Longitudinal changes in habitual physical activity in adult people with cystic fibrosis in the presence or absence of treatment with elexacaftor/tezacaftor/ivacaftor.

Background: Habitual physical activity (PA) and exercise training are accepted as important aspects of care for people with cystic fibrosis (pwCF) to improve health-related measures of physical fitness, which in turn have a positive impact on quality of life and prognosis. In the last decade, effective CFTR modulator therapies have become a promising treatment for pwCF by targeting the underlying cause of CF. This highly effective therapy improves clinical outcomes and quality of life in people with specific CFTR mutations. Little is known about the longitudinal pattern of PA or the impact of the highly effective modulator therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) on PA in adult pwCF. This study assessed the course of device-based PA measurement in adult pwCF and evaluated the effects of ETI on habitual physical activity in those who were eligible for ETI. Methods: Data from adult pwCF (aged ≥18 years) were analysed at baseline and follow-up, using identical assessments at both time points. Outcome parameters were PA in steps/day and the intensity of PA. The group that received ETI was treated for an average of 33 weeks and not for the entire duration of the period. The data were collected between 2021 and 2022, following the removal of absolute pandemic restrictions/lockdowns. Results: Follow-up duration was 5.6 years in pwCF with ETI (ETI group, n = 21) and 6.5 years in pwCF without ETI (non-ETI group, n = 6). From baseline to follow-up, pwCF treated with ETI had a significant increase in steps/day (+25%, p = 0.019) and a non-significant increase in moderate-to-vigorous intensity time (+5.6%, p = 0.352). Conversely, individuals in the non-ETI group showed a non-significant decrease in both steps/day -3.2%, p = 0.893) and moderate-to-vigorous intensity time (-25%, p = 0.207). The ETI group showed a significant decrease in percent predicted forced expiratory volume in 1 s (ppFEV1) and FEV1 z-score before the start of ETI treatment, both of which improved significantly after therapy initiation. Body weight and body mass index also improved significantly with ETI use. Conclusions: These data suggest that ETI treatment has a positive effect on habitual physical activity behavior in the adult pwCF studied.

Longitudinal Evaluation of Physical Fitness in Adults with Cystic Fibrosis in the Era of CFTR-Modulating-Therapies.

Purpose: Maintaining physical fitness plays an important role in the management of people with cystic fibrosis (pwCF). Longitudinal data on the course of physical fitness and the potential impact of the introduction of highly effective CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) in adult pwCF are scarce. Methods: Health-related and skill-related components of physical fitness were assessed using an incremental cycle test (Wpeak), plus forward bend (FB), prone bent knee hip extension (HE), plank leg raise (PLR), standing long jump (SLJ), and standing on one leg (OLS). Relevant disease-specific clinical data (body mass index [BMI] and forced expiratory volume in 1 second [FEV1]) were recorded. Results: Twenty-eight adult pwCF (age 26.0 ± 7.8 years) were followed over 5.6 ± 0.9 years; 21 started ETI therapy during this period. Significant improvements from baseline were noted in BMI (p < 0.001) and health-related fitness components (HE, p = 0.002; PLR, p = < 0.001), whereas Wpeak and FB remained stable over time (all p > 0.05). Skill-related components (SLJ, OLS) showed no change (all p > 0.05). Subgroup analysis revealed significant improvements in BMI, FEV1, and health-related fitness measures of muscular strength and endurance (HE, p = 0.009; PLR, p < 0.001) only in pwCF using ETI. Conclusion: Despite the improvements, the impact of ETI on the individual parameters was small. Other factors than implementation of ETI alone need to be considered on the way to a high level of physical fitness in adult pwCF.

Impact of habitual physical activity and exercise capacity on quality of life in adolescents and adults with cystic fibrosis.

