Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2).

BACKGROUND: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. PATIENTS AND METHODS: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. RESULTS: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. CONCLUSIONS: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively.

Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

Asymmetrical nature of the Trollius-Chiastocheta interaction: insights into the evolution of nursery pollination systems

The mutualistic versus antagonistic nature of an interaction is defined by costs and benefits of each partner, which may vary depending on the environment. Contrasting with this dynamic view, several pollination interactions are considered as strictly obligate and mutualistic. Here, we focus on the interaction between Trollius europaeus and Chiastocheta flies, considered as a specialized and obligate nursery pollination system - the flies are thought to be exclusive pollinators of the plant and their larvae develop only in T.europaeus fruits. In this system, features such as the globelike flower shape are claimed to have evolved in a coevolutionary context. We examine the specificity of this pollination system and measure traits related to offspring fitness in isolated T.europaeus populations, in some of which Chiastocheta flies have gone extinct. We hypothesize that if this interaction is specific and obligate, the plant should experience dramatic drop in its relative fitness in the absence of Chiastocheta. Contrasting with this hypothesis, T.europaeus populations without flies demonstrate a similar relative fitness to those with the flies present, contradicting the putative obligatory nature of this pollination system. It also agrees with our observation that many other insects also visit and carry pollen among T.europaeus flowers. We propose that the interaction could have evolved through maximization of by-product benefits of the Chiastocheta visits, through the male flower function, and selection on floral traits by the most effective pollinator. We argue this mechanism is also central in the evolution of other nursery pollination systems.

Conflicto, colaboración y consenso en la enseñanza de las ciencias sociales = Conflict, collaboration and consensus in the teaching of the Social sciences

This article suggests the study of the key concept of conflict as a means of implementing a critical and communicativecurriculum based on the study of relevant social themes. To this end we put forward the principal characteristics of thecritical/communicative curriculum. We offer a didactic proposal about conflict and explain the results of its application intwo Secondary Education classrooms

AVOIDING FIRST-YEAR UNIVERSITY CHEMISTRY TEXTBOOKS’ MISREPRESENTATIONS IN THE TEACHING OF SPONTANEOUS REACTIONS

This paper summarizes the misrepresentations related to Gibbs energy in general chemistry textbooks. These misrepresentations arise from a problem in the terminology textbooks use. Thus, after reviewing the proper definition of each of the terms analyzed, we present two problems to exemplify the correct treatment of the quantities involved, which may help in the discussion and clarification of the misleading conventions and assumptions reported in this study.

A long way to the rainbow country : understanding the foreign market expansion process of Finnish corporations into the Republic of South Africa between 1999 and 2005

De afrikanska ekonomierna växer med nära fyra procent per år och detta är en god indikation på kontinentens växande betydelse. Under kalla kriget hade afrikanska regeringar haft ett begränsat utrymme för opportunistisk köpslående, och därmed även en marginal att positionera sig strategiskt. Alltför ofta uppmuntrade och beskyddade stormakterna diktatorer och små lokala eliter som främst ville berika sig själv. I och med att globaliseringen tog fart och USA allt mera kom att dominera globalt, började en ny era i fråga om förändringar. Trots dessa förändringar på den globala arenan, har Afrika som kontinent hamnat i bakgrunden och jämfört med andra utvecklingsländer har Afrika attraherat ett fåtal utländska investeringar. Fortfarande, speciellt i Norden, finns det lite kunskap om hur utländska företag expanderar sin affärsverksamhet på den afrikanska kontinenten. Det råder brist på empiriska undersökningar om vilken inverkan afrikanska institutionella förändringar och lokala affärsmiljöer har på internationaliseringen och på de utländska företagens affärsutvecklingsstrategier på den afrikanska kontinenten. Med denna avhandling vill jag lyfta fram ett exempel på ett land (Sydafrika), som har lyckat dra nytta av de förändringar som 1990-talet förde med sig. I denna avhandling har jag intervjuat olika personer i ledande positioner inom olika finländska företag i Finland och i Sydafrika. Avhandlingen skapar en referensram för att öka förståelse och fördjupa analys av hur en kombination av olika interna och externa resurser ökar företagens konkurrenskraft och på det sättet bidrar till en framgångsrik affärsutveckling i Afrika. De politiska och sociala aktörerna samt aktörerna inom affärslivet besitter resurser som ambitiösa företag kan dra nytta av i sin strävan att erövra de nya framgångsrika marknaderna i Afrika. Gradvis ökar finländska företag sina insatser på den afrikanska kontinenten i strävan att skapa mervärde för sina kunder. Den värdeskapande processen gör att parterna måste närma sig varandra utgående från sina egna strategiska målsättningar. Hittills har finländska företag varit intresserad att sälja till Afrika men inte intresserad att köpa därifrån. Förutom de praktiska råden till olika företag, föreslår avhandlingen hur den finska staten och den sydafrikanska staten kunde agera tillsammans för att främja ömsesidigt handelsutbyte.

