Novel circulating microRNA signature as a potential non-invasive multi-marker test in ER-positive early-stage breast cancer:A case control study

INTRODUCTION: There are currently no highly sensitive and specific minimally invasive biomarkers for detection of early-stage breast cancer. MicroRNAs (miRNAs) are present in the circulation and may be unique biomarkers for early diagnosis of human cancers. The aim of this study was to investigate the differential expression of miRNAs in the serum of breast cancer patients and healthy controls.METHODS: Global miRNA analysis was performed on serum from 48 patients with ER-positive early-stage breast cancer obtained at diagnosis (24 lymph node-positive and 24 lymph node-negative) and 24 age-matched healthy controls using LNA-based quantitative real-time PCR (qRT-PCR). A signature of miRNAs was subsequently validated in an independent set of 111 serum samples from 60 patients with early-stage breast cancer and 51 healthy controls and further tested for reproducibility in 3 independent data sets from the GEO Database.RESULTS: A multivariable signature consisting of 9 miRNAs (miR-15a, miR-18a, miR-107, miR-133a, miR-139-5p, miR-143, miR-145, miR-365, miR-425) was identified that provided considerable discrimination between breast cancer patients and healthy controls. Further, the ability of the 9 miRNA signature to stratify samples from breast cancer patients and healthy controls was confirmed in the validation set (p = 0.012) with a corresponding AUC = 0.665 in the ROC-curve analysis. No association between miRNA expression and tumor grade, tumor size, menopausal- or lymph node status was observed. The signature was also successfully validated in a previously published independent data set of circulating miRNAs in early-stage breast cancer (p = 0.024).CONCLUSIONS: We present herein a 9 miRNA signature capable of discriminating between ER-positive breast cancer and healthy controls. Using a specific algorithm based on the 9 miRNA signature, the risk for future individuals can be predicted. Since microRNAs are highly stable in blood components, this signature might be useful in the development of a blood-based multi-marker test to improve early detection of breast cancer. Such a test could potentially be used as a screening tool to identify individuals who would benefit from further diagnostic assessment.</p

Metabolic mapping by use of high-resolution magic angle spinning1H MR spectroscopy for assessment of apoptosis in cervical carcinomas

Background High-resolution magic angle proton magnetic resonance spectroscopy (HR1H MAS MRS) provides a broad metabolic mapping of intact tumor samples and allows for microscopy investigations of the samples after spectra acquisition. Experimental studies have suggested that the method can be used for detection of apoptosis, but this has not been investigated in a clinical setting so far. We have explored this hypothesis in cervical cancers by searching for metabolites associated with apoptosis that were not influenced by other histopathological parameters like tumor load and tumor cell density. Methods Biopsies (n = 44) taken before and during radiotherapy in 23 patients were subjected to HR MAS MRS. A standard pulse-acquire spectrum provided information about lipids, and a spin-echo spectrum enabled detection of non-lipid metabolites in the lipid region of the spectra. Apoptotic cell density, tumor cell fraction, and tumor cell density were determined by histopathological analysis after spectra acquisition. Results The apoptotic cell density correlated with the standard pulse-acquire spectra (p < 0.001), but not with the spin-echo spectra, showing that the lipid metabolites were most important. The combined information of all lipids contributed to the correlation, with a major contribution from the ratio of fatty acid -CH2 to CH3 (p = 0.02). In contrast, the spin-echo spectra contained the main information on tumor cell fraction and tumor cell density (p < 0.001), for which cholines, creatine, taurine, glucose, and lactate were most important. Significant correlations were found between tumor cell fraction and glucose concentration (p = 0.001) and between tumor cell density and glycerophosphocholine (GPC) concentration (p = 0.024) and ratio of GPC to choline (p < 0.001). Conclusion Our findings indicate that the apoptotic activity of cervical cancers can be assessed from the lipid metabolites in HR MAS MR spectra and that the HR MAS data may reveal novel information on the metabolic changes characteristic of apoptosis. These changes differed from those associated with tumor load and tumor cell density, suggesting an application of the method to explore the role of apoptosis in the course of the disease

Existence and stability of viscoelastic shock profiles

We investigate existence and stability of viscoelastic shock profiles for a class of planar models including the incompressible shear case studied by Antman and Malek-Madani. We establish that the resulting equations fall into the class of symmetrizable hyperbolic--parabolic systems, hence spectral stability implies linearized and nonlinear stability with sharp rates of decay. The new contributions are treatment of the compressible case, formulation of a rigorous nonlinear stability theory, including verification of stability of small-amplitude Lax shocks, and the systematic incorporation in our investigations of numerical Evans function computations determining stability of large-amplitude and or nonclassical type shock profiles.Comment: 43 pages, 12 figure

The 3-string vertex and the AdS/CFT duality in the PP-wave limit

We pursue the study of string interactions in the PP-wave background and show that the proposal of hep-th/0211188 can be extended to a full supersymmetric vertex. Then we compute some string amplitudes in both the bosonic and fermionic sector, finding agreement with the field theory results at leading order in lambda'.Comment: Latex, 25 pages. Comments added and typos correcte

Edging your bets: advantage play, gambling, crime and victimisation

Consumerism, industrial development and regulatory liberalisation have underpinned the ascendance of gambling to a mainstream consumption practice. In particular, the online gambling environment has been marketed as a site of ‘safe risks’ where citizens can engage in a multitude of different forms of aleatory consumption. This paper offers a virtual ethnography of an online ‘advantage play’ subculture. It demonstrates how advantage players have reinterpreted the online gambling landscape as an environment saturated with crime and victimisation. In this virtual world, advantage play is no longer simply an instrumental act concerned with profit accumulation to finance consumer desires. Rather, it acts as an opportunity for individuals to engage in a unique form of edgework, whereby the threat to one’s well-being is tested through an ability to avoid crime and victimisation. This paper demonstrates how mediated environments may act as sites for edgeworking and how the potential for victimisation can be something that is actively engaged with

CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial

Background Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms. Methods We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor-positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction-based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43). Conclusions CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxife

Quality-Based Thermokinetic Optimization of Ready-to-Eat Whole Edible Crab (Cancer pagurus) Pasteurisation Treatments

Traditional processing practices used in the manufacture of ready-to-eat edible crab products include a double-heat treatment involving an initial cooking step followed by washing and packaging and finally, a second heat pasteurisation. The latter, pasteurisation step, results in the most severe impact on product quality. The main objective of this research was to optimise this pasteurisation step using quality index degradation kinetic approach. Preliminary work involved the characterisation of temperature rise in the crab cold-spot during pasteurisation. Equivalent treatments (F90°C 10°C = 10 min) were defined in order to assess the impact of pasteurisation temperature on different crab quality indexes in both crab meat types, white and brown. Colour degradation of crab white meat was defined as the critical quality parameter to be monitored during thermal pasteurisation. The effect of time and temperature on the kinetics of white meat colour change (¿E*) were characterised and fitted to an exponential equation. Following this, an industry focus group was used to define white meat colour change vs product quality and defined ‘good’ (¿E* = 7), ‘acceptable’ (7 &lt; ¿E* &lt; 9) and ‘unacceptable’ (¿E* = 9) quality. Finally, using the developed equations, optimal pasteurisation conditions were defined and validated. To produce ‘good’ quality crab, optimal temperatures ranged between 96 and 100 °C while temperatures between 104 and 108 °C produced ‘acceptable’ quality in crabs of 400 and 800 g, respectively. Overall, the results show that the equations obtained could be used in a decision support system (DSS) to define heat pasteurisation conditions to optimise the quality of ready-to-eat edible crab

Understanding the Interactions Between Loading, Pain Dynamics, and Imaging Characteristics for Osgood Schlatter:A Cross-Sectional Study

