Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic

Metallothionein genes: no association with Crohn's disease in a New Zealand population

Metallothioneins (MTs) are excellent candidate genes for Inflammatory Bowel Disease (IBD) and have previously been shown to have altered expression in both animal and human studies of IBD. This is the first study to examine genetic variants within the MT genes and aims to determine whether such genetic variants have an important role in this disease. 28 tag SNPs in genes MT1 (subtypes A, B, E, F, G, H, M, X), MT2, MT3 and MT4 were selected for genotyping in a well-characterized New Zealand dataset consisting of 406 patients with Crohn's Disease and 638 controls. We did not find any evidence of association for MT genetic variation with CD. The lack of association indicates that genetic variants in the MT genes do not play a significant role in predisposing to CD in the New Zealand population

Transgressive phenotypes and generalist pollination in the floral evolution of Nicotiana polyploids

This is the author's proofThe file attached is the Accepted/final draft post-refereeing version of the article. 6 month embargo now lapsed

Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

PPARα L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males

<p>Abstract</p> <p>Background</p> <p>Of the five sub-phenotypes defining metabolic syndrome, all are known to have strong genetic components (typically 50–80% of population variation). Studies defining genetic predispositions have typically focused on older populations with metabolic syndrome and/or type 2 diabetes. We hypothesized that the study of younger populations would mitigate many confounding variables, and allow us to better define genetic predisposition loci for metabolic syndrome.</p> <p>Methods</p> <p>We studied 610 young adult volunteers (average age 24 yrs) for metabolic syndrome markers, and volumetric MRI of upper arm muscle, bone, and fat pre- and post-unilateral resistance training.</p> <p>Results</p> <p>We found the PPARα L162V polymorphism to be a strong determinant of serum triglyceride levels in young White males, where carriers of the V allele showed 78% increase in triglycerides relative to L homozygotes (LL = 116 ± 11 mg/dL, LV = 208 ± 30 mg/dL; p = 0.004). Men with the V allele showed lower HDL (LL = 42 ± 1 mg/dL, LV = 34 ± 2 mg/dL; p = 0.001), but women did not. Subcutaneous fat volume was higher in males carrying the V allele, however, exercise training increased fat volume of the untrained arm in V carriers, while LL genotypes significantly decreased in fat volume (LL = -1,707 ± 21 mm³, LV = 17,617 ± 58 mm³; p = 0.002), indicating a systemic effect of the V allele on adiposity after unilateral training. Our study suggests that the primary effect of PPARα L162V is on serum triglycerides, with downstream effects on adiposity and response to training.</p> <p>Conclusion</p> <p>Our results on association of PPARα and triglycerides in males showed a much larger effect of the V allele than previously reported in older and less healthy populations. Specifically, we showed the V allele to increase triglycerides by 78% (p = 0.004), and this single polymorphism accounted for 3.8% of all variation in serum triglycerides in males (p = 0.0037).</p

Further phenotypic characterization of the primitive lineage− CD34+CD38−CD90+CD45RA− hematopoietic stem cell/progenitor cell sub-population isolated from cord blood, mobilized peripheral blood and patients with chronic myelogenous leukemia

The most primitive hematopoietic stem cell (HSC)/progenitor cell (PC) population reported to date is characterized as being Lin−CD34+CD38−CD90+CD45R. We have a long-standing interest in comparing the characteristics of hematopoietic progenitor cell populations enriched from normal subjects and patients with chronic myelogenous leukemia (CML). In order to investigate further purification of HSCs and for potential targetable differences between the very primitive normal and CML stem/PCs, we have phenotypically compared the normal and CML Lin−CD34+CD38−CD90+CD45RA− HSC/PC populations. The additional antigens analyzed were HLA-DR, the receptor tyrosine kinases c-kit and Tie2, the interleukin-3 cytokine receptor, CD33 and the activation antigen CD69, the latter of which was recently reported to be selectively elevated in cell lines expressing the Bcr-Abl tyrosine kinase. Notably, we found a strikingly low percentage of cells from the HSC/PC sub-population isolated from CML patients that were found to express the c-kit receptor (<1%) compared with the percentages of HSC/PCs expressing the c-kitR isolated from umbilical cord blood (50%) and mobilized peripheral blood (10%). Surprisingly, Tie2 receptor expression within the HSC/PC subset was extremely low from both normal and CML samples. Using in vivo transplantation studies, we provide evidence that HLA-DR, c-kitR, Tie2 and IL-3R may not be suitable markers for further partitioning of HSCs from the Lin−CD34+CD38−CD90+CD45RA− sub-population

