Group-3 medulloblastoma (MBL) is highly resistant to radiation (IR) and chemotherapy and has the worst prognosis. Hence, there is an urgent need to elucidate targets that sensitize these tumors to chemotherapy and IR. Employing standard assays for viability and sensitization to IR, we identified PRDX1 as a therapeutic target in Group-3 MBL. Specifically, targeting PRDX1 by RNAi or inhibition by Adenanthin led to specific killing and sensitization to IR of Group-3 MBL cells. We rescued sensitization of Daoy and UW228 cells by hypermorphic expression of PRDX1. PRDX1 knockdown caused oxidative DNA damage and induced apoptosis. We correlated PRDX1 expression to patient outcomes in a validated MBL tumor-microarray. Whole genome sequencing identified pathways/genes that were dysregulated with PRDX1 inhibition or silencing. Our in vivo studies in mice employing flank/orthotopic tumors from patient derived xenografts/Group-3 MBL cells confirmed in vitro observations. Animals with tumors in which PRDX1 was targeted by RNAi or Adenanthin (using mini osmotic pumps) showed decreased tumor burden and increased survival when compared to controls. Since, Adenanthin does not cross the blood brain barrier (BBB) we used HAV6 peptide to transiently disrupt the BBB and deliver Adenanthin to the tumor. Immunohistochemistry confirmed that targeting PRDX1 resulted in increased oxidative DNA damage, apoptosis and decreased proliferation. In summary, we have validated PRDX1 as a therapeutic target in group-3 MBL, identified Adenanthin as a potent chemical inhibitor of PRDX1 and confirmed the role of HAV peptide (in the transient modulation of BBB permeability) in an orthotopic model of group-3 MBL.

Perovskite compositions are used to investigate the relationship between the minor components (i.e. LREE, Fe3+ and Nb) and the oxygen fugacity (fo2) of perovskite in four different kimberlite lithofacies from the Dutoitspan pipe, Kimberley, South Africa, which range from diamondiferous to barren. The perovskite textures and chemical variations provide insight into magmatic and eruptive processes. Some crystals display cores with rims separated by a sharp boundary. The cores contain larger Na and LREE contents relative to the rims, which show a large increase in Fe3+ and Al. The mid-grade and barren kimberlites have bi-modal cores, reflected in the mineral chemistry, signifying multiple batches of magma and magma mixing. The fo2 of the magma is determined by an Fe-Nb oxygen barometer. The most diamondiferous kimberlite has the greatest Fe3+ content and highest fo2 (NNO –3.6 to –1.1). The kimberlite containing large diamonds has the smallest Fe3+ content and lowest fo2 (NNO –5.2 to –3.0). The barren and mid-grade kimberlites display a wide range of fo2,(NNO –5.3 to –1.5) as a result of perovskites forming in different melts and subsequently mixing together. Chemical and petrological evidence suggests that the volatile content, degassing, decompression and rate of crystallization can influence the rate at which the magma is erupted. One possibility is that the most oxidized magma, containing the highest volatile content, is therefore erupted much more rapidly, preserving diamond as a consequence.

It has been suggested that individuals might be more readily colonized with bacteria that cause meningitis through enhanced binding of the bacteria to virusinfected epithelial cells. As respiratory syncytial virus (RSV) affects infants and children in the age group also susceptible to bacterial meningitis, we tested the hypothesis that infection of HEp-2 cells by RSV might enhance binding of Neisseria meningitidis or Haemophilus influenzae type b (Hib). Attachment of fluorescein-labelled bacteria to HEp-2 cells was measured by flow cytometry, and RSV-infected cells bound significantly more meningococci (P < 0·001) and Hib (P < 0·01) than uninfected cells. Although the isolates expressed different antigenic characteristics (3 meningococci and 5 Hib), all showed a similar pattern of binding. The results are discussed with reference to the methods used for detection of bacterial binding and to interactions that might explain the increased binding to RSV-infected cells.

