Sphingosine Kinase 1 Promotes Malignant Progression in Colon Cancer and Independently Predicts Survival of Patients With Colon Cancer by Competing Risk Approach in South Asian Population

OBJECTIVES: Sphingosine kinase 1 (SphK1) phosphorylates the membrane sphingolipid, sphingosine, to sphingosine-1-phosphate (S1P), an oncogenic mediator, which drives tumor cell growth and survival. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colon cancer remains uncertain. We investigated the clinical relevance of SphK1 expression in colon cancer as well as its inhibitory effects in vitro.

METHODS: SphK1 expression in human colon tumor tissues was determined by immunohistochemistry and its clinicopathological significance was ascertained in 303 colon cancer cases. The effects of SphK1 inhibition on colon cancer cell viability and the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway were investigated using a SphK1-selective inhibitor-compound 5c (5c). The cytotoxicity of a novel combination using SphK1 inhibition with the chemotherapeutic drug, 5-fluorouracil (5-FU), was also determined.

RESULTS: High SphK1 expression correlated with advanced tumor stages (AJCC classification). Using a competing risk analysis model to take into account disease recurrence, we found that SphK1 is a significant independent predictor for mortality in colon cancer patients. In vitro, the inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/Akt signaling. Inhibition of SphK1 also enhanced the sensitivity of colon cancer cells to 5-FU.

CONCLUSION: Our findings highlight the impact of SphK1 in colon cancer progression and patient survival, and provide evidence supportive of further development in combination strategies that incorporate SphK1 inhibition with current chemotherapeutic agents to improve colon cancer outcomes.

Prevalence and Diagnostic Approach to Sleep Apnea in Hemodialysis Patients: A Population Study.

BACKGROUND: Previous observations found a high prevalence of obstructive sleep apnea (OSA) in the hemodialysis population, but the best diagnostic approach remains undefined. We assessed OSA prevalence and performance of available screening tools to propose a specific diagnostic algorithm. METHODS: 104 patients from 6 Swiss hemodialysis centers underwent polygraphy and completed 3 OSA screening scores: STOP-BANG, Berlin's Questionnaire, and Adjusted Neck Circumference. The OSA predictors were identified on a derivation population and used to develop the diagnostic algorithm, which was validated on an independent population. RESULTS: We found 56% OSA prevalence (AHI ≥ 15/h), which was largely underdiagnosed. Screening scores showed poor performance for OSA screening (ROC areas 0.538 [SE 0.093] to 0.655 [SE 0.083]). Age, neck circumference, and time on renal replacement therapy were the best predictors of OSA and were used to develop a screening algorithm, with higher discriminatory performance than classical screening tools (ROC area 0.831 [0.066]). CONCLUSIONS: Our study confirms the high OSA prevalence and highlights the low diagnosis rate of this treatable cardiovascular risk factor in the hemodialysis population. Considering the poor performance of OSA screening tools, we propose and validate a specific algorithm to identify hemodialysis patients at risk for OSA for whom further sleep investigations should be considered.

The Axiomatic Approach to Population Ethics

This paper examines several families of population principles in the light of a set of axioms. In addition to the critical-level utilitarian, number-sensitive critical-level utilitarian and number-dampened families and their generalized counterparts, we consider the restricted number-dampened family (suggested by Hurka) and introduce two new families : the restricted critical-level and restricted number-dependent critical-level families. Subsets of the restricted families have nonnegative critical levels and avoid both the repugnant and sadistic conclusions but fail to satisfy an important independence condition. We defend the critical-level principles with positive critical levels.

Harsanyi’s Social Aggregation Theorem : A Multi-Profile Approach with Variable-Population Extensions

This paper provides new versions of Harsanyi’s social aggregation theorem that are formulated in terms of prospects rather than lotteries. Strengthening an earlier result, fixed-population ex-ante utilitarianism is characterized in a multi-profile setting with fixed probabilities. In addition, we extend the social aggregation theorem to social-evaluation problems under uncertainty with a variable population and generalize our approach to uncertain alternatives, which consist of compound vectors of probability distributions and prospects.

A novel parallel approach to the likelihood-based estimation of admixture in population genetics

Inferring population admixture from genetic data and quantifying it is a difficult but crucial task in evolutionary and conservation biology. Unfortunately state-of-the-art probabilistic approaches are computationally demanding. Effectively exploiting the computational power of modern multiprocessor systems can thus have a positive impact to Monte Carlo-based simulation of admixture modeling. A novel parallel approach is briefly described and promising results on its message passing interface (MPI)-based C implementation are reported.

