Stereotactic Body Radiotherapy: is less fractionation more effective in adrenal and renal malignant lesions?

PURPOSE: Stereotactic body radiotherapy (SBRT) has become an excellent non-invasive alternative for many patients with primary renal cell carcinoma (RCC) and adrenal malignancies (AM). The aims of this study were to analyse how tumor-, patient- and treatment-related factors may influence the outcomes and side effects of SBRT and to assess its benefits as an alternative to surgery. METHODS: This retrospective, multicenter study included 25 lesions in 23 patients treated with SBRT using different devices (LINAC, CyberKnife® and Tomotherapy®). A multivariate linear regression was used for the statistical study. RESULTS: Local control time was higher than six months in more than 87% of patients and treatment response was complete for 73.68%. There was an overall 2-year survival of 40% and none of the deaths were secondary to renal or adrenal local progression. Patients treated with lower total radiation dose (mean [m] = 55 Gy) but less fractions with more dose per fraction (> 8.5 Gy) showed better outcome. Patients with previous chemotherapy and surgery treatments also showed higher complete response and disease-free survival (> 6 months). CONCLUSIONS: This study highlights the importance of ultra-hypofractionated regimens with higher doses per session. Thus, the referral of patients with RCC and AM to Radiotherapy and Oncology departments should be encouraged supporting the role of SBRT as a minimally invasive and outpatient treatment.

Is the sustainability of exposure to non-ionizing electromagnetic radiation possible?

Technological advances imply an increase in artificially generating sources of electromagnetic fields (EMF), therefore, resulting in a permanent exposure of people and the environment (electromagnetic pollution). Inconsistent results have been published considering the evaluated health effects. The purpose of this study was to review scientific literature on EMF to provide a global and retrospective perspective, on the association between human exposure to non-ionizing radiation (NIR, mainly radiofrequency-EMF) and health and environmental effects. Studies on the health effects of 5G radiation exposure have not yet been performed with sufficient statistical power, as the exposure time is still relatively short and also the latency and intensity of exposure to 5G. The safety standards only consider thermal effects, do not contemplate non-thermal effects. We consider relevant to communicate this knowledge to the general public to improve education in this field, and to healthcare professionals to prevent diseases that may result from RF-EMF exposures.

Analysis of Dynamic Plantar Pressure and Influence of Clinical-Functional Measures on Their Performance in Subjects with Bimalleolar Ankle Fracture at 6 and 12 Months Post-Surgery.

Recovery after ankle fracture surgery can be slow and even present functional deficits in the long term, so it is essential to monitor the rehabilitation process objectively and detect which parameters are recovered earlier or later. The aim of this study was (1) to evaluate dynamic plantar pressure and functional status in patients with bimalleolar ankle fracture 6 and 12 months after surgery, and (2) to study their degree of correlation with previously collected clinical variables. Twenty-two subjects with bimalleolar ankle fractures and eleven healthy subjects were included in the study. Data collection was performed at 6 and 12 months after surgery and included clinical measurements (ankle dorsiflexion range of motion and bimalleolar/calf circumference), functional scales (AOFAS and OMAS), and dynamic plantar pressure analysis. The main results found in plantar pressure were a lower mean/peak plantar pressure, as well as a lower contact time at 6 and 12 months with respect to the healthy leg and control group and only the control group, respectively (effect size 0.63 ≤ d ≤ 0.97). Furthermore, in the ankle fracture group there is a moderate negative correlation (-0.435 ≤ r ≤ 0.674) between plantar pressures (average and peak) with bimalleolar and calf circumference. The AOFAS and OMAS scale scores increased at 12 months to 84.4 and 80.0 points, respectively. Despite the evident improvement one year after surgery, data collected using the pressure platform and functional scales suggest that recovery is not yet complete.

Narrow Leafed Lupin (Lupinus angustifolius L.) ß-Conglutin Seed Proteins as a New Natural Cytotoxic Agents against Breast Cancer Cells.

Breast cancer (BC) is the most widespread tumor in women and the second type of most common cancer worldwide. Despite all the technical and medical advances in existing therapies, between 30 and 50% of patients with BC will develop metastasis, which contributes to the failure of existing treatments. This situation urges the need to find more effective prevention and treatment strategies like the use of plant-based nutraceutical compounds. In this context, we purified three Narrow Leafed Lupin (NLL) ß-conglutins isoforms using affinity-chromatography and evaluated their effectiveness in terms of viability, proliferation, apoptosis, stemness properties, and mechanism of action on both BC cell lines and a healthy one. NLL ß-conglutins proteins have very promising effects at the molecular level on BC cells at very low concentrations, emerging as a potential natural cytotoxic agent and preserving the viability of healthy cells. These proteins could act through a dual mechanism involving tumorigenic and stemness-related genes such as SIRT1 and FoxO1, depending on the state of p53. More studies must be carried out to completely understand the underlying mechanisms of action of these nutraceutical compounds in BC in vitro and in vivo, and their potential use for the inhibition of other cancer cell types.