Genes in S and T Subgenomes Are Responsible for Hybrid Lethality in Interspecific Hybrids between Nicotiana tabacum and Nicotiana occidentalis

Many species of Nicotiana section Suaveolentes produce inviable F(1) hybrids after crossing with Nicotiana tabacum (genome constitution SSTT), a phenomenon that is often called hybrid lethality. Through crosses with monosomic lines of N. tabacum lacking a Q chromosome, we previously determined that hybrid lethality is caused by interaction between gene(s) on the Q chromosome belonging to the S subgenome of N. tabacum and gene(s) in Suaveolentes species. Here, we examined if hybrid seedlings from the cross N. occidentalis (section Suaveolentes)×N. tabacum are inviable despite a lack of the Q chromosome.Hybrid lethality in the cross of N. occidentalis×N. tabacum was characterized by shoots with fading color. This symptom differed from what has been previously observed in lethal crosses between many species in section Suaveolentes and N. tabacum. In crosses of monosomic N. tabacum plants lacking the Q chromosome with N. occidentalis, hybrid lethality was observed in hybrid seedlings either lacking or possessing the Q chromosome. N. occidentalis was then crossed with two progenitors of N. tabacum, N. sylvestris (SS) and N. tomentosiformis (TT), to reveal which subgenome of N. tabacum contains gene(s) responsible for hybrid lethality. Hybrid seedlings from the crosses N. occidentalis×N. tomentosiformis and N. occidentalis×N. sylvestris were inviable.Although the specific symptoms of hybrid lethality in the cross N. occidentalis×N. tabacum were similar to those appearing in hybrids from the cross N. occidentalis×N. tomentosiformis, genes in both the S and T subgenomes of N. tabacum appear responsible for hybrid lethality in crosses with N. occidentalis

