5,327 research outputs found
Radioimmunotherapy of non-hodgkin's lymphoma
No full textThe work described in this thesis has focused on clarifying some of the important determinants and mechanisms of effective RIT of syngeneic B-cell lymphoma, both in vivo and in vitro. A successful animal model of RIT in B cell lymphomas was established by initially generating a panel of antibodies against mouse B cell antigens. The in vitro characteristics of these antibodies have been compared with their subsequent performance, in biodistribution studies and RIT in vivo. For the first time in an in vivo model the relative contributions of antibody and irradiation are described. Some antibodies including anti-MHC Class II were shown to be effective delivery vehicles of low doses of Iondine-131. These antibodies, which appear to be inactive delivery vehicles can cure animals with low burdens of tumour. However antibodies such as anti-idiotype and anti-CD40 which are active as "naked" antibodies are required to eradicate larger tumour burdens and to cure animals. For anti-idiotype antibodies the antibody and irradiation were shown to have an additive effect in vitro and in vivo in increasing the amount of tumour apoptosis. This increased therapeutic efficacy translated into animals with large tumour burdens being cured. These results strongly imply that RIT is much more than targeted irradiation and suggest potential mechanisms for the successes in the clinic.During the course of this work a new in vivo and in vitro variant of the BCL1 tumour was isolated Π-BCL1. In contrast to the BCL1 tumour this variant establishes as a syngeneic nodular lymphoma in vivo and grows in free suspension in vitro. This tumour model has provided a useful tool to investigate the induction of apoptosis both in vitro and in vivo.Finally apoptosis induced by irradiation and antibody were investigated in murine and human lymphoma cells in vitro. The murine radiosensitive B- and T-cell lymphomas were demonstrated to induce large amounts of early apoptosis within 24 hours.</p
Nuclear envelope-limited chromatin sheets are part of mitotic death
No full textNuclear envelope-limited chromatin sheets (ELCS) are enigmatic membranous structures of uncertain function. This study describes the induction of ELCS in p53 mutated Burkitt's lymphoma cell lines after treatment with irradiation or the microtubule inhibitor, SK&F 96365. Both treatments evoked similar mitotic death, involving metaphase arrest followed by extensive endopolyploidisation and delayed apoptosis, although the kinetics were different. We found that induction of ELCS and nuclear segmentation correlated with the amount and kinetics of M-phase arrest, mitosis restitution and delayed apoptosis of endopolyploid cells. In metaphases undergoing restitution, ELCS are seen participating in the restoration of the nuclear envelope, mediating the attachment of peripheral chromatin to it. In interphase cells, ELCS join nuclear segments, ectopically linking and fusing with heterochromatin regions. In cells with segmented nuclei, continued DNA replication was observed, along with activation and redistribution of Ku70, suggestive of non-homologous DNA end-joining. Induction of ELCS also parallels the induction of cytoplasmic stacked membrane structures, such as confronting cisternae and annulate lamellae, which participate in the turnover and degeneration of ELCS. The results suggest that arrest at a spindle checkpoint and the uncoupling of mitosis from DNA replication lead to the emergence of ELCS in the resulting endopolyploid cells
Cyclophosphamide inhibition of anti-CD40 monoclonal antibody-based therapy of B cell lymphoma is dependent on CD11b+ cells
No full textMonoclonal antibody (mAb)–based immunotherapy is now established as an important option for treating some cancers. The antitumor effects may be further enhanced by combining mAb with conventional chemotherapy. Certain novel immunomodulatory mAbs such as anti-CD40 have shown significant activity in preclinical models. We therefore assessed the efficacy of combining anti-CD40 mAb, known to elicit CTL responses against murine lymphoma models with the commonly used cytotoxic drug, cyclophosphamide. Using the syngeneic tumor model, BCL1, we have shown that timing of cyclophosphamide relative to mAb is critical to therapeutic outcome. Pretreatment with cyclophosphamide 7 to 10 days prior to mAb results in markedly reduced survival levels, similar to that achieved with cyclophosphamide alone. Conversely, when anti-CD40 is given before cyclophosphamide, the level of tumor protection was moderately increased. In vivo tracking experiments reveal that pretreatment with cyclophosphamide leads to diminished CTL expansion, as well as an increased number of CD11b+ cells that display an activated phenotype. These latter cells are able to inhibit T-cell proliferation, at least in part via production of nitric oxide, but do not induce T-cell apoptosis. Furthermore, adoptive transfer of the induced CD11b+ cells is sufficient to inhibit anti-CD40 therapy in tumor-bearing recipients. We have shown that the timing of cyclophosphamide relative to mAb administration is critical to the therapeutic outcome, and although the combination can improve survival, cyclophosphamide given prior to immunotherapy may generate a population of myeloid cells that can interfere with CTL responses and compromise the therapeutic outcome
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Anti-CD40 monoclonal antibody therapy in combination with irradiation results in a CD8 T-cell-dependent immunity to B-cell lymphoma
