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Targeting aberrantly expressed kinases in malignant pleural mesothelioma (MPM) is a promising therapeutic strategy. We here investigated the effect of the novel and highly selective Phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib (IOA-244) on MPM cells and on the immune cells in MPM microenvironment.To this aim, we analyzed the expression of PI3K-δ by immunohistochemistry in specimens from primary MPM, cell viability and death in three different MPM cell lines treated with roginolisib alone and in combination with ipatasertib (AKT inhibitor) and sapanisertib (mTOR inhibitor). In a co-culture model of patient-derived MPM cells, autologous peripheral blood mononuclear cells and fibroblasts, the tumor cell viability and changes in immune cell composition were investigated after treatment of roginolisib with nivolumab and cisplatin. PI3K-δ was detected in 66/89 (74%) MPM tumors and was associated with reduced overall survival (12 vs. 25 months, P=0.0452). Roginolisib induced apoptosis in MPM cells and enhanced the anti-tumor efficacy of AKT and mTOR kinase inhibitors by suppressing PI3K-δ/AKT/mTOR and ERK1/2 signaling. Furthermore, the combination of roginolisib with chemotherapy and immunotherapy re-balanced the immune cell composition, increasing effector T-cells and reducing immune suppressive cells. Overall, roginolisib induces apoptosis in MPM cells and increases the antitumor immune cell effector function when combined with nivolumab and cisplatin.These results provide first insights on the potential of roginolisib as a therapeutic agent in patients with MPM and its potential in combination with established immunotherapy regimen.

Treatment with anaplastic lymphoma kinase (ALK) inhibitors significantly improves outcome for non‐small‐cell lung cancer (NSCLC) patients with ALK‐rearranged tumors. However, clinical resistance typically develops over time and, in the majority of cases, resistance mechanisms are ALK‐independent. We generated tumor cell cultures from multiple regions of an ALK‐rearranged clinical tumor specimen and deployed functional drug screens to identify modulators of ALK‐inhibitor response. This identified a role for PI3Kβ and EGFR inhibition in sensitizing the response regulating resistance to ALK inhibition. Inhibition of ALK elicited activation of EGFR, and subsequent MAPK and PI3K‐AKT pathway reactivation. Sensitivity to ALK targeting was enhanced by inhibition or knockdown of PI3Kβ. In ALK‐rearranged primary cultures, the combined inhibition of ALK and PI3Kβ prevented the EGFR‐mediated ALK‐inhibitor resistance, and selectively targeted the cancer cells. The combinatorial effect was seen also in the background of TP53 mutations and in epithelial‐to‐mesenchymal transformed cells. In conclusion, combinatorial ALK‐ and PI3Kβ‐inhibitor treatment carries promise as a treatment for ALK‐rearranged NSCLC.

IntroductionMalignant pleural mesothelioma (MPM) is a neoplasm with dismal prognosis and notorious resistance to the standard therapeutics cisplatin and pemetrexed. Chalcone derivatives are efficacious anti-cancer agents with minimal toxicity and have, therefore, gained pharmaceutical interest. Here, we investigated the efficacy of CIT-026 and CIT-223, two indolyl-chalcones (CITs), to inhibit growth and viability of MPM cells and defined the mechanism by which the compounds induce cell death.MethodsThe effects of CIT-026 and CIT-223 were analyzed in five MPM cell lines, using viability, immunofluorescence, real-time cell death monitoring, and tubulin polymerization assays, along with siRNA knockdown. Phospho-kinase arrays and immunoblotting were used to identify signaling molecules that contribute to cell death.ResultsCIT-026 and CIT-223 were toxic in all cell lines at sub-micromolar concentrations, in particular in MPM cells resistant to cisplatin and pemetrexed, while normal fibroblasts were only modestly affected. Both CITs targeted tubulin polymerization via (1) direct interaction with tubulin and (2) phosphorylation of microtubule regulators STMN1, CRMP2 and WNK1. Formation of aberrant tubulin fibers caused abnormal spindle morphology, mitotic arrest and apoptosis. CIT activity was not reduced in CRMP2-negative and STMN1-silenced MPM cells, indicating that direct tubulin targeting is sufficient for toxic effects of CITs.DiscussionCIT-026 and CIT-223 are highly effective inducers of tumor cell apoptosis by disrupting microtubule assembly, with only modest effects on non-malignant cells. CITs are potent anti-tumor agents against MPM cells, in particular cells resistant to standard therapeutics, and thus warrant further evaluation as potential small-molecule therapeutics in MPM.

