Multi Scale Curriculum CNN for Context-Aware Breast MRI Malignancy Classification

Classification of malignancy for breast cancer and other cancer types is usually tackled as an object detection problem: Individual lesions are first localized and then classified with respect to malignancy. However, the drawback of this approach is that abstract features incorporating several lesions and areas that are not labelled as a lesion but contain global medically relevant information are thus disregarded: especially for dynamic contrast-enhanced breast MRI, criteria such as background parenchymal enhancement and location within the breast are important for diagnosis and cannot be captured by object detection approaches properly. In this work, we propose a 3D CNN and a multi scale curriculum learning strategy to classify malignancy globally based on an MRI of the whole breast. Thus, the global context of the whole breast rather than individual lesions is taken into account. Our proposed approach does not rely on lesion segmentations, which renders the annotation of training data much more effective than in current object detection approaches. Achieving an AUROC of 0.89, we compare the performance of our approach to Mask R-CNN and Retina U-Net as well as a radiologist. Our performance is on par with approaches that, in contrast to our method, rely on pixelwise segmentations of lesions.Comment: Accepted to MICCAI 201

Pharmacinema: teaching resource in the learning of Pharmacology and Clinical Pharmacy

Introducción: El objetivo prioritario de la actividad Farmacinema es favorecer el proceso de enseñanza-aprendizaje de los estudiantes de Farmacología (Licenciatura o Grado en Farmacia), con una metodología complementaria a la empleada en la enseñanza tradicional, utilizando películas comerciales para reforzar aspectos terapéuticos y bioéticos. Los estudiantes.Metodología: Los estudiantes pueden asistir a 3 sesiones distintas durante el curso: 2 en grupo amplio (80-100 estudiantes) y una sesión en grupos reducidos (16), que se realiza en las prácticas de Farmacia Clínica. Las películas seleccionadas han sido: El aceite de la vida y Despertares en las sesiones generales, en el primer y segundo trimestre de curso, respectivamente; Los chicos de la señorita Evers y El jardinero fiel en las sesiones en prácticas. En cada sesión el procedimiento utilizado es similar: breve introducción sobre las características técnicas más importantes de la película así como los puntos fuertes, aspectos a destacar para enfocar el interés de los estudiantes a lo que creemos más útil para conseguir los objetivos propuestos; visualización de la película y debate. Para motivar la atención del alumno hacia estos “puntos fuertes”, se les entrega un tríptico con la información básica sobre la película y con una serie de cuestiones que tienen que ir contestando a lo largo de la sesión o bien al acabar ésta. Estas cuestiones sirven de base para plantear y suscitar el debate. Resultados y conclusión: La asistencia es voluntaria y ha ido aumentando en los tres años que se ha ofertado esta actividad. Los estudiantes valoran muy positivamente el Farmacinema.Introduction: The main objective of Pharmacinema is to favour the teaching-learning process of Pharmacology students of the School of Pharmacy, as a complementary method to the conventionally used one, using commercial movies to reinforce therapeutic and bioethical aspects. Methodology: Students may assist to 3 different sessions throughout the school year: 2 in big groups (80-100 students) and one in small groups (16 students) to be performed during the practical lessons of Clinical Pharmacy. The selected movies were: Lorenzo’s oil and Awakenings for the general sessions of the first and second trimesters respectively, Mrs Evers’ boys and The constant gardener for the practical lessons sessions. The procedure used for each session was similar: a brief introduction stating the major technical characteristics of the movie ant the strong points, aspects to be pointed out in order to address the students’ interest towards what we consider most relevant to achieve the proposed objectives; movie visualization and debate. To motivate the student’s attention towards these strong points, the students received a flyer with the basic information about the movie and a series of questions that they have to answer during or at the end of the session. These questions also are used as a start point for the debate. Results and conclusion: Assistance to the general sessions is voluntary, and has increased over the three years in which this activity has been offered. Students have evaluated Pharmacinema as a very positive activity

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Broadband microwave photonic fully tunable filter using a single heterogeneously integrated III-V/SOI-microdisk-based phase shifter

