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Paclitaxel is a widely used chemotherapeutic agent for the treatment of breast cancer (BC), including as a front-line treatment for triple-negative breast cancer (TNBC) patients. However, resistance to paclitaxel remains one of the major causes of death associated with treatment failure. Multiple studies have demonstrated that miRNAs play a role in paclitaxel resistance and are associated with both disease progression and metastasis. In the present study, we used a miRNA-encoding lentiviral library as a gain-of-function screen for paclitaxel resistance in the MDA-MB-231 TNBC cell line. We identified that miR-181b, miR-29a, miR-30c, miR-196 and miR-1295 conferred a resistant phenotype to cells. The expression of miR-29a also induced resistance to eribulin and vinorelbine, while miR-181b and miR-30c induced resistance to vinorelbine. We measured the levels of these miRNAs in breast cancer patients and observed higher levels of miR-29a in treatment-refractory patients. Taken together, we suggest that miR-29a and miR-181b may be good candidates for miRNA inhibition to overcome resistance to chemotherapy. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is an incurable disease accounting for almost one‐third of leukemias in the Western world. Aberrant expression of microRNAs (miRNAs) is a well‐established characteristic of CLL, and the robust nature of miRNAs makes them eminently suitable liquid biopsy biomarkers. Using a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), the predictive values of five promising human miRNAs (hsa‐miR‐16‐5p, hsa‐miR‐29a‐3p, hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐223‐3p), identified in a pilot study, were examined in serum of 224 CLL cases (diagnosed 3 months to 18 years after enrollment) and 224 matched controls using Taqman based assays. Conditional logistic regressions were applied to adjust for potential confounders. The median time from blood collection to CLL diagnosis was 10 years (p25–p75: 7–13 years). Overall, the upregulation of hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐29a‐3p was associated with subsequent risk of CLL [OR1∆Ct‐unit increase (95%CI) = 1.42 (1.18–1.72), 1.64 (1.31–2.04) and 1.75 (1.31–2.34) for hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐29a‐3p, respectively] and the strongest associations were observed within 10 years of diagnosis. However, the predictive performance of these miRNAs was modest (area under the curve <0.62). hsa‐miR‐16‐5p and hsa‐miR‐223‐3p levels were unrelated to CLL risk. The findings of this first prospective study suggest that hsa‐miR‐29a, hsa‐miR‐150‐5p and hsa‐miR‐155‐5p were upregulated in early stages of CLL but were modest predictive biomarkers of CLL risk. What's new? Aberrant circulating microRNA (miRNA) levels are a well‐established characteristic of chronic lymphocytic leukemia (CLL), but pre‐diagnosis data remain scarce. In this nested case–control study within the European Prospective Investigation into Cancer and Nutrition Study, circulating hsa‐miRNA‐29a‐3p, ‐150‐5p, and ‐155‐5p were upregulated up to 10 years before CLL diagnosis compared to controls, suggesting a role in early disease progression. However, these biomarkers were suboptimal to discriminate CLL from controls. No difference was observed in hsa‐miRNA‐16‐5p and ‐223‐3p expression between pre‐CLL and controls. The ability to detect pre‐clinical biomarkers may help better understand CLL development and open new avenues for personalized treatment. [ABSTRACT FROM AUTHOR]

The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer biomarkers that can act as surrogate markers to biopsy-based sampling. The non-invasive nature of these "liquid biopsies" ultimately means that cancer detection may be earlier and that the ability to monitor disease progression and/or treatment response represents a paradigm shift in the treatment of cancer patients. Below, we review one of the most promising classes of circulating cancer biomarkers: microRNAs (miRNAs). In particular, we will consider their history, the controversy surrounding their origin and biology, and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice. [ABSTRACT FROM AUTHOR]

