Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes

BACKGROUND:Cardiovascular disease (CVD) and its most common manifestations - including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) - are major causes of morbidity and mortality. In many industrialized countries, cardiovascular disease (CVD) claims more lives each year than any other disease. Heart disease and stroke are the first and third leading causes of death in the United States. Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes.METHODS:In 1345 Framingham Heart Study participants from the largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of 70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118; myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the condition at entry were included in proportional hazards models. We analyzed model-based deviance residuals using generalized estimating equations to test associations between SNP genotypes and traits in additive genetic models restricted to autosomal SNPs with minor allele frequency [greater than or equal to]0.10, genotype call rate [greater than or equal to]0.80, and Hardy-Weinberg equilibrium p-value [greater than or equal to] 0.001.RESULTS:Six associations yielded p <10-5. The lowest p-values for each CVD trait were as follows: major CVD, rs499818, p = 6.6 x 10-6; major CHD, rs2549513, p = 9.7 x 10-6; AF, rs958546, p = 4.8 x 10-6; HF: rs740363, p = 8.8 x 10-6. Of note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7 - 1.9 x 10-5) and major CHD (p 2.5 - 3.5 x 10-4) that confirm associations with CHD in two recently reported genome-wide association studies. Also, rs10501920 in CNTN5 was associated with AF (p = 9.4 x 10-6) and HF (p = 1.2 x 10-4). Complete results for these phenotypes can be found at the dbgap website http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:No association attained genome-wide significance, but several intriguing findings emerged. Notably, we replicated associations of chromosome 9p21 with major CVD. Additional studies are needed to validate these results. Finding genetic variants associated with CVD may point to novel disease pathways and identify potential targeted preventive therapies.

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.

Cancer mortality in IBM endicott plant workers, 1969-2001: An update on a NY production plant

BACKGROUND: In response to concerns expressed by workers at a public meeting, we analyzed the mortality experience of workers who were employed at the IBM plant in Endicott, New York and died between 1969-2001. An epidemiologic feasibility assessment indicated potential worker exposure to several known and suspected carcinogens at this plant. METHODS: We used the mortality and work history files produced under a court order and used in a previous mortality analysis. Using publicly available data for the state of New York as a standard of comparison, we conducted proportional cancer mortality (PCMR) analysis. RESULTS: The results showed significantly increased mortality due to melanoma (PCMR = 367; 95% CI: 119, 856) and lymphoma (PCMR = 220; 95% CI: 101, 419) in males and modestly increased mortality due to kidney cancer (PCMR = 165; 95% CI: 45, 421) and brain cancer (PCMR = 190; 95% CI: 52, 485) in males and breast cancer (PCMR = 126; 95% CI: 34, 321) in females. CONCLUSION: These results are similar to results from a previous IBM mortality study and support the need for a full cohort mortality analysis such as the one being planned by the National Institute for Occupational Safety and Health.

Urinary naphthalene and phenanthrene as biomarkers of occupational exposure to polycyclic aromatic hydrocarbons.

OBJECTIVES: The study investigated the utility of unmetabolised naphthalene (Nap) and phenanthrene (Phe) in urine as surrogates for exposures to mixtures of polycyclic aromatic hydrocarbons (PAHs). METHODS: The report included workers exposed to diesel exhausts (low PAH exposure level, n = 39) as well as those exposed to emissions from asphalt (medium PAH exposure level, n = 26) and coke ovens (high PAH exposure level, n = 28). Levels of Nap and Phe were measured in urine from each subject using head space-solid phase microextraction and gas chromatography-mass spectrometry. Published levels of airborne Nap, Phe and other PAHs in the coke-producing and aluminium industries were also investigated. RESULTS: In post-shift urine, the highest estimated geometric mean concentrations of Nap and Phe were observed in coke-oven workers (Nap: 2490 ng/l; Phe: 975 ng/l), followed by asphalt workers (Nap: 71.5 ng/l; Phe: 54.3 ng/l), and by diesel-exposed workers (Nap: 17.7 ng/l; Phe: 3.60 ng/l). After subtracting logged background levels of Nap and Phe from the logged post-shift levels of these PAHs in urine, the resulting values (referred to as ln(adjNap) and ln(adjPhe), respectively) were significantly correlated in each group of workers (0.71 < or = Pearson r < or = 0.89), suggesting a common exposure source in each case. Surprisingly, multiple linear regression analysis of ln(adjNap) on ln(adjPhe) showed no significant effect of the source of exposure (coke ovens, asphalt and diesel exhaust) and further suggested that the ratio of urinary Nap/Phe (in natural scale) decreased with increasing exposure levels. These results were corroborated with published data for airborne Nap and Phe in the coke-producing and aluminium industries. The published air measurements also indicated that Nap and Phe levels were proportional to the levels of all combined PAHs in those industries. CONCLUSION: Levels of Nap and Phe in urine reflect airborne exposures to these compounds and are promising surrogates for occupational exposures to PAH mixtures.