Inferring population history with DIY ABC: a user-friendly approach to approximate Bayesian computation

Genetic data obtained on population samples convey information about their evolutionary history. Inference methods can extract part of this information but they require sophisticated statistical techniques that have been made available to the biologist community (through computer programs) only for simple and standard situations typically involving a small number of samples. We propose here a computer program (DIY ABC) for inference based on approximate Bayesian computation (ABC), in which scenarios can be customized by the user to fit many complex situations involving any number of populations and samples. Such scenarios involve any combination of population divergences, admixtures and population size changes. DIY ABC can be used to compare competing scenarios, estimate parameters for one or more scenarios and compute bias and precision measures for a given scenario and known values of parameters (the current version applies to unlinked microsatellite data). This article describes key methods used in the program and provides its main features. The analysis of one simulated and one real dataset, both with complex evolutionary scenarios, illustrates the main possibilities of DIY ABC.

An approximate Bayesian computation approach to overcome biases that arise when using amplified fragment length polymorphism markers to study population structure

There is great interest in using amplified fragment length polymorphism (AFLP) markers because they are inexpensive and easy to produce. It is, therefore, possible to generate a large number of markers that have a wide coverage of species genotnes. Several statistical methods have been proposed to study the genetic structure using AFLP's but they assume Hardy-Weinberg equilibrium and do not estimate the inbreeding coefficient, F-IS. A Bayesian method has been proposed by Holsinger and colleagues that relaxes these simplifying assumptions but we have identified two sources of bias that can influence estimates based on these markers: (i) the use of a uniform prior on ancestral allele frequencies and (ii) the ascertainment bias of AFLP markers. We present a new Bayesian method that avoids these biases by using an implementation based on the approximate Bayesian computation (ABC) algorithm. This new method estimates population-specific F-IS and F-ST values and offers users the possibility of taking into account the criteria for selecting the markers that are used in the analyses. The software is available at our web site (http://www-leca.uif-grenoble.fi-/logiciels.htm). Finally, we provide advice on how to avoid the effects of ascertainment bias.

Extending Zelterman’s approach for robust estimation of population size to zero-truncated clustered data

Estimation of population size with missing zero-class is an important problem that is encountered in epidemiological assessment studies. Fitting a Poisson model to the observed data by the method of maximum likelihood and estimation of the population size based on this fit is an approach that has been widely used for this purpose. In practice, however, the Poisson assumption is seldom satisfied. Zelterman (1988) has proposed a robust estimator for unclustered data that works well in a wide class of distributions applicable for count data. In the work presented here, we extend this estimator to clustered data. The estimator requires fitting a zero-truncated homogeneous Poisson model by maximum likelihood and thereby using a Horvitz-Thompson estimator of population size. This was found to work well, when the data follow the hypothesized homogeneous Poisson model. However, when the true distribution deviates from the hypothesized model, the population size was found to be underestimated. In the search of a more robust estimator, we focused on three models that use all clusters with exactly one case, those clusters with exactly two cases and those with exactly three cases to estimate the probability of the zero-class and thereby use data collected on all the clusters in the Horvitz-Thompson estimator of population size. Loss in efficiency associated with gain in robustness was examined based on a simulation study. As a trade-off between gain in robustness and loss in efficiency, the model that uses data collected on clusters with at most three cases to estimate the probability of the zero-class was found to be preferred in general. In applications, we recommend obtaining estimates from all three models and making a choice considering the estimates from the three models, robustness and the loss in efficiency. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Farm income, population and farmland prices: a relative information approach

This paper uses an entropy-based information approach to determine if farmland values are more closely associated with urban pressure or farm income. The basic question is: how much information on changes in farm real estate values is contained in changes in population versus changes in returns to production agriculture? Results suggest population is informative, but changes in farmland values are more strongly associated with changes in the distribution of returns. However, this relationship is not true for every region nor does it hold over time, as for some regions and time periods changes in population are more informative. Results have policy implications for both equity and efficiency.