Osgood Schlatter's disease (OSD) is characterized by pain at the tibial tuberosity provoked during knee-loading activities, and is common in adolescent athletes. The aim of this study was to characterize clinical, pain and ultrasound imaging characteristics in participants with OSD compared to controls. This cross-sectional study included adolescents diagnosed with OSD and matched controls. Following baseline evaluation including ultrasound, participants completed the following aggravating activities in a randomized order: single-leg isometric knee hold, single-leg squat, single-leg vertical jump, hopping, running, cutting, lunges, and walking. Participants rated pain intensity on a numeric rating scale (0–10; no pain to worst pain imaginable) and localization during activities. We included 35 participants with OSD (48.5% females, age 13.0 [SD 1.5]) and 21 controls (47.6% females, age 13.4 [SD1.4]). Doppler signal was more prevalent in OSD participants at the tendon (77% vs. 30%) and tuberosity (29% vs. 10%). Tendon thickness was greater in OSD at distal (mean difference = 4.5 mm 95% CI 1.5–7.5) and proximal sites (mean difference = 4.2 95% CI 0.1–8.3). Aggravating activities induced higher pain in OSD. The greatest differences between OSD and control were the dynamic single-leg squat (mean difference = 4.2 (95% CI 3.22–5.1)). Pain was localized at the tibial tuberosity and patellar tendon during activities. Sex, sports participation, bilateral pain, and Doppler were associated with greater pain during aggravating activities. Single-leg activities loading the tibial tuberosity through the tendon appear to provoke OSD-related pain more than other sports specific movements. This may be useful to guide adolescents on which activities are likely to aggravate pain.</p

Multiple Dimensions of Work Intensity: Ambulance Work as Edgework.

Working life in public sector professions is undergoing significant change and becoming increasingly demanding. This article explores work intensity in NHS ambulance services in England, describing four distinct but interrelated dimensions of intensity: temporal; physical; emotional; and organizational. We use the concept of edgework to explore the complexities involved in how emergency workers attempt to negotiate the rewards and risks associated with multidimensional work intensity. Although certain parts of ambulance work may be intrinsically intense and can provide an important source of validation, organizational elements have the potential to push work intensity to unnecessary extremes. Ambulance services are ‘professionalizing’, but as work in ambulance trusts continues to intensify, issues over dignity, staff retention and the meaning of work are becoming ever more challenging, just as they are in other public service professions.</p

Crab-meat-isolated psychrophilic spore forming bacteria inactivation by electron beam ionizing radiation

The present work was performed to evaluate the potential of electron beam ionizing radiation for the inactivation of three psychrophilic spore forming bacteria (Bacillus mycoides, Bacillus weihenstephanensis and Psychrobacillus psychrodurans) isolated from ready-to-eat brown crab (Cancer pagurus). Inactivation curves for the three spores were performed in both types of crab meat, brown and white. Also the effect of pH and water activity (aw) on the lethal efficacy of ionizing radiation, for the three different psychrophilic spore forming bacteria, was evaluated. The effects of pH, aw and their possible interactions were assessed in citrate-phosphate buffers of different pH, ranging between 7 and 4, and aw, ranging from 0.99 and 0.90, while an aw reduction from 0.90 to 0.80 had a minor impact on their resistance. In contrast to aw, the effect of pH showed a greater variability depending on the spore species. While pH did not affect the resistance of B. weihenstephanensis at any aw, B. mycoides showed slightly higher resistance at pH 5.5¿at aw of 0.90 and 0.80. pH showed a significant effect on the resistance of P. psychrodurans. For the two types of crab meat, slightly differences were observed in 6D values. B. weihenstephanensis was the most resistant, requiring 7.3–7.6¿kGy to inactivate 6 Log10-cycles of this spore forming bacterium, while for B. mycoides and P. psychrodurans 6.1–6.3 and 5.4–5.3¿kGy respectively were necessary to reach the same inactivation level in crab meat. An agreement between spore resistance in crab meats and lab media, with similar characteristics in pH and aw, was also observed. The results obtained in this research demonstrated the potential for ionizing radiation to achieve an appropriate inactivation level of spores naturally present in brown crab with the application of doses lower than 10¿kGy