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Quantitation of glucose uptake in tumors by dynamic FDG-PET has less glucose bias and lower variability when adjusted for partial saturation of glucose transport
Simon-Peter Williams, Judith E Flores-Mercado, Ruediger E Port, Thomas Bengtsson
EJNMMI Research , 2012, DOI: 10.1186/2191-219x-2-6
Abstract: Patlak-Gjedde analysis was used to compute Ki from 30-min dynamic PET scans in tumor-bearing mice. MRGluc was calculated by factoring in the blood glucose level and a lumped constant equal to unity. Alternatively, we assumed that glucose consumption is saturable according to Michaelis-Menten kinetics and estimated a hypothetical maximum rate of glucose consumption [MRGlucMAX] by multiplying Ki and (KM + [glucose]), where KM is a half-saturation Michaelis constant for glucose uptake. Results were computed for 112 separate studies of 8 to 12 scans each; test-retest statistics were measured in a suitable subset of 201 mice.A KM value of 130 mg/dL was determined from the data based on minimizing the average correlation between blood glucose and the uptake metric. Using MRGlucMAX resulted in the following benefits compared to using MRGluc: (1) the median correlation with blood glucose was practically zero, and yet (2) the test-retest coefficient of variation [COV] was reduced by 13.4%, and (3) the between-animal COVs were reduced by15.5%. In statistically equivalent terms, achieving the same reduction in between-animal COV while using the traditional MRGluc would require a 40% increase in sample size.MRGluc appeared to overcorrect tumor FDG data for changing glucose levels. Applying partial saturation correction using MRGlucMAX offered reduced bias, reduced variability, and potentially increased statistical power. We recommend further investigation of MRGlucMAX in quantitative studies of tumor FDG uptake.We considered 2-deoxy-2-(18F)fluoro-D-glucose-positron-emission tomography [FDG-PET] as a pharmacodynamic marker of antitumor activity during treatments that alter systemic blood glucose levels, for example the Akt inhibitors [1], and sought a metric of tumor glucose uptake that had minimal glucose bias. Inverse correlations of blood glucose with tumor FDG uptake have been demonstrated in multiple settings (see Figures 1 and 2, [2-6]), and this effect was to be expected
The power of FDG-PET to detect treatment effects is increased by glucose correction using a Michaelis constant
Simon-Peter Williams, Judith E Flores-Mercado, Andreas R Baudy, Ruediger E Port, Thomas Bengtsson
EJNMMI Research , 2012, DOI: 10.1186/2191-219x-2-35
Abstract: We compared Ki, MRgluc (both with and without glucose normalization), and M R gluc max as FDG-PET measures of treatment-induced changes in tumor glucose uptake independent of any systemic changes in blood glucose caused either by natural variation or by side effects of drug action. Data from three xenograft models with independent evidence of altered tumor cell glucose uptake were studied and generalized with statistical simulations and mathematical derivations. To obtain representative simulation parameters, we studied the distributions of Ki from FDG-PET scans and blood [glucose] values in 66 cohorts of mice (665 individual mice). Treatment effects were simulated by varying M R gluc max and back-calculating the mean Ki under the Michaelis-Menten model with KM?=?130?mg/dL. This was repeated to represent cases of low, average, and high variability in Ki (at a given glucose level) observed among the 66 PET cohorts.There was excellent agreement between derivations, simulations, and experiments. Even modestly different (20%) blood glucose levels caused Ki and especially MRgluc to become unreliable through false positive results while M R gluc max remained unbiased. The greatest benefit occurred when Ki measurements (at a given glucose level) had low variability. Even when the power benefit was negligible, the use of M R gluc max carried no statistical penalty. Congruent with theory and simulations, M R gluc max showed in our experiments an average 21% statistical power improvement with respect to MRgluc and 10% with respect to Ki (approximately 20% savings in sample size). The results were robust in the face of imprecise blood glucose measurements and KM values.When evaluating the direct effects of treatment on tumor tissue with FDG-PET, employing a Michaelis-Menten glucose correction factor gives the most statistically powerful results. The well-known alternative ‘correction’, multiplying Ki by blood glucose (or normal
FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973
Andreas R Baudy, Taner Dogan, Judith E Flores-Mercado, Klaus P Hoeflich, Fei Su, Nicholas van Bruggen, Simon-Peter Williams
EJNMMI Research , 2012, DOI: 10.1186/2191-219x-2-22
