Detection and characterization of environmentally persistent free radicals (EPFRs) in soils and sediments from superfund sites

Environmentally persistent free radicals (EPFRs) from combustion-generated PM have been demonstrated to form via reactions of molecular precursors with redox-active transition metals at 150-500C thermal reactions in a few seconds reaction times. While ambient temperatures are much lower, soils/sediments contain similar transition metals, and reaction times of contaminants in soils/sediments are years, rather than seconds. This questions whether EPFRs could be formed at ambient temperatures in soils/sediments from Superfund sites that are contaminated with hazardous materials. Superfund soils contaminated with PCP from Georgia and Montana, and sediments contaminated with PAHs from Washington. Using EPR spectroscopy, EPFR concentrations and structural assignments were determined. Contaminated soils/sediments were ~30x, ~12x, ~2x higher than the background at the Georgia, Montana, and Washington sites, respectively. Conventional humic substances extraction procedures revealed ~90% of the EPFRs originated from clays/minerals/humins fraction. Similarity of EPR signals in the Georgia and Montana PCP contaminated soils were observed (g = 2.00300 and ΔHp-p = 6.0 G), whereas, signals in the Washington sediments were similar to other PAH contaminated soils (g = 2.00270 and ΔHp-p = 9.0G). Several methods of analyses (Total Carbon Content, GC-MS, ICP-AES, Vapor and gas/liquid phase dosing) confirm pentachlorophenoxyl EPFR. Chemisorption and electron transfer from PCP or PAHs to transition metals and other electron sinks in soil are indicated for EPFRs formation. Low temperature thermal treatment of PCP contaminated soil in an open type heating system indicated the formation of a more oxygen-centered structure of the pentachlorophenoxyl radical or new, similar radicals. Both type of heating system, open and closed, demonstrated an EPFR concentrations that peaked at ~10 x 10E+18 spins/g of soil at ~75-100C, with lifetimes of 2 – 24 days at room temperature in ambient air indicating persistency in the environment. Discovery of EPFRs formed in PCP contaminated soils indicates that EPFRs are not only confined to combustion-generated particles. Studies on EPFR similar to pentachlorophenoxyl cause cardiopulmonary dysfunctions via induction of oxidative stress. The existence of potentially toxic EPFRs questions the long held belief that sorption of an organic pollutant to a soil matrix is a method of mitigating its environmental impact

Search for strongly interacting massive particles generating trackless jets in proton–proton collisions ats=13 TeV\sqrt{s} = 13\,\text {TeV}

A search for dark matter in the form of strongly interacting massive particles (SIMPs) using the CMS detector at the LHC is presented. The SIMPs would be produced in pairs that manifest themselves as pairs of jets without tracks. The energy fraction of jets carried by charged particles is used as a key discriminator to suppress efficiently the large multijet background, and the remaining background is estimated directly from data. The search is performed using proton–proton collision data corresponding to an integrated luminosity of 16.1fb$^{-1}$, collected with the CMS detector in 2016. No significant excess of events is observed above the expected background. For the simplified dark matter model under consideration, SIMPs with masses up to 100GeV are excluded and further sensitivity is explored towards higher masses

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

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

Formation of environmentally persistent free radical (EPFR) in iron(III) cation-exchanged smectite clay

© 2016 The Royal Society of Chemistry. Environmentally persistent free radicals (EPFRs) have been found at a number of Superfund sites, with EPFRs being formed via a proposed redox process at ambient environmental conditions. The possibility of such a redox process taking place at ambient environmental conditions is studied utilizing a surrogate soil system of phenol and iron(iii)-exchanged calcium montmorillonite clay, Fe(iii)CaM. Sorption of phenol by the Fe(iii)CaM is demonstrated by Fourier-transformed infra-red (FT-IR) spectroscopy, as evidenced by the peaks between 1345 cm-1 and 1595 cm-1, and at lower frequencies between 694 cm-1 and 806 cm-1, as well as X-ray diffraction (XRD) spectroscopy, as shown by an increase in interlayer spacing within Fe(iii)CaM. The formation and characterization of the EPFRs is determined by electron paramagnetic resonance (EPR) spectroscopy, showing phenoxyl-type radical with a g-factor of 2.0034 and ΔHP-P of 6.1 G at an average concentration of 7.5 × 1017 spins per g. EPFRs lifetime data are indicative of oxygen and water molecules being responsible for EPFR decay. The change in the oxidation state of the iron redox center is studied by X-ray absorption near-edge structure (XANES) spectroscopy, showing that 23% of the Fe(iii) is reduced to Fe(ii). X-ray photoemission spectroscopy (XPS) results confirm the XANES results. These findings, when combined with the EPFR concentration data, demonstrate that the stoichiometry of the EPFR formation under the conditions of this study is 1.5 × 10-2 spins per Fe(ii) atom

Assessment of environmentally persistent free radicals in soils and sediments from three Superfund sites

We previously reported the presence of environmentally persistent free radicals (EPFRs) in pentachlorophenol (PCP) contaminated soils at a closed wood treatment facility site in Georgia. The reported EPFRs were pentachlorophenoxyl radicals formed on soils under ambient conditions via electron transfer from PCP to electron acceptors in the soil. In this study, we present results for soil and sediment samples from additional Superfund sites in Montana and Washington. Paramagnetic centers associated with different chemical environments were characterized by distinct g-factors and line widths (ΔHp-p). EPFR concentrations in contaminated samples were ∼30×, ∼12×, and ∼2× higher than background samples at the Georgia, Montana, and Washington sites, respectively. EPR signals in the Montana contaminated soils were very similar to those previously observed for pentachlorophenol contaminated soils at the Georgia site, i.e., g = 2.00300 and ΔHp-p = 6.0 G, whereas signals in the Washington sediment samples were similar to those previously observed for other PAH contaminated soils, i.e., g = 2.00270 and ΔHp-p = 9.0 G. Total carbon content measurements exhibited direct correlation with EPFR concentration. The presence of radicals in sites contaminated a decade to a century ago suggests continuous formation of EPFRs from molecular contaminants in the soil and sediment. © 2014 The Royal Society of Chemistry