Radiotherapy-Compatible Robotic System for Multi-Landmark Positioning in Head and Neck Cancer Treatments

The spine flexibility creates one of the most significant challenges to proper positioning in radiation therapy of head and neck cancers. Even though existing immobilization techniques can reduce the positioning uncertainty, residual errors (2–3 mm along the cervical spine) cannot be mitigated by single translation-based approaches. Here, we introduce a fully radiotherapy-compatible electro-mechanical robotic system, capable of positioning a patient’s head with submillimeter accuracy in clinically acceptable spatial constraints. Key mechanical components, designed by finite element analysis, are fabricated with 3D printing and a cyclic loading test of the printed materials captures a great mechanical robustness. Measured attenuation of most printed components is lower than analytic estimations and radiographic imaging shows no visible artifacts, implying full radio-compatibility. The new system evaluates the positioning accuracy with an anthropomorphic skeletal phantom and optical tracking system, which shows a minimal residual error (0.7 ± 0.3 mm). This device also offers an accurate assessment of the post correction error of aligning individual regions when the head and body are individually positioned. Collectively, the radiotherapy-compatible robotic system enables multi-landmark setup to align the head and body independently and accurately for radiation treatment, which will significantly reduce the need for large margins in the lower neck

Auditor quality and the role of accounting information in explaining UK stock returns

Using a variance decomposition approach, we examine the importance of accounting information – in particular the cash flow and accruals components of earnings – in explaining the variation in UK company stock returns. We extend prior research by analysing whether auditor quality moderates the role of accruals and cash flows in driving returns on both a relative and an absolute basis. Moreover, we employ a new orthogonal variance decomposition which reduces the influence of the covariance terms on the variance decomposition results. In general, our results indicate that both components of earnings are important drivers of stock returns and suggest that the significance of both earnings components varies conditional on auditor quality. Although there are some similarities with US-based research, a number of differences are also evident. In particular, cash flow news seems more important in the UK than in the US

BMI, All-Cause and Cause-Specific Mortality in Chinese Singaporean Men and Women: The Singapore Chinese Health Study

Background: The optimal range of relative weight for morbidity and mortality in Asian populations is an important question in need of more thorough investigation, especially as obesity rates increase. We aimed to examine the association between body mass index (BMI), all cause and cause-specific mortality to determine the optimal range of BMI in relation to mortality in Chinese men and women in Singapore. Methodology/Principal Findings: We analyzed data from a prospective cohort study of 51,251 middle-aged or older (45– 74) Chinese men and women in the Singapore Chinese Health Study. Participants were enrolled and data on body weight and covariates were collected in 1993–1998 and participants were followed through 2008. The analysis accounted for potential methodological issues through stratification on smoking and age, thorough adjustment of demographic and lifestyle confounders and exclusion of deaths early in the follow-up. Conclusions/Significance: Increased risk of mortality was apparent in underweight (,18.5) and obese BMI categories ($27.5) independent of age and smoking. Regardless of age or BMI, smoking considerably increased the rate of mortality and modified the association between BMI and mortality. The most favorable range of BMI for mortality rates and risk in non-smoking persons below age 65 was 18.5–21.4 kg/m 2, and for non-smoking persons aged 65 and above was 21.5

Metabolomic profiling of the synergistic effects of melittin in combination with cisplatin on ovarian cancer cells

Melittin, the main peptide present in bee venom, has been proposed as having potential for anticancer therapy; the addition of melittin to cisplatin, a first line treatment for ovarian cancer, may increase the therapeutic response in cancer treatment via synergy, resulting in improved tolerability, reduced relapse, and decreased drug resistance. Thus, this study was designed to compare the metabolomic effects of melittin in combination with cisplatin in cisplatin-sensitive (A2780) and resistant (A2780CR) ovarian cancer cells. Liquid chromatography (LC) coupled with mass spectrometry (MS) was applied to identify metabolic changes in A2780 (combination treatment 5 μg/mL melittin + 2 μg mL cisplatin) and A2780CR (combination treatment 2 μg/mL melittin + 10 μg/mL cisplatin) cells. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) multivariate data analysis models were produced using SIMCA-P software. All models displayed good separation between experimental groups and high-quality goodness of fit (R2) and goodness of prediction (Q2), respectively. The combination treatment induced significant changes in both cell lines involving reduction in the levels of metabolites in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, purine and pyrimidine metabolism, and the arginine/proline pathway. The combination of melittin with cisplatin that targets these pathways had a synergistic effect. The melittin-cisplatin combination had a stronger effect on the A2780 cell line in comparison with the A2780CR cell line. The metabolic effects of melittin and cisplatin in combination were very different from those of each agent alone

