Implication of the Autologous Immune System in BCR-ABL Transcript Variations in Chronic Myelogenous Leukemia Patients Treated with Imatinib.

International audienceImatinib and other tyrosine kinase inhibitors (TKI) have improved treatment of chronic myelogenous leukemia (CML); however, most patients are not cured. Deeper mechanistic understanding may improve TKI combination therapies to better control the residual leukemic cell population. In analyzing our patients' data, we found that many patients who otherwise responded well to imatinib therapy still showed variations in their BCR-ABL transcripts. To investigate this phenomenon, we applied a mathematical model that integrates CML and an autologous immune response to the patients' data. We define an immune window or a range of leukemic loads for which the autologous immune system induces an improved response. Our modeling results suggest that, at diagnosis, a patient's leukemic load is able to partially or fully suppress the autologous immune response developed in a majority of patients, toward the CML clone(s). Imatinib therapy drives the leukemic population into the "immune window," allowing the patient's autologous immune cells to expand and eventually mount an efficient recognition of the residual leukemic burden. This response drives the leukemic load below this immune window, allowing the leukemic population to partially recover until another weaker immune response is initiated. Thus, the autologous immune response may explain the oscillations in BCR-ABL transcripts regularly observed in patients on imatinib

Comparison of the Hemostatic Efficacy of Pathogen-Reduced Platelets vs Untreated Platelets in Patients With Thrombocytopenia and Malignant Hematologic Diseases: A Randomized Clinical Trial

Importance: Pathogen reduction of platelet concentrates may reduce transfusion-transmitted infections but is associated with qualitative impairment, which could have clinical significance with regard to platelet hemostatic capacity. Objective: To compare the effectiveness of platelets in additive solution treated with amotosalen-UV-A vs untreated platelets in plasma or in additive solution in patients with thrombocytopenia and hematologic malignancies. Design, Setting, and Participants: The Evaluation of the Efficacy of Platelets Treated With Pathogen Reduction Process (EFFIPAP) study was a randomized, noninferiority, 3-arm clinical trial performed from May 16, 2013, through January 21, 2016, at 13 French tertiary university hospitals. Clinical signs of bleeding were assessed daily until the end of aplasia, transfer to another department, need for a specific platelet product, or 30 days after enrollment. Consecutive adult patients with bone marrow aplasia, expected hospital stay of more than 10 days, and expected need of platelet transfusions were included. Interventions: At least 1 transfusion of platelets in additive solution with amotosalen-UV-A treatment, in plasma, or in additive solution. Main Outcomes and Measures: The proportion of patients with grade 2 or higher bleeding as defined by World Health Organization criteria. Results: Among 790 evaluable patients (mean [SD] age, 55 [13.4] years; 458 men [58.0%]), the primary end point was observed in 126 receiving pathogen-reduced platelets in additive solution (47.9%; 95% CI, 41.9%-54.0%), 114 receiving platelets in plasma (43.5%; 95% CI, 37.5%-49.5%), and 120 receiving platelets in additive solution (45.3%; 95% CI, 39.3%-51.3%). With a per-protocol population with a prespecified margin of 12.5%, noninferiority was not achieved when pathogen-reduced platelets in additive solution were compared with platelets in plasma (4.4%; 95% CI, -4.1% to 12.9%) but was achieved when the pathogen-reduced platelets were compared with platelets in additive solution (2.6%; 95% CI, -5.9% to 11.1%). The proportion of patients with grade 3 or 4 bleeding was not different among treatment arms. Conclusions and Relevance: Although the hemostatic efficacy of pathogen-reduced platelets in thrombopenic patients with hematologic malignancies was noninferior to platelets in additive solution, such noninferiority was not achieved when comparing pathogen-reduced platelets with platelets in plasma. Trial Registration: clinicaltrials.gov Identifier: NCT01789762

Indirect calorimetry: Techniques, computations and applications

The use of indirect calorimetry to measure the heat production of men and animals has increased rapidly since the pioneering work of Lavoisier. Measurement of the consumption of oxygen and production of carbon dioxide are the basis for the measurement of heat production. Today, applications of indirect calorimetry are available in many species. Combining these measurements with accurate climate control, recording of physical activity and feed intake, use of stable isotopes and sophisticated modelling techniques allow scientists to make progress in various research areas. This book provides a scientific basis for indirect calorimetry, dealing with smart ways to design calorimeters, gas measurements and computational techniques to deal with complex data. Novel techniques allow the connection between short term changes in energy expenditure, protein turnover and substrate oxidation, e.g. using stable isotopes. Various applications o

