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- Molecular changes in cardiac tissue as a new marker to predict cardiac dysfunction induced by radiotherapyPublication . Ribeiro, Sónia; Simões, Ana Rita; Rocha, Filipe; Vala, Inês Sofia; Pinto, Ana Teresa; Ministro, Augusto; Poli, Maria Esmeralda; Diegues, Isabel Maria; Pina, Maria Filomena; Benadjaoud, Mohamed Amine; Flamant, Stephane; Tamarat, Radia; Osório, Hugo; Pais, Diogo; Casal, Diogo; Pinto, Fausto J.; Matthiesen, Rune; Fiuza, Manuela; Santos, Susana Constantino RosaThe contribution of radiotherapy, per se, 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 27.6 Gy, respectively. We demonstrate that myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of >15% from baseline) in a dose-dependent manner at 18 months. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Before GLS impairment detection, several tools (qRT-PCR, mass spectrometry, and western blot) were used to assess molecular changes in the cardiac tissue. The number/expression of several genes, proteins, and KEGG pathways, related to inflammation, fibrosis, and cardiac muscle contraction, were differently expressed in the cardiac tissue according to the cumulative dose. Subclinical cardiac dysfunction occurs in a dose-dependent manner as detected by molecular changes in cardiac tissue, a predictor of the severity of global longitudinal strain impairment. Moreover, there was no dose threshold below which no myocardial deformation impairment was detected. Our findings i) contribute to developing new markers and exploring non-invasive magnetic resonance imaging to assess cardiac tissue changes as an early predictor of cardiac dysfunction; ii) should raise red flags, since there is no dose threshold below which no myocardial deformation impairment was detected and should be considered in radiation-based imaging and -guided therapeutic cardiac procedures; and iii) highlights the need for personalized clinical approaches.
- Low doses of ionizing radiation activate endothelial cells and induce angiogenesis in peritumoral tissuesPublication . Gil Marques, Filipa; Poli, Maria Esmeralda; Malaquias, João; Carvalho, Tânia; Portêlo, Ana; Ramires, Afonso; Aldeia, Fernando; Ribeiro, Ruy M.; Vitorino, Emília; Diegues, Isabel; Costa, Luis; Coutinho, João; Pina, Maria Filomena; Mareel, Marc; Santos, Susana Constantino RosaPurpose: During radiotherapy the peritumoral tissues are daily exposed to subtherapeutic doses of ionizing radiation. Herein, the biological and molecular effects of doses lower than 0.8 Gy per fraction (LDIR), previously described as angiogenesis inducers, were assessed in human peritumoral tissues. Material and methods: Paired biopsies of preperitoneal adipose tissue were surgically collected from 16 patients diagnosed with locally advanced rectal cancer who underwent neo-adjuvant radiotherapy. One of the biopsies is located in the vicinity of the region where the tumor received the prescribed dose of radiation, and thus exposed to LDIR; the other specimen, outside all beam apertures, was used as an internal calibrator (IC). Microvessel density (MDV) was quantified by immunohistochemistry and the expression of angiogenic, pro-inflammatory, adhesion and oxidative stress genes was assessed by quantitative RT-PCR using exclusively endothelial cells (ECs) isolated by laser capture microdissection microscopy. Results: LDIR activated peritumoral ECs by significantly up-regulating the expression of several pro-angiogenic genes such as VEGFR1, VEGFR2, ANGPT2, TGFB2, VWF, FGF2, HGF and PDGFC and down-regulating the pro-inflammatory IL8 marker. Accordingly, the MVD was significantly increased in peritumoral tissues exposed to LDIR, compared to the IC. The patients that yielded a larger pro-angiogenic response, also showed the highest MVD. Conclusions: LDIR activate ECs in peritumoral tissues that are associated with increased MVD. Although the technological advances in radiotherapy have contributed to reduce the damage to healthy tissues over the past years, the anatomical regions receiving LDIR should be taken into account in the treatment plan report for patient follow-up and in future studies to correlate these doses with tumor dissemination.