Retrospective observational study correlating traumatic pelvic fractures and their associated injuries according to the Tile classification.

INTRODUCTION: Pelvic fractures due to high energy trauma present a high risk of associated injuries that compromise the functional and vital prognosis of the patients. The objective of this study was to analyze the relationship between traumatic pelvic fractures and their associated injuries according to the Tile classification. METHODS: Retrospective observational study of patients who suffered traumatic pelvic fractures (Type A, B or C of the Tile classification) with concomitant associated injuries, analyzing hemoglobin levels, between 6/2013 and 1/2016. RESULTS: A total of 42 patients were included; of those 69% (n = 29) were males, mean age was 48 years. 45% (n = 19) suffered traffic accidents and 26.2% (n = 11) falls. There was a different proportion in pelvic injuries: Tile A (n = 15, 35.7%), B (n = 20, 47.6%), and C (n = 7, 16.6%) of cases. 54.8% (n = 23) underwent surgery, 21.4% (n = 9) needed temporary or definitive external fixation. Significant differences were found between Tile A type and scapula fractures (P = .032), and Tile B with sacral fractures (P = .033) and visceral injuries (P = .049), while there is a tendency without a statistical significal between Tile C and costal fractures. 61.9% (n = 26) needed blood transfusion; 9.5% (n = 4) presented hypovolemic shock. CONCLUSIONS: Tile A pelvic fractures were associated with scapular fractures, and Tile B with transforaminal fractures of the sacrum and with visceral injuries (lungs, liver and genitourinary). The small number of Tile C prevent us to confirm an association with any pathology, although they are the ones which presnt more hemodynamically instability and thoracic injuries.

Influence of awake bruxism behaviors on fatigue of the masticatory muscles in healthy young adults

Abstract The present cross-sectional study aimed to analyze the relationship between awake bruxism and fatigue of masticatory muscles in healthy young adults. For this purpose, 121 graduate students participated in this study. Frequency of awake bruxism was collected for 7 consecutive days by ecological momentary assessment (EMA) using an online survey (mentimeter). Muscle fatigue was tested one day after EMA assessment, which consisted of voluntarily and continuously clenching at 30% (kgf/cm2) of maximum bite force (MBF) until exhaustion. The percentage of change in MBF after the clenching task, as compared to the MBF before the clenching task was measured. The average frequency of awake bruxism was 45.5% during 7 days. Sustained clenching resulted in a significant reduction in MBF values in the total sample (p < 0.05). Nevertheless, no significant correlation was found between frequency of awake bruxism behaviors and percent of change in MBF and endurance time during the fatigue test. Therefore, it can be concluded that young healthy adults present a relatively high frequency of awake bruxism behaviors that do not seem to impact the degree of masticatory muscle fatigue.

Matrix Metalloproteinases and Their Inhibitors as Potential Prognostic Biomarkers in Head and Neck Cancer after Radiotherapy.

Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour's biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy.

TFG-ß Nuclear Staining as a Potential Relapse Risk Factor in Early-Stage Non-Small-Cell Lung Cancer.

Nowadays, the impact of the tumor-immune microenvironment (TME) in non-small-cell lung cancer (NSCLC) prognosis and treatment response remains unclear. Thus, we evaluated the expression of PD-L1, tumor-infiltrating lymphocytes (TILs), and transforming growth factor beta (TGF-ß) in NSCLC to identify differences in TME, detect possible new prognostic factors, and assess their relationship. We retrospectively analyzed 55 samples from patients who underwent NSCLC surgery and had over a 5-year follow-up. PD-L1 expression was determined by immunohistochemistry following standard techniques. The presence of TILs was evaluated at low magnification and classified into two categories, "intense" and "non-intense". Cytoplasmic TGF-ß staining visualization was divided into four categories, and unequivocal nuclear staining in >1% of viable tumor cells was defined as "present" or "absent". Our aim was to identify differences in disease-free survival (DFS) and overall survival (OS). Tumor stage was the only objective prognostic factor for OS. PD-L1 expression and the presence of TILs had no prognostic impact, neither their combination. There seems to be a lower expression of PD-L1 and a higher expression of TILs in early stages of the disease. Our TGF-ß nuclear staining analysis was promising, since it was associated with worse DFS, revealing this protein as a possible prognostic biomarker of recurrence for resectable NSCLC.

