample. These lead to a detuning of the optical system, as the focal positions shift in a wavelength dependent manner and finally to a decrease in the spatial resolution. We present the correction of chromatic aberrations by using an electrical tunable achromatic lens driven by reinforcement learning. The tunable achromatic lens consists of two lens chambers filled with different optical oils and sealed with deformable glass membranes. By deforming the membranes of both chambers in a targeted manner, the chromatic aberrations present in the system can be manipulated to tackle both systematic and sample induced aberrations. We demonstrate chromatic aberration correction of up to 2200 mm and shift of the focal spot positions of 4000 mm. For control of this non-linear system with four input voltages, several reinforcement learning agents are trained and compared. The experimental results show that the trained agent can correct system and sample induced aberration and thereby improve the imaging quality, this is demonstrated using biomedical samples. In this case human thyroid was used for demonstration.

Fully refractive telecentric f-theta microscope based on adaptive elements for 3D raster scanning of biological tissues.

Various techniques in microscopy are based on point-wise acquisition, which provides advantages in acquiring sectioned images, for example in confocal or two-photon microscopy. The advantages come along with the need to perform three-dimensional scanning, which is often realized by mechanical movement achieved by stage-scanning or piezo-based scanning in the axial direction. Lateral scanning often employs galvo-mirrors, leading to a reflective setup and hence to a folded beam path. In this paper, we introduce a fully refractive microscope capable of three-dimensional scanning, which employs the combination of an adaptive lens, an adaptive prism, and a tailored telecentric f-theta objective. Our results show that this microscope is capable to perform flexible three-dimensional scanning, with low scan-induced aberrations, at a uniform resolution over a large tuning range of X=Y=6300 µ m and Z=480 µ m with only transmissive components. We demonstrate the capabilities at the example of volumetric measurements on the transgenic fluorescence of the thyroid of a zebrafish embryo and mixed pollen grains. This is the first step towards flexible aberration-free volumetric smart microscopy of three-dimensional samples like embryos and organoids, which could be exploited for the demands in both lateral and axial dimensions in biomedical samples without compromising image quality.

Patient Portals as Facilitators of Engagement in Patients With Diabetes and Chronic Heart Disease: Scoping Review of Usage and Usability.

BACKGROUND: Patient portals have the potential to improve care for chronically ill patients by engaging them in their treatment. These platforms can work, for example, as a standalone self-management intervention or a tethered link to treatment providers in routine care. Many different types of portals are available for different patient groups, providing various features. OBJECTIVE: This scoping review aims to summarize the current literature on patient portals for patients with diabetes mellitus and chronic heart disease regarding usage behavior and usability. METHODS: We conducted this review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement for scoping reviews. We performed database searches using PubMed, PsycInfo, and CINAHL, as well as additional searches in reviews and reference lists. We restricted our search to 2010. Qualitative and quantitative studies, and studies using both approaches that analyzed usage behavior or usability of patient portals were eligible. We mapped portal features according to broad thematic categories and summarized the results of the included studies separately according to outcome and research design. RESULTS: After screening, we finally included 85 studies. Most studies were about patients with diabetes, included patients younger than 65 years, and were conducted in the United States. Portal features were categorized into educational/general information, reminder, monitoring, interactivity, personal health information, electronic/personal health record, and communication. Portals mostly provided educational, monitoring, and communication-related features. Studies reported on usage behavior including associated variables, usability dimensions, and suggestions for improvement. Various ways of reporting usage frequency were identified. A noticeable decline in portal usage over time was reported frequently. Age was most frequently studied in association with portal use, followed by gender, education, and eHealth literacy. Younger age and higher education were often associated with higher portal use. In two-thirds of studies reporting on portal usability, the portals were rated as user friendly and comprehensible, although measurement and reporting were heterogeneous. Portals were considered helpful for self-management through positive influences on motivation, health awareness, and behavioral changes. Helpful features for self-management were educational/general information and monitoring. Barriers to portal use were general (eg, aspects of design or general usability), related to specific situations during portal use (eg, login procedure), or not portal specific (eg, user skills and preferences). Frequent themes were aspects of design, usability, and technology. Suggestions for improvement were mainly related to technical issues and need for support. CONCLUSIONS: The current state of research emphasizes the importance of involving patients in the development and evaluation of patient portals. The consideration of various research designs in a scoping review is helpful for a deeper understanding of usage behavior and usability. Future research should focus on the role of disease burden, and usage behavior and usability among older patients.

