Multivariate discovery and replication of five novel loci associated with Immunoglobulin G <i>N</i>-glycosylation

Multivariate analysis methods can uncover the relationship between phenotypic measures characterised by modern omic techniques. Here the authors conduct a multivariate GWAS on IgG N-glycosylation phenotypes and identify 5 novel loci enriched in immune system genes

Mechanisms of relapse in acute leukaemia: involvement of p53 mutated subclones in disease progression in acute lymphoblastic leukaemia

Mutations of the p53 tumour suppressor gene are infrequent at presentation of both acute myeloblastic leukaemia (AML) and acute lymphoblastic leukaemia (ALL), being found in between 5–10% of AML and 2–3% of ALL. Here we have studied the frequency of detection of p53 mutations at relapse of both AML and B-precursor ALL. In those patients with detectable mutations at relapse we investigated whether the mutation was detectable at presentation and was thus an early initiating event or whether it had arisen as a late event associated with relapse. Bone marrow samples from 55 adults and children with relapsed AML (n = 41) or ALL (n = 14) were analysed for p53 gene alterations by direct sequencing of exons 5–9. For samples where a p53 mutation was found at relapse, analysis of presentation samples was carried out by direct sequencing of the exon involved, or by allele-specific polymerase chain reaction (PCR) if the mutation could not be detected using direct sequencing. A p53 mutated gene was found at relapse in seven out of 55 cases. The frequency was higher in relapsed ALL (four out of 14 cases; 28.6%) compared to AML (three out of 41 cases; 7.3%). In five out of the seven cases presentation samples were available to study for the presence of the mutation. In two out of two AML patients the p53 mutation was detectable in the presentation sample by direct sequencing. In three ALL patients analysis of presentation material by direct sequencing showed a small mutant peak in one case, the other two being negative despite the sample analysed containing > 90% blast cells. However in both of these patients, the presence of p53 mutation was confirmed in the presentation sample using allele-specific PCR. In one of these patients the emergence of a subclone at relapse was confirmed by clonality analysis using IgH fingerprinting. Our results confirm that in ALL p53 mutations are present in a proportion of patients at relapse. Furthermore cells carrying the mutation are detectable at presentation in a minor clone suggesting that p53 mutations in ALL may be a mechanism contributing to disease relapse. © 1999 Cancer Research Campaig

Neutron Activated ¹⁵³Sm Sealed in Carbon Nanocapsules for in Vivo Imaging and Tumor Radiotherapy

Radiation therapy along with chemotherapy and surgery remain the main cancer treatments. Radiotherapy can be applied to patients externally (external beam radiotherapy) or internally (brachytherapy and radioisotope therapy). Previously, nanoencapsulation of radioactive crystals within carbon nanotubes, followed by end-closing, resulted in the formation of nanocapsules that allowed ultrasensitive imaging in healthy mice. Herein we report on the preparation of nanocapsules initially sealing "cold" isotopically enriched samarium (152Sm), which can then be activated on demand to their "hot" radioactive form (153Sm) by neutron irradiation. The use of "cold" isotopes avoids the need for radioactive facilities during the preparation of the nanocapsules, reduces radiation exposure to personnel, prevents the generation of nuclear waste, and evades the time constraints imposed by the decay of radionuclides. A very high specific radioactivity is achieved by neutron irradiation (up to 11.37 GBq/mg), making the "hot" nanocapsules useful not only for in vivo imaging but also therapeutically effective against lung cancer metastases after intravenous injection. The high in vivo stability of the radioactive payload, selective toxicity to cancerous tissues, and the elegant preparation method offer a paradigm for application of nanomaterials in radiotherapy

Neutron Activated 153Sm Sealed in Carbon Nanocapsules for in Vivo Imaging and Tumor Radiotherapy

Radiation therapy along with chemotherapy and surgery remain the main cancer treatments. Radiotherapy can be applied to patients externally (external beam radiotherapy) or internally (brachytherapy and radioisotope therapy). Previously, nanoencapsulation of radioactive crystals within carbon nanotubes, followed by end-closing, resulted in the formation of nanocapsules that allowed ultrasensitive imaging in healthy mice. Herein we report on the preparation of nanocapsules initially sealing "cold" isotopically enriched samarium (Sm), which can then be activated on demand to their "hot" radioactive form (Sm) by neutron irradiation. The use of "cold" isotopes avoids the need for radioactive facilities during the preparation of the nanocapsules, reduces radiation exposure to personnel, prevents the generation of nuclear waste, and evades the time constraints imposed by the decay of radionuclides. A very high specific radioactivity is achieved by neutron irradiation (up to 11.37 GBq/mg), making the "hot" nanocapsules useful not only for in vivo imaging but also therapeutically effective against lung cancer metastases after intravenous injection. The high in vivo stability of the radioactive payload, selective toxicity to cancerous tissues, and the elegant preparation method offer a paradigm for application of nanomaterials in radiotherapy