Irene Calvente

Matrix metalloproteinases: potential therapy to prevent the development of second malignancies after breast radiotherapy.

Radiotherapy is widely used in the treatment of patients with breast cancer, but ionizing radiation-induced carcinogenesis has been described in several studies. Matrix metalloproteinases (MMPs) are a wide family of proteases secreted by tumour and microenvironmental cells that are directly linked with invasion and metastasis through complete extracellular matrix (ECM) breakage. In the past decade, MMPs have been associated with other carcinogenesis steps, including tumour growth and angiogenesis promotion. Moreover, in vitro studies have demonstrated an enhanced migration, invasiveness, and angiogenic ability of cancer cells after radiation exposure through an increase in MMP activity. These findings are consistent with clinical observations of breast cancer metastases raised in bone, lung and brain tissues after radiotherapy. The aim of this review was to analyse the current state of research on MMPs and report new insights into the potential of MMP-targeted therapy in combination with radiotherapy to decrease the risk of radiation-induced second malignancies and to improve the overall survival of breast cancer patients.

Tumor microenvironment and breast cancer progression: a complex scenario.

It is now widely accepted that the development and progression of a tumor toward the malignant phenotype is highly dependent on interactions between tumor cells and the tumor microenvironment. Different components of the tumor microenvironment may have stimulatory or inhibitory effects on tumor progression by regulating the gene expression repertoire in tumor cells and stromal cells. This review analyzes novel research findings on breast cancer progression, discussing acquisition of the metastatic phenotype in breast disease in relation to different aspects of cross-talk among components of the tumor microenvironment. Knowledge of the interaction of all of these factors would contribute to elucidating the mechanisms that disrupt regulatory/signaling cascades and downstream effects in breast cancer.

Involvement of free radicals in breast cancer

Researchers have recently shown an increased interest in free radicals and their role in the tumor microenvironment. Free radicals are molecules with high instability and reactivity due to the presence of an odd number of electrons in the outermost orbit of their atoms. Free radicals include reactive oxygen and nitrogen species, which are key players in the initiation and progression of tumor cells and enhance their metastatic potential. In fact, they are now considered a hallmark of cancer.However, both reactive species may contribute to improve the outcomes of radiotherapy in cancer patients. Besides, high levels of reactive oxygen species may be indicators of genotoxic damage in non-irradiated normal tissues. The purpose of this article is to review recent research on free radicals and carcinogenesis in order to understand the pathways that contribute to tumor malignancy.This review outlines the involvement of free radicals in relevant cellular events, including their effects on genetic instability through (growth factors and tumor suppressor genes, their enhancement of mitogenic signals, and their participation in cell remodeling, proliferation, senescence, apoptosis, and autophagy processes; the possible relationship between free radicals and inflammation is also explored. This knowledge is crucial for evaluating the relevance of free radicals as therapeutic targets in cancer.

Outdoor characterization of radio frequency electromagnetic fields in a Spanish birth cohort

There is considerable public concern in many countries about the possible adverse effects of exposure to non-ionizing radiation electromagnetic fields, especially in vulnerable populations such as children. The aim of this study was to characterize environmental exposure profiles within the frequency range 100kHz-6GHz in the immediate surrounds of the dwellings of 123 families from the INMA-Granada birth cohort in Southern Spain, using spot measurements. The arithmetic mean root mean-square electric field (ERMS) and power density (SRMS) values were, respectively, 195.79mV/m (42.3% of data were above this mean) and 799.01µW/m(2) (30% of values were above this mean); median values were 148.80mV/m and 285.94µW/m(2), respectively. Exposure levels below the quantification limit were assigned a value of 0.01V/m. Incident field strength levels varied widely among different areas or towns/villages, demonstrating spatial variability in the distribution of exposure values related to the surface area population size and also among seasons. Although recorded values were well below International Commission for Non-Ionizing Radiation Protection reference levels, there is a particular need to characterize incident field strength levels in vulnerable populations (e.g., children) because of their chronic and ever-increasing exposure. The effects of incident field strength have not been fully elucidated; however, it may be appropriate to apply the precautionary principle in order to reduce exposure in susceptible groups.

Does exposure to environmental radiofrequency electromagnetic fields cause cognitive and behavioral effects in 10-year-old boys?

The relationship between exposure to electromagnetic fields from non-ionizing radiation and adverse human health effects remains controversial. We aimed to explore the association of environmental radiofrequency-electromagnetic fields (RF-EMFs) exposure with neurobehavioral function of children. A subsample of 123 boys belonging to the Environment and Childhood cohort from Granada (Spain), recruited at birth from 2000 through 2002, were evaluated at the age of 9-11 years. Spot electric field measurements within the 100 kHz to 6 GHz frequency range, expressed as both root mean-square (S(RMS) and maximum power density (S(MAX)) magnitudes, were performed in the immediate surrounds of childreńs dwellings. Neurocognitive and behavioral functions were assessed with a comprehensive battery of tests. Multivariate linear and logistic regression models were used, adjusting for potential confounders. All measurements were lower than reference guideline limits, with median S(RMS) and S(MAX) values of 285.94 and 2759.68 μW/m(2), respectively. Most of the cognitive and behavioral parameters did not show any effect, but children living in higher RF exposure areas (above median S(RMS) levels) had lower scores for verbal expression/comprehension and higher scores for internalizing and total problems, and obsessive-compulsive and post-traumatic stress disorders, in comparison to those living in areas with lower exposure. These associations were stronger when S(MAX) values were considered. Although some of our results may suggest that low-level environmental RF-EMF exposure has a negative impact on cognitive and/or behavior development in children; given limitations in the study design and that the majority of neurobehavioral functioning tasks were not affected, definitive conclusions cannot be drawn.

