Minorhistocompatibility antigens (mHags) are molecular targets of alloimmunity associated with hematopoietic stem cell transplantation (HSCT) and involved in graft-versus-host disease, but they also have beneficial antitumor activity. mHags are typically defined by host SNPs that are not shared by the donor and are immunologically recognized by cytotoxic T cells isolated from post-HSCT patients. However, the number of molecularly identified mHags is still too small to allow prospective studies of their clinical importance in transplantation medicine, mostly due to the lack of an efficient method for isolation. Here we show that when combined with conventional immunologic assays, the large data set from the International HapMap Project can be directly used for genetic mapping of novel mHags. Based on the immunologically determined mHag status in HapMap panels, a target mHag locus can be uniquely mapped through whole genome association scanning taking advantage of the unprecedented resolution and power obtained with more than 3 000 000 markers. The feasibility of our approach could be supported by extensive simulations and further confirmed by actually isolating 2 novel mHags as well as 1 previously identified example. The HapMap data set represents an invaluable resource for investigating human variation, with obvious applications in genetic mapping of clinically relevant human traits. (Blood. 2009;113:5041-5048) IntroductionThe antitumor activity of allogeneic hematopoietic stem cell transplantation (HSCT), which is a curative treatment for many patients with hematologic malignancies, is mediated in part by immune responses that are elicited as a consequence of incompatibility in genetic polymorphisms between the donor and the recipient. 1,2 Analysis of patients treated for posttransplantation relapse with donor lymphocytes has shown tumor regression to be correlated with expansion of cytotoxic T lymphocytes (CTLs) specific for hematopoiesis-restricted minor histocompatibility antigens (mHags). 3,4 mHags are peptides, presented by major histocompatibility complex (MHC) molecules, derived from intracellular proteins that differ between donor and recipient due mostly to single nucleotide polymorphisms (SNPs) or copy number variations (CNVs). 1,2,5 Identification and characterization of mHags that are specifically expressed in hematopoietic but not in other normal tissues could contribute to graft-versus-leukemia/lymphoma (GVL) effects, while minimizing unfavorable graft-versus-host disease, one of the most serious complications of allo-HSCT. 1,2 Unfortunately, however, efforts to prospectively target mHags to invoke T cell-mediated selective GVL effects have been hampered by the scarcity of eligible mHags, largely due to the lack of efficient methods for mapping the relevant genetic loci. Several methods have been developed to identify mHags, including peptide elution from MHC, 6,7 cDNA expression cloning, 8,9 and linkage analysis. 3,10 We have recently reported a novel genetic method that combines whole genome as...

This study identifies important characteristics of a good death for children with cancer. These findings may help medical staffs provide optimal care for children with cancer and their families, enabling them to achieve a good death.

West syndrome (WS) is a generalized epileptic syndrome of infancy and early childhood with various etiologies, and consists of a triad of infantile spasm, arrest or regress of psychomotor development and specific electroencephalogram (EEG) pattern of hypsarrhythmia. WS had been believed to be refractory, but recent evidence supports effectiveness of adrenocorticotropic hormone (ACTH) treatment. The ACTH treatment, however, has a problem that it is often accompanied by adverse autonomic symptoms. We therefore examined heart rate variability (HRV) for assessing cardiac autonomic functions in WS and prospectively observed the changes during ACTH treatment. We studied 15 patients with WS and 9 age-matched controls during sleep (EEG stage 2). Compared with controls, the patients with WS were greater in the low-frequency component (LF) of HRV, an index reflecting sympatho-vagal interaction ( p = 0.02), but were comparable for high-frequency component (HF) and LF-to-HF ratio (LF/HF), indices reflecting cardiac vagal activity and sympathetic predominance, respectively. During ACTH treatment, heart rate decreased ( p < 0.01), LF and HF increased ( p < 0.01), and LF/HF did not differ significantly. These results indicate that West syndrome might be accompanied by autonomic changes and that ACTH treatment enhances parasympathetic function and causes bradycardia. West syndrome; ACTH; heart rate variability; bradycardia; autonomic function

The efficient isolation and ex vivo expansion of antigen-specific T cells are crucial for successful adoptive immunotherapy against uncontrollable infections and cancers. Several methods have been reported for this purpose, for example, employing MHC-multimeric complexes, interferon-gamma secretion, and antibodies specific for molecules expressed on T-cell surfaces, including CD25, CD69, CD107a, CD137, and CD154. Of the latter, CD137 has been shown to be one of the most promising targets since it is only expressed on CD8(+) T cells early after encountering antigen, while being almost undetectable on resting cells. However, detailed comparisons between CD137-based and other methods have not yet been conducted. In this study, we therefore compared three approaches (with CD137, CD107a, and tetramers) using HLA-A24-restricted CMV pp65 and EBV BRLF1 epitopes as model antigens. We found that the CD137-based isolation of antigen-stimulated CD8(+) T cells was comparable to tetramer-based sorting in terms of purity and superior to the other two methods in terms of subsequent cell expansion. The method was less applicable to CD4(+) T cells since their CD137 upregulation is not sufficiently high. Collectively, this approach is most likely to be optimal among the methods tested for the isolation and expansion of antigen-specific CD8(+) cells.