Going deeper through the Gleason scoring scale: An automatic end-to-end system for histology prostate grading and cribriform pattern detection

[EN] Background and Objective: Prostate cancer is one of the most common diseases affecting men worldwide. The Gleason scoring system is the primary diagnostic and prognostic tool for prostate cancer. Further-more, recent reports indicate that the presence of patterns of the Gleason scale such as the cribriform pattern may also correlate with a worse prognosis compared to other patterns belonging to the Glea-son grade 4. Current clinical guidelines have indicated the convenience of highlight its presence during the analysis of biopsies. All these requirements suppose a great workload for the pathologist during the analysis of each sample, which is based on the pathologist's visual analysis of the morphology and or-ganisation of the glands in the tissue, a time-consuming and subjective task. In recent years, with the development of digitisation devices, the use of computer vision techniques for the analysis of biopsies has increased. However, to the best of the authors' knowledge, the development of algorithms to automatically detect individual cribriform patterns belonging to Gleason grade 4 has not yet been studied in the literature. The objective of the work presented in this paper is to develop a deep-learning-based system able to support pathologists in the daily analysis of prostate biopsies. This analysis must include the Gleason grading of local structures, the detection of cribriform patterns, and the Gleason scoring of the whole biopsy. Methods: The methodological core of this work is a patch-wise predictive model based on convolutional neural networks able to determine the presence of cancerous patterns based on the Gleason grading system. In particular, we train from scratch a simple self-design architecture with three filters and a top model with global-max pooling. The cribriform pattern is detected by retraining the set of filters of the last convolutional layer in the network. Subsequently, a biopsy-level prediction map is reconstructed by bi-linear interpolation of the patch-level prediction of the Gleason grades. In addition, from the re-constructed prediction map, we compute the percentage of each Gleason grade in the tissue to feed a multi-layer perceptron which provides a biopsy-level score. Results: In our SICAPv2 database, composed of 182 annotated whole slide images, we obtained a Cohen's quadratic kappa of 0.77 in the test set for the patch-level Gleason grading with the proposed architec-ture trained from scratch. Our results outperform previous ones reported in the literature. Furthermore, this model reaches the level of fine-tuned state-of-the-art architectures in a patient-based four groups cross validation. In the cribriform pattern detection task, we obtained an area under ROC curve of 0.82. Regarding the biopsy Gleason scoring, we achieved a quadratic Cohen's Kappa of 0.81 in the test subset. Shallow CNN architectures trained from scratch outperform current state-of-the-art methods for Gleason grades classification. Our proposed model is capable of characterising the different Gleason grades in prostate tissue by extracting low-level features through three basic blocks (i.e. convolutional layer + max pooling). The use of global-max pooling to reduce each activation map has shown to be a key factor for reducing complexity in the model and avoiding overfitting. Regarding the Gleason scoring of biopsies, a multi-layer perceptron has shown to better model the decision-making of pathologists than previous simpler models used in the literature.This work was supported by the Spanish Ministry of Economy and Competitiveness through project DPI2016-77869. The Titan V used for this research was donated by the NVIDIA Corporation.Silva-Rodríguez, J.; Colomer, A.; Sales, MA.; Molina, R.; Naranjo Ornedo, V. (2020). Going deeper through the Gleason scoring scale: An automatic end-to-end system for histology prostate grading and cribriform pattern detection. Computer Methods and Programs in Biomedicine. 195:1-18. https://doi.org/10.1016/j.cmpb.2020.105637S118195Gordetsky, J., & Epstein, J. (2016). Grading of prostatic adenocarcinoma: current state and prognostic implications. Diagnostic Pathology, 11(1). doi:10.1186/s13000-016-0478-2Epstein, J. I., Egevad, L., Amin, M. B., Delahunt, B., Srigley, J. R., & Humphrey, P. A. (2016). The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. American Journal of Surgical Pathology, 40(2), 244-252. doi:10.1097/pas.0000000000000530Sharma, M., & Miyamoto, H. (2018). Percent Gleason pattern 4 in stratifying the prognosis of patients with intermediate-risk prostate cancer. Translational Andrology and Urology, 7(S4), S484-S489. doi:10.21037/tau.2018.03.20Kweldam, C. F., van der Kwast, T., & van Leenders, G. J. (2018). On cribriform prostate cancer. Translational Andrology and Urology, 7(1), 145-154. doi:10.21037/tau.2017.12.33Remotti, H. (2012). Tissue Microarrays: Construction and Use. Pancreatic Cancer, 13-28. doi:10.1007/978-1-62703-287-2_2KHOUJA, M. H., BAEKELANDT, M., SARAB, A., NESLAND, J. M., & HOLM, R. (2010). Limitations of tissue microarrays compared with whole tissue sections in survival analysis. Oncology Letters, 1(5), 827-831. doi:10.3892/ol_00000145Gertych, A., Ing, N., Ma, Z., Fuchs, T. J., Salman, S., Mohanty, S., … Knudsen, B. S. (2015). Machine learning approaches to analyze histological images of tissues from radical prostatectomies. Computerized Medical Imaging and Graphics, 46, 197-208. doi:10.1016/j.compmedimag.2015.08.002Ren, J., Sadimin, E., Foran, D. J., & Qi, X. (2017). Computer aided analysis of prostate histopathology images to support a refined Gleason grading system. 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Tavassoli, D. Turbin, C.F. Villamil, G. Wang, R.S. Wilson, K.A. Iczkowski, M.S. Lucia, P.C. Black, P. Abolmaesumi, S.L. Goldenberg, S.E. Salcudean, Automatic grading of prostate cancer in digitized histopathology images: Learning from multiple experts, 2018. 10.1016/j.media.2018.09.005Nir, G., Karimi, D., Goldenberg, S. L., Fazli, L., Skinnider, B. F., Tavassoli, P., … Salcudean, S. E. (2019). Comparison of Artificial Intelligence Techniques to Evaluate Performance of a Classifier for Automatic Grading of Prostate Cancer From Digitized Histopathologic Images. JAMA Network Open, 2(3), e190442. doi:10.1001/jamanetworkopen.2019.0442García, G., Colomer, A., & Naranjo, V. (2019). First-Stage Prostate Cancer Identification on Histopathological Images: Hand-Driven versus Automatic Learning. Entropy, 21(4), 356. doi:10.3390/e21040356Ma, Y., Jiang, Z., Zhang, H., Xie, F., Zheng, Y., Shi, H., … Shi, J. (2018). Generating region proposals for histopathological whole slide image retrieval. Computer Methods and Programs in Biomedicine, 159, 1-10. doi:10.1016/j.cmpb.2018.02.020Li, W., Li, J., Sarma, K. V., Ho, K. C., Shen, S., Knudsen, B. S., … Arnold, C. W. (2019). Path R-CNN for Prostate Cancer Diagnosis and Gleason Grading of Histological Images. IEEE Transactions on Medical Imaging, 38(4), 945-954. doi:10.1109/tmi.2018.2875868Openseadragon, (http://openseadragon.github.io/), Accessed: 10-07-2018.Cohen, J. (1968). Weighted kappa: Nominal scale agreement provision for scaled disagreement or partial credit. Psychological Bulletin, 70(4), 213-220. doi:10.1037/h0026256Swets, J. A. (1988). Measuring the Accuracy of Diagnostic Systems. Science, 240(4857), 1285-1293. doi:10.1126/science.3287615Kweldam, C. F., Nieboer, D., Algaba, F., Amin, M. B., Berney, D. M., Billis, A., … van Leenders, G. J. L. H. (2016). Gleason grade 4 prostate adenocarcinoma patterns: an interobserver agreement study among genitourinary pathologists. Histopathology, 69(3), 441-449. doi:10.1111/his.1297

