Quercetin aglycone is bioavailable in murine pancreas and pancreatic xenografts

Quercetin is a potential chemopreventive and chemotherapeutic agent for pancreatic and other cancers. This study examined the distribution of quercetin in plasma, lung, liver, pancreas, and pancreatic cancer xenografts in a murine in vivo model and the uptake of quercetin in pancreatic cancer MiaPaCa-2 cells in a cellular in vitro model. Mice were randomly allocated to control or 0.2 and 1% quercetin diet groups utilizing the AIN93G-based diet (n = 12 per group) for 6 weeks. In addition, 6 mice from each group were injected weekly with the chemotherapeutic drug gemcitabine (120 mg/kg mouse, ip). MiaPaCa cells were collected from culture medium after cells were exposed to 30 muM quercetin for 0.5, 1, 2, 4, 8, and 24 h. Levels of quercetin and 3-O'-methylquercetin in mouse tissues and MiaPaCa-2 cells were measured by high-pressure liquid chromatography following enzymatic hydrolysis and then extraction. The study showed that quercetin is accumulated in pancreatic cancer cells and is absorbed in the circulating system, tumors, and tissues of pancreas, liver, and lung in vivo. A higher proportion of total quercetin found in tumors and pancreas is aglycones. Gemcitabine cotreatment with quercetin reduced absorption of quercetin in the mouse circulatory system and liver. Results from the study provide important information on the interpretation of the chemotherapeutic efficacy of quercetin.

Córdoban Discourses: A Drama of Interreligious Dialogue

SETTING: Cordoba, Spain, 1135 CE, 29th year of the reign of ‘Ali “amir al-muslimin,” second king of the Berber Almoravid dynasty, rulers of Moorish Spain from 1071 to 1147. Cordoba, the capital of Andalus and the center of the Almoravid holdings in Spain, is a bustling cosmopolitan center, a crossroads for Europe and the Middle East, and the meeting-point of three religious traditions. Most significantly, Cordoba at this time is the hub of European intellectual activity. From the square—itself impressively large and surrounded by a massive collonade, the regularity and ordered beauty of which typifies the Moorish taste for symmetry (so beloved of M.C. Escher)—can be seen the huge Cordoban mosque, erected in the 8th-century by Khalif Abd-er-Rahman I to the glory of Allah, oft forgiving, most merciful. It is the second largest building in Islam, and the bastion of the still entrenched but soon to fade Muslim presence in western Europe. SCENE: Three figures sit upon stone benches beneath the westernmost colonnade of the Cordoban mosque, involved in an animated, though friendly discussion on matters of faith and reason, knowledge and God, language and logic. The host is none other than Jehudah Halevi, and his esteemed guests Master Peter Abelard and the venerable Råmånuja, whose obviously advanced age belies his youthful voice, gleaming eye, quick hands, and general exuberance. It is autumn, early evening…

MicroRNA-21 suppression impedes medulloblastoma cell migration

Medulloblastoma (MB), the most common malignant brain tumour in children, is characterised by a high risk of leptomeningeal dissemination. But little is known about the molecular mechanisms that promote cancer cell migration in MB. Aberrant expression of miR-21 is recognised to be causatively linked to metastasis in a variety of human neoplasms including brain tumours; however its function in MB is still unknown. In this study we investigated the expression level and the role of miR-21 in MB cell migration. miR-21 was found to be up-regulated, compared to normal cerebellum, in 29/29 MB primary samples and 6/6 MB-derived cell lines. Inverse correlation was observed between miR-21 expression and the metastasis suppressor PDCD4, while miR-21 repression increased the release of PDCD4 protein, suggesting negative regulation of PDCD4 by miR-21 in MB cells. Anti-miR-21 decreased protein expression of the tumour cell invasion mediators MAP4K1 and JNK, which are also known to be negatively regulated by PDCD4, and down-regulated integrin protein that is essential for MB leptomeningeal dissemination. Moreover miR-21 knockdown in MB cells increased the expression of two eminent negative modulators of cancer cell migration, E-Cadherin and TIMP2 proteins that are known to be positively regulated by PDCD4. Finally and importantly, suppression of miR-21 decreased the motility of MB cells and reduced their migration across basement membranes in vitro. Together, these compelling data propose miR-21 pathway as a novel mechanism impacting MB cell dissemination and raises the possibility that curability of selected MB may be improved by pharmaceutical strategies directed towards microRNA-21.

