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1.
Article in English | MEDLINE | ID: mdl-38481365

ABSTRACT

BACKGROUND: Intradermal testing (IDT) with iodinated contrast media (ICMs) is an established diagnostic tool in patients with ICM hypersensitivity. Currently, it is unclear which test concentration is the more useful one, up to pure or up to 1:10 diluted ICMs. METHODS: We searched the literature database PubMed for eligible papers dealing with ICM allergy and their IDT results. We analyzed the data presented by the papers and compared the pooled groups tested with diluted and undiluted ICMs. RESULTS: We identified 29 eligible original papers, and extracted data of 1137 patients that formed the study population. Although in the cohort tested with diluted ICMs the number of tested ICMs was greater, the percentage of positive tests was significantly less (9.0% vs. 24.7%; P < 0.0001; OR 0.30 [0.26-0.34]). The frequency of positive tested culprit ICMs was also lesser in the group tested with diluted ICMs (31.0% vs. 72.5%; P < 0.0001; OR 0.17 [0.12-0.23]). The number of drug provocation tests (DPTs) was greater in patients with diluted IDTs (374 vs. 89; P < 0.0001; OR 2.54 [1.93-3.36]). We detected an increased sensitivity in patients with undiluted tests (0.774 vs. 0.282) and a nearly identical specificity in both groups (1 vs. 0.983). CONCLUSIONS: For the first time, we show that IDT up to pure ICM concentrations is superior to using diluted ICMs only. Possibly, we can reduce the number of DPTs when performing IDTs with pure ICMs. In the undiluted group, there were no hints for skin irritations or unspecific test reactions.

2.
Molecules ; 26(22)2021 Nov 09.
Article in English | MEDLINE | ID: mdl-34833859

ABSTRACT

Cisplatin (cisPt) is an important drug that is used against various cancers, including advanced lung cancer. However, drug resistance is still a major ongoing problem and its investigation is of paramount interest. Here, a high-resolution magic angle spinning (HR-MAS) NMR study is presented deciphering the metabolic profile of non-small cell lung cancer (NSCLC) cells and metabolic adaptations at different levels of induced cisPt-resistance, as well as in their de-induced counterparts (cells cultivated in absence of cisPt). In total, fifty-three metabolites were identified and quantified in the 1H-HR-MAS NMR cell spectra. Metabolic adaptations to cisPt-resistance were detected, which correlated with the degree of resistance. Importantly, de-induced cell lines demonstrated similar metabolic adaptations as the corresponding cisPt-resistant cell lines. Metabolites predominantly changed in cisPt resistant cells and their de-induced counterparts include glutathione and taurine. Characteristic metabolic patterns for cisPt resistance may become relevant as biomarkers in cancer medicine.


Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/metabolism , Metabolome , Nuclear Magnetic Resonance, Biomolecular , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology
3.
Quant Imaging Med Surg ; 11(9): 4028-4041, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34476187

ABSTRACT

BACKGROUND: Although several papers deal with "cross-reactivity" in patients with iodinated contrast medium (ICM) hypersensitivity reactions (HSRs), there is no in-depth knowledge of this phenomenon. To define ICM-groups as potential reaction partners and to identify any potential clinical relevance in patients with ICM-HSRs. METHODS: The literature database PubMed was searched for eligible papers dealing with ICM-allergy and "cross-reactivity". The data presented by the papers was analyzed and individual patient data was extracted for re-evaluation based on a definition for both 'polyvalent reactivity' and 'cross-reactivity' as well as for chemical structure-dependent ICM-groups. RESULTS: Twenty-five original papers (with n=340 extracted patients) formed the study population. Incidences of polyvalent reactivity were non-significantly higher than incidences of cross-reactivity (both range from 0% to 100%). Crossover evaluation in reaction pairings (culprit ICM A with ICM B versus culprit ICM B with ICM A) showed concordance of only 30%. Data support rather non-cross-reactivity (individual reaction pattern) than cross-reactivity constellations. CONCLUSIONS: The obtained results favour an individual reaction pattern, rather than a reactivity driven by chemical structures and so-called cross-reactivity.

4.
Int J Mol Sci ; 22(17)2021 Aug 31.
Article in English | MEDLINE | ID: mdl-34502377

ABSTRACT

Platinum compounds such as cisplatin (cisPt) embody the backbone of combination chemotherapy protocols against advanced lung cancer. However, their efficacy is primarily limited by inherent or acquired platinum resistance, the origin of which has not been fully elucidated yet, although of paramount interest. Using single cell inductively coupled plasma mass spectrometry (SC-ICP-MS), this study quantifies cisPt in single cancer cells and for the first time in isolated nuclei. A comparison of cisPt uptake was performed between a wild type (wt) cancer cell line and related resistant sublines. In both, resistant cells, wt cells, and their nuclei, cisPt uptake was measured at different incubation times. A lower amount of cisPt was found in resistant cell lines and their nuclei compared to wt cells. Moreover, the abundance of internalized cisPt decreased with increasing resistance. Interestingly, concentrations of cisPt found within the nuclei were higher than compared to cellular concentrations. Here, we show, that SC-ICP-MS allows precise and accurate quantification of metallodrugs in both single cells and cell organelles such as nuclei. These findings pave the way for future applications investigating the potency and efficacy of novel metallodrugs developed for cancer treatment.


