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Worldwide, states are gazetting new Marine Protected Areas (MPAs) to meet the international commitment of protecting 30% of the seas by 2030. Yet, protection benefits only come into effect when an MPA is implemented with activated regulations and actively managed through continuous monitoring and adaptive management. To assess if actively managed MPAs are the rule or the exception, we used the Mediterranean and Black Seas as a case study, and retrieved information on monitoring activities for 878 designated MPAs in ten European Union (EU) countries. We searched for scientific and grey literature that provides information on the following aspects of MPA assessment and monitoring: ecological (e.g., biomass of commercially exploited fish), social (e.g., perceptions of fishers in an MPA), economic (e.g., revenue of fishers) and governance (e.g., type of governance scheme). We also queried MPA authorities on their past and current monitoring activities using a web-based survey through which we collected 123 responses. Combining the literature review and survey results, we found that approximately 16% of the MPA designations (N = 878) have baseline and/or monitoring studies. Most monitoring programs evaluated MPAs based solely on biological/ecological variables and fewer included social, economic and/or governance variables, failing to capture and assess the social-ecological dimension of marine conservation. To increase the capacity of MPAs to design and implement effective social-ecological monitoring programs, we recommend strategies revolving around three pillars: funding, collaboration, and technology. Following the actionable recommendations presented herein, MPA authorities and EU Member States could improve the low level of MPA monitoring to more effectively reach the 30% protection target delivering benefits for biodiversity conservation.
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Biodiversidad , Conservación de los Recursos Naturales , Animales , Biomasa , Ecosistema , Explotaciones Pesqueras , Peces/fisiología , Océanos y Mares , Encuestas y CuestionariosRESUMEN
Infection with hepatitis B virus (HBV) is a main risk factor for hepatocellular carcinoma (HCC). Extracellular vesicles, such as exosomes, play an important role in tumor development and metastasis, including regulation of HBV-related HCC. In this study, we have characterized exosome microRNA and proteins released in vitro from hepatitis B virus (HBV)-related HCC cell lines SNU-423 and SNU-182 and immortalized normal hepatocyte cell lines (THLE2 and THLE3) using microRNA sequencing and mass spectrometry. Bioinformatics, including functional enrichment and network analysis, combined with survival analysis using data related to HCC in The Cancer Genome Atlas (TCGA) database, were applied to examine the prognostic significance of the results. More than 40 microRNAs and 200 proteins were significantly dysregulated (p < 0.05) in the exosomes released from HCC cells in comparison with the normal liver cells. The functional analysis of the differentially expressed exosomal miRNAs (i.e., mir-483, mir-133a, mir-34a, mir-155, mir-183, mir-182), their predicted targets, and exosomal differentially expressed proteins (i.e., POSTN, STAM, EXOC8, SNX9, COL1A2, IDH1, FN1) showed correlation with pathways associated with HBV, virus activity and invasion, exosome formation and adhesion, and exogenous protein binding. The results from this study may help in our understanding of the role of HBV infection in the development of HCC and in the development of new targets for treatment or non-invasive predictive biomarkers of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Virus de la Hepatitis B , Neoplasias Hepáticas/genética , HepatocitosRESUMEN
Hepatocellular carcinoma (HCC) is a densely vascularized tumor that is highly dependent on angiogenic pathways to direct arterial blood flow to the growing neoplasm, though little is known about how the interaction of tumor and endothelial cells drives these processes and the degree of clinical importance. To this end, we examined the intercellular cross-talk between HepG2 (human HCC) and human endothelial progenitor cells (EPC) in a co-culture system that mimics some aspects of initial tumor parenchyma and stroma interactions. The results showed that the remote cell-to-cell (paracrine) interactions between HepG2 cells and EPC play a critical role in the differentiation and angiogenic activity of endothelial cells, possibly through intercellular signaling function of the exosomes released in the medium by HepG2 cells. The tumor-cell activated phenotype of EPC was associated with increased migration and elevated expression of ephrin-B2, and Delta-like 4 ligand (DLL4). Furthermore, ephrin-B2 was found to be overexpressed in HCC and cholangiocarcinoma tissue samples taken from humans. Overall, our results demonstrate that ephrin-B2 and Dll4 mediated co-dependence of HCC and EPC intercellular crosstalk in the initial stages of HCC establishment and development, a promising target for new clinical strategies.
