KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis

KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium–specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer

Quantitative analysis of dribble volumes and rates using three-dimensional reconstruction of X-ray and diffused back-illumination images of diesel sprays

[EN] Post-injection fuel dribble is known to lead to incomplete atomisation and combustion due to the release of slow-moving, and often surface-bound, liquid fuel after the end of injection. This can have a negative effect on engine emissions, performance and injector durability. To better quantify this phenomenon, we developed an image-processing approach to measure the volume of ligaments produced during the end of injection. We applied our processing approach to an Engine Combustion Network 'Spray B' 3-hole injector, using datasets from 220 injections generated by different research groups, to decouple the effect of gas temperature and pressure on the fuel dribble process. High-speed X-ray phase-contrast images obtained at room temperature conditions (297 K) at the Advanced Photon Source at Argonne National Laboratory, together with diffused back-illumination images captured at a wide range of temperature conditions (293-900 K) by CMT Motores Termicos were analysed and compared quantitatively. We found a good agreement between image sets obtained by Argonne National Laboratory and CMT Motores Termicos using different imaging techniques. The maximum dribble volume within the field of view of the imaging system and the mean rate of fuel dribble were considered as characteristic parameters of the fuel dribble process. Analysis showed that the absolute mean dribble rate increases with temperature when injection pressure is higher than 1000 bar and slightly decreases at high injection pressures (>500 bar) when temperature is close to 293 K. Larger maximum volumes of the fuel dribble were observed at lower gas temperatures (similar to 473 K) and low gas pressures (<30 bar), with a slight dependence on injection pressure.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The image processing research was supported by the United Kingdom's Engineering and Physical Science Research Council (Grants EP/K020528/1 and EP/M009424/1) and BP Formulated Products Technology. The X-ray measurements were performed at the Advanced Photon Source at Argonne National Laboratory. Use of the Advanced Photon Source (APS) is supported by the U.S. Department of Energy (DOE) under Contract No. DEAC02-06CH11357. The X-ray component of this research was partially funded by DOE's Vehicle Technologies Program, Office of Energy Efficiency and Renewable Energy.Sechenyh, V.; Duke, DJ.; Swantek, AB.; Matusik, KE.; Kastengren, AL.; Powell, CF.; Viera, A.... (2020). Quantitative analysis of dribble volumes and rates using three-dimensional reconstruction of X-ray and diffused back-illumination images of diesel sprays. International Journal of Engine Research. 21(1):43-54. https://doi.org/10.1177/1468087419860955S4354211Örley, F., Hickel, S., Schmidt, S. J., & Adams, N. A. (2016). Large-Eddy Simulation of turbulent, cavitating fuel flow inside a 9-hole Diesel injector including needle movement. International Journal of Engine Research, 18(3), 195-211. doi:10.1177/1468087416643901Benajes, J., Novella, R., De Lima, D., & Tribotté, P. (2014). Analysis of combustion concepts in a newly designed two-stroke high-speed direct injection compression ignition engine. International Journal of Engine Research, 16(1), 52-67. doi:10.1177/1468087414562867Moon, S., Huang, W., Li, Z., & Wang, J. (2016). End-of-injection fuel dribble of multi-hole diesel injector: Comprehensive investigation of phenomenon and discussion on control strategy. Applied Energy, 179, 7-16. doi:10.1016/j.apenergy.2016.06.116Kook, S., Pickett, L. M., & Musculus, M. P. B. (2009). Influence of Diesel Injection Parameters on End-of-Injection Liquid Length Recession. SAE International Journal of Engines, 2(1), 1194-1210. doi:10.4271/2009-01-1356Kastengren, A., Powell, C. F., Tilocco, F. Z., Liu, Z., Moon, S., Zhang, X., & Gao, J. (2012). End-of-Injection Behavior of Diesel Sprays Measured With X-Ray Radiography. Journal of Engineering for Gas Turbines and Power, 134(9). doi:10.1115/1.4006981Manin, J., Bardi, M., Pickett, L. M., & Payri, R. (2016). Boundary condition and fuel composition effects on injection processes of high-pressure sprays at the microscopic level. International Journal of Multiphase Flow, 83, 267-278. doi:10.1016/j.ijmultiphaseflow.2015.12.001Payri, R., Bracho, G., Marti-Aldaravi, P., & Viera, A. (2017). NEAR FIELD VISUALIZATION OF DIESEL SPRAY FOR DIFFERENT NOZZLE INCLINATION ANGLES IN NON-VAPORIZING CONDITIONS. Atomization and Sprays, 27(3), 251-267. doi:10.1615/atomizspr.2017017949Gimeno, J., Martí-Aldaraví, P., Carreres, M., & Peraza, J. E. (2018). Effect of the nozzle holder on injected fuel temperature for experimental test rigs and its influence on diesel sprays. International Journal of Engine Research, 19(3), 374-389. doi:10.1177/1468087417751531Payri, R., Salvador, F. J., Manin, J., & Viera, A. (2016). Diesel ignition delay and lift-off length through different methodologies using a multi-hole injector. Applied Energy, 162, 541-550. doi:10.1016/j.apenergy.2015.10.118Duke, D. J., Matusik, K. E., Kastengren, A. L., Swantek, A. B., Sovis, N., Payri, R., … Powell, C. F. (2017). X-ray radiography of cavitation in a beryllium alloy nozzle. International Journal of Engine Research, 18(1-2), 39-50. doi:10.1177/1468087416685965Duke, D., Swantek, A., Kastengren, A., Fezzaa, K., & Powell, C. (2015). Recent Developments in X-ray Diagnostics for Cavitation. SAE International Journal of Fuels and Lubricants, 8(1), 135-146. doi:10.4271/2015-01-0918Walko, D. A., Adams, B. W., Doumy, G., Dufresne, E. M., Li, Y., March, A. M., … Zhu, Y. (2016). Developments in time-resolved x-ray research at APS beamline 7ID. doi:10.1063/1.4952871Fessler, J. A., & Macovski, A. (1991). Object-based 3-D reconstruction of arterial trees from magnetic resonance angiograms. IEEE Transactions on Medical Imaging, 10(1), 25-39. doi:10.1109/42.75608Canny, J. (1986). A Computational Approach to Edge Detection. IEEE Transactions on Pattern Analysis and Machine Intelligence, PAMI-8(6), 679-698. doi:10.1109/tpami.1986.4767851Kastengren, A. L., Tilocco, F. Z., Duke, D. J., Powell, C. F., Zhang, X., & Moon, S. (2014). TIME-RESOLVED X-RAY RADIOGRAPHY OF SPRAYS FROM ENGINE COMBUSTION NETWORK SPRAY A DIESEL INJECTORS. Atomization and Sprays, 24(3), 251-272. doi:10.1615/atomizspr.2013008642Edelsbrunner, H., & Mücke, E. P. (1994). Three-dimensional alpha shapes. ACM Transactions on Graphics, 13(1), 43-72. doi:10.1145/174462.156635Lafarge, T., Pateiro-López, B., Possolo, A., & Dunkers, J. P. (2014). RImplementation of a Polyhedral Approximation to a 3D Set of Points Using theα-Shape. Journal of Statistical Software, 56(4). doi:10.18637/jss.v056.i04Koci, C., Dempsey, A., Nudd, J., & Knier, B. (2017). Understanding Hydrocarbon Emissions in Heavy Duty Diesel Engines Combining Experimental and Computational Methods. SAE International Journal of Engines, 10(3), 1093-1109. doi:10.4271/2017-01-070