Abstract Glioblastoma (GBM) is characterized by a particularly invasive phenotype, supported by oncogenic signals from the fibroblast growth factor (FGF)/ FGF receptor (FGFR) network. However, a possible role of FGFR4 remained elusive so far. Several transcriptomic glioma datasets were analyzed. An extended panel of primary surgical specimen-derived and immortalized GBM (stem)cell models and original tumor tissues were screened for FGFR4 expression. GBM models engineered for wild-type and dominant-negative FGFR4 overexpression were investigated regarding aggressiveness and xenograft formation. Gene set enrichment analyses of FGFR4-modulated GBM models were compared to patient-derived datasets. Despite widely absent in adult brain, FGFR4 mRNA was distinctly expressed in embryonic neural stem cells and significantly upregulated in glioblastoma. Pronounced FGFR4 overexpression defined a distinct GBM patient subgroup with dismal prognosis. Expression levels of FGFR4 and its specific ligands FGF19/FGF23 correlated both in vitro and in vivo and were progressively upregulated in the vast majority of recurrent tumors. Based on overexpression/blockade experiments in respective GBM models, a central pro-oncogenic function of FGFR4 concerning viability, adhesion, migration, and clonogenicity was identified. Expression of dominant-negative FGFR4 resulted in diminished (subcutaneous) or blocked (orthotopic) GBM xenograft formation in the mouse and reduced invasiveness in zebrafish xenotransplantation models. In vitro and in vivo data consistently revealed distinct FGFR4 and integrin/extracellular matrix interactions. Accordingly, FGFR4 blockade profoundly sensitized FGFR4-overexpressing GBM models towards integrin/focal adhesion kinase inhibitors. Collectively, FGFR4 overexpression contributes to the malignant phenotype of a highly aggressive GBM subgroup and is associated with integrin-related therapeutic vulnerabilities.

Functional accounts of boredom propose that boredom serves as an impartial signal to change something about the current situation, which should give rise to adaptive and maladaptive behaviour alike. This seemingly contrasts with research on boredom proneness, which has overwhelmingly shown associations with maladaptive behaviour. To shed light on this discrepancy, we disentangled boredom proneness from individual differences in (i) the urge to avoid and escape boredom and (ii) adaptive and maladaptive ways of dealing with boredom by developing corresponding trait scales. In a study with N = 636 participants, psychometric network modelling revealed tight associations between boredom proneness and less adaptive and (especially) more maladaptive ways of dealing with boredom. However, its associations with the urge to avoid and escape boredom were rather weak. Importantly, a higher urge to avoid and escape boredom was linked not only to more maladaptive but also to more adaptive ways of dealing with boredom. This pattern of results was robust across various specific behaviours that have previously been linked to boredom. Our findings provide novel evidence for functional accounts of boredom from an individual difference perspective, cautioning against a shallow view of boredom as being associated with purely maladaptive behaviour.

