Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in ...living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of life's origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that properties similar to those predicted for the artificial chemistry hold also for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity.
Abstract
Background: The need to identify biomarkers that predict benefit to checkpoint inhibitor therapies has led to the discovery and development of tumor mutational burden (TMB), a measure of ...potential tumor neoantigenicity derived from tissue biopsies that has shown clinical utility across a range of tumor types. A significant fraction of patients, however, are not candidates for tissue biopsies, presenting the need for blood-based methods to determine TMB. Here we describe the development of an assay to identify TMB from cell-free DNA derived from blood (bTMB). We present the analytic validation and clinical feasibility data that support the application of bTMB in a prospective clinical trial, BFAST (NCT03178552), evaluating the anti-PD-L1 agent atezolizumab in patients with non-small cell lung cancer (NSCLC).
Methods: The bTMB assay surveys somatic base substitutions down to 0.5% allele frequency across 394 genes from as little as 1% tumor content in a cell free DNA (cfDNA) sample derived from blood. Analytic validation was focused on establishing accuracy and precision of the bTMB measurement, as well as the minimum amount of cell-free and circulating tumor DNA required to make precise and reliable bTMB calls. The accuracy of two bTMB cutoffs was established against TMB derived from FoundationOne, an analytically validated TMB platform. Precision was evaluated by comparing the reproducibility of bTMB calls across replicate samples. We also retrospectively analyzed plasma samples from the OAK (NCT02008227) and POPLAR (NCT01903993) trials with the bTMB assay to determine the association of bTMB with atezolizumab clinical activity. The biomarker evaluable population (BEP) included 211 patients in POPLAR (intention-to-treat ITT =287) and 583 patients in OAK (excludes patients with known EGFR/ALK mutations; ITT=850), with blood samples available for targeted genomic sequencing. Assay positivity was defined as the presence of a number of somatic base substitutions greater than or equal to the bTMB cutoffs.
Results: The average positive percent agreement (PPA), negative percent agreement (NPA) and positive predictive value (PPV) across the bTMB cutoffs were 95%, 100% and 100%, respectively. The average precision was 96%, with a coefficient of variation of 7%. The assay limit of detection was defined as 1% tumor content in at least 20 ng of cfDNA. In POPLAR, improved progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) with atezolizumab vs docetaxel were observed for patients with bTMB at or above a range of bTMB thresholds compared with the ITT and BEP populations. In OAK, PFS benefit with atezolizumab vs docetaxel was observed at bTMB thresholds ≥10 (cut point ≥10: HR 0.73; n=251) compared with BEP (HR 0.87, 95% CI 0.73-1.04; n=585). bTMB did not correlate with PD-L1 expression as measured by VENTANA SP142 immunohistochemistry.
Conclusions: We have developed and analytically validated a blood-based assay to determine TMB with high accuracy and precision, using as little as 1% tumor content in a sample with 20 ng of cfDNA. Retrospective analyses from POPLAR and OAK data provide the first demonstrations that blood-based measurement of TMB may be associated with atezolizumab clinical efficacy in second-line NSCLC. Thus, the bTMB assay may provide a non-invasive biomarker to identify patients who derive clinical benefit from single agent PD-1/PD-L1 inhibition. Prospective studies using bTMB are currently ongoing in patients with first-line NSCLC, including BFAST and B-F1RST (NCT02848651).
Citation Format: Daniel S. Lieber, Emily White, Jacob Silterra, Shan Zhong, Tina Brennan, Michael Coyne, Mark Kennedy, David R. Gandara, Marcin Kowanetz, Sarah M. Paul, Erica Schleifman, Yan Li, Achim Rittmeyer, Louis Fehrenbacher, Lukas Amler, Todd Riehl, Craig Cummings, Priti S. Hegde, Wei Zou, Alan Sandler, Marcus Ballinger, Tony Mok, David S. Shames, Doron Lipson, Christine Malboeuf, David Fabrizio. Analytic validation and clinical feasibility of a next-generation sequencing assay to assess tumor mutational burden from blood (bTMB) as a biomarker for anti-PD-L1 response in NSCLC abstract. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A41.
Jean de Berry et l’écrit Barry, Mélissa; Blanc-Riehl, Clément; Canteaut, Olivier ...
