Not just a 'usual' Li-Fraumeni syndrome

The Li-Fraumeni syndrome (LFS) is characterised clinically by the appearance of tumours in multiple organs, generally at an early age. This hereditary condition is caused by germinal mutations in the TP53 gene, which codifies for the tumour suppressor gene p53. We present here the case of a patient aged 40 with the diagnosis of LFS who presented with premenopausal breast cancer. She had a positive family history of cancer. As a consequence, she was referred to genetic counselling. Genetic analysis revealed a TP53 germline mutation, which is diagnostic for LFS. However, further genetic analysis of different tissues showed a genetic mosaicism in our patient. Patients with LFS have a high risk for a broad spectrum of tumours. The diagnosis and management of Li-Fraumeni syndrome should be performed by a multidisciplinary team, and genetic counselling should be offered to patients and their relatives. Targeted next-generation sequencing represents an efficient approach for the identification of mutations in families with a heterogeneous phenotype. Theoretically, since mosaics do not have mutations in all of their cells, the cells that do not have mutant p53 are less likely to undergo malignant transformation or have the same risk of everyone else

The role of different VEGF isoforms in scar formation after glaucoma filtration surgery

Vascular endothelial growth factor (VEGF) plays an important role in both physiological and pathological angiogenesis. Our previous studies showed a differential role of VEGF isoforms in retinal physiological angiogenesis. We also demonstrated that non-selective inhibition of VEGF by bevacizumab had a beneficial effect on surgical outcome after glaucoma filtration surgery by reducing angiogenesis as well as fibrosis. However, the function of the VEGF isoforms in pathological angiogenesis and wound healing in the eye still remains unidentified. This study was designed to elucidate the differential roles of VEGF isoforms in scar formation after trabeculectomy. Furthermore, we also investigated whether pegaptanib (Macugen™, Pfizer), an aptamer which specifically blocks VEGF(165), could improve surgical outcome by reducing postoperative scarring. VEGF-R2 and neuropilin-1 (NRP-1) expression was analyzed in vitro by RT-PCR, and were found to be expressed at higher levels in human umbilical vein endothelial cells (HUVEC) as compared to Tenon fibroblasts (TF). The effect of the different VEGF isoforms (VEGF(121), VEGF(165) and VEGF(189)) and pegaptanib on cell proliferation was determined via WST-1 assay. Endothelial cell proliferation was stimulated after addition of VEGF(121) and VEGF(165), whereas VEGF(121) and VEGF(189) increased fibroblast growth. These effects on proliferation were associated with an activation of the ERK pathway, as revealed using the TransAM c-Myc assay. Inhibition of the ERK pathway, by PD98059 administration, significantly reduced VEGF isoform induced cell growth. A dose-dependent reduction of endothelial cell proliferation was observed after pegaptanib administration, while only the highest dose was able to inhibit fibroblast growth. Next, the in vivo effect of pegaptanib was investigated in a rabbit model of trabeculectomy. The surgical outcome was evaluated by performing clinical investigations (IOP, bleb area, height and survival), as well as histomorphometric analyses of angiogenesis (CD31), inflammation (CD45) and fibrosis (Sirius Red). A single postoperative application of pegaptanib had a beneficial impact on surgical outcome, mainly by reducing angiogenesis, but not inflammation or collagen deposition. Repeated injections slightly improved surgical outcome, but again solely by reducing angiogenesis. In summary, our results revealed that the VEGF isoforms play a differential role in ocular wound healing: VEGF(165) and VEGF(121) predominantly affect blood vessel growth, whereas VEGF(189) is rather involved in fibrosis, an important process in wound healing.status: publishe

Mesoporous TiO2 from poly(N,N-dimethylacrylamide)-b-polystyrene block copolymers for long-term acetaldehyde photodegradation

Although already some mesoporous (2-50 nm) sol-gel TiO2 synthesis strategies exist, no pore size control beyond the 12 nm range is possible without using specialized organic structure-directing agents synthetized via controlled anionic/radical polymerizations. Here, we present the use of reversible addition-fragmentation chain transfer (RAFT) polymerization as a straightforward and industrial applicable alternative to the existing controlled polymerization methods for structure-directing agent synthesis. Poly(N,N-dimethylacrylamide)-block-polystyrene (PDMA-b-PS) block copolymer, synthesized via RAFT, was chosen as structure-directing agent for the formation of the mesoporous TiO2. Crack-free thin layers TiO2 with tunable pores from 8 to 45 nm could be acquired. For the first time, in a detailed and systematic approach, the influence of the block size and dispersity of the block copolymer is experimentally screened for their influence on the final meso-TiO2 layers. As expected, the mesoporous TiO2 pore sizes showed a clear correlation to the polystyrene block size and the dispersity of the PDMA-b-PS block copolymer. Surprisingly, the dispersity of the polymer was shown not to be affecting the standard deviation of the pores. As a consequence, RAFT could be seen as a viable alternative to the aforementioned controlled polymerization reactions for the synthesis of structure-directing agents enabling the formation of mesoporous pore size-controlled TiO2. To examine the photocatalytic activity of the mesoporous TiO2 thin layers, the degradation of acetaldehyde, a known indoor pollutant, was studied. Even after 3 years of aging, the TiO2 thin layer retained most of its activity