This paper was published in OPTICS EXPRESS and is made available as an electronic reprint with the permission of OSA. The paper can be found at the following URL on the OSA website: http://dx.doi.org/10.1364/OE.20.010796. Systematic or multiple reproduction or distribution to multiple locations via electronic or other means is prohibited and is subject to penalties under lawA broadband microwave photonic phase shifter based on a single III-V microdisk resonator heterogeneously integrated on and coupled to a nanophotonic silicon-on-insulator waveguide is reported. The phase shift tunability is accomplished by modifying the effective index through carrier injection. A comprehensive semi-analytical model aiming at predicting its behavior is formulated and confirmed by measurements. Quasi-linear and continuously tunable 2 pi phase shifts at radiofrequencies greater than 18 GHz are experimentally demonstrated. The phase shifter performance is also evaluated when used as a key element in tunable filtering schemes. Distortion-free and wideband filtering responses with a tuning range of similar to 100% over the free spectral range are obtained. (C) 2012 Optical Society of AmericaThe authors wish to acknowledge the technical support given by Rajesh Kumar and Pauline Mechet, as well as the financial support of the European Commission Seventh Framework Programme (FP 7) through the projects GOSPEL, WADIMOS and HISTORIC; the Generalitat Valenciana through the Microwave Photonics research Excellency award programme GVA PROMETEO 2008/092 and also the Plan Nacional I + D TEC2011-29120-C05-05 and TEC2008-06145.Lloret Soler, JA.; Morthier, G.; Ramos Pascual, F.; Sales Maicas, S.; Van Thourhout, D.; Spuesens, T.; Olivier, N.... (2012). Broadband microwave photonic fully tunable filter using a single heterogeneously integrated III-V/SOI-microdisk-based phase shifter. Optics Express. 20(10):10796-10806. doi:10.1364/OE.20.010796S1079610806201

Ethanol-Mediated Regulation of Cytochrome P450 2A6 Expression in Monocytes: Role of Oxidative Stress-Mediated PKC/MEK/Nrf2 Pathway

Cytochrome P450 2A6 (CYP2A6) is known to metabolize nicotine, the major constituent of tobacco, leading to the production of toxic metabolites and induction of oxidative stress that result in liver damage and lung cancer. Recently, we have shown that CYP2A6 is induced by ethanol and metabolizes nicotine into cotinine and other metabolites leading to generation of reactive oxygen species (ROS) in U937 monocytes. However, the mechanism by which CYP2A6 is induced by ethanol is unknown. In this study, we have examined the role of the PKC/Nrf2 pathway (protein kinase C-mediated phosphorylation and translocation of nuclear erythroid 2-related factor 2 to the nucleus) in ethanol-mediated CYP2A6 induction. Our results showed that 100 mM ethanol significantly induced CYP2A6 mRNA and protein (∼150%) and increased ROS formation, and induction of gene expression and ROS were both completely blocked by treatment with either a CYP2E1 inhibitor (diallyl sulfide) or an antioxidant (vitamin C). The results suggest the role of oxidative stress in the regulation of CYP2A6 expression. Subsequently, we investigated the role of Nrf2 pathway in oxidative stress-mediated regulation of CYP2A6 expression in U937 monocytes. Our results showed that butylated hydroxyanisole, a stabilizer of nuclear Nrf2, increased CYP2A6 levels >200%. Staurosporine, an inhibitor of PKC, completely abolished ethanol-induced CYP2A6 expression. Furthermore, our results showed that a specific inhibitor of mitogen-activated protein kinase kinase (MEK) (U0126) completely abolished ethanol-mediated CYP2A6 induction and Nrf2 translocation. Overall, these results suggest that CYP2E1-mediated oxidative stress produced as a result of ethanol metabolism translocates Nrf2 into the nucleus through PKC/MEK pathway, resulting in the induction of CYP2A6 in monocytes. An increased level of CYP2A6 in monocytes is expected to further increase oxidative stress in smokers through CYP2A6-mediated nicotine metabolism. Thus, this study has clinical relevance because of the high incidence of alcohol use among smokers, especially in HIV-infected individuals

Suppression of the Nrf2-Dependent Antioxidant Response by Glucocorticoids and 11β-HSD1-Mediated Glucocorticoid Activation in Hepatic Cells

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor regulating a plethora of detoxifying enzymes and antioxidant genes involved in drug metabolism and defence against oxidative stress. The glucocorticoid receptor (GR) is a ligand-induced transcription factor involved in the regulation of energy supply for metabolic needs to cope with various stressors. GR activity is controlled by glucocorticoids, which are synthesized in the adrenal glands and regenerated mainly in the liver from inactive cortisone by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1).; Using transfected HEK-293 cells and hepatic H4IIE cells we show that glucocorticoids, activated by 11β-HSD1 and acting through GR, suppress the Nrf2-dependent antioxidant response. The expression of the marker genes NQO1, HMOX1 and GST2A was suppressed upon treatment of 11β-HSD1 expressing cells with cortisone, an effect that was reversed by 11β-HSD1 inhibitors. Furthermore, our results demonstrate that elevated glucocorticoids lowered the ability of cells to detoxify H(2)O(2). Moreover, a comparison of gene expression in male and female rats revealed an opposite sexual dimorphism with an inverse relationship between 11β-HSD1 and Nrf2 target gene expression.; The results demonstrate a suppression of the cellular antioxidant defence capacity by glucocorticoids and suggest that elevated 11β-HSD1 activity may lead to impaired Nrf2-dependent antioxidant response. The gender-specific differences in hepatic expression levels of 11β-HSD1 and Nrf2 target genes and the impact of pharmacological inhibition of 11β-HSD1 on improving cellular capacity to cope with oxidative stress warrants further studies in vivo