Gender-specific genomic profiling in metastatic colorectal cancer patients treated with 5-fluorouracil and oxaliplatin

AIMS: Survival and response rates in metastatic colorectal cancer remain poor, despite advances in drug development. There is increasing evidence to suggest that gender-specific differences may contribute to poor clinical outcome. We tested the hypothesis that genomic profiling of metastatic colorectal cancer is dependent on gender.

MATERIALS & METHODS: A total of 152 patients with metastatic colorectal cancer who were treated with oxaliplatin and continuous infusion 5-fluorouracil were genotyped for 21 polymorphisms in 13 cancer-related genes by PCR. Classification and regression tree analysis tested for gender-related association of polymorphisms with overall survival, progression-free survival and tumor response.

RESULTS: Classification and regression tree analysis of all polymorphisms, age and race resulted in gender-specific predictors of overall survival, progression-free survival and tumor response. Polymorphisms in the following genes were associated with gender-specific clinical outcome: estrogen receptor β, EGF receptor, xeroderma pigmentosum group D, voltage-gated sodium channel and phospholipase A2.

CONCLUSION: Genetic profiling to predict the clinical outcome of patients with metastatic colorectal cancer may depend on gender.

Beneficial Effects of Berberine on Oxidized LDL-induced Cytotoxicity in Human Retinal Müller Cells

PURPOSE. Limited mechanistic understanding of diabetic retinopathy (DR) has hindered therapeutic advances. Berberine, an isoquinolone alkaloid, has shown favorable effects on glucose and lipid metabolism in animal and human studies, but effects on DR are unknown. We previously demonstrated intraretinal extravasation and modification of LDL in human diabetes, and toxicity of modified LDL to human retinal M¨uller cells. We now explore pathogenic effects of modified LDL on M¨uller cells, and the efficacy of berberine in mitigating this cytotoxicity. METHODS. Confluent human M¨uller cells were exposed to in vitro–modified ‘highly oxidized, glycated (HOG-) LDL versus native-LDL (N-LDL; 200 mg protein/L) for 6 or 24 hours, with/ without pretreatment with berberine (5 lM, 1 hour) and/or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, Compound C (5 lM, 1 hour). Using techniques including Western blots, reactive oxygen species (ROS) detection assay, and quantitative real-time PCR, the following outcomes were assessed: cell viability (CCK-8 assay), autophagy (LC3, Beclin-1, ATG-5), apoptosis (cleaved caspase 3, cleaved poly-ADP ribose polymerase), oxidative stress (ROS, nuclear factor erythroid 2-related factor 2, glutathione peroxidase 1, NADPH oxidase 4), angiogenesis (VEGF, pigment epithelium-derived factor), inflammation (inducible nitric oxide synthase, intercellular adhesion molecule 1, IL-6, IL-8, TNF-a), and glial cell activation (glial fibrillary acidic protein). RESULTS. Native-LDL had no effect on cultured human M¨uller cells, but HOG-LDL exhibited marked toxicity, significantly decreasing viability and inducing autophagy, apoptosis, oxidative stress, expression of angiogenic factors, inflammation, and glial cell activation. Berberine attenuated all the effects of HOG-LDL (all P < 0.05), and its effects were mitigated by AMPK inhibition (P < 0.05). CONCLUSIONS. Berberine inhibits modified LDL-induced M¨uller cell injury by activating the AMPK pathway, and merits further study as an agent for preventing and/or treating DR.