BACKGROUND: The influence of habitual physical activity and exercise capacity on health-related quality of life (HRQoL) in people with cystic fibrosis (pwCF) is poorly characterized. This study investigated the influence of habitual physical activity, exercise capacity, lung function, and body mass index (BMI) on HRQoL in adolescent and adult pwCF. METHOD: Subjects were fitted with an accelerometer to determine habitual physical activity (steps/day), including time spent at different intensities, for up to 4 weeks. Then bicycle ergometry (maximal exercise capacity; Wpeak), lung function (percent predicted forced expiratory volume in 1 s, ppFEV1), BMI, and response to the Cystic Fibrosis Questionnaire-Revised (CFQ-R) were determined. RESULTS: Sixty-five pwCF participated in the study. Physically active pwCF had significantly higher ppFEV1 (p < .001) and exercise capacity (p < .001) than inactive pwCF, and had significantly higher scores on the CFQ-R physical (p = .006), emotional (p = .015), role (p = .008), health (p = .006), and weight (p = .004) subscales. On multiple linear regression analysis, ppFEV1 and, to a lesser extent, exercise capacity, were the most important determinants of HRQoL in pwCF. Time spent in moderate-to-vigorous intensity physical activity did not influence any of the CFQ-R subscales, whereas time spent in vigorous-intensity influenced CFQ-R scores for role (p = .007), body (p = .001), health (p = .009), and weight (p = .01). CONCLUSION: HRQoL in adolescent and adult pwCF was influenced by several factors. Avoiding sedentary behavior and spending time in vigorous-intensity levels positively influenced HRQoL, whereas the total number of steps per day played only a minor role in determining HRQoL. Both ppFEV1 and exercise capacity markedly influenced HRQoL.

Long-Term Follow-Up of Health-Related Quality of Life and Short-Term Intervention with CFTR Modulator Therapy in Adults with Cystic Fibrosis: Evaluation of Changes over Several Years with or without 33 Weeks of CFTR Modulator Therapy.

BACKGROUND: Longitudinal data on changes in health-related quality of life (HRQoL) in adult people with cystic fibrosis (pwCF) and the longitudinal effects of Elexacaftor/Tezacaftor/Ivacaftor therapy (ETI) on HRQoL or HRQoL domains are currently scarce. This study aimed to investigate the effects of ETI on HRQoL and compare them with those of pwCF who did not receive highly effective CFTR modulators over a longer period. METHODS: Baseline assessment and follow-up data for 5.6 years in pwCF with (n = 21) and 6.5 years in pwCF without (n = 6) ETI (≥18 years) were evaluated. The assessment of HRQoL and clinical parameters was identical at both time points. HRQoL was assessed using the CFQ-R, and clinical outcomes included BMI, ppFEV1, and FEV1 z-score. RESULTS: ETI was found to improve all HRQoL domains at more than four points over time, and their increases were significant except for vitality, digestion, treatment burden, and social functioning (p < 0.05). Without ETI, psychosocial domains remained almost constant, whereas most physical domains decreased over time. CONCLUSIONS: The results of the present study show that ETI therapy has a positive effect on HRQoL and clinical outcomes over time but not in pwCF without ETI treatment. Furthermore, our results suggest that disease progression over time affects the physical domains of HRQoL more than the psychosocial domains. Due to the small sample size and the heterogeneity of the study population (CFTR mutation genotype), the results should be interpreted with some caution.

Barriers for Sports and Exercise Participation and Corresponding Barrier Management in Cystic Fibrosis.