Seasonal variation and sources of low molecular weight organic acids in precipitation in the rural area of Anshun

Low mol. wt. (LMW) org. acids are important and ubiquitous chem. constituents in the atm. A comprehensive study of the chem. compn. of pptn. was carried out from June 2007 to June 2008 at a rural site in Anshun, in the west of Guizhou Province, China. During this period, 118 rainwater samples were collected and the main LMW carboxylic acids were detd. using ion chromatog. The av. pH of rainwater was 4.89 which is a typical acidic value. The most abundant carboxylic acids were formic acid (vol. wt. mean concn.: 8.77 μmol L-1) and acetic acid (6.90 μmol L-1), followed by oxalic acid (2.05 μmol L-1). The seasonal variation of concns. and wet deposition fluxes of org. acids indicated that direct vegetation emissions were the main sources of the org. acids. Highest concns. were obsd. in winter and were ascribed to the low winter rainfall and the contribution of other air pollution sources northeast of the study area. The ratio of formic and acetic acids in the pptn. ([F/A]T) was proposed as an indicator of pollution source. This suggested that the pollution resulted from direct emissions from natural or anthropogenic sources. Comparison with acid pptn. in other urban and rural areas in Guizhou showed that there was a decreasing contribution of LMW org. acids to free acidity and all anions in rainwater from urban to remote rural areas. Consequently, it is necessary to control emissions of org. acids to reduce the frequency of acid rain, esp. in rural and remote areas. [on SciFinder(R)]

Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice

We previously reported that excess of deoxycorticosterone-acetate (DOCA)/salt-induced cardiac hypertrophy in the absence of hypertension in one-renin gene mice. This model allows us to study molecular mechanisms of high-salt intake in the development of cardiovascular remodeling, independently of blood pressure in a high mineralocorticoid state. In this study, we compared the effect of 5-wk low- and high-salt intake on cardiovascular remodeling and cardiac differential gene expression in mice receiving the same amount of DOCA. Differential gene and protein expression was measured by high-density cDNA microarray assays, real-time PCR and Western blot analysis in DOCA-high salt (HS) vs. DOCA-low salt (LS) mice. DOCA-HS mice developed cardiac hypertrophy, coronary perivascular fibrosis, and left ventricular dysfunction. Differential gene and protein expression demonstrated that high-salt intake upregulated a subset of genes encoding for proteins involved in inflammation and extracellular matrix remodeling (e.g., Col3a1, Col1a2, Hmox1, and Lcn2). A major subset of downregulated genes encoded for transcription factors, including myeloid differentiation primary response (MyD) genes. Our data provide some evidence that vascular remodeling, fibrosis, and inflammation are important consequences of a high-salt intake in DOCA mice. Our study suggests that among the different pathogenic factors of cardiac and vascular remodeling, such as hypertension and mineralocorticoid excess and sodium intake, the latter is critical for the development of the profibrotic and proinflammatory phenotype observed in the heart of normotensive DOCA-treated mice.

The prevalence of erectile dysfunction and its association with antiretroviral therapy in HIV-infected men: the Swiss HIV Cohort Study

Here, we aimed to determine the prevalence of erectile dysfunction (ED) among HIV-infected men and its association with components of antiretroviral therapy.

NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology

This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH-cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b(5), squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues. Additional mouse models with global or conditional hepatic deletion of cytochrome b(5) are helping to clarify the P450 isoform- and substrate-specific influences of cytochrome b(5) on P450 electron transfer and catalytic function. This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell-culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver. The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism.

The Dynamics of the Policies of Ethnic Cleansing in Silesia in the Nineteenth and Twentieth Centuries

