RAD51 can inhibit PDGF-B-induced gliomagenesis and genomic instability

Faithful replication and DNA repair are vital for maintenance of genome integrity. RAD51 is a central protein in homologous recombination repair and during replication, when it protects and restarts stalled replication forks. Aberrant RAD51 expression occurs in glioma, and high expression has been shown to correlate with prolonged survival. Furthermore, genes involved in DNA damage response (DDR) are mutated or deleted in human glioblastomas, corroborating the importance of proper DNA repair to suppress gliomagenesis. We have analyzed DDR and genomic instability in PDGF-B-induced gliomas and investigated the role of RAD51 in glioma development. We show that PDGF-B-induced gliomas display genomic instability and that co-expression of RAD51 can suppress PDGF-B-induced tumorigenesis and prolong survival. Expression of RAD51 inhibited proliferation and genomic instability of tumor cells independent of Arf status. Our results demonstrate that the RAD51 pathway can prevent glioma initiation and maintain genome integrity of induced tumors, suggesting reactivation of the RAD51 pathway as a potential therapeutic avenue.     

PDGF-B Can Sustain Self-renewal and Tumorigenicity of Experimental Glioma-Derived Cancer-Initiating Cells by Preventing Oligodendrocyte Differentiation

According to the cancer stem cell (CSC)/cancer-initiating cell hypothesis, glioma development is driven by a subpopulation of cells with unique tumor-regenerating capacity. We have characterized sphere-cultured glioma-derived cancer-initiating cells (GICs) from experimental gliomas induced by platelet-derived growth factor-B (PDGF-B) in neonatal Gtv-a Arf^-/- mice. We found that the GICs can maintain their stem cell-like characteristics in absence of exogenous epidermal growth factor and fibroblast growth factor 2 and that this culture condition was highly selective for tumor-initiating cells where as few as five GICs could induce secondary tumor formation after orthotopic transplantation. Addition of FBS to the medium caused the GICs to differentiate into cells coexpressing glial fibrillary acidic protein and Tuj1, and this differentiation process was reversible, suggesting that the GICs are highly plastic and able to adapt to different environments without losing their tumorigenic properties. On inhibition of virally transduced PDGF-B by small interfering RNA treatment, the GICs stopped proliferating, lost their self-renewal ability, and started to uniformly express CNPase, a marker of oligodendrocyte precursor cells and mature oligodendrocytes. Most importantly, PDGF-B depletion completely abrogated the tumor-initiating capacity of the GICs. Our findings suggest that interfering with PDGF-controlled differentiation could be a therapeutic avenue for patients diagnosed with the PDGF-driven proneural subtype of human glioblastoma.     

Prenatal stress and risk of infectious diseases in offspring

Animal studies have suggested that prenatal stress could affect the immune system of the offspring. In a nation-wide cohort of all Danish children born from 1977 to 2004, the authors examined the association between prenatal stress, defined as maternal exposure to a stressful life event during pregnancy or in the 3-year period before conception, and the risk of severe or less severe infectious disease hospitalization in childhood. Log-linear Poisson regression models provided estimates of rate ratios. Compared with nonexposed children, children exposed prenatally to stress had a 25% (rate ratio (RR) = 1.25, 95% confidence interval (CI): 1.06, 1.47) and a 31% (RR = 1.31, 95% CI: 1.27, 1.35) increased risk of being hospitalized with a severe or a less severe infectious disease, respectively. Children born to mothers exposed to a stressful life event during pregnancy, during the 11 months before, or during the 12-35 months before conception were at 71% (RR = 1.71, 95% CI: 1.20, 2.45), 42% (RR = 1.42, 95% CI: 1.13, 1.78), and no increased (RR = 0.86, 95% CI: 0.63, 1.18) risk of severe infectious disease hospitalization. No obvious association between risk of less severe infectious disease hospitalization and timing of maternal exposure was observed. Although the authors could not determine whether this is a biologic effect of prenatal stress or an effect of other factors related indirectly to a stressful life event, their results add new information about the consequences of prenatal stress.     

A survey of women obtaining emergency contraception: are they interested in using the copper IUD?

Background

This study aims to determine if women presenting for emergency contraception (EC) at family planning clinics may be interested in using the copper intrauterine device (IUD) for EC.

Study Design

This convenience sample survey was offered to women who presented for EC at four participating clinics in urban Utah. Anonymous written questionnaires were distributed. The outcome variable of interest was interest in using the copper IUD for EC.