BackgroundPrevious research shows that providing social support in socioevaluative stress situations reduces participants’ stress responses. This stress-buffer effect, however, does not hold for everybody, and some studies even found a stress-amplifying effect of social support. Motive disposition research suggests that social motives (affiliation and power) lead to differential and sometimes even opposing affective and physiological responses to interpersonal interaction processes. We here integrate both lines of research and hypothesize that participants with strong affiliation motives benefit, while participants with strong power motives do not benefit from social support in terms of psychobiological responses to a given stressor. Further, participants with strong affiliation and power motives are expected to respond to social support with the arousal of motive-specific affects and reproductive hormone responses (affiliation: progesterone; power: estradiol and testosterone). In addition, we test sex differences in the response to social support and in the strengths of social motives. ObjectiveThe main objective of this study is to test whether social motives and participants’ sex moderate the effects of social support in stressful situations. MethodsWe aim to collect data from 308 participants recruited at our local university. Participants’ social motives are assessed using a standardized measure in motive research (Picture Story Exercise). Then, the Trier Social Stress Test for Groups (TSST-G) is used to experimentally induce psychosocial stress. One group of participants receives social support from an associate of the experimenter, while the control group does not receive social support. Stress responses will be assessed by a modified version of the state anxiety scale of the State–Trait Anxiety Inventory and by physiological indicators of stress (cortisol and α-amylase from saliva samples) at 7 measurement points. Reproductive hormones will be analyzed in 4 of these 7 saliva samples. Heart rate and heart rate variability will be assessed continuously. We will additionally measure participants’ performance in an interview (part of the TSST-G) using a self-developed categorization system. ResultsThe Ethics Committee of the University of Constance approved the application to conduct the study on December 18, 2018. Furthermore, the study was retrospectively registered in the German Clinical Trials Register (DKRS; ID: DRKS00028503) on March 09, 2022. The start of the experiment was planned for the beginning of 2019, but was postponed to June 2021 due to COVID-19. Publication of the first results is planned for spring 2023. ConclusionsOur theory-driven integration of social motives in social support research and the precise analysis of sex differences might disentangle inconsistent findings in TSST research. The more faceted view on individual differences has direct implications for applied contexts as it provides a framework for tailored conceptualizations of social support programs. Trial RegistrationGerman Clinical Trials Register DRKS00028503; https://tinyurl.com/5a87x4da International Registered Report Identifier (IRRID)PRR1-10.2196/39509

Human-relevant systems that mimic the 3D tumor microenvironment (TME), particularly the complex mechanisms of immuno-modulation in the tumor stroma, in a reproducible and scalable format are of high interest for the drug discovery industry. Here, we describe a novel 3D in vitro tumor panel comprising 30 distinct PDX models covering a range of histotypes and molecular subtypes and cocultured with fibroblasts and PBMCs in planar (flat) extracellular matrix hydrogels to reflect the three compartments of the TME—tumor, stroma, and immune cells. The panel was constructed in a 96-well plate format and assayed tumor size, tumor killing, and T-cell infiltration using high-content image analysis after 4 days of treatment. We screened the panel first against the chemotherapy drug Cisplatin to demonstrate feasibility and robustness, and subsequently assayed immuno-oncology agents Solitomab (CD3/EpCAM bispecific T-cell engager) and the immune checkpoint inhibitors (ICIs) Atezolizumab (anti-PDL1), Nivolumab (anti-PD1) and Ipilimumab (anti-CTLA4). Solitomab displayed a strong response across many PDX models in terms of tumor reduction and killing, allowing for its subsequent use as a positive control for ICIs. Interestingly, Atezolizumab and Nivolumab demonstrated a mild response compared to Ipilimumab in a subset of models from the panel. We later determined that PBMC spatial proximity in the assay setup was important for the PD1 inhibitor, hypothesizing that both duration and concentration of antigen exposure may be critical. The described 30-model panel represents a significant advancement toward screening in vitro models of the tumor microenvironment that include tumor, fibroblast, and immune cell populations in an extracellular matrix hydrogel, with robust and standardized high content image analysis in a planar hydrogel. The platform is aimed at rapidly screening various combinations and novel agents and forming a critical conduit to the clinic, thus accelerating drug discovery for the next generation of therapeutics.

There is an unmet clinical need to identify therapeutic options for the treatment of pancreatic cancer (PDAC). Here the authors present a systematic screening approach for the identification of potential PDAC cell surface target candidates for CAR-T cell based immunotherapy, followed by their functional validation in preclinical models.