Analytical methods to study fate of organic pollutants in environment

Environmental transport of pollutants comprises distinct processes such as volatilization, leaching and surface runoff. Sorption is one of the most important phenomena that affects leaching, and thus the fate of hydrophobic organic pollutants in soils and also control their distribution in the soil/water environment. The work developed focuses the optimization of analytical techniques for monitoring the sorption behaviour of organic pollutants, 17α- ethinylestradiol (EE2) and atrazine, and their fate in aqueous environment. Initially, the development of several analytical techniques, such as micellar electrokinetic chromatography, spectral deconvolution, using UV-Vis and fluorescence spectroscopy, and also enzyme linked immunosorbent assay was performed. Optimization, method performance and recovery tests are described and results discussed. Moreover, in order to evaluate the applicability of the previously optimized method, atrazine and EE2 sorption to soil samples was performed. The work developed provide several options, in terms of methodology to follow sorption of atrazine onto soils, however the choice depends on the laboratory conditions and on the analyst preferences. The advantages and disadvantages of each methodology should be evaluated first. The second part of this work consisted in the sorption behaviour study of those two different hydrophobic organic pollutants onto different soil samples. Soil organic matter chemical characterization, being essential to understand the binding mechanism responsible for the interactions, was made. The results of atrazine binding to organic matter pointed out that carboxyl units and aromaticrich organic matter are the most efficient binding agents for atrazine. EE2 adsorbs strongly to soil organic matter and is mainly stabilized by hydrophobic interactions, through aromatic nuclei face to face with surface and/or another EE2 molecule association. Farmyard manure soil contains higher aromatic and carboxyl units, indicating that this type of manure can be effectively used to minimize the residual toxicity of EE2 and atrazine present in soils, increasing the sorption and reducing leaching onto water resources. Since the final destination of organic pollutants can be ground, surface and/or waste water, atrazine and 17α-ethinylestradiol were quantified in several water samples.

Do Girls and Boys Perceive Themselves as Equally Engaged in School? The Results of an International Study from 12 Countries

This study examined gender differences in student engagement and academic performance in school. Participants included 3420 students (7th, 8th, and 9th graders) from Austria, Canada, China, Cyprus, Estonia, Greece, Malta, Portugal, Romania, South Korea, the United Kingdom, and the United States. The results indicated that, compared to boys, girls reported higher levels of engagement in school andwere rated higher by their teachers in academic performance. Student engagement accounted for gender differences in academic performance, but gender did not moderate the associations among student engagement, academic performance, or contextual supports. Analysis of multiple-group structural equation modeling revealed that perceptions of teacher support and parent support, but not peer support, were related indirectly to academic performance through student engagement. This partial mediation model was invariant across gender. The findings from this study enhance the understanding about the contextual and personal factors associated with girls' and boys' academic performance around the world.

Cultural universality and specificity of student engagement in school: The results of an international study from 12 countries

The Hong Kong subproject was supported by the Quality Education Fund of the Education Bureau in Hong Kong, whereas the Portuguese subproject was supported by the Portuguese Foundation for Science and Technology and by the Institute of Education of the University of Lisbon. The data of this paper were part of the data collected in a multinational project initiated by the International School Psychology Association.

Re-evaluation of a reported increased micronucleus frequency in lymphocytes of workers occupationally exposed to formaldehyde

A replicate evaluation of increased micronucleus (MN) frequencies in peripheral lymphocytes of workers occupationally exposed to formaldehyde (FA) was undertaken to verify the observed effect and to determine scoring variability. May–Grünwald–Giemsa-stained slides were obtained from a previously performed cytokinesis-block micronucleus test (CBMNT) with 56 workers in anatomy and pathology laboratories and 85 controls. The first evaluation by one scorer (scorer 1) had led to a highly significant difference between workers and controls (3.96 vs 0.81 MN per 1000 cells). The slides were coded before re-evaluation and the code was broken after the complete re-evaluation of the study. A total of 1000 binucleated cells (BNC) were analysed per subject and the frequency of MN (in ‰) was determined. Slides were distributed equally and randomly between two scorers, so that the scorers had no knowledge of the exposure status. Scorer 2 (32 exposed, 36 controls) measured increased MN frequencies in exposed workers (9.88 vs 6.81). Statistical analysis with the two-sample Wilcoxon test indicated that this difference was not significant (p = 0.17). Scorer 3 (20 exposed, 46 controls) obtained a similar result, but slightly higher values for the comparison of exposed and controls (19.0 vs 12.89; p = 0.089). Combining the results of the two scorers (13.38 vs 10.22), a significant difference between exposed and controls (p = 0.028) was obtained when the stratified Wilcoxon test with the scorers as strata was applied. Interestingly, the re-evaluation of the slides led to clearly higher MN frequencies for exposed and controls compared with the first evaluation. Bland–Altman plots indicated that the agreement between the measurements of the different scorers was very poor, as shown by mean differences of 5.9 between scorer 1 and scorer 2 and 13.0 between scorer 1 and scorer 3. Calculation of the intra-class correlation coefficient (ICC) revealed that all scorer comparisons in this study were far from acceptable for the reliability of this assay. Possible implications for the use of the CBMNT in human biomonitoring studies are discussed.

