HOXA3 Modulates Injury-Induced Mobilization and Recruitment of Bone Marrow-Derived Cells

The regulated recruitment and differentiation of multipotent bone marrow-derived cells (BMDCs) to sites of injury are critical for efficient wound healing. Previously we demonstrated that sustained expression of HOXA3 both accelerated wound healing and promoted angiogenesis in diabetic mice. In this study, we have used green fluorescent protein-positive bone marrow chimeras to investigate the effect of HOXA3 expression on recruitment of BMDCs to wounds. We hypothesized that the enhanced neovascularization induced by HOXA3 is due to enhanced mobilization, recruitment, and/or differentiation of BMDCs. Here we show that diabetic mice treated with HOXA3 displayed a significant increase in both mobilization and recruitment of endothelial progenitor cells compared with control mice. Importantly, we also found that HOXA3-treated mice had significantly fewer inflammatory cells recruited to the wound compared with control mice. Microarray analyses of HOXA3-treated wounds revealed that indeed HOXA3 locally increased expression of genes that selectively promote stem/progenitor cell mobilization and recruitment while also suppressing expression of numerous members of the proinflammatory nuclear factor κB pathway, including myeloid differentiation primary response gene 88 and toll-interacting protein. Thus HOXA3 accelerates wound repair by mobilizing endothelial progenitor cells and attenuating the excessive inflammatory response of chronic wounds

Reduced Iron in Diabetic Wounds: An Oxidative Stress-Dependent Role for STEAP3 in Extracellular Matrix Deposition and Remodeling

Iron is crucial for maintaining normal bodily function with well-documented roles in erythropoiesis, hemostasis, and inflammation. Despite this, little is known about the temporal regulation of iron during wound healing, or how iron contributes to wound biology and pathology. In this study, we profiled tissue iron levels across a healing time-course, identifying iron accumulation during late-stage repair. Diabetic murine wounds displayed significantly reduced iron levels, delayed extracellular matrix deposition, and dysregulation of iron gene expression. In vitro studies revealed important cellular roles for iron, promoting both the deposition and remodeling of extracellular proteins. Functional studies identified oxidative stress-dependent upregulation of the iron-converting metalloreductase, STEAP3, as a key mediator of extracellular matrix production. Taken together, these data reveal a mechanistic role for iron in facilitating the remodeling stage of wound healing. Indeed, targeting tissue iron could be a promising future strategy to tackle the development and progression of chronic wounds

Effectiveness of insecticide-treated bednets in malaria prevention in Haiti: a case-control study

Background Insecticide-treated bednets (ITNs) are eff ective in preventing malaria where vectors primarily bite indoors and late at night, but their eff ectiveness is uncertain where vectors bite outdoors and earlier in the evening. We studied the eff ectiveness of ITNs following a mass distribution in Haiti from May to September, 2012, where the Anopheles albimanus vector bites primarily outdoors and often when people are awake. Methods In this case-control study, we enrolled febrile patients presenting to outpatient departments at 17 health facilities throughout Haiti from Sept 4, 2012, to Feb 27, 2014, who were tested with malaria rapid diagnostic tests (RDTs), and administered questionnaires on ITN use and other risk factors. Cases were defi ned by positive RDT and controls were febrile patients from the same clinic with a negative RDT. Our primary analysis retrospectively matched cases and controls by age, sex, location, and date, and used conditional logistic regression on the matched sample. A sensitivity analysis used propensity scores to match patients on ITN use propensity and analyse malaria among ITN users and non-users. Additional ITN bioeffi cacy and entomological data were collected. Findings We enrolled 9317 patients, including 378 (4%) RDT-positive cases. 1202 (13%) patients reported ITN use. Post-hoc matching of cases and controls yielded 362 cases and 1201 matched controls, 19% (333) of whom reported consistent campaign net use. After using propensity scores to match on consistent campaign ITN use, 2298 patients, including 138 (7%) RDT-positive cases, were included: 1149 consistent campaign ITN users and 1149 non-consistent campaign ITN users. Both analyses revealed that ITNs did not signifi cantly protect against clinical malaria (odds ratio [OR]=0·95, 95% CI 0·68–1·32, p=0·745 for case-control analysis; OR=0·95, 95% CI 0·45–1·97, p=0·884 for propensity score analysis). ITN and entomological data indicated good ITN physical integrity and bioeffi cacy, and no permethrin resistance among local mosquitoes. Interpretation We found no evidence that mass ITN campaigns reduce clinical malaria in this observational study in Haiti; alternative malaria control strategies should be prioritised

