scholarly journals Intracellular Water Lifetime as a Tumor Biomarker to Monitor Doxorubicin Treatment via FFC-Relaxometry in a Breast Cancer Model

2021 ◽  
Vol 11 ◽  
Author(s):  
Maria Rosaria Ruggiero ◽  
Simona Baroni ◽  
Valeria Bitonto ◽  
Roberto Ruiu ◽  
Smeralda Rapisarda ◽  
...  
Keyword(s):  
Rate Constants ◽  
Predictive Biomarker ◽  
Proton Relaxation ◽  
Tumor Biomarker ◽  
Early Assessment ◽  
Doxorubicin Treatment ◽  
Efflux Rate Constant ◽  
Water Efflux ◽  
Cellular Water

This study aims to explore whether the water exchange rate constants in tumor cells can act as a hallmark of pathology status and a reporter of therapeutic outcomes. It has been shown, using 4T1 cell cultures and murine allografts, that an early assessment of the therapeutic effect of doxorubicin can be detected through changes in the cellular water efflux rate constant kio. The latter has been estimated by analyzing the magnetization recovery curve in standard NMR T1 measurements when there is a marked difference in the proton relaxation rate constants (R1) between the intra- and the extra-cellular compartments. In cellular studies, T1 measurements were carried out on a relaxometer working at 0.5 T, and the required difference in R1 between the two compartments was achieved via the addition of a paramagnetic agent into the extracellular compartment. For in-vivo experiments, the large difference in the R1 values of the two-compartments was achieved when the T1 measurements were carried out at low magnetic field strengths. This task was accomplished using a Fast Field Cycling (FFC) relaxometer that was properly modified to host a mouse in its probe head. The decrease in kio upon the administration of doxorubicin is the result of the decreased activity of Na+/K+-ATPase, as shown in an independent test on the cellular uptake of Rb ions. The results reported herein suggest that kio can be considered a non-invasive, early and predictive biomarker for the identification of responsive patients immediately from the first doxorubicin treatment.

Cellular water and proton relaxation times of Thai rice kernels during grain development and storage

2019 ◽  
Vol 88 ◽  
pp. 65-70 ◽  
Author(s):  
Klitsadee Yubonmhat ◽  
Suriya Chinwong ◽  
Nattawoot Maleelai ◽  
Nath Saowadee ◽  
Wiwat Youngdee
Keyword(s):  
Relaxation Times ◽  
Proton Relaxation ◽  
Grain Development ◽  
Cellular Water ◽  
And Storage

scholarly journals OCT imaging of rod mitochondrial respiration in vivo

2021 ◽  
pp. 153537022110137
Author(s):  
Bruce A Berkowitz ◽  
Haohua Qian
Keyword(s):  
Signaling Pathway ◽  
Mitochondrial Respiration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Body ◽  
Subretinal Space ◽  
Outer Retina ◽  
Water Efflux ◽  
Resolution Imaging

There remains a need for high spatial resolution imaging indices of mitochondrial respiration in the outer retina that probe normal physiology and measure pathogenic and reversible conditions underlying loss of vision. Mitochondria are involved in a critical, but somewhat underappreciated, support system that maintains the health of the outer retina involving stimulus-evoked changes in subretinal space hydration. The subretinal space hydration light–dark response is important because it controls the distribution of vision-critical interphotoreceptor matrix components, including anti-oxidants, pro-survival factors, ions, and metabolites. The underlying signaling pathway controlling subretinal space water management has been worked out over the past 30 years and involves cGMP/mitochondria respiration/pH/RPE water efflux. This signaling pathway has also been shown to be modified by disease-generating conditions, such as hypoxia or oxidative stress. Here, we review recent advances in MRI and commercially available OCT technologies that can measure stimulus-evoked changes in subretinal space water content based on changes in the external limiting membrane-retinal pigment epithelium region. Each step within the above signaling pathway can also be interrogated with FDA-approved pharmaceuticals. A highlight of these studies is the demonstration of first-in-kind in vivo imaging of mitochondria respiration of any cell in the body. Future examinations of subretinal space hydration are expected to be useful for diagnosing threats to sight in aging and disease, and improving the success rate when translating treatments from bench-to-bedside.

