References of "Keunen, Olivier"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailPatient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.
Golebiewska, Anna UL; Hau, Ann-Christin; Oudin, Anaïs et al

in Acta Neuropathologica (2020)

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique ... [more ▼]

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology. [less ▲]

Detailed reference viewed: 170 (15 UL)
Full Text
Peer Reviewed
See detailPrimary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine
Golebiewska, Anna UL; Hau, Ann-Christin; Oudin, Anais et al

E-print/Working paper (2020)

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term ... [more ▼]

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies. [less ▲]

Detailed reference viewed: 136 (6 UL)
Full Text
Peer Reviewed
See detailCardiometabolic risk: leg fat is protective during childhood.
Samouda, Hanen; De Beaufort, Carine UL; Stranges, Saverio et al

in Pediatric diabetes (2015)

BACKGROUND: Childhood obesity is associated with early cardiometabolic risk (CMR), increased risk of adulthood obesity, and worse health outcomes. Leg fat mass (LFM) is protective beyond total fat mass ... [more ▼]

BACKGROUND: Childhood obesity is associated with early cardiometabolic risk (CMR), increased risk of adulthood obesity, and worse health outcomes. Leg fat mass (LFM) is protective beyond total fat mass (TFM) in adults. However, the limited evidence in children remains controversial. OBJECTIVE: We investigated the relationship between LFM and CMR factors in youth. SUBJECTS: A total of 203 overweight/obese children, 7-17-yr-old, followed in the Pediatric Clinic, Luxembourg. METHODS: TFM and LFM by dual energy x-ray absorptiometry and a detailed set of CMR markers were analyzed. RESULTS: After TFM, age, sex, body mass index (BMI) Z-score, sexual maturity status, and physical activity adjustments, negative significant partial correlations were shown between LFM and homeostasis model assessment of insulin resistance (HOMA) (variance explained: 6.05% by LFM*; 7.18% by TFM**), fasting insulin (variance explained: 5.71% by LFM*; 6.97% by TFM**), triglycerides (variance explained: 3.96% by LFM*; 2.76% by TFM*), systolic blood pressure (variance explained: 2.68% by LFM*; 4.33% by TFM*), C-reactive protein (variance explained: 2.31% by LFM*; 4.28% by TFM*), and resistin (variance explained: 2.16% by LFM*; 3.57% by TFM*). Significant positive partial correlations were observed between LFM and high-density lipoprotein (HDL) cholesterol (variance explained: 4.16% by LFM*) and adiponectin (variance explained: 3.09% by LFM*) (*p-value < 0.05 and **p-value < 0.001). In order to adjust for multiple testing, Benjamini-Hochberg method was applied and the adjusted significance level was determined for each analysis. LFM remained significant in the aforementioned models predicting HOMA, fasting insulin, triglycerides, and HDL cholesterol (Benjamini and Hochberg corrected p-value < 0.01). CONCLUSIONS: LFM is protective against CMR in children, at least in terms of insulin resistance and adverse blood lipid profiles. [less ▲]

Detailed reference viewed: 122 (2 UL)