A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Chemotherapy Resistant Prostate Cancer

Prostate cancer is a common malignancy with nearly one million annual diagnoses worldwide. Among a subset of patients, primary disease eventually progresses to disseminated castration resistant prostate cancer (CRPC). In recent years, treatment modalities that improve survival in CRPC have emerged including taxane chemotherapy and second generation androgen signaling inhibitors, among others. Indeed, today the first line chemotherapeutic docetaxel as well as the second line agent cabazitaxel are mainstays of treatment. However, CRPC inexorably progresses to a chemotherapy resistant state that ultimately precedes lethality. Elucidating the molecular determinants of aggressiveness in chemotherapy resistant CRPC may therefore stimulate new therapeutic strategies that improve clinical outcomes. We used laboratory models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Whole genome expression profiling, clinical validation and genetic screening approaches revealed that GATA2 regulates a signature of cancer progression associated genes. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a significant mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this regulatory axis prompted a combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in chemotherapy resistant prostate cancer and identify a therapeutic opportunity in this challenging disease

Calcium Channel CaV2.3 Subunits Regulate Hepatic Glucose Production by Modulating Leptin-Induced Excitation of Arcuate Pro-opiomelanocortin Neurons.

Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the "R-type" channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes

Evaluating a new generation of wearable high-density diffuse optical tomography (HD-DOT) technology via retinotopic mapping in the adult brain

We investigated the performance of a novel HD-DOT system by replicating a series of classic visual stimulation paradigms. Haemodynamic response functions and cortical activation maps replicated the results obtained with larger fibre-based systems

Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation

Objective: Colorectal cancer (CRC) is a major contributor to cancer mortality and morbidity. LIM kinase 2 (LIMK2) promotes tumour cell invasion and metastasis. The objectives of this study were to determine how LIMK2 expression is associated with CRC progression and patient outcome, and to use genetically modified Drosophila and mice to determine how LIMK2 deletion affects gastrointestinal stem cell regulation and tumour development.<p></p> Design: LIMK2 expression and activity were measured by immunostaining tumours from CRC-prone mice, human CRC cell lines and 650 human tumours. LIMK knockdown in Drosophila or Limk2 deletion in mice allowed for assessment of their contributions to gastrointestinal stem cell homeostasis and tumour development.<p></p> Results: LIMK2 expression was reduced in intestinal tumours of cancer-prone mice, as well as in human CRC cell lines and tumours. Reduced LIMK2 expression and substrate phosphorylation were associated with shorter patient survival. Genetic analysis in Drosophila midgut and intestinal epithelial cells isolated from genetically modified mice revealed a conserved role for LIMK2 in constraining gastrointestinal stem cell proliferation. Limk2 deletion increased colon tumour size in a colitis-associated colorectal mouse cancer model.<p></p> Conclusions: This study revealed that LIMK2 expression and activity progressively decrease with advancing stage, and supports the hypothesis that there is selective pressure for reduced LIMK2 expression in CRC to relieve negative constraints imposed upon gastrointestinal stem cells.<p></p&gt

Design of a polishing tool for collaborative robotics using minimum viable product approach

