Gas hydrates stored on continental shelves are susceptible to dissociation triggered by environmental changes. Knowledge of the timescales of gas hydrate dissociation and subsequent methane release ...are critical in understanding the impact of marine gas hydrates on the ocean-atmosphere system. Here we report a methane efflux chronology from five sites, at depths of 220-400 m, in the southwest Barents and Norwegian seas where grounded ice sheets led to thickening of the gas hydrate stability zone during the last glaciation. The onset of methane release was coincident with deglaciation-induced pressure release and thinning of the hydrate stability zone. Methane efflux continued for 7-10 kyr, tracking hydrate stability changes controlled by relative sea-level rise, bottom water warming and fluid pathway evolution in response to changing stress fields. The protracted nature of seafloor methane emissions probably attenuated the impact of hydrate dissociation on the climate system.
Trends in urological stone disease Turney, Benjamin W.; Reynard, John M.; Noble, Jeremy G. ...
BJU international,
April 2012, Letnik:
109, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
•
Urolithiasis is a major clinical and economic burden for health care systems.
•
...International epidemiological data suggest that the incidence and prevalence of stone disease is increasing.
This study demonstrates that the number of diagnoses and procedures relating to kidney stone disease has increased significantly in the last 10 years in the UK.
Management of stone disease comprises a significant and increasing proportion of urological practice in the UK, which has implications for work force planning, training, service delivery and research in this field.
OBJECTIVE
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To summarize the changes in prevalence and treatment of upper urinary tract stone disease in the UK over the last 10 years.
METHODS
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Data from the Hospital Episode Statistics (HES) website (http://www.hesonline.nhs.uk) were extracted, summarized and presented.
RESULTS
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The number of upper urinary tract stone hospital episodes increased by 63% to 83 050 in the 10‐year period.
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The use of shock wave lithotripsy (SWL) for treating all upper tract stones increased from 14 491 cases in 2000–2001 to 22 402 cases in 2010 (a 55% increase) with a 69% increase in lithotripsy for renal stones.
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There was a 127% increase in the number of ureteroscopic stone treatments from 6 283 to 14 242 cases over the 10‐year period with a 49% increase from 2007/2008 to 2009/2010.
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There was a decline in open surgery for upper tract stones from 278 cases in 2000/2001 to 47 cases in 2009/2010 (an 83% reduction).
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Treatment for stone disease has increased substantially in comparison with other urological activity. In 2009/2010, SWL was performed almost as frequently as transurethral resection of the prostate or transurethral resection of bladder tumour, ureteroscopy for stones was performed more frequently than nephrectomy, radical prostatectomy and cystectomy combined, and percutaneous nephrolithotomy was performed more frequently than cystectomy.
CONCLUSIONS
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The present study highlights the increase in prevalence and treatment of stone disease in the UK over the last 10 years.
•
If this trend continues it has important implications for workforce planning, training, service delivery and research in the field of urolithiasis.
Integrated petrography, mineralogy, geochronology and geochemistry of cold seep carbonate crusts and free gas from the Alvheim channel elucidate diagenetic carbonate precipitation and related seepage ...histories in the central North Sea. Free gas isotope characteristics coupled with carbonate δ13C values as low as −66‰ VPDB, indicate a predominantly microbial methane source with minor thermogenic contribution. We estimate that ~70% of the carbon sequestered into carbonate precipitates was derived from local oxidation of methane. The early stage of crust growth is represented by microcrystalline aragonite and Mg-calcite (10 to 40% mol MgCO3) cementing seafloor sediments consisting of clays, quartz, feldspar, and minor detrital low Mg-calcite and dolomite. Typical association of aragonite cement with coarse-grained detritus may reflect elevated fluid flow and flushing of fine particles prior to cementation close to the seafloor. Middle rare earth element enrichment in early generation microcrystalline cements containing framboidal pyrite indicates diagenetic precipitation within the zone of anaerobic methane oxidation contiguous to iron reduction. The later generation diagenetic phase corresponds to less abundant radial fibrous and botryoidal aragonite which lines cavities developed within the crusts. In contrast to early generation cements, late generation cavity infills have rare earth elements and Y patterns with small negative Ce anomalies similar to seawater, consistent with carbonate precipitation in a more open, seawater dominated system. Aragonite U–Th ages indicate carbonate precipitation between 6.09 and 3.46kyr BP in the northern part of the channel, whereas in the southern part precipitation occurred between 1.94 and 0.81kyr BP reflecting regional changes in fluid conduit position.