INVESTIGATION OF OCEAN ACOUSTICS USING AUTONOMOUS INSTRUMENTATION TO QUANTIFY THE WATER-SEDIMENT BOUNDARY PROPERTIES

Sound propagation in shallow water is characterized by interaction with the oceans surface, volume, and bottom. In many coastal margin regions, including the Eastern U.S. continental shelf and the coastal seas of China, the bottom is composed of a depositional sandy-silty top layer. Previous measurements of narrow and broadband sound transmission at frequencies from 100 Hz to 1 kHz in these regions are consistent with waveguide calculations based on depth and frequency dependent sound speed, attenuation and density profiles. Theoretical predictions for the frequency dependence of attenuation vary from quadratic for the porous media model of M.A. Biot to linear for various competing models. Results from experiments performed under known conditions with sandy bottoms, however, have agreed with attenuation proportional to f1.84, which is slightly less than the theoretical value of f2 [Zhou and Zhang, J. Acoust. Soc. Am. 117, 2494]. This dissertation presents a reexamination of the fundamental considerations in the Biot derivation and leads to a simplification of the theory that can be coupled with site-specific, depth dependent attenuation and sound speed profiles to explain the observed frequency dependence. Long-range sound transmission measurements in a known waveguide can be used to estimate the site-specific sediment attenuation properties, but the costs and time associated with such at-sea experiments using traditional measurement techniques can be prohibitive. Here a new measurement tool consisting of an autonomous underwater vehicle and a small, low noise, towed hydrophone array was developed and used to obtain accurate long-range sound transmission measurements efficiently and cost effectively. To demonstrate this capability and to determine the modal and intrinsic attenuation characteristics, experiments were conducted in a carefully surveyed area in Nantucket Sound. A best-fit comparison between measured results and calculated results, while varying attenuation parameters, revealed the estimated power law exponent to be 1.87 between 220.5 and 1228 Hz. These results demonstrate the utility of this new cost effective and accurate measurement system. The sound transmission results, when compared with calculations based on the modified Biot theory, are shown to explain the observed frequency dependence.

On the Emergence of Highly Variable Distributions in the Autonomous System Topology

Recent studies have noted that vertex degree in the autonomous system (AS) graph exhibits a highly variable distribution [15, 22]. The most prominent explanatory model for this phenomenon is the Barabási-Albert (B-A) model [5, 2]. A central feature of the B-A model is preferential connectivity—meaning that the likelihood a new node in a growing graph will connect to an existing node is proportional to the existing node’s degree. In this paper we ask whether a more general explanation than the B-A model, and absent the assumption of preferential connectivity, is consistent with empirical data. We are motivated by two observations: first, AS degree and AS size are highly correlated [11]; and second, highly variable AS size can arise simply through exponential growth. We construct a model incorporating exponential growth in the size of the Internet, and in the number of ASes. We then show via analysis that such a model yields a size distribution exhibiting a power-law tail. In such a model, if an AS’s link formation is roughly proportional to its size, then AS degree will also show high variability. We instantiate such a model with empirically derived estimates of growth rates and show that the resulting degree distribution is in good agreement with that of real AS graphs.