This is an Author's Accepted Manuscript of an article published in Carlos Perez-Vidal, Luis Gracia, Samuel Sanchez-Caballero, J. Ernesto Solanes, Alessandro Saccon & Josep Tornero (2019) Design of a polishing tool for collaborative robotics using minimum viable product approach, International Journal of Computer Integrated Manufacturing, 32:9, 848-857, DOI: 10.1080/0951192X.2019.1637026 [copyright Taylor & Francis], available online at: http://www.tandfonline.com/10.1080/0951192X.2019.1637026[EN] A collaborative tool for robotic polishing is developed in this work in order to allow the simultaneous operation of the robot system and human operator to cooperatively carry out the polishing task. For this purpose, the collaborative environment is detailed and the polishing application is designed. Moreover, the polishing tool is developed and its implementation using the minimum viable product approach is obtained. Furthermore, a robust hybrid position-force control is proposed to use the developed tool attached to a robot system and some experiments are given to show its performance.This work was supported in part by the Ministerio de Ciencia e Innovacion (Spanish Government) under project [DPI2017-87656-C2-1-R] and the Generalitat Valenciana under Grant [VALi+ d APOSTD/2016/044].Perez-Vidal, C.; Gracia Calandin, LI.; Sanchez-Caballero, S.; Solanes Galbis, JE.; Saccon, A.; Tornero Montserrat, J. (2019). Design of a polishing tool for collaborative robotics using minimum viable product approach. International Journal of Computer Integrated Manufacturing. 32(9):848-857. https://doi.org/10.1080/0951192X.2019.1637026S848857329Alders, K., M. Lehe, and G. Wan. 2001. “Method for the Automatic Recognition of Surface Defects in Body Shells and Device for Carrying Out Said Method” US Patent 6,320,654, Accessed 2001 November. https://www.google.ch/patents/US6320654Alexopoulos, K., Mavrikios, D., & Chryssolouris, G. (2013). ErgoToolkit: an ergonomic analysis tool in a virtual manufacturing environment. International Journal of Computer Integrated Manufacturing, 26(5), 440-452. doi:10.1080/0951192x.2012.731610Andres, J., Gracia, L., & Tornero, J. (2011). Calibration and control of a redundant robotic workcell for milling tasks. International Journal of Computer Integrated Manufacturing, 24(6), 561-573. doi:10.1080/0951192x.2011.566284Arnal, L., Solanes, J. E., Molina, J., & Tornero, J. (2017). Detecting dings and dents on specular car body surfaces based on optical flow. Journal of Manufacturing Systems, 45, 306-321. doi:10.1016/j.jmsy.2017.07.006Blank, S. 2010. “Perfection By Subtraction - The Minimum Feature Set”. Accessed 2018 August. http://steveblank.com/2010/03/04/perfection-by-subtraction-the-minimum-feature-set/Dimeas, F., & Aspragathos, N. (2016). Online Stability in Human-Robot Cooperation with Admittance Control. IEEE Transactions on Haptics, 9(2), 267-278. doi:10.1109/toh.2016.2518670Fitzgerald, C. “Developing Baxter, A new industrial robot with common sense for U.S. manufacturing.” 2013.Gracia, L., Sala, A., & Garelli, F. (2012). A supervisory loop approach to fulfill workspace constraints in redundant robots. Robotics and Autonomous Systems, 60(1), 1-15. doi:10.1016/j.robot.2011.07.008Gracia, L., Sala, A., & Garelli, F. (2014). Robot coordination using task-priority and sliding-mode techniques. Robotics and Computer-Integrated Manufacturing, 30(1), 74-89. doi:10.1016/j.rcim.2013.08.003Gracia, L., Solanes, J. E., Muñoz-Benavent, P., Valls Miro, J., Perez-Vidal, C., & Tornero, J. (2018). Adaptive Sliding Mode Control for Robotic Surface Treatment Using Force Feedback. Mechatronics, 52, 102-118. doi:10.1016/j.mechatronics.2018.04.008Julius, R., Schürenberg, M., Schumacher, F., & Fay, A. (2017). Transformation of GRAFCET to PLC code including hierarchical structures. Control Engineering Practice, 64, 173-194. doi:10.1016/j.conengprac.2017.03.012. E. K. (2016). TOWARDS AN AUTOMATED POLISHING SYSTEM - CAPTURING MANUAL POLISHING OPERATIONS. International Journal of Research in Engineering and Technology, 05(07), 182-192. doi:10.15623/ijret.2016.0507030Khan, A. M., Yun, D., Zuhaib, K. M., Iqbal, J., Yan, R.-J., Khan, F., & Han, C. (2017). Estimation of Desired Motion Intention and compliance control for upper limb assist exoskeleton. International Journal of Control, Automation and Systems, 15(2), 802-814. doi:10.1007/s12555-015-0151-7Kirschner, D., Velik, R., Yahyanejad, S., Brandstötter, M., & Hofbaur, M. (2016). YuMi, Come and Play with Me! A Collaborative Robot for Piecing Together a Tangram Puzzle. Interactive Collaborative Robotics, 243-251. doi:10.1007/978-3-319-43955-6_29Mohammad, A. E. K., Hong, J., & Wang, D. (2018). Design of a force-controlled end-effector with low-inertia effect for robotic polishing using macro-mini robot approach. Robotics and Computer-Integrated Manufacturing, 49, 54-65. doi:10.1016/j.rcim.2017.05.011Nagata, F., Hase, T., Haga, Z., Omoto, M., & Watanabe, K. (2007). CAD/CAM-based position/force controller for a mold polishing robot. Mechatronics, 17(4-5), 207-216. doi:10.1016/j.mechatronics.2007.01.003Nakamura, Y., Hanafusa, H., & Yoshikawa, T. (1987). Task-Priority Based Redundancy Control of Robot Manipulators. The International Journal of Robotics Research, 6(2), 3-15. doi:10.1177/027836498700600201Ries, E. 2009. “What is the Minimum Viable Product”. March. Accessed 2018 August. http://venturehacks.com/articles/minimum-viable-productRobinson, F. 2001 “A Proven Methodology to Maximize Return on Risk”. Accessed 2018 August. http://www.syncdev.com/minimum-viable-productShepherd, S., & Buchstab, A. (2014). KUKA Robots On-Site. Robotic Fabrication in Architecture, Art and Design 2014, 373-380. doi:10.1007/978-3-319-04663-1_26SYMPLEXITY. “Symbiotic Human-Robot Solutions for Complex Surface Finishing Operations.” European project funded by E.U. through the H2020. Project no. 637080. Call: H2020-FoF-2014. Topic: FoF-06-2014. Starting date: 01/ 01/2015.Duration: 48 months. Accessed 2019 March. https://www.symplexity.eu/Vihlborg, P., I. Bryngelsson, B. Lindgren, L. G. Gunnarsson, and P. Graff. 2017. “Associatio between vibration exposure and hand-arm vibration symptoms in a Swedish mechanical industry.” February 2017.Vogel, J., Haddadin, S., Jarosiewicz, B., Simeral, J. D., Bacher, D., Hochberg, L. R., … van der Smagt, P. (2015). An assistive decision-and-control architecture for force-sensitive hand–arm systems driven by human–machine interfaces. The International Journal of Robotics Research, 34(6), 763-780. doi:10.1177/027836491456153