Greater interruption of visual processing and memory encoding by visceral than somatic pain in healthy volunteers - An fMRI study.

Visceral pain is regarded as more salient than somatic pain. It has greater affective and emotional components, i.e., it elicits higher levels of pain-related fear and is perceived as more unpleasant than somatic pain. In this fMRI study, we examined the neural effects of painful visceral as compared to painful somatic stimulation on visual processing and memory encoding in a visual categorization and surprise recognition task in healthy volunteers. During the categorization task, participants received either rectal distensions or heat stimuli applied to the forearm, with stimuli being individually matched for unpleasantness. Behaviorally, visceral pain reduced memory encoding as compared to somatic pain (Kleine-Borgmann et al., 2021). Imaging analyses now revealed that visceral pain was associated with reduced activity (i.e., greater pain-related interruption) in neural areas typically involved in visual processing and memory encoding. These include the parahippocampal gyrus, fusiform gyrus, striatum, occipital cortex, insula, and the amygdala. Moreover, reduced engagement of the lateral occipital complex during visual categorization under visceral pain was associated with higher visceral pain-related fear. These findings obtained in healthy volunteers shed light on the neural circuitry underlying the interruptive effect of visceral pain and pave the way for future studies in patient samples.

Can positive expectations help to improve the learning of risk literacy? A cluster-randomized study in undergraduate medical students.

BACKGROUND: Risk literacy, i.e., the ability to calculate and apply risk parameters, represents a key competence for risk communication and medical decision making. However, risk literacy is reportedly low in medical students. The successful acquisition of statistical competencies is often difficult, and can be hampered by emotional learning obstacles, calling for interventions to support learning. In this cluster-randomized study, we aimed to translate findings from placebo research to medical education. Specifically, we tested if the acquisition of risk literacy during a seminar unit can be facilitated by positive expectations, induced by a positive and non-threatening framing of the content and learning goals. METHODS: The study took place during a mandatory 2.5-h seminar on "risk literacy" for 2nd year medical students. The seminar teaches both statistical knowledge and its application in patient communication. To test the effects of expectations on risk literacy acquisition, the (otherwise identical) seminar was framed either as "communication training" (positive framing condition) or "statistics seminar" (negative framing condition). All N = 200 students of the semester were invited to participate, and cluster-randomized to the positive or negative framing condition (4 seminar groups each condition). Risk literacy was assessed with the "Quick Risk Test" (QRT) at the beginning and end of the seminar, along with statistics anxiety and subjective learning success using questionnaires. RESULTS: Data from N = 192 students were included. At the end of the seminar, risk literacy was increased in both framing conditions, with a significantly greater increase in QRT scores in the positive framing condition. Statistics anxiety was significantly decreased in both framing conditions, with no evidence of group differences. Subjective learning success was overall high and comparable between groups. CONCLUSIONS: Supporting our hypothesis, positive framing led to a significantly greater increase in risk literacy (i.e., in QRT scores). Our data offer first support that positive framing of learning goals may help to facilitate the acquisition of statistical knowledge. Expectation-orientated interventions may thus offer a feasible tool to optimize learning settings and framing of learning objectives in medical statistics courses.

Inflammatory bowel disease in South-Eastern Norway III (IBSEN III): a new population-based inception cohort study from South-Eastern Norway.

BACKGROUND AND AIM: Modern treatment strategies for inflammatory bowel disease (IBD) are postulated to change the natural disease course. Inception cohort studies are the gold standard for investigating such changes. We have initiated a new population-based inception cohort study; Inflammatory bowel disease in South Eastern Norway III (IBSEN III). In this article, we describe the study protocol and baseline characteristics of the cohort. METHODS: IBSEN III is an ongoing, population-based observational inception cohort study with prospective follow-up. Adult and pediatric patients with suspected IBD in the South-Eastern Health Region of Norway (catchment area of 2.95 million inhabitants in 2017), during the 3-year period from 2017 to 2019, were eligible for inclusion. Comprehensive clinical, biochemical, endoscopic, demographic, and patient-reported data were collected at the time of diagnosis and throughout standardized follow-up. For a portion of the patients, extensive biological material was biobanked. RESULTS: The study included 2168 patients, of whom 1779 were diagnosed with IBD (Crohn's disease: 626, ulcerative colitis: 1082, IBD unclassified: 71). In 124 patients, there were subtle findings indicative of, but not diagnostic for, IBD. The remaining 265 patients were classified as symptomatic non-IBD controls. CONCLUSION: We have included patients in a comprehensive population-based IBD cohort from a catchment population of 2.95 million, and a unique biobank with materials from newly diagnosed and treatment-naïve IBD patients and symptomatic non-IBD controls. We believe this cohort will add important knowledge about IBD in the years to come.

