Annexin A5-Conjugated Polymeric Micelles For Dual SPECT and Optical Detection of Apoptosis

Apoptosis, a form of programmed cell death, is critical to homoeostasis, normal development, and physiology. Dysregulation of apoptosis can lead to the accumulation of unwanted cells, such as occurs in cancer, and the removal of needed cells or disorders of normal tissues, such as heart, neurodegenerative, and autoimmune diseases. Noninvasive detection of apoptosis may play an important role in the evaluation of disease states and response to therapeutic intervention for a variety of diseases. It is desirable to have an imaging method to accurately detect and monitor this process in patients. In this study, we developed annexin A5-conjugated polymeric micellar nanoparticles dual-labeled with a near-infrared fluorescence fluorophores (Cy7) and a radioisotope (111In), named as 111In-labeled annexin A5-CCPM. In vitro studies demonstrated that annexin A5-CCPM could strongly and specifically bind to apoptotic cells. In vivo studies showed that apoptotic tissues could be clearly visualized by both single photon emission computed tomography (SPECT) and fluorescence molecular tomography (FMT) after intravenous injection of 111In-labeled Annexin A5-CCPM in 6 different apoptosis models. In contrast, there was little signal in respective healthy tissues. All the biodistribution data confirmed imaging results. Moreover, histological analysis revealed that radioactivity count correlated with fluorescence signal from the nanoparticles, and both signals co-localized with the region of apoptosis. In sum, 111In-labeled annexin A5-CCPM allowed visualization of apoptosis by both nuclear and optical imaging techniques. The complementary information acquired with multiple imaging techniques should be advantageous in improving diagnostics and management of patients.

Probabilistic approach to cloud and snow detection on Advanced Very High Resolution Radiometer (AVHRR) imagery

Derivation of probability estimates complementary to geophysical data sets has gained special attention over the last years. Information about a confidence level of provided physical quantities is required to construct an error budget of higher-level products and to correctly interpret final results of a particular analysis. Regarding the generation of products based on satellite data a common input consists of a cloud mask which allows discrimination between surface and cloud signals. Further the surface information is divided between snow and snow-free components. At any step of this discrimination process a misclassification in a cloud/snow mask propagates to higher-level products and may alter their usability. Within this scope a novel probabilistic cloud mask (PCM) algorithm suited for the 1 km × 1 km Advanced Very High Resolution Radiometer (AVHRR) data is proposed which provides three types of probability estimates between: cloudy/clear-sky, cloudy/snow and clear-sky/snow conditions. As opposed to the majority of available techniques which are usually based on the decision-tree approach in the PCM algorithm all spectral, angular and ancillary information is used in a single step to retrieve probability estimates from the precomputed look-up tables (LUTs). Moreover, the issue of derivation of a single threshold value for a spectral test was overcome by the concept of multidimensional information space which is divided into small bins by an extensive set of intervals. The discrimination between snow and ice clouds and detection of broken, thin clouds was enhanced by means of the invariant coordinate system (ICS) transformation. The study area covers a wide range of environmental conditions spanning from Iceland through central Europe to northern parts of Africa which exhibit diverse difficulties for cloud/snow masking algorithms. The retrieved PCM cloud classification was compared to the Polar Platform System (PPS) version 2012 and Moderate Resolution Imaging Spectroradiometer (MODIS) collection 6 cloud masks, SYNOP (surface synoptic observations) weather reports, Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) vertical feature mask version 3 and to MODIS collection 5 snow mask. The outcomes of conducted analyses proved fine detection skills of the PCM method with results comparable to or better than the reference PPS algorithm.

