Publications

Abstract Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation, and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to individual patients. We established a biorepository of 32 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic, or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlate well with responses noted in individual patients’ tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive rectal cancer followed by metastasis to lung and liver. Importantly, engrafted tumors closely reflected the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, in vitro platform coupled with endoluminal propagation in animals.

The incidence of adenocarcinoma at the gastrooesophageal junction increased over the last years. Curative treatment for patients with upper gastrointestinal (UGI) malignancies, such as oesophageal and gastric tumours, is challenging and requires a multidisciplinary approach. Radical surgical resection with complete lymphadenectomy is the cornerstone of UGI cancer treatment. Combined with peri-operative treatment (i.e. by applying CROSS, EOX or FLOT regimen), the survival is even better than with surgery alone. However, peri-operative treatment is not effective in all patients, and the most effective strategy is a topic of active debate, as is reflected by varying treatment guidelines between countries. UGI cancers are (epi)genetically highly heterogeneous. It is thus not likely that a uniform treatment will benefit all patients equally well. Over recent years, patient-derived organoids (PDOs) gained more and more interest as an in vitro prediction model that may assist as a diagnostic tool in the future to select and eventually optimize the best peri-operative treatments for each patient. PDOs can be derived from endoscopic tumour biopsies, which maintain heterogeneity in culture. They can be rapidly established and expanded in a relatively short time for in vitro drug screening experiments. This review summarizes the clinical and molecular aspects of oesophageal and gastric tumours, as well as the current progress and remaining challenges in the use of PDOs for drug and radiation screens.

Key Points HS chains decorating syndecan-1 promote autocrine and paracrine Wnt signaling in MM. Loss of HS inhibits MM cell growth by attenuating Wnt signaling.

. We investigated the psychometric properties of the Italian version of the Dutch Work Addiction Scale (DUWAS) by using an Italian sample (N = 1,027) and a comparable Dutch sample (N = 7,523). We first conducted multigroup confirmatory factor analysis and reliability analysis. We then examined the correlations of the DUWAS with job demands, work-family conflict, job-related affective well-being, and psychological and physical strain. Results showed that a two-factor solution of the DUWAS was equivalent across the Italian and Dutch samples, with data supporting factor variance and covariance equivalence in addition to metric equivalence. Internal consistencies of the DUWAS and its subscales were adequate, and test-retest reliability showed a strong stability of the measure at one year. The DUWAS and its subscales showed a pattern of correlations in the expected direction with the adopted criterion measures. Overall, the Italian version of the DUWAS shows adequate validity and reliability.

Se puede definir el FIoW' como una experiencia optima extremadamente disfrutada, que se caracteriza por la atencion y concentracion focalizada, la existencia de metas retadoras, feedback sobre el desempeno, y control sobre la situacion, la distorsion del tiempo, y el disfrute intrinseco (Csikszentmihalyi, 1990; Moneta y Czikszentmihalyi, 1996; Seligman y Czikszentmihalyi, 2000). El presente estudio examina la estructura factorial de un instrumento desarrollado para medir el Flow en el trabajo, en una muestra de 770 empleados espanoles de diferentes sectores ocupacionales. Los resultados, a partir de analisis factoriales confirmatorios, muestran que el ajuste del modelo de tres factores (satisfaccion intrinseca, absorcion y competencia percibida) es superior al del modelo de un solo factor (experiencia de Flow), confirmando de este modo nuestra hipotesis sobre la multidimensionalidad de la estructura del Flow.

Abstract Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic ‘fetal’ and WNT-high ‘embryonal’, displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes. Gene regulatory network analysis reveals enrichment of regulons related to hepatic functions such as bile acid, lipid and xenobiotic metabolism in the fetal subtype but not in the embryonal subtype. In addition, the dichotomous expression pattern of the transcription factors HNF4A and LEF1 allows for a clear distinction between the fetal and embryonal tumor cells. We also perform high-throughput drug screening using patient-derived tumor organoids and identify sensitivity to HDAC inhibitors. Intriguingly, embryonal and fetal tumor organoids are sensitive to FGFR and EGFR inhibitors, respectively, indicating a dependency on EGF/FGF signaling in hepatoblastoma tumorigenesis. In summary, our data uncover the molecular and drug sensitivity landscapes of hepatoblastoma and pave the way for the development of targeted therapies.

A model of burnout and life satisfaction amongst nurses This study, among 109 German nurses, tested a theoretically derived model of burnout and overall life satisfaction. The model discriminates between two conceptually different categories of working conditions, namely job demands and job resources. It was hypothesized that: (1) job demands, such as demanding contacts with patients and time pressure, are most predictive of exhaustion; (2) job resources, such as (poor) rewards and (lack of) participation in decision making, are most predictive of disengagement from work; and (3) job demands and job resources have an indirect impact on nurses’ life satisfaction, through the experience of burnout (i.e., exhaustion and disengagement). A model including each of these relationships was tested simultaneously with structural equations modelling. Results confirm the strong effects of job demands and job resources on exhaustion and disengagement respectively, and the mediating role of burnout between the working conditions and life satisfaction. These findings contribute to existing knowledge about antecedents and consequences of occupational burnout, and provide guidelines for interventions aimed at preventing or reducing burnout among nurses.

This study aimed to demonstrate the empirical distinctiveness of boredom at work and work engagement in relation to their potential antecedents (job demands and job resources) and consequences (psychological distress and turnover intention) based on the Job Demands-Resources model. A three-wave longitudinal survey was conducted among registered monitors of an Internet survey company in Japan. The questionnaire included scales for boredom at work, work engagement, psychological distress, and turnover intention as well as participants' job characteristics and demographic variables. The hypothesized model was evaluated via structural equation modeling with 1,019 participants who were employed full-time. As expected, boredom at work was negatively associated with quantitative job demands and job resources and positively associated with psychological distress and turnover intention. In contrast, work engagement was positively associated with job resources and negatively associated with turnover intention. Thus, boredom at work and work engagement had different potential antecedents and were inversely related to employee well-being and organizational outcomes. However, contrary to expectations, qualitative job demands were not significantly associated with boredom at work. Further investigation is needed to understand the relationship between boredom and qualitative job demands, which require sustained cognitive load and the use of higher skills.

<p>Comparison myeloid cells originating from Ewing sarcoma and neuroblastoma tissue samples</p>