Business opportunities analysis using GIS: the retail distribution sector

[EN] The retail distribution sector is facing a difficult time as the current landscape is characterized by ever-increasing competition. In these conditions, the search for an appropriate location strategy has the potential to become a differentiating and competitive factor. Although, in theory, an increasing level of importance is placed on geography because of its key role in understanding the success of a business, this is not the case in practice. For this reason, the process outlined in this paper has been specifically developed to detect new business locations. The methodology consists of a range of analyzes with Geographical Information Systems (GISs) from a marketing point of view. This new approach is called geomarketing. First, geodemand and geocompetition are located on two separate digital maps using spatial and non-spatial databases. Second, a third map is obtained by matching this information with the demand not dealt with properly by the current commercial offer. Third, the Kernel density allows users to visualize results, thus facilitating decision-making by managers, regardless of their professional background. The advantage of this methodology is the capacity of GIS to handle large amounts of information, both spatial and non-spatial. A practical application is performed in Murcia (Spain) with 100 supermarkets and data at a city block level, which is the highest possible level of detail. This detection process can be used in any commercial distribution company, so it can be generalized and considered a global solution for retailers.Roig Tierno, H.; Baviera-Puig, A.; Buitrago Vera, JM. (2013). Business opportunities analysis using GIS: the retail distribution sector. Global Business Perspectives. 1(3):226-238. doi:10.1007/s40196-013-0015-6S22623813Alarcón, S. (2011). The trade credit in the Spanish agrofood industry. Mediterranean Journal of Economics, Agriculture and Environment (New Medit), 10(2), 51–57.Alcaide, J. C., Calero, R., & Hernández, R. (2012). Geomarketing. Marketing territorial para vender y fidelizar más. Madrid: ESIC.Applebaum, W., & Cohen, S. B. (1961). The dynamics of store trading areas and market equilibrium. Annals of the Association of American Geographers, 51(1), 73–101.Baviera-Puig, A., Buitrago-Vera, J. M., Escriba, C., & Clemente, J. S. (2009). Geomarketing: Aplicación de los sistemas de información geográfica al marketing. Paper presented at the Octava Conferencia Iberoamericana en Sistemas, Cibernética e Informática, Orlando, FL.Baviera-Puig, A., Buitrago-Vera, J. M., & Mas-Verdú, F. (2012). Trade areas and knowledge-intensive services: The case of a technology centre. Management Decision, 50(8), 1412–1424.Baviera-Puig, A., Buitrago-Vera, J. M., & Rodríguez-Barrio, J. E. (2013). Un modelo de geomarketing para la localización de supermercados: Diseño y aplicación práctica. Documentos de Trabajo de la Cátedra Fundación Ramón Areces de Distribución Comercial (DOCFRADIS), 1, 1–27.Berumen, S. A., & Llamazares, F. (2007). La utilidad los métodos de decisión multicriterio (como el AHP) en un entorno de competitividad creciente. Cuadernos de administración, 20(34), 65–87.Birkin, M., Clarke, G., & Clarke, M. (2002). Retail geography and intelligent network planning. Chichester: Wiley.Chasco, C. (2003). El geomarketing y la distribución commercial. Investigación y Márketing, 79, 6–13.Chen, R. J. C. (2007). Significance and variety of geographic information system (GIS) applications in retail, hospitality, tourism, and consumer services. Journal of Retailing and Consumer Services, 14, 247–248.Church, R. L. (2002). Geographical information systems and location science. Computers and Operations Research, 29, 541–562.Church, R. L., & Murray, A. T. (2009). Business site selection, location analysis and GIS. Hoboken, NJ: Wiley.Clarke, G. (1998). Changing methods of location planning for retail companies. GeoJournal, 45, 289–298.Clarkson, R. M., Clarke-Hill, C. M., & Robinson, T. (1996). UK supermarket location assessment. International Journal of Retail and Distribution Management, 24(6), 22–33.Davis, P. (2006). Spatial competition in retail markets: Movie theaters. The RAND Journal of Economics, 37(4), 964–982.Ghosh, A., & McLafferty, S. L. (1982). Locating stores in uncertain environments: A scenario planning approach. Journal of Retailing, 58(4), 5–22.Härdle, W. (1991). Smoothing techniques with implementation in S. Nueva York, NY: Springer.Harris, B., & Batty, M. (1993). Locational models, geographical information, and planning support systems. Journal of Planning Education and Research, 12, 184–198.Hernandez, T. (2007). Enhancing retail location decision support: The development and application of geovisualization. Journal of Retailing and Consumer Services, 14, 249–258.Hernandez, T., & Bennison, D. (2000). The art and science of retail location decisions. International Journal of Retail and Distribution Management, 28(8), 357–367.Huff, D. (1963). Defining and estimating a trade area. Journal of Marketing, 28, 34–38.Instituto Nacional de Estadística (INE). (2011). Padrón de habitantes 2011. http://www.ine.es . Accessed 9 Oct 2012.Kelly, J. P., Freeman, D. C., & Emlen, J. M. (1993). Competitive impact model for site selection: The impact of competition, sales generators and own store cannibalization. The International Review of Retail, Distribution and Consumer Research, 3, 237–259.Latour, P., & Le Floc’h, J. (2001). Géomarketing: Principes, méthodes et applications. París: Éditions d’Organisation.Mendes, A. B., & Themido, I. H. (2004). Multi-outlet retail site location assessment. International Transactions in Operational Research, 11, 1–18.Moreno, A. (1991). Modelización cartográfica de densidades mediante estimadores Kernel. Treballs de la Societat Catalana de Geografia, 6(30), 155–170.Moreno, A. (2007). Obtención de capas raster de densidad. In A. Moreno (Coord.), Sistemas y Análisis de la información Geográfica. Manual de autoaprendizaje con ArcGIS (pp. 685–691). Madrid: Editorial RA-MA.Murad, A. A. (2003). Creating a GIS application for retail centers in Jeddah City. International Journal of Applied Earth Observation and Geoinformation, 4, 329–338.Murad, A. A. (2007). Using GIS for retail planning in Jeddah City. American Journal of Applied Sciences, 4(10), 820–826.Musyoka, S. M., Mutyauvyu, S. M., Kiema, J. B. K., Karanja, F. N., & Siriba, D. N. (2007). Market segmentation using geographic information systems (GIS). A case study of the soft drink industry in Kenya. Marketing Intelligence and Planning, 25(6), 632–642.Nielsen Database. (2012). Retailers Database. http://www.nielsen.com/global/en.html . Accessed 12 Oct 2012.Ozimec, A. M., Natter, M., & Reutterer, T. (2010). Geographical information systems-based marketing decisions: Effects of alternative visualizations on decision quality. Journal of Marketing, 74, 94–110.Reilly, W. J. (1931). The law of retail gravitation. New York: Knickerbocker Press.Rob, M. A. (2003). Some challenges of integrating spatial and non-spatial datasets using a geographical information system. Information Technology for Development, 10, 171–178.Rosenblatt, M. (1956). Remarks on some nonparametric estimates of a density functions. Annals of Mathematical Statistic, 27, 832–837.Sede Electrónica del Catastro. (2012). Datos Catastrales. https://www.sedecatastro.gob.es . Accessed 10 Oct 2012.Silverman, B. W. (1986). Density estimation for statistics and data analysis. London: Chapman and Hall.Sleight, P., Harris, R., & Webber, R. (2005). Geodemographics, GIS and neighbourhood targeting. Chichester: Wiley.Suárez-Vega, R., Santos-Peñate, D. R., & Dorta-González, P. (2012). Location models and GIS tools for retail site location. Applied Geography, 35, 12–22.Thaler, R. (1986). The psychology and economics conference handbook: Comments on Simon, on Einhorn and Hogarth, and on Tversky and Kahneman. The Journal of Business, 59(4), 279–284.Wood, S., & Reynolds, J. (2012). Leveraging locational insights within retail store development? Assessing the use of location planners’ knowledge in retail marketing. Geoforum, 43, 1076–1087