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Células Progenitoras Endoteliales/metabolismo , Efrina-B2/metabolismo , Exosomas/metabolismo , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Modelos Biológicos , Comunicación Paracrina/genética , Proteínas Adaptadoras Transductoras de Señales , Proteínas de Unión al Calcio , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Muerte Celular , Movimiento Celular , Técnicas de Cocultivo , Colágeno/química , Medios de Cultivo Condicionados/química , Medios de Cultivo Condicionados/farmacología , Medio de Cultivo Libre de Suero/química , Cámaras de Difusión de Cultivos , Combinación de Medicamentos , Células Progenitoras Endoteliales/citología , Células Progenitoras Endoteliales/efectos de los fármacos , Efrina-B2/genética , Exosomas/química , Células Hep G2 , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Laminina/química , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Proteoglicanos/química , Transducción de Señal , Microambiente TumoralRESUMEN
Gene expression of formalin-fixed paraffin-embedded (FFPE) tissue may serve for molecular studies on cardiovascular diseases. Chemotherapeutics, such as doxorubicin (DOX) may cause heart injury, but the mechanisms of these side effects of DOX are not well understood. This study aimed to investigate whether DOX-induced gene expression in archival FFPE heart tissue in experimental rats would correlate with the gene expression in fresh-frozen heart tissue by applying RNA sequencing technology. The results showed RNA from FFPE samples was degraded, resulting in a lower number of uniquely mapped reads. However, DOX-induced differentially expressed genes in FFPE were related to molecular mechanisms of DOX-induced cardiotoxicity, such as inflammation, calcium binding, endothelial dysfunction, senescence, and cardiac hypertrophy signaling. Our data suggest that, despite the limitations, RNA sequencing of archival FFPE heart tissue supports utilizing FFPE tissues from retrospective studies on cardiovascular disorders, including DOX-induced cardiotoxicity.
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Cardiotoxicidad , Doxorrubicina , Formaldehído , Adhesión en Parafina , Análisis de Secuencia de ARN , Transcriptoma , Animales , Cardiotoxicidad/genética , Formaldehído/toxicidad , Doxorrubicina/efectos adversos , Análisis de Secuencia de ARN/métodos , Ratas , Masculino , Fijación del Tejido/métodos , Miocardio/patología , Miocardio/metabolismo , Perfilación de la Expresión Génica/métodos , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Neoadjuvant chemotherapy (NACT) is an increasingly used approach for treatment of breast cancer. The pathological complete response (pCR) is considered a good predictor of disease-specific survival. This study investigated whether circulating exosomal microRNAs could predict pCR in breast cancer patients treated with NACT. METHOD: Plasma samples of 20 breast cancer patients treated with NACT were collected prior to and after the first cycle. RNA sequencing was used to determine microRNA profiling. The Cancer Genome Atlas (TCGA) was used to explore the expression patterns and survivability of the candidate miRNAs, and their potential targets based on the expression levels and copy number variation (CNV) data. RESULTS: Three miRNAs before that NACT (miR-30b, miR-328 and miR-423) predicted pCR in all of the analyzed samples. Upregulation of miR-127 correlated with pCR in triple-negative breast cancer (TNBC). After the first NACT dose, pCR was predicted by exo-miR-141, while miR-34a, exo-miR182, and exo-miR-183 predicted non-pCR. A significant correlation between the candidate miRNAs and the overall survival, subtype, and metastasis in breast cancer, suggesting their potential role as predictive biomarkers of pCR. CONCLUSIONS: If the miRNAs identified in this study are validated in a large cohort of patients, they might serve as predictive non-invasive liquid biopsy biomarkers for monitoring pCR to NACT in breast cancer.
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MicroARN Circulante , MicroARNs , Neoplasias de la Mama Triple Negativas , Biomarcadores de Tumor/genética , MicroARN Circulante/uso terapéutico , Variaciones en el Número de Copia de ADN , Humanos , MicroARNs/genética , Terapia Neoadyuvante , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Doxorubicin (DOX) is a highly effective chemotherapy agent that often causes cardiotoxicity. Despite a number of extensive studies, the risk for DOX cardiotoxicity remains unpredictable. The majority of the studies on DOX-induced cardiotoxicity have been focused on the effects on cardiomyocytes that lead to contractile dysfunction. The roles of systemic inflammation, endothelial injury and neutrophil recruitment, all induced by the DOX, are increasingly recognized as the mechanisms that trigger the development and progression of DOX-induced cardiomyopathy. This review explores recent data regarding the possible mechanisms and biomarkers of early subclinical DOX-associated cardiotoxicity.
