EpCAM aptamer-mediated survivin silencing sensitized cancer stem cells to doxorubicin in a breast cancer model

Understanding the molecular basis of drug resistance and utilising this information to overcome chemoresistance remains a key challenge in oncology. Here we report that survivin, a key protein implicated in drug resistance, is overexpressed in cancer stem cell pool of doxorubicin-resistant breast cancer cells. Moreover, by utilising an active targeting system consisting of an RNA aptamer targeted against the epithelial cell adhesion molecule and a Dicer substrate survivin siRNA, we could deliver a high dose of the siRNA to cancer stem cells in xenograft tumours. Importantly, silencing of survivin with this aptamer-siRNA chimera in cancer stem cell population led to the reversal of chemoresistance, such that combined treatment with low dose of doxorubicin inhibited stemness, eliminated cancer stem cells via apoptosis, suppressed tumour growth, and prolonged survival in mice bearing chemoresistant tumours. This strategy for in vivo cancer stem cell targeting has wide application for future effective silencing of anti-death genes and in fact any dysregulated genes involved in chemoresistance and tumour relapse.

Pharmacological interventions for self-harm in adults

Background
Self-harm (SH; intentional self-poisoning or self-injury) is common, often repeated, and strongly associated with suicide. This is an update of a broader Cochrane review on psychosocial and pharmacological treatments for deliberate SH, first published in 1998 and previously updated in 1999. We have now divided the review in to three separate reviews. This review is focused on pharmacological interventions in adults who self harm.
Objectives
To identify all randomised controlled trials of pharmacological agents or natural products for SH in adults, and to conduct meta-analyses (where possible) to compare the effects of specific treatments with comparison types of treatment (e.g., placebo/alternative pharmacological treatment) for SH patients.
Search methods
For this update the Cochrane Depression, Anxiety and Neurosis Review Group (CCDAN) Trials Search Co-ordinator searched the CCDAN Specialised Register (September 2014). Additional searches of MEDLINE, EMBASE, PsycINFO, and CENTRAL were conducted to October 2013.
Selection criteria
We included randomised controlled trials comparing pharmacological treatments or natural products with placebo/alternative pharmacological treatment in individuals with a recent (within six months) episode of SH resulting in presentation to clinical services.
Data collection and analysis
We independently selected trials, extracted data, and appraised trial quality. For binary outcomes, we calculated odds ratios (ORs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean difference (MD) and 95% CI. Meta-analysis was only possible for one intervention (i.e. newer generation antidepressants) on repetition of SH at last follow-up. For this analysis, we pooled data using a random-effects model. The overall quality of evidence for the primary outcome was appraised for each intervention using the GRADE approach.
Main results
We included seven trials with a total of 546 patients. The largest trial included 167 participants. We found no significant treatment effect on repetition of SH for newer generation antidepressants (n = 243; k = 3; OR 0.76, 95% CI 0.42 to 1.36; GRADE: low quality of evidence), low-dose fluphenazine (n = 53; k = 1; OR 1.51, 95% CI 0. 50 to 4.58; GRADE: very low quality of evidence), mood stabilisers (n = 167; k = 1; OR 0.99, 95% CI 0.33 to 2.95; GRADE: low quality of evidence), or natural products (n = 49; k = 1; OR 1.33, 95% CI 0.38 to 4.62; GRADE: low quality of evidence). A significant reduction in SH repetition was found in a single trial of the antipsychotic flupenthixol (n = 30; k = 1; OR 0.09, 95% CI 0.02 to 0.50), although the quality of evidence for this trial, according to the GRADE criteria, was very low. No data on adverse effects, other than the planned outcomes relating to suicidal behaviour, were reported.
Authors’ conclusions
Given the low or very low quality of the available evidence, and the small number of trials identified, it is not possible to make firm conclusions regarding pharmacological interventions in SH patients. More and larger trials of pharmacotherapy are required. In view of an indication of positive benefit for flupenthixol in an early small trial of low quality, these might include evaluation of newer atypical antipsychotics. Further work should include evaluation of adverse effects of pharmacological agents. Other research could include evaluation of combined pharmacotherapy and psychological treatment.