Muscarinic receptors participation in angiogenic response induced by macrophages from mammary adenocarcinoma-bearing mice

INTRODUCTION: The role of macrophages in tumor progression has generated contradictory evidence. We had previously demonstrated the ability of peritoneal macrophages from LMM3 murine mammary adenocarcinoma-bearing mice (TMps) to increase the angiogenicity of LMM3 tumor cells, mainly through polyamine synthesis. Here we investigate the ability of the parasympathetic nervous system to modulate angiogenesis induced by TMps through the activation of the muscarinic acetylcholine receptor (mAchR). METHODS: Peritoneal macrophages from female BALB/c mice bearing a 7-day LMM3 tumor were inoculated intradermally (3 × 10(5 )cells per site) into syngeneic mice. Before inoculation, TMps were stimulated with the muscarinic agonist carbachol in the absence or presence of different muscarinic antagonists or enzyme inhibitors. Angiogenesis was evaluated by counting vessels per square millimeter of skin. The expression of mAchR, arginase and cyclo-oxygenase (COX) isoforms was analyzed by Western blotting. Arginase and COX activities were evaluated by urea and prostaglandin E(2 )(PGE(2)) production, respectively. RESULTS: TMps, which stimulate neovascularization, express functional mAchR, because carbachol-treated TMps potently increased new blood vessels formation. This response was completely blocked by preincubating TMps with pirenzepine and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), M(1 )and M(3 )receptor antagonists, and partly by the M(2 )receptor antagonist methoctramine. M(1 )receptor activation by carbachol in TMps triggers neovascularization through arginase products because N(ω)-hydroxy-L-arginine reversed the agonist action. Preincubation of TMps with methoctramine partly prevented carbachol-stimulated urea formation. In addition, COX-derived liberation of PGE(2 )is responsible for the promotion of TMps angiogenic activity by M(3 )receptor. We also detected a higher expression of vascular endothelial growth factor (VEGF) in TMps than in macrophages from normal mice. Carbachol significantly increased VEGF expression in TMps, and this effect was totally reversed by methoctramine and pirenzepine. Arginase and COX inhibitors partly decreased VEGF derived from TMps. CONCLUSION: TMps themselves induce a potent angiogenic response that is augmented by carbachol action. mAchR activation triggers arginine metabolism, PGE(2 )synthesis and VEGF production, promoting neovascularization

