Biomedical subjects

Koen K Van de Vijver

Publications and source records attributed to Koen K Van de Vijver.

4 recordsLinked to original sources

PubMed2025

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Journal Article↗

PubMed2006

The host's genetic background determines the extent of angiogenesis induced by schistosome egg antigens.

Schistosomiasis is characterised by periovular granuloma formation within the portal tract and presinusoidal venules. As inflammation wanes, continued attempts to wall off and repair hepatic injury, lead to the development of extensive fibrosis. The codependence of chronic inflammation and angiogenesis is a well-known phenomenon. Neovascularisation is a complex process of endothelial cell proliferation and remodelling of the extracellular matrix. Previous studies demonstrated the ability of schistosome soluble egg antigens (SEAs) to stimulate endothelial cell activation in vitro. In the present study, we investigated the angiogenic potential of SEA in Swiss and BALb/c mice, after infection with Schistosoma mansoni or S. haematobium and by implanting SEA-coated beads into the murine liver. Anti-CD34 and anti-Ki-67 immunohistochemical stainings demonstrated newly formed blood vessels within and at the periphery of the granulomas. However, in one third of the granulomas the pre-existing portal stroma was not destroyed by the granulomatous inflammation, angiogenesis was minimal or absent and further growth of the granuloma was prevented. In C57BL/6J and C3H/HeN inbred mice, this polarisation was even more pronounced. In 91% of the granulomas in C57BL6/J mice the portal stroma was preserved. These mice had significantly smaller granulomas, less fibrosis and less mortality as compared to the high pathology C3H/HeN mice, where 87% of the granulomas were of the angiogenic type with destruction of the pre-existing stroma, leading to more severe chronic pathology. Thus, host's genetic mechanisms regulating the degree of angiogenesis and fibrosis, determine the severity of schistosome-induced pathology.

Animals↗

PubMed2005

LacdiNAc- and LacNAc-containing glycans induce granulomas in an in vivo model for schistosome egg-induced hepatic granuloma formation.

Schistosomes, major parasitic helminths, express numerous glycoconjugates that provoke humoral and cellular immune responses in the infected human host. The main pathology in schistosomiasis is due to the formation of granulomas around tissue-trapped eggs and the resulting organ damage. By using a mouse model of induction of granulomas by hepatic implantation of antigen-coated beads, it has been determined that the glycan part of schistosomal soluble egg antigens (SEA) initiates granulomogenesis. To identify which individual glycan elements in this complex SEA mixture are granulomogenic, we have tested in the same mouse model conjugates of various synthetic oligosaccharides characteristic for schistosome eggs, including GalNAcbeta1-4GlcNAc (LacdiNAc, LDN), Galbeta1-4(Fucalpha1-3)GlcNAc (Lewisx), Fucalpha1-2Fucalpha1-3GlcNAc (DF-Gn), and Fucalpha1-3GalNAcbeta1-4(Fucalpha1-3)GlcNAc (F-LDN-F). Ribonuclease (RNase) A and B, and different fetuin glycoforms were included as controls. Only beads that carry glycoconjugates with terminal LacdiNAc or Galbeta1-4GlcNAc (LacNAc, LN) elements gave rise to granulomas, with macrophage, lymphocyte, and eosinophil levels similar to the granulomatous lesions caused by schistosome eggs in a natural infection. Uncoated beads, and beads coated with fucosylated glycoconjugates or glycoconjugates lacking terminally exposed Gal or GalNAc, only attracted a monolayer of macrophages. These results indicate that the formation of hepatic granulomas is triggered specifically by glycoconjugates which carry terminal LacNAc or LacdiNAc, both constituents of the schistosome egg.

Acetylation↗

PubMed2004

Discrimination between the anti-monomeric and the anti-multimeric Lewis X response in murine schistosomiasis.

Individuals suffering from schistosomiasis raise an immune response against Galbeta1-4(Fucalpha1-3)GlcNAcbeta (Lewis X, LeX), a trisaccharide that is expressed both in monomeric and polymeric form in different life stages of the schistosomes. In order to study a possible immunological discrimination between different presentations of LeX, i.e. as a monomer or as an oligomer (di- or trimer), the levels of antibodies against lacto-N-fucopentaose III (LNFPIII, a pentasaccharide containing monomeric LeX), and against dimeric and trimeric LeX have been measured in sera of mice with a schistosome infection. The antibody response was predominantly of the IgM type. A striking difference in intensity of the antibody response against monomeric and oligomeric LeX was observed. Furthermore, the antibody response against circulating cathodic antigen (CCA), a schistosomal antigen containing multimeric LeX, was also measured, and the response pattern differed from that of the anti-mono, di- and trimeric LeX responses. In addition, the binding pattern of a panel of monoclonal antibodies (Mabs), derived from mice infected with schistosomes, with LNFPIII, di- and trimeric LeX was measured by surface plasmon resonance (SPR). These Mabs could be divided into three different groups according to their interaction with the LeX oligosaccharides. Based on these data, we suggest that the different presentations of LeX give rise to different groups of anti-LeX antibodies.

Amino Sugars↗