Subject(s)
Cisplatin/pharmacology , Drug Resistance, Neoplasm/physiology , Lung Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cisplatin/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Humans , Mass Spectrometry/methods , Neoplasms/drug therapy , Single-Cell Analysis/methods , Spectrum Analysis
5.
Pharmaceuticals (Basel) ; 13(12)2020 Dec 16.
Article in English | MEDLINE | ID: mdl-33339451

ABSTRACT

The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasmagondii tachyzoites constitutively expressing ß-galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited T.gondii proliferation with IC50 values ranging from 90 to 539 nM, and seven derivatives displayed IC50 values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC50 values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC50 values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates 6-10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues 11-14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.

6.
Pharmaceuticals (Basel) ; 13(6)2020 05 29.
Article in English | MEDLINE | ID: mdl-32485798

ABSTRACT

Platinum compounds represent the backbone of combined chemotherapy protocols for advanced lung cancer. The mechanisms responsible for its frequent primary or acquired resistance to cisplatin (cisPt)-based chemotherapy remains enigmatic. The availability of two cell lines of the same origin, one resistant and the other sensitive, will facilitate research to reveal the mechanism of resistance formation. Lung adenocarcinoma cells, A240286S (A24), were cultivated in increasing cisPt concentrations over a prolonged time. After a significant increase in IC50 was measured, cultivation of the cells was continued in absence of cisPt and IC50s determined over a long period (>7 months). As a result, a cell line with lasting, high-level cisPt resistance, designated (D-)A24cisPt8.0, was obtained. The cells were cross-resistant to oxaliplatin and to pemetrexed at a low level. Previous publications have claimed that Leucine-rich repeat-containing protein 8 (LRRC8A and LRRC8D) of the volume-regulated anion channels (VRACs) affect cellular resistance to cisPt. Even though cisPt decreased LRRC8D expression levels, we showed by knockdown and overexpression experiments with LRRC8A and D that these proteins do not govern the observed cisPt resistance. The tumor cell sublines described here provide a powerful model to study the mechanisms of resistance to cisPt in lung cancer cells and beyond.

8.
Radiat Environ Biophys ; 58(2): 295-302, 2019 05.
Article in English | MEDLINE | ID: mdl-30799523

ABSTRACT

Currently, in the context of radiology, irradiation-induced and other genotoxic effects are determined by visualizing DSB-induced DNA repair through γ-H2AX immunofluorescence and direct counting of the foci by epifluorescence microscopy. This procedure, however, neglects the 3D nature of the nucleus. The aim of our study was to use confocal microscopy and 3D reconstructed images to improve documentation and analysis of γ-H2AX fluorescence signals after diagnostic examinations. Confluent, non-dividing MRC-5 lung fibroblasts were irradiated in vitro with a Cs-137 source and exposed to radiation doses up to 1000 mGy before fixation and staining with an antibody recognizing the phosphorylated histone variant γ-H2AX. The 3D distribution of γ-H2AX foci was visualized using confocal laser scanning microscopy. 3D reconstruction of the optical slices and γ-H2AX foci counting were performed using Imaris Image Analysis software. In parallel, γ-H2AX foci were counted visually by epifluorescence microscopy. In addition, whole blood was exposed ex vivo to the radiation doses from 200 to 1600 mGy. White blood cells (WBCs) were isolated and stained for γ-H2AX. In fibroblasts, epifluorescence microscopy alone visualized the entirety of fluorescence signals as integral, without correct demarcation of single foci, and at 1000 mGy yielded on average 11.1 foci by manual counting of 2D images in comparison to 36.1 foci with confocal microscopy and 3D reconstruction (p < 0.001). The procedure can also be applied for studies on WBCs. In contrast to epifluorescence microscopy, confocal microscopy and 3D reconstruction enables an improved identification of DSB-induced γ-H2AX foci, allowing for an unbiased, ameliorated quantification.


