Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the “valley of death” by bridging basic to clinical sciences.

Purpose of ReviewMore than a century of hard rock mining has left a legacy of >160,000 abandoned mines in the Western USA that are home to the majority of Native American lands. This article describes how abrogation of treaty rights, ineffective policies, lack of infrastructure, and a lack of research in Native communities converge to create chronic exposure, ill-defined risks, and tribal health concerns.Recent FindingsRecent results show that Native Americans living near abandoned uranium mines have an increased likelihood for kidney disease and hypertension, and an increased likelihood of developing multiple chronic diseases linked to their proximity to the mine waste and activities bringing them in contact with the waste. Biomonitoring confirms higher than expected exposure to uranium and associated metals in the waste in adults, neonates, and children in these communities.SummaryThese sites will not be cleaned up for many generations making it critical to understand and prioritize exposure-toxicity relationships in Native populations to appropriately allocate limited resources to protect health. Recent initiatives, in partnership with Native communities, recognize these needs and support development of tribal research capacity to ensure that research respectful of tribal culture and policies can address concerns in the future. In addition, recognition of the risks posed by these abandoned sites should inform policy change to protect community health in the future.

SUMMARY

GRAIL (gene related to anergy in lymphocytes) is an ubiquitin-protein isopeptide ligase (E3) ubiquitin ligase necessary for the induction of CD4؉ T cell anergy in vivo. We have extended our previous studies to characterize the expression pattern of GRAIL in other murine CD4؉ T cell types with a described anergic phenotype. These studies revealed that GRAIL expression is increased in naturally occurring (thymically derived) CD4 ؉ CD25 ؉ T regulatory cells (mRNA levels 10-fold higher than naive CD25 ؊ T cells). Further investigation demonstrated that CD25؉ Foxp3 ؉ antigen-specific T cells were induced after a "tolerizing-administration" of antigen and that GRAIL expression correlated with the CD25 ؉ Foxp3 ؉ antigenspecific subset. Lastly, using retroviral transduction, we demonstrated that forced expression of GRAIL in a T cell line was sufficient for conversion of these cells to a regulatory phenotype in the absence of detectable Foxp3. These data demonstrate that GRAIL is differentially expressed in naturally occurring and peripherally induced CD25؉ T regulatory cells and that the expression of GRAIL is linked to their functional regulatory activity. CD4ϩ CD25 ϩ T cells, which comprise from 5 to 10% of peripheral blood CD4 ϩ T cells in normal adult mice and humans, are a subset of regulatory CD4 ϩ T cells (CD25 ϩ Tregs can be induced by antigen exposure in a non-inflammatory context and play an essential role in modulating adaptive immune responses, and clearly defining the similarities and differences between naturally occurring and induced CD25ϩ Treg cells is a high priority for making inroads into potential therapeutics for multiple disease states (6 -8).Characterization of cells with intrinsic anergic properties (termed recessive tolerance) was formally undertaken in the late 1980s after the Schwartz laboratory described a model system in vitro for induction of anergic T cell clones that, following engagement of their T cell receptor, required new protein and mRNA synthesis (reviewed in Ref. 9). This model system has led to numerous studies to identify "anergy factors." Our published work using this in vitro T cell anergy paradigm demonstrated the expression of a novel E3 ubiquitin ligase GRAIL, in T cell clones under anergy-inducing conditions (10). The development of immune unresponsiveness in vivo to neoantigens predates the development of the in vitro T cell clone model by over 20 years (11). An intriguing observation in the early 1970s suggested that there is development de novo of a suppressor population when neoantigen is presented in a non-inflammatory context. Our recent published work demonstrated a correlation between CD4 ϩ T cell anergy in vitro and in vivo and GRAIL expression (12) that is complemented by studies from Heissmeyer et al. (13). These findings, coupled with several recent reports demonstrating an induction of CD25 ϩ Treg cells in vivo after antigen presentation to naive CD4 ϩ T cells in a tolerizing fashion, led us to pursue the role of GRAIL-and antigen-induced tolerance in vivo (6...

Background Residents of aged care facilities usually have a large number of oral health problems. Residents who suffer from dementia are at particular risk. A systematic review of the best available evidence with regard to maintaining the oral health of older people with dementia in residential aged care facilities provided a number of recommendations.