Self-control is a highly adaptive human capacity and research on self-control is booming. To further facilitate self-control research, especially in conditions where time-constraints might render the use of multi-item measures of self-control problematic, a validated time-efficient single item measure would be an asset. However, such a measure has not yet been developed and tested. Here, we address this gap by reporting the psychometric properties of a single item measure of self-control and by assessing its localization within a larger theorized psychometric network consisting of self-control, boredom and if-then planning. In a high-powered (N = 1553) study with paid online workers from the US (gender: 47.3% female, 51.7% male, 1% other; age: 40.36 ± 12.65 years), we found evidence for the convergent validity (Brief Self-Control Scale), divergent validity (Short Boredom Proneness Scale and If-Then Planning Scale), and criterion validity (objective and subjective socio-economic status) of the single item measure of self-control (“How much self-control do you have?”). Network psychometrics further revealed that the single item was part of the self-control subnetwork and clearly distinguishable from boredom and if-then planning, which together with self-control form a larger psychometric network of psychological dispositions that are relevant for orienting goal directed behavior. Thus, the present findings indicate that self-control can be adequately captured with the single item measure presented here, thereby extending the methodological toolbox of self-control researchers by a highly-time efficient measure.

The satisfaction of teachers’ need for relatedness is an important pre-condition for teachers’ wellbeing. Receiving social support plays an important role in satisfying the need for relatedness. Following job crafting theory, the present study aims to examine (1) whether searching for social support results in an increase in the satisfaction of the need for relatedness and (2) whether this effect is mediated by an increase of received social support from the school principal and from colleagues. Using longitudinal data (N = 1071) we calculated residualized change scores and applied structural equation modeling to test the hypothesized mediation model. Results confirmed the beneficial effect of searching for social support on the satisfaction of the need for relatedness. This effect included a direct effect and an indirect effect through the receipt of social support from colleagues. The receipt of social support from the school principal was positively related to searching for social support but was unrelated to the satisfaction of the need for relatedness. These findings emphasize the importance that teachers build strong and supportive relationships within the school team, as this helps to satisfy their need for relatedness, which in turn contributes to better wellbeing among teachers.

Summary: Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense, but not frameshift, mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We further conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds that are approved for non-cancer indications and that perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and for identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.

Basic psychological need satisfaction is essential for the wellbeing of teachers and motivation at work. Transformational leadership contributes to the development and maintenance of a respectful, constructive atmosphere, a supportive working climate, and has been suggested to be a crucial factor for the satisfaction of the need for relatedness of employees. Transformational leadership is also considered as an ideal leadership style in the school setting, but most studies did not distinguish between individual and team effects of this leadership behavior. In the present study, we applied the dual-focused model of transformational leadership and focused on social processes to address the question of whether individual- and group-focused transformational leadership behavior contribute differently to satisfaction of the need for relatedness of teachers. Based on longitudinal data with three measurement points across one school year of N = 1,217 teachers, results of structural equational models supported the notion of the dual effects of transformational leadership: Individual-focused transformational leadership was directly positively related to change in satisfaction of the need for relatedness of teachers. The relationship between group-focused transformational leadership and change in satisfaction of the need for relatedness was mediated by received social support from team members. These findings emphasize the importance of school leadership behavior of principals for satisfaction of the need for relatedness of teachers. The satisfaction of the need for relatedness is, therefore, not only satisfied through the direct interaction between the school principal and the individual teacher but also through interactions of the school principal with the whole team. Our results confirm that school principals should focus their leadership behavior both on individual need satisfaction of teachers as well as on team development.

Abstract A large body of evidence supports the notion that patients with multiple sclerosis (MS) benefit from physical exercise. However, this research-based recommendation has been insufficiently translated into practice. In this commentary article, we highlight the psychological evidence for the intention–behaviour gap and discuss evidence-based recommendations for bridging this gap, with the aim to change behaviour in MS patients. It is accepted that psychological research distinguishes intention formation from intention realization and that these processes have to be considered when the aim is to enhance physical activity in MS patients. We suggest that the transtheoretical model of behaviour change is a useful and general framework for examining the process of intention formation and that a MS-specific perspective is more useful for realizing exercise intention. MS patients are faced with severe self-control demands that hinder the realization of sport and exercise goals. Specifically, MS patients experience fatigue, which imposes substantial self-control demands. Here, we suggest implementation intention as an effective tool that aids in counteracting deficits in intention realization (getting started and staying on track). We also note that research knowledge is not sufficiently translated into clinical practice. Based on an interdisciplinary approach we recommend that therapists of MS patients should be more aware of psychological theories of health behaviour change and that they should use these to improve and optimize treatment approaches.

