Comparative study of the radiosensitising and cell cycle effects of vinflunine and vinorelbine, in vitro

<p>Abstract</p> <p>Background</p> <p>Vinca alkaloids are an important class of anticancer agents and semisynthetic vinca alkaloids are developed to improve the therapeutic index of this class of drugs. In the present study, a direct comparison was made between vinflunine and vinorelbine regarding their radiosensitising and cell cycle effects.</p> <p>Methods</p> <p>Four human tumour cell lines were tested under identical experimental conditions, using equitoxic concentrations of vinflunine and vinorelbine.</p> <p>Results</p> <p>Vinflunine and vinorelbine induced a comparable radiosensitising effect (p-value never below 0.01) when cells were incubated for 24 h immediately prior to radiation. Regarding the cell cycle effects, a statistically significant concentration-dependent G2/M block was seen after 24 h incubation with vinorelbine in all tested cell lines. Similar results, with small cell line-related differences, were observed with vinflunine.</p> <p>Conclusion</p> <p>The radiosensitising effects of both semisynthetic vinca alkaloids were comparable (not statistically different) and nearly always cell line-specific and concentration-dependent. The cell cycle effects could be related to the observed radiosensitising effects. Considering the more favourable toxicity profile of vinflunine, this agent might be more promising than vinorelbine for chemoradiation studies in the clinic.</p

Pensamiento crítico en estudiantes del Grado de Educación Social

El presente artículo se centra en una investigación cualitativa sobre las creencias acerca del pensamiento crítico que poseen 72 estudiantes de tercer curso del Grado de Educación Social de la Universidad de Huelva (España). Los resultados, en consonancia con otras investigaciones, muestran que el alumnado tiene un conocimiento poco detallado aunque certero de lo que significa dicha competencia, ofreciendo explicaciones generales que van en acuerdo con las ideas que tienen acerca de la Universidad, la Sociedad y la finalidad de la Educación Social. La buena disposición que muestra la mayoría del alumnado investigado choca con escasos hábitos para el pensamiento crítico, achacándolo a una formación reproductiva, a la influencia perniciosa de determinados poderes sociales y a un no-saber-hacer-y-actuar de los futuros educadores sociales.This article focuses on qualitative research on the beliefs about critical thinking held by 72 third year students of the Social Education Degree of the University of Huelva (Spain). The results show that the students have a little detailed but accurate knowledge of what this competence means, offering general explanations that are in line with the ideas they have about the University, Society and the purpose of Social Education. The willingness shown by the majority of the students researched clashes with scarce habits for critical thinking, blaming it on reproductive training, the pernicious influence of certain social powers and the non-know-how-to-act of future social educators

Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery

Background-Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. Methods and Results-Here, we report that VEGF(partial derivative/partial derivative) mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. Conclusions-These findings uncover a novel role for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients. (Circulation. 2010; 122: 273-281.

In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells

<p>Abstract</p> <p>Background</p> <p>Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA) and gemcitabine (2',2'-difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising. This <it>in vitro </it>study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules.</p> <p>Methods</p> <p>The cytotoxicity, radiosensitising potential and cell cycle effect of MTA were investigated in A549 (NSCLC) and CAL-27 (SCCHN) cells. Using simultaneous or sequential exposure schedules, the cytotoxicity and radiosensitising effect of 24 h MTA combined with 1 h or 24 h dFdC were analysed.</p> <p>Results</p> <p>Including a time interval between MTA exposure and irradiation seemed favourable to MTA immediately preceding or following radiotherapy. MTA induced a significant S phase accumulation that persisted for more than 8 h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24 h MTA followed by 1 h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect.</p> <p>Conclusions</p> <p>Results from our <it>in vitro </it>model suggest that the sequence 24 h MTA → 1 h dFdC → RT is the most rational design and would, after confirmation in an <it>in vivo </it>setting, possibly provide the greatest benefit in the clinic.</p

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

The interaction between staff and clients with severe or profound intellectual disability and challenging behavior

