Ultraviolet Radiation and the Slug Transcription Factor Induce Proinflammatory and Immunomodulatory Mediator Expression in Melanocytes

Despite extensive investigation, the precise contribution of the ultraviolet radiation (UVR) component of sunlight to melanoma etiology remains unclear. UVR induces keratinocytes to secrete proinflammatory and immunomodulatory mediators that promote inflammation and skin tumor development; expression of the slug transcription factor in keratinocytes is required for maximal production of these mediators. In the present studies we examined the possibility that UVR-exposed melanocytes also produce proinflammatory mediators and that Slug is important in this process. Microarray studies revealed that both UVR exposure and Slug overexpression altered transcription of a variety of proinflammatory mediators by normal human melanocytes; some of these mediators are also known to stimulate melanocyte growth and migration. There was little overlap in the spectra of cytokines produced by the two stimuli. However IL-20 was similarly induced by both stimuli and the NFκB pathway appeared to be important in both circumstances. Further exploration of UVR-induced and Slug-dependent pathways of cytokine induction in melanocytes may reveal novel targets for melanoma therapy

Tumor Suppressor Gene-Based Nanotherapy: From Test Tube to the Clinic

Cancer is a major health problem in the world. Advances made in cancer therapy have improved the survival of patients in certain types of cancer. However, the overall five-year survival has not significantly improved in the majority of cancer types. Major challenges encountered in having effective cancer therapy are development of drug resistance by the tumor cells, nonspecific cytotoxicity, and inability to affect metastatic tumors by the chemodrugs. Overcoming these challenges requires development and testing of novel therapies. One attractive cancer therapeutic approach is cancer gene therapy. Several laboratories including the authors' laboratory have been investigating nonviral formulations for delivering therapeutic genes as a mode for effective cancer therapy. In this paper the authors will summarize their experience in the development and testing of a cationic lipid-based nanocarrier formulation and the results from their preclinical studies leading to a Phase I clinical trial for nonsmall cell lung cancer. Their nanocarrier formulation containing therapeutic genes such as tumor suppressor genes when administered intravenously effectively controls metastatic tumor growth. Additional Phase I clinical trials based on the results of their nanocarrier formulation have been initiated or proposed for treatment of cancer of the breast, ovary, pancreas, and metastatic melanoma, and will be discussed

Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues

Estimating Combined Effects of Climate Change and Land Cover Change on Water Regulation Services of Urban Wetlands in Valdivia, Chile

The relationship between cities and wetland cover varies across the globe, with some cities converting wetlands to low‐ and high‐density urban cover and others preserving, conserving, or restoring wetlands, or constructing new ones. However, the scientific literature lacks studies relating changes in systemic flood risk in an urban stormwater management systems to changes in wetland cover. Furthermore, whether and how such relationships are affected by changing storm intensity under climate change is unknown. We present a case study on the effects of changes in urban wetland extent and storm intensity on flooding in an urban drainage system in Valdivia, Chile, under several co‐produced future scenarios and historical trends of development. We used data derived from stakeholder workshops and historical landcover to determine four plausible scenarios of urban development, plus one business‐as‐usual scenario, in Valdivia through the year 2080. Additionally, we used historical precipitation data and downscaled climate data to estimate event rainfall from extreme storms in the year 2080. We found that system flood volume and time the system was flooded increased with increasing wetland loss and rainfall volume. Mean rate and hour of peak discharge were unaffected by wetland loss. Infiltration\u27s relative role in reducing flooding diminished as wetland loss increased. Cities may still experience dangerous and/or unacceptable flooding even with extensive wetland coverage and will likely need to pair conservation with additional improvements in their stormwater management systems and contributing watersheds

Setting the Stage for Co-Production

Participatory scenario visioning aims to expose, integrate, and reconcile perspectives and expectations about a sustainable, resilient future from a variety of actors and stakeholders. This chapter considers the settings in which transdisciplinary participatory visioning takes place, highlighting lessons learned from the Urban Resilience to Extremes Sustainability Research Network (UREx SRN). It reflects on the benefits of engaging in the co-production process and the challenges that must be considered amid this process

A Framework for Resilient Urban Futures

Resilient urban futures provides a social–ecological–technological systems (SETS) perspective on promoting and understanding resilience. This chapter introduces the concepts, research, and practice of urban resilience from the Urban Resilience to Extremes Sustainability Research Network (UREx SRN). It describes conceptual and methodological approaches to address how cities experience extreme weather events, adapt to climate resilience challenges, and can transform toward sustainable and equitable future

Positive Futures

We describe the rationale and framework for developing scenarios of positive urban futures. The scenario framework is conducted in participatory workshop settings and composed of three distinct scenario approaches that are used to (1) explore potential outcomes of existing planning goals (strategic scenarios), (2) articulate visions that address pressing resilience challenges (adaptive scenarios), and (3) envision radical departures from the status quo in the pursuit of sustainability and equity (transformative scenarios). A series of creative and analytical processes are used to engage the community in imagining, articulating, and scrutinizing visions and pathways of positive futures. The approach offers an alternative and complement to traditional forecasting techniques by applying inspirational stories to resilience research and practice

Effects of Wolf Removal on Livestock Depredation Recurrence and Wolf Recovery in Montana, Idaho and Wyoming

Wolf predation on livestock and management methods used to mitigate conflicts are highly controversial and scrutinized especially where wolf populations are recovering.  Wolves are commonly removed from a local area in attempts to reduce further depredations, but the effectiveness of such management actions is poorly understood.  We compared the effects of 3 management responses to livestock depredation by wolf packs in Montana, Idaho, and Wyoming:  no removal, partial pack removal, and full pack removal.  From 1989 to 2008, we documented 967 depredations by 156 packs: 228 on sheep and 739 on cattle and other stock.  Median time between recurrent depredations was 19 days following no removal (n = 593), 64 days following partial pack removal (n = 326), and 730 days following full pack removal (n = 48).  Partial pack removal was most effective if conducted within the first 7 days following depredation, after which there was only a marginally significant difference between partial pack removal and no action (HR = 0.86, P = 0.07), and no difference after 14 days (HR = 0.99, P = 0.93).   Ultimately, pack size was the best predictor of a recurrent depredation event; the probability of a depredation event recurring within 5 years increased by 7% for each animal left in the pack after the management response.  However, the greater the number of wolves left in a pack, the higher the likelihood the pack met federal criteria to count as a breeding pair the following year toward population recovery goals