Identification of mechanisms controlling the transcriptional activity of nuclear factor kappa B (NF-κB) p65/RelA

Dissertação para a obtenção do grau de doutor em Biologia pelo Instituto de Tecnologia Química e Biológica. Universidade Nova de Lisboa.

Why are offspring born larger when it is colder? Phenotypic plasticity for offspring size in the cladoceran Simocephalus vetulus (Müller)

It has been predicted on theorerical grounds (Sibly & Calow, 1983; Taylor & Williams, 1984) that optimal offspring size should be highly sensitive to juvenile growth and survival rates. To test such models, genetically-identical individuals of Simicephalus vetulus were reared at different temperatures and monitored for offspring size and juvenile growth rate. As adult size correlates negatively with temperature, an analysis of covariance was performed to separate the effects of temperature and maternal size. The result is that offspring size indeed correlates negatively with juvenile growth rate. Comparisons are made with field observation of several authors on seasonal variation of offspring size and alternative explanations are discussed. It is concluded that present experiments support the prediction of the theoretical models.

Pathologie et thérapeutique chirurgicales générales (2e édition française complètement remaniée et très augmentée, traduite d'après la 12e édition allemande) / par Th. Billroth,... Alex. von Winiwarter,...

Titre original : Die allgemeine chirurgische Pathologie und Therapie

Warren Hartman fonds, 1970, 1972-1996, 1998, n.d.

Warren Hartman was born in 1942 in Toronto, Ontario. He received a B.A. in Fine Arts and Drama from Brock University in 1981 and a Masters of Arts in Humanities at the State University of New York at Buffalo in 1987. In the 1950s he did considerable work as a child-actor both in theatre and television. From 1953 to 1961 he was in the New Play Society under the direction of Dora Mavor Moore. His last two years there were spent as a scholarship student. From 1963 to 1966 he did an apprenticeship with Suzanne Mess, Head of Costume Design at The Canadian Opera Company in Toronto. In 1976 Warren attended a Master Class in Scenography at the Banff School of Fine Arts with Josef Svoboda. In the spring of 1970 Warren was a guest designer at Brock University and from 1970 to 1972 he remained at Brock as resident designer and special lecturer. During this time he was also an instructor and costume designer at Sheridan College in Oakville. It was in 1972 that he became the designer-in-residence at Brock University. From 1984 he held the position of Associate Professor at The Department of Fine Arts at Brock University until the fall of 1996. Some of the highlights of Warren’s career also include: stage managager with the Street Hat Players in Port Carling, Ontario, 1960-1961; a freelance designer for over 100 shows; costume coordinator(production manager) for the Canadian Opera Company, 1964 -1970; resident costume designer for The Canadian Opera Company, 1965- 1970; founder and artistic director of Dei Gelosi Campagnia, St.Catharines, Ontario, 1970-1973; freelance director of some thirty-five shows; co-producer for Quebec City Summer Stock Company, Quebec City, Quebec, 1975; a consultant with Alberta Culture for the Provincial Government of Alberta, 1986-1987 and associate artistic director at Theatre Network, Edmonton, Alberta, 1986-1987. Warren Hartman was the recipient of the Jean Chalmers Award for contributions to Canadian Theatre for persons 25 years of age or under, in 1965. He was a founding member of Associated Designers of Canada and was affiliated with Canadian Actors Equity. Warren Hartman died on Feb. 11, 1998 several days after suffering a massive stroke. A memorial service was held at Brock University in May of 1998 and a bursary fund was established in his name.

Declaración breve de la cartilla que manifiesta las heregias y los errores que comprende el manifiesto publicado por el apostata y traidor Miguel Hidalgo y Costilla.

