Factors controlling fluxes of volatile sulfur compounds in Sphagnum peatlands

Exchange of DMS and OCS between the surface of Sphagnum peatlands and the atmosphere were measured with dynamic (S-free sweep air) and static enclosures. DMS emission rates determined by both methods were comparable. The dynamic method provided positive OCS flux rates (emission) for measurements performed at sites containing Sphagnum. Conversely, data from the static method indicated that OCS was consumed from the atmosphere. Short and long-term impacts of increased S deposition on fluxes of volatile S compounds (VSC's) from Sphagnum peatlands were investigated in a poor fen (Mire 239) at the Experimental Lakes Area, Ontario, Canada. Additional experiments were conducted in a poor fen (Sallie's Fen in Barrington, NH, USA). At Mire 239, emissions of VSC's were monitored, before and after acidification, at control and experimental sections within two major physiographic areas of the mire (oligotrophic and minerotrophic). DMS was the predominant VSC released from Mire 239 and varied largely with time and space. Sulfur addition did not affect DMS emissions in a period of hours to a few days. DMS emissions in the experimental oligotrophic area of the mire was approximately 3-fold greater than in the control oligotrophic area, and approximately 10-fold greater than in the minerotrophic zones. These differences could be due to a combination of differences in types of vegetation, nutritional status, and S input. At Sallie's Fen, DMS fluxes were not significantly affected by sulfate amendments, while DMS and MSH concentrations increased greatly with time in the top 10 cm of the peat column. The major environmental factors controlling fluxes of DMS in a Sphagnum-dominated peatland were investigated in Sallie's Fen, NH. DMS emissions from the surface of the peatland varied greatly over 24 hours and seasonally. Temperature seemed to be the major environmental factor controlling these variabilities. Concentrations of dissolved VSC's varied with time and space throughout the fen. Dissolved DMS, MSH, and OCS in the surface of the water table were supersaturated with respect to their concentrations in the atmosphere. Sphagnum mosses did not appear to be a direct source of VSC's, however they increase transport of DMS from the peat surface to the atmosphere

Factors controlling fluxes of volatile sulfur compounds in Sphagnum peatlands

Exchange of DMS and OCS between the surface of Sphagnum peatlands and the atmosphere were measured with dynamic (S-free sweep air) and static enclosures. DMS emission rates determined by both methods were comparable. The dynamic method provided positive OCS flux rates (emission) for measurements performed at sites containing Sphagnum. Conversely, data from the static method indicated that OCS was consumed from the atmosphere. Short and long-term impacts of increased S deposition on fluxes of volatile S compounds (VSCs) from Sphagnum peatlands were investigated in a poor fen (Mire 239) at the Experimental Lakes Area, Ontario, Canada. Additional experiments were conducted in a poor fen (Sallie\u27s Fen) in Barrington, NH, USA. At Mire 239, emissions of VSCs were monitored, before and after acidification, at control and experimental sections within two major physiographic areas of the mire (oligotrophic and minerotrophic). DMS was the predominant VSC released from Mire 239 and varied largely with time and space. Sulfur addition did not affect DMS emissions in a period of hours to a few days. DMS emissions in the experimental oligotrophic area of the mire was $\sim$3-fold greater than in the control oligotrophic area, and $\sim$10-fold greater than in the minerotrophic zones. These differences could be due to a combination of differences in types of vegetation, nutritional status and S input. At Sallie\u27s Fen, DMS fluxes was not significantly affected by sulfate amendments, while DMS and MSH concentrations increased greatly with time in the top 10 cm of the peat column. The major environmental factors controlling fluxes of DMS in a Sphagnum-dominated peatland were investigated in Sallie\u27s Fen, NH. DMS emissions from the surface of the peatland varied greatly over 24 hours and seasonally. Temperature seemed to be the major environmental factor controlling these variabilities. Concentrations of dissolved VSCs varied with time and space throughout the fen. Dissolved DMS, MSH and OCS in the surface of the water table were supersaturated with respect to their concentrations in the atmosphere. Sphagnum mosses did not appear to be a direct source of VSCs, however they increase transport of DMS from the peat surface to the atmosphere

Preclinical and Clinical Pharmacologic Studies of 9-Nitrocamptothecin and its 9-Aminocamptothecin Metabolite

