Easy-to-implement educational interventions to bring climate-smart actions to daily anesthesiologic practice: a cross-sectional before and after study.

BACKGROUND: Anesthesia contributes significantly to a hospital's carbon footprint. Climate-smart actions have the potential to reduce greenhouse gas emissions. Prerequisites for sustainable behavior of providers are knowledge and awareness. We aimed to assess the change in anesthesiologists' climate-friendly behavior before and after educational interventions in three areas that every anesthesiologist can address in their daily clinical routine: 1) energy use; 2) recycling opportunities; 3) consumption of volatile anesthetics. METHODS: We performed a cross-sectional before-and-after single center sub-study within the multicenter "Provider Education and Evaluation Project" at the Department of Anesthesiology, RWTH Aachen University hospital from May3 2021 to May 1 2022. Educational interventions consisted of stickers, posters and a presentation on climate-smart actions in anesthesiologists' work routine between the first and the second assessment. For each cross-sectional assessment, all central 28 ORs were observed for one week. During the before-and-after comparison we analyzed: 1) energy wasted in unoccupied ORs because of running computers and turned-on lights at 9 p.m.; 2) feasibility of recycling preoperative anesthesia plastic packaging by determining the difference between calculated weight of unseparated preoperative plastic waste in the first assessment and the weight of actual separated waste in the second assessment; 3) fresh gas flow in balanced anesthesia cases in steady state at 9 a.m., and purchased hypnotics converted to bottles/1000 general anesthesia cases in 2018-2022. RESULTS: We observed a reduction of wasted energy by 44% in unoccupied ORs. Usage of low fresh gas flow settings increased from 55% to 75%. The average of purchased desflurane in 2018-2020 decreased by 72% in 2022. We calculated 10.33 kg of preoperative plastic waste per week but were unable to implement waste separation for infrastructural and logistical reasons. CONCLUSIONS: We found that environment-friendly working behaviors increased after the implementation of educational interventions. The causality between the interventions and the observed improvements remains to be proven.

The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition.

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.

Mind-over-body beliefs in sport and exercise: A driving force for training volume and performance, but with risks for exercise addiction.

We assume that athletic success is associated with certain beliefs that on the one hand promote performance-enhancing behavior (training volume), but on the other hand can also be detrimental to health (sports addiction). These beliefs are succinctly characterized by the title of the 9-item "Mind-over-Body" scale presented here. They are the three beliefs that 1) athletic performance requires a high level of effort, 2) that willpower plays an important role in athletic success, and 3) that athletic success requires pain tolerance. A total of six web-survey-based studies with a total of 1121 participants (approximately gender parity), including individuals with different levels of athletic performance (no competition; amateur sport; regional, national, or international competition), examined the psychometric network and construct and criterion validity of the MoB scale. Exploratory graph analyses, which included the studies with the largest sample sizes, showed that the three belief components (effort, willpower, pain) form separable communities within the MoB network and that the MoB items form communities distinct from self-control and self-efficacy. Meta-analyzed correlations across all six studies showed low positive correlations with self-control and self-efficacy. In terms of criterion validity, MoB beliefs were positively correlated with training volume and exercise addiction. We discuss MoBs as "on the edge of unhealthy" and place MOBs within a framework of related but distinct concepts.

Indolyl-chalcone derivatives trigger apoptosis in cisplatin-resistant mesothelioma cells through aberrant tubulin polymerization and deregulation of microtubule-associated proteins.

Introduction: Malignant 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. Methods: The 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. Results: CIT-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. Discussion: CIT-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.

A Novel Hydrogel-Based 3D In Vitro Tumor Panel of 30 PDX Models Incorporates Tumor, Stromal and Immune Cell Compartments of the TME for the Screening of Oncology and Immuno-Therapies.

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.

Secreted Frizzled Related Protein 5 (SFRP5) Serum Levels Are Decreased in Critical Illness and Sepsis and Are Associated with Short-Term Mortality.

Sepsis is a major health burden with insufficiently understood mechanisms of inflammation and immune paralysis, leading to a life-threatening critical illness. The secreted frizzled related protein 5 (SFRP5) acts as an anti-inflammatory adipokine by antagonizing the Wnt5a pathway. The aim of this study was to elucidate the role of SFRP5 in critical illness and sepsis and to determine its value as a prognostic biomarker for mortality. We analyzed SFRP5 serum concentrations of 223 critically ill patients at admission to a medical intensive care unit (ICU) and compared those to 24 healthy individuals. SFRP5 serum concentrations were significantly decreased in critical illness as compared to healthy controls (24.66 vs. 100 ng/mL, p = 0.029). Even lower serum concentrations were found in septic as compared to nonseptic critically ill patients (19.21 vs. 32.83 ng/mL, p = 0.031). SFRP5 concentrations correlated with liver disease, age, anti-inflammation, and metabolic parameters. Furthermore, patients with sepsis recovered levels of SFRP5 in the first week of ICU treatment. SFRP5 levels at admission predicted short-term mortality in critically ill but not in septic patients. This study points to the role of the anti-inflammatory mediator SFRP5 not only in sepsis but also in nonseptic critically ill patients and associates high levels of SFRP5 to worse outcomes, predominantly in nonseptic critically ill patients.