UANL

Le rôle des cellules gliales de Müller dans la mort des cellules ganglionnaires de la rétine par des mécanismes cellulaires non-autonomes

Les cellules gliales sont essentielles au fonctionnement du système nerveux. Dans la rétine, les cellules gliales de Müller assurent à la fois l’homéostasie du tissu et la protection des neurones, notamment celle des cellules ganglionnaires de la rétine (CGRs). L’hypothèse principale de la thèse est que les cellules de Müller joueraient un rôle primordial dans la survie neuronale tant au plan de la signalisation des neurotrophines/proneurotrophines par suite d’une blessure que lors des mécanismes d’excitotoxicité. Contrairement au brain-derived neurotrophic factor (BDNF), le nerve growth factor (NGF) n’est pas en mesure d’induire la survie des CGRs après une section du nerf optique. Le premier objectif de la thèse a donc été de localiser les récepteurs p75NTR et TrkA du NGF dans la rétine adulte et d’établir leur fonction respective en utilisant des ligands peptidomimétiques agonistes ou antagonistes spécifiques pour chacun des récepteurs. Nos résultats ont démontré que TrkA est surexprimé par les CGRs après l’axotomie, tandis que p75NTR est spécifiquement exprimé par les cellules de Müller. Alors que NGF n’est pas en mesure d’induire la survie des CGRs, l’activation spécifique de TrkA par des ligands peptidomimétique est nettement neuroprotectrice. De façon surprenante, le blocage sélectif de p75NTR ou l’absence de celui-ci protège les CGRs de la mort induite par l’axotomie. De plus, la combinaison de NGF avec l’antagoniste de p75NTR agit de façon synergique sur la survie des CGRS. Ces résultats révèlent un nouveau mécanisme par lequel le récepteur p75NTR exprimé par les cellules gliales de Müller peut grandement influencer la survie neuronale. Ensuite, nous avons voulu déterminer l’effet des proneurotrophines dans la rétine adulte. Nous avons démontré que l’injection de proNGF induit la mort des CGRs chez le rat et la souris par un mécanisme dépendant de p75NTR. L’expression de p75NTR étant exclusive aux cellules de Müller, nous avons testé l’hypothèse que le proNGF active une signalisation cellulaire non-autonome qui aboutit à la mort des CGRs. En suivant cette idée, nous avons montré que le proNGF induit une forte expression du tumor necrosis factor α (TNFα) dans les cellules de Müller et que l’inhibition du TNF bloque la mort neuronale induite par le proNGF. L’utilisation de souris knock-out pour la protéine p75NTR, son co-récepteur sortiline, ou la protéine adaptatrice NRAGE a permis de montrer que la production de TNF par les cellules gliales était dépendante de ces protéines. Le proNGF semble activer une signalisation cellulaire non-autonome qui cause la mort des neurones de façon dépendante du TNF in vivo. L’hypothèse centrale de l’excitotoxicité est que la stimulation excessive des récepteurs du glutamate sensibles au N-Methyl-D-Aspartate (NMDA) est dommageable pour les neurones et contribue à plusieurs maladies neurodégénératives. Les cellules gliales sont soupçonnées de contribuer à la mort neuronale par excitotoxicité, mais leur rôle précis est encore méconnu. Le dernier objectif de ma thèse était d’établir le rôle des cellules de Müller dans cette mort neuronale. Nos résultats ont démontré que l’injection de NMDA induit une activation du nuclear factor κB (NF-κB) dans les cellules de Müller, mais pas dans les CGRs, et que l’utilisation d’inhibiteurs du NF-κB empêche la mort des CGRs. De plus, nous avons montré que les cellules de Müller en réaction à l’activation du NF-κB produisent la protéine TNFα laquelle semble être directement impliquée dans la mort des CGRs par excitotoxicité. Cette mort cellulaire se produit principalement par l’augmentation à la surface des neurones des récepteurs AMPA perméables au Ca2+, un phénomène dépendant du TNFα. Ces donnés révèlent un nouveau mécanisme cellululaire non-autonome par lequel les cellules gliales peuvent exacerber la mort neuronale lors de la mise en jeu de mécanismes excitotoxiques.