BACKGROUND: Nowadays physical activity (PA)/exercise is an important component of cystic fibrosis (CF) therapy. The aim of the study was to assess the barriers to PA and the barrier management and to explore the effect of supervision on the barriers and barrier management during an exercise program. METHODS: In total, 88 people with CF (pwCF) of the ages 6 to 50 years old (mean 24.2 ± 7.9 yrs) participated in the partially supervised 12-month exercise program and filled in a structured and validated questionnaire about barriers to sports and barrier management at baseline. Additionally, 23 pwCF filled in the questionnaire after 6 months and 12 months. The items were clustered into physical and psychosocial barriers and into preventive counter strategies and situational counter strategies and analyzed at baseline and over time. RESULTS: Physical barriers were more relevant than psychosocial barriers and no trend could be seen in the situational and preventive counter strategies. When divided in subgroups, the less active pwCF (<7500 steps/day), more active pwCF (>7500 steps/day), physical barriers, and psychosocial barriers showed no significant differences. However physical barriers showed a tendency to have a higher value in the less active group compared to the more active group (p > 0.05). Stratified by age or FEV1%pred between the subgroups, no differences could be seen regarding barriers and counter strategies. CONCLUSIONS: Physical barriers seemed to have a higher priority when it comes to not participating in PA/exercise. Supervision over 6 months during an exercise program did not show a beneficial effect on barriers and barrier management. Besides the motivational aspect of sport counselling, the volitional aspect seemed to be more important to incorporate more PA into daily life. Individual barriers and their concrete counter strategies should be discussed with the patient with CF. Sport counselling is needed permanently and should be part of the CF routine care.

Effects of a Long-Term Monitored Exercise Program on Aerobic Fitness in a Small Group of Children with Cystic Fibrosis.

Background: The aim of this study was to investigate the effects of a monitored exercise program on aerobic fitness in children with cystic fibrosis (CF). Methods: Six children (2f/4m) with ages ranging from 6 to 14 years (11.3 ± 3.3 years.) and a mean ppFEV1 102.5 ± 13.5% pred. participated in the partially monitored 12-month exercise program. VO2peak and Wpeak were used as parameters of aerobic fitness. Incremental Cardio-Pulmonary Exercise Tests (CPETs) were performed before the program began (T1), after 6 months (T3) of monitoring, and after a further 6 months (T4) without monitoring. Habitual physical activity (HPA) was assessed with accelerometry. Results: The values of VO2peak and Wpeak improved slightly from T1 to T3 (p > 0.05), without a further increase after monitoring was stopped (T4). However, the VO2peak and Wpeak values were higher after monitoring was stopped compared to at T1. The exercise program with and without monitoring (p > 0.05) had no or only a slight effect on the FEV1 values, steps/day, and the intensity of HPA. Conclusions: Monitoring seems to facilitate the achievement of beneficial effects on physical fitness in CF children. For that reason, continuous individual exercise monitoring programs that involve close contact with an exercise therapist should be provided to maintain long-term motivation and participation in physical activities and sport activities during leisure time.

Casein Kinase 1D Encodes a Novel Drug Target in Hedgehog-GLI-Driven Cancers and Tumor-Initiating Cells Resistant to SMO Inhibition.

(1) Background: Aberrant activation of the hedgehog (HH)-GLI pathway in stem-like tumor-initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH-GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH-GLI-driven malignancies. (2) Methods: We genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity, and monitored the oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) Results: We show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO inhibitor-sensitive and -resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent TIC in vitro and in vivo. (4) Conclusions: Pharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor-sensitive and -resistant tumors.

Health-Related and Motor Performance-Related Fitness and Physical Activity Among Youth With Cystic Fibrosis.

Little is known about motor competence and the longitudinal development of motor performance among youth with cystic fibrosis (CF). In this study, we assessed aspects of motor performance in different age groups of young patients with CF and compared them with a healthy reference group of same aged children. We also examined the development of motor performance among different age groups of these children with CF, using The Deutscher Motorik Test (DMT) to assess attributes of health-related and motor performance-related fitness. We used an incremental ergometer cycle test to determine maximal exercise capacity (expressed as peak workload). We evaluated and recorded habitual physical activity (PA) as measured by the number of steps per day and the time spent in different PA intensities (expressed in metabolic equivalents). In total, 31 children and adolescents with CF agreed to participate (13 girls,18 boys) aged 6-17 years (M = 11.3, SD =3.3 years); they had a mean one second forced expiratory volume (expressed as a percentage of predicted value [% pred]) of 87.2% (SD = 22.3%). We found their values of health-related and motor performance-related fitness to be significantly lower (p < 0.05) than those of their healthy peer participants. In contrast to the reference group, participants with CF up to 14 years of age showed a linear improvement in these values and in their PA, followed by a plateau or even a nonsignificant decrease after age 14. These findings have important implications for the development and prescription of exercise programs for children with CF. Besides aerobic and strength exercises, we recommend that neuromuscular training be integrated into exercise programs to improve the coordinative abilities of youth with CF. More attention should be paid to vulnerable older adolescents to ensure their long-term motivation to maintain exercise participation.