Large Scale Searches for Brown Dwarfs and Free-Floating Planets

Searches of large scale surveys have resulted in the discovery of over 1000 brown dwarfs in the Solar neighbourhood. In this chapter we review the progress in finding brown dwarfs in large datasets, highlighting the key science goals, and summarising the surveys that have contributed most significantly to the current sample.Comment: Accepted to appear in the Handbook of Exoplanets (Springer); Editors: Hans J. Deeg & Juan Antonio Belmont

Malaria vector research and control in Haiti: a systematic review

BACKGROUND: Haiti has a set a target of eliminating malaria by 2020. However, information on malaria vector research in Haiti is not well known. This paper presents results from a systematic review of the literature on malaria vector research, bionomics and control in Haiti. METHODS: A systematic search of literature published in French, Spanish and English languages was conducted in 2015 using Pubmed (MEDLINE), Google Scholar, EMBASE, JSTOR WHOLIS and Web of Science databases as well other grey literature sources such as USAID, and PAHO. The following search terms were used: malaria, Haiti, Anopheles, and vector control. RESULTS: A total of 132 references were identified with 40 high quality references deemed relevant and included in this review. Six references dealt with mosquito distribution, seven with larval mosquito ecology, 16 with adult mosquito ecology, three with entomological indicators of malaria transmission, eight with insecticide resistance, one with sero-epidemiology and 16 with vector control. In the last 15 years (2000–2015), there have only been four published papers and three-scientific meeting abstracts on entomology for malaria in Haiti. Overall, the general literature on malaria vector research in Haiti is limited and dated. DISCUSSION: Entomological information generated from past studies in Haiti will contribute to the development of strategies to achieve malaria elimination on Hispaniola. However it is of paramount importance that malaria vector research in Haiti is updated to inform decision-making for vector control strategies in support of malaria elimination

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Secretion of SDF-1α by bone marrow-derived stromal cells enhances skin wound healing of C57BL/6 mice exposed to ionizing radiation

Patients treated for cancer therapy using ionizing radiation (IR) have delayed tissue repair and regeneration. The mechanisms mediating these defects remain largely unknown at present, thus limiting the development of therapeutic approaches. Using a wound healing model, we here investigate the mechanisms by which IR exposure limits skin regeneration. Our data show that induction of the stromal cell-derived growth factor 1α (SDF-1α) is severely impaired in the wounded skin of irradiated, compared to non-irradiated, mice. Hence, we evaluated the potential of bone marrow-derived multipotent stromal cells (MSCs), which secrete high levels of SDF-1α, to improve skin regeneration in irradiated mice. Injection of MSCs into the wound margin led to remarkable enhancement of skin healing in mice exposed to IR. Injection of irradiated MSCs into the wound periphery of non-irradiated mice delayed wound closure, also suggesting an important role for the stromal microenvironment in skin repair. The beneficial actions of MSCs were mainly paracrine, as the cells did not differentiate into keratinocytes. Specific knockdown of SDF-1α expression led to drastically reduced efficiency of MSCs in improving wound closure, indicating that SDF-1α secretion by MSCs is largely responsible for their beneficial action. We also found that one mechanism by which SDF-1α enhances wound closure likely involves increased skin vascularization. Our findings collectively indicate that SDF-1α is an important deregulated cytokine in irradiated wounded skin, and that the decline in tissue regeneration potential following IR can be reversed, given adequate microenvironmental suppor