A Maxwell relation for a reaction rate constant (or other dynamical timescale) obtained under constant pressure,
p
, and temperature,
T
, is introduced and discussed. Examination of this relationship ...in the context of fluctuation theory provides insight into the
p
and
T
dependence of the timescale and the underlying molecular origins. This Maxwell relation motivates a suggestion for the general form of the timescale as a function of pressure and temperature. This is illustrated by accurately fitting simulation results and existing experimental data on the self-diffusion coefficient and shear viscosity of liquid water. A key advantage of this approach is that each fitting parameter is physically meaningful.
A Maxwell relation for dynamical timescales motivates a physically meaningful description of the timescale over broad pressure and temperature ranges.
N-nitroso compounds (NOC) formed endogenously after nitrate/nitrite ingestion and disinfection by-products (DBPs) are suspected colorectal carcinogens, but epidemiologic evidence of these ...associations is limited.
We investigated the relationship between drinking water exposures and incident colorectal cancers in a cohort of postmenopausal women.
Using historical nitrate-nitrogen (NO3-N) measurements and estimates of total trihalomethanes (TTHM), the sum of 5 or 6 haloacetic acids (HAAs), and individual DBPs in public water supplies (PWS), we computed average exposures and years of exposure above one-half the U.S. maximum contaminant level (>1/2-MCL; >5 mg/L NO3-N and >40 μg/L TTHM). Nitrate/nitrite intakes from dietary sources were estimated using a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression models. We assessed NO3-N interactions with DBPs and with factors influencing endogenous NOC formation.
We identified 624 colon and 158 rectal cancers (1986–2010) among 15,910 women reporting PWS use >10 years. Ingestion of NO3-N from drinking water was not associated with risk. Colon cancer risks were non-significantly associated with the average TTHM levels >17.7 μg/L (HRQ5vsQ1 = 1.13, CI = 0.89–1.44; ptrend = 0.11) and were elevated for any duration of exposure >1/2-MCL. Rectal cancer risks were associated with the highest TTHM levels (HRQ5vsQ1 = 1.71, CI = 1.00–2.92; ptrend = 0.22) but not with years >1/2-MCL. Bromodichloromethane (HRQ4vsQ1 = 1.89, CI = 1.17–3.00; ptrend = 0.09) and trichloroacetic acid (HRQ4vsQ1 = 1.92, CI = 1.20–3.09; ptrend = 0.18) levels were also associated with risk of rectal cancer. We found no evidence of interaction between TTHM and NO3-N on the risk of either cancer. Dietary analyses yielded a positive colon cancer association with red meat, but not with processed meat intake or estimated nitrate/nitrite from specific dietary sources.
Our results suggest that exposure to TTHM in drinking water is associated with increased risk of rectal cancer. Positive findings for individual THMs and HAAs for both colon and rectal cancers require replication in other studies. We found no associations for nitrate overall or in subgroups with presumed higher NOC exposure.
•Nitrate in drinking water was not associated with risk of colon or rectal cancers.•Exposure to total trihalomethanes in drinking water is associated with the risk of rectal cancer.•Risks of colon and rectal cancers associated with other disinfection byproducts are plausible and require replication.•Red meat intake was associated with colon cancer risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The dynamics and structure of water in polyacrylamide hydrogels (PAAm-HG), polyacrylamide, and acrylamide solutions are investigated using ultrafast infrared experiments on the OD stretch of dilute ...HOD/H2O and molecular dynamics simulations. The amide moiety of the monomer/polymers interacts strongly with water through hydrogen bonding (H-bonding). The FT-IR spectra of the three systems indicate that the range of H-bond strengths is relatively unchanged from bulk water. Vibrational population relaxation measurements show that the amide/water H-bonds are somewhat weaker but fall within the range of water/water H-bond strengths. A previous study of water dynamics in PAAm-HG suggested that the slowing observed was due to increasing confinement with concentration. Here, for the same concentrations of the amide moiety, the experimental results demonstrate that the reorientational dynamics (infrared pump–probe experiments) and structural dynamics (two-dimensional infrared spectroscopy) are identical in the three acrylamide systems studied. Molecular dynamics simulations of the water orientational relaxation in aqueous solutions of the acrylamide monomer, trimer, and pentamer are in good agreement with the experimental results and are essentially chain length independent. The simulations show that there is a slower, low-amplitude (<7%) decay component not accessible by the experiments. The simulations examine the dynamics and structure of water H-bonded to acrylamide, in the first solvent shell, and beyond for acrylamide monomers and short chains. The experiments and simulations show that the slowing of water dynamics in PAAm-HG is not caused by confinement in the polymer network but rather by interactions with individual acrylamide moieties.