Les dimensions spatiales de la transition énergétique

International audienceEnergy transition is fundamentally acknowledged as a geographical process that happens in particular places, transforms landscape features, produces uneven development and, more generally, entails reconfiguring current spatial patterns of economic and social activities. The way in which spatial processes shape new energy technologies and influence their capacity for transformation, however, has rarely been a focus of analyses. To investigate further the role of space in the energy transition, this chapter proposes to take into account the diffuse materiality of renewable energy resources. Our aim is to contribute to an emerging agenda about the spatialities of energy resources and their political issues at the crossroad of materiality and space. The chapter is divided into four sections. The first briefly presents the field of the geography of energy resources and explains the approach of renewable energy resources as a 'turbulent' materiality. The second proposes theoretical elements inspired by works on the vertical dimension of space to study the processes through which space is configured as a manageable 'volume' for controlling energy material flows. The third examines five case studies from France, Germany and Tunisia. Finally, a discussion about emerging politics of 'volume' in the energy transition aims at providing a critical geographical appraisal of the current development of renewable energie

Deriving heat production from gaseous exchange: validity of the approach

The use of indirect calorimetry as a means to quantify heat production (Q) and net substrate oxidation has increased rapidly since the pioneering work of Lavoisier, and today, indirect calorimetry is often used as a reference for other measures of Q. Simple equations were developed and widely adopted to calculate the production of heat from the measurement of the production of CO2 and CH4, the consumption of O2 and urinary nitrogen loss. The coefficients in these equations were derived from stoichiometry of the complete oxidation of carbohydrates, fat and protein. In this chapter, taking the Brouwer equation as an example, these calculations are explained and their validity to compute Q is discussed. Particular attention is paid to anaerobic fermentation and de novo lipogenesis from carbohydrates. It is concluded that Q can be predicted satisfactorily from the O2 consumed and CO2 produced using factors derived from oxidation of carbohydrates, fat and protein. Caution is required for corrections for CH4, particularly in ruminants, although quantitatively, the impact of these corrections on the estimates of Q seems limited. The approach is also valid when de novo lipogenesis from carbohydrates is substantial. As it is assumed that O2 and CO2 pools within the body do not change within a measurement period, a critical attitude towards this approach is required whenever pushing a biological system with e.g. a diet or infusate while using it to estimate short term variation in Q. Examples of these include strenuous exercise or an environmental challenge, e.g. heat stress, during which energy containing intermediates can be temporarily stored in the body and/or the bicarbonate pool fluctuates. Lastly, the measurement of retained energy based on indirect calorimetry in growing subjects is compared with other techniques. Comparison with the comparative slaughter technique in growing subjects reveals that measurement based on indirect calorimetry tends to lead to higher estimates of retained energy, but treatment differences within studies are quantified accurately. It can be argued that the bias reflects a true difference in Q, related to differences in e.g. housing conditions. Comparison of indirect calorimetry with the carbon-nitrogen balance technique and with direct calorimetry, reveal a very close match between these techniques. In conclusion, although a critical attitude is appropriate, Q can be accurately derived from gaseous exchange measurements using the simple equations developed in the previous century, with coefficients based on the complete oxidation of carbohydrates, fat and protei

Quantifying physical activity heat in farm animals

The time dependent character of data generated by modern calorimetry equipment provides the unique opportunity to monitor short term changes in energy expenditure related to physical activity, feeding pattern and other experimental interventions. When timed recordings of physical activity are available, total heat production can be decomposed into heat production due to physical activity and resting metabolism. Based on additional measurements and assumptions, further separation of the thermic effect of feeding is possible. When separating total heat production into its components, the separation of activity energy is a key step, even if activity energy is not the main interest of the study. This chapter provides an overview of a current methodology used to measure physical activity within the setting of indirect calorimetry. An approach to decompose total heat production into activity related and resting metabolic rate, the latter including the short term effect of feeding, is presented. In regression analysis, the energetic costs of each unit of physical activity, as well as the resting metabolic rate are assumed to be constant. Improved methodology is available using penalized least squares regression to model time dependent variation in the resting metabolic rate. The impact of experimental variables and settings, e.g. sampling frequency and chamber washout time are discussed. In addition, housing conditions, including ambient temperature, and feeding methods can impact on the relationship between physical activity and total heat production, affecting the reliability with which total heat production can be decomposed into resting metabolic rate and heat production related to physical activity. Finally, single housing conditions, often difficult to avoid in indirect calorimetry experiments, can modify behaviour, induce stress and therefore substantially influence activity related heat production and the results of calorimetry experiments. The effect of single vs group housing in growing pigs extracted from previously unpublished data and from the literature, suggest that single housing may increase activity heat production possibly because of induced stress. From behavioural and calorimetry data obtained in calves it is also demonstrated that the energetic costs of stereotyped behaviours can be very high