The life in a gradient: calcium, the lncRNA SPRR2C and mir542/mir196a meet in the epidermis to regulate the aging process.

The turnover of the epidermis beginning with the progenitor cells in the basal layer to the fully differentiated corneocytes is tightly regulated by calcium. Calcium more than anything else promotes the differentiation of keratinocytes which implies the need for a calcium gradient with low concentrations in the stratum basale and high concentrations in the stratum granulosum. One of the hallmarks of skin aging is a collapse of this gradient that has a direct impact on the epidermal fitness. The rise of calcium in the stratum basale reduces cell proliferation, whereas the drop of calcium in the stratum granulosum leads to a changed composition of the cornified envelope. We showed that keratinocytes respond to the calcium induced block of cell division by a large increase of the expression of several miRNAs (hsa-mir542-5p, hsa-mir125a, hsa-mir135a-5p, hsa-mir196a-5p, hsa-mir491-5p and hsa-mir552-5p). The pitfall of this rescue mechanism is a dramatic change in gene expression which causes a further impairment of the epidermal barrier. This effect is attenuated by a pseudogene (SPRR2C) that gives rise to a lncRNA. SPRR2C specifically resides in the stratum granulosum/corneum thus acting as a sponge for miRNAs.

A Self-Ordered Nanostructured Transparent Electrode of High Structural Quality and Corresponding Functional Performance.

The preparation of a highly ordered nanostructured transparent electrode based on a combination of nanosphere lithography and anodization is presented. The size of perfectly ordered pore domains is improved by an order of magnitude with respect to the state of the art. The concomitantly reduced density of defect pores increases the fraction of pores that are in good electrical contact with the underlying transparent conductive substrate. This improvement in structural quality translates directly and linearly into an improved performance of energy conversion devices built from such electrodes in a linear manner.

Trainability of Health-Related and Motor Performance Fitness in Adults with Cystic Fibrosis within a 12-Month Partially Supervised Exercise Program.

BACKGROUND: Regular physical activity plays an important role in the treatment of patients with cystic fibrosis (CF). This study is aimed at investigating the effects of a 12-month partially supervised exercise program on attributes of health-related and motor performance fitness, lung function (ppFEV1), BMI, and habitual physical activity (HPA, steps/day) in adults with CF. METHODS: Attributes of health-related and motor performance fitness were examined at the beginning (T0), after 6 (T1), and 12 months (T2) on the basis of five test items: forward bend (FB), bent knee hip extension (HE), plank leg raise (PLR), standing long jump (SLJ), and standing on one leg (OLS). Additionally, we recorded HPA by accelerometry, peak exercise performance (W peak) by an incremental cycle test, ppFEV1, and BMI. During the first six months, there was close supervision by an experienced sport therapist. RESULTS: 26 CF patients (8 female, mean age 26.5 ± 7.9 years; ppFEV1 53.7 ± 21.0) completed the exercise program. Significant improvements were recorded from T0 to T1 (FB: p ≤ 0.05; PLR, OLS: p ≤ 0.01) and from T0 to T2 (FB, PLR: p ≤ 0.01 and HE, OLS: p ≤ 0.05). W peak, ppFEV1, BMI, and HPA showed no significant improvement between the single test points and over the entire study period (all p > 0.05). CONCLUSION: Our results show trainability of adults with CF in aspects of health-related and motor performance fitness during a partially supervised exercise program. Close supervision positively influences the results. Using a simple test setup seems to be a promising tool for evaluating the effects of exercise programs in CF and could serve as an additional outcome parameter in future clinical trials. Trial registration: ClinicalTrials.gov (retrospectively registered May 8, 2018).