PI3Kß inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer.

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 PI3Kß 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 PI3Kß. In ALK-rearranged primary cultures, the combined inhibition of ALK and PI3Kß 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 PI3Kß-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.

School principals' social support and teachers' basic need satisfaction: The mediating role of job demands and job resources.

Many teachers report high levels of occupational stress. Teachers' basic need satisfaction is essential for teachers' well-being at work. Social support from school principals is assumed to play an important role for teachers' basic need satisfaction. However, the underlying mechanisms of the relationship between social support from school principals and teachers' basic need satisfaction are mostly unknown. Previous research suggests that job demands and job resources may play an important mediating role. Therefore, we examine whether teachers' perceived job demands and job resources serve as mediators between social support from the school principal and teachers' basic need satisfaction. Using longitudinal data of N = 1071 teachers over the course of one school year, we applied structural equation modelling to test the hypothesised mediation model. Results showed that the relationship between social support from the school principal and teachers' basic need satisfaction was mediated by teachers' perceived job demands and job resources. Particularly, the job demand 'unclear organisational conditions' and job resource 'social support from colleagues' indicated the strongest effects on teachers' basic need satisfaction. These findings emphasise the responsibility of school principals to provide social support to their teachers and create a well-structured and supportive workplace. In doing so, school principals contribute to a work environment in which teachers can thrive.

Metadata Correction: Social Support as a Stress Buffer or Stress Amplifier and the Moderating Role of Implicit Motives: Protocol for a Randomized Study.

[This corrects the article DOI: .].

Boredom is the root of all evil-or is it? A psychometric network approach to individual differences in behavioural responses to boredom.

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.

Social Support as a Stress Buffer or Stress Amplifier and the Moderating Role of Implicit Motives: Protocol for a Randomized Study.

BACKGROUND: Previous 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. OBJECTIVE: The main objective of this study is to test whether social motives and participants' sex moderate the effects of social support in stressful situations. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: Our 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 REGISTRATION: German Clinical Trials Register DRKS00028503; https://tinyurl.com/5a87x4da. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/39509.

24 Hours on the Run-Does Boredom Matter for Ultra-Endurance Athletes' Crises?

Sport and exercise can be boring. In the general population, thinking of sports as boring has been linked to exercising less. However, less is known about the role of boredom in people who participate in ultra-endurance competitions: Do these athletes also associate their sports with boredom, and does boredom pose a self-regulatory challenge that predicts if they encounter a crisis during an ultra-endurance competition? Here, we investigate these questions with a sample of N = 113 (n = 34 female) competitors of a 24 h hour running competition, aged M = 37.6 ± 13.8 years. In this study, n = 23 very extreme athletes competed as single starters or in a relay team of 2, and n = 84 less extreme athletes competed in relay teams of 4 or 6. Before the run, athletes completed self-report measures on sport-specific trait boredom, as well as the degree to which they expected boredom, pain, effort, and willpower to constitute self-regulatory challenges they would have to cope with. After the run, athletes reported the degree to which they actually had to deal with these self-regulatory challenges and if they had faced an action crisis during the competition. Analyses revealed that very extreme athletes displayed a significantly lower sport-specific trait boredom than less extreme athletes (p = 0.024, d=-0.48). With respect to self-regulatory challenges, willpower, pain, and effort were expected and reported at a much higher rate than boredom. However, only boredom was as a significant predictor of experiencing a crisis during the competition (odds ratio = 12.5, p = 0.02). Our results show that boredom also matters for highly active athletes. The fact that the experience of boredom-and not more prototypical competition-induced challenges, such as pain or effort-were linked to having an action crisis highlights the relevance of incorporating boredom into the preparation for a race and to the performance management during competition.

What makes a violent mind? The interplay of parental rearing, dark triad personality traits and propensity for violence in a sample of German adolescents.

Machiavellianism, narcissism and psychopathy are socially aversive personality traits that are strongly linked to the propensity of violence. A central determinate of aggression and violence is parental rearing. Interestingly, while the origin of the development of Dark Triad is not yet entirely understood, next to genetic and environmental factors, literature points towards an influence of parenting styles to the development of dark traits. Therefore, in a sample of 1366 9th grade students (mean age 14.89,), we assessed the interplay between parental rearing, dark triad traits, observation of violence among peers and their propensity for violence. The sample has a good representativeness on school types. Results reveal a positive association between the experience of parental rejection by both parents and punishment as well as parental control and overprotection and Machiavellianism, narcissism and psychopathy. Parental emotional warmth was associated negatively with Machiavellianism and psychopathy while no significant association with narcissism was seen. In a path model, parental rearing, dark triad traits and observation of violence among peers significantly contributed to the propensity of violence. However, differences between the experienced parenting behaviour of mothers and fathers should be noted. Both rejection and overly harsh punishments by fathers and emotional warmth by mothers have no significant influence on the dark triad. It is interesting that the effects regarding maternal parenting behaviour are stronger overall than the effects regarding paternal parenting behaviour. These results underline the importance of parental rearing on the development of Machiavellianism, narcissism and psychopathy and suggest a significant role of parental rearing and the dark triad traits on propensity for violence in adolescents. Parenting trainings and family interventions may be a promising starting point to prevent antisocial behavior linked to the dark triad and to prevent violent behavior in future generations.