scholarly journals Survey of water proton longitudinal relaxation in liver in vivo

2021 ◽  
Author(s):  
John Charles Waterton
Keyword(s):  
Normal Liver ◽  
Population Variation ◽  
Water Proton ◽  
Proton Relaxation ◽  
Literature Searching ◽  
Repeatability Error ◽  
Coefficients Of Variation ◽  
Weighted Means ◽  
Propagation Of Errors

Abstract Objective To determine the variability, and preferred values, for normal liver longitudinal water proton relaxation rate R1 in the published literature. Methods Values of mean R1 and between-subject variance were obtained from literature searching. Weighted means were fitted to a heuristic and to a model. Results After exclusions, 116 publications (143 studies) remained, representing apparently normal liver in 3392 humans, 99 mice and 249 rats. Seventeen field strengths were included between 0.04 T and 9.4 T. Older studies tended to report higher between-subject coefficients of variation (CoV), but for studies published since 1992, the median between-subject CoV was 7.4%, and in half of those studies, measured R1 deviated from model by 8.0% or less. Discussion The within-study between-subject CoV incorporates repeatability error and true between-subject variation. Between-study variation also incorporates between-population variation, together with bias from interactions between methodology and physiology. While quantitative relaxometry ultimately requires validation with phantoms and analysis of propagation of errors, this survey allows investigators to compare their own R1 and variability values with the range of existing literature.

scholarly journals Synergistic Experimental and Computational Investigation of the Bioorthogonal Reactivity of Substituted Aryltetrazines

2021 ◽  
Author(s):  
Umberto Battisti ◽  
Rocío García-Vázquez ◽  
Dennis Svatunek ◽  
Barbara Herrmann ◽  
Andreas Löffler ◽  
...  
Keyword(s):  
Kinetic Study ◽  
Solvent Effects ◽  
Rate Constants ◽  
Biomedical Applications ◽  
Aqueous Systems ◽  
Phenyl Substituent ◽  
Computational Investigation ◽  
Radiation Burden ◽  
Intrinsic Reactivity

Tetrazines (Tz) have been applied as bioorthogonal agents for various biomedical applications including pretargeted imaging approaches. In radioimmunoimaging, pretargeting increases the target-to-background ratio while simultaneously reducing the radiation burden. We have recently reported a strategy to directly 18F-label highly reactive tetrazines based on a 3-(3-fluorophenyl)-Tz core structure. Herein, we report a kinetic study on this versatile scaffold. A library of 40 different tetrazines was prepared, fully characterized, and investigated with emphasis on second order rate constants for the reaction with trans-cyclooctene (TCO). Our results reveal the effects of various substitution patterns and moreover demonstrate the importance of measuring reactivities in the solvent of interest, as click rates in different solvents do not necessarily correlate well. In particular, we report that tetrazines modified in 2-position of the phenyl substituent show high intrinsic reactivity towards TCO, which is diminished in aqueous systems by unfavorable solvent effects. The obtained results enable the prediction of the bioorthogonal reactivity and thereby facilitate the development of the next-generation of substituted aryltetrazines for in vivo application.

scholarly journals Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation

2020 ◽  
Author(s):  
Kui Wu ◽  
Nathan Yee ◽  
Sangeetha Srinivasan ◽  
Amir Mahmoodi ◽  
Michael Zakharian ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Unmet Need ◽  
Sodium Hyaluronate ◽  
Maximum Tolerated Dose ◽  
The Body ◽  
In Vivo Studies ◽  
Tumor Biomarker ◽  
Tumor Site

<div> <div> <div> <p>A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)- modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapy. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. Studies in rodents show that a single injection of the tetrazine-modified biopolymer, SQL70, efficiently captures SQP33 protodrug doses given at 10.8-times the maximum tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. </p> </div> </div> </div>

scholarly journals Specific cellular water dynamics observed in vivo by neutron scattering and NMR

2010 ◽  
Vol 12 (35) ◽  
pp. 10154 ◽  
Author(s):  
Marion Jasnin ◽  
Andreas Stadler ◽  
Moeava Tehei ◽  
Giuseppe Zaccai
Keyword(s):  
Neutron Scattering ◽  
Water Dynamics ◽  
Cellular Water

scholarly journals A New Approach for Early Assessment of the Epileptogenic Potential of Quinolones