Association between habitual physical activity (HPA) and sleep quality in patients with cystic fibrosis.

PURPOSE: Sleep disturbances and poor sleep quality are known to be present in patients with CF. Regular physical activity plays an important role in the treatment of CF patients due to its positive influence on progression of disease and quality of life. The aim of this work is to create a home-based sleep and activity profile and to investigate the influence of habitual physical activity (HPA) on sleep quality in children, adolescents, and adults with CF. METHODS: A total of 109 CF patients (64 male, mean age 22.7 ± 12.0 years; mean ppFEV1 63.0 ± 26.7) were equipped with an actigraph for a home-based collection of data on sleep and activity over 4 weeks. RESULTS: Age, FEV1, and BMI affect sleep and activity in CF patients. Especially younger age and higher FEV1 show a great influence on certain aspects of sleep (SE, TST, TIB, WASO, # of awakenings) and activity and its different intensities. General HPA does not affect sleep, but there is a strong correlation between times spent in vigorous to very vigorous intensities and better sleep quality. CONCLUSION: Besides younger age and higher FEV1, daily activity in higher intensities influences sleeping behavior of CF patients in a positive way. Patients with poor sleep quality and sleep disturbances possibly benefit from an intensification of physical activity in the home environment. TRAIL REGISTRATION: number: 14-6117-BO (University Duisburg-Essen) and NCT03518697 (clinical trials).

Effects of a long-term exercise program on motor performance in children and adolescents with CF.

OBJECTIVES: The aim of this study was to examine motor performance and trainability in youths with cystic fibrosis (CF). METHODS: Twenty-two children and adolescents (11 f/11 m), age range 6-17 years (11.3 ± 3.3 years), mean FEV1 91.0 ± 21.7% pred.finished the partially monitored 12-months exercise program. Patients performed the Deutsche Motorik Test (DMT) to assess flexibility, balance, strength, power and totalmotor performance. An incremental ergometer cycle test was used to assess maximal exercise capacity (Wpeak). All tests were performed before (T1), after 6 months of monitored exercise training (T3) and another 6 months without monitoring (T4). RESULTS: Motor Competence in total and test-items of the DMT (except foreward bend) improved to T3 (p < .05). No further improvement could be observed after the end of the monitoring (T3). However, the values remained stable at the improved level (T4). Girls scored lower in test items depending on strength/power but scored higher in balancing compared to boys (p > .05). Wpeak and FEV1 were not influenced by the training program. From T3 to T4 a slight decrease was observed (p ≤ .05). CONCLUSIONS: The findings demonstrate benefits of an individualizedmonitored long-term exercise intervention on motor performance in CF with improvements of test-tasks to predicted normal. Monitoringseems to be a facilitator in maintaining motivation toward physical activity as no further increase in motor performance was observed after stopping supervision. The results suggest that an individually tailored monitoredregular exercise program should include all aspects of physical fitness with a variety of movement experiences.

Phosphoproteomics of short-term hedgehog signaling in human medulloblastoma cells.