Results

Of survey respondents, 320 (34.0%) of 941 said they would be interested in an EC method that was long term, highly effective and reversible. Interested women were not significantly different from noninterested women in relation to age, marital status, education, household income, gravidity, previous abortions, previous sexually transmitted infections (STIs) or relationship status. One hundred twenty women (37.5% of those interested or 12.8% of all those surveyed) would wait an hour, undergo a pelvic exam to get the method and would still want the method knowing it was an IUD. However, only 12.3% of these women could also pay $350 or more for the device. Multivariable regression found the following predictors of interest in the IUD among EC users: non-Hispanic minorities (OR=2.12, 95% CI=1.14–3.93), desire to never be pregnant in the future (OR=2.87, 95% CI=1.38–5.66) and interest in adoption (OR=1.96, 95% CI=1.00–5.73) or abortion (OR=2.68, 95% CI=1.24–4.14) if pregnant when presenting for EC.

Conclusion

While one third of EC users surveyed at family planning clinics were interested in a long-term, highly effective method of contraception, only a small portion of all EC users may be interested in the copper IUD for EC. Cost is a potential barrier.     

Relative validity of fruit and vegetable intake estimated from an FFQ, using carotenoid and flavonoid biomarkers and the method of triads

The aim of the present study was to validate the intakes of fruit, juice and vegetables from an FFQ. In sub-study I (n 147), intakes from the FFQ were evaluated against 7 d weighed food records (WR) and plasma carotenoid concentrations, whereas in sub-study II (n 85), the intakes were evaluated against plasma carotenoid concentrations and amounts of flavonoids in 24 h urine samples. Relative validity was evaluated by comparing median intakes, estimating correlation coefficients and validity coefficients using the method of triads. In sub-study I, we observed no significant difference in daily median fruit intake between the FFQ and the WR, whereas the intake of vegetables was higher from the FFQ than from the WR. The correlations between intakes from the FFQ and the WR ranged from 0·31 to 0·58. In sub-study II, the intakes of fruit and vegetables correlated significantly with plasma carotenoid concentrations and urinary flavonoids. The validity coefficients for the intakes of fruit and vegetables from the FFQ ranged from 0·61 to 0·88 in sub-study I and from 0·60 to 0·94 in sub-study II. In summary, based on the associations observed between intakes from the FFQ and the biomarkers and the FFQ validity coefficients, the FFQ was found valid and suitable for ranking individuals according to their usual intake of fruit, juice and vegetables.     

New insights into the mucoadhesion of pectins by AFM roughness parameters in combination with SPR

The high content of surfactants is one of the major limits to microemulsions (MEs) use in pharmaceutical and cosmetic field. In this work MEs with low surfactant content were prepared by the phase inversion temperature (PIT) method using different oil phases and emulsifiers. The effects of vehicle composition on in vitro release and skin permeation of octylmethoxycinnamte (OMC), one of the most used UVB filter, was evaluated. These MEs showed droplet sizes in the range 32-77nm and a single peak in size distribution. MEs prepared using the most lipophilic lipids (decyl oleate or cetyl stearyl isononanoate) showed the lowest stability. In vitro release and skin permeation profiles were affected by both lipophilicty and structure of the lipid used as internal phase and the formulation that released the lowest amount of OMC provided the lowest active compound skin permeation. It is noteworthy that no OMC release and skin permeation were observed using oleth-20/glyceryl oleate as emulsifiers. Furthermore, a skin permeation enhancement effect was observed depending on the vehicle components. The results of this work suggest that PIT MEs could provide controlled skin drug delivery by choosing proper associations of oil phase lipids and emulsifiers.     

Increased cocaine self-administration in M<Subscript>4</Subscript> muscarinic acetylcholine receptor knockout mice

Rationale  

The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M₄ receptor subtype plays an important role in regulation of dopaminergic neurotransmission.     

Forward lunge as a functional performance test in ACL deficient subjects: Test–retest reliability

The forward lunge movement may be used as a functional performance test of anterior cruciate ligament (ACL) deficient and reconstructed subjects. The purposes were 1) to determine the test–retest reliability of a forward lunge in healthy subjects and 2) to determine the required numbers of repetitions necessary to yield satisfactory reliability. Nineteen healthy subjects performed four trials of a forward lunge on two different days. The movement time, impulses of the ground reaction forces (IFz, IFy), knee joint kinematics and dynamics during the forward lunge were calculated. The relative reliability was determined by calculation of Intraclass Correlation Coefficients (ICC). The IFz, IFy and the positive work of the knee extensors showed excellent reliability (ICC > 0.75). All other variables demonstrated acceptable reliability (0.4 > ICC < 0.75). The relative reliability increased when more than a single forward lunge was used. In conclusion, the reliability was acceptable. It is recommended to represent the biomechanical variables as an average of at least three trials of the forward lunge.