Comparative Baseline Levels of Heavy Metals and Histopathological Notes in Fish From two Coastal Ecosystems of South-West of Spain

This work reports the comparative study of heavy metal water concentrations from two coastal ecosystems of Cadiz Gulf (SWSpain): Bay of Cadiz and Ria ofHuelva estuary in samples taken on years 1999-2000. Sampling zones showed different heavymetal levels. Statistical analysis of dissolved trace metal concentrations (Cu, Zn, Cd and Pb) showed significant differences between Huelva and Cadiz zones based on the Cu level, with a marked seasonal factor and different metal sources (Industrial, geological, urban,...), observing a higher Cu concentration in Ria de Huelva respect to Bay of Cadiz. On the other hand, to evaluate the pollutant effects on aquatic biota, a histopathological analysis have been conducted in specimens of flat fish, Solea senegalensis from both zones. Lesions weremore severe in fish fromRia ofHuelva, being themost significant alterations: gill hyperplasia, fusion of secondary lamellae, disorganization of the hepatic parenchyma, cellular hypertrophy and vascular congestion in liver and tubular occlusion, loss of interstitial tissue and lipid-like vacuoles in kidney. Obtained results are useful as reference data for future environmental monitoring studies in these zones where to establish a heavy metal concentration temporal trend would be necessary

Treatment in vitro with PPARα and PPARγ ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice

AbstractTrypanosoma cruzi, the etiological agent of Chagas' disease, induces a persistent inflammatory response. Macrophages are a first line cell phenotype involved in the clearance of infection. Upon parasite uptake, these cells increase inflammatory mediators like NO, TNF-α, IL-1β and IL-6, leading to parasite killing. Although desired, inflammatory response perpetuation and exacerbation may lead to tissue damage. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that, besides regulating lipid and carbohydrate metabolism, have a significant anti-inflammatory effect. This is mediated through the interaction of the receptors with their ligands. PPARγ, one of the PPAR isoforms, has been implicated in macrophage polarization from M1, the classically activated phenotype, to M2, the alternatively activated phenotype, in different models of metabolic disorders and infection. In this study, we show for the first time that, besides PPARγ, PPARα is also involved in the in vitro polarization of macrophages isolated from T. cruzi-infected mice. Polarization was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers like Arginase I, Ym1, mannose receptor and TGF-β. Besides, macrophage phagocytic activity was significantly enhanced, leading to increased parasite load. We suggest that modulation of the inflammatory response by both PPARs might be due, at least in part, to a change in the profile of inflammatory macrophages. The potential use of PPAR agonists as modulators of overt inflammatory response during the course of Chagas' disease deserves further investigation

