Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma.

Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse with recalcitrant disease. This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus caspase inhibitor (IZ) treatment selectively induced a tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines and patient xenografts. The induction of necroptosis was common in ovarian cancer, with expression of catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, and in fact sufficient to compromise survival of RIPK3-negative, necroptosis-resistant ovarian cancer cells. The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed. RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death. Abundant RIPK3 transcript is common in serous ovarian cancers, suggesting that further evaluation and targeting of this RIPK3-dependent pathway may be of clinical benefit

Relationships of trace gases and aerosols and the emission characteristics at Lin'an, a rural site in eastern China, during spring 2001

We present measurements of trace gases and fine aerosols obtained from a rural site in eastern China during 18 February to 30 April 2001. The field program aimed to characterize the variations in aerosol and gaseous pollutant concentrations and the emission signatures from the inland region of eastern China in the spring season. The data included O3, CO, NO, NOy*, SO2, methane, C2-C8 nonmethane hydrocarbons (NMHCs), C 1-C2 halocarbons, and the chemical composition of PM2.5. The average hourly mixing ratios (±standard deviation) of CO, SO2, and NOy* were 677 (±315) ppbv, 15.9 (±14.6) ppbv, and 13.8 (±7.2) ppbv, respectively. The mean daytime ozone mixing ratio was 41 (± 19) ppbv. The most abundant NMHC was ethane (3189 ± 717 pptv), followed by ethyne (2475 ± 1395 pptv), ethene (1679 ± 1455 pptv), and toluene (1529 ± 1608 pptv). Methyl chloride was the most abundant halocarbon (1108 ± 653 pptv). The average concentrations of particulate organic matter (POM, as organic carbon, OC, times 1.4) and elemental carbon (EC) in PM2.5 were 21.5 (±7) μg/m3 and 2.5 (±0.7) μg/m3, respectively, and sulfate and nitrate levels were 17.3 (±6.6) and 6.5 (±4) μg/m3, respectively. CO showed moderate to good correlation with NOy* (r2 = 0.59), OC (r2 = 0.65), CH3Cl (r2 = 0.59), soluble potassium (r2 = 0.53), and many NMHCs, indicating contributions from the burning of biofuel/biomass. CO also correlated with an industrial tracer, C2Cl4, indicative of some influence from industrial sources. SO2, on the other hand, correlated well with EC (r2 = 0.56), reflecting the contribution from the burning of coal. Ammonium was sufficiently abundant to fully neutralize sulfate and nitrate, indicating that there were strong emissions of ammonia from agricultural activities. Silicon and calcium had poor correlations with iron and aluminum, revealing the presence of source(s) for Si and Ca other than from soil. Examination of C2H2/CO, C3H8/C 2H6, nitrate/(nitrate + NOy* , and sulfate/(SO2 + sulfate) suggested that relatively fresh air masses had been sampled at the study site in the spring season. Comparison of the observed ratios/slopes with those derived from emission inventories showed that while the observed SO2/NO y* ratio (1.29 ppbv/ppbv) in March was comparable (within 20%) to the inventory-derived ratio for the study region, the measured CO/NOy* slope (37 ppbv/ppbv) was about 200% larger. The observed slope of CO relative to NMHC (including ethane, propane, butanes, ethene, and ethyne) also indicated the presence of excess CO, compared to the ratios from the inventories. These results strongly suggest that emissions of CO in eastern China have been underrepresented. The findings of this study highlight the importance of characterizing trace gases and aerosols within source regions of the Asian continent. The springtime results were also compared with data previously collected at the site in 1999-2000 and with those obtained on the Transport and Chemical Evolution over the Pacific (TRACE-P) aircraft and from a coastal site in South China for the same study period. Copyright 2004 by the American Geophysical Union

A simple reproducible method of preventing lobar torsion

Torsion of remaining lobes after pulmonary resection is a potentially serious complication with high reported morbidity and mortality. A range of additional procedures has been described, we have used a simple, effective, quick and easy to reproduce minor procedure to prevents torsion

Solid state NMR of isotope labelled murine fur: a powerful tool to study atomic level keratin structure and treatment effects

