Measurement of radiotherapy x-ray skin dose on a chest wall phantom

Sufficient skin dose needs to be delivered by a radiotherapy chest wall treatment regimen to ensure the probability of a near surface tumor recurrence is minimized. To simulate a chest wall treatment a hemicylindrical solid water phantom of 7.5 cm radius was irradiated with 6 MV x-rays using 20×20 cm2 and 10×20 cm2 fields at 100 cm source surface distance (SSD) to the base of the phantom. A surface dose profile was obtained from 0 to 180°, in 10° increments around the circumference of the phantom. Dosimetry results obtained from radiochromic film (effective depth of 0.17 mm) were used in the investigation, the superficial doses were found to be 28% (of Dmax) at the 0° beam entry position and 58% at the 90° oblique beam position. Superficial dose results were also obtained using extra thin thermoluminescent dosimeters (TLD) (effective depth 0.14 mm) of 30% at 0°, 57% at 90°, and a metal oxide semiconductor field effect transistor (MOSFET) detector (effective depth 0.5 mm) of 43% at 0°, 62% at 90°. Because the differences in measured superficial doses were significant and beyond those related to experimental error, these differences are assumed to be mostly attributable to the effective depth of measurement of each detector. We numerically simulated a bolus on/bolus off technique and found we could increase the coverage to the skin. Using an alternate “bolus on,” “bolus off” regimen, the skin would receive 36.8 Gy at 0° incidence and 46.4 Gy at 90° incidence for a prescribed midpoint dose of 50 Gy. From this work it is evident that, as the circumference of the phantom is traversed the SSD increases and hence there is an inverse square fluence fall-off, this is more than offset by the increase in skin dose due to surface curvature to a plateau at about 90°. Beyond this angle it is assumed that beam attenuation through the phantom and inverse square fall-off is causing the surface dose to reduce

Quercetin elevates p27Kip1 and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1

Our previous work with primary bovine fibroblasts demonstrated that quercetin, a potent mutagen found in high levels in bracken fern (Pteridium aquilinum), arrested cells in G1 and G2/M, in correlation with p53 activation. The expression of bovine papillomavirus type 4 (BPV-4) E7 overcame this arrest and lead to the development of tumorigenic cells lines (Beniston et al., 2001). Given the possible link between papillomavirus infection, bracken fern in the diet and cancer of the upper gastrointestinal (GI) tract in humans, we investigated whether a similar situation would occur in human cells transformed by human papillomavirus type 16 (HPV-16) oncoproteins. Quercetin arrested primary human foreskin keratinocytes in G1. Arrest was linked to an elevation of the cyclin-dependent kinase inhibitor (cdki) p27Kip1. Expression of the HPV16 E6 and E7 oncoproteins in transformed cells failed to abrogate cell cycle arrest. G1 arrest in the transformed cells was also linked to an increase of p27Kip1 with a concomitant reduction of cyclin E-associated kinase activity. This elevation of p27Kip1 was due not only to increased protein half-life, but also to increased mRNA transcription

On reminder effects, drop-outs and dominance: evidence from an online experiment on charitable giving

We present the results of an experiment that (a) shows the usefulness of screening out drop-outs and (b) tests whether different methods of payment and reminder intervals affect charitable giving. Following a lab session, participants could make online donations to charity for a total duration of three months. Our procedure justifying the exclusion of drop-outs consists in requiring participants to collect payments in person flexibly and as known in advance and as highlighted to them later. Our interpretation is that participants who failed to collect their positive payments under these circumstances are likely not to satisfy dominance. If we restrict the sample to subjects who did not drop out, but not otherwise, reminders significantly increase the overall amount of charitable giving. We also find that weekly reminders are no more effective than monthly reminders in increasing charitable giving, and that, in our three months duration experiment, standing orders do not increase giving relative to one-off donations

Transient Photoreceptor Deconstruction by CNTF Enhances rAAV-Mediated Cone Functional Rescue in Late Stage CNGB3-Achromatopsia

Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs \u3c0.5 years of age, but treatment is minimally effective in dogs \u3e1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy

Canine CNGA3 Gene Mutations Provide Novel Insights Into Human Achromatopsia-Associated Channelopathies and Treatment