Approximately Uniform Random Sampling in Sensor Networks

Recent work in sensor databases has focused extensively on distributed query problems, notably distributed computation of aggregates. Existing methods for computing aggregates broadcast queries to all sensors and use in-network aggregation of responses to minimize messaging costs. In this work, we focus on uniform random sampling across nodes, which can serve both as an alternative building block for aggregation and as an integral component of many other useful randomized algorithms. Prior to our work, the best existing proposals for uniform random sampling of sensors involve contacting all nodes in the network. We propose a practical method which is only approximately uniform, but contacts a number of sensors proportional to the diameter of the network instead of its size. The approximation achieved is tunably close to exact uniform sampling, and only relies on well-known existing primitives, namely geographic routing, distributed computation of Voronoi regions and von Neumann's rejection method. Ultimately, our sampling algorithm has the same worst-case asymptotic cost as routing a point-to-point message, and thus it is asymptotically optimal among request/reply-based sampling methods. We provide experimental results demonstrating the effectiveness of our algorithm on both synthetic and real sensor topologies.

Seed Scheduling for Peer-to-Peer Networks

The initial phase in a content distribution (file sharing) scenario is a delicate phase due to the lack of global knowledge and the dynamics of the overlay. An unwise distribution of the pieces in this phase can cause delays in reaching steady state, thus increasing file download times. We devise a scheduling algorithm at the seed (source peer with full content), based on a proportional fair approach, and we implement it on a real file sharing client [1]. In dynamic overlays, our solution improves up to 25% the average downloading time of a standard protocol ala BitTorrent.

Optimisation of granola breakfast cereal manufacturing process by wet granulation and pneumatic conveying

This study has considered the optimisation of granola breakfast cereal manufacturing processes by wet granulation and pneumatic conveying. Granola is an aggregated food product used as a breakfast cereal and in cereal bars. Processing of granola involves mixing the dry ingredients (typically oats, nuts, etc.) followed by the addition of a binder which can contain honey, water and/or oil. In this work, the design and operation of two parallel wet granulation processes to produce aggregate granola products were incorporated: a) a high shear mixing granulation process followed by drying/toasting in an oven. b) a continuous fluidised bed followed by drying/toasting in an oven. In high shear granulation the influence of process parameters on key granule aggregate quality attributes such as granule size distribution and textural properties of granola were investigated. The experimental results show that the impeller rotational speed is the single most important process parameter which influences granola physical and textural properties. After that binder addition rate and wet massing time also show significant impacts on granule properties. Increasing the impeller speed and wet massing time increases the median granule size while also presenting a positive correlation with density. The combination of high impeller speed and low binder addition rate resulted in granules with the highest levels of hardness and crispness. In the fluidised bed granulation process the effect of nozzle air pressure and binder spray rate on key aggregate quality attributes were studied. The experimental results show that a decrease in nozzle air pressure leads to larger in mean granule size. The combination of lowest nozzle air pressure and lowest binder spray rate results in granules with the highest levels of hardness and crispness. Overall, the high shear granulation process led to larger, denser, less porous and stronger (less likely to break) aggregates than the fluidised bed process. The study also examined the particle breakage of granola during pneumatic conveying produced by both the high shear granulation and the fluidised bed granulation process. Products were pneumatically conveyed in a purpose built conveying rig designed to mimic product conveying and packaging. Three different conveying rig configurations were employed; a straight pipe, a rig consisting two 45° bends and one with 90° bend. Particle breakage increases with applied pressure drop, and a 90° bend pipe results in more attrition for all conveying velocities relative to other pipe geometry. Additionally for the granules produced in the high shear granulator; those produced at the highest impeller speed, while being the largest also have the lowest levels of proportional breakage while smaller granules produced at the lowest impeller speed have the highest levels of breakage. This effect clearly shows the importance of shear history (during granule production) on breakage during subsequent processing. In terms of the fluidised bed granulation, there was no single operating parameter that was deemed to have a significant effect on breakage during subsequent conveying. Finally, a simple power law breakage model based on process input parameters was developed for both manufacturing processes. It was found suitable for predicting the breakage of granola breakfast cereal at various applied air velocities using a number of pipe configurations, taking into account shear histories.