Calibration and Characterization of the IceCube Photomultiplier Tube

Over 5,000 PMTs are being deployed at the South Pole to compose the IceCube neutrino observatory. Many are placed deep in the ice to detect Cherenkov light emitted by the products of high-energy neutrino interactions, and others are frozen into tanks on the surface to detect particles from atmospheric cosmic ray showers. IceCube is using the 10-inch diameter R7081-02 made by Hamamatsu Photonics. This paper describes the laboratory characterization and calibration of these PMTs before deployment. PMTs were illuminated with pulses ranging from single photons to saturation level. Parameterizations are given for the single photoelectron charge spectrum and the saturation behavior. Time resolution, late pulses and afterpulses are characterized. Because the PMTs are relatively large, the cathode sensitivity uniformity was measured. The absolute photon detection efficiency was calibrated using Rayleigh-scattered photons from a nitrogen laser. Measured characteristics are discussed in the context of their relevance to IceCube event reconstruction and simulation efforts.Comment: 40 pages, 12 figure

Linking Customer Interaction and Innovation: The Mediating Role of New Organizational Practices

The notion that firms can improve their innovativeness by tapping users and customers for knowledge has become prominent in innovation studies. Similar arguments have been made in the marketing literature. We argue that neither literatures take sufficient account of firm organization. Specifically, firms that attempt to leverage user and customer knowledge in the context of innovation must design an internal organization appropriate to support it. This can be achieved in particular through the use of new organizational practices, notably, intensive vertical and lateral communication, rewarding employees for sharing and acquiring knowledge, and high levels of delegation of decision rights. In this paper, six hypotheses were developed and tested on a data set of 169 Danish firms drawn from a 2001 survey of the 1,000 largest firms in Denmark. A key result is that the link from customer knowledge to innovation is completely mediated by organizational practices

