Greenresilient: Innovative Cropping Systems In Organic Greenhouse Production

European organic greenhouse production systems are extremely differentiated. The more intensive ones have been object of debates, in the last decade, and a strong request for innovative solutions to reduce the level of intensification comes from the “organic sector”. An agroecological approach to organic production in protected conditions can be an option. This paper describes how scientists with competencies in soil science, agronomy, plant pathology, entomology and environmental sustainability assessment interact in the framework of GREENRESILIENT project (CORE Organic Cofund) to implement more resilient cropping systems in protected conditio

Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations

NFKB1 haploinsufficiengcy was first described in 2015 in three families with common variable immunodeficiency (CVID), presenting heterogeneously with symptoms of increased infectious susceptibility, skin lesions, malignant lymphoproliferation and autoimmunity. The described mutations all led to a rapid degradation of the mutant protein, resulting in a p50 haploinsufficient state. Since then, more than 50 other mutations have been reported, located throughout different domains of NFKB1 with the majority situated in the N-terminal Rel homology domain (RHD). The clinical spectrum has also expanded with possible disease manifestations in almost any organ system. In silico prediction tools are often used to estimate the pathogenicity of NFKB1 variants but to prove causality between disease and genetic findings, further downstream functional validation is required. In this report, we studied 2 families with CVID and two novel variants in NFKB1 (c.1638-2A>G and c.787G>C). Both mutations affected mRNA and/or protein expression of NFKB1 and resulted in excessive NLRP3 inflammasome activation in patient macrophages and upregulated interferon stimulated gene expression. Protein-protein interaction analysis demonstrated a loss of interaction with NFKB1 interaction partners for the p.V263L mutation. In conclusion, we proved pathogenicity of two novel variants in NFKB1 in two families with CVID characterized by variable and incomplete penetrance.Peer reviewe

Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations

NFKB1 haploinsufficiengcy was first described in 2015 in three families with common variable immunodeficiency (CVID), presenting heterogeneously with symptoms of increased infectious susceptibility, skin lesions, malignant lymphoproliferation and autoimmunity. The described mutations all led to a rapid degradation of the mutant protein, resulting in a p50 haploinsufficient state. Since then, more than 50 other mutations have been reported, located throughout different domains of NFKB1 with the majority situated in the N-terminal Rel homology domain (RHD). The clinical spectrum has also expanded with possible disease manifestations in almost any organ system. In silico prediction tools are often used to estimate the pathogenicity of NFKB1 variants but to prove causality between disease and genetic findings, further downstream functional validation is required. In this report, we studied 2 families with CVID and two novel variants in NFKB1 (c.1638-2A>G and c.787G>C). Both mutations affected mRNA and/or protein expression of NFKB1 and resulted in excessive NLRP3 inflammasome activation in patient macrophages and upregulated interferon stimulated gene expression. Protein-protein interaction analysis demonstrated a loss of interaction with NFKB1 interaction partners for the p.V263L mutation. In conclusion, we proved pathogenicity of two novel variants in NFKB1 in two families with CVID characterized by variable and incomplete penetrance.Peer reviewe

MDM4 proteine, een veelbelovend doelwit voor kankertherapie

Cutaneous melanoma arises from uncontrolled growth of melanocytes in the basal layer of the skin. It is a very aggressive disease and its incidence has been rising faster than any other cancer type since the mid 1950’s. Once the cancer has metastasized to other organs, it becomes very difficult to manage. Recently, the melanoma field was revolutionized by the upcoming of MAPK-based targeted therapeutics and immunotherapy. In spite of initial successes in overall and progression-free survival, most patients become resistant to the treatment and relapse shortly after the start of the therapy. Novel therapies are urgently needed to use alone or in combination with existing treatments, in order to induce a more durable or even curative response in patients. Murine Double Minute 4 (MDM4) is a potent oncogene that is expressed in about 65% of all melanoma patients. It mostly works as a transcriptional squelcher for p53, meaning that it keeps p53 from exerting tumor suppressive functions. Moreover, recent data indicates that MDM4 possesses p53-independent oncogenic functions as well. Therefore, rather than disrupting the interaction between p53 and MDM4, which appears to be a very challenging task, we reasoned that directly targeting MDM4 protein abundance may be a more efficient alternative. As it was not clear how MDM4 is being upregulated in human cancers, the central aim of this PhD thesis was to unravel the mechanism(s) that contribute to high MDM4 protein expression in cancer, and in particular in melanoma. We found that melanoma cells hijack an otherwise embryonic alternative splicing event to include exon 6 in the MDM4 pre-mRNA, resulting in the generation of a full-length protein-coding transcript. Antisense oligonucleotides (ASOs) were designed to specifically force exon 6 skipping, thereby creating a premature stop codon which marks the shorter transcript for nonsense-mediated decay (NMD). We show that treating melanoma cells with MDM4-targeting ASOs reactivated p53 function in vitro and resulted in reduced colony growth. Moreover, this treatment decreased tumor growth in three different patient-derived melanoma xenografts (PDX) models, indicating that MDM4 ASOs could be used in an in vivo/preclinical setting. Interestingly, it also greatly sensitized melanoma cells to MAPK-based therapeutics. At the timepoint where BRAF inhibitor-treated mice already had become resistant to the treatment and tumors were quickly regrowing, mice that received the BRAF inhibition/MDM4 ASO combination were still sensitive. This suggests that MDM4 ASOs are able to delay the development of BRAF inhibition-induced resistance. Before uncovering this alternative splicing switch event that contributes to MDM4 upregulation, our knowledge of MDM4 expression in cancer was largely based on copy number alterations and transcriptomic analyses. By looking at the ratio of the alternatively spliced transcripts of MDM4, careful in silico re-analysis of many different tumor samples revealed that we may have been dramatically underestimating how widespread MDM4 expression is in other tumor types. The innovative targeting strategy we developed could therefore potentially be applicable to a wide variety of tumors. In conclusion, in this PhD project, we unraveled an important mechanism of MDM4 upregulation in cancer. An alternative splicing-based therapy was designed and validated in melanoma cells and in PDX. As oncogenic MDM4 is predicted to be expressed in a wide variety of other tumor types, many cancers could benefit from this ASO-based therapeutic strategy.status: publishe