The camptothecins are DNA topoisomerase I-interactive anticancer agents and have a wide range of antitumor activity. Currently approved camptothecin analogues (i.e., topotecan and irinotecan) are only available for IV administration. 9-Nitrocamptothecin (9NC) is administered orally and is partially metabolized to an active metabolite, 9-aminocamptothecin (9AC). As with other camptothecin analogues, 9NC and 9AC undergo a reversible, pH-dependent reaction between the active-lactone and inactive-hydroxy acid forms. In vitro and in vivo preclinical studies suggest that protracted administration of low doses of camptothecin analogues produces better antitumor activity than the less frequent administration of higher doses. Oral administration of 9NC could mimic the protracted schedule and maximize patient convenience. However, the optimal oral dose and schedule of 9NC and other camptothecin analogues are currently unclear. In addition, oral administration of camptothecin analogues has been characterized by extensive inter- and intra-patient variability in bioavailability. The primary goal of this dissertation research was to evaluate the pharmacokinetics and pharmacogenetics of 9NC and its 9AC metabolite in preclinical models and in patients as part of phase I and II trails.Daily administration of 9NC orally for 5 days per week for two consecutive weeks repeated every four weeks is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. The responses seen in xenografts models evaluating the same regimen of 9NC as evaluated in the phase I study occurred at systemic exposures that are tolerable in patients. There was significant inter- and intra-patient variability in the pharmacokinetics of 9NC and 9AC when 9NC was administered under fasting conditions. Most of the drug remained in the 9NC form with an overall ratio of 9NC to 9AC of 4:1. Co-administration of 9NC with food reduces the oral absorption of 9NC; however there was no difference in the exposure of 9AC. The functional consequences of known single nucleotide polymorphisms in genes of known ATP-binding cassette (ABC) transporters were evaluated as potential sources of the pharmacokinetic variability of 9NC and 9AC. Our findings suggest that the inter-individual variability in the disposition of 9AC, but not 9NC, may be influenced, in part, by ABCG2 genotype. The factors associated with the high inter- and intra-patient variability remain unclear

Factors controlling sulfur gas exchange in Sphagnum-dominated wetlands

Atmosphere-peatland exchange of reduced sulfur gases was determined seasonally in fen in NH, and in an artificially-acidified fen at the Experimental Lakes Area (ELA) in Canada. Dimethyl sulfide (DMS) dominated gas fluxes at rates as high as 400 nmol/m(sup -2)hr(sup -1). DMS fluxes measured using enclosures were much higher than those calculated using a stagnant-film model, suggesting that Sphagnum regulated efflux. Temperature controlled diel and seasonal variability in DMS emissions. Use of differing enclosure techniques indicated that vegetated peatlands consume atmospheric carbonyl sulfide. Sulfate amendments caused DMS and methane thiol concentrations in near-surface pore waters to increase rapidly, but fluxes of these gases to the atmosphere were not affected. However, emission data from sites experiencing large differences in rates of sulfate deposition from the atmosphere suggested that chronic elevated sulfate inputs enhance DMS emissions from northern wetlands

Sulfur gas exchange in Sphagnum-dominated wetlands

Sulfur gases are important components of the global cycle of S. They contribute to the acidity of precipitation and they influence global radiation balance and climate. The role of terrestrial sources of biogenic S and their effect on atmospheric chemistry remain as major unanswered questions in our understanding of the natural S cycle. The role of northern wetlands as sources and sinks of gaseous S was investigated by measuring rates of S gas exchange as a function of season, hydrologic conditions, and gradients in trophic status. The effects of inorganic S input on the production and emission of gaseous S were also investigated. Experiments were conducted in wetlands in New Hampshire, particularly a poor fen, fens within the Experimental Lakes Area (ELA) in Ontario, Canada and in freshwater and marine tundra. Emissions were determined using Teflon enclosures, gas cryotrapping methods, and gas chromatography (GC) with flame photometric detection. Dynamic (sweep flow) and static enclosures were employed. Dissolved gases were determined by gas stripping followed by GC

A sensitive high performance liquid chromatography assay for the quantification of doxorubicin associated with DNA in tumor and tissues