The effects of national legislation on the implementation of IFRS in Finland and Russia

This study examines the possible differences in IFRS implementation between Finnish and Russian companies as well as reasons behind them by theoretical means as well as by incorporating a case study of two companies.

Using Moodle to provide added value in the teaching of a software development course

The rate of adoption and use of learning management systems to support teaching and learning processes in academic institutions is growing rapidly. Universities are acquiring systems with functionalities that can match with their specific needs and requirements. Moodle is one of the most popular and widely deployed learning management systems in academic institutions today. However, apart from the system, universities tend to maintain other applications for the purpose of supplementing their teaching and learning processes. This situation is similar to Lappeenranta University of Technology (LUT), which is our case study in this project. Apart from Moodle, the university also maintains other systems such as Oodi, Noppa and Uni portal for the purpose of supporting its educational activities. This thesis has two main goals. The first goal is to understand the specific role of Moodle at LUT. This information is fundamental in assessing whether Moodle is needed in the university’s current teaching and learning environment. The second aim is to provide insights to teachers and other departmental stakeholders on how Moodle can provide added value in the teaching of a software development course. In response to this, a Moodle module for a software development course is created and the underlying features are tested. Results of the constructive work proposed some improvements through (i) the use of Moodle for in-class surveys, (ii) transfer of grades from Moodle to Oodi, (iii) use of Moodle in self-study courses and MOOCs, (iv) online examinations, and (v) Moodle integrations with third party applications. The proposed items were then evaluated for their utility through interviews of five expert interviews. The final results of this work are considered useful to LUT administration and management specifically on ways that Moodle can bring changes to the university at managerial, economical and technical level. It also poses some challenges on platform innovations and research.

Extending the Hydra Head to Create a Pluggable, Extensible Architecture: Diving into the Technology of Hydramata

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

Insights into the role of hydration in protein structure and stability obtained through hydrostatic pressure studies

A thorough understanding of protein structure and stability requires that we elucidate the molecular basis for the effects of both temperature and pressure on protein conformational transitions. While temperature effects are relatively well understood and the change in heat capacity upon unfolding has been reasonably well parameterized, the state of understanding of pressure effects is much less advanced. Ultimately, a quantitative parameterization of the volume changes (at the basis of pressure effects) accompanying protein conformational transitions will be required. The present report introduces a qualitative hypothesis based on available model compound data for the molecular basis of volume change upon protein unfolding and its dependence on temperature.

Personality traits and personal values : an investigation into the importance of each in the prediction of behaviour /

