Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.

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The term 'therapeutic landscapes' was first coined by health geographer, Wilbert Gesler, in 1992 to explore why certain environments seem to contribute to a healing sense of place. Since then, the concept and its applications have evolved and expanded as researchers have examined the dynamic material, affective and socio-cultural roots and routes to experiences of health and wellbeing in specific places. Drawing on a scoping review of studies of these wider therapeutic landscapes published between 2007 and 2016, this paper explores how, where, and to what benefit the 'therapeutic landscapes' concept has been applied to date, and how such applications have contributed to its critical evolution as a relevant and useful concept in health geography. Building on themes included in two earlier (1999, 2007) edited volumes on Therapeutic Landscapes, we summarise the key themes identified in the review, broadly in keeping with the core material, social, spiritual and symbolic dimensions of the concept initially posited by Gesler. Through this process, we identify strengths and limitations of the concept and its applications, as well as knowledge gaps and promising future directions for work in this field, reflecting critically on its value within health geography and its potential contribution to wider interdisciplinary discussions and debates around 'healthy' spaces, places, and related practices.

We have proposed previously that hemopoietic myeloid progenitors contribute to the ongoing recruitment of proinflammatory cells, namely eosinophils, to sites of allergen challenge in allergic diseases such as asthma. In this study, we investigated the involvement of bone marrow-derived progenitors in the development of allergen-induced pulmonary inflammation in mild asthmatic subjects. By flow cytometry, we enumerated the level of expression of CD34, a hemopoietic progenitor cell marker, on bone marrow aspirates taken before and 24 h after allergen challenge. In addition, the coexpression of the ␣ -subunits of IL-3 receptor (IL-3R) and IL-5 receptor (IL-5R) on CD34 ϩ cells was investigated. After allergen-challenge, although no significant change in total BM CD34 ϩ cell numbers was observed, a significant increase in the proportion of CD34 ϩ cells expressing IL-5R ␣ , but not IL-3R ␣ , was detected in the 24-h post-allergen, compared with the pre-allergen bone marrow. This was associated with a significant blood and sputum eosinophilia and increased methacholine airway responsiveness, 24 h post-allergen. Using simultaneous in situ hybridization and immunocytochemistry, we colocalized the expression of messenger RNA for membrane-bound IL-5R ␣ to CD34 ϩ cells. In summary, our data suggest that increased expression of IL-5R ␣ on CD34 ϩ cells favors eosinophilopoiesis and may thus contribute to the subsequent development of blood and tissue eosinophilia, a hallmark of allergic inflammation. ( J. Clin. Invest. 1997. 100:2466-2475.)

There is an urgent need to develop new tuberculosis (TB) vaccines to safely and effectively boost Bacille Calmette-Guérin (BCG)-triggered T cell immunity in humans. AdHu5Ag85A is a recombinant human type 5 adenovirus (AdHu5)-based TB vaccine with demonstrated efficacy in a number of animal species, yet it remains to be translated to human applications. In this phase 1 study, we evaluated the safety and immunogenicity of AdHu5Ag85A in both BCG-naïve and previously BCG-immunized healthy adults. Intramuscular immunization of AdHu5Ag85A was safe and well tolerated in both trial volunteer groups. Moreover, although AdHu5Ag85A was immunogenic in both trial volunteer groups, it much more potently boosted polyfunctional CD4(+) and CD8(+) T cell immunity in previously BCG-vaccinated volunteers. Furthermore, despite prevalent preexisting anti-AdHu5 humoral immunity in most of the trial volunteers, we found little evidence that such preexisting anti-AdHu5 immunity significantly dampened the potency of AdHu5Ag85A vaccine. This study supports further clinical investigations of the AdHu5Ag85A vaccine for human applications. It also suggests that the widely perceived negative effect of preexisting anti-AdHu5 immunity may not be universally applied to all AdHu5-based vaccines against different types of human pathogens.