Cyclic nucleotide-gated (CNG) ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in CNGA3 and CNGB3, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia (ACHM). ACHM is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness and photophobia. Here, we report the first canine models for CNGA3-associated channelopathy caused by R424W or V644del mutations in the canine CNGA3 ortholog that accurately mimic the clinical and molecular features of human CNGA3-associated ACHM. These two spontaneous mutations exposed CNGA3 residues essential for the preservation of channel function and biogenesis. The CNGA3-R424W results in complete loss of cone function in vivoand channel activity confirmed by in vitro electrophysiology. Structural modeling and molecular dynamics (MD) simulations revealed R424-E306 salt bridge formation and its disruption with the R424W mutant. Reversal of charges in a CNGA3-R424E-E306R double mutant channel rescued cGMP-activated currents uncovering new insights into channel gating. The CNGA3-V644del affects the C-terminal leucine zipper (CLZ) domain destabilizing intersubunit interactions of the coiled-coil complex in the MD simulations; the in vitro experiments showed incompetent trimeric CNGA3 subunit assembly consistent with abnormal biogenesis of in vivochannels. These newly characterized large animal models not only provide a valuable system for studying cone-specific CNG channel function in health and disease, but also represent prime candidates for proof-of-concept studies of CNGA3 gene replacement therapy for ACHM patients

A study on the functions of ubiquitin metabolic system related gene FBG2 in gastric cancer cell line

<p>Abstract</p> <p>Background</p> <p>FBG2 (F-BOX6) gene is an important member in ubiquitin metabolic system F-BOX family, and forms E3 complex with the other members in the family. But its role in gastric cancer is still not clear. In the present study, we intended to investigate the influence of FBG2 on the growth, proliferation, apoptosis, invasion and cell cycle of the gastric cancer line MKN45 and gastric cell line HFE145.</p> <p>Methods</p> <p>As a critical component of ubiquitin-protein ligase complex, FBG2 cDNA was subcloned into a constitutive vector PCDNA3.1 followed by transfection in MKN45 and HFE145 by using liposome. Then stable transfectants were selected and appraised. The apoptosis and cell cycles of these clones were analyzed by using flow cytometry. The growth and proliferation were analyzed by cell growth curves and colony-forming assay respectively. The invasion of these clones was tested by using cancer cell migration assay. The FBG2 stable expression clones(MKN-FBG2 and HFE-FBG2) and their control groups were detected and compared respectively.</p> <p>Results</p> <p>MKN-FBG2 grew faster than MKN45 and MKN-PC(MKN45 transfected with PCDNA3.1 vector). HFE-FBG2 grew faster than HFE145 and HFE-PC(HFE145 transfected with PCDNA3.1 vector). The cell counts of MKN-FBG2 in the forth, fifth, sixth and seventh days were significantly more than those of others (P < 0.05). Cell cycle analysis showed that MKN-FBG2 and HFE-FBG2 proliferated faster, proportions of cells in G2-M and S were different significantly with control groups (P < 0.05). Results of colony-forming assay showed that the colony formation rates of MKN-FBG2 and HFE-FBG2 were higher than those of control groups (P < 0.05). The results of cell migration assay were all negative.</p> <p>Conclusion</p> <p>FBG2 can promote the growth and proliferation of gastric cancer cells and normal gastric cells. It can help tumor cell maintain malignant phenotype too. But it can have a negative influence on the apoptosis or the ability of invasion of gastric cancer cells.</p

Embodying limb absence in the negotiation of sexual intimacy

Some people with physical disabilities experience difficulties in forming and maintaining intimate and sexual relationships (Taleporos and McCabe, 2001). Individuals with physical impairments may variously be seen as inferior, ‘not up to scratch’ and can be less valued than those thought to embody the cultural ideal of ‘normality’ (Edwards and Imrie, 2003). The loss of an anatomical part such as an arm or a leg can therefore set up a complex series of perceptual, emotional and psychological responses that can limit or prevent individuals from fully experiencing the kinds of intimate relationships that many of their ‘non-disabled’ counterparts can more freely enjoy (Oliver, 1990). Drawing on a series of semi-structured interviews and a group visual workshop with five men and two women with varying acquired and congenital limb absences, this study explores the variety of ways in which sexual relationships and intimacies are negotiated and managed. Certain participants reported a great deal of anxiety regarding their perceptions of sexual attractiveness, and experienced feelings of loss of desirability as a sexual partner. Others reported engaging in an ‘active management of visual information’ about the body, through methods of concealment and exposure. Compensatory strategies were also reported as a way to effectively maintain existing intimate relationships. Finally, hyper-masculine or hyper-feminine enactments of sexuality were described within a range of social and intimate contexts as a means to ‘normalise’ the disabled body. The findings of this study provide a richer and more contextualised understanding of the highly complex adjustment process faced by individuals with limb absence, who actively engage in sexual and intimate relationships