Elevated MYC levels can sensitize tumor cells to apoptosis. In this study, the authors demonstrate that AMPK activation and BCL-2/BCL-XL inhibition have a synergistic effect on apoptosis, and that together with anti PD-1 therapy they can suppress Myc-driven mammary tumor growth.

Physical activity counteracts some of the negative consequences associated with chronic neurological diseases. Here, we describe the levels of physical activity (PA) and sports activity (Sport) in patients with multiple sclerosis (pMS, n = 59) and chronic stroke (pStroke, n = 67) and test compliance with the recommendation for health-promoting physical activity of the World-Health Organization (WHO). Secondly, we tested for differences between the groups of patients, and thirdly, we examined relationships between PA and Sport with psychological indicators of perceived energy (fatigue and vitality) and self-beliefs (self-efficacy and self-control). Psychological constructs were assessed with validated measures from different disciplines in Psychology. A statistical aim was to describe interpretations gained by (non-) parametric Bayesian and Null-Hypothesis-Significance Testing statistics (NHST) on the example of the conducted tests for differences and relationships. Descriptive analyses revealed that pMS and pStroke complied with recommendations of the WHO, but with large variance indicating that patient groups are not homogenous. Tests for differences showed that the PA difference between pMS and pStroke can be attributed to the higher proportion of women in the pMS sample as they engage more in household chores (important part of PA). Tests for relationships showed that for pStroke, vitality, self-control, and self-efficacy were positively related to the level of sports activity. Furthermore, pStroke who were sport active had lower fatigue and higher self-control and self-efficacy scores than sport inactive people. Although they address slightly different questions, the Bayesian and the NHST approach led to similar general conclusions.

Endurance sports pose a plethora of mental demands that exercisers have to deal with. Unfortunately, investigations of exercise-specific demands and strategies to deal with them are insufficiently researched, leading to a gap in knowledge about athletic requirements and strategies used to deal with them. Here, we investigated which obstacles exercisers experience during an anaerobic (Wingate test) and an aerobic cycling test (incremental exercise test), as well as the strategies they considered helpful for dealing with these obstacles (qualitative analysis). In addition, we examined whether thinking of these obstacles and strategies in terms of if-then plans (or implementation intentions; i.e., “If I encounter obstacle O, then I will apply strategy S!”) improves performance over merely setting performance goals (i.e., goal intentions; quantitative analysis). N = 59 participants (age: M = 23.9 ± 6.5 years) performed both tests twice in a 2-within (Experimental session: 1 vs. 2) × 2-between (Condition: goal vs. implementation intention) design. Exercisers’ obstacles and strategies were assessed using structured interviews in Session 1 and subjected to thematic analysis. In both tests, feelings of exertion were the most frequently stated obstacle. Motivation to do well, self-encouragement, and focus on the body and on cycling were frequently stated strategies in both tests. There were also test-specific obstacles, such as boredom reported in the aerobic test. For session 2, the obstacles and strategies elicited in Session 1 were used to specify if-then plans. Bayesian mixed-factor ANOVA suggests, however, that if-then plans did not help exercisers to improve their performance. These findings shed novel light into the mental processes accompanying endurance exercise and the limits they pose on performance.

In a gedankenexperiment, we pose the philosophical question as to whether human breast cancer cells or tissues can still be considered human after transplantation into another species. Alongside medical research images illustrating xenotransplantation, we provide descriptions of how tissues were prepared for imaging. In addition, we discuss how such models enable further understanding of cancer and provide invaluable tools for testing new therapies.