In vitro and in vivo assessment of docetaxel formulation developed for esophageal stents

Esophageal cancer (EC) mostly affects the elderly population and is frequently diagnosed at an advanced stage. Self-expanding metal stents (SEMS) are the most popular mode of palliation, but they are associated with reocclusion caused by tumor growth. To overcome this problem, docetaxel (DTX)-loaded polyurethane formulations were prepared for stent application. The films were evaluated against the cancer cell lines, OE-19 and OE-21, and normal esophageal cell line Het-1A. The DTX and the formulations were evaluated in vitro for the cytotoxicity and in vivo in nude mice. It was found that DTX and the formulations have a weak activity against the EC cell lines and an even weaker activity against Het-1A cell line. Preliminary in vivo studies showed skin toxicity in nude mice necessitating modification of the formulation. Reevaluation in a mouse xenograft model resulted in toxicity at high dose formulations while the low dose formulation exhibited modest advantage over commercial IV formulation; however, there was no significant difference between the commercial IV and blank formulation. DTX combination with an anti-cancer agent having complementary mode of action and non-overlapping toxicity could yield better outcome in future.

Increased hypoxic dose after training at low altitude with 9h per night at 3000m normobaric hypoxia

This study examined effects of low altitude training and a live-high: train-low protocol (combining both natural and simulated modalities) on haemoglobin mass (Hbmass), maximum oxygen consumption (VO2max), time to exhaustion, and submaximal exercise measures. Eighteen elite-level race-walkers were assigned to one of two experimental groups; lowHH (low Hypobaric Hypoxia: continuous exposure to 1380 m for 21 consecutive days; n = 10) or a combined low altitude training and nightly Normobaric Hypoxia (lowHH+NHnight: living and training at 1380 m, plus 9 h.night-1 at a simulated altitude of 3000 m using hypoxic tents; n = 8). A control group (CON; n = 10) lived and trained at 600 m. Measurement of Hbmass, time to exhaustion and VO2max was performed before and after the training intervention. Paired samples t-tests were used to assess absolute and percentage change pre and post-test differences within groups, and differences between groups were assessed using a one-way ANOVA with least significant difference post-hoc testing. Statistical significance was tested at p < 0.05. There was a 3.7% increase in Hbmass in lowHH+NHnight compared with CON (p = 0.02). In comparison to baseline, Hbmass increased by 1.2% (±1.4%) in the lowHH group, 2.6% (±1.8%) in lowHH+NHnight, and there was a decrease of 0.9% (±4.9%) in CON. VO2max increased by ~4% within both experimental conditions but was not significantly greater than the 1% increase in CON. There was a ~9% difference in pre and post-intervention values in time to exhaustion after lowHH+NH-night (p = 0.03) and a ~8% pre to post-intervention difference (p = 0.006) after lowHH only. We recommend low altitude (1380 m) combined with sleeping in altitude tents (3000 m) as one effective alternative to traditional altitude training methods, which can improve Hbmass.

1-14C-Linoleic Acid distrubution in various tissue lipids of guinea pigs following an oral dose

A recent study on the metabolism of 1-¹⁴C-α-linolenic acid in the guinea pig revealed that the fur had the highest specific activity of all tissues examined, 48 h after dosing. The present study investigated the pattern of tissue lipid labeling following an oral dose of 1-¹⁴C-linoleic acid after the animals had been dosed for the same time as above. Guinea pigs were fed one of two diets with a constant linoleic acid content (18% total fatty acids) and a different content of α-linolenic acid (0.3 or 17.3%) from weaning for 3 wk and 1-¹⁴C-linoleic acid was given orally to each animal for 48 h prior to sacrifice. The most highly labeled tissues (dpm/mg of linoleic acid) were liver, followed by brain, lung and spleen, heart, kidney and adrenal and intestines, in both diet groups. The liver had almost a three-fold higher specific activity than skin and fur which was more extensively labeled than the adipose and carcass. Approximately two-thirds of the label in skin plus fur was found in the fur which, because of a low lipid mass, would indicate that the fur was highly labeled. All tissues derived from animals on the diet with the low α-linolenic acid level were significantly more labeled than the tissues from the animals on the high α-linolenic acid diet, by a factor of 1.5 to 3. The phospholipid fraction was the most highly labeled fraction in the liver, free fatty acids were the most labeled fraction in skin & fur, while triacyglycerols were the most labeled in the carcass and adipose tissue. In these tissues, more than 90% of the radioactivity was found in fatty acids with 2-double bonds in the tissue lipids. These data indicate that the majority of label found in guinea pig tissues 48 h after dosing was still associated with a fatty acid fraction with 2-double bonds, which suggests there was little metabolism of linoleic acid to more highly unsaturated fatty acids in this time frame. In this study, the labeling of guinea pig tissues with linoleic acid, 48 h after dosing, was quite different from the labeling with α-linolenic acid reported previously. The retention of the administered radioactivity from ¹⁴C-linoleic acid in the whole body lipids was 1.6 times higher in the group fed the low α-linolenic acid diet (diet contained a total of 1.8 g PUFA/100 g diet)compared with the group fed the high α-linolenic acid diet (diet contained 3.6 g PUFA/100 g diet). The lack of retention of ¹⁴C-labeled lipids in the whole body would be consistent with an increased rate of β-oxidation of the labeled fatty acid on the diet rich in PUFA, a result supported by other studies using direct measurement of labeled carbon dioxide.