Pollinator community responses to the spatial population structure of wild plants: A pan-European approach

Land-use changes can alter the spatial population structure of plant species, which may in turn affect the attractiveness of flower aggregations to different groups of pollinators at different spatial scales. To assess how pollinators respond to spatial heterogeneity of plant distributions and whether honeybees affect visitation by other pollinators we used an extensive data set comprising ten plant species and their flower visitors from five European countries. In particular we tested the hypothesis that the composition of the flower visitor community in terms of visitation frequencies by different pollinator groups were affected by the spatial plant population structure, viz. area and density measures, at a within-population (‘patch’) and among-population (‘population’) scale. We found that patch area and population density were the spatial variables that best explained the variation in visitation frequencies within the pollinator community. Honeybees had higher visitation frequencies in larger patches, while bumblebees and hoverflies had higher visitation frequencies in sparser populations. Solitary bees had higher visitation frequencies in sparser populations and smaller patches. We also tested the hypothesis that honeybees affect the composition of the pollinator community by altering the visitation frequencies of other groups of pollinators. There was a positive relationship between visitation frequencies of honeybees and bumblebees, while the relationship with hoverflies and solitary bees varied (positive, negative and no relationship) depending on the plant species under study. The overall conclusion is that the spatial structure of plant populations affects different groups of pollinators in contrasting ways at both the local (‘patch’) and the larger (‘population’) scales and, that honeybees affect the flower visitation by other pollinator groups in various ways, depending on the plant species under study. These contrasting responses emphasize the need to investigate the entire pollinator community when the effects of landscape change on plant–pollinator interactions are studied.

Palaeobiology of the medieval population of Albano (Rome, Italy): a combined morphological and biomolecular approach

Recent years have seen increased interest in skeletal populations from the Imperial Roman Age in Italy, but much less is known about diet and standards of living in the subsequent medieval period. To fill this gap, we conducted a morphological analysis of human remains from Albano, an Italian town near Rome, as well as a stable isotope analysis of bone collagen to reconstruct diet. The sample was recovered from a Medieval cemetery (1040–1220 cal. yr. BP) located in the gardens of the historical Palazzo Doria Pamphili in Albano. A minimum number of 40 individuals (31 adults and 9 sub-adults) were examined using standard methods. Though the general health status of the population was good, signs of cribra orbitalia and diffuse enthesopathies were noted during the morphological examination. Stable carbon and nitrogen isotope analyses of the bone collagen from 24 adult humans and three faunal bones indicate that the diet of the population may be described as predominantly terrestrial and C3-plant based although the data for some of the individuals suggest a modest consumption of C4-(millet) based or aquatic proteins. No evidence of significant dietary differences between the sexes was found. The comparison of the isotope data from Albano with those from populations recovered in the same region is consistent with a shift from a terrestrial, possibly plant foods-dominated subsistence in the Early Middle Ages to a diet with a higher contribution from animal proteins, both terrestrial and aquatic, in the Later Middle Ages.

Fuzzy subset approach in coupled population dynamics of blowflies

This paper is a study on the population dynamics of blowflies employing a density-dependent. non-linear mathematical model and a coupled population formalism. In this Study, we investigated the coupled population dynamics applying fuzzy subsets to model the Population trajectory. analyzing demographic parameters such as fecundity, Survival, and migration. The main results suggest different possibilities in terms of dynamic behavior produced by migration in coupled Populations between distinct environments and the rescue effect generated by the connection between populations. It was possible to conclude that environmental heterogeneity can play an important role in blowfly metapopulation systems. The implications of these results for population dynamics of blowflies are discussed.

Population ageing, longevity and migration: an overlapping generations approach

The silent demographic revolution characterizing the main industrialized countries is an unavoidable factor which has major economic, social, cultural and psychological implications. This thesis studies the main consequences of population ageing and the connections with the phenomenon of migration, The theoretical analysis is developed using Overlapping Generations Models (OLG). The thesis is divided in the following four chapters: 1) “A Model for Determining Consumption and Social Assistance Demand in Uncertainty Conditions”, focuses on the relation between demographic impact and social insurance and proposes the institution of a non selfsufficiency fund for the elderly. 2) "Population Ageing, Longevity and Health", analyzes the effects of health investment on intertemporal individual behaviour and capital accumulation. 3) "Population Ageing and the Nursing Flow", studies the consequences of migration in the nursing sector. 4) "Quality of Multiculturalism and Minorities' Assimilation", focuses on the problem of assimilation and integration of minorities.