On classical and other methods of discriminant analysis and estimation of log-odds

For two multinormal populations with equal covariance matrices the likelihood ratio discriminant function, an alternative allocation rule to the sample linear discriminant function when n1 ≠ n2 ,is studied analytically. With the assumption of a known covariance matrix its distribution is derived and the expectation of its actual and apparent error rates evaluated and compared with those of the sample linear discriminant function. This comparison indicates that the likelihood ratio allocation rule is robust to unequal sample sizes. The quadratic discriminant function is studied, its distribution reviewed and evaluation of its probabilities of misclassification discussed. For known covariance matrices the distribution of the sample quadratic discriminant function is derived. When the known covariance matrices are proportional exact expressions for the expectation of its actual and apparent error rates are obtained and evaluated. The effectiveness of the sample linear discriminant function for this case is also considered. Estimation of true log-odds for two multinormal populations with equal or unequal covariance matrices is studied. The estimative, Bayesian predictive and a kernel method are compared by evaluating their biases and mean square errors. Some algebraic expressions for these quantities are derived. With equal covariance matrices the predictive method is preferable. Where it derives this superiority is investigated by considering its performance for various levels of fixed true log-odds. It is also shown that the predictive method is sensitive to n1 ≠ n2. For unequal but proportional covariance matrices the unbiased estimative method is preferred. Product Normal kernel density estimates are used to give a kernel estimator of true log-odds. The effect of correlation in the variables with product kernels is considered. With equal covariance matrices the kernel and parametric estimators are compared by simulation. For moderately correlated variables and large dimension sizes the product kernel method is a good estimator of true log-odds.

The role played by angiotensin (1-7) in the regulation of renal haemodynamics and excretory function in anesthetized rats

Initial studies have demonstrated that intra- renal infusion of Ang (1-7) caused a diuresis and natriuresis that was proportional to the degree of activation of the Renin Angiotensin Aldosterone System (RAAS). This raised the question as why the magnitude of this diuresis and natriuresis was compromised in rats receiving a high sodium diet (suppressed RAAS) and enhanced in low sodium fed rats (activated RAAS)? Could the answer lie with changes in intra-renal AT1 or Mas receptor expression? Interestingly, the observed Ang (1-7) induced increases in sodium and water excretion in rats receiving either a low or normal sodium diet were and blocked in the presence of the AT 1 receptor antagonist (Losartan) in the presence of the, 'Mas' receptor antagonist (A-779). These data suggest that both AT1 and 'Mas' receptors need to be functional in order to fully mediate the renal responses to intra-renal Ang (1-7) infusion. Importantly, further experimentation also revealed that there is a proportional relationship between AT 1 receptor expression in the rat renal cortex and the magnitude of the excretory actions of intra renal Ang (1-7) infusion, which is only partially dependent on the level of 'Mas' receptor expression. These observations suggest that although Ang (1-7) induced increases in sodium and water excretion are mediated by the Mas receptor, the magnitude of these excretory responses appear to be dependent upon the level of AT 1 receptor expression and more specifically Ang II/ AT 1 receptor signalling. Thus in rats receiving a low sodium diet, Ang (1-7) acts via the Mas receptor to inhibit Ang II/ AT 1 receptor signalling. In rats receiving a high sodium diet the down regulated AT 1 receptor expression implies a reduction in Ang II/ AT 1 receptor signalling which renders the counter-regulatory effects of intra-renal Ang (1-7) infusion redundant.