Through studying German, Polish and Czech publications on Silesia, Mr. Kamusella found that most of them, instead of trying to objectively analyse the past, are devoted to proving some essential "Germanness", "Polishness" or "Czechness" of this region. He believes that the terminology and thought-patterns of nationalist ideology are so deeply entrenched in the minds of researchers that they do not consider themselves nationalist. However, he notes that, due to the spread of the results of the latest studies on ethnicity/nationalism (by Gellner, Hobsbawm, Smith, Erikson Buillig, amongst others), German publications on Silesia have become quite objective since the 1980s, and the same process (impeded by under funding) has been taking place in Poland and the Czech Republic since 1989. His own research totals some 500 pages, in English, presented on disc. So what are the traps into which historians have been inclined to fall? There is a tendency for them to treat Silesia as an entity which has existed forever, though Mr. Kamusella points out that it emerged as a region only at the beginning of the 11th century. These same historians speak of Poles, Czechs and Germans in Silesia, though Mr. Kamusella found that before the mid-19th century, identification was with an inhabitant's local area, religion or dynasty. In fact, a German national identity started to be forged in Prussian Silesia only during the Liberation War against Napoleon (1813-1815). It was concretised in 1861 in the form of the first Prussian census, when the language a citizen spoke was equated with his/her nationality. A similar census was carried out in Austrian Silesia only in 1881. The censuses forced the Silesians to choose their nationality despite their multiethnic multicultural identities. It was the active promotion of a German identity in Prussian Silesia, and Vienna's uneasy acceptance of the national identities in Austrian Silesia which stimulated the development of Polish national, Moravian ethnic and Upper Silesian ethnic regional identities in Upper Silesia, and Polish national, Czech national, Moravian ethnic and Silesian ethnic identities in Austrian Silesia. While traditional historians speak of the "nationalist struggle" as though it were a permanent characteristic of Silesia, Mr. Kamusella points out that such a struggle only developed in earnest after 1918. What is more, he shows how it has been conveniently forgotten that, besides the national players, there were also significant ethnic movements of Moravians, Upper Silesians, Silesians and the tutejsi (i.e. those who still chose to identify with their locality). At this point Mr. Kamusella moves into the area of linguistics. While traditionally historians have spoken of the conflicts between the three national languages (German, Polish and Czech), Mr Kamusella reminds us that the standardised forms of these languages, which we choose to dub "national", were developed only in the mid-18th century, after 1869 (when Polish became the official language in Galicia), and after the 1870s (when Czech became the official language in Bohemia). As for standard German, it was only widely promoted in Silesia from the mid 19th century onwards. In fact, the majority of the population of Prussian Upper Silesia and Austrian Silesia were bi- or even multilingual. What is more, the "Polish" and "Czech" Silesians spoke were not the standard languages we know today, but a continuum of West-Slavic dialects in the countryside and a continuum of West-Slavic/German creoles in the urbanised areas. Such was the linguistic confusion that, from time to time, some ethnic/regional and Church activists strove to create a distinctive Upper Silesian/Silesian language on the basis of these dialects/creoles, but their efforts were thwarted by the staunch promotion of standard German, and after 1918, of standard Polish and Czech. Still on the subject of language, Mr. Kamusella draws attention to a problem around the issue of place names and personal names. Polish historians use current Polish versions of the Silesian place names, Czechs use current Polish/Czech versions of the place names, and Germans use the German versions which were in use in Silesia up to 1945. Mr. Kamusella attempted to avoid this, as he sees it, nationalist tendency, by using an appropriate version of a place name for a given period and providing its modern counterpart in parentheses. In the case of modern place names he gives the German version in parentheses. As for the name of historical figures, he strove to use the name entered on the birth certificate of the person involved, and by doing so avoid such confusion as, for instance, surrounds the Austrian Silesian pastor L.J. Sherschnik, who in German became Scherschnick, in Polish, Szersznik, and in Czech, Sersnik. Indeed, the prospective Silesian scholar should, Mr. Kamusella suggests, as well as the three languages directly involved in the area itself, know English and French, since many documents and books on the subject have been published in these languages, and even Latin, when dealing in depth with the period before the mid-19th century. Mr. Kamusella divides the policies of ethnic cleansing into two categories. The first he classifies as soft, meaning that policy is confined to the educational system, army, civil service and the church, and the aim is that everyone learn the language of the dominant group. The second is the group of hard policies, which amount to what is popularly labelled as ethnic cleansing. This category of policy aims at the total assimilation and/or physical liquidation of the non-dominant groups non-congruent with the ideal of homogeneity of a given nation-state. Mr. Kamusella found that soft policies were consciously and systematically employed by Prussia/Germany in Prussian Silesia from the 1860s to 1918, whereas in Austrian Silesia, Vienna quite inconsistently dabbled in them from the 1880s to 1917. In the inter-war period, the emergence of the nation-states of Poland and Czechoslovakia led to full employment of the soft policies and partial employment of the hard ones (curbed by the League of Nations minorities protection system) in Czechoslovakian Silesia, German Upper Silesia and the Polish parts of Upper and Austrian Silesia. In 1939-1945, Berlin started consistently using all the "hard" methods to homogenise Polish and Czechoslovakian Silesia which fell, in their entirety, within the Reich's borders. After World War II Czechoslovakia regained its prewar part of Silesia while Poland was given its prewar section plus almost the whole of the prewar German province. Subsequently, with the active involvement and support of the Soviet Union, Warsaw and Prague expelled the majority of Germans from Silesia in 1945-1948 (there were also instances of the Poles expelling Upper Silesian Czechs/Moravians, and of the Czechs expelling Czech Silesian Poles/pro-Polish Silesians). During the period of communist rule, the same two countries carried out a thorough Polonisation and Czechisation of Silesia, submerging this region into a new, non-historically based administrative division. Democratisation in the wake of the fall of communism, and a gradual retreat from the nationalist ideal of the homogeneous nation-state with a view to possible membership of the European Union, caused the abolition of the "hard" policies and phasing out of the "soft" ones. Consequently, limited revivals of various ethnic/national minorities have been observed in Czech and Polish Silesia, whereas Silesian regionalism has become popular in the westernmost part of Silesia which remained part of Germany. Mr. Kamusella believes it is possible that, with the overcoming of the nation-state discourse in European politics, when the expression of multiethnicity and multilingualism has become the cause of the day in Silesia, regionalism will hold sway in this region, uniting its ethnically/nationally variegated population in accordance with the principle of subsidiarity championed by the European Union.