Surface antigens of three stages of three species of the filarial nematode genus Brugia have been analysed by radio-iodination and immunoprecipitation. These surface antigens have been shown to be characteristic for each stage by polyacrylamide gel electrophoresis. For example, infective larvae and adult worms have relatively complex patterns while microfilariae have few bands which are not found when other stages are radio-isotope labelled by the same technique. The surface antigens of Brugia malayi, B. timori and B. pahangi adult worms are all closely homologous, as are the surface antigens of infective larvae of the same three species, and of microfilariae of B. malayi and B. pahangi. Immunoprecipitation revealed that antibody raised in mice against one stage or species reacted with surface antigens from other stages and species. For example, sera raised against B. pahangi male adults reacted strongly with surface antigens from all three species. This cross-reactivity was dominant despite the apparent stage-specificity of the surface pattern seen on SDS-PAGE analysis. Moreover, in cross-immunization experiments, infective larvae were able to stimulate a secondary antibody response in mice previously primed with microfilarial surface antigens. The major microfilarial surface antigens (of mol. wt 65−70000 Daltons) were recognized by serum antibody from microfilariae-, infective larvae- or adult-infected animals. Thus, although the dominant antigens from each stage are of different molecular weight, cross-reactions with stage-specific antisera suggest that there must be shared epitopes on Brugia surface antigens from each stage. Such shared antigenic determinants dominate the immune response, although other evidence, including the differences in molecular weight, indicates the existence of stage-and species-specific components.

In rats treated with compound 48/80 or histamine, worm expulsion was inhibited. Treatment with a histidine decarboxylase inhibitor accelerated worm expulsion. Treatment with compound 48/80 elevates histamine and histidine decarboxylase levels and reduces circulating reagin titres. These results show that histamine is not responsible for worm expulsion.

Compounds such as isoprenaline and theophylline which increase cellular levels of cyclic 3′,5-AMP, prevented worm expulsion.

It is concluded that the evidence that amines are involved in worm expulsion needs reassessing and that cellular release mechanisms in general may be affected by drugs thought to act solely on amine release. In particular, the release of effector substances from sensitized lymphocytes on contact with antigen may be affected by these treatments.

The skilful technical assistance of Miss R. Keist and Miss I. Beeger is gratefully acknowledged. We thank Mr H. Berchtold, Biostatistisches Zentrum der Universität Zürich, for the statistical evaluation of the data.

When adult Nippostrongylus brasiliensis were maintained in vitro they became damaged. Using the criteria of ultrastructural morphology, acetylcholinesterase isoenzyme pattern and the behaviour of the worms after transfer to a normal rat, this damage appeared to be similar to that produced by the in vivo action of antibodies.

Antibodies were shown to be responsible for the anterior migration of adult worms which occurs during primary infections in mature rats and in the prolonged infections seen in lactating and immature rats.

Antibody damaged worms and worms unaffected by antibodies were equally able to stimulate the immune response required for worm expulsion. Apparently antibody damage is not required for the initiation of the second immune component necessary for expulsion of this parasite.

Adult Onchocerca volvulus worms obtained by enzyme digestion from nodules of infected Mexicans were radio-isotope labelled by the chloramine-T or Bolton–Hunter methods. No antigenic determinants were detected in extracts of worms labelled by the chloramine-T method but 3 antigens were detected in extracts of the Bolton–Hunter labelled worms. Two were present in such small amounts that it was impractical to investigate them further, but a major component of mol. wt 20 kDa was purified by gel filtration and used in a serological survey of inhabitants of villages in Southern Mexico. Using the 20 kDa antigen, which is superficially located on both sexes of O. volvulus, sera from both non-endemic and endemic regions were analysed by radio-immunoprecipitation of this antigen. In Southern Mexico, the average sensitivity of the test was 92%, and the specificity 98%. Whilst the 20 kDa antigen did not detect antibodies in the sera of Trinidadians infected with Wuncheria bancrofti or Mansonella ozzardi, this antigen detected high levels of antibodies in Indians exposed to W. bancrofti.