BACKGROUND: Aberrant hedgehog (HH) signaling is implicated in the development of various cancer entities such as medulloblastoma. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Increased phosphorylation of essential effectors such as Smoothened (SMO) and GLI proteins by kinases including Protein Kinase A, Casein Kinase 1, and Glycogen Synthase Kinase 3 ß controls effector activity, stability and processing. However, a deeper and more comprehensive understanding of phosphorylation in the signal transduction remains unclear, particularly during early response processes involved in SMO activation and preceding GLI target gene regulation. METHODS: We applied temporal quantitative phosphoproteomics to reveal phosphorylation dynamics underlying the short-term chemical activation and inhibition of early hedgehog signaling in HH responsive human medulloblastoma cells. Medulloblastoma cells were treated for 5.0 and 15 min with Smoothened Agonist (SAG) to induce and with vismodegib to inhibit the HH pathway. RESULTS: Our phosphoproteomic profiling resulted in the quantification of 7700 and 10,000 phosphosites after 5.0 and 15 min treatment, respectively. The data suggest a central role of phosphorylation in the regulation of ciliary assembly, trafficking, and signal transduction already after 5.0 min treatment. ERK/MAPK signaling, besides Protein Kinase A signaling and mTOR signaling, were differentially regulated after short-term treatment. Activation of Polo-like Kinase 1 and inhibition of Casein Kinase 2A1 were characteristic for vismodegib treatment, while SAG treatment induced Aurora Kinase A activity. Distinctive phosphorylation of central players of HH signaling such as SMO, SUFU, GLI2 and GLI3 was observed only after 15 min treatment. CONCLUSIONS: This study provides evidence that phosphorylation triggered in response to SMO modulation dictates the localization of hedgehog pathway components within the primary cilium and affects the regulation of the SMO-SUFU-GLI axis. The data are relevant for the development of targeted therapies of HH-associated cancers including sonic HH-type medulloblastoma. A deeper understanding of the mechanisms of action of SMO inhibitors such as vismodegib may lead to the development of compounds causing fewer adverse effects and lower frequencies of drug resistance. Video Abstract.

Unraveling the Microstructure-Related Device Stability for Polymer Solar Cells Based on Nonfullerene Small-Molecular Acceptors.

As the power conversion efficiency (PCE) of organic solar cells (OSCs) has surpassed the 17% baseline, the long-term stability of highly efficient OSCs is essential for the practical application of this photovoltaic technology. Here, the photostability and possible degradation mechanisms of three state-of-the-art polymer donors with a commonly used nonfullerene acceptor (NFA), IT-4F, are investigated. The active-layer materials show excellent intrinsic photostability. The initial morphology, in particular the mixed region, causes degradation predominantly in the fill factor (FF) under illumination. Electron traps are formed due to the reorganization of polymers and diffusion-limited aggregation of NFAs to assemble small isolated acceptor domains under illumination. These electron traps lead to losses mainly in FF, which is in contradistinction to the degradation mechanisms observed for fullerene-based OSCs. Control of the composition of NFAs close to the thermodynamic equilibrium limit while keeping adequate electron percolation and improving the initial polymer and NFA ordering are of the essence to stabilize the FF in NFA-based solar cells, which may be the key tactics to develop next-generation OSCs with high efficiency as well as excellent stability.

Comprehensive Investigation and Analysis of Bulk-Heterojunction Microstructure of High-Performance PCE11:PCBM Solar Cells.

Worldwide research efforts have been devoted to organic photovoltaics in the hope of a large-scale commercial application in the near future. To meet the industrial production requirements, organic photovoltaics that can reach power conversion efficiency (PCE) of over 10% along with promising operational device stability are of utmost interest. In the study, we take PCE11:PCBM as a model system, which can achieve over 11% PCE when processed from nonhalogen solvents, to deeply investigate the morphology-performance-stability correlation. We demonstrate that four batches of PCE11 with varying crystalline properties can achieve similar high performance in combination with PCBM. Careful device optimization is necessary in each case to properly address the requirements for the quite distinct microstructures. The bulk-heterojunction (BHJ) microstructure is comprehensively investigated as a function of the macromolecular weight and crystallinity. It is demonstrated that small differences in morphology significantly affect the kinetics and thermodynamic equilibrium of the BHJ microstructure as well as the photostability and thermal stability of the PCE11:PCBM solar cells.

Overcoming efficiency and stability limits in water-processing nanoparticular organic photovoltaics by minimizing microstructure defects.

There is a strong market driven need for processing organic photovoltaics from eco-friendly solvents. Water-dispersed organic semiconducting nanoparticles (NPs) satisfy these premises convincingly. However, the necessity of surfactants, which are inevitable for stabilizing NPs, is a major obstacle towards realizing competitive power conversion efficiencies for water-processed devices. Here, we report on a concept for minimizing the adverse impact of surfactants on solar cell performance. A poloxamer facilitates the purification of organic semiconducting NPs through stripping excess surfactants from aqueous dispersion. The use of surfactant-stripped NPs based on poly(3-hexylthiophene) / non-fullerene acceptor leads to a device efficiency and stability comparable to the one from devices processed by halogenated solvents. A record efficiency of 7.5% is achieved for NP devices based on a low-band gap polymer system. This elegant approach opens an avenue that future organic photovoltaics processing may be indeed based on non-toxic water-based nanoparticle inks.