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•Approximately 70% of carbon in carbonates is derived from microbial methane carbon.•Distinct REY patterns differ with carbonate phases rather than mineralogy.•U–Th ages constrain two distinct seepage events between 6.1 and 0.8ka BP.•Late generation aragonites correspond to carbonate hosted methanotrophy.
Purines and related heterocycles substituted at C-2 with 4′-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over ...CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10–80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-(1,1′-biphenyl-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC50 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor–kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.
Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated ...by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions.
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•CDK inhibitors and D-type cyclins competitively sequester CDK4/6 from Cdc37-Hsp90•Binding of ATP-competitive inhibitors causes CDK4/6 to be displaced from Cdc37-Hsp90•Cancer-associated p16INK4a mutants distinguish CDK4 and CDK6•A model for the assembly factor activity of CIP/KIP CDK inhibitors is proposed
Hallett et al. reconstitute CDK4/6 client kinase handover from Cdc37-Hsp90 to CDK regulatory partners and propose a model for the assembly factor activity of CIP/KIP CDK inhibitors. They find that CDK4/6 inhibitors in clinical use can displace G1 CDKs from the Cdc37-Hsp90 chaperone system at submicromolar concentrations.
Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the ...monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients' tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed
: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks
resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death
and reduced CA46 disease burden
These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.
We evaluated the therapeutic potential of combining the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with the mitochondrial respiratory Complex I inhibitor IACS-010759, for the treatment of ...diffuse large B-cell lymphoma (DLBCL), a potential clinically actionable strategy to target tumour metabolism.
AZD3965 and IACS-010759 sensitivity were determined in DLBCL cell lines and tumour xenograft models. Lactate concentrations, oxygen consumption rate and metabolomics were examined as mechanistic endpoints. In vivo plasma concentrations of IACS-010759 in mice were determined by LC-MS to select a dose that reflected clinically attainable concentrations.
In vitro, the combination of AZD3965 and IACS-010759 is synergistic and induces DLBCL cell death, whereas monotherapy treatments induce a cytostatic response. Significant anti-tumour activity was evident in Toledo and Farage models when the two inhibitors were administered concurrently despite limited or no effect on the growth of DLBCL xenografts as monotherapies.
This is the first study to examine a combination of two distinct approaches to targeting tumour metabolism in DLBCL xenografts. Whilst nanomolar concentrations of either AZD3965 or IACS-010759 monotherapy demonstrate anti-proliferative activity against DLBCL cell lines in vitro, appreciable clinical activity in DLBCL patients may only be realised through their combined use.
Inhibition of murine double minute 2 (MDM2)-p53 protein–protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, ...structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
We have determined
238U/
235U ratios for a suite of commonly used natural (CRM 112a, SRM 950a, and HU-1) and synthetic (IRMM 184 and CRM U500) uranium reference materials by thermal ionisation ...mass-spectrometry (TIMS) using the IRMM 3636
233U–
236U double spike to accurately correct for mass fractionation. Total uncertainty on the
238U/
235U determinations is estimated to be <0.02% (2σ). These natural
238U/
235U values are different from the widely used ‘consensus’ value (137.88), with each standard having lower
238U/
235U values by up to 0.08%. The
238U/
235U ratio determined for CRM U500 and IRMM 184 are within error of their certified values; however, the total uncertainty for CRM U500 is substantially reduced (from 0.1% to 0.02%). These reference materials are commonly used to assess mass-spectrometer performance and accuracy, calibrate isotope tracers employed in U, U–Th and U–Pb isotopic studies, and as a reference for terrestrial and meteoritic
238U/
235U variations. These new
238U/
235U values will thus provide greater accuracy and reduced uncertainty for a wide variety of isotopic determinations.
A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We ...proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition–elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.
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