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IN VIVO QUANTIFICATION OF HEAVY METALS IN BONE AND TOENAIL USING X-RAY FLUORESCENCE (XRF)Xinxin Zhang (8974130) 23 June 2020 (has links)
<p><b><i>Background and
Objective:</i></b> Pb
is a well-known toxic metal that can accumulate in bones over time and still
threatening large populations nowadays, even those who are environmentally
exposed to it. Strontium (Sr) is a metal directly related to bone health and
has been used in the treatment of osteoporosis disease as a supplement. Manganese
(Mn) is an essential nutrient in the body, yet excessive Mn is toxic and
affecting many organ systems. Another toxic metal, mercury (Hg), has been
poising different populations primarily through seafood consumptions,
especially inducing neurological disorders in infants and fetuses. Even though significant associations between
the above metal exposures and health outcomes have been recognized over the decades,
the current technologies are limited in assessing cumulative long-term
exposures <i>in vivo</i> to evaluate such
associations further. Bone and toenail are appropriate biomarkers to reflect
long-term exposure due to the longer half-life of these metals in them than in the traditional biomarkers. Therefore, this work evaluated the usefulness of portable x-ray
fluorescence (XRF) technology on <i>in
vivo</i> quantification of Pb and Sr in bone, and Mn and Hg in toenail.</p>
<p><b><i>Materials and
Methods:</i></b> The
portable XRF device was calibrated by using the Pb- and Sr-doped
bone-equivalent phantoms, and Mn- and Hg-doped nail-equivalent phantoms, correspondingly
in different projects. Seventy-six adults (38-95 years of age, 63 ± 11 years)
from Indiana, USA, were recruited to participate in this study. For the <i>in vivo</i> bone measurements, each
participant was measured at the mid-tibia bone using the portable XRF and K-shell
XRF system (KXRF). We estimated the correlation between the bone Pb concentration
measured by both devices to evaluate the use of the portable XRF in the bones. Using
the portable XRF, the bone Sr exposure of the study population were
simultaneously assessed with the bone Pb exposures. Besides, we analyzed the
mid-tibia bone Sr data of a Chinese population, which were measured with the
same portable XRF device by our research group. We also examined the extent to
which the detection limit (DL) of the portable XRF was influenced by scan time
and overlying soft tissue thickness for both Pb and Sr. </p>
<p>For the
exposure assessment of Mn and Hg in toenails, we first established system
calibrations and determined the DL with phantoms. In order to validate the portable XRF in a population
study, the recruited participants were measured at the big toenail by the device,
and their toenail clippings were analyzed by the inductively coupled plasma
spectrometry (ICP-MS). Besides, we analyzed the toenail data of an
occupationally-exposed population, collected by our collaborators in Boston. A
portable XRF device with the same model as ours was used in that study. </p>
<p><b><i>Results:</i></b> The uncertainty of <i>in vivo</i>
individual bone measurement increased with higher soft tissue thickness
overlying bone, and reduced with extending measurement time. With thickness ranging
from 2 to 6 mm, the uncertainty of a 3-minute <i>in vivo</i> measurement ranged from 1.8 to 6.3 ug/g (ppm) for bone Pb and from
1.3 to 2.3 ppm for bone Sr. Bone Pb measurements via portable XRF and KXRF were
highly correlated: R=0.48 for all participants, and R=0.73 among participants
with soft tissue thickness < 6 mm (72% of the sample). A trend of different bone
Sr concentrations was observed across the races and sexes. </p>
<p>The DL
of the portable XRF with 3-minute toenail measurements was 3.59 ppm for Mn and
0.58 ppm for Hg. The portable XRF and ICP-MS measurements were highly
correlated in the occupational populations for both Mn (R = 0.59) and Hg (R =
0.75). A positive correlation
(R = 0.34) was found for toenail Mn measurements in the environmentally-exposed
population, while a non-significant correlation was observed for toenail Hg due to the extremely low-level
of Hg (Mean = 0.1 ppm) in the study population. </p>
<p><b><i>Discussion and
Conclusion:</i></b>
The portable XRF could be a valuable tool for non-invasive <i>in vivo</i> quantification of bone Pb and Sr, especially for people
with thinner soft tissue; and of toenail Mn and Hg, especially for people with
moderate- to high-level exposures. </p>
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Anticancer water-soluble organoruthenium complexes: synthesis and preclinical evaluationPitto-Barry, Anaïs, Azmanova, Maria, Rafols, Laia, Cooper, Patricia A., Seaton, Colin C., Shnyder, Steven 18 July 2022 (has links)
Yes / The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on ROS production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay. / The support of the Royal Society (University Research Fellowship No. URF150295, and RGF\EA\201001), the Academy of Medical Sciences/ The Wellcome Trust/ The Government Department of Business, Energy and Industrial/ The British Heart Foundation Springboard Award (SBF003\1170), and the CNRS is acknowledged. LRP is supported by a PhD studentship funded by the University of Bradford.
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Preclinical Anticancer Activity of an Electron-Deficient Organoruthenium(II) ComplexSoldevila-Barreda, Joan J., Azmanova, Maria, Pitto-Barry, Anaïs, Cooper, Patricia A., Shnyder, Steven, Barry, Nicolas P.E. 04 September 2020 (has links)
Yes / Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt-resistance mechanisms. Electron-deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron-deficient organoruthenium complex [(p-cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53−/−), and non-small cell lung H460 cancer cell lines. It shows no cross-resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53-independent. In vivo evaluation in the hollow-fibre assay across a panel of cancer cell types and subcutaneous H460 non-small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow-up, this work is the first preclinical study of electron-deficient half-sandwich complexes and highlights their promise as anticancer drug candidates. / UF150295/Royal Society; University of Bradford; Government Department of Business, Energy and Industrial Strategy; SBF003\1170/British Heart Foundation Springboard Award; AMS_/Academy of Medical Sciences/United Kingdom
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