Droplet-based vitrification of adherent human induced pluripotent stem cells on alginate microcarrier influenced by adhesion time and matrix elasticity.

The gold standard in cryopreservation is still conventional slow freezing of single cells or small aggregates in suspension, although major cell loss and limitation to non-specialised cell types in stem cell technology are known drawbacks. The requirement for rapidly available therapeutic and diagnostic cell types is increasing constantly. In the case of human induced pluripotent stem cells (hiPSCs) or their derivates, more sophisticated cryopreservation protocols are needed to address this demand. These should allow a preservation in their physiological, adherent state, an efficient re-cultivation and upscaling upon thawing towards high-throughput applications in cell therapies or disease modelling in drug discovery. Here, we present a novel vitrification-based method for adherent hiPSCs, designed for automated handling by microfluidic approaches and with ready-to-use potential e.g. in suspension-based bioreactors after thawing. Modifiable alginate microcarriers serve as a growth surface for adherent hiPSCs that were cultured in a suspension-based bioreactor and subsequently cryopreserved via droplet-based vitrification in comparison to conventional slow freezing. Soft (0.35%) versus stiff (0.65%) alginate microcarriers in concert with adhesion time variation have been examined. Findings revealed specific optimal conditions leading to an adhesion time and growth surface (matrix) elasticity dependent hypothesis on cryo-induced damaging regimes for adherent cell types. Deviations from the found optimum parameters give rise to membrane ruptures assessed via SEM and major cell loss after adherent vitrification. Applying the optimal conditions, droplet-based vitrification was superior to conventional slow freezing. A decreased microcarrier stiffness was found to outperform stiffer material regarding cell recovery, whereas the stemness characteristics of rewarmed hiPSCs were preserved.

A novel human pluripotent stem cell-based assay to predict developmental toxicity.

There is a great need for novel in vitro methods to predict human developmental toxicity to comply with the 3R principles and to improve human safety. Human-induced pluripotent stem cells (hiPSC) are ideal for the development of such methods, because they are easy to retrieve by conversion of adult somatic cells and can differentiate into most cell types of the body. Advanced three-dimensional (3D) cultures of these cells, so-called embryoid bodies (EBs), moreover mimic the early developing embryo. We took advantage of this to develop a novel human toxicity assay to predict chemically induced developmental toxicity, which we termed the PluriBeat assay. We employed three different hiPSC lines from male and female donors and a robust microtiter plate-based method to produce EBs. We differentiated the cells into cardiomyocytes and introduced a scoring system for a quantitative readout of the assay-cardiomyocyte contractions in the EBs observed on day 7. Finally, we tested the three compounds thalidomide (2.3-36 µM), valproic acid (25-300 µM), and epoxiconazole (1.3-20 µM) on beating and size of the EBs. We were able to detect the human-specific teratogenicity of thalidomide and found the rodent toxicant epoxiconazole as more potent than thalidomide in our assay. We conclude that the PluriBeat assay is a novel method for predicting chemicals' adverse effects on embryonic development.

ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-ß-hydroxylase.

The copper (Cu) transporters ATPase copper-transporting alpha (ATP7A) and ATPase copper-transporting beta (ATP7B) are essential for the normal function of the mammalian central nervous system. Inactivation of ATP7A or ATP7B causes the severe neurological disorders, Menkes disease and Wilson disease, respectively. In both diseases, Cu imbalance is associated with abnormal levels of the catecholamine-type neurotransmitters dopamine and norepinephrine. Dopamine is converted to norepinephrine by dopamine-ß-hydroxylase (DBH), which acquires its essential Cu cofactor from ATP7A. However, the role of ATP7B in catecholamine homeostasis is unclear. Here, using immunostaining of mouse brain sections and cultured cells, we show that DBH-containing neurons express both ATP7A and ATP7B. The two transporters are located in distinct cellular compartments and oppositely regulate the export of soluble DBH from cultured neuronal cells under resting conditions. Down-regulation of ATP7A, overexpression of ATP7B, and pharmacological Cu depletion increased DBH retention in cells. In contrast, ATP7B inactivation elevated extracellular DBH. Proteolytic processing and the specific activity of exported DBH were not affected by changes in ATP7B levels. These results establish distinct regulatory roles for ATP7A and ATP7B in neuronal cells and explain, in part, the lack of functional compensation between these two transporters in human disorders of Cu imbalance.