A HPLC method was validated to quantify doxorubicin associated to DNA from tissue.Successfully applied to an in vivo mouse-based pharmacokinetic study.Important tool for future studies evaluating intracellular pharmacokinetics.Doxorubicin, a widely used anticancer agent, exhibits antitumor activity against a wide variety of malignancies. The drug exerts its cytotoxic effects by binding to and intercalating within the DNA of tumor and tissue cells. However, current assays are unable to accurately determine the concentration of the intracellular active form of doxorubicin. Thus, the development of a sample processing method and a high-performance liquid chromatography (HPLC) methodology was performed in order to quantify doxorubicin that is associated with DNA in tumors and tissues, which provided an intracellular cytotoxic measure of doxorubicin exposure after administration of small molecule and nanoparticle formulations of doxorubicin. The assay uses daunorubicin as an internal standard; liquid–liquid phase extraction to isolate drug associated with DNA; a Shimadzu HPLC with fluorescence detection equipped with a Phenomenex Luna C18 (2 μm, 2.0 × 100 mm) analytical column and a gradient mobile phase of 0.1% formic acid in water or acetonitrile for separation and quantification. The assay has a lower limit of detection (LLOQ) of 10 ng/mL and is shown to be linear up to 3000 ng/mL. The intra- and inter-day precision of the assay expressed as a coefficient of variation (CV%) ranged from 4.01 to 8.81%. Furthermore, the suitability of this assay for measuring doxorubicin associated with DNA in vivo was demonstrated by using it to quantify the doxorubicin concentration within tumor samples from SKOV3 and HEC1A mice obtained 72 h after administration of PEGylated liposomal doxorubicin (Doxil®; PLD) at 6 mg/kg IV x 1. This HPLC assay allows for sensitive intracellular quantification of doxorubicin and will be an important tool for future studies evaluating intracellular pharmacokinetics of doxorubicin and various nanoparticle formulations of doxorubicin

Fluxos de óxido nitroso na interface ar-mar na Baía de Guanabara

In Surface water concentrations of N2O were measured at 37 stations in Guanabara Bay and fluxes estimated across the air-sea interface. Concentrations averaged 8.2 ± 2.2 nmol L-1 and 90% of the stations showed supersaturation averaging 33%. N2O fluxes were estimated using a two-film model which is given by the product of the concentration difference across the film and the gas transfer coefficient (k w). Two parametrizations of k w were used which provided average fluxes of 0.3 and 3.0 µg N m-2 h-1. Flux measurements using floating chambers (not reported here) seem to agree with the upper limit of these estimates

Flagellin-Deficient Legionella Mutants Evade Caspase-1- and Naip5-Mediated Macrophage Immunity

Macrophages from C57BL/6J (B6) mice restrict growth of the intracellular bacterial pathogen Legionella pneumophila. Restriction of bacterial growth requires caspase-1 and the leucine-rich repeat-containing protein Naip5 (Birc1e). We identified mutants of L. pneumophila that evade macrophage innate immunity. All mutants were deficient in expression of flagellin, the primary flagellar subunit, and failed to induce caspase-1-mediated macrophage death. Interestingly, a previously isolated flagellar mutant (fliI) that expresses, but does not assemble, flagellin did not replicate in macrophages, and induced macrophage death. Thus, flagellin itself, not flagella or motility, is required to initiate macrophage innate immunity. Immunity to Legionella did not require MyD88, an essential adaptor for toll-like receptor 5 (TLR5) signaling. Moreover, flagellin of Legionella and Salmonella induced cytotoxicity when delivered to the macrophage cytosol using Escherichia coli as a heterologous host. It thus appears that macrophages sense cytosolic flagellin via a TLR5-independent pathway that leads to rapid caspase-1-dependent cell death and provides defense against intracellular bacterial pathogens

Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients

S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic–pharmacodynamic (PK–PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK–PD models were developed and fit simultaneously to the PK–PD data, using NONMEM®. The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis–Menten kinetics in the myelosuppression-based model. The mechanism-based PK–PD model characterized the nonlinear PK disposition, and the bidirectional PK–PD interaction between S-CKD602 and monocytes

Factors Affecting the Pharmacokinetics and Pharmacodynamics of PEGylated Liposomal Irinotecan (IHL-305) in Patients with Advanced Solid Tumors

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged \u3c60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes