New relationships between breast microcalcifications and cancer.

PublishedJournal ArticleResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Cancer Research UK via the DOI in this record.BACKGROUND: Breast microcalcifications are key diagnostically significant radiological features for localisation of malignancy. This study explores the hypothesis that breast calcification composition is directly related to the local tissue pathological state. METHODS: A total of 236 human breast calcifications from 110 patients were analysed by mid-Fouries transform infrared (FTIR) spectroscopy from three different pathology types (112 invasive carcinoma (IC), 64 in-situ carcinomas and 60 benign). The biochemical composition and the incorporation of carbonate into the hydroxyapatite lattice of the microcalcifications were studied by infrared microspectroscopy. This allowed the spectrally identified composition to be directly correlated with the histopathology grading of the surrounding tissue. RESULTS: The carbonate content of breast microcalcifications was shown to significantly decrease when progressing from benign to malignant disease. In this study, we report significant correlations (P<0.001) between microcalcification chemical composition (carbonate content and protein matrix : mineral ratios) and distinct pathology grades (benign, in-situ carcinoma and ICs). Furthermore, a significant correlation (P<0.001) was observed between carbonate concentrations and carcinoma in-situ sub-grades. Using the two measures of pathology-specific calcification composition (carbonate content and protein matrix : mineral ratios) as the inputs to a two-metric discriminant model sensitivities of 79, 84 and 90% and specificities of 98, 82 and 96% were achieved for benign, ductal carcinoma in situ and invasive malignancies, respectively. CONCLUSIONS: We present the first demonstration of a direct link between the chemical nature of microcalcifications and the grade of the pathological breast disease. This suggests that microcalcifications have a significant association with cancer progression, and could be used for future objective analytical classification of breast pathology. A simple two-metric model has been demonstrated, more complex spectral analysis may yeild greater discrimination performance. Furthermore there appears to be a sequential progression of calcification composition.Professor Nicholas Stone is supported by a National Institute of Health Research (NIHR) Career Scientist (Senior) Research Fellowship. Rebecca Baker performed the study, performed the data analysis and wrote the paper. Keith Rogers designed and supervised the study and wrote the paper. Neil Shepherd provided expert histopathology support and discussion. Nicholas Stone designed and supervised the study and wrote the paper. The authors declare no conflicts of interest. Ethical approval for this study was provided by the Gloucestershire Local Research Ethics Committee, UK

X-ray diffraction from bone employing annular and semi-annular beams

This is the final version of the article. Available from the publisher via the DOI in this record.There is a compelling need for accurate, low cost diagnostics to identify osteo-tissues that are associated with a high risk of fracture within an individual. To satisfy this requirement the quantification of bone characteristics such as 'bone quality' need to exceed that provided currently by densitometry. Bone mineral chemistry and microstructure can be determined from coherent x-ray scatter signatures of bone specimens. Therefore, if these signatures can be measured, in vivo, to an appropriate accuracy it should be possible by extending terms within a fracture risk model to improve fracture risk prediction.In this preliminary study we present an examination of a new x-ray diffraction technique that employs hollow annular and semi-annular beams to measure aspects of 'bone quality'. We present diffractograms obtained with our approach from ex vivo bone specimens at Mo Kα and W Kα energies. Primary data is parameterized to provide estimates of bone characteristics and to indicate the precision with which these can be determined.We acknowledge gratefully the funding provided by the UK Engineering and Physical Sciences Research Council (EPSRC) grant number EP/K020196/

Sporadic absorption tomography using a conical shell X-ray beam

We demonstrate tomography by measuring a sporadic sequence of ring shaped projections collected during a translational scan. We show that projections using 10% sampling may be used to construct optical sections with peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM) of the order of 40 dB and 0.9, respectively. This relatively small degradation in image fidelity was achieved for a 90% potential reduction in X-ray dose coupled with a reduction in scan time. Our approach is scalable in both X-ray energy and inspection volume. A driver for our method is to complement previously reported conical shell beam techniques concerning the measurement of diffracted flux for structural analysis. This work is of great relevance to time critical analytical scanning applications in security screening, process control and diagnostic imaging

Energy-dispersive X-ray diffraction using an annular beam

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.We demonstrate material phase identification by measuring polychromatic diffraction spots from samples at least 20 mm in diameter and up to 10 mm thick with an energy resolving point detector. Within our method an annular X-ray beam in the form of a conical shell is incident with its symmetry axis normal to an extended polycrystalline sample. The detector is configured to receive diffracted flux transmitted through the sample and is positioned on the symmetry axis of the annular beam. We present the experiment data from a range of different materials and demonstrate the acquisition of useful data with sub-second collection times of 0.5 s; equating to 0.15 mAs. Our technique should be highly relevant in fields that demand rapid analytical methods such as medicine, security screening and non-destructive testing.We acknowledge gratefully the funding provided by the UK Engineering and Physical Sciences Research Council (EPSRC) grant number EP/K020196/1

Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

The Interstellar Medium In Galaxies Seen A Billion Years After The Big Bang

Evolution in the measured rest frame ultraviolet spectral slope and ultraviolet to optical flux ratios indicate a rapid evolution in the dust obscuration of galaxies during the first 3 billion years of cosmic time (z>4). This evolution implies a change in the average interstellar medium properties, but the measurements are systematically uncertain due to untested assumptions, and the inability to measure heavily obscured regions of the galaxies. Previous attempts to directly measure the interstellar medium in normal galaxies at these redshifts have failed for a number of reasons with one notable exception. Here we report measurements of the [CII] gas and dust emission in 9 typical (~1-4L*) star-forming galaxies ~1 billon years after the big bang (z~5-6). We find these galaxies have >12x less thermal emission compared with similar systems ~2 billion years later, and enhanced [CII] emission relative to the far-infrared continuum, confirming a strong evolution in the interstellar medium properties in the early universe. The gas is distributed over scales of 1-8 kpc, and shows diverse dynamics within the sample. These results are consistent with early galaxies having significantly less dust than typical galaxies seen at z<3 and being comparable to local low-metallicity systems.Comment: Submitted to Nature, under review after referee report. 22 pages, 4 figures, 4 Extended Data Figures, 5 Extended Data table

Positive psychology of Malaysian students: impacts of engagement, motivation, self-compassion and wellbeing on mental health

Malaysia plays a key role in education of the Asia Pacific, expanding its scholarly output rapidly. However, mental health of Malaysian students is challenging, and their help-seeking is low because of stigma. This study explored the relationships between mental health and positive psychological constructs (academic engagement, motivation, self-compassion, and wellbeing), and evaluated the relative contribution of each positive psychological construct to mental health in Malaysian students. An opportunity sample of 153 students completed the measures regarding these constructs. Correlation, regression, and mediation analyses were conducted. Engagement, amotivation, self-compassion, and wellbeing were associated with, and predicted large variance in mental health. Self-compassion was the strongest independent predictor of mental health among all the positive psychological constructs. Findings can imply the strong links between mental health and positive psychology, especially selfcompassion. Moreover, intervention studies to examine the effects of self-compassion training on mental health of Malaysian students appear to be warranted.N/

Defining the phenotypes of sickle cell disease.

The sickle cell gene is pleiotropic in nature. Although it is a single gene mutation, it has multiple phenotypic expressions that constitute the complications of sickle cell disease. The frequency and severity of these complications vary considerably both latitudinally in patients and longitudinally in the same patient over time. Thus, complications that occur in childhood may disappear, persist or get worse with age. Dactylitis and stroke, for example, occur mostly in childhood, whereas leg ulcers and renal failure typically occur in adults. It is essential that the phenotypic manifestations of sickle cell disease be defined accurately so that communication among providers and researchers facilitates the implementation of appropriate and cost-effective diagnostic and therapeutic modalities. The aim of this review is to define the complications that are specific to sickle cell disease based on available evidence in the literature and the experience of hematologists in this field

An internal ribosome entry site in the 5′ untranslated region of epidermal growth factor receptor allows hypoxic expression

The expression of epidermal growth factor receptor (EGFR/ERBB1/HER1) is implicated in the progress of numerous cancers, a feature that has been exploited in the development of EGFR antibodies and EGFR tyrosine kinase inhibitors as anti-cancer drugs. However, EGFR also has important normal cellular functions, leading to serious side effects when EGFR is inhibited. One damaging characteristic of many oncogenes is the ability to be expressed in the hypoxic conditions associated with the tumour interior. It has previously been demonstrated that expression of EGFR is maintained in hypoxic conditions via an unknown mechanism of translational control, despite global translation rates generally being attenuated under hypoxic conditions. In this report, we demonstrate that the human EGFR 5′ untranslated region (UTR) sequence can initiate the expression of a downstream open reading frame via an internal ribosome entry site (IRES). We show that this effect is not due to either cryptic promoter activity or splicing events. We have investigated the requirement of the EGFR IRES for eukaryotic initiation factor 4A (eIF4A), which is an RNA helicase responsible for processing RNA secondary structure as part of translation initiation. Treatment with hippuristanol (a potent inhibitor of eIF4A) caused a decrease in EGFR 5′ UTR-driven reporter activity and also a reduction in EGFR protein level. Importantly, we show that expression of a reporter gene under the control of the EGFR IRES is maintained under hypoxic conditions despite a fall in global translation rates