B-cell lymphomas represent a group of more than 35 recognized mature B-cell neoplasms differentiated largely on the basis of immunohistochemical staining patterns that are often challenging to accurately diagnose. Despite having been only formally recognized just over 10 years ago, microRNAs (miRNAs) have become one of the trendiest topics in biology. Dysregulation of miRNAs is a ubiquitous feature of cancer in general, including B-cell lymphomas. Many of the miRNAs aberrantly expressed in B-cell lymphomas also play a crucial regulatory role in normal hematopoietic function. MiRNAs show great potential as novel biomarkers of cancer, as they can differentiate cancers according to diagnosis and developmental stage, even discriminating between cancers that are poorly separated histologically. Furthermore, they can be robustly measured from routinely prepared formalin-fixed paraffin-embedded biopsy material and biological fluids such as blood. Here, we consider the identity, function, and biomarker potential of miRNAs in B-cell lymphomas and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Clear cell renal cell carcinoma (ccRCC) is a frequent cancer that causes more than 100,000 deaths every year. Treatment with drugs that target enzymes that help tumours grow such as sunitinib have greatly improved the prospects for ccRCC patients, however a large proportion of patients become resistant. We created sunitinib resistant cell lines and identified consequent changes in gene (and miRNA) expression by microarray analyses. Using this approach, we identified different pathways of resistance suggesting that tumour cells have many ways to overcome sunitinib treatment. We were able to overcome resistance in cells by inhibiting a protein, PD-L1, that is targeted by many immunotherapeutics currently in use for ccRCC patients suggesting a combination of immunotherapy and sunitinib may benefit patients. In addition, we identified miRNAs that are common to multiple resistance mechanisms suggesting they may be useful targets for future studies. The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common cancer of men and is typically slow-growing and asymptomatic. The use of blood PSA as a screening method has greatly improved PCa diagnosis, but high levels of false positives has raised much interest in alternative biomarkers. We used next-generation sequencing (NGS) to elucidate the urinary transcriptome of whole urine collected from high-stage and low-stage PCa patients as well as from patients with the confounding diagnosis of benign hyperplasia (BPH). We identified and validated five differentially expressed protein-coding genes (FTH1 BRPF1, OSBP, PHC3, and UACA) in an independent validation cohort of small-volume (1 mL) centrifuged urine (n = 94) and non-centrifuged urine (n = 84) by droplet digital (dd)PCR. These biomarkers were able to discriminate between BPH and PCa patients and healthy controls using either centrifuged or non-centrifuged whole urine samples, suggesting that the urinary transcriptome is a valuable source of non-invasive biomarkers for PCa that warrants further investigation. [ABSTRACT FROM AUTHOR]

Background : The outcome for oestrogen receptor positive (ER+) breast cancer patients has improved greatly in recent years largely due to targeted therapy. However, the presence of involved multiple synchronous lymph nodes remains associated with a poor outcome. Consequently, these patients would benefit from the identification of new prognostic biomarkers and therapeutic targets. The expression of G-protein-coupled receptor kinase-interacting protein 1 (GIT1) has recently been shown to be an indicator of advanced stage breast cancer. Therefore, we investigated its expression and prognostic value of GIT1 in a cohort of 140 ER+ breast cancer with synchronous lymph node involvement. Methods : Immunohistochemistry was employed to assess GIT1 expression in a tissue microarray (TMA) containing duplicate non-adjacent cores with matched primary tumour and lymph node tissue (n=140). GIT1 expression in tumour cells was scored and statistical correlation analyses were carried out. Results : The results revealed a sub-group of patients that displayed discordant expression of GIT1 between the primary tumour and the lymph nodes (i.e. spatial intratumoural heterogeneity). We observed that loss of GIT1 expression in the metastasis was associated with a shorter time to recurrence, poorer overall survival, and a shorter median survival time. Moreover, multivariate analysis demonstrated that GIT1 expression was an independent prognostic indicator. Conclusions : GIT1 expression enabled the identification of a sub-class of ER+ patients with lymph node metastasis that have a particularly poor prognostic outcome. We propose that this biomarker could be used to further stratify ER+ breast cancer patients with synchronous lymph node involvement and therefore facilitate adjuvant therapy decision making., Competing Interests: Competing interests: No competing interests were disclosed.

The main objective of this paper is to address the performance of immunochemical assays for the detection of the residues of three pesticides [atrazine, bromopropylate, and 2,4,6-trichlorophenol (TCP)] in real winery samples, such as wine, grapes, and grape juice. Different approaches have been evaluated to minimize interferences from the matrixes, and suitable working protocols have been established in order to achieve the necessary LODs, accuracy, and precision for real samples. A simple dilution of the sample proved to be sufficient for the determination of atrazine and bromopropylate in red and white wine and grape juice at the required levels of concentration. However, for TCP, an SPE procedure has been optimized using amino cartridges. The recoveries were above 85% in all cases, and the LOD values were below the parts per billion level, except for bromopropylate, which ranged between 2 and 50 microg/L, depending on the matrix. The grape matrix effect could be resolved by a simple extraction with methanol. Complete recoveries were obtained, and the final measurement procedures were able to determine selected pesticides below their maximum residue levels. The newly developed methods have been compared with standard chromatographic methods.