Dose-dependent increases in heart rate variability and arterial compliance in overweight and obese adults with DHA-rich fish oil supplementation

Heart rate (HR) variability and large arterial compliance can be improved using fish oils. DHA, a component of fish oil, has cardiovascular health benefits, but its effect on HR variability (HRV) and arterial compliance is yet to be quantified. Sixty-seven overweight or obese adults (thirty-six males and thirty-one females; 53 (sem 2) year; BMI 31·7 (sem 1·1) kg/m²) were randomly allocated to consume either 6 g/d sunola oil (control; n 17), fish oil (260 mg DHA+60 mg EPA per g) at doses of 2 g/d (n 16), 4 g/d (n 17) or 6 g/d (n 17). Blood pressure, HR and compliance of large and small arteries were measured while supine at baseline and after 12 weeks in all participants, and HRV was assessed in a subgroup of forty-six participants. There was no effect of fish oil on blood pressure, small artery compliance or HR. However, the low frequency:high frequency ratio of HRV decreased with increasing doses of fish oil (r − 0·34, P = 0·02), while large artery compliance increased (r 0·34, P = 0·006). Moreover, the changes in these biomarkers were significantly correlated (r − 0·31, P = 0·04) and may reflect fish oil-induced improvements in arterial function and cardiac autonomic regulation.

Predictors of vitamin D-containing supplement use in the Australian population and associations between dose and serum 25-hydroxyvitamin D concentrations

Despite concerns about vitamin D deficiency in the Australian population, little is known about the prevalence and predictors of vitamin D-containing supplement use. We described the use of vitamin D-containing supplements, and investigated associations between supplemental vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) concentrations, using a single 24-h dietary recall from the 2011-2013 Australian Health Survey (n = 12,153; ages ≥ 2 years). Multiple regression models were used to investigate predictors of vitamin D-containing supplement use in adults, and associations between dose and serum 25(OH)D concentrations/vitamin D sufficiency (≥50 nmol/L), adjusting for potential confounders. The prevalence of vitamin D-containing supplement use was 10%, 6% and 19% in children, adolescents and adults, respectively. Predictors of vitamin D-containing supplement use in adults included being female, advancing age, higher educational attainment, higher socio-economic status, not smoking, and greater physical activity. After adjusting for potential confounders, a 40 IU (1 µg) increase in vitamin D intake from supplements was associated with an increase of 0.41 nmol/L in serum 25(OH)D concentrations (95% CI 0.35, 0.47; p < 0.001). However, the prevalence of vitamin D-containing supplement use was generally low in the Australian population, particularly for single vitamin D supplements, with most supplement users obtaining only low levels of vitamin D from other supplement types.

Temozolomide in pediatric low-grade glioma

BACKGROUND: We describe a retrospective series of children with low-grade glioma who received temozolomide. PROCEDURE: Eligible patients had had a diagnosis of low-grade glioma with or without histological confirmation. Temozolomide was administered at a dose of 200 mg/m(2) daily for 5 days, in a 4-week cycle. Therapy was stopped on completion of the targeted 12 cycles of chemotherapy or on evidence of tumor progression. RESULTS: Thirteen eligible patients were identified, eight male and five female. Median age at diagnosis was 5.5 years (range 2.6-15.0 years) and at commencement of temozolomide treatment was 9.0 years (range 3.8-15.2 years). Nine patients had a histological diagnosis of pilocytic astrocytoma. Twelve patients had received carboplatin prior to temozolomide, including three in combination with vincristine. A total of 111 cycles of therapy have been administered. Hematological toxicity and nausea were the most common adverse effects. Median time to progression was 6.7 months (range 1.5-41.8 months). Event-free survival rate at 3 years was 57%. Twelve of 13 patients remain alive at the time of report. Eleven have stable disease (SD). CONCLUSION: Temozolomide appears to be active in pediatric low-grade glioma, with the advantage of oral administration and excellent tolerability.