EMT, Stemness, and Drug Resistance in Biological Context: A 3D Tumor Tissue/In Silico Platform for Analysis of Combinatorial Treatment in NSCLC with Aggressive KRAS-Biomarker Signatures.

Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRASG12C or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-ß. To investigate further determinants of drug response, we tested several drugs in combination with a KRASG12C inhibitor in KRASG12C mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.

Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness.

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.

Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment.

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 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 which are approved for non-cancer indications and which perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.

Teachers' perceived time pressure, emotional exhaustion and the role of social support from the school principal.

Many teachers experience high levels of work-related strain due to time pressure, which over time can lead to various health problems, such as emotional exhaustion. However, there is growing evidence that this could be a reciprocal effect. Moreover, it is known that perceived social support can buffer the negative effects of stress, such as time pressure, on health outcomes. Less is known about buffering effects of received social support. Based on longitudinal data of n = 1071 Swiss primary and secondary school teachers over the course of one school year, the present study examined the reciprocal relationship between teachers' perceived time pressure and emotional exhaustion and whether received social support from the school principal buffers this relationship. Results of a random intercept cross-lagged panel model show a strong relationship between teachers' perceived time pressure and emotional exhaustion at the between-person level, but no effects at the within-person level. Further, received social support was directly related to less perceived time pressure and less emotional exhaustion. The results showed neither evidence for reciprocal effects between perceived time pressure and emotional exhaustion nor for a buffering effect of received social support from the school principal. Concluding, present findings indicate that the receipt of social support from the school principal is a central job resource that beneficially relates to teachers' experience of time pressure and emotional exhaustion.

Struggles and strategies in anaerobic and aerobic cycling tests: A mixed-method approach with a focus on tailored self-regulation strategies.

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.

Targeting mitotic exit in solid tumors.

Targeting mitosis by taxanes is one of the most common chemotherapeutic approaches in various malignant solid tumors, but cancer cells may survive antimitotic treatment with attainable in vivo concentrations due to mitotic slippage with a residual activity of the ubiquitin ligase anaphase-promoting complex (APC/C) and a continuous slow ubiquitin-proteasome-dependent cyclin B-degradation leading to mitotic exit. Therefore, blocking cyclin B-proteolysis via additional proteasome (PI) or APC/C-inhibition may have the potential to enhance tumor cell eradication by inducing a more robust mitotic block and mitotic cell death. Here, we analyzed this approach in different cell lines and more physiological patient-derived xenografts (PDX) from lung and breast cancer. The sequential combination of paclitaxel with the PI bortezomib enhanced cell death, but in contrast to the hypothesis during interphase and not in mitosis in both lung and breast cancer. APC/C-inhibition alone or in sequential combination with paclitaxel led to strong mitotic cell death in lung cancer. But in breast cancer, with high expression of the anti-apoptotic regulator Mcl-1, cell death in interphase was induced. Here, combined APC/C- and Mcl-1-inhibition with or without paclitaxel was highly lethal but still resulted in interphase cell death. Taken together, the combination of antimitotic agents with a clinically approved PI or inhibitors of the APC/C and Mcl-1 is a promising approach to improve treatment response in different solid tumors, even though they act entity-dependent at different cell cycle phases.

Stromal fibroblasts shape the myeloid phenotype in normal colon and colorectal cancer and induce CD163 and CCL2 expression in macrophages.

Colorectal cancer (CRC) accounts for about 10% of cancer deaths worldwide. Colon carcinogenesis is critically influenced by the tumor microenvironment. Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) represent the major components of the tumor microenvironment. TAMs promote tumor progression, angiogenesis and tissue remodeling. However, the impact of the molecular crosstalk of tumor cells (TCs) with CAFs and macrophages on monocyte recruitment and their phenotypic conversion is not known in detail so far. In a 3D human organotypic CRC model, we show that CAFs and normal colonic fibroblasts are critically involved in monocyte recruitment and for the establishment of a macrophage phenotype, characterized by high CD163 expression. This is in line with the steady recruitment and differentiation of monocytes to immunosuppressive macrophages in the normal colon. Cytokine profiling revealed that CAFs produce M-CSF, and IL6, IL8, HGF and CCL2 secretion was specifically induced by CAFs in co-cultures with macrophages. Moreover, macrophage/CAF/TCs co-cultures increased TC invasion. We demonstrate that CAFs and macrophages are the major producers of CCL2 and, upon co-culture, increase their CCL2 production twofold and 40-fold, respectively. CAFs and macrophages expressing high CCL2 were also found in vivo in CRC, strongly supporting our findings. CCL2, CCR2, CSF1R and CD163 expression in macrophages was dependent on active MCSFR signaling as shown by M-CSFR inhibition. These results indicate that colon fibroblasts and not TCs are the major cellular component, recruiting and dictating the fate of infiltrated monocytes towards a specific macrophage population, characterized by high CD163 expression and CCL2 production.