Cinética de biodegradación de un nonilfenol polietoxilado en agua de río

[ES] En el presente trabajo se aborda el estudio cinético del proceso de biodegradación de uno de los tensioactivos sintéticos más consumidos en el mundo a nivel industrial, los alquilfenoles polietoxilados (APEO), en un medio natural como es el agua de río. El método de ensayo empleado ha sido el "River die away test" y para el análisis de la materia tensioactiva se ha empleado cromatografía líquida de alta resolución. El modelo cinético propuesto por los autores, ha sido aplicado a los datos de biodegradación obtenidos bajo diversas condiciones de temperatura y concentración inicial de materia activa. Los resultados muestran que el modelo se ajusta tanto a situaciones de periodos de inducción breves como prolongados y permite obtener parámetros cinéticos de interés como son, el contenido en substrato no biodegradable y la velocidad máxima de crecimiento microbiano.Manzano Quiñones, MA.; Perales Vargas-Machuca, JA.; Sales Márquez, D.; Quiroga Alonso, JM. (1998). Cinética de biodegradación de un nonilfenol polietoxilado en agua de río. Ingeniería del Agua. 5(3):27-32. https://doi.org/10.4995/ia.1998.2763SWORD273253Bayley, J. y Ollis, D. (1980) Biochemical Engineering Fundamentals. Ed. McGraw Hill.Gaden, E. (1959) Fermentation process kinetics. J. Biochem. Microbiol. Tech. Eng, 1. pp 63-70Larson, R. y Payne, A. (1981) Fate of the benzene ring of linear alkylbenzene sulfonate in natural waters. Appl. Environ. Microbiol, 41, 3, pp 621 -627.Okpokwasili, G.C. y Olisa, A.O. (1991) River-water biodegradation of surfactants in liquid detergents and shampoos. Water Research, 25.11, pp 1425-1429.Quiroga, J.M. y Sales, D. (1989) Ensayos de degradación con cepas puras de microorganismos. Ingeniería Química. Junio, pp 179-183.Quiroga, J.M. y Sales, D. (1991) Surfactant biodegradation in sea water. Tenside Surfactants Detergents, 28, 3, pp 200-203.Raymond, A. (1996) The global outlook for surfactant from a U.S. perspective. 4th World Surfactant Congress, Vol. 1, pp 21-36.Romero, L.; Perez, M.; Sales, D. (1997) Degradation kinetics of distillery wastewaters by immobilized anaerobic mixed cultures. The 8th International Conference on Anaerobic Digestion (AD-97). IAWQ. Japan, May.Schröder, H, Fr. (1993) Surfactants: non-biodegradable, significant pollutants in sewage treatment plant effluents. Journal of Chromatography, 647, pp 219-234.Sivak, A., Goyer, M. y Perwak, J. (1982) Environmental and human aspects of commercially important surfactants. Solution behaviour of surfactants. Ed. Plenum Publishing Corp.Vol 1, pp 161-188.Wang, Z. y Fingas, M. (1993) Rapid separation of non-ionic surfactants of polyethoxylated octylphenol and determination of ethylene oxide oligomer distribution by C1 column reversed-phase liquid chromatography. Journal of Chromatography, 637, pp 145-156.Yoshimura, K. (1986) Biodegradation and fish toxicity of nonionic surfactants. Japan Surface Active Agent Association. 63, 12, pp 1590-159

Temperature effects on energy production by salinity exchange

This is an unedited version of this paper. The publisher version can be reached in this URL: http://pubs.acs.org/doi/abs/10.1021/es500634fIn recent years, the capacitance of the interface between charged electrodes and ionic solutions (the electric double layer) has been investigated as a source of clean energy. Charge is placed on the electrodes either by means of ion-exchange membranes or of an external power source. In the latter method, net energy is produced by simple solution exchange in open circuit, due to the associated decrease in the capacitance of the electric double layer. In this work, we consider the change in capacitance associated with temperature variations: the former decreases when temperature is raised, and, hence, a cycle is possible in which some charge is put on the electrode at a certain potential and returned at a higher one. We demonstrate experimentally that it is thus viable to obtain energy from electric double layers if these are successively contacted with water at different temperatures. In addition, we show theoretically and experimentally that temperature and salinity variations can be conveniently combined to maximize the electrode potential increase. The resulting available energy is also estimated.Departamento de Física AplicadaThe research leading to these results received funding from the European Union 7th Frame-work Programme (FP7/2007-2013) under agreement No. 256868. Further Financial supports from Junta de Andalucía, project FQM 694, and Ministerio de Economía y Competitividad (Spain), project FIS2013-47666-C3-1-R

Metric analysis of the information visibility and diffusion about the European Higher Education Area on Spanish university websites.