The staff-client interaction plays an important role in the development and maintenance or challenging behaviour of individuals with intellectual disabilities. Particularly^ the mutuality between staff behaviour and client behaviour is important in this context. Furthermore, severe challenging behaviour seems to elicit negative emotional reactions trom staff and these emotions may influence their behaviour. Another variable that influences staff behaviour are the beliefs that staff have about the challenging behaviour (Hastings, 2005). Although some studies have been dons in this domain, further research with more objective measurements is needed to confirm the relevance of these factors. In a first study, wβ have investigated the challenging behaviour of clients, and the beliefs, the emotional reactions, and the behavioural responses of staff members towards this challenging behaviour. We were interested in the possible relationships between these variables. We used four written questionnaires: the 'Challenging Behaviour Attributions scale' (Hastings, lθ≡7)∣ the "Emotional Reactions to Challenging Behaviours scales" (Jones & Hastings, 2003; Mitchell & Hastings, 1998); the “Reactions to Challenging Behaviours scale' (Lambrechts & Maes, 2006); and the ‘Behaviour Problems Inventory’ (Rojahn, Matson, Lott, Esbensen, & Smalls, 2001). One hundred fifty-two staff members working in 20 different residential settings participated. We were interested in specific staff-client dyads and focused on clients with severe or profound intellectual disabilities who displayed self-injurious behaviour, stereotyped behaviour, and/or aggressive/destructive behaviour. In a second study we will further investigate the relations between staff behaviour and challenging behaviour, between staff emotions and staff behaviour, and finally between staff beliefs and staff behaviour. The staff reactions to challenging behaviour will be observed by means of video recording. Staff emotional reactions and staff beliefs will be examined by semi-structured interviews. We will be able to investigate the circumstances that influence challenging behaviour and to look for an answer to the question if it is possible to observe mutual reinforcement processes between care staff and clients. Furthermore, we will have a more detailed and thorough view on staff emotional reactions and staff beliefs. Finally, we will figure out if it is possible to find a link between the reactions to challenging behaviour and the variables examined in the semi-structured interview.status: publishe

Staff emotions, beliefs, and reactions towards challenging behaviour of clients with a severe or profound intellectual disability

