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Computed Tomography Imaging in Radiotherapy
Published in W. P. M. Mayles, A. E. Nahum, J.-C. Rosenwald, Handbook of Radiotherapy Physics, 2021
The tissue assignment is performed using subsets (or bins) of material types with boundary values derived from tables such as Table 32.3. The selection of the boundaries is somewhat arbitrary but can be optimised to mitigate the risk of significant error in dose calculation (du Plessis et al. 1998). The stoichiometric approach provides useful complementary information (Vanderstraeten et al. 2007). A given selection of boundaries may not be valid for all patients; but fortunately, for most high-energy photon and electron beam dose computation, mis-assignment of media has only a small dosimetric impact (Bazalova et al. 2008). The number of bins used for tissue segmentation is often limited to five (as in Figure 32.7), but it seems that a larger number is not required except perhaps for the controversial determination of absorbed dose to bone (Vanderstraeten et al. 2007) (see Section 27.3.2).
Introduction: Background Material
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
This is a stoichiometric equation, where stoichiometry is concerned with the relative quantities of reactants and products in a chemical reaction, and a stoichiometric equation shows the quantitative relationship between reactants and products. A proper stoichiometric equation must be balanced, that is, the number of atoms of any element must be the same on both sides of the equation in accordance with conservation of mass. Thus, in Equation 1.39, there are two atoms of oxygen and four atoms of hydrogen on either side. The number multiplying each species in the stoichiometric equation is the stoichiometric coefficient.
Plasma Protein Function in Hemostasis
Published in Genesio Murano, Rodger L. Bick, Basic Concepts of Hemostasis and Thrombosis, 2019
Since other micelles (bile salts, for example) can substitute13 in vitro for platelet factor 3, it appears that phospholipids serve as a surface support upon which the enzyme (Factor Xa), the determiner (Factor V)**, and the substrate (prothrombin) can interact in complex mediated by calcium ions. Factor V binds to the prothrombin fragment 2 portion of prothrombin,55 and calcium ions bind to the prothrombin fragment 1 portion of prothrombin, which contains γ-carboxyglutamic acid residues. 13,20,24,43,44,47,48,55 Reduction in the concentration of any one of the five components composing the complex results in a paramount reduction in the rate and yield of thrombin.13 A precise stoichiometric relationship is essential. Any perturbation of this equilibrium results in less than optimal yields of thrombin, which is reflected in delayed coagulation in vivo.13,44,45 As already pointed out in the fibrin formation section, thrombin has a very restricted substrate specificity. This property is imparted by the structural characteristics of the substrate in the area immediately adjacent to the arginyl-glycine peptide bond cleaved by thrombin (Figure 10).
PROTAC antibiotics: the time is now
Published in Expert Opinion on Drug Discovery, 2023
Jickky Palmae Sarathy, Courtney C. Aldrich, Mei-Lin Go, Thomas Dick
Targeted protein degradation (TPD) is a novel paradigm in drug discovery across human disease areas, mostly cancers [10]. Like most drugs, traditional antibacterials encompass small to large molecular weight compounds and typically modulate the activity of a protein target [11] (Figure 1a). TPD employs a fundamentally different on-target mechanism: a TPD agent binds to its target (protein of interest, POI) and trigger its degradation via the endogenous proteolytic machinery [12]. As a result of their ‘event-driven’ on-target mechanism, TPD agents are only required in catalytical amounts and can reengage POI molecules for multiple rounds of degradation [13]. This contrasts with the ‘occupancy-driven’ mechanism of traditional drugs which requires stoichiometric binding to the POI for achieving whole-cell activity [10]. Proteolysis targeting chimeras (PROTACs) are the most established TPD agents [14]. PROTACs are heterobifunctional molecules that bind to their POI and an E3 ligase. The latter covalently modifies the POI with ubiquitin, which in turn targets the POI for degradation by the cell’s proteasome (Figure 1b) [13]. Due to the PROTAC’s modular structure and mechanism of action [13], any intracellular or transmembrane (but not extracellular) POI can be targeted for degradation by linking a specific POI ligand – as long as such ligand can be generated – to an E3 ligase ligand [15].
Host-mycobiome metabolic interactions in health and disease
Published in Gut Microbes, 2022
Neelu Begum, Azadeh Harzandi, Sunjae Lee, Mathias Uhlen, David L. Moyes, Saeed Shoaie
Genome-scale metabolic models (GSMM) are a systematic and curated method to establish genotype-phenotype relationships. GSMM aim to bridge together the complex network of genes, reactions and thousands of metabolites in silico while sustaining full metabolic flux functionality of the system. The functionality of a model refers to the natural ability of the model to undertake reactions, a realistic rate of energy consumption, rate of energy production and apply physio-chemical laws and environmental input to create a system that is true-to-life.168 The conversion of the reactions into a stoichiometric matrix allows mathematical inferences to integrate data into a predictive biological framework called constraint-based modelling.169 This developmental process of integration requires automated and manual curation for efficient quality standards. The GSMM community has developed a MEMOTE suite package to ensure the models’ standardisation and functional feasibility.170 With synthetic biology approach of genome engineering techniques pave the way for validating fungal species’ biological mechanisms underlying these systematic alterations in response to different environmental changes such as response to anti-fungal drug and the host organism’s reaction during fungal infection (Martins-Santana et al., 2018).142Figure 2 demonstrates the step-by-step inferences for creating a GSMM and synthetic biology to determine the interaction of mycobiome within the community.
An affinity threshold for maximum efficacy in anti-PD-1 immunotherapy
Published in mAbs, 2022
Sarah C. Cowles, Allison Sheen, Luciano Santollani, Emi A. Lutz, Brianna M. Lax, Joseph R. Palmeri, Gordon J. Freeman, K. Dane Wittrup
Next, we sought to understand the pharmacokinetic clearance rate of our antibodies. Clearance rates were determined by measuring the concentration of the fluorophore-conjugated antibodies in the blood of tumor-bearing C57CL/6 mice over time (Figure 2). All the antibodies in our panel demonstrate similar rates of clearance both in a first rapid phase of tissue distribution and then a slow phase of excretion. Similar clearance rates were measured in non-tumor-bearing C57CL/6 mice (Supplemental Figure 8). As expected, for a low concentration target such as PD-1, pharmacokinetic curves do not show evidence of target-mediated drug disposition when comparing clearance rates in tumor-bearing and non-tumor bearing mice (Figure 2 and Figure S8). Thus, stoichiometric depletion is not expected to play a significant role in drug trafficking. The data show a somewhat slower clearance rate of the low-affinity antibodies, which may result from protein diffusion back from the tissue, as they do not bind as tightly to the target. While we expected a difference between the monovalent and bivalent constructs resulting from the differences in protein size,31 the data do not demonstrate any significant differences. These data demonstrated the consistent internalization and pharmacokinetic clearance rates of all our antibody constructs.