Metabolism of synthetic cannabinoid receptor agonists encountered in clinical casework: major in vivo phase I metabolites of JWH-007, JWH-019, JWH-203, JWH-307, UR-144, XLR-11, AM-2201, MAM-2201 and AM-694 in human urine using LC-MS/MS

Background: `Herbal mixtures` containing synthetic cannabinoid receptor agonists (SCRAs) are promoted as legal alternative to marihuana and are easily available via the Internet. Keeping analytical methods for the detection of these SCRAs up-to-date is a continuous challenge for clinicians and toxicologists due to the high diversity of the chemical structures and the frequent emergence of new compounds. Since many SCRAs are extensively metabolized, analytical methods used for urine testing require previous identification of the major metabolites of each compound. Objective: The aim of this study was to identify the in vivo major metabolites of nine SCRAs (AM-694, AM-2201, JWH-007, JWH-019, JWH-203, JWH-307, MAM-2201, UR-144, XLR-11) for unambiguous detection of a drug uptake by analysis of urine samples. Method: Positive urine samples from patients of hospitals, detoxification and therapy centers as well as forensic-psychiatric clinics were analyzed by means of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-quadrupol time-of-flight mass spectrometry (LC-qToF-MS) for investigation of the in vivo major metabolites. Results: For all investigated SCRAs, monohydroxylation, dihydroxylation and/or formation of the N-pentanoic acid metabolites were among the most abundant metabolites detected in human urine samples. Substitution of the fluorine atom was observed to be an important metabolic reaction for compounds carrying an N-(5-fluoropentyl) chain. Dealkylated metabolites were not detected in vivo. Conclusion: The investigated metabolites facilitate the reliable detection of drug uptake by analysis of urine samples. For distinction between uptake of the fluorinated and the non-fluorinated analogs, the N-(4-hydroxypentyl) metabolite of the non-fluorinated analog was identified as a useful analytical target and consumption marker

Efficient organic carbon burial in the Bengal fan sustained by the Himalayan erosional system

Author Posting. © Nature Publishing Group, 2007. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature 450 (2007): 407-410, doi:10.1038/nature06273.Continental erosion controls atmospheric carbon dioxide levels on geological timescales through silicate weathering, riverine transport and subsequent burial of organic carbon in oceanic sediments. The efficiency of organic carbon deposition in sedimentary basins is however limited by the organic carbon load capacity of the sediments and organic carbon oxidation in continental margins. At the global scale, previous studies have suggested that about 70 per cent of riverine organic carbon is returned to the atmosphere, such as in the Amazon basin. Here we present a comprehensive organic carbon budget for the Himalayan erosional system, including source rocks, river sediments and marine sediments buried in the Bengal fan. We show that organic carbon export is controlled by sediment properties, and that oxidative loss is negligible during transport and deposition to the ocean. Our results indicate that 70 to 85 per cent of the organic carbon is recent organic matter captured during transport, which serves as a net sink for atmospheric carbon dioxide. The amount of organic carbon deposited in the Bengal basin represents about 10 to 20 per cent of the total terrestrial organic carbon buried in oceanic sediments. High erosion rates in the Himalayas generate high sedimentation rates and low oxygen availability in the Bay of Bengal that sustain the observed extreme organic carbon burial efficiency. Active orogenic systems generate enhanced physical erosion and the resulting organic carbon burial buffers atmospheric carbon dioxide levels, thereby exerting a negative feedback on climate over geological timescales

Winter weather controls net influx of atmospheric CO2 on the north-west European shelf

Shelf seas play an important role in the global carbon cycle, absorbing atmospheric carbon dioxide (CO2) and exporting carbon (C) to the open ocean and sediments. The magnitude of these processes is poorly constrained, because observations are typically interpolated over multiple years. Here, we used 298500 observations of CO2 fugacity (fCO2) from a single year (2015), to estimate the net influx of atmospheric CO2 as 26.2 ± 4.7 Tg C yr-1 over the open NW European shelf. CO2 influx from the atmosphere was dominated by influx during winter as a consequence of high winds, despite a smaller, thermally-driven, air-sea fCO2 gradient compared to the larger, biologically-driven summer gradient. In order to understand this climate regulation service, we constructed a carbon-budget supplemented by data from the literature, where the NW European shelf is treated as a box with carbon entering and leaving the box. This budget showed that net C-burial was a small sink of 1.3 ± 3.1 Tg C yr-1, while CO2 efflux from estuaries to the atmosphere, removed the majority of river C-inputs. In contrast, the input from the Baltic Sea likely contributes to net export via the continental shelf pump and advection (34.4 ± 6.0 Tg C yr-1)

Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas

Recent data suggested an increased frequency of KIT aberrations in mucosal melanomas, whereas c-KIT in most types of cutaneous melanomas does not appear to be of pathogenetic importance. However, studies investigating the status of the KIT gene in larger, well-characterised groups of patients with mucosal melanomas are lacking. We analysed 44 archival specimens of 39 well-characterised patients with mucosal melanomas of different locations. c-KIT protein expression was determined by immunhistochemistry, KIT gene mutations were analysed by PCR amplification and DNA sequencing of exons 9, 11, 13, 17 and 18. c-KIT protein expression could be shown in 40 out of 44 (91%) tumours in at least 10% of tumour cells. DNA sequence analysis of the KIT was successfully performed in 37 patients. In 6 out of 37 patients (16%) KIT mutations were found, five in exon 11 and one in exon 18. The presence of mutations in exon 11 correlated with a significant stronger immunohistochemical expression of c-KIT protein (P=0.015). Among the six patients with mutations, in two patients the primary tumour was located in the head/neck region, in three patients in the genitourinary tract and in one patient in the anal/rectal area. In conclusion, KIT mutations can be found in a subset of patients with mucosal melanomas irrespective of the location of the primary tumour. Our data encourage therapeutic attempts with tyrosine kinase inhibitors blocking c-KIT in these patients