Prevalence of overweight and obesity in children aged 6–13 years—alarming increase in obesity in Cracow, Poland

This study in children aged 6–13 years (n = 1,499) was performed between October 2008 and March 2009. Height and weight measurements were taken to calculate BMI. The prevalence of overweight and obesity was determined by means of IOTF cut-offs with respect to age. Alarming is the fact that the percentage of obese children in Cracow increased dramatically from 1.04% in boys and 0.20% in girls in 1971 to 7% in boys and 3.6% in girls in 2009. In this report, a higher percentage of overweight boys was observed in rural boys (28.14%) than in urban ones (27.31%). Obesity was identified in an almost twice as high percentage of urban boys (7.78%) as in rural ones (3.52%). A higher percentage of overweight girls was registered in rural areas (16.49%) than in urban ones (16.09%). Obesity was prevailing in rural girls (4.12%) relative to their urban counterparts (3.44%). The highest number of overweight urban boys was diagnosed in the group of 12-year-olds (n = 48) and rural boys in the group of 10-year-olds (n = 39), as well as in urban girls aged 11 (n = 17) and rural girls aged 9 (n = 9). The highest number of obesity was observed in rural boys aged 12 (n = 3) and in urban boys aged 9 and 10 (n = 9 in both groups). In the group of girls, obesity prevailed in urban 9-year-olds (n = 5) and in rural 7-year-olds (n = 5). Conclusions: Overweight and obesity affect boys almost twice as frequently as girls. Obesity is twice as frequent in urban boys as in their rural peers

Measurement and comparison of individual external doses of high-school students living in Japan, France, Poland and Belarus -- the "D-shuttle" project --

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter "D-shuttle" for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the background radiation level of other regions/countries

M-health and health promotion: the digital cyborg and surveillance society

The new mobile wireless computer technologies and social media applications using Web 2.0 platforms have recently received attention from those working in health promotion as a promising new way of achieving their goals of preventing ill-health and promoting healthy behaviours at the population level. There is very little critical examination in this literature of how the use of these digital technologies may affect the targeted groups, in terms of the implications for how individuals experience embodiment, selfhood and social relationships. This article addresses these issues, employing a range of social and cultural theories to do so. It is argued that m-health technologies produce a digital cyborg body. They are able to act not only as prostheses but also as interpreters of the body. The subject produced through the use of m-health technologies is constructed as both an object of surveillance and persuasion and as a responsible citizen who is willing and able to act on the health imperatives issuing forth from the technologies and to present their body/self as open to continual measurement and assessment. The implications of this new way of surveilling the body’s health are discussed

Loss of the Urothelial Differentiation Marker FOXA1 Is Associated with High Grade, Late Stage Bladder Cancer and Increased Tumor Proliferation

Approximately 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastatic disease, which is almost invariably lethal. However, our understanding of pathways that drive aggressive behavior of MIBC is incomplete. Members of the FOXA subfamily of transcription factors are implicated in normal urogenital development and urologic malignancies. FOXA proteins are implicated in normal urothelial differentiation, but their role in bladder cancer is unknown. We examined FOXA expression in commonly used in vitro models of bladder cancer and in human bladder cancer specimens, and used a novel in vivo tissue recombination system to determine the functional significance of FOXA1 expression in bladder cancer. Logistic regression analysis showed decreased FOXA1 expression is associated with increasing tumor stage (p<0.001), and loss of FOXA1 is associated with high histologic grade (p<0.001). Also, we found that bladder urothelium that has undergone keratinizing squamous metaplasia, a precursor to the development of squamous cell carcinoma (SCC) exhibited loss of FOXA1 expression. Furthermore, 81% of cases of SCC of the bladder were negative for FOXA1 staining compared to only 40% of urothelial cell carcinomas. In addition, we showed that a subpopulation of FOXA1 negative urothelial tumor cells are highly proliferative. Knockdown of FOXA1 in RT4 bladder cancer cells resulted in increased expression of UPK1B, UPK2, UPK3A, and UPK3B, decreased E-cadherin expression and significantly increased cell proliferation, while overexpression of FOXA1 in T24 cells increased E-cadherin expression and significantly decreased cell growth and invasion. In vivo recombination of bladder cancer cells engineered to exhibit reduced FOXA1 expression with embryonic rat bladder mesenchyme and subsequent renal capsule engraftment resulted in enhanced tumor proliferation. These findings provide the first evidence linking loss of FOXA1 expression with histological subtypes of MIBC and urothelial cell proliferation, and suggest an important role for FOXA1 in the malignant phenotype of MIBC