Liposomal doxorubicin improves radiotherapy response in hypoxic prostate cancer xenografts

<p>Abstract</p> <p>Background</p> <p>Tumor vasculature frequently fails to supply sufficient levels of oxygen to tumor tissue resulting in radioresistant hypoxic tumors. To improve therapeutic outcome radiotherapy (RT) may be combined with cytotoxic agents.</p> <p>Methods</p> <p>In this study we have investigated the combination of RT with the cytotoxic agent doxorubicin (DXR) encapsulated in pegylated liposomes (PL-DXR). The PL-DXR formulation Caelyx^®was administered to male mice bearing human, androgen-sensitive CWR22 prostate carcinoma xenografts in a dose of 3.5 mg DXR/kg, in combination with RT (2 Gy/day × 5 days) performed under normoxic and hypoxic conditions. Hypoxic RT was achieved by experimentally inducing tumor hypoxia by clamping the tumor-bearing leg five minutes prior to and during RT. Treatment response evaluation consisted of tumor volume measurements and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) with subsequent pharmacokinetic analysis using the Brix model. Imaging was performed pre-treatment (baseline) and 8 days later. Further, hypoxic fractions were determined by pimonidazole immunohistochemistry of excised tumor tissue.</p> <p>Results</p> <p>As expected, the therapeutic effect of RT was significantly less effective under hypoxic than normoxic conditions. However, concomitant administration of PL-DXR significantly improved the therapeutic outcome following RT in hypoxic tumors. Further, the pharmacokinetic DCE MRI parameters and hypoxic fractions suggest PL-DXR to induce growth-inhibitory effects without interfering with tumor vascular functions.</p> <p>Conclusions</p> <p>We found that DXR encapsulated in liposomes improved the therapeutic effect of RT under hypoxic conditions without affecting vascular functions. Thus, we propose that for cytotoxic agents affecting tumor vascular functions liposomes may be a promising drug delivery technology for use in chemoradiotherapy.</p

Sonosensitive dioleoylphosphatidylethanolamine-containing liposomes with prolonged blood circulation time of doxorubicin

This article is part of Tove Julie Evjen's doctoral thesis, which is available in Munin at http://hdl.handle.net/10037/3373Ultrasound sensitive (sonosensitive liposomes) are drug delivery systems designed for releasing their drug load upon exposure to ultrasound (US). Inclusion of dioleoylphosphatidylethanolamine (DOPE) in liposome membranes was previously shown to induce sonosensitivity. For efficient US mediated drug delivery to solid tumours, a long blood circulation time of the liposomal drug providing high tumour uptake is required. In this study, blood pharmacokinetics of DOPE-based liposomal doxorubicin (DXR) were evaluated in mice. A markedly faster blood clearance of DXR was observed for DOPE-rich liposomes compared to Caelyx! (standard liposomal DXR). Subsequently, liposome membrane composition was altered to improve drug retention in the bloodstream, while maintaining sonosensitivity. Formulations with reduced blood clearance of DXR were obtained by reducing the content of DOPE from 62 to 32 or 25 mol%. These formulations showed long blood circulation time, as approximately 20% of the administered DXR dose was present in the bloodstream 24 h after intravenous injection. The reduction in liposomal DOPE content did not significantly reduce US mediated DXR release in vitro, indicating that DOPE is a potent modulator to sonosensitivity. The novel liposome formulations, containing moderate amounts of DOPE, displayed similar blood pharmacokinetic profiles as standard liposomal DXR, but a markedly improved sonosensitivity

Self-oriented perfectionism and socially prescribed perfectionism: Differential relationships with intrinsic and extrinsic motivation and test anxiety

Previous studies suggest that self-oriented and socially prescribed perfectionism show differential relationships with intrinsic–extrinsic motivation and test anxiety, but the findings are ambiguous. Moreover, they ignored that test anxiety is multidimensional. Consequently, the present study re-investigated the relationships in 104 university students examining how the two forms of perfectionism are related to intrinsic–extrinsic motivation and multidimensional test anxiety (worry, emotionality, interference, lack of confidence, and total anxiety). Regarding motivation, self-oriented perfectionism showed positive correlations with intrinsic reasons for studying, and socially prescribed perfectionism positive correlations with extrinsic reasons. Regarding test anxiety, only socially prescribed perfectionism showed positive correlations with total anxiety. Moreover, socially prescribed perfectionism showed positive correlations with interference and lack of confidence, whereas self-oriented perfectionism showed positive correlations with worry, but negative correlations with interference and lack of confidence. The findings confirm that socially prescribed perfectionism is a maladaptive form of perfectionism associated with extrinsic motivation for studying and higher anxiety in exams. Self-oriented perfectionism, however, is an ambivalent form associated with intrinsic motivation for studying and with both higher and lower anxiety (higher worry, lower interference, lower lack of confidence) in exams

Initiativ og responsmønstre i boklesingsdialoger mellom barnehagelærer og barn med minoritetsspråklig bakgrunn