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Chemotherapy with doxorubicin (DOX) may cause unpredictable cardiotoxicity. This study aimed to determine whether the methylation signature of peripheral blood mononuclear cells (PBMCs) prior to and after the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) by >10%. DNA methylation of PBMCs from 9 patients with abnormal LVEF and 10 patients with normal LVEF were examined using Infinium HumanMethylation450 BeadChip. We have identified 14,883 differentially methylated CpGs at baseline and 18,718 CpGs after the first cycle of chemotherapy, which significantly correlated with LVEF status. Significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SLFN12, IRF6 and RNF39 in patients with abnormal LVEF. The pathway analysis found enrichment for regulation of transcription, mRNA splicing, pathways in cancer and ErbB2/4 signaling. The preliminary results from this study showed that the DNA methylation profile of PBMCs may predict the risk of DOX-induced cardiotoxicity prior to chemotherapy. Further studies with larger cohorts of patients are needed to confirm these findings.
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Doxorubicin (DOX), a widely used anticancer drug, has a dose-dependent cardiotoxicity, attributed mainly to free radical formation. The cardiomyocyte oxidative stress occurs rapidly after DOX treatment, resulting in harmful modifications to proteins, lipids, and DNA. Previous data showed that oral l-glutamine (Gln) prevented cardiac lipid peroxidation and maintained normal cardiac glutathione (GSH) levels in DOX-treated rats. Our aim in this study was to examine the effect of Gln on DOX-induced cardiac oxidative stress in a tumor-bearing host. Female Fisher344 rats with implanted MatBIII mammary tumors were randomized into 2 groups: a Gln group that received l-Gln (1 g.kg(-1).d(-1)) (n = 10) via a Gln-enriched diet and/or gavage with 50% Gln suspension during the whole experiment and a control group that was fed the same diet formulation without Gln and/or were gavaged with water. All rats received a single injection of 12 mg/kg DOX and were killed 3 d later. GSH levels of hearts, livers, tumors, and blood, as well as cardiac histological alterations, lipid peroxidation, peroxinitrite levels, and caspase-3 activation were determined. Cardiac physiologic alterations were assessed by ultrasound imaging before and 3 d after DOX administration. The Gln supplementation resulted in lower cardiac lipid peroxidation and peroxintrite levels and elevated cardiac catalase enzyme activity and GSH compared with the controls, without affecting those of the tumors. DOX-induced alterations of the echocardiographic parameters were significantly reduced in the Gln-supplemented rats. These data indicate that Gln is able to reduce the oxidative damage of cardiomyocytes that occurs soon after DOX administration and thus protects the heart of a tumor-bearing host from DOX-induced cardiomyopathy.
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Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , Glutamina/administración & dosificación , Glutamina/farmacología , Cardiopatías/inducido químicamente , Animales , Ingestión de Alimentos/efectos de los fármacos , Femenino , Glutatión/metabolismo , Cardiopatías/prevención & control , Peroxidación de Lípido/efectos de los fármacos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ácido Peroxinitroso/metabolismo , Ratas , Ratas Endogámicas F344RESUMEN
Radiofrequency ablation (RFA), a minimally invasive surgical procedure has an increasing application in the surgical treatment of tumors. Data indicate that RFA might stimulate anti-cancer immunity possibly through the induction of necrosis and heat shock proteins (HSP) expression. This study tests a hypothesis that RFA leads to bidirectional immunoregulation. Experimental rat breast tumors were treated with RFA, surgical excision or sham operation. RFA resulted in the highest NK cells infiltration, increased HSP70 expression and activation of caspase-3 enzyme in the tumor margins. A significant reduction of the circulatory regulatory T (Treg) cells was found in both RFA- and excision-treated rats, although less pronounced in the RFA-group. The splenocyte proliferation to tumor cell lysate was stronger in the RFA-treated rats in comparison with untreated tumor-bearing rats. The potential role of self-HSP for immunomodulation was examined using in vitro proliferation assay to tetanus toxoid using human peripheral leukocytes. The response to the tetanus toxoid was significantly suppressed by HSP90 plus auto-antibodies versus HSP90 or auto-antibodies alone. In conclusion, RFA reduced the circulatory Tregs although not as efficient as tumor excision. HSPs plus natural antibodies suppress the anti-tumor response probably by stimulating Tregs. Therefore, RFA may play a role in anti-cancer therapy if combined with Tregs suppression.