Effects of Systemic or Local Administration of Mesenchymal Stem Cells from Patients with Osteoporosis or Osteoarthritis on Femoral Fracture Healing in a Mouse Model.

The purpose of this study was to analyze the regenerative capacity of mesenchymal stem cells (MSCs) in the treatment of fractures. MSCs extracted from patients with osteoporotic hip fractures or hip osteoarthritis undergoing hip replacement surgeries were cultured and injected into mice with femoral fracture. Two experimental models were established, one for the systemic administration of MSCs (n = 29) and another one for local administration (n = 30). Fracture consolidation was assessed by micro-CT and histology. The degree of radiological consolidation and corticalization was better with MSCs from osteoporosis than from osteoarthritis, being significant after systemic administration (p = 0.0302 consolidation; p = 0.0243 corticalization). The histological degree of consolidation was also better with MSCs from osteoporosis than from osteoarthritis. Differences in histological scores after systemic infusion were as follows: Allen, p = 0.0278; Huo, p = 0.3471; and Bone Bridge, p = 0.0935. After local administration at the fracture site, differences in histological scores were as follows: Allen, p = 0.0764; Huo, p = 0.0256; and Bone Bridge, p = 0.0012. As osteoporosis and control groups were similar, those differences depended on an inhibitory influence by MSCs from patients with osteoarthritis. In conclusion, we found an unexpected impairment of consolidation induced by MSCs from patients with osteoarthritis. However, MSCs from patients with osteoporosis compared favorably with cells from patients with osteoarthritis. In other words, based on this study and previous studies, MSCs from patients with osteoporosis do not appear to have worse bone-regenerating capabilities than MSCs from non-osteoporotic individuals of similar age.

Measuring Recovery and Understanding Long-Term Deficits in Balance, Ankle Mobility and Hip Strength in People after an Open Reduction and Internal Fixation of Bimalleolar Fracture and Their Impact on Functionality: A 12-Month Longitudinal Study.

To analyze how balance and other physical capacities evolved after surgery in patients with a bimalleolar fracture and how these capacities and clinical variables (immobilization or unloading time) contribute to restoring patients' functionality, 22 patients and 10 healthy people (HC) were assessed for static and dynamic balance (Y-Balance test, YBT), dorsiflexion ankle mobility (ADFROM) and hip strength at 6 and 12 months after surgery. Patients' functional status was assessed through the Olerud Molander Ankle Score (OMAS) and the American Orthopaedic Foot and Ankle Society (AOFAS) score. Twenty-one patients with ankle fractures who completed the study showed a worse static and dynamic balance at 6 months. The YBT in the anterior direction (YBTA) revealed balance deficits in the operated limb at 12 months compared to the non-operated limb (-5.6%) and the HC (-6.7%). They also showed a decreased ADFROM compared to the non-operated limb (-7.4°) and the HC (-11°). In addition, medium-term (6 months) deficits in abductor strength hip but no hip strength deficits were found at 12 months after surgery. Relative weight analyses showed that ADFROM and hip strength explained 35-63% of the YBTA variance and AOFAS/OMAS scores. Balance, hip strength and ADFROM seem to be reliable indexes for assessing the functional status of these patients. These results could help to understand the relationship between these physical capacities and the patients' perceived functional status.

Clinical-Functional Evaluation and Test-Retest Reliability of the G-WALK Sensor in Subjects with Bimalleolar Ankle Fractures 6 Months after Surgery.

Ankle fractures can cause significant functional impairment in the short and long term. In recent years, gait analysis using inertial sensors has gained special relevance as a reliable measurement system. This study aimed to evaluate the differences in spatiotemporal gait parameters and clinical−functional measurements in patients with bimalleolar ankle fracture and healthy subjects, to study the correlation between the different variables, and to analyze the test−retest reliability of a single inertial sensor in our study population. Twenty-two subjects with bimalleolar ankle fracture six months after surgery and eleven healthy subjects were included in the study. Spatiotemporal parameters were analyzed with the G-WALK sensor. Functional scales and clinical measures were collected beforehand. In the ankle fracture group, the main differences were obtained in bilateral parameters (effect size: 0.61 ≤ d ≤ 0.80). Between-group differences were found in cadence, speed, stride length, and stride time (effect size: 1.61 ≤ d ≤ 1.82). Correlation was moderate (0.436 < r < 0.554) between spatiotemporal parameters and clinical−functional measures, explaining up to 46% of gait performance. Test−retest reliability scores were high to excellent (0.84 ≤ ICC ≤ 0.98), with the worst results in the gait phases. Our study population presents evident clinical−functional impairments 6 months after surgery. The G-WALK can be considered a reliable tool for clinical use in this population.

