In-vitro model to mimic T cell subset change in human PDAC organoid co-culture.

PURPOSE: Immunotherapies have largely failed as treatment options for pancreatic ductal adenocarcinoma (PDAC). In this field, clinical translational studies into personalized treatment are of fundamental importance. In our study, we model tumor-cell immune-cell interactions in a co-culture of primary human PDAC organoids and matched peripheral blood mononuclear cells (PBMCs). METHODS: Using flow cytometry, we evaluated changes in T cell subtypes upon co-culture of patient-derived PDAC organoids and matched PBMCs. RESULTS: After co-culturing PDAC organoids with PBMCs, we observed changes in CD4+, CD8+ and Treg cell populations. We observed favorable clinical outcome in patients whose PBMCs reacted to the co-culture with organoids. CONCLUSION: This experimental model allows to investigate interactions between patient derived PDAC organoids and their PBMCs. This co-culture system could serve as a preclinical platform to guide personalized therapeutic strategies in the future.

In vivo functional dissection of a context-dependent role for Hif1α in pancreatic tumorigenesis.

Hypoxia-inducible factor 1α (Hif1α) is a key regulator of cellular adaptation and survival under hypoxic conditions. In pancreatic ductal adenocarcinoma (PDAC), it has been recently shown that genetic ablation of Hif1α accelerates tumour development by promoting tumour-supportive inflammation in mice, questioning its role as the key downstream target of many oncogenic signals of PDAC. Likely, Hif1α has a context-dependent role in pancreatic tumorigenesis. To further analyse this, murine PDAC cell lines with reduced Hif1α expression were generated using shRNA transfection. Cells were transplanted into wild-type mice through orthotopic or portal vein injection in order to test the in vivo function of Hif1α in two major tumour-associated biological scenarios: primary tumour growth and remote colonization/metastasis. Although Hif1α protects PDAC cells from stress-induced cell deaths in both scenarios-in line with the general function Hif1α-its depletion leads to different oncogenic consequences. Hif1α depletion results in rapid tumour growth with marked hypoxia-induced cell death, which potentially leads to a persistent tumour-sustaining inflammatory response. However, it simultaneously reduces tumour colonization and hepatic metastases by increasing the susceptibility to anoikis induced by anchorage-independent conditions. Taken together, the role of Hif1α in pancreatic tumorigenesis is context-dependent. Clinical trials of Hif1α inhibitors need to take this into account, targeting the appropriate scenario, for example palliative vs adjuvant therapy.

WNT6 is a novel target gene of caveolin-1 promoting chemoresistance to epirubicin in human gastric cancer cells.

Resistance to chemotherapy is a major obstacle for curative treatment of human gastric cancer (GC). However, the underlying molecular mechanisms are largely unknown. Wingless-type MMTV integration site family members (WNTs) are secreted glycoproteins involved in embryogenesis and, on inappropriate expression in the adult, in cancer. Here, we show expression of WNT6 in GC patient specimens, human GC cell lines and in a mouse model of GC. In human GC cells, WNT6 expression was enhanced by caveolin-1 (Cav1), a scaffold protein of plasma membrane caveolae. WNT6 knock-down and overexpression experiments demonstrated that WNT6 increased the resistance to apoptotic cell death induced by the anthracycline chemotherapeutics epirubicin (Epi) and doxorubicin (Dox). Epi increased the activity of the human WNT6 promoter through Cav1-dependent binding of ß-catenin to the proximal WNT6 promoter. Epi increased both WNT6/Wnt6 and Cav1 expression in human GC cells and within the tumor area of a murine model of GC (CEA424-SV40 TAg). In GC patients, WNT6 expression was positively associated with the tumor stage and the nodal status, and inversely correlated with the response to ECF (Epi, cisplatin, 5-fluorouracil) chemotherapy. These results showed that WNT6 and Cav1 are upregulated by chemotherapeutics and enhance the resistance of GC cells to anthracycline drugs. Understanding the molecular mechanisms driving WNT6/Cav1-induced drug resistance will provide benefits in developing new therapies for GC.

[Questionnaire on professional satisfaction with psychiatric emergency services: the professionals' opinion]. / Enquête de satisfaction auprès des utilisateurs d'un service d'urgence psychiatrique: l'avis des professionnels.

Professional's satisfaction concerning medical wards to which they address their patients are scarce, but is part of quality evaluation. The primary care network criticizes often the access to specialized psychiatric cares in emergency. The rapid emergency crisis team (ERIC) is a mobile emergency and post-emergency crisis team depending from public services. It has for purpose to offer early access to specialized care before admission to psychiatric hospital, which general practitioners or other members of social network alert it for a crisis psychiatric situation. The aim of this study was to evaluate the adequacy of ERIC to the needs of professionals, and to improve the collaboration within the network. We performed a mailed study using a questionnaire to 150 general practitioners, 25 private psychiatrists, 7 social circonscriptions, and 5 police departments depending on our intervention's catchment area. Forty-two percent of the professionals answered. Emergency psychiatric crisis situations are scarce, and professional's satisfaction is excellent. ERIC is considered as useful, and the accessibility is underlined. However, information transmitted at the end of the intervention is criticized by the professionals. This study allows to improve some of the procedures and will help to an evolution of our functioning. Moreover, it allows to propose a strategy of prevention oriented to early access to specialized cares.

[Security and home emergency psychiatric interventions]. / Sécurité et interventions psychiatriques à domicile en urgence.

Sectorisation of cares leads professionals to a confrontation with violent home patients. These interventions need a maximal security for professionals. Emergency Mobile Crisis Team (ERIC) has more than 6,000 crisis home interventions' experience. The aim of this study was to assess violent situations during a 42 months experience. We present 70 situations of danger for professionals, and their consequences. Difficulties lead to procedural safety measures, which are presented. Prevention of violence during intervention needs an acute preparation, a clear evaluation of context, and passive or active securisation measures. Occurrence of acting-out is low, but situations considered as dangerous are frequent. We propose some pragmatic issues to increase security in crisis home interventions.