Personality traits and personal values are two important domains of individual differences. Traits are enduring and distinguishable patterns of behaviour whereas values are societally taught, stable, individual preferences that guide behaviour in order to reach a specific end state. The purpose of the present study was to investigate the relations between self and peer report within the domains of personality traits and values, to examine the correlations between values and traits, and to explore the amount of incremental validity of traits and values in predicting behaviour. Two hundred and fiftytwo men and women from a university setting completed self and peer reports on three questionnaires. In order to assess personality traits, the HEXACO-PI (Lee & Ashton, 2004) was used to identify levels of 6 major dimensions of personality in participants. To assess values, the Schwartz Value Survey (Schwartz, 1992) was used to identify the importance each participant placed on each of Schwartz's 10 value types. To measure behaviour, a Behavior Scale, created by Bardi and Schwartz (2003), consisting of items designed to measure the frequency of value-expressive behaviour was used. As expected, correlations between self and peer reports for the personality scales were high indicating that personality traits are easily observable to other people. Correlations between self and peer reports for the values and behaviour scales were only moderate, suggesting that some goals, and behaviours expressive of those goals, may not always be observable to others. Consistent with previous research, there were many strong correlations between traits and values. In addition to the similarities with past research, the present study found that the personality factor Honesty-Humility was correlated strongly with values scales (with five correlations exceeding .25). In the prediction of behaviour, it was found that both personahty and values were able to account for significant and similar amounts of variance. Personality outpredicted values for some behaviours, but the opposite was true of other behaviours. Each domain provided incremental validity beyond the other domain. The impUcations for these findings, along with limitations, and possibilities for future research are also discussed.

An investigation into the oxidation of organic sulphides, organic selenides and simple hydrocarbons by Mortierella isabellina NRRL 1757

The work presented in this thesis is divided into three separate sections 4!> Each' 'section is involved wi th a different problem, however all three are involved with a microbial oxidation of a substrate~ A series of 'aryl substituted phenyl a.nd be,nzyl methyl sulphides were oxidized to the corre~pondi~g sulphoxides by 'Mo:rtierellai's'a'b'e'llina NRR.L17'S7 @ For this enzymic Qxidation, based on 180 labeled experiments, the oxygen atom is derived fr'orn the atmosphere and not from water. By way of an u~.traviolet analysis, the rates of oxidation, in terms of sulphox~ de appearance, were obtained and correlated with the Hatnmett p s~grna constants for the phenyl methyl sulphide series. A value of -0.67 was obtained and, is interpreted in terms of a mechanism of oxidation that involves an electrophilic attack on the sulphide sulphur by an enzymic ironoxygen activated complex and the conversion of the resulti!lg sulphur cation to sulphoxide. A series of alkyl phenyl selen~des have been incubated with the fu~gi, Aspergillus niger ATCC9l42, Aspergillus fO'etidus NRRL 337, MIIJisabellina NF.RLl757 and'He'lminth'osparium sp'ecies NRRL 4671 @l These fu?gi have been reported to be capable of carrying out the efficient oxidation of sulphide to sulphoxide, but in no case was there any evidence to supp'ort the occurrence of a microbialox,idation. A more extensive inves·t~gation was carried out with'M,e 'i's'a'b'e'l'l'i'na, this fu~gus was capable of oxidizing the correspondi~g sulphides to sulphoxi.de·s·$ Usi:ng a 1abel.edsubstra.te, [Methyl-l4c]-methyl phenyl selenide, the fate of this compound was invest~gated followi!lg an i'ncubation wi th Me isabellina .. BeSUldes th. e l4C-ana1YS1Q S-,'. a quant"ltta"lve selen'lum ana1Y"S1S was carried out with phenyl methyl selenide. These techniques indicate that thesel'enium was capable of enteri!1g thefu!1gal cell ef'ficiently but that s'ome metabolic cleav~ge of the seleni'um-carbon bond' may take plac'e Ie The l3c NMR shifts were assigned to the synthesized alkyl phenyl sulphides and selenides@ The final section involved the incubation ofethylben~ zene and p-e:rtr.hyltoluene wi th'M ~ 'isab'e'llina NRRL 17574b Followi~ g this incubation an hydroxylated product was isolated from the medium. The lH NMR and mass spectral data identify the products as I-phenylethanol and p-methyl-l-phenylethanol. Employi!lg a ch'iral shift re~gent,tri~ (3-heptafluorobutyl-dcamphorato)'- europium III, the enantiomeric puri ty of these products was invest~gated. An optical rotation measurement of I-phenylethanol was in ~greement with the results obtained with the chiral shift re~gen,te 'M.isabe'l'lina is capable of carryi~g out an hydroxylation of ethylbenzene and p-ethyltoluene at the ~ position.