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Sacred Zones: Examing Wilderness in Yellowstone, Maine and Russia

This thesis seeks to examine issues of resource conservation and recreational access in three regions of immense historical and ecological significance: Yellowstone National Park, the North Woods of Maine, and the protected nature reserve system of Siberia. By applying a combination of direct professional experience, current research and ongoing environmental policy action, the thesis attempts to provide an accurate picture of current and future challenges facing the three regions. Part I, “Yellowstone Paradox,” traces the roots of Yellowstone’s restrictions on recreational boating access in a post-WWII discourse of consumer recreation, the development of a sustainability ethic and its deployment as a rhetorical tactic by both advocates and opponents of park paddling access. Part II, “The Mill and the Mountain,” examines the transition from logging to tourism in an economically depressed former mill town outside of Baxter State Park, where land managers struggle to balance visitor use and safety with the “forever wild” vision of the park’s founder, Percival Baxter. Playing a key role in the region’s future is Roxanne Quimby, founder of Burt’s Bees Cosmetics, who proposes to found a 75,000 acre North Woods National Park adjacent to Baxter State Park. Part III, “Zapovednik,” examines the zapodvedniki (biological reserves) of the Russian Federation, where no-access conservation areas long protected by the Soviet government now face new pressures from resource extraction, poaching, and international ecotourism. As we continue into the 21st century, the three areas grow ever more vulnerable to resource degradation, climate change, and growing human impact. On a policy level, ongoing conservation efforts will require reevaluation of access regulations and new strategies for balancing the needs of visitors with protection of the resource. On a more abstract level, the future preservation of these areas demands an increased sense of stewardship through environmental education and engagement

The Effect of Resin Bonding on Long-Term Success of High-Strength Ceramics

Digital manufacturing, all-ceramics, and adhesive dentistry are currently the trendiest topics in clinical restorative dentistry. Tooth- and implant-supported fixed restorations from computer-aided design (CAD)/computer-aided manufacturing (CAM)–fabricated high-strength ceramics—namely, alumina and zirconia—are widely accepted as reliable alternatives to traditional metal-ceramic restorations. Most recent developments have focused on high-translucent monolithic full-contour zirconia restorations, which have become extremely popular in a short period of time, due to physical strength, CAD/CAM fabrication, and low cost. However, questions about proper resin bonding protocols have emerged, as they are critical for clinical success of brittle ceramics and treatment options that rely on adhesive bonds, specifically resin-bonded fixed dental prostheses or partial-coverage restorations such as inlays/onlays and veneers. Resin bonding has long been the gold standard for retention and reinforcement of low- to medium-strength silica-based ceramics but requires multiple pretreatment steps of the bonding surfaces, increasing complexity, and technique sensitivity compared to conventional cementation. Here, we critically review and discuss the evidence on resin bonding related to long-term clinical outcomes of tooth- and implant-supported high-strength ceramic restorations. Based on a targeted literature search, clinical long-term studies indicate that porcelain-veneered alumina or zirconia full-coverage crowns and fixed dental prostheses have high long-term survival rates when inserted with conventional cements. However, most of the selected studies recommend resin bonding and suggest even greater success with composite resins or self-adhesive resin cements, especially for implant-supported restorations. High-strength ceramic resin-bonded fixed dental prostheses have high long-term clinical success rates, especially when designed as a cantilever with only 1 retainer. Proper pretreatment of the bonding surfaces and application of primers or composite resins that contain special adhesive monomers are necessary. To date, there are no clinical long-term data on resin bonding of partial-coverage high-strength ceramic or monolithic zirconia restorations. © 2017, © International & American Associations for Dental Research 2017

Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards

Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research

Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer

SummaryCancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1+ CD11b+ cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1+ CD11b+ cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1+ CD11b+ cells to the tumor microenvironment and blocked tumor development—a finding that was dependent on CD8+ T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment

Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for alpha-1-antitrypsin deficiency

Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder alpha-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects

Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand

Introduction Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. Aims To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. Results Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. Conclusions 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes