An ultra performance liquid chromatography-tandem MS assay for tamoxifen metabolites profiling in plasma: first evidence of 4'-hydroxylated metabolites in breast cancer patients.

There is increasing evidence that the clinical efficacy of tamoxifen, the first and most widely used targeted therapy for estrogen-sensitive breast cancer, depends on the formation of the active metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Large inter-individual variability in endoxifen plasma concentrations has been observed and related both to genetic and environmental (i.e. drug-induced) factors altering CYP450s metabolizing enzymes activity. In this context, we have developed an ultra performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) requiring 100 μL of plasma for the quantification of tamoxifen and three of its major metabolites in breast cancer patients. Plasma is purified by a combination of protein precipitation, evaporation at room temperature under nitrogen, and reconstitution in methanol/20 mM ammonium formate 1:1 (v/v), adjusted to pH 2.9 with formic acid. Reverse-phase chromatographic separation of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen is performed within 13 min using elution with a gradient of 10 mM ammonium formate and acetonitrile, both containing 0.1% formic acid. Analytes quantification, using matrix-matched calibration samples spiked with their respective deuterated internal standards, is performed by electrospray ionization-triple quadrupole mass spectrometry using selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of relative matrix effects variability, as well as tamoxifen and metabolites short-term stability in plasma and whole blood. The method is precise (inter-day CV%: 2.5-7.8%), accurate (-1.4 to +5.8%) and sensitive (lower limits of quantification comprised between 0.4 and 2.0 ng/mL). Application of this method to patients' samples has made possible the identification of two further metabolites, 4'-hydroxy-tamoxifen and 4'-hydroxy-N-desmethyl-tamoxifen, described for the first time in breast cancer patients. This UPLC-MS/MS assay is currently applied for monitoring plasma levels of tamoxifen and its metabolites in breast cancer patients within the frame of a clinical trial aiming to assess the impact of dose increase on tamoxifen and endoxifen exposure.

Motivating Students to Learn English: Intrinsic and Extrinsic Strategies to Meet the Needs of First Time Learners

Motivation is the key to learning. The present study is about the relationship between intrinsic and extrinsic motivation as they affect learning with regard to students who are learning EFL for the first time. Cape Verdean seventh grade students learning English for the first time are generally very enthusiastic about the language before they start learning it in the high school. However, that enthusiasm seems not to be maintained throughout the school year and oftentimes teachers hear them complain about the difficulties of mastering aspects of the language. It seems that for some reason their motivation is undermined. Why does that happen? Is it the students’ fault or the teacher’s? If it the teacher’s fault, which motivation strategies work best to cope with this problem: intrinsic or extrinsic? With this in mind I asked the question: What is the relationship between students’ needs, interests, goals and expectations to learn English as a foreign language and teachers’ roles as facilitators and motivators? There are many studies that have been carried out in the field of motivation, and up to now, there seems to be no consensus of which is the best. For the purposes of this paper, three main theories will be discussed that have prevailed in the field of motivational psychology: the behavioural, the cognitive and the humanistic theories. Within these theories sub-theories are discussed and their relationship is explained with intrinsic and extrinsic motivation regarding Cape Verdean students learning English for the first time.

Purification and ligand binding of a soluble class I major histocompatibility complex molecule consisting of the first three domains of H-2Kd fused to beta 2-microglobulin expressed in the baculovirus-insect cell system.

A recombinant baculovirus encoding a single-chain murine major histocompatibility complex class I molecule in which the first three domains of H-2Kd are fused to beta 2-microglobulin (beta 2-m) via a 15-amino acid linker has been isolated and used to infect lepidopteran cells. A soluble, 391-amino acid single-chain H-2Kd (SC-Kd) molecule of 48 kDa was synthesized and glycosylated in insect cells and could be purified in the absence of detergents by affinity chromatography using the anti-H-2Kd monoclonal antibody SF1.1.1.1. We tested the ability of SC-Kd to bind antigenic peptides using a direct binding assay based on photoaffinity labeling. The photoreactive derivative was prepared from the H-2Kd-restricted Plasmodium berghei circumsporozoite protein (P.b. CS) peptide 253-260 (YIPSAEKI), a probe that we had previously shown to be unable to bind to the H-2Kd heavy chain in infected cells in the absence of co-expressed beta 2-microglobulin. SC-Kd expressed in insect cells did not require additional mouse beta 2-m to bind the photoprobe, indicating that the covalently attached beta 2-m could substitute for the free molecule. Similarly, binding of the P.b. CS photoaffinity probe to the purified SC-Kd molecule was unaffected by the addition of exogenous beta 2-m. This is in contrast to H-2KdQ10, a soluble H-2Kd molecule in which beta 2-m is noncovalently bound to the soluble heavy chain, whose ability to bind the photoaffinity probe is greatly enhanced in the presence of an excess of exogenous beta 2-m. The binding of the probe to SC-Kd was allele-specific, since labeling was selectively inhibited only by antigenic peptides known to be presented by the H-2Kd molecule.

Are Voting Advice Applications (VVAs) more than Toys ? : First findings on Impact and Accountability of VAAs

To what extent do Voting Advice Applications (VAA) have an influence on voting behaviour and to what extent should providers be hold accountable for such tools? This paper puts forward some empirical evidence from the Swiss VAA smartvote. The enormous popularity of smartvote in the last national elections in 2007 and the feedback of users and candidates let us come to the conclusion that smartvote is more than a toy and likely to have an influence on the voting decisions. Since Swiss citizens not only vote for parties but also for candidates, and the voting recommendation of smartvote is based on the political positions of the candidates, smartvote turns out to be particularly helpful. Political scientists must not keep their hands off such tools. Scientific research is needed to understand their functioning and possibilities to manipulate elections. On the bases of a legal study we come to the conclusion, that a science driven way of setting up such tools is essential for their legitimacy. However, we do not believe that there is a single best way of setting up such a tool and rather support a market like solution with different competing tools, provided they meet minimal standards like transparency and equal access for all parties and candidates. Once the process of selecting candidates and parties are directly linked to the act of voting, all these questions will become even more salient.

First impressions matter: Signalling as a source of policy dynamics

We first establish that policymakers on the Bank of England's Monetary PolicyCommittee choose lower interest rates with experience. We then reject increasingconfidence in private information or learning about the structure of the macroeconomy as explanations for this shift. Instead, a model in which voters signal theirhawkishness to observers better fits the data. The motivation for signalling is consistent with wanting to control inflation expectations, but not career concerns orpleasing colleagues. There is also no evidence of capture by industry. The papersuggests that policy-motivated reputation building may be important for explainingdynamics in experts' policy choices.

Discrete devaluations and multiple equilibria in a first generation model of currency crises

The first generation models of currency crises have often been criticized because they predict that, in the absence of very large triggering shocks, currency attacks should be predictable and lead to small devaluations. This paper shows that these features of first generation models are not robust to the inclusion of private information. In particular, this paper analyzes a generalization of the Krugman-Flood-Garber (KFG) model, which relaxes the assumption that all consumers are perfectly informed about the level of fundamentals. In this environment, the KFG equilibrium of zero devaluation is only one of many possible equilibria. In all the other equilibria, the lack of perfect information delays the attack on the currency past the point at which the shadow exchange rate equals the peg, giving rise to unpredictable and discrete devaluations.

Abcès du sein: privilégier la ponction-aspiration échoguidée [Ultrasonography-guided drainage should be considered as the first-line approach for breast abscesses treatment].

The abscesses of the breast are puerperal or non puerperal. The Staphylococcus aureus is the most common germ. The diagnosis is based on clinical criterias and confirmed by the ultrasonography. The percutaneous ultrasonography-guided drainage must be proposed in first intent to treat. Surgical treatment is still valid with a relapsing or chronic abscess, or after the non operative processes have failed.

First records of Collembola (Ellipura) from the State of Paraíba, Northeastern Brazil

This paper presents the first records of the Collembola fauna in four localities of State of Paraíba, Northeastern Brazil. These records represent the first list of species of Collembola for the State of Paraíba. The research adds new records for Brazil of six genera and one species. Furthermore, thirteen undescribed species are presented.

Improving Transition Outcomes: Prototype First Year Highlights

Highlights from the community demonstration prototypes first year.

Sclérose en plaques: au-delà des traitements de première ligne [Multiple sclerosis: beyong first line therapies].

We are currently experiencing a key period in the management of patients with relapsing remitting multiple sclerosis. The application of new criteria allows early diagnosis, thus at a stage when the available immune treatments are the most likely to show a good efficacy. The therapeutic offer is expanding but its complexity too. It is thus important, for a given patient, to assess as precisely as possible the degree of severity of his/her disease, in order to give the drug with the optimal risk/benefit ratio.

High prevalence of major cardiovascular risk factors in first-degree relatives of individuals with familial premature coronary artery disease--the GENECARD project.

BACKGROUND: Hypertension, hypercholesterolemia, obesity and smoking are highly prevalent among patients with familial premature coronary artery disease (FP-CAD). Whether these risk factors equally affect other family members remains unknown. METHODS: We examined 222 FP-CAD patients, 158 unaffected sibs, 197 offspring and 94 spouses in 108 FP-CAD families (> or = 2 sibs having survived CAD diagnosed before age 51 (M)/56 (F)), and compared them to population controls. RESULTS: Unaffected sibs had a higher prevalence of hypertension (49% versus 24%, p<0.001), hypercholesterolemia (47% versus 34%, p=0.002), abdominal obesity (35% versus 24%, p=0.006) and smoking (39% versus 24%, p=0.001) than population controls. Offspring had a higher prevalence of hypertension (females), hypercholesterolemia and abdominal obesity than population controls. No difference was observed between spouses and controls. Compared to unaffected sibs, FP-CAD affected sibs had a similar risk factor profile, except for smoking, which was more prevalent (76% versus 39%, p=0.008). CONCLUSIONS: Hypertension, obesity and hypercholesterolemia are highly prevalent among first-degree relatives, but not spouses, of patients with FP-CAD. These persons deserve special medical attention due to their familial/genetic susceptibility to atherogenic metabolic abnormalities. In these families, smoking may be the trigger for FP-CAD.

Improving social measurements: The experience of the ESS first rounds in Spain

With the two aims of monitoring social change and improving social measurement, the European Social Survey is now closing its third round. This paper shows how the accumulated experience of the two first rounds has been used to validate the questionnaire, better adapt the sampling design to the country characteristics and efficiently commit fieldwork in Spain. For example, the dynamic character of the population nowadays makes necessary to estimated design effects at each round from the data of the previous round. The paper also demonstrates how, starting with a response rate of 52% at first round, a 66% response rate is achieved at the third round thanks to an extensive quality control conducted by the polling agency and the ESS national team and based on a detailed analysis of the non-response cases and the incidences reported by the interviewed in the contact form.