Synergistic cross-talk of hedgehog and interleukin-6 signaling drives growth of basal cell carcinoma.

Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin-6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis-regulatory sequences by co-binding of GLI and STAT3 to common HH-IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI-driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH-IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC-202 blocks oncogenic hedgehog-GLI signaling and overcomes smoothened inhibitor resistance.

Aberrant activation of Hedgehog (HH)/GLI signaling is causally involved in numerous human malignancies, including basal cell carcinoma (BCC) and medulloblastoma. HH pathway antagonists targeting smoothened (SMO), an essential effector of canonical HH/GLI signaling, show significant clinical success in BCC patients and have recently been approved for the treatment of advanced and metastatic BCC. However, rapid and frequent development of drug resistance to SMO inhibitors (SMOi) together with severe side effects caused by prolonged SMOi treatment call for alternative treatment strategies targeting HH/GLI signaling downstream of SMO. In this study, we report that 4SC-202, a novel clinically validated inhibitor of class I histone deacetylases (HDACs), efficiently blocks HH/GLI signaling. Notably, 4SC-202 treatment abrogates GLI activation and HH target gene expression in both SMOi-sensitive and -resistant cells. Mechanistically, we propose that the inhibition of HDACs 1/2/3 is crucial for targeting oncogenic HH/GLI signaling, and that class I HDAC inhibitors either in combination with SMOi or as second-line therapy may improve the treatment options for HH-associated malignancies with SMOi resistance.

Understanding cell signaling in cancer stem cells for targeted therapy - can phosphoproteomics help to reveal the secrets?

BACKGROUND: Cancer represents heterogeneous and aberrantly proliferative manifestations composed of (epi)genetically and phenotypically distinct cells with a common clonal origin. Cancer stem cells (CSC) make up a rare subpopulation with the remarkable capacity to initiate, propagate and spread a malignant disease. Furthermore, CSC show increased therapy resistance, thereby contributing to disease relapse. Elimination of CSC, therefore, is a crucial aim to design efficacious treatments for long-term survival of cancer patients. In this article, we highlight the nature of CSC and propose that phosphoproteomics based on unbiased high-performance liquid chromatography-mass spectrometry provides a powerful tool to decipher the molecular CSC programs. Detailed knowledge about the regulation of signaling processes in CSC is a prerequisite for the development of patient-tailored multi-modal treatments including the elimination of rare CSC. MAIN BODY: Phosphorylation is a crucial post-translational modification regulating a plethora of both intra- and intercellular communication processes in normal and malignant cells. Small-molecule targeting of kinases has proven successful in the therapy, but the high rates of relapse and failure to stem malignant spread suggest that these kinase inhibitors largely spare CSC. Studying the kinetics of global phosphorylation patterns in an unbiased manner is, therefore, required to improve strategies and successful treatments within multi-modal therapeutic regimens by targeting the malignant behavior of CSC. The phosphoproteome comprises all phosphoproteins within a cell population that can be analyzed by phosphoproteomics, allowing the investigation of thousands of phosphorylation events. One major aspect is the perception of events underlying the activation and deactivation of kinases and phosphatases in oncogenic signaling pathways. Thus, not only can this tool be harnessed to better understand cellular processes such as those controlling CSC, but also applied to identify novel drug targets for targeted anti-CSC therapy. CONCLUSION: State-of-the-art phosphoproteomics approaches focusing on single cell analysis have the potential to better understand oncogenic signaling in heterogeneous cell populations including rare, yet highly malignant CSC. By eliminating the influence of heterogeneity of populations, single-cell studies will reveal novel insights also into the inter- and intratumoral communication processes controlling malignant CSC and disease progression, laying the basis for improved rational combination treatments.