No full textThe mechanisms of interaction between anti-CD40 monoclonal antibody (mAb) therapy and external beam irradiation were investigated in 2 syngeneic B-cell lymphoma models. We have established doses of anti-CD40 mAb and irradiation which, although ineffective when given singly, were capable of providing long-term protection when used in combination. Furthermore, such treatment was not only critically dependent on the dose of mAb and irradiation but also on tumor load, with greater efficacy only occurring at higher tumor burden. Using blocking antibody, the potency of treatment was shown to be totally dependent on CD8+ T cells, with protective levels of CD8+ cells occurring only in mice receiving the combination of anti-CD40 and irradiation. Interestingly, the ratio of T cells (CD8+) to tumor cells in mice receiving combination treatment was between 10 and 15 times that seen in animals given anti-CD40 or irradiation alone. In vivo tracking experiments revealed a 2-phase decrease in tumor burden, the first resulting directly from the external irradiation and the second, occurring 5 days later, concomitant with the rise in tumor-specific CD8+ cells. We suggest that the external irradiation induced an initial kill of lymphoma cells, probably by apoptosis, which releases tumor antigens and slows the progression of the malignancy to allow generation of a curative cytotoxic T lymphocyte (CTL) response promoted by the anti-CD40 mAb. Combining irradiation with immunomodulatory mAb as described here appears to provide a powerful new approach to the management of cancer.<br/
Upregulation of meiosis-specific genes in lymphoma cell lines following genotoxic insult and induction of mitotic catastrophe
Full text linkBackgroundWe have previously reported that p53 mutated radioresistant lymphoma cell lines undergo mitotic catastrophe after irradiation, resulting in metaphase arrest and the generation of endopolyploid cells. A proportion of these endopolyploid cells then undergo a process of de-polyploidisation, stages of which are partially reminiscent of meiotic prophase. Furthermore, expression of meiosis-specific proteins of the cancer/testis antigens group of genes has previously been reported in tumours. We therefore investigated whether expression of meiosis-specific genes was associated with the polyploidy response in our tumour model.MethodsThree lymphoma cell lines, Namalwa, WI-L2-NS and TK6, of varying p53 status were exposed to a single 10 Gy dose of gamma radiation and their responses assessed over an extended time course. DNA flow cytometry and mitotic counts were used to assess the kinetics and extent of polyploidisation and mitotic progression. Expression of meiotic genes was analysed using RT-PCR and western blotting. In addition, localisation of the meiotic cohesin REC8 and its relation to centromeres was analysed by immunofluorescence.ResultsThe principal meiotic regulator MOS was found to be significantly post-transcriptionally up-regulated after irradiation in p53 mutated but not p53 wild-type lymphoma cells. The maximum expression of MOS coincided with the maximal fraction of metaphase arrested cells and was directly proportional to both the extent of the arrest and the number of endopolyploid cells that subsequently emerged. The meiotic cohesin REC8 was also found to be up-regulated after irradiation, linking sister chromatid centromeres in the metaphase-arrested and subsequent giant cells. Finally, RT-PCR revealed expression of the meiosis-prophase genes, DMC1, STAG3, SYCP3 and SYCP1.ConclusionWe conclude that multiple meiotic genes are aberrantly activated during mitotic catastrophe in p53 mutated lymphoma cells after irradiation. Furthermore, we suggest that the coordinated expression of MOS and REC8 regulate the extent of arrested mitoses and polyploidy
Money piece by Timothy P. Agnew, chief executive officer of the Finance Author
No full textMoney piece by Timothy P. Agnew, chief executive officer of the Finance Authority of Maine, about the increased availability of credit for Maine\u27s small businesses
Endopolyploid cells produced after severe genotoxic damage have the potential to repair DNA double strand breaks
No full textp53 mutant tumour cells respond to genotoxic insults by bypassing G1 arrest and halting in G2. Following release from G2 arrest they undergo mitotic catastrophe, whereby mitotic cycling is suppressed, delayed apoptosis begins and endopolyploid cells are produced. The ability of these endopolyploid cells to participate in the restitution process is controversial. To facilitate recovery, these endopolyploid cells must repair the extensive DNA damage induced. DNA damage and its resolution were studied by observing the kinetics of {gamma}-H2AX foci formation and by comet assay analysis. Subsequently, the kinetics and distribution of Rad51 foci were studied as a measure of homologous recombination. Here we present evidence of the resolution of DNA damage in endopolyploid cells through a decrease of tail moment by comet assay and in the number of cells expressing {gamma}-H2AX foci. Rad51 foci expression reached a maximum in endopolyploid cells on days 5-6 after irradiation, when delayed apoptosis was maximal, indicating that cells were being selected for survival at this time. Furthermore, the proportion of Annexin-V-positive polyploid cells decreased as they continued ongoing rounds of DNA replication, suggesting endoreduplication is involved in selecting cells resistant to apoptosis. Our findings suggest that after severe genotoxic insult endopolyploid cells have a transient survival advantage that may contribute to radioresistance of tumours that undergo mitotic catastrophe
The management of primary mediastinal B-cell lymphoma: a British Society for Haematology Good Practice Paper
No full textThis Good Practice Paper was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines. The BSH produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org and is also detailed in Table 1
Timothy Meyer serves as a contributing author for UN report
No full textAssistant Professor Timothy Meyer served as a contributing author for the United Nations Industrial Development Organization\u27s report titled Networks for Prosperity: Connecting Development Knowledge Beyond 2015. The document, which was released during November, analyzes the nexus between the global connectedness of a country and its economic success, sustainability and government effectiveness. Meyer was one of only approximately 20 academic and practical experts from around the world selected to serve as a contributor after a global call for proposals.
Learn more View the full repor
- …
