Deficiencies in monitoring practices of marine protected areas in southern European seas.

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.

Exosomal MicroRNA and Protein Profiles of Hepatitis B Virus-Related Hepatocellular Carcinoma Cells.

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.

Circulating Exosomal microRNAs as Predictive Biomarkers of Neoadjuvant Chemotherapy Response in Breast Cancer.

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.

Genome-Wide DNA Methylation Signatures Predict the Early Asymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer.

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.

Subclinical doxorubicin-induced cardiotoxicity update: role of neutrophils and endothelium.

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.

Chaotic genetic structure and past demographic expansion of the invasive gastropod Tritia neritea in its native range, the Mediterranean Sea.

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.

Biomarkers of inflammation, hypercoagulability and endothelial injury predict early asymptomatic doxorubicin-induced cardiotoxicity in breast cancer patients.

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.

Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00203502.

Dantrolene Attenuates Cardiotoxicity of Doxorubicin Without Reducing its Antitumor Efficacy in a Breast Cancer Model.

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.

Effects of Different Exercise Interventions on Quality of Life in Breast Cancer Patients: A Randomized Controlled Trial.

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.

Tumor-endothelial cell interaction in an experimental model of human hepatocellular carcinoma.

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.

Immune response proteins as predictive biomarkers of doxorubicin-induced cardiotoxicity in breast cancer patients.

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.

Circulating miRNA Profiles of Doxorubicin-induced Cardiotoxicity in Breast Cancer Patients.

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.

Polymorphic Variations Associated With Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients.

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.

Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients.

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.

Biomarkers for Presymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients.

Cardiotoxicity of doxorubicin (DOX) remains an important health concern. DOX cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. No biomarker for presymptomatic detection of DOX cardiotoxicity has been validated. Our hypothesis is that peripheral blood cells (PBC) gene expression induced by the early doses of DOX-based chemotherapy could identify potential biomarkers for presymptomatic cardiotoxicity in cancer patients. PBC gene expression of 33 breast cancer patients was conducted before and after the first cycle of DOX-based chemotherapy. Cardiac function was evaluated before the start of chemotherapy and at its completion. Differentially expressed genes (DEG) of patients who developed DOX-associated cardiotoxicity after the completion of chemotherapy were compared with DEG of patients who did not. Ingenuity database was used for functional analysis of DEG. Sixty-sevens DEG (P<0.05) were identified in PBC of patients with DOX-cardiotoxicity. Most of DEG encode proteins secreted by activated neutrophils. The functional analysis of the DEG showed enrichment for immune- and inflammatory response. This is the first study to identify the PBC transcriptome signature associated with a single dose of DOX-based chemotherapy in cancer patients. We have shown that PBC transcriptome signature associated with one dose of DOX chemotherapy in breast cancer can predict later impairment of cardiac function. This finding may be of value in identifying patients at high or low risk for the development of DOX cardiotoxicity during the initial doses of chemotherapy and thus to avoid the accumulating toxic effects from the subsequent doses during treatment.

Patterns and mechanisms of dispersal in a keystone seagrass species.

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.

Oral glutamine reduces radiation morbidity in breast conservation surgery.

This study examined the effect of oral glutamine (Gln) on radiation injury in breast cancer patients undergoing radiation therapy. The radiation injury was evaluated using Radiation Therapy Oncology Group (RTOG) scales. Cosmesis was scored. Blood Gln and glutathione (GSH) levels were determined. Serum protein profiling was determined using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Patients receiving Gln scored significantly better in RTOG score than the patients receiving placebo. Cosmetic scores averaged excellent in the Gln group vs fair to good in the placebo group. Blood Gln and GSH levels were significantly higher in the Gln group vs the placebo group. Serum protein profiling with SELDI-TOF MS identified a novel Gln-responsive protein that showed amino acid similarity with myoglobin. These results suggest that Gln is an effective way to reduce radiation morbidity to breast cancer and is associated with the increased expression of a novel serum protein biomarker.

Transcriptome profiling of peripheral blood cells identifies potential biomarkers for doxorubicin cardiotoxicity in a rat model.

AIMS: Doxorubicin (DOX), a widely used anticancer agent, can cause an unpredictable cardiac toxicity which remains a major limitation in cancer chemotherapy. There is a need for noninvasive, sensitive and specific biomarkers which will allow identifying patients at risk for DOX-induced cardiotoxicity to prevent permanent cardiac damage. The aim of this study was to investigate whether the expression of specific genes in the peripheral blood can be used as surrogate marker(s) for DOX-induced cardiotoxicity. METHODS/RESULTS: Rats were treated with a single dose of DOX similar to one single dose that is often administered in humans. The cardiac and peripheral blood mononuclear cells (PBMCs) genome-wide expression profiling were examined using Illumina microarrays. The results showed 4,409 differentially regulated genes (DRG) in the hearts and 4,120 DRG in PBMC. Of these 2411 genes were similarly DRG (SDRG) in both the heart and PBMC. Pathway analysis of the three datasets of DRG using Gene Ontology (GO) enrichment analysis and Ingenuity Pathways Analysis (IPA) showed that most of the genes in these datasets fell into pathways related to oxidative stress response and protein ubiquination. IPA search for potential eligible biomarkers for cardiovascular disease within the SDRG list revealed 188 molecules. CONCLUSIONS: We report the first in-depth comparison of DOX-induced global gene expression profiles of hearts and PBMCs. The high similarity between the gene expression profiles of the heart and PBMC induced by DOX indicates that the PBMC transcriptome may serve as a surrogate marker of DOX-induced cardiotoxicity. Future directions of this research will include analysis of PBMC expression profiles of cancer patients treated with DOX-based chemotherapy to identify the cardiotoxicity risk, predict DOX-treatment response and ultimately to allow individualized anti-cancer therapy.

Increased efficacy and reduced cardiotoxicity of metronomic treatment with cyclophosphamide in rat breast cancer.

BACKGROUND/AIM: It has been reported that continuous low-dose (metronomic) administration of cytotoxic drugs may be better tolerated and may have greater antitumor effects than a single high-dose chemotherapy. The aim of this study was to examine the efficacy and cardiotoxicity of metronomic administration of two of the most commonly used anticancer agents, cyclophosphamide (CPA) and doxorubicin (DOX), on an experimental breast cancer of rats. MATERIALS AND METHODS: Breast tumors were induced in Fisher 344 female rats by implanting Mat B III cells. Rats with tumors were randomized into three groups and were treated with a total dose of 160 mg/kg CPA and a total dose of 12 mg/kg DOX, administered twice per week for four weeks. Control rats were injected with saline according to the same schedule. Echocardiography was performed before the start of treatment and before sacrifice, which took place two weeks after the last injection, when plasma troponin was also measured. RESULTS: The metronomic CPA eradicated the tumors and preserved body weight and echocardiographic parameters. The metronomic DOX slowed tumor growth, but was not able to prevent DOX-induced cardiotoxicity. CONCLUSION: These results suggest that the success of a metronomic chemotherapy in terms of both efficacy and toxicity depends on the target, the class and the route of administration of the anticancer agent.