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Alcohol intake is a strong and well established risk factor for oesophageal squamous cell carcinoma (OSCC), but the association with oesophageal adenocarcinoma (OA) or adjacent tumours of the ...oesophagogastric junction (OGJA), remains unclear. Therefore, the association of alcohol intake with OSCC, OA, and OGJA was determined in nine case-control studies and two cohort studies of the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium (BEACON).
Information was collected on alcohol intake, age, sex, education, body mass index, gastro-oesophageal reflux, and tobacco smoking from each study. Along with 10,854 controls, 1821 OA, and 1837 OGJA, seven studies also collected OSCC cases (n=1016). Study specific ORs and 95% CIs were calculated from multivariate adjusted logistic regression models for alcohol intake in categories compared to non-drinkers. Summary risk estimates were obtained by random effects models. Results No increase was observed in the risk of OA or OGJA for increasing levels of any of the alcohol intake measures examined. ORs for the highest frequency category (≥ 7 drinks per day) were 0.97 (95% CI 0.68 to 1.36) for OA and 0.77 (95% CI = 0.54 to 1.10) for OGJA. Suggestive findings linked moderate intake (eg, 0.5 to <1 drink per day) to decreased risk of OA (OR 0.63, 95% CI 0.41 to 0.99) and OGJA (OR 0.78, 95% CI 0.62 to 0.99). In contrast, alcohol intake was strongly associated with increased risk of OSCC (OR for ≥ 7 drinks per day 9.62, 95% CI 4.26 to 21.71).
In contrast to OSCC, higher alcohol consumption was not associated with increased risk of either OA or OGJA. The apparent inverse association observed with moderate alcohol intake should be evaluated in future prospective studies.
The structure and dynamics of phospholipid reverse micelles are studied by molecular dynamics. We report all-atom unconstrained simulations of 1,2-dioleoyl-sn-phosphatidylcholine (DOPC) reverse ...micelles in benzene of increasing sizes, with water-to-surfactant number ratios ranging from W 0 = 1 to 16. The aggregation number, i.e., the number of DOPC molecules per reverse micelle, is determined to fit experimental light-scattering measurements of the reverse micelle diameter. The simulated reverse micelles are found to be approximately spherical. Larger reverse micelles (W 0 > 4) exhibit a layered structure with a water core and the hydration structure of DOPC phosphate head groups is similar to that found in phospholipid membranes. In contrast, the structure of smaller reverse micelles (W 0 ≤ 4) cannot be described as a series of concentric layers successively containing water, surfactant head groups, and surfactant tails, and the head groups are only partly hydrated and frequently present in the core. The dynamics of water molecules within the phospholipid reverse micelles slow down as the reverse micelle size decreases, in agreement with prior studies on AOT and Igepal reverse micelles. However, the average water reorientation dynamics in DOPC reverse micelles is found to be much slower than in AOT and Igepal reverse micelles with the same W 0 ratio. This is explained by the smaller water pool and by the stronger interactions between water and the charged head groups, as confirmed by the red-shift of the computed infrared line shape with decreasing W 0.
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Over recent years the role of biomarkers in anticancer drug development has expanded across a spectrum of applications ranging from research tool during early discovery to surrogate endpoint in the ...clinic. However, in Europe when biomarker measurements are performed on samples collected from subjects entered into clinical trials of new investigational agents, laboratories conducting these analyses become subject to the Clinical Trials Regulations. While these regulations are not specific in their requirements of research laboratories, quality assurance and in particular assay validation are essential. This review, therefore, focuses on a discussion of current thinking in biomarker assay validation. Five categories define the majority of biomarker assays from ‘absolute quantitation’ to ‘categorical’. Validation must therefore take account of both the position of the biomarker in the spectrum towards clinical end point and the level of quantitation inherent in the methodology. Biomarker assay validation should be performed ideally in stages on ‘a fit for purpose’ basis avoiding unnecessarily dogmatic adherence to rigid guidelines but with careful monitoring of progress at the end of each stage. These principles are illustrated with two specific examples: (a) absolute quantitation of protein biomarkers by mass spectrometry and (b) the M30 and M65 ELISA assays as surrogate end points of cell death.
