Intravenously Administered Alphavirus Vector VA7 Eradicates Orthotopic Human Glioma Xenografts in Nude Mice

VA7 is a neurotropic alphavirus vector based on an attenuated strain of Semliki Forest virus. We have previously shown that VA7 exhibits oncolytic activity against human melanoma xenografts in immunodeficient mice. The purpose of this study was to determine if intravenously administered VA7 would be effective against human glioma.In vitro, U87, U251, and A172 human glioma cells were infected and killed by VA7-EGFP. In vivo, antiglioma activity of VA7 was tested in Balb/c nude mice using U87 cells stably expressing firefly luciferase in subcutaneous and orthotopic tumor models. Intravenously administered VA7-EGFP completely eradicated 100% of small and 50% of large subcutaneous U87Fluc tumors. A single intravenous injection of either VA7-EGFP or VA7 expressing Renilla luciferase (VA7-Rluc) into mice bearing orthotopic U87Fluc tumors caused a complete quenching of intracranial firefly bioluminescence and long-term survival in total 16 of 17 animals. In tumor-bearing mice injected with VA7-Rluc, transient intracranial and peripheral Renilla bioluminescence was observed. Virus was well tolerated and no damage to heart, liver, spleen, or brain was observed upon pathological assessment at three and ninety days post injection, despite detectable virus titers in these organs during the earlier time point.VA7 vector is apathogenic and can enter and destroy brain tumors in nude mice when administered systemically. This study warrants further elucidation of the mechanism of tumor destruction and attenuation of the VA7 virus

The type of the functional cardiovascular response to upright posture is associated with arterial stiffness: a cross-sectional study in 470 volunteers

Background: In a cross-sectional study we examined whether the haemodynamic response to upright posture could be divided into different functional phenotypes, and whether the observed phenotypes were associated with known determinants of cardiovascular risk.Methods: Volunteers (n = 470) without medication with cardiovascular effects were examined using radial pulse wave analysis, whole-body impedance cardiography, and heart rate variability analysis. Based on the passive head-up tilt induced changes in systemic vascular resistance and cardiac output, the principal determinants of blood pressure, a cluster analysis was performed.Results: The haemodynamic response could be clustered into 3 categories: upright increase in vascular resistance and decrease in cardiac output were greatest in the first (+ 45 % and -27 %, respectively), smallest in the second (+ 2 % and -2 %, respectively), and intermediate (+ 22 % and -13 %, respectively) in the third group. These groups were named as 'constrictor' (n = 109), 'sustainer' (n = 222), and 'intermediate' (n = 139) phenotypes, respectively. The sustainers were characterized by male predominance, higher body mass index, blood pressure, and also by higher pulse wave velocity, an index of large arterial stiffness, than the other groups (p < 0.01 for all). Heart rate variability analysis showed higher supine and upright low frequency/high frequency (LF/HF) ratio in the sustainers than constrictors, indicating increased sympathovagal balance. Upright LF/HF ratio was also higher in the sustainer than intermediate group. In multivariate analysis, independent explanatory factors for higher pulse wave velocity were the sustainer (p < 0.022) and intermediate phenotypes (p < 0.046), age (p < 0.001), body mass index (p < 0.001), and hypertension (p < 0.001).Conclusions: The response to upright posture could be clustered to 3 functional phenotypes. The sustainer phenotype, with smallest upright decrease in cardiac output and highest sympathovagal balance, was independently associated with increased large arterial stiffness. These results indicate an association of the functional haemodynamic phenotype with an acknowledged marker of cardiovascular risk

Exploring earned value management in the Spanish construction industry as a pathway to competitive advantage