1998 ◽  
Vol 42 (10) ◽  
pp. 2756-2758 ◽  
Author(s):  
Annie Delon ◽  
Claudine Pariat ◽  
Philippe Courtois ◽  
Serge Bouquet ◽  
William Couet
Keyword(s):  
Cerebrospinal Fluid ◽  
Animal Species ◽  
Early Assessment ◽  
New Approach ◽  
Drug Concentrations ◽  
Quinolone Antibiotics ◽  
Concentration Ratios

ABSTRACT The epileptogenic potential of pefloxacin and norfloxacin, two quinolone antibiotics, was investigated in vivo in three different animal species by measuring drug concentrations in cerebrospinal fluid (CSF), which is part of the biophase, at the onset of convulsions. Interestingly, the pefloxacin-to-norfloxacin concentration ratios in CSF were virtually constant across the species (7.0, 6.6, and 6.0 in mice, rats, and rabbits, respectively), suggesting that this approach could be used to predict the relative epileptogenic potential of quinolones in humans.

HUMAN MEIZOTHROMBIN 1, ITS ISOLATION AND PROPERTIES

1987 ◽  
Author(s):  
Zbigniew S Latallo ◽  
Craig M Jackson
Keyword(s):  
Rate Constants ◽  
Antithrombin Iii ◽  
Order Rate Constant ◽  
Red Cross ◽  
Apparent Lack ◽  
First Order ◽  
Order Rate ◽  
Matching Grant ◽  
Echis Carinatus

Meizothrombin (MT) and meizothrombin des Fragment 1 (MT1) are intermediates in the conversion of prothrombin to α-thrombin (αTH). Due to their transient character, properties of these enzymes are difficult to establish. Isolation of MT1 was achieved by affinity chromatography on D-Phe-Pro-Arginal (FPRal)immobilized on Affi-Gel 10 as originally employed for thrombin purification (Patel et al. Biochim.Biophys. Acta 748,321 (1983)). Human prethrombin 1 was activated with the purified activator from Echis carinatus venom in the presence of Ca++;, benzamidine and FPRal gel at pH 7.8. After exhaustive washing the MT1 was eluted with 0.1 M hydroxylamine in 0.15 M Na acetate buffer, pH 5.5. Under these conditions the MT1 is stable and can bestored at -70°C. Upon changing the pH of the preparation to 8.0, complete conversion into aTH occurred atroom temperature within 48 hours. Homogeneity of both preparations wasdemonstrated by PAGE. The Km and ke, values for MT1 measured on Tos-Gly-Pro-Arg pNA(0.1 M NaCl, 0.01 M TRIS, 0.01 M HEPES, 0.1% PEG, pH 7.8, 25°C) were 15.7 /iM and 126 s-1. The kinetic con stants for the aTH resulting from autocatalytic degradation of MT1 were indistinguishable from those previously established forαTH obtained by Xa activation i.e. 4.77 /μM and 126 s-1. Clotting activity of MT1 was found to be only one fifth as high as that of the resulting μTH(746 u/mg vs. 3900 u/mg as tested using the NIH standard) .Inhibitionof MTl by antithrombin III was alsomuch less rapid than αTH andmost importantly, it was not affected by high affinity heparin( Mr20,300). Under conditions of the experiment (0.3 M NaCl, 0.0rl M TRIS, 0.01 M HEPES, 2.5 mM EDTA, 0.1% PEG, pH 7.8, 25°C; [ATIII] 100 nM, [E] 10 nM), the pseudo first order rate constants in the absence of heparin were 4.04 × 10-3V1 (MTl) and 1.13 × 10-3V1 (αTH), giving apparent second order rate constants of 4.04 × 103 and 1.13 × 10-4M-1s-1. In the presence of 4.5 nM of heparin the observed first order rate constant for MTl remained unchanged whereas it increased to 6.241 × 10-3s-1 (5.5 fold) for αTH. This apparent lack of an effect of heparin may be of significance in vivo.Supported by a Matching Grant from the American National Red Cross and by the Southeastern Michigan Blood Service.

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