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Ablación por Catéter , Proteínas HSP70 de Choque Térmico/biosíntesis , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/cirugía , Mastectomía Segmentaria , Animales , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama , Caspasa 3/metabolismo , Recuento de Células , Proliferación Celular , Activación Enzimática , Femenino , Proteínas HSP70 de Choque Térmico/genética , Humanos , Inmunomodulación , Células Asesinas Naturales/patología , Neoplasias Mamarias Experimentales/patología , Ratas , Linfocitos T Reguladores/patología , Escape del TumorRESUMEN
Doxorubicin (DOX)-induced cardiotoxicity is a major limitation to its clinical application. Cardiotoxicity of DOX is dose-dependent that begins with the first dose. Oxidative stress and inflammation are involved in DOX-related cardiotoxicity. This study aimed to determine whether multiple markers of inflammation, hypercoagulability and endothelial injury correlate with the risk of early DOX-induced cardiotoxicity in breast cancer patients. Blood samples of 51 breast cancer patients treated with DOX-based chemotherapy were collected before (baseline) and after the first cycle of chemotherapy. The risk of cardiotoxicity was defined as an asymptomatic reduction of cardiac left ventricle ejection fraction (LVEF) >10% at completion of chemotherapy versus baseline. Plasma samples were examined for multiple biomarkers of inflammation, hypercoagulability and endothelial dysfunction, including C-reactive protein (CRP), thrombomodulin (TM), thrombin-antithrombin complex (TAT), myeloperoxidase (MPO), von Willebrand factor (vWF) and P-selectin. Surrogate markers of neutrophil extracellular traps (NETs) nucleosomes and double stranded DNA (dsDNA) were also measured. Patients with abnormal decline of LVEF >10% (n=21) had significantly elevated levels of MPO and TM both at baseline, and after the first dose of DOX-based chemotherapy relative to patients with normal LVEF (n=30) after adjusting for race, age, BMI and type of breast cancer. The first dose of DOX also induced significantly higher circulating levels of TAT complex and nucleosomes in patients at risk of cardiotoxicity in comparison with patients without. The comparison between the means of the biomarkers in after-before DOX-based chemotherapy of the two groups of patients showed significant differences for MPO, TAT complex and CRP. The results from this study suggest that the risk of DOX-induced cardiotoxicity in breast cancer is associated with endothelial dysfunction, inflammation and prothrombotic state before and after the first dose of chemotherapy.
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TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00203502.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama , Metilación de ADN/efectos de los fármacos , ADN de Neoplasias/metabolismo , Terapia Neoadyuvante , Regiones Promotoras Genéticas , Adulto , Bevacizumab/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Islas de CpG , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Factores de Transcripción/metabolismo , ADN Metiltransferasa 3BRESUMEN
Dysregulation of calcium homeostasis is a major mechanism of doxorubicin (DOX)-induced cardiotoxicity. Treatment with DOX causes activation of sarcoplasmic reticulum (SR) ryanodine receptor (RYR) and rapid release of Ca2+ in the cytoplasm resulting in depression of myocardial function. The aim of this study was to examine the effect of dantrolene (DNT) a RYR blocker on both the cardiotoxicity and antitumor activity of DOX in a rat model of breast cancer. Female F344 rats with implanted MAT B III breast cancer cells were randomized to receive intraperitoneal DOX twice per week (12 mg/kg total dose), 5 mg/kg/day oral DNT or a combination of DOX + DNT for 3 weeks. Echocardiography and blood troponin I levels were used to measure myocardial injury. Hearts and tumors were evaluated for histopathological alterations. Blood glutathione was assessed as a measure of oxidative stress. The results showed that DNT improved DOX-induced alterations in the echocardiographic parameters by 50%. Histopathologic analysis of hearts showed reduced DOX induced cardiotoxicity in the group treated with DOX + DNT as shown by reduced interstitial edema, cytoplasmic vacuolization, and myofibrillar disruption, compared with DOX-only-treated hearts. Rats treated with DNT lost less body weight, had higher blood GSH levels and lower troponin I levels than DOX-treated rats. These data indicate that DNT is able to provide protection against DOX cardiotoxicity without reducing its antitumor activity. Further studies are needed to determine the optimal dosing of DNT and DOX in a tumor-bearing host.