[EN] As a well established discipline and profession, project management has its distinctive tools and techniques. One of them that has been considered the embodiment of the core principles of project management is the Earned Value Management (EVM). In managing construction projects, the EVM has been considered as a suitable tool and hence, has been implemented in various construction industry but absent in some others. Taking into account the dynamic environment where construction companies have to operate, particularly in turbulence environments as the direct result of recent global economic downturn, this paper explores the potential implementation of EVM in one of the construction industry, the Spanish construction industry. The outcomes confirm the needs for and feasibility of implementing EVM as a structured approach in the industry to reposition the Spanish construction industry with the long term view to increase its project management maturity level as a pathway to gaining competitive advantage.Universitat Politecnica de Valencia [grant number 19701344]Sutrisna, M.; Pellicer, E.; Torres-Machí, C.; Picornell, M. (2018). Exploring earned value management in the Spanish construction industry as a pathway to competitive advantage. International Journal of Construction Management. 20(1):1-12. https://doi.org/10.1080/15623599.2018.1459155S112201Anbari, F. T. (2004). Earned value project management method and extensions. IEEE Engineering Management Review, 32(3), 97-97. doi:10.1109/emr.2004.25113Aram, J. D., & Walochik, K. (1996). Improvisation and the Spanish Manager. International Studies of Management & Organization, 26(4), 73-89. doi:10.1080/00208825.1996.11656695Brandon, D. M. (1998). Implementing Earned Value Easily and Effectively. Project Management Journal, 29(2), 11-18. doi:10.1177/875697289802900204Brown, A., & Adams, J. (2000). Measuring the effect of project management on construction outputs: a new approach. International Journal of Project Management, 18(5), 327-335. doi:10.1016/s0263-7863(99)00026-5Bryde, D. J. (2003). Modelling project management performance. International Journal of Quality & Reliability Management, 20(2), 229-254. doi:10.1108/02656710310456635Chen, H. L., Chen, W. T., & Lin, Y. L. (2016). Earned value project management: Improving the predictive power of planned value. International Journal of Project Management, 34(1), 22-29. doi:10.1016/j.ijproman.2015.09.008De la Cruz, M. P., del Caño, A., & de la Cruz, E. (2006). Downside Risks in Construction Projects Developed by the Civil Service: The Case of Spain. Journal of Construction Engineering and Management, 132(8), 844-852. doi:10.1061/(asce)0733-9364(2006)132:8(844)Din, S., Abd-Hamid, Z., & Bryde, D. J. (2011). ISO 9000 certification and construction project performance: The Malaysian experience. International Journal of Project Management, 29(8), 1044-1056. doi:10.1016/j.ijproman.2010.11.001Eldin, N. N. (1989). Measurement of Work Progress: Quantitative Technique. Journal of Construction Engineering and Management, 115(3), 462-474. doi:10.1061/(asce)0733-9364(1989)115:3(462)Gidado, K. I. (1996). Project complexity: The focal point of construction production planning. Construction Management and Economics, 14(3), 213-225. doi:10.1080/014461996373476Hastak, M., Halpin, D. W., & Vanegas, J. (1996). COMPASS—New Paradigm for Project Cost Control Strategy and Planning. Journal of Construction Engineering and Management, 122(3), 254-264. doi:10.1061/(asce)0733-9364(1996)122:3(254)D. Holt, G., & S. Goulding, J. (2014). Conceptualisation of ambiguous-mixed-methods within building and construction research. Journal of Engineering, Design and Technology, 12(2), 244-262. doi:10.1108/jedt-02-2013-0020Ibbs, C. W., & Kwak, Y. H. (2000). Assessing Project Management Maturity. Project Management Journal, 31(1), 32-43. doi:10.1177/875697280003100106Jugdev, K., & Thomas, J. (2002). 2002 Student Paper Award Winner: Project Management Maturity Models: The Silver Bullets of Competitive Advantage? Project Management Journal, 33(4), 4-14. doi:10.1177/875697280203300402Kim, E., Wells, W. G., & Duffey, M. R. (2003). A model for effective implementation of Earned Value Management methodology. International Journal of Project Management, 21(5), 375-382. doi:10.1016/s0263-7863(02)00049-2Kim, T., Kim, Y.-W., & Cho, H. (2016). Customer Earned Value: Performance Indicator from Flow and Value Generation View. Journal of Management in Engineering, 32(1), 04015017. doi:10.1061/(asce)me.1943-5479.0000377Laufer, A., & Tucker, R. L. (1987). Is construction project planning really doing its job? A critical examination of focus, role and process. Construction Management and Economics, 5(3), 243-266. doi:10.1080/01446198700000023Liberatore, M. J., Pollack-Johnson, B., & Smith, C. A. (2001). Project Management in Construction: Software Use and Research Directions. Journal of Construction Engineering and Management, 127(2), 101-107. doi:10.1061/(asce)0733-9364(2001)127:2(101)Mir, F. A., & Pinnington, A. H. (2014). Exploring the value of project management: Linking Project Management Performance and Project Success. International Journal of Project Management, 32(2), 202-217. doi:10.1016/j.ijproman.2013.05.012Navon, R., & Haskaya, I. (2006). Is detailed progress monitoring possible without designated manual data collection? Construction Management and Economics, 24(12), 1225-1229. doi:10.1080/01446190600999097Onwuegbuzie, A. J., & Leech, N. L. (2005). Taking the «Q» Out of Research: Teaching Research Methodology Courses Without the Divide Between Quantitative and Qualitative Paradigms. Quality & Quantity, 39(3), 267-295. doi:10.1007/s11135-004-1670-0Oviedo-Haito, R. J., Jiménez, J., Cardoso, F. F., & Pellicer, E. (2014). Survival Factors for Subcontractors in Economic Downturns. Journal of Construction Engineering and Management, 140(3), 04013056. doi:10.1061/(asce)co.1943-7862.0000811Pellicer, E., Sanz, M. A., Esmaeili, B., & Molenaar, K. R. (2016). Exploration of Team Integration in Spanish Multifamily Residential Building Construction. Journal of Management in Engineering, 32(5), 05016012. doi:10.1061/(asce)me.1943-5479.0000438Potts, K., & Ankrah, N. (2008). Construction Cost Management. doi:10.4324/9780203933015Vanhoucke, M. (2012). Project Management with Dynamic Scheduling. doi:10.1007/978-3-642-25175-7Yazici, H. J. (2009). The Role of Project Management Maturity and Organizational Culture in Perceived Performance. Project Management Journal, 40(3), 14-33. doi:10.1002/pmj.20121Yu, A. G., Flett, P. D., & Bowers, J. A. (2005). Developing a value-centred proposal for assessing project success. International Journal of Project Management, 23(6), 428-436. doi:10.1016/j.ijproman.2005.01.00

Genetic Associations and Architecture of Asthma-COPD Overlap

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field