We have prepared mouse fur extensively $^{13}$C,$^{15}$N-labelled in all amino acid types enabling application of 2D solid state NMR techniques which establish covalent and spatial proximities within, and in favorable cases between, residues. $^{13}$C double quantum-single quantum correlation and proton driven spin diffusion techniques are particularly useful for resolving certain amino acid types. Unlike 1D experiments on isotopically normal material, the 2D methods allow the chemical shifts of entire spin systems of numerous residue types to be determined, particularly those with one or more distinctively shifted atoms such as Gly, Ser, Thr, Tyr, Phe, Val, Leu, Ile and Pro. Also the partial resolution of the amide signals into two signal envelopes comprising of $\alpha$-helical, and $\beta$-sheet/random coil components, enables resolution of otherwise overlapped $\alpha$-carbon signals into two distinct cross peak families corresponding to these respective secondary structural regions. The increase in resolution conferred by extensive labelling offers new opportunities to study the chemical fate and structural environments of specific atom and amino acid types under the influence of commercial processes, and therapeutic or cosmetic treatments.Medical Research Council (Grant ID: RG75828), Engineering and Physical Sciences Research Council (Ph.D. studentships), National Institute of Health Researc

Genetic Code Mutations: The Breaking of a Three Billion Year Invariance

The genetic code has been unchanging for some three billion years in its canonical ensemble of encoded amino acids, as indicated by the universal adoption of this ensemble by all known organisms. Code mutations beginning with the encoding of 4-fluoro-Trp by Bacillus subtilis, initially replacing and eventually displacing Trp from the ensemble, first revealed the intrinsic mutability of the code. This has since been confirmed by a spectrum of other experimental code alterations in both prokaryotes and eukaryotes. To shed light on the experimental conversion of a rigidly invariant code to a mutating code, the present study examined code mutations determining the propagation of Bacillus subtilis on Trp and 4-, 5- and 6-fluoro-tryptophans. The results obtained with the mutants with respect to cross-inhibitions between the different indole amino acids, and the growth effects of individual nutrient withdrawals rendering essential their biosynthetic pathways, suggested that oligogenic barriers comprising sensitive proteins which malfunction with amino acid analogues provide effective mechanisms for preserving the invariance of the code through immemorial time, and mutations of these barriers open up the code to continuous change

In situ characterization of advanced glycation end products (AGEs) in collagen and model extracellular matrix by solid state NMR

Non-enzymatic glycation of extracellular matrix with (U-13C5)-Dribose- 5-phosphate (R5P), enables in situ 2D ssNMR identification of many deleterious protein modifications and crosslinks, including previously unreported oxalamido and hemiaminal (CH3- CH(OH)NHR) substructures. Changes in charged residue proportions and distribution may be as important as crosslinking in provoking and understanding harmful tissue changes

A baseline evaluation of oceanographic and sea ice conditions in the Hudson Bay Complex during 2016-2018

In this paper, we examine sea surface temperatures (SSTs) and sea ice conditions in the Hudson Bay Complex as a baseline evaluation for the BaySys 2016–2018 field program time frame. Investigated in particular are spatiotemporal patterns in SST and sea ice state and dynamics, with rankings of the latter to highlight extreme conditions relative to the examined 1981–2010 climatology. Results from this study show that SSTs in northwestern Hudson Bay from May to July, 2016–2018, are high relative to the climatology for SST (1982–2010). SSTs are also warmer in 2016 and 2017 than in 2018 relative to their climatology. Similarly, unusually low sea ice cover existed from August to December of 2016 and July to September of 2017, while unusually high sea ice cover existed in January, February, and October of 2018. The ice-free season was approximately 20 days longer in 2016 than in 2018. Unusually high ice-drift speeds occurred in April of 2016 and 2017 and in May of 2018, coinciding with strong winds in 2016 and 2018 and following strong winds in March 2017. Strong meridional circulation was observed in spring of 2016 and winter of 2017, while weak meridional circulation existed in 2018. In a case study of an extreme event, a blizzard from 7 to 9 March 2017, evaluated using Lagrangian dispersion statistics, is shown to have suppressed sea ice deformation off the coast of Churchill. These results are relevant to describing and planning for possible future pathways and scenarios under continued climate change and river regulation

The effect of nurse initiated patient/family education strategy on people with schizophrenia in Beijing

2004-2005 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Study protocol : the empirical investigation of methods to correct for measurement error in biobanks with dietary assessment

Peer reviewedPublisher PD