Subject(s)
Cesium Radioisotopes , DNA Breaks, Double-Stranded , Fibroblasts/radiation effects , Histones/metabolism , Cell Line , Fibroblasts/metabolism , Fluorescence , Humans , Leukocytes/metabolism , Leukocytes/radiation effects , Microscopy, Confocal , Microscopy, Fluorescence
9.
Eur Radiol ; 29(8): 4044-4049, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30643943

ABSTRACT

PURPOSE: The aim of this study is to identify the micro-mechanical characteristics that define biopsy performance in normal ex vivo animal organs. MATERIALS AND METHODS: Three biopsy systems with differences of needle external diameter, tray height and effective tray length were assessed. Sampling was performed in porcine liver and kidneys with commercially labelled 14G, 16G and 18G, using 2-cm throw needle systems. Five samples were obtained per needle size and per organ, and the experiment was repeated twice for a total of 90 biopsy cores. Samples were analysed and compared in terms of macroscopic aspect, sample length, weight and tissue architecture. RESULTS: The system with the longest effective needle tray (system A) has shown significant superiority (p < 0.001) versus the other systems regarding the mean weight of tissue obtained for all needle sizes. Furthermore, the 14G needle of system A has shown superiority regarding the number of portal spaces and the 16G regarding the length of kidney fragments obtained. CONCLUSION: The outcomes obtained with the different biopsy systems were not equal. The micro-mechanical characteristic that appears to influence the quantity and quality of the obtained tissue is the effective needle tray length and not the needle external diameter or the needle tray height. This information should be taken into account in the future design of biopsy needle systems, particularly when potentially used in the assessment of biomarkers and the characterisation of tumour micro-environment. KEY POINTS: • The amount of obtained tissue mass is not the same among percutaneous biopsy needle systems. • There are different micro-mechanical characteristics that condition the amount of obtained tissue. • The micro-mechanical characteristic that offers more tissue mass for the same calibre is the effective length of the needle tray.


Subject(s)
Biopsy, Large-Core Needle/instrumentation , Kidney Diseases/diagnosis , Kidney/pathology , Liver Diseases/diagnosis , Liver/pathology , Animals , Disease Models, Animal , Equipment Design , Swine
10.
Acta Radiol ; 60(3): 315-326, 2019 Mar.
Article in English | MEDLINE | ID: mdl-29890843

ABSTRACT

BACKGROUND: Mouse models of human-malignant-melanoma (MM) are important tools to study tumor dynamics. The enhanced green fluorescent protein (EGFP) is widely used in molecular imaging approaches, together with optical scanners, and fluorescence imaging. PURPOSE: Currently, there are no data available as to whether other fluorescent proteins are more suitable. The goal of this preclinical study was to analyze two fluorescent proteins of the GFP superfamily under real-time in vivo conditions using fluorescence reflectance imaging (FRI). MATERIAL AND METHODS: The human melanoma cell line MeWo was stable transfected with one plasmid: pEGFP-C1 or pDsRed1-N1. We investigated two severe combined immunodeficiency (SCID)-mice groups: A (solid xenografts) and B (xenografts as metastases). After three weeks, the animals were weekly imaged by FRI. Afterwards the mice were euthanized and metastases were imaged in situ: to quantify the cutis-dependent reduction of emitted light, we compared signal intensities obtained by metastases in vivo with signal intensities obtained by in situ liver parenchyma preparations. RESULTS: More than 90% of cells were stable transfected. EGFP-/DsRed-xenograft tumors had identical growth kinetics. In vivo the emitted light by DsRed tumors/metastases was much brighter than by EGFP. DsRed metastases were earlier (3 vs. 5 weeks) and much more sensitive detectable than EGFP metastases. Cutis-dependent reduction of emitted light was greater in EGFP than in DsRed mice (tenfold). Autofluorescence of DsRed was lower than of EGFP. CONCLUSION: We established an in vivo xenograft mouse model (DsRed-MeWo) that is reliable, reproducible, and superior to the EGFP model as a preclinical tool to study innovative therapies by FRI under real-time in vivo conditions.


Subject(s)
Green Fluorescent Proteins/pharmacokinetics , Melanoma/diagnostic imaging , Animals , Cell Line, Tumor , Disease Models, Animal , Heterografts , Humans , Luminescent Proteins/pharmacokinetics , Male , Mice , Mice, SCID , Microscopy, Fluorescence , Random Allocation , Transfection , Tumor Burden
11.
Magn Reson Imaging ; 49: 1-3, 2018 06.
Article in English | MEDLINE | ID: mdl-29247752

ABSTRACT

Anaphylaxis against gadolinium based contrast agents (GBCAs) has been reported in all severity grades but is less frequent than hypersensitivity/allergy against iodinated contrast materials. Once a patient acquires such an adverse reaction a life-long premedication is usually the consequence in concert with GBCA-enhanced MR-imaging procedures. The usefulness of this prophylaxis has been questioned, and discussed controversially during the past. The herein presented case may shed some light into the dynamic of contrast-medium-induced hypersensitivity reactions.


Subject(s)
Contrast Media/adverse effects , Drug Hypersensitivity/etiology , Drug Hypersensitivity/physiopathology , Gadolinium/adverse effects , Adult , Drug Hypersensitivity/diagnosis , Humans , Remission, Spontaneous
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