GREENRESILIENT – applying agroecology to organic greenhouse production

Some organic greenhouse production systems are very intensive with potentially negative effects on the public trust on organic products as a whole. In this context, the year-round production of high quality and tasty vegetables in unheated and low-energy greenhouses or polytunnels, using resilient, sustainable and local systems, is a challenge, especially in areas with long winters and low light, low temperature conditions. The CORE Organic Cofund transnational project titled “Organic and biodynamic vegetable production in low-energy GREENhouses NDASH sustainable, RESILIENT and innovative food production systems” (GREENRESILIENT) has taken up the challenge and aims to demonstrate that an agroecological approach to greenhouse production is feasible and allows the establishment of robust agroecosystems in different European areas. The use of agroecological practices in organic greenhouse production systems is an innovative approach and a team of scientists with multidisciplinary competences (agronomy, agroecology, soil chemistry, entomology, plant pathology, weed science, life cycle analysis) from 12 research centres in eight European countries are involved. Research activities are carried out in five experimental sites (two in Mediterranean countries and three in central and northern countries), comparing innovative systems in unheated or frost protected conditions to a standard organic system specific for each experimental site. Results obtained will be used for actors' involvement (farmers, consumers and policy makers) and sustainability assessment

Correlation between peripapillary choroidal thickness and retinal vessel oxygen saturation in young healthy individuals

status: publishe

Different Levels of Twist1 Regulate Skin Tumor Initiation, Stemness, and Progression

Twist1 promotes epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and cancer stem cell (CSC) properties. However, it remains unclear whether Twist1 is also required for tumor initiation and whether Twist1-induced cancer stemness and EMT are functionally linked. Using a conditional deletion of Twist1 at different stages of skin carcinogenesis, we show that Twist1 is required for skin tumor initiation and progression in a gene-dosage-dependent manner. Moreover, conditional ablation of Twist1 in benign tumors leads to increased apoptosis, reduced cell proliferation, and defective tumor maintenance and propagation independently of its EMT-inducing abilities. Concomitant deletion of Twist1 and p53 rescues the apoptotic response, but not the cell proliferation and propagation defects. These results reveal that Twist1 is required for tumor initiation and maintenance in a p53-dependent and -independent manner. Importantly, our findings also indicate that tumor stemness and EMT can be regulated by distinct mechanisms.SCOPUS: ar.jSCOPUS: ar.jinfo:eu-repo/semantics/publishe

A randomized, observer-blind phase Ib study to identify formulations and vaccine schedules of a trivalent Group B Streptococcus vaccine for use in non-pregnant and pregnant women

A

Amplification of 1q32.1 refines the molecular classification of endometrial carcinoma

Molecular classification of endometrial cancer (EC) identified distinct molecular subgroups. However, the largest subset of ECs remains poorly characterized and is referred to as the 'non-specific molecular profile' (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy number aberrations (SCNAs).status: publishe

Amplification of 1q32.1 Refines the Molecular Classification of Endometrial Carcinoma

Purpose: Molecular classification of endometrial cancer identified distinct molecular subgroups. However, the largest subset of endometrial cancers remains poorly characterized and is referred to as the "nonspecific molecular profile" (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy-number aberrations (SCNAs).Experimental Design: SCNAs were analyzed in 141 endometrial cancers using whole-genome SNP arrays and pooled with 361 endometrial cancers from The Cancer Genome Atlas. Genomic Identification of Significant Targets in Cancer (GISTIC) identified statistically enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 endometrial cancers from the PORTEC-1/2 trials. Copy-number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated in vitro using antisense oligonucleotide-based strategy.Results: SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR, 2.12; 95% CI, 1.26-3.59; P = 0.005). This effect was replicated in NSMP endometrial cancers from PORTEC-1/2 (HR, 2.34; 95% CI, 1.17-4.70; P = 0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. MDM4 gene expression strongly correlated with 1q32.1 amplification. Silencing MDM4 inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in those without MDM4 amplification. Vice versa, increasing MDM4 expression in nonamplified cell lines stimulated cell proliferation.Conclusions: 1q32.1 amplification was identified as a prognostic marker for poorly characterized NSMP endometrial cancers, refining the molecular classification of this subgroup. We functionally validated MDM4 as a potential oncogenic driver in the 1q32.1 region. Clin Cancer Res; 23(23); 7232-41. ©2017 AAC