NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation: Report from the Committee on Prevention of Relapse Following Allogeneic Cell Transplantation for Hematologic Malignancies

Prevention of relapse after allogeneic hematopoietic stem cell transplantation is the most likely approach to improve survival of patients treated for hematologic malignancies. Herein we review the limits of currently available transplant therapies and the innovative strategies being developed to overcome resistance to therapy or to fill therapeutic modalities not currently available. These novel strategies include nonimmunologic therapies, such as targeted preparative regimens and posttransplant drug therapy, as well as immunologic interventions, including graft engineering, donor lymphocyte infusions, T cell engineering, vaccination, and dendritic cell-based approaches. Several aspects of the biology of the malignant cells as well as the host have been identified that obviate success of even these newer strategies. To maximize the potential for success, we recommend pursuing research to develop additional targeted therapies to be used in the preparative regimen or as maintenance posttransplant, better characterize the T cell and dendritic cells subsets involved in graft-versus-host disease and the graft-versus-leukemia/tumor effect, identify strategies for timing immunologic or nonimmunologic therapies to eliminate the noncycling cancer stem cell, identify more targets for immunotherapies, develop new vaccines that will not be limited by HLA, and develop methods to identify populations at very high risk for relapse to accelerate clinical development and avoid toxicity in patients not at risk for relapse

IL10 and IL10 receptor gene variation and outcomes after unrelated and related hematopoietic cell transplantation.

BACKGROUND: Results of a previous study with human leukocyte antigen (HLA)-identical siblings showed individual and synergistic associations of single nucleotide polymorphisms in the promoter region of the recipient's IL10 gene and the donor's IL10 receptor beta (IL-10RB) gene with development of grades III-IV acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. METHODS: In this study of 936 patients who had unrelated donors, genotypes of single nucleotide polymorphisms in the IL10 gene and the IL-10RB gene were evaluated as correlates with outcomes after transplantation. RESULTS: We found no statistically significant associations of polymorphisms at positions -3575, -2763, -1082, and -592 of the IL10 gene or codon 238 of the IL10RB gene with severe acute GVHD, extensive chronic GVHD or nonrelapse mortality after hematopoietic cell transplantation. Among HLA-matched unrelated pairs, the patient's IL10/-592 genotype and donor's IL10RB/c238 genotype showed trends suggesting individual and combined associations with grades III-IV acute GVHD similar to those observed among patients with HLA-identical sibling donors. CONCLUSIONS: Although genetic variation in IL10 pathway affects risk of acute GVHD and non-relapse mortality in HLA-identical sibling transplants, the current results indicate that genetic variation in the IL10 pathway does not significant affect these outcomes in unrelated donor transplants suggesting that the strength of the alloimmune response in the latter exceeds the anti-inflammatory activity of IL10

Both loved and feared: third party punishers are viewed as formidable and likeable, but these reputational benefits may only be open to dominant individuals

Journal ArticleResearch Support, Non-U.S. Gov'tCopyright: © 2014 Gordon et al.The datasets associated with this article are available in ORE at http://hdl.handle.net/10871/15639Third party punishment can be evolutionarily stable if there is heterogeneity in the cost of punishment or if punishers receive a reputational benefit from their actions. A dominant position might allow some individuals to punish at a lower cost than others and by doing so access these reputational benefits. Three vignette-based studies measured participants' judgements of a third party punisher in comparison to those exhibiting other aggressive/dominant behaviours (Study 1), when there was variation in the success of punishment (Study 2), and variation in the status of the punisher and the type of punishment used (Study 3). Third party punishers were judged to be more likeable than (but equally dominant as) those who engaged in other types of dominant behaviour (Study 1), were judged to be equally likeable and dominant whether their intervention succeeded or failed (Study 2), and participants believed that only a dominant punisher could intervene successfully (regardless of whether punishment was violent or non-violent) and that subordinate punishers would face a higher risk of retaliation (Study 3). The results suggest that dominance can dramatically reduce the cost of punishment, and that while individuals can gain a great deal of reputational benefit from engaging in third party punishment, these benefits are only open to dominant individuals. Taking the status of punishers into account may therefore help explain the evolution of third party punishment.School of Psychology, University of Exete

Entrepreneurs’ mental health and well-being:A review and research agenda

Interest in entrepreneurs’ mental health and well-being (MWB) is growing in recognition of the role of MWB in entrepreneurs’ decision making, motivation, and action. Yet relevant knowledge is dispersed across disciplines, which makes what we currently understand about entrepreneurs’ MWB unclear. In this systematic review I integrate insights from 144 empirical studies. These studies show that research is focused on three research questions: (1) Do different types of entrepreneurs differ in their MWB? What are the (2) antecedents and (3) consequences of entrepreneurs’ MWB? The review systematizes evidence on known antecedents and consequences of entrepreneurs’ MWB but also reveals overlooked and undertheorized sources and outcomes of entrepreneurs’ MWB. The review provides a mapping and framework that advance research on entrepreneurs’ MWB and help to position entrepreneurs’ MWB more centrally in management and entrepreneurship research. It calls for researchers to go beyond applying models developed for employees to understand entrepreneurs. Instead, the findings point the way to developing a dedicated theory of entrepreneurial work and MWB that is dynamic, socialized, and open to considering context and acknowledges variability and fluidity across entrepreneurs’ life domains, as well as the centrality of work for entrepreneurs’ identity

History of clinical transplantation

How transplantation came to be a clinical discipline can be pieced together by perusing two volumes of reminiscences collected by Paul I. Terasaki in 1991-1992 from many of the persons who were directly involved. One volume was devoted to the discovery of the major histocompatibility complex (MHC), with particular reference to the human leukocyte antigens (HLAs) that are widely used today for tissue matching.1 The other focused on milestones in the development of clinical transplantation.2 All the contributions described in both volumes can be traced back in one way or other to the demonstration in the mid-1940s by Peter Brian Medawar that the rejection of allografts is an immunological phenomenon.3,4 © 2008 Springer New York

History of clinical transplantation

The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations is surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipient had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts

Stress Processes: An Essential Ingredient in the Entrepreneurial Process

The entrepreneurial process is associated with high uncertainty. Uncertainty is also a major source of stress. Therefore, a core aim of entrepreneurs is to reduce uncertainty to an extent that allows the entrepreneurial process to unfold. However, entrepreneurship scholars have insufficiently addressed stress processes that may be associated with this uncertainty. We argue that uncertainty is the concept connecting both the entrepreneurial and stress processes. We discuss the link between the two processes regarding: (1) opportunity recognition, (2) opportunity exploitation, and (3) associated outcomes. We then illustrate how future research should incorporate the interaction between the two processes using a morphological box and discuss how such research would change the way we specify entrepreneurial process models and study entrepreneurial behavior