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Some minor histocompatibility antigens (mHags) are expressed exclusively on patient hematopoietic and malignant cells, and this unique set of antigens enables specific targeting of hematological malignancies after human histocompatability leucocyte antigen (HLA) – matched allogeneic stem cell transplantation (allo-SCT). We report the fi rst hematopoietic mHag presented by HLA class II (HLA-DQA1*05/B1*02) molecules to CD4 + T cells. This antigen is encoded by a single-nucleotide polymorphism (SNP) in the B cell lineagespecifi c CD19 gene, which is an important target antigen for immunotherapy of most B cell malignancies. The CD19 L -encoded antigen was identifi ed using a novel and powerful genetic strategy in which zygosity-genotype correlation scanning was used as the key step for fi ne mapping the genetic locus defi ned by pairwise l...
With great interest, we have read the article by Beers et al1 documenting a potent B-cell depleting ability for type II (or tositumumab-like) CD20 antibodies. The authors conclude that complement-dependent cytotoxicity (CDC) is of little importance for B-cell depletion induced not only by type II, but also by type I (or rituximab-like) CD20 antibodies. Unfortunately, the experimental design chosen by Beers et al does not allow such a conclusion, and the data in our view appear to suggest the reverse.
Therapeutic monoclonal antibodies against the epidermal growth factor receptor (EGFR) have advanced the treatment of colon and head and neck cancer, and show great promise for the development of treatments for other solid cancers. Antibodies against EGFR have been shown to act via inhibition of receptor signaling and induction of antibody-dependent cellular cytoxicity. However, complement-dependent cytotoxicity, which is considered one of the most powerful cell killing mechanisms of antibodies, seems inactive for such antibodies. Here, we show a remarkable synergy for EGFR antibodies. Combinations of antibodies against EGFR were identified, which resulted in potent complement activation via the classic pathwayand effective lysis of tumor cells. Studies on a large panel of antibodies indicated that the observed synergy is a general mech...
The epidermal growth factor receptor (EGFR) serves as a molecular target for novel cancer therapeutics such as tyrosine kinase inhibitors (TKI) and EGFR Abs. Recently, specific mutations in the EGFR kinase domain of lung cancers were identified, which altered the signaling capacity of the receptor and which correlated with clinical response or resistance to TKI therapy. In the present study, we investigated the impact of such EGFR mutations on antitumor cell activity of EGFR Abs. Thus, an EGFR-responsive cell line model was established, in which cells with tumor-derived EGFR mutations (L858R, G719S, delE746-A750) were significantly more sensitive to TKI than wild-type EGFR-expressing cells. A clinically relevant secondary mutation (T790M) abolished TKI sensitivity. Significantly, antitumor effects of EGFR Abs, including signaling and g...
The human leukocyte antigen (HLA) B57 allele and the closely related HLA-B5801 allele are overrepresented among human immunodeficiency virus type 1 (HIV-1)–infected individuals with a long-term nonprogressive clinical course of disease (known as “long-term nonprogressors” [LTNPs]). These alleles are, however, also present among individuals with normal disease progression (known as “progressors”). In a comparison of HLAB57/ 5801–expressing progressors and LTNPs, we observed a similar prevalence of escape mutations in 4 Nef epitopes and a similar reactivity of CD8+ T cells against 3 of 4 of these epitopes and their autologous escape variants. However, LTNPs tended to have frequent and preserved CD8+ T cell interferon- responses against the wild-typeHW9Nef epitope, whereas progressors did not maintain a specific CD8+ T cell response. Thi...
The aims of this thesis were, first, to investigate the toxicities associated with trans-arterial chemoembolization (TACE) of liver tumors and to evaluate the use of MR imaging in characterizing tumor response after this locoregional therapy, second, to further develop intra-arterial therapy of liver tumors with 3-bromopyruvate (3-BrPA), a novel anti-cancer agent, and finally, to assess the value of new MR imaging techniques in the characterization of liver lesions. In Chapter 1, the general introduction, an overview of these aims and an outline of the thesis are presented.
the present thesis I have described how we investigated some of the neural phenomena that generate these deficits. By focusing on the neural basis of social perception, and paying particular attention to the amygdala, we were able to demonstrate that abnormalities in amygdala function are likely to contribute to the social cognitive deficits that are often observed in patients with schizophrenia. Furthermore, the inclusion of unaffected siblings of patients enabled us to demonstrate that siblings, like their affected family members, display abnormalities in social perception, although the severity of these symptoms is reduced compared to those observed in patients. Finally, the combined use of genetic and functional neuroimaging techniques revealed that variation in the serotonin transporter linked polymorphic region (5-HTTLPR) influen...
Based on the results of the studies presented in this thesis it is concluded that minimally invasive surgical treatment of acute AT ruptures with functional after-treatment allows patients to return to their original level of their professional and athletic activities and should be regarded best treatment until otherwise proven. Conservative treatment by functional bracing might still be a potentially valuable alternative, but our studies failed to prove so, mainly because of a higher complication risk. More clinical trials with large statistical power and of rigorous methodology are needed to identify best management of acute Achilles tendon ruptures. Re-rupture and severe wound infection should be included as important outcome measure. Routine use of thromboprophylaxis is not warranted in patients with temporary below-knee immobiliza...
Despite the fact that 11 SCA genes have already been identified, 30% of the ADCA families still remain undiagnosed. These so-called “SCA-negative” Dutch families are the basis of this research. The aim of this project was to collect genetic material from these Dutch families and to localize and identify novel SCA genes that cause ADCA. Linkage analysis was used to localize the disease-genes in two large Dutch ADCA families, in whom no mutations had been identified in the known SCA genes. After exclusion of the already identified SCA loci with two-point lod scores < -2, we performed genomewide screens and identified two additional SCA loci in the Dutch ADCA population, SCA19 (Chapter 2) and SCA23 (Chapter 3), respectively. However, the majority of the SCA-negative families are too small for traditional linkage analysis and an alternativ...
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