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<p>Single-cell architecture of primary Ewing sarcoma. <b>A,</b> Graphical overview of primary patient-derived tissue dissociated and sorted for scRNA-seq. <b>B,</b> Uniform Manifold Approximation and Projection (UMAP) plot colored by patient origin. <b>C,</b> Heat map of top 10 differentially expressed genes per main cell type by average log-normalized expression. <b>D,</b> UMAP with expression of Ewing diagnostic marker (<i>CD99</i>) and a selection of <i>EWS-FLI1</i> candidate target genes (<i>CAV1, CCND1, HES1, KDSR, PAPPA</i>). Dotted line highlights the tumor cell clusters. NA: not expressed. <b>E,</b> Feature plots showing HLA class I module scores (<i>HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, B2M</i>) of main cell types.</p>

Carcinogenesis results from the sequential acquisition of oncogenic mutations that convert normal cells into invasive, metastasizing cancer cells. Colorectal cancer exemplifies this process through its well-described adenoma-carcinoma sequence, modeled previously using clustered regularly interspaced short palindromic repeats (CRISPR) to induce four consecutive mutations in wild-type human gut organoids. Here, we demonstrate that long-term culture of mismatch-repair-deficient organoids allows the selection of spontaneous oncogenic mutations through the sequential withdrawal of Wnt agonists, epidermal growth factor (EGF) agonists and the bone morphogenetic protein (BMP) antagonist Noggin, while TP53 mutations were selected through the addition of Nutlin-3. Thus, organoids sequentially acquired mutations in AXIN1 and AXIN2 (Wnt pathway), TP53, ACVR2A and BMPR2 (BMP pathway) and NRAS (EGF pathway), gaining complete independence from stem cell niche factors. Quadruple-pathway (Wnt, EGF receptor, p53 and BMP) mutant organoids formed solid tumors upon xenotransplantation. This demonstrates that carcinogenesis can be recapitulated in a DNA repair-mutant background through in vitro selection that targets four consecutive cancer pathways.

We explored the relationship between frequency and perceived burden of different self-management activities and HbA1c%, symptoms of diabetes, fatigue, depression, and quality of life in 292 employees between 30 and 60 years of age with insulin-treated diabetes. Participants completed questionnaires that assess self-management and health-related variables. t-Tests were performed for type 1 (DM1) and type 2 diabetes (DM2) separately to compare the mean health scores of individuals who frequently or infrequently perform self-management activities and who do or do not perceive this as a burden. Participants frequently perform their self-management activities, particularly injection of insulin (96.1%), following dietary guidelines (70.8%) and eating regularly (65.6%). Dietary self-management is most often seen as a burden (70.4%), while injecting insulin is seen as least burdensome (12.8%). The perceived burden of self-management is more strongly related to health than the frequency of self-management. Frequency of self-management especially relates to HbA1c% in DM1. People with DM2 who frequently follow the dietary guidelines have more positive health outcomes. Participants who perceive dietary self-management and injecting insulin as a burden have more negative health outcomes. Because different relationships were found between frequency and perceived burden of self-management and health indicators, both aspects should be assessed and considered separately when evaluating self-management and examining patient's health.

Purpose This study examined who benefits most from a cognitive behavioural therapy (CBT)-based intervention that aims to enhance return to work (RTW) among employees who are absent due to common mental disorders (CMDs) (e.g., depression, anxiety, or adjustment disorder). We researched the influence of baseline work-related self-efficacy and mental health (depressive complaints and anxiety) on treatment outcomes of two psychotherapeutic interventions. Methods Using a quasi-experimental design, 12-month follow-up data of 168 employees were collected. Participants either received work-focused cognitive behavioural therapy (W-CBT) that integrated work aspects early into the treatment (n = 89) or regular cognitive behavioural therapy (R-CBT) without a focus on work (n = 79). Results Compared with R-CBT, W-CBT resulted in a faster partial RTW, irrespective of baseline self-efficacy. Among individuals with high self-efficacy, W-CBT also resulted in faster full RTW. The effectiveness of W-CBT on RTW did not depend on baseline depressive complaints or anxiety. The decline of mental health complaints did not differ between the two interventions, nor depended on baseline self-efficacy or mental health. Conclusions Considering the benefits of W-CBT for partial RTW, we recommend this intervention as a preferred method for employees with CMDs, irrespective of baseline self-efficacy, depression and anxiety. For individuals with high baseline self-efficacy, this intervention also results in higher full RTW. For those with low self-efficacy, extra exercises or components may be needed to promote full RTW.