Dataset Information

Cardiac tissue remodeling as a new marker to predict cardiac dysfunction induced by radiotherapy.

ABSTRACT: The contribution of radiotherapy, per se, in late cardiotoxicity remains controversial. An experimental model was developed, in which rat hearts were exposed to a range of ionizing radiation doses, to clarify its impact on the development of early cardiac dysfunction. Rat’s hearts were exposed to daily doses of 0.04, 0.3 and 1.2 Gy, for 23 days, achieving cumulative doses of 0.92, 6.9 and 27.6 Gy, respectively. Myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of > 15% from baseline) in a dose-dependent manner. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Prior to GLS impairment detection, several tools (qRT-PCR, mass spectrometry and western blot) were used to assess cardiac tissue remodeling. The number/expression of several genes, proteins and KEGG pathways, related to inflammation, fibrosis and cardiac muscle contraction, were found to be differently expressed in the cardiac tissue, according to the cumulative dose. Subclinical cardiac dysfunction occurred in a dose-dependent manner as detected by cardiac tissue remodeling, a predictor of the severity of global longitudinal strain impairment. Moreover, there is no dose threshold below which no myocardial deformation impairment was detected. These findings may contribute to i) develop new markers and explore non-invasive magnetic resonance imaging to assess cardiac tissue remodeling as an early predictor of cardiac dysfunction; ii) improve radiation-based diagnostic and therapeutic cardiac procedures; iii) highlight the need for personalized clinical approaches.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart

SUBMITTER: Hugo Osorio

LAB HEAD: Susana Constantino Rosa Santos

PROVIDER: PXD033194 | Pride | 2022-09-08

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 109

Publications

Molecular Changes In Cardiac Tissue As A New Marker To Predict Cardiac Dysfunction Induced By Radiotherapy.

Ribeiro Sónia S Simões Ana Rita AR Rocha Filipe F Vala Inês Sofia IS Pinto Ana Teresa AT Ministro Augusto A Poli Esmeralda E Diegues Isabel Maria IM Pina Filomena F Benadjaoud Mohamed Amine MA Flamant Stephane S Tamarat Radia R Osório Hugo H Pais Diogo D Casal Diogo D Pinto Fausto José FJ Matthiesen Rune R Fiuza Manuela M Constantino Rosa Santos Susana S

Frontiers in oncology 20220726

The contribution of radiotherapy, <i>per se</i>, to late cardiotoxicity remains controversial. To clarify its impact on the development of early cardiac dysfunction, we developed an experimental model in which the hearts of rats were exposed, in a fractionated plan, to clinically relevant doses of ionizing radiation for oncological patients that undergo thoracic radiotherapy. Rat hearts were exposed to daily doses of 0.04, 0.3, and 1.2 Gy for 23 days, achieving cumulative doses of 0.92, 6.9, and ...[more]

PMID: 35957913

Similar Datasets

Project description:Background: The effects of dose-rate and its implications on radiation biodosimetry methods are not well studied in the context of large-scale radiological scenarios. There are significant health risks to individuals exposed to an acute dose in such an event, but the most realistic scenario would be a combination of exposure to both high and low dose-rates, from both external and internal radioactivity. It is important therefore, to understand the biological response to prolonged exposure; and further, discover biomarkers that can be used to estimate the extent of damage from low-dose rate exposure and propose appropriate clinical treatment. Methods: We irradiated human whole blood ex vivo to three doses, 0.56 Gy, 2.25 Gy and 4.45 Gy, using two dose rates: 1.1Gy/min and 3.1mGy/min. After 24 hours, we isolated RNA from blood cells and hybridized these to Agilent Whole Human genome microarrays. We validated the microarray results using qRT-PCR. Results: Microarray results showed that there were 454 significantly differentially expressed genes after prolonged exposure to all doses. After acute exposure, 598 genes were differentially expressed to all doses combined. Gene ontology terms enriched in both sets of genes were related to immune processes and B cell mediated immunity. Genes responding to acute exposure was also enriched in functions related to natural killer cell activation and cell-to-cell signaling. As expected, p53 pathway was found to be significantly enriched at all doses and by both dose-rates of radiation. Prediction algorithms were able to distinguish between low dose-rate and acute exposures, on the basis of a group of genes. These maybe candidates for preliminary testing as markers for differences in gene expression based on dose-rate. Radiation induced gene expression was measured in ex vivo irradiated human blood, at the 24hr time point after irradiation. Doses (0.56 Gy, 2.2 Gy and 4.45 Gy) were delivered by two dose rates, acute dose rate of 1Gy/min and low dose rate of 3.1 mGy/min.

Project description:Purpose: The International Commission on Radiological Protection (ICRP) recently recommended reducing the occupational equivalent dose limit for the lens of the eye. Based primarily on a review of epidemiological data, the absorbed dose threshold is now considered to be 0.5 Gy for induction of acute opacities, reduced from the previous threshold of 2 Gy. However, direct mechanistic evidence to support an understanding of the underlying molecular mechanisms of damage is still lacking. To this end, we explored the effects of a broad dose-range of ionizing radiation exposure on gene expression changes in a human lens epithelial (HLE) cell-line in order to better understand the shape of the dose-response relationship and identify transcriptional thresholds of effects. Methods: HLE cells were exposed to doses of 0, 0.01, 0.05, 0.25, 0.5, 2, and 5 Gy of X-ray radiation at two dose rates (1.62 cGy/min and 38.2 cGy/min). Cell culture lysates were collected 20 h post-exposure and analysed using whole-genome RNA-sequencing. Pathways and dose-thresholds of biological effects were identified using benchmark dose (BMD) modeling. Results: Transcriptional responses were minimal at doses less than 2 Gy. At higher doses there were a significant number of differentially expressed genes (DEGs) (p < 0.05, fold change > |1.5|) at both dose rates, with 1308 DEGs for the low dose rate (LDR) and 840 DEGs for the high dose rate (HDR) exposure. Dose-response modeling showed that a number of genes exhibited non-linear bi-phasic responses, which was verified by digital droplet PCR. BMD analysis showed the majority of the pathways responded at BMD median values in the dose range of 1.5-2.5 Gy, with the lowest BMD median value being 0.6 Gy for the HDR exposure. The minimum pathway BMD median value for LDR exposure, however, was 2.5 Gy. Although the LDR and HDR exposures shared pathways involved in extracellular matrix reorganization and collagen production with BMD median value of 2.9 Gy, HDR exposures were more effective in activating pathways associated with DNA damage response, apoptosis, and cell cycling relative to LDR exposure. Conclusion: Overall, the results suggest that radiation induces complex non-linear transcriptional dose-response relationships that are dose-rate dependent. Pathways shared between the two dose rates may be important contributors to radiation-induced cataractogenesis. BMD analysis suggests that the majority of pathways are activated above 0.6 Gy, which supports current ICRP identified dose thresholds for deterministic effects to the lens of the eye of 0.5 Gy.

			Action	DRS
	B1.mzML	Mzml
	B1.mzid.gz	Mzid
	B1.raw	Raw
	B10.mzML	Mzml
	B10.mzid.gz	Mzid