Improvement of breast cancer (BC) patient's outcome is directly related to early detection. However, there is still a lack of reliable biomarkers for diagnosis, prognosis and, treatment follow up in BC, leading researchers to study the potential of liquid biopsy based on circulating microRNAs (c-miRNAs). These c-miRNAs can be cellfree or associated with extracellular vesicles (EVs), and have great advantages such as stability in biofluids, noninvasive accessibility compared to current techniques (core-biopsy and surgery), and expression associated with pathogenic conditions. Recently, a new promising field of EV-derived miRNAs (EV-miRNAs) as cancer biomarkers has emerged, receiving special attention due to their selective vesicle sorting which makes them accurate for disease detection. In this review, we discuss new findings about c-miRNA and their potential as biomarkers for BC diagnosis, prognosis, and therapy. Additionally, we address the impact of limitations associated with the standardization of analysis techniques and methods on the implementation of these biomarkers in the clinical setting. (Translational Research 2020; 223:40À60) Abbreviations: BC = breast cancer; c-miRNAs = circulating microRNAs; cf-miRNAs = cell-free microRNAs; EVs = extracellular vesicles; EV-miRNAs = EV-derived miRNAs; ER = estrogen receptor; PR = progesterone receptor; ERBB2 = human epidermal growth factor receptor 2; TNBC = triple negative breast cancer; CTCs = circulating tumor cells; CA15-3 = cancer antigen 15-3; CEA = carcinoembryonic antigen; RANTES/CCL5 = chemokine (CÀC motif) ligand 5; OPN = osteopontin; PAI-1 = plasminogen activator inhibitor-1; AUC = area under the curve; RT-qPCR = reverse transcription quantitative polymerase chain reaction; CT = controls; OS = overall survival; dPCR = digital PCR; NGS = next generation sequencing BACKGROUND Breast cancer (BC) is the most frequently diagnosed cancer in females and the leading cause of death by cancer worldwide, with the mortality rate predicted to reach around 626,679 deaths worldwide in 2018. 1 This cancer can be classified in several ways, one of the methods of clinical evaluation being the immunohistochemistry classification. 2 According to this classification, BC is stratified based on the expression of 4 main protein markers À estrogen receptor (ER), progesterone, receptor (PR), the proliferation marker and

Components of the complement system and atypical parameters of coagulation were reported in COVID-19 patients, as well as the exacerbation of the inflammation and coagulation activity. Mannose binding lectin (MBL)-associated serine proteases (MASPs) play an important role in viral recognition and subsequent activation of the lectin pathway of the complement system and blood coagulation, connecting both processes. Genetic variants of MASP1 and MASP2 genes are further associated with different levels and functional efficiency of their encoded proteins, modulating susceptibility and severity to diseases. Our review highlights the possible role of MASPs in SARS-COV-2 binding and activation of the lectin pathway and blood coagulation cascades, as well as their associations with comorbidities of COVID-19. MASP-1 and/or MASP-2 present an increased expression in patients with COVID-19 risk factors: diabetes, arterial hypertension and cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and cerebrovascular disease. Based also on the positive results of COVID-19 patients with anti-MASP-2 antibody, we propose the use of MASPs as a possible biomarker of the progression of COVID-19 and the investigation of new treatment strategies taking into consideration the dual role of MASPs, including MASP inhibitors as promising therapeutic targets against COVID-19.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality among women. Two thirds of patients are classified as hormone receptor positive, based on expression of estrogen receptor alpha (ERα), the main driver of breast cancer cell proliferation, and/or progesterone receptor, which is regulated by ERα. Despite presenting the best prognosis, these tumors can recur when patients acquire resistance to treatment by aromatase inhibitors or antiestrogen such as tamoxifen (Tam). The mechanisms that are involved in Tam resistance are complex and involve multiple signaling pathways. Recently, roles for microRNAs and lncRNAs in controlling ER expression and/or tamoxifen action have been described, but the underlying mechanisms are still little explored. In this review, we will discuss the current state of knowledge on the roles of microRNAs and lncRNAs in the main mechanisms of tamoxifen resistance in hormone receptor positive breast cancer. In the future, this knowledge can be used to identify patients at a greater risk of relapse due to the expression patterns of ncRNAs that impact response to Tam, in order to guide their treatment more efficiently and possibly to design therapeutic strategies to bypass mechanisms of resistance.

Breast cancer (BC) is a heterogeneous disease, and establishing biomarkers is essential to patient management. We previously described that extracellular vesicle–derived miRNAs (EV-miRNAs) miR-142-5p, miR-150-5p, miR-320a, and miR-4433b-5p in serum discriminated BC from control samples, either alone or combined in a panel. Using these previously described markers, we intend to evaluate whether the same markers identified in EVs are also potential biomarkers in tissue and serum. Expression analysis using RT-qPCR was performed using serum of 67 breast cancer patients (BC-S), 19 serum controls (CT), 83 fresh tumor tissues (BC-T), and 29 adjacent nontumor tissue samples (NT). In addition, analysis from The Cancer Genome Atlas (TCGA) data (832 BC-T and 136 NT) was performed. In all comparisons, we found concordant high expression levels of miR-320a and miR-4433b-5p in BC-S compared to CT in both EVs and cell-free miRNAs (cf-miRNAs). Although miR-150-5p and miR-142-5p were not found to be differentially expressed in serum, panels including these miRNAs improved sensitivity and specificity, supporting our previous findings in EVs. Fresh tissue and data from the TCGA database had, in most comparisons, an opposite behavior when compared to serum and EVs: lower levels of all miRNAs in BC-T than those in NT samples. TCGA analyses revealed reduced expression levels of miR-150-5p and miR-320a-3p in BC-T than those in NT samples and the overexpression of miR-142-5p in BC-T, unlike our RT-qPCR results from tissue in the Brazilian cohort. The fresh tissue analysis showed that all miRNAs individually could discriminate between BC-T and NT in the Brazilian cohort, with high sensitivity and sensibility. Furthermore, combining panels showed higher AUC values and improved sensitivity and specificity. In addition, lower levels of miR-320a-3p in serum were associated with poor overall survival in BC Brazilian patients. In summary, we observed that miR-320a and miR-4433b-5p distinguished BC from controls with high specificity and sensibility, regardless of the sample source. In addition, lower levels of miR-150-5p and higher levels of miR-142-5p were statistically significant biomarkers in tissue, according to TCGA. When combined in panels, all combinations could distinguish BC patients from controls. These results highlight a potential application of these miRNAs as BC biomarkers.

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