Abstract: 18?F-FDG uptake was measured in vitro in cells with wild-type and mutant (V600) BRAF, and in melanoma cells with an acquired resistance to vemurafenib. We treated the cells with vemurafenib alone or in combination with MEK inhibitor GDC-0973. PET imaging was used in mice to measure FDG uptake in A375 melanoma xenografts and in A375 R1, a vemurafenib-resistant derivative. Histological and biochemical studies of glucose transporters, the MAPK and glycolytic pathways were also undertaken.We demonstrate that vemurafenib is equally effective at reducing FDG uptake in cell lines harboring either heterozygous or homozygous BRAFV600 but ineffective in cells with acquired resistance or having WT BRAF status. However, combination with GDC-0973 results in a highly significant increase of efficacy and inhibition of FDG uptake across all twenty lines. Drug-induced changes in FDG uptake were associated with altered levels of membrane GLUT-1, and cell lines harboring RAS mutations displayed enhanced FDG uptake upon exposure to vemurafenib. Interestingly, we found that vemurafenib treatment in mice bearing drug-resistant A375 xenografts also induced increased FDG tumor uptake, accompanied by increases in Hif-1α, Sp1 and Ksr protein levels. Vemurafenib and GDC-0973 combination efficacy was associated with decreased levels of hexokinase II, c-RAF, Ksr and p-MEK protein.We have demonstrated that 18?F-FDG-PET imaging reflects vemurafenib and GDC-0973 action across a wide range of metastatic melanomas. A delayed post-treatment increase in tumor FDG uptake should be considered carefully as it may well be an indication of acquired drug resistance.ClinicalTrials.gov NCT01271803Melanoma is the deadliest of all skin cancers, and its incidence has been steadily increasing over the past few decades, especially in Caucasians [1]. Advanced melanoma patients have an 8-month median time of survival, a figure that has improved little in the past decades despite enormous research efforts [2]. This,
Mujeres de metal, mujeres de madera: Música p'urhépecha y relaciones de género en las bandas de viento en Tingambato, Michoacán
Flores Mercado, B. Georgina;
Cuicuilco , 2009,
Abstract: traditional music and brass bands are important symbolic reference points for p'urhepecha identity in the town of tingambato, michoacan. in tingambato there are some 12 brass bands, only 2 of which are dedicated to traditional regional music. today brass bands are generally made up of young males whilst in the bands which play traditional music we see increasing numbers of women playing instruments and learning to read music. this is a descriptive research project which deals with the experience of women in the world of traditional p'urhepecha music, their participation in brass bands and how they see themselves as musicians. identification with traditional music and with the p'urhepecha people helps them to deal with gender discrimination which they frequently experience within the brass bands.
Antes se tocaba papel, se estudiaba con un maestro: Remembranzas de la educación musical rural en Totolapan, Morelos
Flores Mercado, B. Georgina;
Alteridades , 2011,
Abstract: the current article is the result of an ethnographic research in the town of totolapan, morelos, its aim was to recover the collective memory of the wind band music through the interviews with musicians between the 60 and 90 years old, or with their widows. musical education is an aspect that comes across strongly in the narratives of the interviewees as a form of social cohesion among yesterday and today musicians. musicians' education and formation in rural and indigenous areas has seldom been studied by researchers of different disciplines and this article seeks to make a contribution to the knowledge of this not so well researched field.
Las fiestas populares en la modernidad: celebración y sufrimiento en la fiesta mayor de Gracia de Barcelona
Bertha Georgina Flores Mercado
Revista Mal-estar e Subjetividade , 2006,
Abstract: El presente artículo es resultado de una investigación más amplia realizada en un barrio de la ciudad de Barcelona sobre la Fiesta Mayor de Gracia. En este artículo me centro en la relación de la fiesta, la celebración, el sufrimiento y la modernidad. De esta forma trato de argumentar que el proceso de modernización de la sociedad y por lo tanto de la fiesta popular ha producido un sujeto que tiene la libertad de celebrar sus fiestas populares pero a la vez este sujeto sufre la fiesta al estar ésta inmersa en relaciones individualistas y mercantilistas. Para llevar acabo lo anterior, en un primer momento describo cómo se entiende la fiesta popular en el contexto urbano moderno y sus modificaciones en relación con la sociedad rural, industrial y de consumo. El artículo tiene un sentido fenomenológico en tanto que trata de dar cuenta de las vivencias de los y las participantes durante la organización y celebración de la fiesta. Dichas vivencias son el resultado de 3 a os de investigación etnográfica y de entrevistas realizadas a diferentes participantes de la Fiesta Mayor de Gracia.