Infection of the malaria mosquito, Anopheles gambiae, with two species of entomopathogenic fungi: effects of concentration, co-formulation, exposure time and persistence

<p>Abstract</p> <p>Background</p> <p>Entomopathogenic fungi <it>Metarhizium anisopliae </it>and <it>Beauveria bassiana </it>isolates have been shown to infect and reduce the survival of mosquito vectors.</p> <p>Methods</p> <p>Here four different bioassays were conducted to study the effect of conidia concentration, co-formulation, exposure time and persistence of the isolates <it>M. anisopliae </it>ICIPE-30 and <it>B. bassiana </it>I93-925 on infection and survival rates of female <it>Anopheles gambiae sensu stricto</it>. Test concentrations and exposure times ranged between 1 × 10⁷- 4 × 10¹⁰conidia m^-2and 15 min - 6 h. In co-formulations, 2 × 10¹⁰conidia m^-2of both fungus isolates were mixed at ratios of 4:1, 2:1, 1:1,1:0, 0:1, 1:2 and 1:4. To determine persistence, mosquitoes were exposed to surfaces treated 1, 14 or 28 d previously, with conidia concentrations of 2 × 10⁹, 2 × 10¹⁰or 4 × 10¹⁰.</p> <p>Results</p> <p>Mosquito survival varied with conidia concentration; 2 × 10¹⁰conidia m^-2was the concentration above which no further reductions in survival were detectable for both isolates of fungus. The survival of mosquitoes exposed to single and co-formulated treatments was similar and no synergistic or additive effects were observed. Mosquitoes were infected within 30 min and longer exposure times did not result in a more rapid killing effect. Fifteen min exposure still achieved considerable mortality rates (100% mortality by 14 d) of mosquitoes, but at lower speed than with 30 min exposure (100% mortality by 9 d). Conidia remained infective up to 28 d post-application but higher concentrations did not increase persistence.</p> <p>Conclusion</p> <p>Both fungus isolates are effective and persistent at low concentrations and short exposure times.</p