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To better predict population evolution of invasive species in introduced areas it is critical to identify and understand the mechanisms driving genetic diversity and structure in their native range. Here, we combined analyses of the mitochondrial COI gene and 11 microsatellite markers to investigate both past demographic history and contemporaneous genetic structure in the native area of the gastropod Tritia neritea, using Bayesian skyline plots (BSP), multivariate analyses and Bayesian clustering. The BSP framework revealed population expansions, dated after the last glacial maximum. The haplotype network revealed a strong geographic clustering. Multivariate analyses and Bayesian clustering highlighted the strong genetic structure at all scales, between the Black Sea and the Adriatic Sea, but also within basins. Within basins, a random pattern of genetic patchiness was observed, suggesting a superimposition of processes involving natural biological effects (no larval phase and thus limited larval dispersal) and putative anthropogenic transport of specimens. Contrary to the introduced area, no isolation-by-distance patterns were recovered in the Mediterranean or the Black Seas, highlighting different mechanisms at play on both native and introduced areas, triggering unknown consequences for species' evolutionary trajectories. These results of Tritia neritea populations on its native range highlight a mixture of ancient and recent processes, with the effects of paleoclimates and life history traits likely tangled with the effects of human-mediated dispersal.
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Gastrópodos/genética , Especies Introducidas , Animales , Teorema de Bayes , ADN Mitocondrial/genética , Ecosistema , Genética de Población , Mar Mediterráneo , Crecimiento DemográficoRESUMEN
Purpose: The aim of the present study was to evaluate the effects of different exercise interventions on quality of life parameters in breast cancer patients during 1 year of outpatient rehabilitation. Material and Methods: A total of 115 breast cancer patients met the eligibility criteria and completed the study. Participants were randomly allocated for the water exercise interventions (group A, n = 45), for the Pilates exercise interventions (group B, n = 40), and yoga exercise interventions (group C, n = 30). The 3 groups attended relevant programs for 1 year and received 144 rehabilitation sessions. Quality of life parameters were assessed using the Functional Assessment of Cancer Therapy questionnaire with a specific module for breast cancer patients (FACT-B). Quality of life data were recorded at baseline and after 6 and 12 months of exercise interventions. Results: A significant increase in quality of life indicators was observed in participants of all groups. Based on the results of the 12-month monitoring, patients of group A scored significantly more points for emotional well-being compared with group B and group C by 1.40 points (P < .05) and 1.69 points (P < .01), respectively, as well as by breast cancer subscale by 2.15 points (P < .05) compared with group B. Patients in group C scored significantly better compared with group A in social/family well-being by 2.80 points (P < .01). Conclusions: It was found that using water exercise intervention is more effective for improving emotional well-being and decreasing negative symptoms associated with breast cancer treatment compared with Pilates and yoga interventions, while yoga was more effective in improving social/family well-being. Further research on water interventions for different populations is warranted.
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Neoplasias de la Mama/fisiopatología , Neoplasias de la Mama/psicología , Ejercicio Físico/fisiología , Ejercicio Físico/psicología , Emociones/fisiología , Terapia por Ejercicio/métodos , Femenino , Humanos , Salud Mental , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Encuestas y Cuestionarios , Yoga/psicologíaRESUMEN
Malignancy depletes host glutathione (GSH) levels to increase treatment-related toxicity and increases itself to resist the treatments. Our previous studies have shown that dietary glutamine (GLN) prevented 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors through enhancing gut GSH release and reducing tumor GSH level. In addition, GSH synthesis, metabolism, and recycling are accomplished in gamma-glutamyl cycle. We hypothesized that the GLN prevention might be through a differential regulation of the gamma-glutamyl cycle enzymes. Female Sprague-Dawley rats were randomized into DMBA-tumor bearing, DMBA-treated, and control groups subdivided into GLN and water groups. GLN supplementation was given at 1 g/kg/day by gastric gavage. The activities and messenger RNA levels of gamma-glutamyl transpeptidase (GTP), gamma-glutamylcysteine synthetase (GCS), 5-oxo-L-prolinase (OPase), gamma-glutamyl transferase (GTF), and glutaminase (GLNase) were determined in gut mucosa and breast tumor using specific enzyme assays and semiquantitative reverse transcription polymerase chain reaction. GLN upregulated gut GTP, GCS, OPase, and GLNase in DMBA-tumor bearing, DMBA-treated, and/or control rats; however, it downregulated these enzymes in the tumor. The paradoxical effect of GLN on key GSH recycling enzymes in the gut versus tumor suggests that dietary supplemental GLN could be used in the clinical practice to increase the therapeutic index of cancer treatments by protecting normal tissues from, and sensitizing tumor cells to, chemotherapy and radiation-related injury.
