Gene expression profiling of patient‐derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts

Abstract c‐MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient‐derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC‐high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC‐low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC‐high group and six transcripts increased in the MYC‐low group. We validated the ability of these markers panel to identify MYC‐high patient‐derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC‐high patients are more sensitive to JQ1 treatment compared to MYC‐low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics

Temporary successful results of ventral rectopexy for enterocele surgical correction, about 138 patients

International audienc

Implications of SDHB genetic testing in patients with sporadic pheochromocytoma

International audiencePURPOSE: Succinate dehydrogenase B (SDHB) associated pheochromocytomas (PHEOs) are associated with a higher risk of tumor aggressiveness and malignancy. The aim of the present study was to evaluate (1) the frequency of germline SDHB mutations in apparently sporadic patients with PHEO who undergo preoperative genetic testing and (2) the ability to predict pathogenic mutations.METHODS: From 2012 to 2016, 82 patients underwent a PHEO surgical resection. Sixteen were operated in the context of hereditary PHEO and were excluded from analysis. Among the 66 remaining cases, 48 were preoperatively screened for an SDHB mutation. In addition to imaging studies with specific radiopharmaceuticals (123I-MIBG or 18F-FDOPA) for exclusion of multifocality/metastases, 36 patients underwent 18F-FDG PET/CT.RESULTS: From the 48 genetically screened patients, genetic testing found a germline SDHB variant in two (4.2%) cases: a variant of unknown significance, exon 1, c.14T>G (p.Val5Gly), and a most likely pathogenic mutation, exon 5, c.440A>G (p.Tyr147Cys), according to in silico analysis. Structural and functional analyses of the protein predicted that p.Tyr147Cys mutant was pathogenic. Both tumors exhibited moderate 18F-FDG PET uptake with similar uptake patterns to non-SDHB mutated PHEOs. The two patients underwent total laparoscopic adrenalectomies. Of the remaining patients, 44 underwent a laparoscopic adrenalectomy, and two had an open approach. Pathological analysis of the tumors from patients bearing two germline SDHB variants revealed a typical PHEO (PASS 0 and 2). Ex-vivo analyses (metabolomics, SDHB immunohistochemistry, loss of heterozygosity analysis) allowed a reclassification of the two SDHB variants as probably non-pathogenic variants.CONCLUSIONS:This study illustrates that SDHx mutational analysis can be misleading, even if structural and functional analyses are done. Surgeons should be aware of the difficulty of classifying new SDHB variants prior to implementing SDHB mutation status into a tailored surgical management strategy of a patient

A representation of the phosphorus cycle for ORCHIDEE (revision 4520)

Paper contact with Daniel Goll: [email protected]ïments: S. Zaehle was supported by the QUINCY project of the European Research Council (ERC-2014-CoG-647204). We thank two anonymous referees and the editor H. Sato for their constructive comments. Further, we thank the TRY initiative and database, which is hosted, developed, and maintained by J. Kattge and G. Boenisch (Max Planck Institute for Biogeochemistry, Jena, DE), for additional leaf stoichiometric data on Metrosideros, Ying-Ping Wang and Ben Houlton for sharing their data compilation on the Hawaiian sites, and Sebastiaan Luysseart for the discussions related to biomass allocation.Land surface models rarely incorporate the terrestrial phosphorus cycle and its interactions with the carbon cycle, despite the extensive scientific debate about the importance of nitrogen and phosphorus supply for future land carbon uptake. We describe a representation of the terrestrial phosphorus cycle for the ORCHIDEE land surface model, and evaluate it with data from nutrient manipulation experiments along a soil formation chronosequence in Hawaii. ORCHIDEE accounts for the influence of the nutritional state of vegetation on tissue nutrient concentrations, photosynthesis, plant growth, biomass allocation, biochemical (phosphatase-mediated) mineralization, and biological nitrogen fixation. Changes in the nutrient content (quality) of litter affect the carbon use efficiency of decomposition and in return the nutrient availability to vegetation. The model explicitly accounts for root zone depletion of phosphorus as a function of root phosphorus uptake and phosphorus transport from the soil to the root surface. The model captures the observed differences in the foliage stoichiometry of vegetation between an early (300-year) and a late (4.1?Myr) stage of soil development. The contrasting sensitivities of net primary productivity to the addition of either nitrogen, phosphorus, or both among sites are in general reproduced by the model. As observed, the model simulates a preferential stimulation of leaf level productivity when nitrogen stress is alleviated, while leaf level productivity and leaf area index are stimulated equally when phosphorus stress is alleviated. The nutrient use efficiencies in the model are lower than observed primarily due to biases in the nutrient content and turnover of woody biomass. We conclude that ORCHIDEE is able to reproduce the shift from nitrogen to phosphorus limited net primary productivity along the soil development chronosequence, as well as the contrasting responses of net primary productivity to nutrient addition

Luzerne références: Edition 2016-2018

Luzerne références. Edition 2016-201

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC

A highly virulent variant of HIV-1 circulating in the Netherlands

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence