Increased sensitivity to SMAC mimetic LCL161 identified by longitudinal ex vivo pharmacogenomics of recurrent, KRAS mutated rectal cancer liver metastases

Tumor heterogeneity is a primary cause of treatment failure. However, changes in drug sensitivity over time are not well mapped in cancer. Patient-derived organoids (PDOs) may predict clinical drug responses ex vivo and ofer an opportunity to evaluate novel treatment strategies in a personalized fashion. Here we have evaluated spatio-temporal functional and molecular dynamics of fve PDO models established after hepatic re-resections and neoadjuvant combination chemotherapies in a patient with microsatellite stable and KRAS mutated metastatic rectal cancer. Histopathological diferentiation phenotypes of the PDOs corresponded with the liver metastases, and ex vivo drug sensitivities generally refected clinical responses and selection pressure, assessed in comparison to a reference data set of PDOs from metastatic colorectal cancers. PDOs from the initial versus the two recurrent metastatic settings showed heterogeneous cell morphologies, protein marker expression, and drug sensitivities. Exploratory analyses of a drug screen library of 33 investigational anticancer agents showed the strongest ex vivo sensitivity to the SMAC mimetic LCL161 in PDOs of recurrent disease compared to those of the initial metastasis. Functional analyses confrmed target inhibition and apoptosis induction in the LCL161 sensitive PDOs from the recurrent metastases. Gene expression analyses indicated an association between LCL161 sensitivity and tumor necrosis factor alpha signaling and RIPK1 gene expression. In conclusion, LCL161 was identifed as a possible experimental therapy of a metastatic rectal cancer that relapsed after hepatic resection and standard systemic treatment

Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation

Background and aims We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5’-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). Methods We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. Results In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. Conclusions Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. Impact and implications We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.publishedVersio

A participatory physical and psychosocial intervention for balancing the demands and resources among industrial workers (PIPPI): study protocol of a cluster-randomized controlled trial

Background: Need for recovery and work ability are strongly associated with high employee turnover, well-being and sickness absence. However, scientific knowledge on effective interventions to improve work ability and decrease need for recovery is scarce. Thus, the present study aims to describe the background, design and protocol of a cluster randomized controlled trial evaluating the effectiveness of an intervention to reduce need for recovery and improve work ability among industrial workers. Methods/Design: A two-year cluster randomized controlled design will be utilized, in which controls will also receive the intervention in year two. More than 400 workers from three companies in Denmark will be aimed to be cluster randomized into intervention and control groups with at least 200 workers (at least 9 work teams) in each group. An organizational resources audit and subsequent action planning workshop will be carried out to map the existing resources and act upon initiatives not functioning as intended. Workshops will be conducted to train leaders and health and safety representatives in supporting and facilitating the intervention activities. Group and individual level participatory visual mapping sessions will be carried out allowing team members to discuss current physical and psychosocial work demands and resources, and develop action plans to minimize strain and if possible, optimize the resources. At all levels, the intervention will be integrated into the existing organization of work schedules. An extensive process and effect evaluation on need for recovery and work ability will be carried out via questionnaires, observations, interviews and organizational data assessed at several time points throughout the intervention period. Discussion: This study primarily aims to develop, implement and evaluate an intervention based on the abovementioned features which may improve the work environment, available resources and health of industrial workers, and hence their need for recovery and work ability

'Same, but different' : a mixed methods realist evaluation of a cluster-randomized controlled participatory organizational intervention

Participatory organizational interventions are a recommended approach to improve the psychosocial work environment. As interventions of this type are shaped by employees and managers, their implementation can vary considerably, making evaluation challenging. This study contributes to our understanding of interventions by focusing on how the intervention mechanisms and the organizational context interact. In a mixed-methods design, we use multi-group structural equation modelling of pre-and post-intervention survey data (N = 204) to test multiple mediational mechanisms in three different contexts. We then analyse interviews (N = 67) and field observations of workshops to identify the role of contextual factors. The findings suggest that participatory organizational interventions do not produce one-size-fits-all results; on the contrary, intervention results are better understood as products of multiple intervention mechanisms interacting with the specific organizational contexts