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9,10-Dimetil-1,2-benzantraceno , Carcinógenos , Glutamina/farmacología , Glutatión/metabolismo , Neoplasias Mamarias Animales/enzimología , Animales , Dieta , Femenino , Glutamato-Cisteína Ligasa/genética , Glutamato-Cisteína Ligasa/metabolismo , Glutaminasa/genética , Glutaminasa/metabolismo , Glutatión/análisis , Mucosa Intestinal/química , Mucosa Intestinal/enzimología , Neoplasias Mamarias Animales/inducido químicamente , Piroglutamato Hidrolasa/genética , Piroglutamato Hidrolasa/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , gamma-Glutamiltransferasa/genética , gamma-Glutamiltransferasa/metabolismoRESUMEN
Cancer treatment with doxorubicin (DOX) can induce cumulative dose-dependent cardiotoxicity. Currently, there are no specific biomarkers that can identify patients at risk during the initial doses of chemotherapy. The aim of this study was to examine plasma cytokines/chemokines and potential cardiovascular biomarkers for the prediction of DOX-induced cardiotoxicity. Plasma samples were collected before (T0), and after the first (T1) and the second (T2) cycles of DOX-based chemotherapy of 27 breast cancer patients, including five patients who presented with >10% decline of left ventricular ejection fraction (LVEF), five patients with LVEF decline of 5-10%, and 17 patients who maintained normal LVEF at the end of chemotherapy (240 mg/m2 cumulative dose of DOX from four cycles of treatment). Multiplex immunoassays were used to screen plasma samples for 40 distinct chemokines, nine matrix metalloproteinases, 33 potential markers of cardiovascular diseases, and the fourth-generation cardiac troponin T assay. The results showed that the patients with abnormal decline of LVEF (>10%) had lower levels of CXCL6 and sICAM-1 and higher levels of CCL23 and CCL27 at T0; higher levels of CCL23 and lower levels of CXCL5, CCL26, CXCL6, GM-CSF, CXCL1, IFN-γ, IL-2, IL-8, CXCL11, CXCL9, CCL17, and CCL25 at T1; and higher levels of MIF and CCL23 at T2 than the patients who maintained normal LVEF. Patients with LVEF decline of 5-10% had lower plasma levels of CXCL1, CCL3, GDF-15, and haptoglobin at T0; lower levels of IL-16, FABP3, and myoglobin at T1; and lower levels of myoglobin and CCL23 at T2 as compared to the patients who maintained normal LVEF. This pilot study identified potential biomarkers that may help predict which patients are vulnerable to DOX-induced cardiotoxicity although further validation is needed in a larger cohort of patients. Impact statement Drug-induced cardiotoxicity is one of the major concerns in drug development and clinical practice. It is critical to detect potential cardiotoxicity early before onset of symptomatic cardiac dysfunction or heart failure. Currently there are no qualified clinical biomarkers for the prediction of cardiotoxicity caused by cancer treatment such as doxorubicin (DOX). By using multiplex immunoassays, we identified proteins with significantly changed plasma levels in a group of breast cancer patients who were treated with DOX-based chemotherapy and produced cardiotoxicity. These proteins were associated with immune response and were identified before DOX treatment or at early doses of treatment, thus they could be potential predictive biomarkers of cardiotoxicity although further validation is required to warrant their clinical values.