The new bern PET cyclotron, its research beam line, and the development of an innovative beam monitor detector

The new Bern cyclotron laboratory aims at industrial radioisotope production for PET diagnostics and multidisciplinary research by means of a specifically conceived beam transfer line, terminated in a separate bunker. In this framework, an innovative beam monitor detector based on doped silica and optical fibres has been designed, constructed, and tested. Scintillation light produced by Ce and Sb doped silica fibres moving across the beam is measured, giving information on beam position, shape, and intensity. The doped fibres are coupled to commercial optical fibres, allowing the read-out of the signal far away from the radiation source. This general-purpose device can be easily adapted for any accelerator used in medical applications and is suitable either for low currents used in hadrontherapy or for currents up to a few μA for radioisotope production, as well as for both pulsed and continuous beams.

Corneal cross-linking in keratoconus using the standard and rapid treatment protocol: differences in demarcation line and 12-month outcomes.

PURPOSE To compare the occurrence rate and depth of the demarcation line and topographical outcome after corneal cross-linking (CXL) for keratoconus using two different treatment protocols. METHODS A retrospective analysis of 131 eyes with progressive keratoconus treated with CXL using riboflavin and UV-A was performed. Eyes were treated either with the standard Dresden protocol (30 minutes irradiation, 3 mW/cm(2), UV-XTM 1000) or a rapid protocol (10 minutes irradiation, 9 mW/cm(2), UV-XTM 2000). The presence and depth of the corneal demarcation line was assessed with an anterior segment optical coherence tomography device 1 month after CXL by a masked observer. Corneal topography and tomography was performed at baseline and at 12-month follow-up with Pentacam and the TMS (Topographic Modeling System) device. RESULTS In the standard protocol group, 76.5% (62/81) of treated corneas revealed a demarcation line 1 month after CXL, whereas such a demarcation line was observed in only 22% (11/50) of eyes treated with the rapid protocol (P < 0.0001). The demarcation line was significantly more superficial in the rapid protocol group (P = 0.004). Corneal topography values between baseline and 12 months after CXL showed a mean change of -0.76 diopters (D) in Kmax (SD ± 2.7) in the standard protocol group versus a mean change of +0.72 D in Kmax (SD ± 1.5) in the rapid protocol (P = 0.007). CONCLUSIONS The rapid CXL protocol negatively influences the occurrence and depth of the demarcation line 1 month after CXL. Our results show a negative effect on the topographical outcome 1 year after CXL.

Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model

Hepatic angiosarcoma (AS) is a rare and highly aggressive tumor of endothelial origin with dismal prognosis. Studies of the molecular biology of AS and treatment options are limited as animal models are rare. We have previously shown that inducible knockout of Notch1 in mice leads to spontaneous formation of hepatic AS. The aims of this study were to: (1) establish and characterize a cell line derived from this murine AS, (2) identify molecular pathways involved in the pathogenesis and potential therapeutic targets, and (3) generate a tumor transplantation model. AS cells retained specific endothelial properties such as tube formation activity, as well as expression of CD31 and Von Willebrand factor. However, electron microscopy analysis revealed signs of dedifferentiation with loss of fenestrae and loss of contact inhibition. Microarray and pathway analysis showed substantial changes in gene expression and revealed activation of the Myc pathway. Exposing the AS cells to sorafenib reduced migration, filopodia dynamics, and cell proliferation but did not induce apoptosis. In addition, sorafenib suppressed ERK phosphorylation and expression of cyclin D2. Injection of AS cells into NOD/SCID mice resulted in formation of undifferentiated tumors, confirming the tumorigenic potential of these cells. In summary, we established and characterized a murine model of spontaneous AS formation and hepatic AS cell lines as a useful in vitro tool. Our data demonstrate antitumor activity of sorafenib in AS cells with potent inhibition of migration, filopodia formation, and cell proliferation, supporting further evaluation of sorafenib as a novel treatment strategy. In addition, AS cell transplantation provides a subcutaneous tumor model useful for in vivo preclinical drug testing.Laboratory Investigation advance online publication, 24 November 2014; doi:10.1038/labinvest.2014.141.