Éditions de la Sorbonne,
2019
Book
Odprti dostop
De Jean de Berry, l’histoire a retenu l’image d’un prince mécène et bibliophile, ardent défenseur de la couronne au temps de Charles V et de Charles VI. Doté d’une principauté au centre du royaume, ...tenue en apanage, il a développé une administration dont les contours ont déjà été reconnus. Sa chancellerie, en revanche, a peu retenu l’attention. C’est autour des pratiques de l’écrit documentaire, actes en tête, que s’organise la présente publication. Celle-ci se veut une contribution à une meilleure connaissance de l’acte princier des xive et xve siècles, un domaine qui, s’il a été illustré par divers historiens et diplomatistes, ne l’a été jusqu’à maintenant que de façon discontinue et incomplète. Par l’extension géographique et la variété de ses pouvoirs, par sa proximité avec la personne royale (il a été successivement fils, frère, oncle de roi), par la durée de son activité (une soixantaine d’années, de 1356 à 1416), Jean de Berry a légué un corpus central pour l’étude de l’acte princier. Un acte princier qui devient, à l’époque, une pièce importante de la production diplomatique et, par la captation de traits royaux, un outil efficace de la genèse de l’État moderne et de l’apprentissage de la sujétion. Organisation, recrutement, fonctionnement de la chancellerie, gestion de la mémoire des actes, traits internes et externes des productions, manifestations du pouvoir dans les titulatures et les sceaux, méthodes d’édition… sont scrutés dans les contributions de ce volume, non seulement pour Berry, mais aussi, de façon délibérément comparative, pour plusieurs de ses contemporains (princes anglais et navarrais, ducs de Bourbon, d’Anjou et de Bretagne).
Researching the social economy Mook, Laurie; Quarter, Jack; Ryan, Sherida
Researching the social economy,
c2010, 20101201, 2010, 2010-01-01, 20100101
eBook
Researching the Social Economyenriches our understanding of how this important cluster of organizations contributes to Canadian society in both economic and social terms, and lays the groundwork for ...future study.
Central glutamatergic relays are known to be present in the central sympathetic pathways. Ifenprodil (an N-methyl-D-aspartate antagonist) and baclofen (a gamma-aminobutyric acid(B) agonist) are both ...modulators of these synapses; we previously reported their ability to reduce the cardiovascular responses induced by a central hypothalamic stimulation in rabbits. In this work, we investigated the actions of chronic treatments with these two drugs on the increase of myocardial oxygen demand induced by exercise in normotensive rats. Moreover, their effects on the baroreceptor heart rate reflex were observed. Male normotensive WKY rats were treated with placebo (two groups), baclofen, or ifenprodil for 14 days. They were then submitted to a progressively increased exercise test on a treadmill. In another three groups of animals, the same treatment was applied but, at the end, a baroreflex study was performed by the injection of phenylephrine (vagal component of the reflex) and of sodium nitroprusside (sympathetic component). Ifenprodil and baclofen reduced by nearly 50% the level of the increase of the rate x pressure product during exercise as compared with control rats. This effect appeared to be mainly due to a reduction of the hypertensive response. In the same conditions, neither baclofen nor ifenprodil significantly altered the baroreceptor heart rate reflex. The fact that these two drugs are capable of reducing the myocardial oxygen demand encourages us to test them in a model of myocardial ischemia associated with sympathetic hyperactivity.
Published by the American Geophysical Union as part of the Geophysical Monograph Series, Volume 198.Climates, Landscapes, and Civilizations brings together a collection of studies on the history of ...complex interrelationships between humans and their environment by integrating Earth science with archeology and anthropology. At a time when climate change, overpopulation, and scarcity of resources are increasingly affecting our ways of life, the lessons of the past provide multiple reference frames that are valuable for informing our future decisions and action plans. Volume highlights include discussions of multiple connotations of the Anthropocene, landscapes as a link between climate and humans, synoptic approaches to explore large-scale cultural patterns, regional studies for contextualizing cultural complexity, and environmental determinism and social theory. Straddling the fields of Earth sciences, anthropology, and archaeology and presenting research from across several continents, Climates, Landscapes, and Civilizations will appeal to a wide readership among scientists, scholars, and the public at large.
PDF
