Reciprocal changes in gene expression profiles of cocultured breast epithelial cells and primary fibroblasts

The importance of epithelial‐stroma interaction in normal breast development and tumor progression has been recognized. To identify genes that were regulated by these reciprocal interactions, we cocultured a nonmalignant (MCF10A) and a breast cancer derived (MDA‐MB231) basal cell lines, with fibroblasts isolated from breast benign‐disease adjacent tissues (NAF) or with carcinoma‐associated fibroblasts (CAF), in a transwell system. Gene expression profiles of each coculture pair were compared with the correspondent monocultures, using a customized microarray. Contrariwise to large alterations in epithelial cells genomic profiles, fibroblasts were less affected. In MDA‐MB231 highly represented genes downregulated by CAF derived factors coded for proteins important for the specificity of vectorial transport between ER and golgi, possibly affecting cell polarity whereas the response of MCF10A comprised an induction of genes coding for stress responsive proteins, representing a prosurvival effect. While NAF downregulated genes encoding proteins associated to glycolipid and fatty acid biosynthesis in MDA‐MB231, potentially affecting membrane biogenesis, in MCF10A, genes critical for growth control and adhesion were altered. NAFs responded to coculture with MDA‐MB231 by a decrease in the expression of genes induced by TGFβ1 and associated to motility. However, there was little change in NAFs gene expression profile influenced by MCF10A. CAFs responded to the presence of both epithelial cells inducing genes implicated in cell proliferation. Our data indicate that interactions between breast fibroblasts and basal epithelial cells resulted in alterations in the genomic profiles of both cell types which may help to clarify some aspects of this heterotypic signaling. © 2009 UICC     

Reduction of the dose to the elective neck in head and neck squamous cell carcinoma,a randomized clinical trial using intensity modulated radiotherapy (IMRT). Dosimetrical analysis and effect on acute toxicity

Background and purpose

A randomized trial was initiated to investigate whether a reduction of the dose to the elective nodal sites and the swallowing apparatus delivered by IMRT would result in a reduction of acute and late side effects without compromising tumor control. The aim of this paper is to report on dosimetrical analysis and acute toxicity.

Materials & methods

Two-hundred patients were randomized. In the standard arm, elective nodal volumes (PTV_elect) were irradiated up to an equivalent dose of 50 Gy. In the experimental arm an equivalent dose of 40 Gy was prescribed to the PTV_elect. The dose to the swallowing apparatus was kept as low as possible without compromising therapeutic PTV (PTV_ther) coverage.

Results

No significant difference was seen between both arms concerning PTV_ther coverage. The median D₉₅ of the PTV_elect was significantly lower in the experimental arm (39.5 vs 49.8 Gy; p < 0.001). Concerning the organs at risk, the dose to swallowing structures and spinal cord was significantly reduced. There was no significant difference in acute toxicity. Three months after radiotherapy there was significantly less grade ?3 dysphagia in the experimental arm (2% vs 11%; p = 0.03). With a median follow-up of 6 months no significant differences were observed in locoregional control, disease free survival or overall survival.

Conclusions

Using IMRT we were able to significantly reduce the dose to the PTV_elect and several organs at risk without compromising PTV_ther coverage. This resulted in a significant reduction of severe dysphagia 3 months after radiotherapy. Further follow-up is necessary to investigate whether these observations translate into a benefit on late treatment related dysphagia without affecting treatment outcome.     

The nature of care in light of Emmanuel Levinas

Abstract  The discipline of nursing is still struggling with the differences that need to be clearly defined between the notions of care and nursing care. To be able to clarify this distinction, agreement must first be reached on the meaning of care itself. The present article proposes a conception of care in light of the philosophy of Emmanuel Levinas (1906–1995). This philosopher's thought throws considerable light on the ontology of care, thanks especially to his focus on the deeper implications of human encounter. A profound sense of responsibility towards the other enables Levinas to bring out such dimensions of the concept of care as the relation involved, the feeling of affection, and the interventions. We examine here what these entail regarding nursing care.     

Characterization of binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethylcellulose used in the preparation of controlled release tablets

Cross-linked amylose starch (CLA), hydroxypropylmethylcellulose (HPMC), and HPMC/CLA matrices were prepared by direct compression. HPMC was used to slow down the enzymatic degradation of CLA matrices. CLA was either granulated alone and mixed with HPMC or cogranulated with the latter. Compaction characteristics of the powder, hydration and mechanical properties of the resulting matrices, as well as the release profiles of three model drugs were investigated. The results showed that wet granulation of CLA in the presence of 10% HPMC improved significantly the flow properties of the powder without compromising its compactibility. Both CLA and HPMC deformed mainly by plastic flow (yield pressures are 75 and 124 MPa, respectively), but CLA exhibited a stronger elastic component (elastic recoveries are 18.4 and 11.5%, respectively). The values of yield pressure increased linearly with the concentration of HPMC. The addition of HPMC to CLA slightly decreased the resistance to consolidation but the crushing force of the final compacts was found to be proportional to the HPMC concentration. Mechanical studies on swollen matrices revealed that CLA formed a stronger gel than HPMC or CLA/HPMC mixture, and swelling and erosion of the tablets increased with HPMC content and incubation time. The in vitro release kinetics of three model drugs (pseudeoephedrine sulfate, sodium diclofenac, and prednisone) showed a clear effect of drug solubility and presence of alpha-amylase in the dissolution medium on the release rate. The addition of HPMC to CLA protected the tablets against alpha-amylase hydrolysis and reduced the release rate of prednisone and sodium diclofenac. The release of pseudoephedrine sulfate was fast and independent of HPMC and occurred mainly by diffusion.     