British Journal of Pharmacology (2008) 153, 646–656; doi:10.1038/sj.bjp.0707441; published online 17 September 2007
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Osteoarthritis and rheumatoid arthritis are debilitating conditions, affecting millions of people. Both osteoarthritis and rheumatoid arthritis degrade the articular cartilage (AC) at the ends of ...long bones, resulting in weakened tissue prone to further damage. This degradation impairs the cartilage’s mechanical properties leading to areas of thinned cartilage and exposed bone which compromises the integrity of the joint. No preventative measures exist for joint destruction. Discovering a way to slow the degradation of AC or prevent it would slow the painful progression of the disease, allowing millions to live pain-free. Recently, that the articular injection of the polyphenol epigallocatechin-gallate (EGCG) slows AC damage in an arthritis rat model. It was suggested that EGCG crosslinks AC and makes it resistant to degradation. However, direct evidence that intraarticular injection of EGCG crosslinks cartilage collagen and changes its compressive properties are not known. The aim of this study was to investigate the effects of intraarticular injection of EGCG induced biomechanical properties of AC. We hypothesize that in vivo exposure EGCG will bind and crosslink to AC collagen and alter its biomechanical properties. We developed a technique of nano-indentation to investigate articular cartilage properties by measuring cartilage compressive properties and quantifying differences due to EGCG exposure. In this study, the rat knee joint was subjected to a series of intraarticular injections of EGCG and contralateral knee joint was injected with saline. After the injections animals were sacrificed, and the knees were removed and tested in an anatomically relevant model of nanoindentation. All mechanical data was normalized to the measurements in the contralateral knee to better compare data between the animals. The data demonstrated significant increases for reduced elastic modulus (57.5%), hardness (83.2%), and stiffness (17.6%) in cartilage treated with injections of EGCG normalized to those treated with just saline solution when compared to baseline subjects without injections, with a significance level of alpha = 0.05. This data provides evidence that EGCG treated cartilage yields a strengthened cartilage matrix as compared to AC from the saline injected knees. These findings are significant because the increase in cartilage biomechanics will translate into resistance to degradation in arthritis. Furthermore, the data suggest for the first time that it is possible to strengthen the articular cartilage by intraarticular injections of polyphenols. Although this data is preliminary, it suggests that clinical applications of EGCG treated cartilage could yield strengthened tissue with the potential to resist or compensate for matrix degradation caused by arthritis.
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During the past several decades, an increasing incidence of thyroid cancer has been reported in many parts of the world. To date, no study has compared the trends in thyroid cancer incidence across ...continents. We examined incidence data from cancer incidence in five continents (CI5) over the 30-year period 1973–2002 from 19 populations in the Americas, Asia, Europe, and Oceania. Thyroid cancer rates have increased from 1973–1977 to 1998–2002 for most of the populations except Sweden, in which the incidence rates decreased about 18% for both males and females. The average increase was 48.0% among males and 66.7% among females. More recently, the age-adjusted international thyroid cancer incidence rates from 1998 to 2002 varied 5-fold for males and nearly 10-fold for females by geographic region. Considerable variation in thyroid cancer incidence was present for every continent but Africa, in which the incidence rates were generally low. Our analysis of published CI5 data suggests that thyroid cancer rates increased between 1973 and 2002 in most populations worldwide, and that the increase does not appear to be restricted to a particular region of the world or by the underlying rates of thyroid cancer.
Nanoporous silica materials are important in catalysis, energy, and materials applications in which water is an essential component. System performance is intimately connected to the water dynamics ...occurring in the confined environment. However, the dynamics and associated structures of water in nanoporous silica have proven challenging to measure and predict. Here, confined water dynamics are examined via the ultrafast infrared spectroscopy of selenocyanate (SeCN–) dissolved in the hydrated ∼2.4 nm silica mesopores of MCM41. Polarization selective pump–probe and two-dimensional infrared measurements on the CN stretching mode of SeCN– are used to probe the effect of confinement on orientational relaxation and spectral diffusion dynamics. The dynamics of SeCN– provide information on the surrounding water hydrogen bond dynamics. The long CN stretch lifetime (∼36 ps), relative to the water hydroxyl stretch (<2 ps), significantly extends the time scales that can be accessed. Complete orientational relaxation (C 2(t), orientational correlation function) and spectral diffusion (C ω(t), frequency–frequency correlation function) dynamics are presented and compared to the simulated time correlation functions in a model silica pore of the same size. A slow decay component not present in the bulk liquid is observed in both experiments, indicating that the hydrogen bond dynamics are significantly altered by confinement. The simulations reveal a qualitative difference in the functional dependence of C 2(t;d) and C ω(t;d) on d, the distance from the interface. The former becomes exponentially faster with distance while the latter makes an abrupt transition from slower to faster dynamics midway between the surface and pore center, d ≅ 6 Å.
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