Survival analysis of adult tuberculosis disease

Background: We conducted a survival analysis of all the confirmed cases of Adult Tuberculosis (TB) patients treated in Cork-City, Ireland. The aim of this study was to estimate Survival time (ST), including median time of survival and to assess the association and impact of covariates (TB risk factors) to event status and ST. The outcome of the survival analysis is reported in this paper. Methods: We used a retrospective cohort study research design to review data of 647 bacteriologically confirmed TB patients from the medical record of two teaching hospitals. Mean age 49 years (Range 18–112). We collected information on potential risk factors of all confirmed cases of TB treated between 2008–2012. For the survival analysis, the outcome of interest was ‘treatment failure’ or ‘death’ (whichever came first). A univariate descriptive statistics analysis was conducted using a non- parametric procedure, Kaplan -Meier (KM) method to estimate overall survival (OS), while the Cox proportional hazard model was used for the multivariate analysis to determine possible association of predictor variables and to obtain adjusted hazard ratio. P value was set at <0.05, log likelihood ratio test at >0.10. Data were analysed using SPSS version 15.0. Results: There was no significant difference in the survival curves of male and female patients. (Log rank statistic = 0.194, df = 1, p = 0.66) and among different age group (Log rank statistic = 1.337, df = 3, p = 0.72). The mean overall survival (OS) was 209 days (95%CI: 92–346) while the median was 51 days (95% CI: 35.7–66). The mean ST for women was 385 days (95%CI: 76.6–694) and for men was 69 days (95%CI: 48.8–88.5). Multivariate Cox regression showed that patient who had history of drug misuse had 2.2 times hazard than those who do not have drug misuse. Smokers and alcohol drinkers had hazard of 1.8 while patients born in country of high endemicity (BICHE) had hazard of 6.3 and HIV co-infection hazard was 1.2. Conclusion: There was no significant difference in survival curves of male and female and among age group. Women had a higher ST compared to men. But men had a higher hazard rate compared to women. Anti-TNF, immunosuppressive medication and diabetes were found to be associated with longer ST, while alcohol, smoking, RICHE, BICHE was associated with shorter ST.

A microscopic study of structural and electronic properties of functionalized silicon surfaces based on first-principles

