5,976 research outputs found
Microscopic intratumoral dosimetry of radiolabeled antibodies is a critical determinant of successful radioimmunotherapy in B-cell lymphoma
Full text linkRadioimmunotherapy is a highly effective treatment for some hematologic malignancies; however, the underlying mechanisms of tumor clearance remain poorly understood. We have previously shown that both targeted radiation using I-131-labeled anti-MHC class II (MHCII) monoclonal antibody (mAb) plus mAb signaling with unlabeled anti-idiotype are required for the long-term clearance of tumor in syngeneic murine lymphoma models. In this study, we have investigated how the microdistribution of the targeted radiation component of this combination affects the long-term clearance of lymphoma. I-131-labeled mAb targeting CD45 and MHCII antigens was found to deliver similar doses of radiation to tumor-bearing organ using conventional dosimetry (similar to 1.0 Gy per MBq when I-131 was labeled to 500 mu g mAb and given i.v. per mouse), but when used as radiation vectors in combination therapy only, I-131-anti-MHCII plus anti-idiotype produced long-term survival. The profound differences in therapy did not seem to be dependent on levels of I-131-mAb tumor-binding or antibody-dependent cytotoxicity. Instead, the microscopic intratumoral dosimetry seemed to be critical with the I-131-anti-MHCII, delivering more concentrated and therefore substantially higher radiation dose to tumor cells. When the administered activity of I-131-anti-CD45 was increased, a radiation dose response was shown in the presence of anti-idiotype and long-term survival was seen. We believe that these new insights should influence the selection of new antigen targets and the design of dosimetric methods in radioinimnnotherapy of lymphoma
Radiation therapy with tositumomab (B1) anti-CD20 monoclonal antibody initiates extracellular signal-regulated kinase/mitogen-activated protein kinase-dependent cell death that overcomes resistance to apoptosis
Full text linkPurpose: the use of targeted radiation therapy (RT) in conjunction with anti-CD20 monoclonal antibodies (mAb) delivers high clinical response rates in B-cell lymphomas as part of radioimmunotherapy. The mechanisms underlying these impressive responses, particularly in patients whose lymphomas have become refractory to chemotherapy, are poorly understood. Experimental design: in this study, we have investigated the signaling pathways and mode of cell death induced in B-cell lymphoma cells after the combination of RT and either type I (rituximab) or type II (tositumomab/B1) anti-CD20 mAb. Results: increased tumor cell death was observed when RT was combined with tositumomab, but not rituximab. This additive cell death was found to be mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)–dependent and could be reversed with mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors, as well as small interfering RNA targeting MEK1/2. Furthermore, we found that this increased death was associated with ERK1/2 nuclear accumulation after tositumomab treatment, which was enhanced in combination with RT. Importantly, although Bcl-2 overexpression resulted in resistance to RT-induced apoptosis, it had no effect on the tumor cell death induced by tositumomab plus RT, indicating a nonapoptotic form of cell death. Conclusions: these findings indicate that RT and type II anti-CD20 mAb combine to stimulate a prodeath function of the MEK-ERK1/2 pathway, which is able to overcome apoptotic resistance potentially explaining the efficacy of this modality in treating patients with chemoresistant disease
Treatment with the anti-CD20 antibody (B1) and irradiation result in synergistic cytotoxicity that is dependent on MAPK activation
No full textRadioimmunotherapy using radiolabeled anti-CD20 antibodies (mAb) is an effective new treatment in non-Hodgkin lymphoma with high response rates. However, the molecular mechanisms behind these impressive clinical responses are poorly understood. To elucidate these mechanisms we studied the signaling events evoked in a panel of lymphoma cell lines following treatment with anti-CD20 mAb alone or in combination with irradiation. In all three lymphoma cell-lines tested a synergistic cytotoxic effect was observed when the anti-CD20 mAb B1 was combined with irradiation. The additive effect seen with B1 mAb and radiation was not observed with Rituximab and could be reversed with MEK inhibitors U0126 and PD98059 as well as siRNA targeting MEK1 or 2. Moreover, addition of U0126 reversed the decrease in clonogenic survival triggered by treatment with B1 and irradiation. To further probe the mechanism of this synergistic cell death we used cell lines over-expressing BCL2 or crmA, to block mitochondrial and death receptor pathways, respectively. Although BCL2 and crmA over-expression mediated protection against radiation alone, it had no impact on the increased cytotoxicity induced by B1+irradiation. Morphological studies revealed gross vacuolization of the cytoplasm, yet relatively well preserved nuclei in cells treated with B1+irradiation. Taken together our data indicate that activation of the MAPK cascade is an important factor that contributes to the synergistic effect of anti-CD20 (B1) antibody and irradiation and provides important new insights into how this treatment may work in the clinic
Novel Methods to Improve the Efficiency of Radioimmunotherapy for Non-Hodgkin Lymphoma
No full textRadioimmunotherapy (RIT) is a novel strategy for treating non-Hodgkin lymphoma (NHL). Several studies have shown the promising results of using RIT in NHL, which have led to FDA approval for two RIT agents in treating low grade NHL. In spite of these favorable results in low-grade NHL, most of the aggressive or relapsed/refractory NHL subjects experience relapses following RIT. Although more aggressive treatments such as myeloablative doses of RIT followed by stem cell transplantation appear to be able to provide a longer survival for some patients these approaches are associated with significant treatment-related adverse events and challenging to deliver in most centers. Therefore, it seems reasonable to develop treatment approaches that enhance the efficiency of RIT, while reducing its toxicity. In this paper, novel methods that improve the efficiency of RIT and reduce its toxicity through various mechanisms are reviewed. Further clinical development of these methods could expand the NHL patient groups eligible for receiving RIT, and even extend the use of RIT to new indications and disease groups in future.</p
Do dolphins benefit from nonlinear mathematics when processing their sonar returns?
No full textAn interview with author Tim Leighton about the paper
Opportunities for linking young surveyors across professional surveying member organisations and FIG
No full textTim Di Muzio on 'Sabotage'
No full textIn a series of essays published in 2013 and 2014 on capitaspower.com, political economist Tim Di Muzio explored the concept of ‘sabotage’ as it applies to capitalist power. I recently rediscovered these essays and was so impressed by them that I have reposted them here as a single piece.
About the author: Tim Di Muzio is a researcher at the University of Wollongong. He is the author of numerous books, including Debt as power, Carbon capitalism, and The 1% and the Rest of us
1996-1997 Tim Gautreaux
No full textTim Gautreaux is the author of three novels and two earlier short story collections. His work has appeared in The New Yorker, The Best American Short Stories, The Atlantic, Harper’s, and GQ. After teaching for thirty years at Southeastern Louisiana University, he now lives, with his wife, in Chattanooga, Tennessee. (Photo credit: Randy Bergeron)https://egrove.olemiss.edu/grisham_res/1023/thumbnail.jp
Phase 3 trial of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients (pts) with CD30+mature T-cell lymphomas (MTCL)
No full textPhase III trial of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients (pts) with CD30+mature T-cell lymphomas (MTCL).
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