Left, right and interval bivariate censored data: Evaluating screening mammography in the presence of lead -time bias, length bias and over-detection

Of the large clinical trials evaluating screening mammography efficacy, none included women ages 75 and older. Recommendations on an upper age limit at which to discontinue screening are based on indirect evidence and are not consistent. Screening mammography is evaluated using observational data from the SEER-Medicare linked database. Measuring the benefit of screening mammography is difficult due to the impact of lead-time bias, length bias and over-detection. The underlying conceptual model divides the disease into two stages: pre-clinical (T0) and symptomatic (T1) breast cancer. Treating the time in these phases as a pair of dependent bivariate observations, (t0,t1), estimates are derived to describe the distribution of this random vector. To quantify the effect of screening mammography, statistical inference is made about the mammography parameters that correspond to the marginal distribution of the symptomatic phase duration (T1). This shows the hazard ratio of death from breast cancer comparing women with screen-detected tumors to those detected at their symptom onset is 0.36 (0.30, 0.42), indicating a benefit among the screen-detected cases. ^

Synthesized grounding line and ice shelf mask for Antarctica

Iceberg calving has been assumed to be the dominant cause of mass loss for the Antarctic ice sheet, with previous estimates of the calving flux exceeding 2,000 gigatonnes per year. More recently, the importance of melting by the ocean has been demonstrated close to the grounding line and near the calving front. So far, however, no study has reliably quantified the calving flux and the basal mass balance (the balance between accretion and ablation at the ice-sheet base) for the whole of Antarctica. The distribution of fresh water in the Southern Ocean and its partitioning between the liquid and solid phases is therefore poorly constrained. Here we estimate the mass balance components for all ice shelves in Antarctica, using satellite measurements of calving flux and grounding-line flux, modelled ice-shelf snow accumulation rates and a regional scaling that accounts for unsurveyed areas. We obtain a total calving flux of 1,321 ± 144 gigatonnes per year and a total basal mass balance of -1,454 ± 174 gigatonnes per year. This means that about half of the ice-sheet surface mass gain is lost through oceanic erosion before reaching the ice front, and the calving flux is about 34 per cent less than previous estimates derived from iceberg tracking. In addition, the fraction of mass loss due to basal processes varies from about 10 to 90 per cent between ice shelves. We find a significant positive correlation between basal mass loss and surface elevation change for ice shelves experiencing surface lowering and enhanced discharge. We suggest that basal mass loss is a valuable metric for predicting future ice-shelf vulnerability to oceanic forcing.

Benford's Law and Fraud Detection. Facts and Legends

Is Benford's law a good instrument to detect fraud in reports of statistical and scientific data? For a valid test the probability of "false positives" and "false negatives" has to be low. However, it is very doubtful whether the Benford distribution is an appropriate tool to discriminate between manipulated and non-manipulated estimates. Further research should focus more on the validity of the test and test results should be interpreted more carefully.

PDR with a foot-mounted IMU and ramp detection

The localization of persons in indoor environments is nowadays an open problem. There are partial solutions based on the deployment of a network of sensors (Local Positioning Systems or LPS). Other solutions only require the installation of an inertial sensor on the person’s body (Pedestrian Dead-Reckoning or PDR). PDR solutions integrate the signals coming from an Inertial Measurement Unit (IMU), which usually contains 3 accelerometers and 3 gyroscopes. The main problem of PDR is the accumulation of positioning errors due to the drift caused by the noise in the sensors. This paper presents a PDR solution that incorporates a drift correction method based on detecting the access ramps usually found in buildings. The ramp correction method is implemented over a PDR framework that uses an Inertial Navigation algorithm (INS) and an IMU attached to the person’s foot. Unlike other approaches that use external sensors to correct the drift error, we only use one IMU on the foot. To detect a ramp, the slope of the terrain on which the user is walking, and the change in height sensed when moving forward, are estimated from the IMU. After detection, the ramp is checked for association with one of the existing in a database. For each associated ramp, a position correction is fed into the Kalman Filter in order to refine the INS-PDR solution. Drift-free localization is achieved with positioning errors below 2 meters for 1,000-meter-long routes in a building with a few ramps.