Long-Term Outcomes of Dose-Escalated Hypofractionated Radiotherapy in Localized Prostate Cancer.

This retrospective study aimed to provide some clinical outcomes regarding effectiveness, toxicity, and quality of life in PCa patients treated with dose-escalated moderately hypofractionated radiation therapy (HFRT). Patients received HFRT to a total dose of 66 Gy in 22 fractions (3 Gy/fraction) delivered via volume modulated arc therapy (VMAT) in 2011-2016. Treatment effectiveness was measured by the biochemical failure-free survival rate. Toxicity was assessed according to the criteria of the Radiation Therapy Oncology Group (RTOG) and quality of life according to the criteria of the European Organization for Research and Treatment of Cancer (EORTC). In this regard, quality of life (QoL) was measured longitudinally, at a median of 2 and 5 years after RT. Enrolled patients had low-risk (40.2%), intermediate-risk (47.5%), and high-risk (12.3%) PCa. Median follow-up was 75 months. The biochemical failure-free survival rate was 94.2%. The incidence of acute grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicity was 9.84% and 28.69%, respectively. The incidence rate of late grade 2 or higher GI and GU toxicity was 1.64% and 4.10%, respectively. Expanded Prostate Cancer Index Composite (EPIC) scores showed that the majority of patients maintained their QoL. HFRT to 66 Gy with VMAT was associated with adequate biochemical control, low toxicity and good reported GU and GI quality of life.

Effective Osteogenic Priming of Mesenchymal Stem Cells through LNA-ASOs-Mediated Sfrp1 Gene Silencing.

Mesenchymal stem cell (MSC) transplantation has emerged as a promising approach for bone regeneration. Importantly, the beneficial effects of MSCs can be improved by modulating the expression levels of specific genes to stimulate MSC osteogenic differentiation. We have previously shown that Smurf1 silencing by using Locked Nucleic Acid-Antisense Oligonucleotides, in combination with a scaffold that sustainably releases low doses of BMP-2, was able to increase the osteogenic potential of MSCs in the presence of BMP-2 doses significantly smaller than those currently used in the clinic. This would potentially allow an important reduction in this protein in MSs-based treatments, and thus of the side effects linked to its administration. We have further improved this system by specifically targeting the Wnt pathway modulator Sfrp1. This approach not only increases MSC bone regeneration efficiency, but is also able to induce osteogenic differentiation in osteoporotic human MSCs, bypassing the need for BMP-2 induction, underscoring the regenerative potential of this system. Achieving successful osteogenesis with the sole use of LNA-ASOs, without the need of administering pro-osteogenic factors such as BMP-2, would not only reduce the cost of treatments, but would also open the possibility of targeting these LNA-ASOs specifically to MSCs in the bone marrow, allowing us to treat systemic bone loss such as that associated with osteoporosis.

Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development.

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%->50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity (p = 0.043) and MMP-3 percentage (p = 0.018) and intensity, (p = 0.025) present statistically significant associations with the variable group (control-case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.

Methylation of the Sclerostin (SOST) Gene in Serum Free DNA: A New Bone Biomarker?

Introduction: Cell-free DNA (cfDNA) methylation is an important molecular biomarker, which provides information about the regulation of gene expression in the tissue of origin. There is an inverse correlation between SOST gene methylation and expression levels. Methods: We analyzed SOST promoter methylation in cfDNA from serum, and compared it with DNA from blood and bone cells from patients undergoing hip replacement surgery. We also measured cfDNA methylation in 28 osteoporotic patients at baseline and after 6 months of antiosteoporotic therapy (alendronate, teriparatide, or denosumab). Results: SOST gene promoter methylation levels in serum cfDNA were very similar to those of bone-derived DNA (79% ± 12% and 82% ± 7%, respectively), but lower than methylation levels in blood cell DNA (87% ± 10%). Furthermore, there was a positive correlation between an individual's SOST DNA methylation values in serum and bone. No differences in either serum sclerostin levels or SOST methylation were found after 6-months of therapy with antiosteoporotic drugs. Conclusions: Our results suggest that serum cfDNA does not originate from blood cells, but rather from bone. However, since we did not confirm changes in this marker after therapy with bone-active drugs, further studies examining the correlation between bone changes of SOST expression and SOST methylation in cfDNA are needed to confirm its potential role as a bone biomarker.