Quantifying physical activity heat in farm animals

The time dependent character of data generated by modern calorimetry equipment provides the unique opportunity to monitor short term changes in energy expenditure related to physical activity, feeding pattern and other experimental interventions. When timed recordings of physical activity are available, total heat production can be decomposed into heat production due to physical activity and resting metabolism. Based on additional measurements and assumptions, further separation of the thermic effect of feeding is possible. When separating total heat production into its components, the separation of activity energy is a key step, even if activity energy is not the main interest of the study. This chapter provides an overview of a current methodology used to measure physical activity within the setting of indirect calorimetry. An approach to decompose total heat production into activity related and resting metabolic rate, the latter including the short term effect of feeding, is presented. In regression analysis, the energetic costs of each unit of physical activity, as well as the resting metabolic rate are assumed to be constant. Improved methodology is available using penalized least squares regression to model time dependent variation in the resting metabolic rate. The impact of experimental variables and settings, e.g. sampling frequency and chamber washout time are discussed. In addition, housing conditions, including ambient temperature, and feeding methods can impact on the relationship between physical activity and total heat production, affecting the reliability with which total heat production can be decomposed into resting metabolic rate and heat production related to physical activity. Finally, single housing conditions, often difficult to avoid in indirect calorimetry experiments, can modify behaviour, induce stress and therefore substantially influence activity related heat production and the results of calorimetry experiments. The effect of single vs group housing in growing pigs extracted from previously unpublished data and from the literature, suggest that single housing may increase activity heat production possibly because of induced stress. From behavioural and calorimetry data obtained in calves it is also demonstrated that the energetic costs of stereotyped behaviours can be very high

Estimation of milk leakage into the rumen of milk-fed calves through an indirect and repeatable method

In milk-fed calves, quantification of the milk that enters the rumen (ruminal milk volume, RMV) because of malfunction of the esophageal groove reflex may explain part of the variability observed between animals in their growth performance. The RMV can directly be quantified by adding an indigestible marker to the diet and measuring its recovery in the rumen at slaughter, but this technique cannot be repeated in time in the same animal. The objective of the study was to evaluate three indirect methods for estimating RMV. The first method was based on the assumption that ruminal drinking delays and limits acetaminophen appearance in blood after ingestion of milk supplemented with acetaminophen. The second method was based on a negative linear relationship between RMV and urinary recovery of non-metabolizable monosaccharides (3-O-methylglucose, l-rhamnose and d-xylose) added to the milk, owing to rumen fermentation. In the third method, RMV was calculated as the difference between total milk intake and the increase in abomasal milk volume (AMV) at feeding, measured through ultrasonography shortly after feeding, or estimated from the mathematical extrapolation of AMV to feeding time, based on consecutive measurements. These methods were tested in three experiments where calves (n=22, 10 and 13) were bucket fed or partly tube fed (i.e. by inserting milk replacer into the rumen via a tube to mimic ruminal drinking). In addition, Co-EDTA and Cr-EDTA were used as an indigestible marker in one experiment to trace bucket-fed or tube-fed milk replacer, respectively, to measure RMV. The relationship between AMV measured by ultrasonography and AMV measured at slaughter improved when kinetics of AMV were extrapolated to the time of slaughter by mathematical modeling (error between predicted and measured AMV equaled 0.49 l). With this technique, RMV during feeding averaged 17% and 24% of intake in Experiments 2 and 3, respectively. Plasma acetaminophen kinetics and recovery of non-metabolizable monosaccharides in urine were partly associated with ruminal drinking, but these techniques are not considered quantitatively accurate without further information of rumen degradation and absorption. The recovery of indigestible marker measured at slaughter gave a quantitative estimate of RMV (2% in Experiment 3), but improper measurement of emptying rate of fluid from the rumen may lead to underestimation. In conclusion, measuring changes in AMV by ultrasonography, in response to milk feeding, was the most promising indirect method to quantify RMV in veal calves