An explicit achievement motive is intuitively related to good performance. In contrast, the present paper directs attention to conditions where individuals with a strong explicit achievement motive display poor performance. We hypothesized that participants with a strong achievement motive perform worse in a bicycle ergometer task when task instructions lack achievement incentives than when the instructions include achievement incentives. Furthermore, we expected that, when achievement incentives are lacking, they show even worse performance than participants with a weak achievement motive. For the latter, we assumed that they are relatively unaffected by the achievement incentive content of the instructions. In a within-subject experimental design (N = 55) with two blocks (achievement incentives vs. lack of achievement incentives; each block consisted of three trials), our hypotheses were partly supported. The lack of achievement incentives brought out the worst (regarding performance), but the presence of achievement incentives did not bring out the best of participants with a strong achievement motive. In the discussion, we suggest how to improve future experimental achievement settings and reflect the results within the framework of the differentiation into implicit and explicit motives.

Abstract Organotypic, three-dimensional (3D) cancer models have enabled investigations of complex microtissues in increasingly realistic conditions. However, a drawback of these advanced models remains the poor biological relevance of cancer cell lines, while higher clinical significance would be obtainable with patient-derived cell cultures. Here, we describe the generation and data analysis of 3D microtissue models from patient-derived xenografts (PDX) of non-small cell lung carcinoma (NSCLC). Standard of care anti-cancer drugs were applied and the altered multicellular morphologies were captured by confocal microscopy, followed by automated image analyses to quantitatively measure phenotypic features for high-content chemosensitivity tests. The obtained image data were thresholded using a local entropy filter after which the image foreground was split into local regions, for a supervised classification into tumor or fibroblast cell types. Robust statistical methods were applied to evaluate treatment effects on growth and morphology. Both novel and existing computational approaches were compared at each step, while prioritizing high experimental throughput. Docetaxel was found to be the most effective drug that blocked both tumor growth and invasion. These effects were also validated in PDX tumors in vivo. Our research opens new avenues for high-content drug screening based on patient-derived cell cultures, and for personalized chemosensitivity testing.

Objective: This study utilized different theoretical perspectives to better understand motor performance. We refered to concepts of achievement motive-goal incongruence and assessed cortical correlates of self-control. We assumed that more self-control is required when people act in conformance with an incongruent goal which, in turn, results in impaired performance. We considered the activation of a brain area associated with self-control (dorsolateral prefrontal cortex, dLPFC) as a consequence of motive-goal incongruence. Furthermore, we analyzed whether trait self-control buffers the negative effects of achievement motive—goal incongruence.Method: Twenty-eight participants (17 women, mean age: 24 years), whose implicit achievement motives were assessed at the beginning of the study, performed a handgrip task in an achievement goal condition and in three incongruent conditions, while their dLPFC oxygenation was monitored continuously (using functional near-infrared spectroscopy, fNIRS).Results: None of the two-way interactions (motive × goal condition) reached significance. A significant three-way interaction (motive × trait self-control × goal condition) showed that trait self-control buffered the detrimental effects of incongruence on motor performance. The nature of the three-way interaction predicting dLPFC oxygenation was unexpected.Conclusions: Although our results have to be treated with caution due to a small sample size, we see them as an encouraging starting point for further research on the interplay between motive-goal incongruence and trait and cortical correlates of state self-control that we assume to be important to understand performance in strenuous tasks.

Trait self-control predicts success in various walks of life. Sports is a prototypical domain, where self-control is required, and there is evidence that successful athletes display superior self-control. Here, we assess if self-control already differs between athletes that were selected for a talent development program and non-selected athletes. Self-reported trait self-control was assessed in n = 25 (7 = female, 13.2 ± 1.7 years) youth football players who were part of the German talent development program and in n = 27 (6 = female, 13.6 ± 1.8 years) age and sex matched youth football players, who trained at the same clubs but had not been selected for the program. A one-sided Bayesian two-sample t-test yielded a Bayes factor of 54.99, indicating very strong evidence for the hypothesis that elite youth football players have higher trait self-control than non-elite youth football players. The 95% credibility interval indicates that the true value of δ lies between 0.28 and 1.42, indicating some uncertainty regarding the effects’ magnitude. We show that already at young age, elite athletes display higher levels of self-control than their less successful peers. This underlines the importance of self-control as an important personality factor for success. These findings might have implications for talent selection and for sport psychological training.