Los ámbitos normativos, la gestión de la calidad y la inocuidad alimentaria: una visión integral
Mercado,Carmen E;
Agroalimentaria , 2007,
Abstract: the food crisis of the 1990?s and the increase in transmittable diseases from foods, pointed out the difficulty for sanitary control systems to confront demographic changes, consumption and intensive production techniques, transformation and food conservation. this caused a change in food innocuity from a posteriori approach to a reactive and punitive one in order to prevent and reduce the long term risk of the food chain. to guarantee innocuous food and quality work on three fronts must be carried out: 1) the design of a modern normative framework in agreement with the international norm particularly, codex alimentarius; 2) the prevention of innocuity in the food chain based on good practices and 3) the design and management of a national system of food controls with institutions that make operational legislation, control, inspection and information, education, and communication. in this work three development experiences in these areas are presented. the first shows three projects developed by the fao to improve normative capacity and the management of codex alementarius. the second, shows the implementation of the chilean agency for food innocuity. the third, shows the experience of the sicofhor program from argentina, which encourages good practices in the cash crop and fruit chains
Desarrollo de las estadísticas del medio ambiente: planteamientos y conclusionesa
Alfonso Mercado,Carlos Roberto López,Arturo Flores,Francisco Giner
Estudios Demográficos y Urbanos , 2009,
Abstract:
La filosofía del sujeto y la sociología del conocimiento en las teorías de Ju rgen Habermas y Niklas Luhmann
Sánchez Flores, Mónica Judith
CONfines de relaciones internacionales y ciencia política , 2007,
Abstract: In this article I show that, in spite of essential differences between Habermas and Luhmann with respect to the philosophy of the subject, they both depend on the modern idea of the individual self to pose their theories of meaning (Habermas 1989 and 1990, Luhmann 1998). Habermas and Luhmann belong to divergent theoretical schools (critical and functionalist respectively) and yet they both use essential lessons about language from the German “sciences of the spirit” (Geisteswissenschaften); the phenomenological perspective and the sociology of knowledge. Even though their positions on the value of the modern individual self are opposed, the latter is an essential element in the theoretical perspectives of both sociologists: Habermas describes the individual subject as a linguistically competent, rational, and critical entity; while Luhmann rejects this anthropocentric conception outright and contemplates society as a set of systems oriented towards their own functionality. Luhmann produces a very useful sociological perspective, but rhetorically rejects the substantive aspect of the philosophy of the subject without recognizing that his perspective depends on the consciousness of the subject that he rejects at the same time. In the light of this dilemma I argue that it is necessary to remember essential lessons from Max Weber’s methodology of the social sciences.
Características de secado de nopal (Opuntia ficus-indica) por lecho fluidizado Características de secado de nopal (Opuntia ficus-indica) por lecho fluidizado
Gerardo Martínez Soto,Adrián Flores Ortega,Juan Mercado Flores,Melva López Orozco
Acta Universitaria , 2012,
Abstract: The effect of blanching and drying air temperature on nopal pieces was investigated. Their drying behavior in a fluidized bed was studied at four different temperatures (50 oC, 60 oC, 70 oC and 80 oC). Drying curves were constructed using dimensionless moisture ratio (MR) and time; and their behavior was modeled using Henderson-Pabis, Power, Peleg and Page models. The results indicated that drying took place mainly when the period of dry-ing rate decreased. The moisture effective diffusivity (Def) values varied from 0.818x10-7 to 3.25x10-7 m2 s-1 depending on drying conditions. The activation energy (Ea) values were: 35.85 kJ/mol for the nopal without blanching and 28.21 kJ/mol for the blanching nopal respectively. Peleg and Page′s models were found the most suitable for describing the dry-ing behavior of nopal. Se investigó el efecto del escaldado y la temperatura del aire de secado en trozos de nopal. El experimento se realizó en un secador de lecho fluidizado a cuatro temperaturas diferentes (50 oC, 60 oC, 70 oC y 80 oC). Las curvas de secado se obtuvieron al graficar la razón de humedad adimensional (MR) contra el tiempo de secado; su comportamiento se modeló utilizando los modelos de Henderson-Pabis, Potencia, Peleg y Page. Los resultados mostraron que el secado se llevó a cabo principalmente en el periodo de velocidad decreciente. Los valores de la difusividad efectiva (Def) variaron de 0.818x10-7 a 3.25x10-7 m2 s
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