Modularität und Wiederverwendung

Tagungsband - Vorträge vom Automation Symposium 2006

Alltag, Organisationskultur und beruflicher Habitus

Aus der Einleitung: "Weder in den klassischen, allgemein erziehungswissenschaftlichen Hand- und Wörterbüchern der letzten drei Dekaden (vgl. u.a. Speck/Wehle 1970; Lenzen 1989; Krüger/Grunert 2004) noch in den entsprechenden Überblickspublikationen der Sozialpädagogik (vgl. u.a. Deutscher Verein für öffentliche und private Fürsorge 2002; Lauermann/Knapp 2003; Otto/Thiersch 2005; Kreft/Mielenz 2005) werden Frage- und Problemstellungen der Relation von Distanz und Nähe – zumindest nicht unter dieser Titulatur – diskutiert. Demgegenüber wird in den pflegeorientierten und gesundheitspräventiven wie auch patientenbezogenen Diskussionen der Medizin, in der Theologie und Ethnologie, in der Medien- und Migrationwissenschaft, der Germanistik und der vergleichenden Geschichtswissenschaft sowie in den psychotherapeutischen Diskursen der Nähe-Distanz-Problematik größere Aufmerksamkeit zuteil als in den pädagogischen und erziehungswissenschaftlichen Reflexionen und Diskursen. Wenn sie dennoch Objekt von erziehungswissenschaftlich gefärbten Beobachtungen wird, dann nur mittelbar und allenfalls in Randnotizen, wenn es – thematisch eingegrenzt – um das Ausbalancieren von Distanz und Nähe in den Beziehungen von PädagogInnen und AdressatInnen und der in diesem pädagogischen Verhältnis eingelagerten Intimität geht (vgl. u. a. Bittner/Rehm 1966). Die 'Erotik' im pädagogischen Alltag, die Ängste und die Verdrängungen dieser Dimension durch Aufbau von Distanz oder schließlich die Angst, durch eine zu große Nähe zu den AdressatInnen 'Kontrolle' über den Beruf zu 'verlieren', bleiben weitgehend ebenso unbeleuchtet wie eine nähere Betrachtung der Auswirkungen von zu viel Nähe zu Beruf und AdressatInnen auf die privaten, intimen wie freundschaftlichen Beziehungen (aus ethnopsychoanalytischer Perspektive hierzu u. a. Parin 1978). Zudem wird das Verhältnis von Nähe und Distanz – wenn überhaupt – jeweils spezifisch und auf eine je eigene Art als ein individuelles, nicht jedoch als ein in die Organisation des Pädagogischen immanent eingelagertes Problem beleuchtet, das sich zusätzlich aus den in den jeweiligen pädagogischen Arbeitsfeldern eingelagerten Handlungslogiken speist. Selbstverständlich kann das ambivalente Verhältnis von Nähe und Distanz nicht aus dem personalen Kontext entlassen werden. Wie immer es auch gewendet und thematisiert wird, es bleibt eine in Interaktionen eingewobene Polarität. Doch, und darauf zielen die Suchbewegungen in diesem Beitrag ab, wird es im pädagogischen Alltag von der jeweiligen Kultur der Organisation des Pädagogischen respektive der Sozialen Arbeit gerahmt – quasi kontextualisiert – und geprägt von den jeweils different modellierten beruflichen Habitus der professionellen AkteurInnen. Organisationskulturelle und habituelle Rahmungen des interaktiven Geschehens wiederum sind nicht ohne die Betrachtung der jeweils vorzufindenden feldspezifischen Regeln (vgl. Bourdieu/Wacquant 1996; zur Berücksichtigung einer Theorie des pädagogischen Feldes für Professionalisierung und Qualität vgl. Honig 2004). Diesen Rahmungen von Distanz und Nähe wird nachfolgend nachgespürt, indem erstens einige Beobachtungen aus dem sozialpädagogischen Alltag vorgestellt (1) und sie zweitens hinsichtlich der Ausbuchstabierung von Distanz und Nähe betrachtet werden (2). Drittens werden die bisherigen Überlegungen mit einem weiteren Fallportrait angereichert (3), um schließlich zu rekonstruieren, in welche Modalitäten Nähe und Distanz habituell, organisationskulturell und feldspezifisch eingebunden sind (4)."