Patients with multiple sclerosis (PwMS) frequently suffer from fatigue, but this debilitating symptom is not yet fully understood. We propose that self-control can be conceptually and mechanistically linked to the fatigue concept and might help explain some of the diversity on how PwMS who suffer from fatigue deal with this symptom. To test this claim, we first assessed how cortical oxygenation and measures of motor and cognitive state fatigue change during a strenuous physical task, and then we tested the predictive validity of trait fatigue and trait self-control in explaining the observed changes. A sample of N=51 PwMS first completed a test battery to collect trait measures of fatigue and self-control. PwMS then performed an isometric hand contraction task at 10% of their maximum voluntary contraction until exhaustion while we repeatedly assessed ratings of perceived cognitive and motor exertion. In addition, we continuously measured oxygenation of the prefrontal cortex (PFC) using functional near-infrared spectroscopy. Linear mixed-effect models revealed significant increases in perceived motor and cognitive exertion, as well as increases in PFC oxygenation. Hierarchical stepwise regression analyses showed that higher trait self-control predicted a less steep increase in PFC oxygenation and perceived cognitive exertion, while trait fatigue did not predict change in any dependent variable. These results provide preliminary evidence for the suggested link between self-control and fatigue. As self-control can be enhanced with training, this finding possibly has important implications for devising nonpharmacological interventions to help patients deal with symptoms of fatigue.

Background: Systemic treatment options for metastatic renal cell carcinoma (RCC) have significantly expanded in recent years. However, patients refractory to tyrosine kinase and immune checkpoint inhibitors still have limited treatment options and patient-individualized approaches are largely missing. Patients and Methods: In vitro drug screening of tumor-derived short-term cultures obtained from seven patients with clear cell RCC was performed. For one patient, a patient-derived xenograft (PDX) mouse model was established for in vivo validation experiments. Drug effects were further investigated in established RCC cell lines. Results: The proteasome inhibitor carfilzomib was among the top hits identified in three of four patients in which an in vitro drug screening could be performed successfully. Carfilzomib also showed significant acute and long-term cytotoxicity in established RCC cell lines. The in vivo antitumoral activity of carfilzomib was confirmed in a same-patient PDX model. The cytotoxicity of carfilzomib was found to correlate with the level of accumulation of ubiquitinated proteins. Conclusions: In this proof-of-concept study, we show that patient-individualized in vitro drug screening and preclinical validation is feasible. However, the fact that carfilzomib failed to deliver a clinical benefit in RCC patients in a recent phase II trial unrelated to the present study underscores the complexities and limitations of this strategy.

Most sports are self-control demanding. For example, during a sprint start, athletes have to respond as fast as possible to the start signal (action initiation) while suppressing the urge to start too early (action inhibition). Here, we examined the cortical hemodynamic response to these demands by measuring activity in the two lateral prefrontal cortices (lPFC), a central area for self-control processes. We analyzed activity within subregions of the lPFC, while subjects performed a sprint start, and we assessed if activation varied as a function of hemisphere and gender. In a counterbalanced within-subject design, 39 participants (age: mean (M) = 22.44, standard deviation (SD) = 5.28, 22 women) completed four sprint start conditions (blocks). In each block, participants focused on inhibition (avoid false start), initiation (start fast), no start (do not start) and a combined condition (start fast; avoid false start). We show that oxyhemoglobin in the lPFC increased after the set signal and this increase did not differ between experimental conditions. Increased activation was primarily observed in ventral areas of the lPFC, but only in males, and this increase did not vary between hemispheres. This study provides further support for the involvement of the ventral lPFC during a sprint start, while highlighting gender differences in the processing of sprint start-induced self-control demands.