Thyroid status and its association with cognitive functioning in healthy boys at 10 years of age.

OBJECTIVE Thyroid hormones (THs) are crucial for the correct maturation of the CNS and the neurodevelopment of the child. We aimed to investigate the association of TSH and free thyroxine (FT4) levels with cognitive functioning in children from the INMA-Granada cohort studied during their follow-up at the age of 9-11 years. DESIGN We evaluated 300 children from the original cohort, which comprised 668 eligible mother-son pairs recruited at birth from 2000 to 2002 in Granada (Spain). METHODS FT4 and TSH concentrations were measured, and cognitive development was assessed using neuropsychological tests (n=187). Children with chronic disease related to thyroid function and/or cognitive development were excluded. RESULTS Median TSH and FT4 levels were 3.1 μIU/ml and 1.2 ng/dl respectively. In multivariable regression analyses adjusted for maternal and child characteristics, children with TSH levels in the top tertile had worse verbal comprehension and immediate and long-term recall. Children with FT4 levels in the top tertile had better attention and lower impulsivity and were at a lower risk of scoring below the 20th percentile in intelligence quotient (OR=0.24; 95% CI=0.08-0.74; P=0.013) and in abstract reasoning ability (OR=0.28; 95% CI=0.09-0.88; P=0.029). CONCLUSION Our findings indicate that circulating THs and TSH may in the top tertile have an impact on cognitive functions; thus, higher TSH slightly but significantly increased the risk of a lower score in certain neuropsychological tests.

Characterization of Indoor Extremely Low Frequency and Low Frequency Electromagnetic Fields in the INMA-Granada Cohort

Objective To characterize the exposure to electric fields and magnetic fields of non-ionizing radiation in the electromagnetic spectrum (15 Hz to 100 kHz) in the dwellings of children from the Spanish Environment and Childhood-“INMA” population-based birth cohort. Methodology The study sample was drawn from the INMA-Granada cohort. Out of 300 boys participating in the 9–10 year follow-up, 123 families agreed to the exposure assessment at home and completed a specific ad hoc questionnaire gathering information on sources of non-ionizing radiation electric and magnetic fields inside the homes and on patterns of use. Long-term indoor measurements were carried out in the living room and bedroom. Results Survey data showed a low exposure in the childrens homes according to reference levels of the International Commission on Non-Ionizing Radiation Protection but with large differences among homes in mean and maximum values. Daytime electrostatic and magnetic fields were below the quantification limit in 78.6% (92 dwellings) and 92.3% (108 dwellings) of houses, with an arithmetic mean value (± standard deviation) of 7.31±9.32 V/m and 162.30±91.16 nT, respectively. Mean magnetic field values were 1.6 lower during the night than the day. Nocturnal electrostatic values were not measured. Exposure levels were influenced by the area of residence (higher values in urban/semi-urban versus rural areas), type of dwelling, age of dwelling, floor of the dwelling, and season. Conclusion Given the greater sensitivity to extremely low-frequency electromagnetic fields of children and following the precautionary principle, preventive measures are warranted to reduce their exposure.

Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells

Abstract Purpose: To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition. Material and methods: Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 μM trichostatin-A (TSA)]. Results: IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression of mmp-1, mmp-3 and mmp-13 and of their regulators timp-1 and timp-2 relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhanced mmp and timp mRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA. Conclusion: These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition.

Radiofrequency exposure in the Neonatal Medium Care Unit

Abstract The aims of this study were to characterize electromagnetic fields of radiofrequency (RF‐EMF) levels generated in a Neonatal Medium Care Unit and to analyze RF‐EMF levels inside unit’s incubators. Spot and long‐term measurements were made with a dosimeter. The spot measurement mean was 1.51±0.48 V/m. Higher values were found in the proximity to the window and to the incubator evaluated. Mean field strength for the entire period of 17 h was 0.81 (±0.07) V/m and the maximum value was 1.58 V/m for long‐term RF‐EMF measurements in the incubator. Values found during the night period were higher than those found during the day period. It is important to consider RF‐EMF exposure levels in neonatal care units, due to some evidence of adverse health effects found in children and adults. Characterization of RF‐EMF exposure may be important to further investigate the mechanisms and underlying effects of electromagnetic fields (EMF) on infant health. A prudent avoidance strategy should be adopted because newborns are at a vulnerable stage of development and the actual impact of EMF on premature infants is unknown. HighlightsThe increasing use of RF‐EMF suggests an urgent need for more research in this field.Health consequences of RF‐EMF exposure on infants are not well known.Description of RF‐EMF exposure is vital in further study mechanisms on infant health.Considering newborns vulnerability, it is wise to adopt a prudent avoidance strategy.