Localization and activity detection Based on the fusion of environment And inertial sensors = Localización y detección de actividad Basadas en integración de sensores y dispositivos inerciales

Los sensores inerciales (acelerómetros y giróscopos) se han ido introduciendo poco a poco en dispositivos que usamos en nuestra vida diaria gracias a su minituarización. Hoy en día todos los smartphones contienen como mínimo un acelerómetro y un magnetómetro, siendo complementados en losmás modernos por giróscopos y barómetros. Esto, unido a la proliferación de los smartphones ha hecho viable el diseño de sistemas basados en las medidas de sensores que el usuario lleva colocados en alguna parte del cuerpo (que en un futuro estarán contenidos en tejidos inteligentes) o los integrados en su móvil. El papel de estos sensores se ha convertido en fundamental para el desarrollo de aplicaciones contextuales y de inteligencia ambiental. Algunos ejemplos son el control de los ejercicios de rehabilitación o la oferta de información referente al sitio turístico que se está visitando. El trabajo de esta tesis contribuye a explorar las posibilidades que ofrecen los sensores inerciales para el apoyo a la detección de actividad y la mejora de la precisión de servicios de localización para peatones. En lo referente al reconocimiento de la actividad que desarrolla un usuario, se ha explorado el uso de los sensores integrados en los dispositivos móviles de última generación (luz y proximidad, acelerómetro, giróscopo y magnetómetro). Las actividades objetivo son conocidas como ‘atómicas’ (andar a distintas velocidades, estar de pie, correr, estar sentado), esto es, actividades que constituyen unidades de actividades más complejas como pueden ser lavar los platos o ir al trabajo. De este modo, se usan algoritmos de clasificación sencillos que puedan ser integrados en un móvil como el Naïve Bayes, Tablas y Árboles de Decisión. Además, se pretende igualmente detectar la posición en la que el usuario lleva el móvil, no sólo con el objetivo de utilizar esa información para elegir un clasificador entrenado sólo con datos recogidos en la posición correspondiente (estrategia que mejora los resultados de estimación de la actividad), sino también para la generación de un evento que puede producir la ejecución de una acción. Finalmente, el trabajo incluye un análisis de las prestaciones de la clasificación variando el tipo de parámetros y el número de sensores usados y teniendo en cuenta no sólo la precisión de la clasificación sino también la carga computacional. Por otra parte, se ha propuesto un algoritmo basado en la cuenta de pasos utilizando informaiii ción proveniente de un acelerómetro colocado en el pie del usuario. El objetivo final es detectar la actividad que el usuario está haciendo junto con la estimación aproximada de la distancia recorrida. El algoritmo de cuenta pasos se basa en la detección de máximos y mínimos usando ventanas temporales y umbrales sin requerir información específica del usuario. El ámbito de seguimiento de peatones en interiores es interesante por la falta de un estándar de localización en este tipo de entornos. Se ha diseñado un filtro extendido de Kalman centralizado y ligeramente acoplado para fusionar la información medida por un acelerómetro colocado en el pie del usuario con medidas de posición. Se han aplicado también diferentes técnicas de corrección de errores como las de velocidad cero que se basan en la detección de los instantes en los que el pie está apoyado en el suelo. Los resultados han sido obtenidos en entornos interiores usando las posiciones estimadas por un sistema de triangulación basado en la medida de la potencia recibida (RSS) y GPS en exteriores. Finalmente, se han implementado algunas aplicaciones que prueban la utilidad del trabajo desarrollado. En primer lugar se ha considerado una aplicación de monitorización de actividad que proporciona al usuario información sobre el nivel de actividad que realiza durante un período de tiempo. El objetivo final es favorecer el cambio de comportamientos sedentarios, consiguiendo hábitos saludables. Se han desarrollado dos versiones de esta aplicación. En el primer caso se ha integrado el algoritmo de cuenta pasos en una plataforma OSGi móvil adquiriendo los datos de un acelerómetro Bluetooth colocado en el pie. En el segundo caso se ha creado la misma aplicación utilizando las implementaciones de los clasificadores en un dispositivo Android. Por otro lado, se ha planteado el diseño de una aplicación para la creación automática de un diario de