ASSOCIATON TESTS THAT ACCOMMODATE GENOTYPING ERRORS

High-throughput SNP arrays provide estimates of genotypes for up to one million loci, often used in genome-wide association studies. While these estimates are typically very accurate, genotyping errors do occur, which can influence in particular the most extreme test statistics and p-values. Estimates for the genotype uncertainties are also available, although typically ignored. In this manuscript, we develop a framework to incorporate these genotype uncertainties in case-control studies for any genetic model. We verify that using the assumption of a “local alternative” in the score test is very reasonable for effect sizes typically seen in SNP association studies, and show that the power of the score test is simply a function of the correlation of the genotype probabilities with the true genotypes. We demonstrate that the power to detect a true association can be substantially increased for difficult to call genotypes, resulting in improved inference in association studies.

TRIO LOGIC REGRESSION - DETECTION OF SNP - SNP INTERACTIONS IN CASE-PARENT TRIOS

Statistical approaches to evaluate higher order SNP-SNP and SNP-environment interactions are critical in genetic association studies, as susceptibility to complex disease is likely to be related to the interaction of multiple SNPs and environmental factors. Logic regression (Kooperberg et al., 2001; Ruczinski et al., 2003) is one such approach, where interactions between SNPs and environmental variables are assessed in a regression framework, and interactions become part of the model search space. In this manuscript we extend the logic regression methodology, originally developed for cohort and case-control studies, for studies of trios with affected probands. Trio logic regression accounts for the linkage disequilibrium (LD) structure in the genotype data, and accommodates missing genotypes via haplotype-based imputation. We also derive an efficient algorithm to simulate case-parent trios where genetic risk is determined via epistatic interactions.

Detection of Progressive Deterioration in Early Onset Schizophrenia with a New Statistical Method

Much controversy exists over whether the course of schizophrenia, as defined by the lengths of repeated community tenures, is progressively ameliorating or deteriorating. This article employs a new statistical method proposed by Wang and Chen (2000) to analyze the Denmark registry data in Eaton, et al (1992). The new statistical method correctly handles the bias caused by induced informative censoring, which is an interaction of the heterogeneity of schizophrenia patients and long-term follow-up. The analysis shows a progressive deterioration pattern in terms of community tenures for the full registry cohort, rather than a progressive amelioration pattern as reported for a selected sub-cohort in Eaton, et al (1992). When adjusted for the long-term chronicity of calendar time, no significant progressive pattern was found for the full cohort.

Additive Hazards Models with Latent Treatment Effectiveness Lag Time

In many clinical trials to evaluate treatment efficacy, it is believed that there may exist latent treatment effectiveness lag times after which medical procedure or chemical compound would be in full effect. In this article, semiparametric regression models are proposed and studied to estimate the treatment effect accounting for such latent lag times. The new models take advantage of the invariance property of the additive hazards model in marginalizing over random effects, so parameters in the models are easy to be estimated and interpreted, while the flexibility without specifying baseline hazard function is kept. Monte Carlo simulation studies demonstrate the appropriateness of the proposed semiparametric estimation procedure. Data collected in the actual randomized clinical trial, which evaluates the effectiveness of biodegradable carmustine polymers for treatment of recurrent brain tumors, are analyzed.

Anti-inflammatory properties of alpha- and gamma-tocopherol

Natural vitamin E consists of four different tocopherol and four different tocotrienol homologues (alpha,beta, gamma, delta) that all have antioxidant activity. However, recent data indicate that the different vitamin E homologues also have biological activity unrelated to their antioxidant activity. In this review, we discuss the anti-inflammatory properties of the two major forms of vitamin E, alpha-tocopherol (alphaT) and gamma-tocopherol (gammaT), and discuss the potential molecular mechanisms involved in these effects. While both tocopherols exhibit anti-inflammatory activity in vitro and in vivo, supplementation with mixed (gammaT-enriched) tocopherols seems to be more potent than supplementation with alphaT alone. This may explain the mostly negative outcomes of the recent large-scale interventional chronic disease prevention trials with alphaT only and thus warrants further investigation.