The purpose of the study proposed in this paper is to evaluate the Spanish public university websites dedicated to the European Higher Education Area (EHEA). To do so, the quality of these resources has been analysed in the light of data provided by a series of indicators grouped in seven criteria, most of which were used to determine what information is made available and in what way. The criteria used in our analysis are: visibility, authority, updatedness, accesibility, correctness and completeness, quality assessment and navigability. All in all, the results allow us to carry out an overall diagnosis of the situation and also provide us with information about the situation at each university, thus revealing their main strengths, namely authority and navegability, and also their chief shortcomings: updatedness, accessibility and quality assessment. In this way it is possible to detect the best practices in each of the aspects evaluated so that they can serve as an example and guide for universities with greater deficiencies and thus help them to improve their EHEA websites

Effect of Solution Composition on the Energy Production by Capacitive Mixing in Membrane-Electrode Assembly

The final edited version of the paper can be found at: http://pubs.acs.org/articlesonrequest/AOR-c9UMxSzGY3eiU5SENNgT The complete citation is: Ahualli, S.; et al. Effect of Solution Composition on the Energy Production by Capacitive Mixing in Membrane-Electrode Assembly. Journal of Physical Chemistry, 118(29): 15590-15599 (2014). DOI:10.1021/jp504461mOpen access in the Journal on May 26, 2015In this work we consider the extent to which the presence of multi-valent ions in solution modifies the equilibrium and dynamics of the energy production in a capacitive cell built with ion-exchange membranes in contact with high surface area electrodes. The cell potential in open circuit (OCV) is controlled by the difference between both membrane potentials, simulated as constant volume charge regions. A theoretical model is elaborated for steady state OCV, first in the case of monovalent solutions, as a reference. This is compared to the results in multi-ionic systems, containing divalent cations in concentrations similar to those in real sea water. It is found that the OCV is reduced by about 25 % (as compared to the results in pure NaCl solutions) due to the presence of the divalent ions, even in low concentrations. Interestingly, this can be related to the “uphill” transport of such ions against their concentration gradients. On the contrary, their effect on the dynamics of the cell potential is negligible in the case of highly charged membranes. The comparison between model predictions and experimental results shows a very satisfactory agreement, and gives clues for the practical application of these recently introduced energy production methods.The research leading to these results received funding from the European Union 7th Framework Programme (FP7/2007-2013) under agreement No. 256868. Further financial support from Junta de Andalucia, Spain (PE2012-FQM 694) is also acknowledged. One of us, M.M.F., received financial support throughan FPU grant from the Universityof Granada

Informe Científico-Técnico: Nuevo sistema para la reducción del impacto de la pesca de arrastre de fondo en las costas españolas del Mediterráneo

Se presentan los resultados de un proyecto de desarrollo de un sistema de arte de arrastre alternativo, basado en el uso de unas puertas que no contactan con el fondo marino y que no implican ninguna otra modificación en el resto del arte de pesca. Del 4 Abril 2011 al 18 Mayo 2011 se llevó a cabo una campaña piloto, a bordo del B/P Nueva Joven Josefina, en aguas del Menorca (Islas Baleares). Durante la misma se realizaron un total de 43 pescas comerciales de arrastre de fondo entre 124 y 669 m de profundidad, 20 con un arte tradicional y 23 con un arte experimental, que a diferencia del anterior llevaba puertas Thyboron Tipo 15VFS, unidas a las malletas mediante cable y cadenas de 175 kg. La geometría de la red y el consumo de combustible se estimaron con sensores ITI y caudalimetros, integrados en el sistema SDR-10. Además se calcularon los rendimientos comerciales y los descartes, así como las distribuciones de tallas de las principales especies capturadas. Se capturaron un total de 213433 ejemplares correspondientes a 192 especies o categorías comerciales, con un peso de 5781 kg, de los cuales 3712 kg (64%) fueron captura comercial y 2069 kg (36%) descartes. Se midieron un total 29493 ejemplares de 109 especies. El arte experimental no ha mostrado diferencias significativas respecto del arte tradicional, por lo que se refiere a las maniobras de pesca comerciales, la composición de la captura total, los rendimientos de las principales especies comerciales y los descartes. Las distribuciones de tallas de estas especies tampoco han mostrado un patrón claro que diferencie los dos artes comparados. Dónde sí se han observado diferencias ha sido en el consumo de combustible, ya que con el arte experimental se ha reducido un 14% en la plataforma y un 4% en el talud, manteniendo e incluso aumentando las dimensiones del aparejo trabajando sobre el fondo. Un aspecto, este último, que puede conllevar un incremento del área barrida y, por tanto, del esfuerzo efectivo de pesca respecto al arte tradicional, y que será necesario gestionar/limitar en caso de que el uso de este tipo de puertas se extienda. Este cambio realizado con el arte experimental, unido a otras posibles modificaciones, muestran la posibilidad de seguir mejorando la pesquería de arrastre de fondo, con el objetivo de intentar hacerla ecológica y económicamente sostenible. Los resultados del presente proyecto han sido difundidos al sector pesquero de las Islas Baleares y, en general, a través de los medios de comunicació