viaje a partir de la detección de eventos importantes. Esta aplicación toma como entrada la información procedente de la estimación de actividad y de localización además de información almacenada en bases de datos abiertas (fotos, información sobre sitios) e información sobre sensores reales y virtuales (agenda, cámara, etc.) del móvil. Abstract Inertial sensors (accelerometers and gyroscopes) have been gradually embedded in the devices that people use in their daily lives thanks to their miniaturization. Nowadays all smartphones have at least one embedded magnetometer and accelerometer, containing the most upto- date ones gyroscopes and barometers. This issue, together with the fact that the penetration of smartphones is growing steadily, has made possible the design of systems that rely on the information gathered by wearable sensors (in the future contained in smart textiles) or inertial sensors embedded in a smartphone. The role of these sensors has become key to the development of context-aware and ambient intelligent applications. Some examples are the performance of rehabilitation exercises, the provision of information related to the place that the user is visiting or the interaction with objects by gesture recognition. The work of this thesis contributes to explore to which extent this kind of sensors can be useful to support activity recognition and pedestrian tracking, which have been proven to be essential for these applications. Regarding the recognition of the activity that a user performs, the use of sensors embedded in a smartphone (proximity and light sensors, gyroscopes, magnetometers and accelerometers) has been explored. The activities that are detected belong to the group of the ones known as ‘atomic’ activities (e.g. walking at different paces, running, standing), that is, activities or movements that are part of more complex activities such as doing the dishes or commuting. Simple, wellknown classifiers that can run embedded in a smartphone have been tested, such as Naïve Bayes, Decision Tables and Trees. In addition to this, another aim is to estimate the on-body position in which the user is carrying the mobile phone. The objective is not only to choose a classifier that has been trained with the corresponding data in order to enhance the classification but also to start actions. Finally, the performance of the different classifiers is analysed, taking into consideration different features and number of sensors. The computational and memory load of the classifiers is also measured. On the other hand, an algorithm based on step counting has been proposed. The acceleration information is provided by an accelerometer placed on the foot. The aim is to detect the activity that the user is performing together with the estimation of the distance covered. The step counting strategy is based on detecting minima and its corresponding maxima. Although the counting strategy is not innovative (it includes time windows and amplitude thresholds to prevent under or overestimation) no user-specific information is required. The field of pedestrian tracking is crucial due to the lack of a localization standard for this kind of environments. A loosely-coupled centralized Extended Kalman Filter has been proposed to perform the fusion of inertial and position measurements. Zero velocity updates have been applied whenever the foot is detected to be placed on the ground. The results have been obtained in indoor environments using a triangulation algorithm based on RSS measurements and GPS outdoors. Finally, some applications have been designed to test the usefulness of the work. The first one is called the ‘Activity Monitor’ whose aim is to prevent sedentary behaviours and to modify habits to achieve desired objectives of activity level. Two different versions of the application have been implemented. The first one uses the activity estimation based on the step counting algorithm, which has been integrated in an OSGi mobile framework acquiring the data from a Bluetooth accelerometer placed on the foot of the individual. The second one uses activity classifiers embedded in an Android smartphone. On the other hand, the design of a ‘Travel Logbook’ has been planned. The input of this application is the information provided by the activity and localization modules, external databases (e.g. pictures, points of interest, weather) and mobile embedded and virtual sensors (agenda, camera, etc.). The aim is to detect important events in the journey and gather the information necessary to store it as a journal page.