I denne studien undersøker vi dynamikken i dialoger mellom barne–hagelærer og barn med minoritetsspråklig bakgrunn i to boklesingssituasjoner. Vi ser på hvordan barnehagelæreren inviterer barnet med i dialogen, og hvordan barnet svarer. Åtte samspill med barnehagelærer og barn ble videofilmet mens de sammen leste i to bøker. Dialogene ble analyserte i to faser: Først brukte vi Initiativ – Responsanalyser (IR). Med grunnlag i det registrerte initiativ-responsmønsteret gjorde vi deretter mer dyptgående analyser av utvalgte dialogiske fenomen, som hvordan den voksne inviterer barnet med i dialogen, og hvordan barnet svarer på ulike typer spørsmål. Resultatene viste at barna var svært passive og barne–hagelærerne relativt aktive i dialogene. En betydelig del av samtalebidragene fra barnehagelærerne bestod av lukkede spørsmål, mens barnas bidrag hovedsakelig var korte verbale eller non-verbale svar. I et språklæringsperspektiv er det viktig at barn som lærer et andrespråk, får erfaringer med både å forstå og å produsere språk. Resultatene fra den foreliggende studien kan indikere at barn med minoritetsspråklig bakgrunn i norske barnehager kan få begrensede erfaringer med selv å bruke andrespråket

Adolescent weak decoders writing in a shallow orthography: process and product

It has been hypothesised that students with dyslexia struggle with writing because of a word level focus that reduces attention to higher level textual features (structure, theme development). This may result from difficulties with spelling and/or from difficulties with reading. 26 Norwegian upper secondary students (M = 16.9 years) with weak decoding skills and 26 age-matched controls composed expository texts by keyboard under two conditions: normally and with letters masked to prevent them reading what they were writing. Weak decoders made more spelling errors and produced poorer quality text. Their inter key-press latencies were substantially longer pre-word, at word-end, and within-word. These findings provide some support for the word-level focus hypothesis, although we found that weak decoders were slightly less likely to engage in word-level editing. Masking did not affect differences between weak decoders and controls indicating that reduced fluency was associated with production rather than monitoring what they had produced

Cognitive predictors of shallow-orthography spelling speed and accuracy in 6th grade children

Spelling accuracy and time course was investigated in a sample of 100 Norwegian 6th grade students completing a standardized spelling-to-dictation task. Students responded by keyboard with accurate recordings of response-onset latency (RT) and inter-keypress interval (IKI). We determined effects of a number of child-level cognitive ability factors, and of word-level factors—particularly the location within the word of a spelling challenge (e.g., letter doubling), if present. Spelling accuracy was predicted by word reading (word split) performance, non-word spelling accuracy, keyboard key-finding speed and short-term memory span. Word reading performance predicted accuracy just for words with spelling challenges. For correctly spelled words, RT was predicted by non-word spelling response time and by speed on a key-finding task, and mean IKI by non-verbal cognitive ability, word reading, non-word spelling response time, and key-finding speed. Compared to words with no challenge, mean IKI was shorter for words with an initial challenge and longer for words with a mid-word challenge. These findings suggest that spelling is not fully planned when typing commences, a hypothesis that is confirmed by the fact that IKI immediately before within word challenges were reliably longer than elsewhere within the same word. Taken together our findings imply that routine classroom spelling tests better capture student competence if they focus not only on accuracy but also on production time course

Level and Change in Alcohol Consumption, Depression and Dysfunctional Attitudes among Females Treated for Alcohol Addiction

Aims: To examine whether individual changes in alcohol consumption among female alcoholics under treatment are predicted by level of and changes in depression and dysfunctional attitudes. Method: A total of 120 women who were treated for alcohol addiction at the Karolinska Hospital in Stockholm (Sweden) were assessed twice over a 2-year period using the Depression scale from the Symptom Checklist-90, the Alcohol Use Inventory and the Dysfunctional Attitude Scale (DAS). Latent growth curve analysis was used. Results: Decrease in alcohol consumption, depression and dysfunctional attitude variables were found at group level. The results also showed significant individual variation in change. Changes in alcohol consumption were predicted by baseline alcohol drinking, as well as by level and changes in depression. Stronger reduction in depression was related to higher level of depression at baseline, and with reduction in dysfunctional attitudes. Different DAS sub-scales resulted in different magnitude of the model relations. Good treatment compliance was related to lower baseline level in depression, but also with higher baseline level in dysfunctional attitudes, and predicted stronger reduction in alcohol consumption. Conclusion: This paper shows the importance of incorporating both individual level and change in depression as predictors of change in alcohol consumption among subjects treated for alcohol addiction. Also, dysfunctional attitudes are both indirectly and directly related to treatment outcome. By incorporating alcohol consumption, depression and dysfunctional attitudes as targets of intervention, treatment compliance and outcome may be enhanced

Academically buoyant students are less anxious about and perform better in high-stakes examinations.

BACKGROUND: Prior research has shown that test anxiety is negatively related to academic buoyancy, but it is not known whether test anxiety is an antecedent or outcome of academic buoyancy. Furthermore, it is not known whether academic buoyancy is related to performance on high-stakes examinations. AIMS: To test a model specifying reciprocal relations between test anxiety and academic buoyancy and to establish whether academic buoyancy is related to examination performance. SAMPLE: A total of 705 students in their final year of secondary education (Year 11). METHODS: Self-report data for test anxiety and academic buoyancy were measured in two waves in Year 11. Examination performance was taken from the mean English, mathematics, and science scores from the high-stakes General Certificate of Secondary Education (GCSE) examinations taken at the end of Year 11. RESULTS: Measurement invariance was demonstrated for test anxiety and academic buoyancy across both waves of measurement. The worry component of test anxiety, but not the tension component, showed reciprocal relations with academic buoyancy. Worry predicted lower mean GCSE score and academic buoyancy predicted a higher mean GCSE score. Tension did not predict mean GCSE score. CONCLUSION: Academic buoyancy protects against the appraisal of examinations as threatening by influencing self-regulative processes and enables better examination performance. Worry, but not tension, shows a negative feedback loop to academic buoyancy