Effect of bee venom and its fractions on the release of pro-inflammatory cytokines in PMA-differentiated U937 cells co-stimulated with LPS

The venom of Apis mellifera (honey bee) has been reported to play a role in immunotherapy, but existing evidence to support its immuno-modulatory claims is insufficient. Four fractions from whole bee venom (BV) were separated using medium pressure liquid chromatography. Their ability to induce the production of cytokines TNFα, IL-1β and IL-6 in phorbol-12-myristate-13-acetate (PMA)-treated U937 cells was assessed. The levels of the three cytokines produced by stimulation with the four fractions and crude BV without LPS were not significantly different from negative control values. However, co-stimulation of the cells with LPS and Fraction 4 (F-4) induced a 1.6-fold increase in TNF-α level (p < 0.05) compared to LPS alone. Likewise, LPS-induced IL-1β production was significantly synergised in the presence of F-1 (nine-fold), F-2 (six-fold), F-3 (four-fold) and F-4 (two-fold) fractions, but was only slightly enhanced with crude BV (1.5-fold) relative to LPS. Furthermore, the LPS-stimulated production of IL-6 was not significantly increased in cells co-treated with F-2 and F-3, but the organic fraction (F-4) showed an inhibitory effect (p < 0.05) on IL-6 production. The latter was elucidated by NMR spectroscopy and found to contain(Z)-9-eicosen-1-ol. The effects observed with the purified BV fractions were more marked than those obtained with the crude sample

Identification of a new p53/MDM2 inhibitor motif inspired by studies of chlorofusin

Previous studies on the natural product chlorofusin have shown that the full peptide and azaphilone structure are required for inhibition of the interaction between MDM2 and p53. In the current work, we utilized the cyclic peptide as a template and introduced an azidonorvaline amino acid in place of the ornithine/azaphilone of the natural product and carried out click chemistry with the resulting peptide. From this small library the first ever non-azaphilone containing chlorofusin analogue with MDM2/p53 activity was identified. Further studies then suggested that the simple structure of the Fmoc-norvaline amino acid that had undergone a click reaction was also able to inhibit MDM2/p53 interaction. This is an example where studies of a natural product have led to the serendipitous identification of a new small molecule inhibitor of a protein-protein interaction

PGxMine: Text Mining for Curation of PharmGKB

Precision medicine tailors treatment to individuals personal data including differences in their genome. The Pharmacogenomics Knowledgebase (PharmGKB) provides highly curated information on the effect of genetic variation on drug response and side effects for a wide range of drugs. PharmGKB's scientific curators triage, review and annotate a large number of papers each year but the task is challenging. We present the PGxMine resource, a text-mined resource of pharmacogenomic associations from all accessible published literature to assist in the curation of PharmGKB. We developed a supervised machine learning pipeline to extract associations between a variant (DNA and protein changes, star alleles and dbSNP identifiers) and a chemical. PGxMine covers 452 chemicals and 2,426 variants and contains 19,930 mentions of pharmacogenomic associations across 7,170 papers. An evaluation by PharmGKB curators found that 57 of the top 100 associations not found in PharmGKB led to 83 curatable papers and a further 24 associations would likely lead to curatable papers through citations. The results can be viewed at https://pgxmine.pharmgkb.org/ and code can be downloaded at https://github.com/jakelever/pgxmine

Movement of the inner retina complex during the development of primary full-thickness macular holes: implications for hypotheses of pathogenesis

Background: The inner retinal complex is a well-defined layer in spectral-domain OCT scans of the retina. The central edge of this layer at the fovea provides anatomical landmarks that can be observed in serial OCT scans of developing full-thickness macular holes (FTMH). Measurement of the movement of these points may clarify the mechanism of FTMH formation. Method: This is a retrospective study of primary FTMH that had a sequence of two OCT scans showing progression of the hole. Measurements were made of the dimensions of the hole, including measurements using the central edge of the inner retinal complex (CEIRC) as markers. The inner retinal separation (distance between the CEIRC across the centre of the fovea) and the Height-IRS (average height of CEIRC above the retinal pigment epithelium) were measured. Results: Eighteen cases were identified in 17 patients. The average increase in the base diameter (368 microns) and the average increase in minimum linear dimension (187 microns) were much larger than the average increase in the inner retinal separation (73 microns). The average increase in Height-IRS was 103 microns. Conclusion: The tangential separation of the outer retina to produce the macular hole is much larger than the tangential separation of the inner retinal layers. A model based on the histology of the Muller cells at the fovea is proposed to explain the findings of this study