Assessment of trace metal contamination in a historical freshwater canal (Buckingham Canal), Chennai, India

The present study was done to assess the sources and the major processes controlling the trace metal distribution in sediments of Buckingham Canal. Based on the observed geochemical variations, the sediments are grouped as South Buckingham Canal and North Buckingham Canal sediments (SBC and NBC, respectively). SBC sediments show enrichment in Fe, Ti, Mn, Cr, V, Mo, and As concentrations, while NBC sediments show enrichment in Sn, Cu, Pb, Zn, Ni, and Hg. The calculated Chemical Index of Alteration and Chemical Index of Weathering values for all the sediments are relatively higher than the North American Shale Composite and Upper Continental Crust but similar to Post-Archaean Average Shale, and suggest a source area with moderate weathering. Overall, SBC sediments are highly enriched in Mo, Zn, Cu, and Hg (geoaccumulation index (Igeo) class 4– 6), whereas NBC sediments are enriched in Sn, Cu,Zn, and Hg (Igeo class 4–6). Cu, Ni, and Cr show higher than Effects-Range Median values and hence the biological adverse effect of these metals is 20%; Zn, which accounts for 50%, in the NBC sediments, has a more biological adverse effect than other metalsfound in these sediments. The calculated Igeo, Enrichment Factor, and Contamination Factor values indicate that Mo, Hg, Sn, Cu, and Zn are highly enriched in the Buckingham Canal sediments, suggesting the rapid urban and industrial development of Chennai MetropolitanCity have negatively influenced on the surrounding aquatic ecosystem

The inhibition of FGF receptor 1 activity mediates sorafenib-induced antiproliferative effects in human mesothelioma tumor-initiating cells

Tumor-initiating cells (TICs), the subset of cells within tumors endowed with stem-like features, being highly resistant to conventional cytotoxic drugs, are the major cause of tumor relapse. The identification of molecules able to target TICs remains a significant challenge in cancer therapy. Using TIC-enriched cultures (MM1, MM3 and MM4), from 3 human malignant pleural mesotheliomas (MPM), we tested the effects of sorafenib on cell survival and the intracellular mechanisms involved. Sorafenib inhibited cell-cycle progression in all the TIC cultures, but only in MM3 and MM4 cells this effect was associated with induction of apoptosis via the down-regulation of Mcl-1. Although sorafenib inhibits the activity of several tyrosine kinases, its effects are mainly ascribed to Raf inhibition. To investigate the mechanisms of sorafenib-mediated antiproliferative activity, TICs were treated with EGF or bFGF causing, in MM3 and MM4 cells, MEK, ERK1/2, Akt and STAT3 phosphorylation. These effects were significantly reduced by sorafenib in bFGF-treated cells, while a slight inhibition occurred after EGF stimulation, suggesting that sorafenib effects are mainly due to FGFR inhibition. Indeed, FGFR1 phosphorylation was inhibited by sorafenib. A different picture was observed in MM1 cells, which, releasing high levels of bFGF, showed an autocrine activation of FGFR1 and a constitutive phosphorylation/activation of MEK-ERK1/2. A powerful inhibitory response to sorafenib was observed in these cells, indirectly confirming the central role of sorafenib as FGFR inhibitor. These results suggest that bFGF signaling may impact antiproliferative response to sorafenib of MPM TICs, which is mainly mediated by a direct FGFR targeting

A revised nitrogen budget for the Arabian Sea

Despite its importance for the global oceanic nitrogen (N) cycle, considerable uncertainties exist about the N fluxes of the Arabian Sea. On the basis of our recent measurements during the German Arabian Sea Process Study as part of the Joint Global Ocean Flux Study (JGOFS) in 1995 and 1997, we present estimates of various N sources and sinks such as atmospheric dry and wet depositions of N aerosols, pelagic denitrification, nitrous oxide (N2O) emissions, and advective N input from the south. Additionally, we estimated the N burial in the deep sea and the sedimentary shelf denitrification. On the basis of our measurements and literature data, the N budget for the Arabian Sea was reassessed. It is dominated by the N loss due to denitrification, which is balanced by the advective input of N from the south. The role of N fixation in the Arabian Sea is still difficult to assess owing to the small database available; however, there are hints that it might be more important than previously thought. Atmospheric N depositions are important on a regional scale during the intermonsoon in the central Arabian Sea; however, they play only a minor role for the overall N cycling. Emissions of N2O and ammonia, deep-sea N burial, and N inputs by rivers and marginal seas (i.e., Persian Gulf and Red Sea) are of minor importance. We found that the magnitude of the sedimentary denitrification at the shelf might be ∼17% of the total denitrification in the Arabian Sea, indicating that the shelf sediments might be of considerably greater importance for the N cycling in the Arabian Sea than previously thought. Sedimentary and pelagic denitrification together demand ∼6% of the estimated particulate organic nitrogen export flux from the photic zone. The main northward transport of N into the Arabian Sea occurs in the intermediate layers, indicating that the N cycle of the Arabian Sea might be sensitive to variations of the intermediate water circulation of the Indian Ocean