Copper and the brain noradrenergic system.

Copper (Cu) plays an essential role in the development and function of the brain. In humans, genetic disorders of Cu metabolism may cause either severe Cu deficiency (Menkes disease) or excessive Cu accumulation (Wilson disease) in the brain tissue. In either case, the loss of Cu homeostasis results in catecholamine misbalance, abnormal myelination of neurons, loss of normal brain architecture, and a spectrum of neurologic and/or psychiatric manifestations. Several metabolic processes have been identified as particularly sensitive to Cu dis-homeostasis. This review focuses on the role of Cu in noradrenergic neurons and summarizes the current knowledge of mechanisms that maintain Cu homeostasis in these cells. The impact of Cu misbalance on catecholamine metabolism and functioning of noradrenergic system is discussed.

Exercise improves functional capacity and lean body mass in patients with gastrointestinal cancer during chemotherapy: a single-blind RCT.

PURPOSE: Although growing evidence underlines the benefits of physical activity as supportive intervention for cancer patients, sparse data are available for exercise in patients with advanced disease stages, in particular for gastrointestinal cancer (GIC) patients who experience specific disease-associated limitations. Thus, the aim of this study is to evaluate the effects of home-based moderate intensity exercise on functional capacity, activities of daily living (ADL) and body composition in patients with advanced GIC during first-line chemotherapy. METHODS: Participants (GIC, UICC III-IV; n = 44) were randomly assigned to home-based physical activity programme of 150 min moderate walking per week or a control group (CG). Functional status (SPPB: gait speed, balance, lower extremity muscle strength), postural sway, chemotherapy-induced peripheral neuropathy, nutritional state (Mini Nutritional Assessment, MNA) and lean body mass were assessed according to established recommendations. All tests were performed before chemotherapy (T0), after two chemotherapy cycles (T1) and after 12 weeks (T2). RESULTS: SPPB changes from T1 to T2 differed between groups with a comparably greater decrease in the CG (p < .05), but no changes or group differences over the whole study period (T0 to T2) were found. Exercise improved postural sway (T0 to T1; T0 toT2) and lean body mass (T1 to T2; T0 to T2) compared to the control group (p < .05). Gait speed, peripheral neuropathy and strength did not differ between groups (p > .05). CONCLUSIONS: Our results indicate that a home-based physical activity improves postural sway and body composition and might stabilize functional capacity in patients with advanced GIC during chemotherapy. Although the other outcomes did not differ between groups, aforementioned effects might contribute to a maintenance of independency in ADL and a better treatment tolerance and thus enhance patients' quality of life.

The transcription factor Dach1 is essential for podocyte function.

Dedifferentiation and loss of podocytes are the major cause of chronic kidney disease. Dach1, a transcription factor that is essential for cell fate, was found in genome-wide association studies to be associated with the glomerular filtration rate. We found that podocytes express high levels of Dach1 in vivo and to a much lower extent in vitro. Parietal epithelial cells (PECs) that are still under debate to be a type of progenitor cell for podocytes expressed Dach1 only at low levels. The transfection of PECs with a plasmid encoding for Dach1 induced the expression of synaptopodin, a podocyte-specific protein, demonstrated by immunocytochemistry and Western blot. Furthermore, synaptopodin was located along actin fibres in a punctate pattern in Dach1-expressing PECs comparable with differentiated podocytes. Moreover, dedifferentiating podocytes of isolated glomeruli showed a significant reduction in the expression of Dach1 together with synaptopodin after 9 days in cell culture. To study the role of Dach1 in vivo, we used the zebrafish larva as an animal model. Knockdown of the zebrafish ortholog Dachd by morpholino injection into fertilized eggs resulted in a severe renal phenotype. The glomeruli of the zebrafish larvae showed morphological changes of the glomerulus accompanied by down-regulation of nephrin and leakage of the filtration barrier. Interestingly, glomeruli of biopsies from patients suffering from diabetic nephropathy showed also a significant reduction of Dach1 and synaptopodin in contrast to control biopsies. Taken together, Dach1 is a transcription factor that is important for podocyte differentiation and proper kidney function.

