Publications

Thepurposeofthecurrentstudywastoconductalongitudinaltestofthemoderating effect of both job control and social support on the relationbetween job demands and burnout in human service work. To adapt thestudy to human service work, quantitative as well as emotional demandswereexamined.Alongitudinalsurveywitha1-yeartimeintervalyieldedapanelgroupencompassing2,255employeesfromtheSocialInsuranceOr-ganizationinSweden.Hierarchicalregressionanalyseswereused,control-lingfordemographicvariablesandtherelateddependentvariableatTime1.Theanalyseswereconductedforquantitativeandemotionaldemandssepa-ratelyandrevealedmaineffects.Slightlymoremaineffectswerefoundforemotional demands. In addition, 1 interaction effect was found betweenemotionaldemandsandjobcontrolwithregardtoemotionalexhaustion.In

Abstract KRAS is mutated and activated in an estimated 40% of colon cancers but has proven difficult to target directly due to the lack of drug-binding pockets on the surface of Ras. Thus, identifying effectors that transmit signals from oncogenic Ras is a critical step in targeting vulnerabilities in the tumors of patients with colorectal cancer (CRC). Kinase Suppressor of Ras 1 (KSR1) is a molecular scaffold that coordinates the interaction of effectors in the Raf/MEK/ERK signaling cascade downstream of Ras. KSR1 is necessary for oncogenic transformation of cells expressing mutated Ras but is dispensable for normal cell growth making KSR1 an attractive therapeutic target for Ras-driven colon cancers. In CRC cells, KSR1 and ERK mediate Ras-dependent effects on protein translation, notably driving cap-dependent and cap-independent translation of the Myc oncogene. Depletion of KSR1 or treatment with ERK inhibitor (SCH772984) leads to a decrease in phophorylated 4EBP1 and a decrease in PDCD4, which collectively impair protein translation, notably leading to a decrease in Myc translation. Patient-derived CRC organoids with deletion of APC, p53, and SMAD4, and an activating G12D mutation in KRAS treated with ERK inhibitor show a marked decrease in Myc protein expression, coincident with changes in PDCD4 and 4EBP1 that impair protein translation. These observations indicate that the KSR1-dependent ERK activation observed in CRC cell lines is present in pre-clinical colon tumoroid models. Genome-wide polysome profiling in CRC cell lines HCT116 and HCT15 depleted of KSR1 identified mRNAs that were preferentially translated in a KSR1 and ERK-dependent manner. Several of these mRNAs were previously predicted by our Functional Signature Ontology (FUSION) screen to be critical to CRC viability but dispensable for normal cell growth. GSEA identified functional classes of mRNAs whose translation is KSR1-dependent, including mediators of oncogenic signaling in pathways that regulate mTOR, MAPK, WNT and JAK-STAT. Our data suggest that an essential component of oncogenic Ras-induced and KSR1-dependent signaling is the preferential translation of mRNAs supporting the transformed phenotype of CRC cells. Citation Format: Heidi Vieira, Chaitra Rao, Adrian R. Black, Siddesh Southekal, Tomohiro Mizutani, Babu Guda, Hans Clevers, Jennifer D. Black, Robert E. Lewis. KSR1-dependent modulation of the translational landscape in Ras-driven colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 307.

Additional file 4. Table S4

2573 Background: Current patient-derived organoid (PDO) models are largely devoid of immune components. We developed a precision microfluidic and membrane platform to generate patient-derived micro-organospheres (MOS) that retain tumor-resident immune and stromal components for personalized immuno-oncology (IO) assays. Methods: MOS were generated from lung, kidney, and colorectal cancer patients. The composition and function of patient tumor-resident immune cells in MOS were characterized by flow cytometry, single-cell RNA-seq, antibody staining, and TCR-seq. High-content and longitudinal imaging with AI analyses were used to quantify tumor cell death and immune cell dynamics inside MOS in response to IO therapies including checkpoint inhibitors, T cell bispecific antibodies, and adoptive tumor infiltrating lymphocyte (TIL) therapies, followed by single-cell analyses. Results: Tumor and stromal cells quickly form tissue niches inside MOS to sustain the viability and function of encapsulated immune cells. MOS derived from lung and kidney cancer patients respond to Nivolumab, indicated by the Annexin V apoptosis marker. ESK1* (TCB antibody targeting HLA-A2/WT1) induces killing in eight lung tumor patients derived MOS. We further developed a MOS T-cell potency assay as autologous TILs or PBMC efficiently infiltrate MOS from lung, kidney and CRC patients and induce tumor cell apoptosis. Adjunctive therapies combining TCB with TILs enhanced the potency of adoptive cell therapy against lung tumor. Based on the data, three ongoing and upcoming personalize IO clinical trials will further validate the ability of the MOS assay to predict patient response to TCB, checkpoint combinations, and adoptive cell therapy. Conclusions: MOS provide a rapid and scalable personalized platform for developing and testing IO therapies such as checkpoint inhibitors, bispecific antibodies, and T cell therapies on patient tumor models that still retain the original tumor microenvironments.

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

<p>Differential sgRNA enrichment from CRISPR-Cas9 genome-wide screens</p>

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.

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.