Relative lack of cognitive effects of methylphenidate in elderly male volunteers

Rationale Methylphenidate, a dopaminergic and noradrenergic reuptake inhibitor, has been shown in young, healthy adult volunteers to produce pronounced effects on working memory and sustained attention. We were interested in assessing whether similar improvements could be conferred upon elderly volunteers in order to gain a more complete understanding of the effects of age on monoaminergic manipulations of working memory and attention, as well as to explore the potential for pharmacological intervention in attention and executive dysfunction disorders in this age group. Objectives The main aim of the study was to characterise the dose-related effects of methylphenidate on a range of neuropsychological functions in elderly healthy volunteers. Methods Sixty healthy elderly adult male volunteers received either a single oral dose of placebo, 20 mg or 40 mg methylphenidate prior to performing a variety of tasks designed to assess memory, attention and executive function. A randomised double-blind, between-subjects design was used. Results Methylphenidate had significant cardiovascular and subjective effects. However, unlike in younger volunteers, no significant effects of drug on working memory (spatial span and spatial working memory), response inhibition (stop-signal) or sustained attention (rapid visual information processing) were seen. Subtle effects on latency similar to those in younger volunteers were identified: both doses of methylphenidate resulted in a slowing in response time during set-shifting and decision-making. Conclusions The results of this study demonstrate that, in elderly subjects, the cognitive effects of methylphenidate are grossly attenuated and distinct from the profile previously described in younger volunteers. It is suggested that methylphenidate may not be appropriate as a pharmacological intervention in elderly patient groups, such as those reporting age-related cognitive decline.     

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.     

Effects of soy protein supplemented with methionine on blood lipids and adiposity of rats

OBJECTIVE: The effects of soy protein isolate (SPI) versus casein on blood lipids and adiposity were investigated in rats fed methionine-equivalent diets. METHODS: Twenty-eight male Sprague-Dawley rats (230 to 250 g) were assigned in equal numbers to groups consuming SPI- or casein-based diets (20%) supplemented with L-methionine. After 28 d, blood was collected for triacylglycerol, total cholesterol, and high-density lipoprotein cholesterol assessment and epididymal fat pads were weighed. RESULTS: Food intake (519 +/- 90 versus 490 +/- 115 g), weight gain (144 +/- 35 versus 133 +/- 28 g), food efficiency ratio (0.29 +/- 0.09 versus 0.28 +/- 0.06), epididymal fat pad weights (5.409 +/- 2.076 versus 4.768 +/- 1.867 g), and serum concentrations of triacylglycerol (96.3 +/- 41.8 versus 93.4 +/- 37.4 mg/dL) and high-density lipoprotein cholesterol (32.6 +/- 7.4 versus 33.8 +/- 4.4 mg/dL) were similar between the casein and SPI groups, respectively. However, total cholesterol (73.8 +/- 17.8 versus 59.3 +/- 11.9 mg/dL) concentration was higher for the casein-fed rats than for the SPI-fed rats, respectively (P < 0.05). CONCLUSIONS: These results suggest that methionine supplementation may eliminate the decreased fat deposition previously ascribed to soy protein; however, methionine did not abolish the commonly observed hypocholesterolemic effects of soy.     

Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis

BACKGROUND: The duration and cost of cancer clinical trials could be reduced if a surrogate endpoint were used in place of survival. We did a meta-analysis to assess the extent to which two surrogates, tumour response and time to progression, are predictive of mortality in metastatic colorectal cancer and non-small-cell lung cancer. METHODS: Summary data (median time to progression, proportion of patients responding to treatment, and median overall survival) from randomised trials of first-line treatment in colorectal cancer (146 trials) and lung cancer (191 trials) were identified. Data were extracted and analysed by linear regression. We used prediction bands for trials with 250, 500, and 750 patients to identify the surrogate threshold effect that would predict a significant difference in survival. FINDINGS: Response to treatment and time to progression correlated with improvement in survival for both lung cancer (p<0.0001 and p=0.0003, respectively) and colorectal cancer (p<0.0001 for both). To predict a significant survival gain in colorectal cancer trials, an improvement of 20% in the number of patients responding to treatment was required in trials with 750 patients, increasing to 26% in trials with 500 patients and 38% in trials with 250 patients. In lung cancer trials, the same prediction required differences in response of 18% for 750 patients, 21% for 500 patients, and 30% for 250 patients. For time to progression for both cancer types, the incremental gain needed to predict a survival improvement was a median of 1.8 months for trials with 750 patients, 2.2 months for 500 patients, and 3.3 months for 250 patients. INTERPRETATION: Irrespective of trial size, large differences in tumour response rate are needed to predict a significant survival benefit. If surrogates are chosen as the primary endpoint in a clinical trial, time to progression is the preferred measure because more modest and achievable differences are needed for a significant survival benefit. Trials in metastatic lung cancer and colorectal cancer should measure survival as their primary outcome unless the surrogate outcome difference is anticipated to exceed the threshold effect size.     

Neoadjuvant hormonal treatment combined with external irradiation in the management of prostate cancer

RTOG and EORTC trials have paved the way of the combination of radiation therapy and androgen suppression. Localized carcinoma with intermediate prognostic factors (cT2b, Gleason 7, or baseline PSA ranging between 10 and 20 ng/mL) may be submitted to a 4-month complete androgene blockade with 2 months before irradiation, unless to include patients in ongoing randomized trials. High risk cancers (cT2c, or Gleason > 7, or PSA > 20 ng/ml) should receive a 4-month or 6-month complete androgen blockade (RTOG trial 86-10), knowing that the results of EORTC trial 22961 are eagerly expected to tell us whether a 3- year androgen suppression is preferable. Very high risk prostate cancers, T3-4 N0 M0 or pelvic lymph node involvement (c or pN1) whatever the UICC T stage, need a long term androgen suppression of 3 years or more.