Surface modification of silicon with organic monolayers tethered to the surface by different linkers is an important process in realizing future (opto-)electronic devices. Understanding the role played by the nature of the linking group and the chain length on the adsorption structures and electronic properties of these assemblies is vital to advance this technology. This Thesis is a study of such properties and contributes in particular to a microscopic understanding of induced changes in the work function of experimentally studied functionalized silicon surfaces. Using first-principles density functional theory (DFT), at the first step, we provide predictions for chemical trends in the work function of hydrogenated silicon (111) surfaces modified with various terminations. For nonpolar terminating atomic species such as F, Cl, Br, and I, the change in the work function is directly proportional to the amount of charge transferred from the surface, thus relating to the difference in electronegativity of the adsorbate and silicon atoms. The change is a monotonic function of coverage in this case, and the work function increases with increasing electronegativity. Polar species such as −TeH, −SeH, −SH, −OH, −NH2, −CH3, and −BH2 do not follow this trend due to the interaction of their dipole with the induced electric field at the surface. In this case, the magnitude and sign of the surface dipole moment need to be considered in addition to the bond dipole to generally describe the change in work function. Compared to hydrogenated surfaces, there is slight increase in the work function of H:Si(111)-XH, where X = Te, Se, and S, whereas reduction is observed for surfaces covered with −OH, −CH3, and −NH2. Next, we study the hydrogen passivated Si(111) surface modified with alkyl chains of the general formula H:Si–(CH2)n–CH2 and H:Si–X–(CH2)n–CH3, where X = NH, O, S and n = (0, 1, 3, 5, 7, 9, 11), at half coverage. For (X)–Hexyl and (X)–Dodecyl functionalization, we also examined various coverages up to full monolayer grafting in order to validate the result of half covered surface and the linker effect on the coverage. We find that it is necessary to take into account the van der Waals interaction between the alkyl chains. The strongest binding is for the oxygen linker, followed by S, N, and C, irrespective of chain length. The result revealed that the sequence of the stability is independent of coverage; however, linkers other than carbon can shift the optimum coverage considerably and allow further packing density. For all linkers apart from sulfur, structural properties, in particular, surface-linker-chain angles, saturate to a single value once n > 3. For sulfur, we identify three regimes, namely, n = 0–3, n = 5–7, and n = 9–11, each with its own characteristic adsorption structures. Where possible, our computational results are shown to be consistent with the available experimental data and show how the fundamental structural properties of modified Si surfaces can be controlled by the choice of linking group and chain length. Later we continue by examining the work function tuning of H:Si(111) over a range of 1.73 eV through adsorption of alkyl monolayers with general formula -[Xhead-group]-(CnH2n)-[Xtail-group], X = O(H), S(H), NH(2). The work function is practically converged at 4 carbons (8 for oxygen), for head-group functionalization. For tail-group functionalization and with both head- and tail-groups, there is an odd-even effect in the behavior of the work function, with peak-to-peak amplitudes of up to 1.7 eV in the oscillations. This behavior is explained through the orientation of the terminal-group's dipole. The shift in the work function is largest for NH2-linked and smallest for SH-linked chains and is rationalized in terms of interface dipoles. Our study reveals that the choice of the head- and/or tail-groups effectively changes the impact of the alkyl chain length on the work function tuning using self-assembled monolayers and this is an important advance in utilizing hybrid functionalized Si surfaces. Bringing together the understanding gained from studying single type functionalization of H:Si(111) with different alkyl chains and bearing in mind how to utilize head-group, tail-group or both as well as monolayer coverage, in the final part of this Thesis we study functionalized H:Si(111) with binary SAMs. Aiming at enhancing work function adjustment together with SAM stability and coverage we choose a range of terminations and linker-chains denoted as –X–(Alkyl) with X = CH3, O(H), S(H), NH(2) and investigate the stability and work function of various binary components grafted onto H:Si(111) surface. Using binary functionalization with -[NH(2)/O(H)/S(H)]-[Hexyl/Dodecyl] we show that work function can be tuned within the interval of 3.65-4.94 eV and furthermore, enhance the SAM’s stability. Although direct Si-C grafted SAMs are less favourable compared to their counterparts with O, N or S linkage, regardless of the ratio, binary functionalized alkyl monolayers with X-alkyl (X = NH, O) is always more stable than single type alkyl functionalization with the same coverage. Our results indicate that it is possible to go beyond the optimum coverage of pure alkyl functionalized SAMs (50%) by adding a linker with the correct choice of the linker. This is very important since dense packed monolayers have fewer defects and deliver higher efficiency. Our results indicate that binary anchoring can modify the charge injection and therefore bond stability while preserving the interface electronic structure.

Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over.

PURPOSE: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival ¿PFS) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m(2), 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m(2), intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS: Objective response in first-line therapy was significantly better (P =.003) for doxorubicin (response rate ¿RR, 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P <.001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P =.38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.

Baseline health-related quality-of-life data as prognostic factors in a phase III multicentre study of women with metastatic breast cancer.

The potential value of baseline health-related quality-of-life (HRQOL) and clinical factors in predicting prognosis was examined using data from an international randomised phase III trial which compared doxorubicin and paclitaxel with doxorubicin and cylophosphamide as first line chemotherapy in 275 women with metastatic breast cancer. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the related breast module (QLQ-BR23) were used to assess baseline HRQOL data. The Cox proportional-hazards regression model was used for both univariate and multivariate analyses of survival. In the univariate analyses, performance status (P<0.001) and number of sites involved (P=0.001) were the most important clinical prognostic factors. The HRQOL variables at baseline most strongly associated with longer survival were better appetite, physical and role functioning, as well as less fatigue (P<0.001). The final multivariate model retained performance status (P<0.001) and appetite loss (P=0.005) as the variables best predicting survival. Substantial loss of appetite was the only independent HRQOL factor predicting poor survival and was strongly correlated (/r/>0.5) with fatigue, role and physical functioning. In addition to known clinical factors, appetite loss appears to be a significant prognostic factor for survival in women with metastatic breast cancer. However, the mechanism underlying this association remains to be precisely defined in future studies.