Exercise and prostate cancer: From basic science to clinical applications.

Prostate cancer (PCa) is a disease of increasing medical significance worldwide. In developed countries, PCa is the most common non-skin cancer in men, and one of the leading causes of cancer-related deaths. Exercise is one of the environmental factors that have been shown to influence cancer risk. Moreover, systemic reviews and meta-analysis have suggested that total physical activity is related to a decrease in the risk of developing PCa. In addition, epidemiological studies have shown that exercise, after diagnosis, has benefits regarding PCa development, and positive outcome in patients under treatment. The standard treatment for locally advanced or metastatic PCa is Androgen deprivation therapy (ADT). ADT produces diverse side effects, including loss of libido, changes in body composition (increase abdominal fat), and reduced muscle mass, and muscle tone. Analysis of numerous research publications showed that aerobic and/or resistance training improve patient's physical condition, such us, cardiorespiratory fitness, muscle strength, physical function, body composition, and fatigue. Therefore, exercise might counteract several ADT treatment-induced side effects. In addition of the aforementioned benefits, epidemiological, and in vitro studies have shown that exercise might decrease PCa development. Thus, physical activity might attenuate the risk of PCa and supervised exercise intervention might improve deleterious effects of cancer treatment, such as ADT side effects. This review article provides evidence indicating that exercise could complement, and potentiate, the current standard treatments for advanced PCa, probably by creating an unfavorable microenvironment that can negatively affect tumor development, and progression.

Protocol for the "Chemobrain in Motion - study" (CIM - study): a randomized placebo-controlled trial of the impact of a high-intensity interval endurance training on cancer related cognitive impairments in women with breast cancer receiving first-line chemotherapy.

BACKGROUND: Up to 80% of breast cancer patients suffer from Cancer Related Cognitive Impairments (CRCI). Exercise is suggested as a potential supportive care option to reduce cognitive decline in cancer patients. This study will investigate the effects of a high-intensity interval endurance training (HIIT) on CRCI in breast cancer patients. Potentially underlying immunological and neurobiological mechanisms, as well as effects on patients' self-perceived cognitive functioning and common cancer related side-effects, will be explored. METHODS: A single-blinded randomized controlled trial will be carried out. The impact of HIIT on CRCI will be compared to that of a placebo-intervention (supervised myofascial release training). Both interventions will be conducted simultaneously with the patients' first-line chemotherapy treatment typically lasting 12-18 weeks. Fifty-nine women with breast cancer will be included in each of the two groups. The study is powered to detect (α = .05, ß = .2) a medium effect size difference between the two groups (d = .5) in terms of patients' change in cognitive testing performances, from baseline until the end of the exercise-intervention. The cognitive test battery, recommended by the International Cancer and Cognition Task Force to assess CRCI, will be used as primary measure. This includes the Hopkins Verbal Learning Test (learning/verbal memory), the Controlled Oral Word Association Test (verbal fluency) and the Trail-Making-Test A/B (attention/set-switching). The following endpoints will be assessed as secondary measures: Go-/No-Go test performance (response inhibition), self-perceived cognitive functioning, serum levels of pro- and antiinflammatory markers (tumor necrosis factor alpha, Interleukin-6, Interleukin-1 alpha, Interleukin-1 beta, C-reactive protein, Interleukin-1 receptor antagonist and Interleukin-10), serum levels of neurotrophic and growth factors (brain-derived neurotrophic factor, insulin-like growth factor 1 and vascular endothelial growth factor), as well as common cancer-related side effects (decrease in physical capacity, fatigue, anxiety and depression, sleep disturbances, quality of life and chemotherapy compliance). DISCUSSION: This study will provide data on the question whether HIIT is an effective supportive therapy that alleviates CRCI in breast cancer patients. Moreover, the present study will help shed light on the underlying mechanisms of potential CRCI improving effects of exercise in breast cancer patients. TRIAL REGISTRATION: DRKS.de, German Clinical Trials Register (DRKS), ID: DRKS00011390 , Registered on 17 January 2018.