Initiating and maintaining sports and exercise behavior are usually discussed in terms of strategies for promoting health. In the present study, we analyzed a sample of extreme endurance sport athletes and set out to predict exercise addiction, which is a facet of a sport-related health risk. We therefore draw on self-determination theory (Deci and Ryan, 1985, 2000), according to which low basic psychological need satisfaction can lead to excessive compensatory behavior. We aim to disentangle the effects of need satisfaction in the activity itself (exercising) and outside the activity (work/leisure) on exercise addiction. Furthermore, we propose anxious self-motivation as a mediator and tested whether it links low basic need satisfaction with exercise dependence. A correlational study with 323 multi-triathlon athletes confirmed our hypothesis that need satisfaction in work/leisure (but not in sports) is negatively related to exercise addiction. Furthermore, only need for competence in both domains (sport, work/leisure) is associated with anxious self-motivation. Mediation models showed that low competence satisfaction leads to anxious self-motivation that in turn predicts exercise addiction. The results are discussed critically in terms of their practical and theoretical implications for promoting health through sport and exercise.

Abstract Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial–mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT‐activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR‐203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR‐203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism‐based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer.

It has been proposed that one reason physical effort is perceived as costly is because of the self-control demands that are necessary to persist in a physically demanding task. The application of control has been conceptualized as a value-based decision, that hinges on an optimization of the costs of control and available reward. Here, we drew on labor supply theory to investigate the effects of an Income Compensated Wage Decrease (ICWD) on persistence in a strenuous physical task. Research has shown that an ICWD reduced the amount of self-control participants are willing to apply, and we expected this to translate to a performance decrement in a strenuous physical task. Contrary to our expectations, participants in the ICWD group outperformed the control group in terms of persistence, without incurring higher levels of muscle fatigue or ratings of perceived exertion. Improved performance was accompanied by increases in task efficiency and a lesser increase in oxygenation of the prefrontal cortex, an area of relevance for the application of self-control. These results suggest that the relationship between the regulation of physical effort and self-control is less straightforward than initially assumed: less top-down self-control might allow for more efficient execution of motor tasks, thereby allowing for improved performance. Moreover, these findings indicate that psychological manipulations can affect physical performance, not by modulating how much one is willing to deplete limited physical resources, but by altering how tasks are executed.

The original version of this Article contained an error in Fig. 7. In panel b, the survival curves were shifted relative to the y axis. This error has been corrected in both the PDF and HTML versions of the Article.

Isothiocyanates from plants of the order Brassicales are considered promising cancer chemotherapeutic phytochemicals. However, their selective cytotoxicity on liver cancer has been barely researched. Therefore, in the present study, we systematically studied the chemotherapeutic potency of 4-methylthiobutyl isothiocyanate (MTBITC). Selective toxicity was investigated by comparing its effect on liver cancer cells and their chemoresistant subpopulations to normal primary hepatocytes and liver tissue slices. Additionally, in a first assessment, the in vivo tolerability of MTBITC was investigated in mice. Growth arrest at G2/M and apoptosis induction was evident in all in vitro cancer models treated with MTBITC, including populations with cancer initiating characteristics. This was found independent from TP53; however cell death was delayed in p53 compromised cells as compared to wt-p53 cells which was probably due to differential BH3 only gene regulation i. e. Noxa and its antagonist A1. In normal hepatocytes, no apoptosis or necrosis could be detected after repeated administration of up to 50 µM MTBITC. In mice, orally applied MTBITC was well tolerated over 18 days of treatment for up to 50 mg/kg/day, the highest dose tested. In conclusion, we could show here that the killing effect of MTBITC has a definite selectivity for cancer cells over normal liver cells and its cytotoxicity even applies for chemoresistant cancer initiating cells. Our study could serve for a better understanding of the chemotherapeutic properties of isothiocyanates on human liver-derived cancer cells.

The farnesoid X receptor (FXR) is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR(-/-) mice develop hepatocellular carcinoma (HCC) and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2) has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies.We show reduced NDRG2 mRNA in livers of FXR(-/-) mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcription via IR1-type element(s) identified in the first introns of the human, mouse and rat NDRG2 genes. NDRG2 mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three different human hepatoma cell lines was increased when ectopically expressing human FXR. Growth and metastasis of SK-Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expression of FXR in SK-Hep1 cells reduced tumor growth and metastasis potential of corresponding cells and increased the anti-tumor efficacy of FXR agonists, which may be partly mediated via increased NDRG2 expression. FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options.