Greet Lambrechts, Emoties, overtuigingen, en reacties van begeleiders te n opzichte van probleemgedrag van cliënten met een ernstig of diep verst andelijke beperking. Proefschrift aangeboden tot het verkrijgen van de graad van Doctor in de Pedagogische Wetenschappen, 2010. Promotor: Prof. Dr. Bea Maes Een belangrijke factor in het ontstaan en het blijven voortduren van pro bleemgedrag, is de interactie tussen een individu met een verstandelijke beperking en zijn of haar begeleider. Reacties van begeleiders ten opzi chte van probleemgedrag worden beïnvloed door een combinatie van gedrags factoren, cognitieve factoren en factoren aangaande het welbevinden van begeleiders en hun emoties. Cognitieve factoren impliceren overtuigingen van begeleiders over wat probleemgedrag is, wat het veroorzaakt en hoe het best aangepakt kan worden. Tot factoren inzake het welbevinden van b egeleiders en hun emoties behoren variabelen als psychologisch welbevind en, copingstrategieën, zelfverzekerdheid, geuite emoties en emotionele r eacties. Het doel van dit proefschrift was het nagaan van emoties en ove rtuigingen van begeleiders aangaande probleemgedrag van cliënten met een ernstig of diep verstandelijke beperking en de relatie tussen deze vari abelen en reacties van begeleiders. Algemeen wordt aangenomen dat overtu igingen van begeleiders ten opzichte van probleemgedrag een invloed hebb en op de manier waarop ze omgaan met cliënten die probleemgedrag vertone n. Aan de andere kant heeft probleemgedrag een aversieve connotatie en k an er verwacht worden dat begeleiders negatieve gevoelens vertonen ten o pzichte van probleemgedrag en dat die emoties op hun beurt ook het gedra g van begeleiders beïnvloeden. Tot nu toe werden vooral cognitief-emotio nele modellen van begeleidergedrag gebruikt in dit onderzoeksdomein. Dit proefschrift bestaat uit vijf manuscripten die gepubliceerd of ingedien d zijn in een internationaal tijdschrift. In het eerste manuscript wordt een systematisch overzicht gegeven van de bestaande literatuur over variabelen die een invloed hebben op react ies ten aanzien van probleemgedrag van cliënten met een verstandelijke b eperking. De verschillende aspecten die bijdragen tot de complexiteit va n dit onderzoeksdomein worden op een rijtje gezet en de suggestie wordt gegeven om in de toekomst gebruik te maken van het kader van Hastings (2 005). In de volgende twee manuscripten werd een vragenlijstonderzoek opg ezet, rekening houdend met verschillende methodologische opmerkingen. In het tweede manuscript werd het voorkomen van zelfverwondend gedrag, agressief/destructief gedrag, en stereotiep gedrag, gerapporteerd door b egeleiders, onder de loep genomen. We vergeleken de antwoorden van versc hillende begeleiders over dezelfde cliënt en kwamen tot het besluit dat begeleiders verschillen in hun rapportage over de frequentie van problee mgedrag. Een gedeelte van deze variabiliteit werd verklaard door verschi llen in begeleidervariabelen. In het derde manuscript werden de emoti es, overtuigingen en reacties van begeleiders ten opzichte van probleemg edrag en eventuele relaties tussen deze variabelen onderzocht. We gingen na of er op een verschillende manier gerapporteerd werd over verschille nde types van probleemgedrag en of verschillende reacties van begeleider s gerelateerd waren aan verschillende types van probleemgedrag. Verder o nderzochten we mogelijke associaties tussen reacties van begeleiders en probleemgedrag en tussen emoties van begeleiders en probleemgedrag. Ten slotte testten we of de attributietheorie van Weiner toepasbaar is in de ze context. We vonden bepaalde associaties tussen reacties van begeleide rs en probleemgedrag, en tussen emoties van begeleiders en probleemgedra g. Zoals in eerder onderzoek, konden ook onze resultaten de attributieth eorie niet bevestigen. Omdat begeleidergedragingen ten opzichte van prob leemgedrag zo belangrijk zijn en omdat er nood is aan onderzoek naar dez e gedragingen in de dagdagelijkse omgeving, hebben we een observatiestud ie opgezet. In het vierde manuscript onderzochten we de sequentiële a ssociaties tussen probleemgedrag en reacties van begeleiders. Begeleider s maakten veel gebruik van verbale reacties en reacties nodig om het pro bleemgedrag te stoppen. Een uitgebreide lijst met mogelijke concrete en observeerbare reacties van begeleiders werd opgesteld. En opnieuw werden relaties tussen bepaalde types van probleemgedrag en reacties van begel eiders gevonden. In manuscript vijf werd de exacte betekenis van de c oncepten emoties, overtuigingen en reacties ten opzichte van probleemged rag en mogelijke relaties tussen deze concepten onderzocht via interview s met de begeleiders. Begeleiders vertelden dat ze vaak bezig waren met de interventies die nodig waren wanneer cliënten probleemgedrag vertoond en. Het grootste gedeelte van deze gedachten behoort tot de overtuiginge n van begeleiders die al opgenomen zijn in eerder onderzoek. Er zijn ech ter nog bepaalde vragen en onzekerheden die een belangrijke rol spelen b ij het werk van begeleiders die van een andere orde zijn en nog niet ond erzocht werden in het verleden. Verder werd het vooral via de resultaten over mogelijke relaties tussen emoties en reacties en tussen overtuigin gen en reacties duidelijk dat er in de toekomst andere invalshoeken nodi g zijn in dit onderzoeksdomein. De resultaten van dit proefschrift hebben theoretische en methodologisch e implicaties en openen nieuwe wegen voor verder onderzoek. Ook werden e r interessante en relevante aspecten voor de praktijk aangehaald.status: publishe

Staff emotional reactions and experiences towards challenging behaviour: an interview study

More and more attention is given to the psychological effects of challenging behaviour on others. Staff members' emotional reactions and experiences are important variables in this context, and need to be studied using direct measurement of staff exposure to challenging behaviours. In this study, 12 staff members were confronted with video recordings of their own behaviour in situations, in which a client was showing challenging behaviour. They were interviewed about their emotions and emotional experiences. Next to positive and negative emotions, staff members often mentioned the importance of the help they received from their colleagues. Some emotions were linked to the frequency of the challenging behaviour, and often, staff members referred to thoughts, questions, and doubts that were playing in their head. © The British Society of Developmental Disabilities 2012.status: publishe