ANIMATE: Wearable, flexible, and ultra-lightweight high-density diffuse optical tomography technologies for functional neuroimaging of newborns

We have developed a series of wearable high-density diffuse optical tomography (HD-DOT) technologies specifically for neonatal applications. These systems provide an ultra-lightweight form factor, a low profile and high mechanical flexibility. This new technology is validated using a novel, anatomically accurate dynamic phantom

A pipeline for making 31 P NMR accessible for small- and large-scale lipidomics studies

Abstract: Detailed molecular analysis is of increasing importance in research into the regulation of biochemical pathways, organismal growth and disease. Lipidomics in particular is increasingly sought after as it provides insight into molecular species involved in energy storage, signalling and fundamental cellular structures. This has led to the use of a range of tools and techniques to acquire lipidomics data. 31P NMR for lipidomics offers well-resolved head group/lipid class analysis, structural data that can be used to inform and strengthen interpretation of mass spectrometry data and part of a priori structural determination. In the present study, we codify the use of 31P NMR for lipidomics studies to make the technique more accessible to new users and more useful for a wider range of questions. The technique can be used in isolation (phospholipidomics) or as a part of determining lipid composition (lipidomics). We describe the process from sample extraction to data processing and analysis. This pipeline is important because it allows greater thoroughness in lipidomics studies and increases scope for answering scientific questions about lipid-containing systems

Measurement off f(s)/f(u) Variation with Proton-Proton Collision Energy and B-Meson Kinematics

The ratio of the B0s and B+ fragmentation fractions fs and fu is studied with B0s→J/ψϕ and B+→J/ψK+ decays using data collected by the LHCb experiment in proton-proton collisions at 7, 8, and 13 TeV center-of-mass energies. The analysis is performed in bins of B-meson momentum, longitudinal momentum, transverse momentum, pseudorapidity, and rapidity. The fragmentation-fraction ratio fs/fu is observed to depend on the B-meson transverse momentum with a significance of 6.0σ. This dependency is driven by the 13 TeV sample (8.7σ), while the results for the other collision energies are not significant when considered separately. Furthermore, the results show a 4.8σ evidence for an increase of fs/fu as a function of collision energy

Agricultural intensification and the evolution of host specialism in the enteric pathogen Campylobacter jejuni.

Modern agriculture has dramatically changed the distribution of animal species on Earth. Changes to host ecology have a major impact on the microbiota, potentially increasing the risk of zoonotic pathogens being transmitted to humans, but the impact of intensive livestock production on host-associated bacteria has rarely been studied. Here, we use large isolate collections and comparative genomics techniques, linked to phenotype studies, to understand the timescale and genomic adaptations associated with the proliferation of the most common food-born bacterial pathogen (Campylobacter jejuni) in the most prolific agricultural mammal (cattle). Our findings reveal the emergence of cattle specialist C. jejuni lineages from a background of host generalist strains that coincided with the dramatic rise in cattle numbers in the 20th century. Cattle adaptation was associated with horizontal gene transfer and significant gene gain and loss. This may be related to differences in host diet, anatomy, and physiology, leading to the proliferation of globally disseminated cattle specialists of major public health importance. This work highlights how genomic plasticity can allow important zoonotic pathogens to exploit altered niches in the face of anthropogenic change and provides information for mitigating some of the risks posed by modern agricultural systems

Dual wavelength spread-spectrum time-resolved diffuse optical instrument for the measurement of human brain functional responses

Near-infrared spectroscopy has proven to be a valuable method to monitor tissue oxygenation and haemodynamics non-invasively and in real-time. Quantification of such parameters requires measurements of the time-of-flight of light through tissue, typically achieved using picosecond pulsed lasers, with their associated cost, complexity, and size. In this work, we present an alternative approach that employs spread-spectrum excitation to enable the development of a small, low-cost, dual-wavelength system using vertical-cavity surface-emitting lasers. Since the optimal wavelengths and drive parameters for optical spectroscopy are not served by commercially available modules as used in our previous single-wavelength demonstration platform, we detail the design of a custom instrument and demonstrate its performance in resolving haemodynamic changes in human subjects during apnoea and cognitive task experiments