Long Noncoding RNAs as Bone Marrow Stem Cell Regulators in Osteoporosis.

Long noncoding RNAs (lncRNAs) contribute toward regulating gene expression and cell differentiation and may be involved in the pathogenesis of several diseases. The objective of this study was to determine the expression patterns of lncRNAs in bone marrow mesenchymal stem cells (BMSCs) derived from patients with osteoporotic fractures and their relevance to osteogenic function. The BMSCs were isolated from the femoral head of patients with hip fractures (FRX) and controls with osteoarthritis (OA). We found 74 differentially expressed genes between FRX and OA, of which 33 were of the lncRNA type. Among them, 52 genes (20 lncRNAs) were replicated in another independent dataset. The differentially expressed lncRNAs were over-represented among those correlated with differentially expressed protein-coding genes. In addition, the comparison of pre- and post-differentiated paired samples revealed 163 differentially expressed genes, of which 99 were of the lncRNA type. Among them, the overexpression of LINC00341 induced an upregulation of typical osteoblastic genes. In conclusion, the analysis of lncRNA expression in BMSCs shows specific patterns in patients with osteoporotic fractures, as well as changes associated with osteogenic differentiation. The regulation of bone genes through lncRNAs might bring new opportunities for designing bone anabolic therapies in systemic and localized bone disorders.

CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer.

Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial-mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.

miRNAs as radio-response biomarkers for breast cancer stem cells.

In breast cancer (BC), the presence of cancer stem cells (CSCs) has been related to relapse, metastasis, and radioresistance. Radiotherapy (RT) is an extended BC treatment, but is not always effective. CSCs have several mechanisms of radioresistance in place, and some miRNAs are involved in the cellular response to ionizing radiation (IR). Here, we studied how IR affects the expression of miRNAs related to stemness in different molecular BC subtypes. Exposition of BC cells to radiation doses of 2, 4, or 6 Gy affected their phenotype, functional characteristics, pluripotency gene expression, and in vivo tumorigenic capacity. This held true for various molecular subtypes of BC cells (classified by ER, PR and HER-2 status), and for BC cells either plated in monolayer, or being in suspension as mammospheres. However, the effect of IR on the expression of eight stemness- and radioresistance-related miRNAs (miR-210, miR-10b, miR-182, miR-142, miR-221, miR-21, miR-93, miR-15b) varied, depending on cell line subpopulation and clinicopathological features of BC patients. Therefore, clinicopathological features and, potentially also, chemotherapy regimen should be both taken into consideration, for determining a potential miRNA signature by liquid biopsy in BC patients treated with RT. Personalized and precision RT dosage regimes could improve the prognosis, treatment, and survival of BC patients.

Matrix metalloproteases and TIMPs as prognostic biomarkers in breast cancer patients treated with radiotherapy: A pilot study.

Breast cancer (BC) is the most common tumour in women and one of the most important causes of cancer death worldwide. Radiation therapy (RT) is widely used for BC treatment. Some proteins have been identified as prognostic factors for BC (Ki67, p53, E-cadherin, HER2). In the last years, it has been shown that variations in the expression of MMPs and TIMPs may contribute to the development of BC. The aim of this pilot work was to study the effects of RT on different MMPs (-1, -2, -3, -7, -8, -9, -10, -12 and -13) and TIMPs (-1 to -4), as well as their relationship with other variables related to patient characteristics and tumour biology. A group of 20 BC patients treated with RT were recruited. MMP and TIMP serum levels were analysed by immunoassay before, during and after RT. Our pilot study showed a slight increase in the levels of most MMP and TIMP with RT. However, RT produced a significantly decrease in TIMP-1 and TIMP-3 levels. Significant correlations were found between MMP-3 and TIMP-4 levels, and some of the variables studied related to patient characteristics and tumour biology. Moreover, MMP-9 and TIMP-3 levels could be predictive of RT toxicity. For this reason, MMP-3, MMP-9, TIMP-3 and TIMP-4 could be used as potential prognostic and predictive biomarkers for BC patients treated with RT.

Radiation and Stemness Phenotype May Influence Individual Breast Cancer Outcomes: The Crucial Role of MMPs and Microenvironment.

Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor development.