A semiquantitative MRI-Score can predict loss of lung function in patients with cystic fibrosis: Preliminary results.

OBJECTIVES: To evaluate the applicability of a semiquantitative MRI scoring system (MR-CF-S) as a prognostic marker for clinical course of cystic fibrosis (CF) lung disease. METHODS: This observational study of a single-centre CF cohort included a group of 61 patients (mean age 12.9 ± 4.7 years) receiving morphological and functional pulmonary MRI, pulmonary function testing (PFT) and follow-up of 2 years. MRI was analysed by three raters using MR-CF-S. The inter-rater agreement, correlation of score categories with forced expiratory volume in 1 s (FEV1) at baseline, and the predictive value of clinical parameters, and score categories was assessed for the whole cohort and a subgroup of 40 patients with moderately impaired lung function. RESULTS: The inter-rater agreement of MR-CF-S was sufficient (mean intraclass correlation coefficient 0.92). MR-CF-S (-0.62; p < 0.05) and most of the categories significantly correlated with FEV1. Differences between patients with relevant loss of FEV1 (>3%/year) and normal course were only significant for MR-CF-S (p < 0.05) but not for clinical parameters. Centrilobular opacity (CO) was the most promising score category for prediction of a decline of FEV1 (area under curve: whole cohort 0.69; subgroup 0.86). CONCLUSIONS: MR-CF-S is promising to predict a loss of lung function. CO seems to be a particular finding in CF patients with an abnormal course. KEY POINTS: • Lung imaging is essential in the diagnostic work-up of CF patients • MRI serves as a powerful, radiation-free modality in paediatric CF patients • Observational single-centre study showed significant correlation of MR-CF score and FEV 1 • MR-CF score is promising in predicting a loss of lung function.

Impact of the initial fitness level on the effects of a structured exercise therapy during pediatric stem cell transplantation.

BACKGROUND: Before and after hematopoietic stem cell transplantation (HSCT), most patients suffer from psychophysical limitations due to the treatment. Exercise interventions demonstrate beneficial effects on, for example, strength, endurance, or health-related quality of life during and after HSCT, but with a great variation among patients concerning the response to exercise. This study examines the influence of the initial fitness on the effects of an exercise therapy in pediatric HSCT. PROCEDURE: Fifty-three children and adolescents (10.9 ± 3.5 years) scheduled for HSCT were randomized into an exercise intervention group (IG) or a control group (CG). During hospitalization, the IG performed endurance, strength, and flexibility training three times per week. The CG included a nonexercise program. A 6-min walk test was completed before and after the inpatient period. Baseline results (6-min walking distance [6MWD]) were used to split both groups into the following: IGUNFIT , n = 14; IGFIT , n = 12; CGUNFIT , n = 16; CGFIT , n = 11. Differences in outcome changes between groups were analyzed with H-test. RESULT: Intergroup comparison revealed significant differences between IGUNFIT and CGUNFIT (P < 0.05). The IGUNFIT increased their 6MWD by +8% (vs. IGFIT , +1%); both CGs presented a decline in 6MWD (CGUNFIT , -14%; CGFIT , -16%). At discharge, the IGFIT achieved 85.5 ± 10.3% of healthy reference values. CONCLUSIONS: The current results indicate that exercise during pediatric HSCT is feasible and contributes to prevention of treatment-related loss of physical function. As seen in healthy persons, patients' benefits might depend on their initial fitness level. As a diminished physical capability may result in higher training effects, impaired especially patients should engage in exercise.

Atrx promotes heterochromatin formation at retrotransposons.

More than 50% of mammalian genomes consist of retrotransposon sequences. Silencing of retrotransposons by heterochromatin is essential to ensure genomic stability and transcriptional integrity. Here, we identified a short sequence element in intracisternal A particle (IAP) retrotransposons that is sufficient to trigger heterochromatin formation. We used this sequence in a genome-wide shRNA screen and identified the chromatin remodeler Atrx as a novel regulator of IAP silencing. Atrx binds to IAP elements and is necessary for efficient heterochromatin formation. In addition, Atrx facilitates a robust and largely inaccessible heterochromatin structure as Atrx knockout cells display increased chromatin accessibility at retrotransposons and non-repetitive heterochromatic loci. In summary, we demonstrate a direct role of Atrx in the establishment and robust maintenance of heterochromatin.