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Antibióticos Antineoplásicos/toxicidad , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/tratamiento farmacológico , Quimiocinas/sangre , Doxorrubicina/toxicidad , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Antibióticos Antineoplásicos/uso terapéutico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/inmunología , Cardiotoxicidad , Doxorrubicina/uso terapéutico , Femenino , Humanos , Metaloproteinasas de la Matriz/sangre , Persona de Mediana Edad , Proyectos PilotoRESUMEN
Doxorubicin (DOX) cardiotoxicity is unpredictable and begins with the first dose of chemotherapy. This study aimed to obtain information about circulating microRNA of cancer patients in the early dose of DOX chemotherapy, who either did or did not develop cardiac abnormality after the completion of chemotherapy. Plasma of 20 patients treated for breast cancer with DOX-chemotherapy was analyzed using quantitative RT-PCR. Circulating microRNA profiles of patients with DOX cardiotoxicity were compared to microRNA profiles of patients without DOX cardiotoxicity by quantitative real-time PCR. Thirty-two microRNAs were significantly dysregulated in the patients with abnormal cardiac function. Functional analysis of the 32 miRNAs suggested association with cell death, cell cycle, and inflammation. We have identified a miRNA signature associated with early doses of DOX-based chemotherapy that may potentially predict later impairment of cardiac function in breast cancer patients. Our data lay a foundation for future studies to identify biomarkers for presymptomatic DOX-induced cardiotoxicity.
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Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Cardiotoxicidad/sangre , Cardiotoxicidad/genética , MicroARN Circulante/sangre , MicroARN Circulante/genética , Doxorrubicina/efectos adversos , Transcriptoma , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Redes Reguladoras de Genes , HumanosRESUMEN
Doxorubicin (DOX) is a commonly used antineoplastic agent for the treatment of various malignancies, and its use is associated with unpredictable cardiotoxicity. Susceptibility to DOX cardiotoxicity is largely patient dependent, suggesting genetic predisposition. We have previously found that individual sensitivity to DOX cardiotoxicity was associated with differential expression of genes implicated in inflammatory response and immune trafficking, which was consistent with the increasing number of reports highlighting the important role of human leukocyte antigen (HLA) complex polymorphism in hypersensitivity to drug toxicity. This pilot study aimed to investigate DNA from patients treated with DOX-based chemotherapy for breast cancer and to correlate the results with the risk for DOX-associated cardiotoxicity. We have identified 18 SNPs in nine genes in the HLA region (NFKBIL1, TNF-α, ATP6V1G2-DDX39B, MSH5, MICA, LTA, BAT1, and NOTCH4) and in the psoriasis susceptibility region of HLA-C as potential candidates for association with DOX cardiotoxicity. These results, albeit preliminary and involving a small number of patients, are consistent with reports showing the presence of susceptibility loci within the HLA gene region for several inflammatory and autoimmune diseases, and with our previous findings indicating that the increased sensitivity to DOX cardiotoxicity was associated with dysregulation of genes implicated both in inflammation and autoimmune disorders.
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Antibióticos Antineoplásicos/efectos adversos , Neoplasias de la Mama/complicaciones , Cardiotoxicidad/etiología , Doxorrubicina/efectos adversos , Adulto , Anciano , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
BACKGROUND: We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). METHODS: DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. RESULTS: After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. CONCLUSION: Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00203502.
Asunto(s)
Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Angiopoyetina 1/genética , Angiopoyetina 2/genética , Neoplasias de la Mama/etnología , Ensayos Clínicos Fase II como Asunto , Etnicidad , Femenino , Factor 2 de Crecimiento de Fibroblastos/genética , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/genética , Persona de Mediana Edad , Terapia Neoadyuvante , Neovascularización Patológica/genética , Estudios Observacionales como Asunto , Estudios Prospectivos , Receptor TIE-2/genética , Análisis de Regresión , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Mechanisms and vectors of long-distance dispersal remain unknown for many coastal benthic species, including plants. Indications for the possibility for long-distance dispersal come from dispersal modelling and from genetic assessments, but have rarely been assessed with both methods. To this end, we assessed dispersal of the seagrass Zostera noltei, an important foundation species of the coastal zone. We investigate whether small scale seed dispersal and long-distance propagule dispersal do play a role for meta-population dynamics, using both genetic assessments based on eight microsatellite markers and physical modelling of ocean currents. Such assessments enhance our understanding of the biology and population dynamics of an important coastal foundation species. They are relevant for large scale conservation strategies as they give insights in the maintenance of genetic diversity and connectivity that may enhance resilience and resistance to stresses associated with seagrass loss.