De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome.</p> <p>Methods</p> <p>The pre-treatment sera of 42 stage II-III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II-III BC patients was used to assess the power of identified miRNA markers.</p> <p>Results</p> <p>More than 800 miRNA species were detected in the circulation, and observed patterns showed association with histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundance determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II-III BC patients.</p> <p>Conclusions</p> <p>Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.</p

Cancer-Secreted miR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis

SummaryCancer-secreted microRNAs (miRNAs) are emerging mediators of cancer-host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in nonmetastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. miR-105 can be detected in the circulation at the premetastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer

The Effect of Viewing Eccentricity on Enumeration

Visual acuity and contrast sensitivity progressively diminish with increasing viewing eccentricity. Here we evaluated how visual enumeration is affected by visual eccentricity, and whether subitizing capacity, the accurate enumeration of a small number (∼3) of items, decreases with more eccentric viewing. Participants enumerated gratings whose (1) stimulus size was constant across eccentricity, and (2) whose stimulus size scaled by a cortical magnification factor across eccentricity. While we found that enumeration accuracy and precision decreased with increasing eccentricity, cortical magnification scaling of size neutralized the deleterious effects of increasing eccentricity. We found that size scaling did not affect subitizing capacities, which were nearly constant across all eccentricities. We also found that size scaling modulated the variation coefficients, a normalized metric of enumeration precision, defined as the standard deviation divided by the mean response. Our results show that the inaccuracy and imprecision associated with increasing viewing eccentricity is due to limitations in spatial resolution. Moreover, our results also support the notion that the precise number system is restricted to small numerosities (represented by the subitizing limit), while the approximate number system extends across both small and large numerosities (indexed by variation coefficients) at large eccentricities

Call for emergency action to restore dietary diversity and protect global food systems in times of COVID-19 and beyond: Results from a cross-sectional study in 38 countries

Background: The COVID-19 pandemic has revealed the fragility of the global food system, sending shockwaves across countries\u27 societies and economy. This has presented formidable challenges to sustaining a healthy and resilient lifestyle. The objective of this study is to examine the food consumption patterns and assess diet diversity indicators, primarily focusing on the food consumption score (FCS), among households in 38 countries both before and during the first wave of the COVID-19 pandemic. Methods: A cross-sectional study with 37 207 participants (mean age: 36.70 ± 14.79, with 77 % women) was conducted in 38 countries through an online survey administered between April and June 2020. The study utilized a pre-tested food frequency questionnaire to explore food consumption patterns both before and during the COVID-19 periods. Additionally, the study computed Food Consumption Score (FCS) as a proxy indicator for assessing the dietary diversity of households. Findings: This quantification of global, regional and national dietary diversity across 38 countries showed an increment in the consumption of all food groups but a drop in the intake of vegetables and in the dietary diversity. The household\u27s food consumption scores indicating dietary diversity varied across regions. It decreased in the Middle East and North Africa (MENA) countries, including Lebanon (p \u3c 0.001) and increased in the Gulf Cooperation Council countries including Bahrain (p = 0.003), Egypt (p \u3c 0.001) and United Arab Emirates (p = 0.013). A decline in the household\u27s dietary diversity was observed in Australia (p \u3c 0.001), in South Africa including Uganda (p \u3c 0.001), in Europe including Belgium (p \u3c 0.001), Denmark (p = 0.002), Finland (p \u3c 0.001) and Netherland (p = 0.027) and in South America including Ecuador (p \u3c 0.001), Brazil (p \u3c 0.001), Mexico (p \u3c 0.0001) and Peru (p \u3c 0.001). Middle and older ages [OR = 1.2; 95 % CI = [1.125–1.426] [OR = 2.5; 95 % CI = [1.951–3.064], being a woman [OR = 1.2; 95 % CI = [1.117–1.367], having a high education (p \u3c 0.001), and showing amelioration in food-related behaviors [OR = 1.4; 95 % CI = [1.292–1.709] were all linked to having a higher dietary diversity. Conclusion: The minor to moderate changes in food consumption patterns observed across the 38 countries within relatively short time frames could become lasting, leading to a significant and prolonged reduction in dietary diversity, as demonstrated by our findings

Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the pre-metastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the pre-metastatic niche. Mechanistically cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase (PKM). In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that by modifying glucose utilization by recipient pre-metastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression

Distinct effects of attention on the neural responses to form and motion processing:a SSVEP source-imaging study

We measured neural responses to local and global aspects of form and motion stimuli using frequency-tagged, steady-state visual evoked potentials (SSVEPs) combined with magnetic resonance imaging (MRI) data. Random dot stimuli were used to portray either dynamic Glass patterns (Glass, 1969) or coherent motion displays. SSVEPs were used to estimate neural activity in a set of fMRI-defined visual areas in each subject. To compare activity associated with local versus global processing, we analyzed two frequency components of the SSVEP in each visual area: the high temporal frequency at which the local dots were updated (30 Hz) and the much lower frequency corresponding to updates in the global structure (0.83 Hz). Local and global responses were evaluated in the context of two different behavioral tasks—subjects had to either direct their attention toward or away from the global coherence of the stimuli. The data show that the effect of attention on global and local responses is both stimulus and visual area dependent. When attention was directed away from stimulus coherence, both local and global responses were higher in the coherent motion than Glass pattern condition. Directing attention to coherence in Glass patterns enhanced global activity in areas LOC, hMT+, V4, V3a, and V1, while attention to global motion modulated responses by a smaller amount in a smaller set of areas: V4, hMT+, and LOC. In contrast, directing attention towards stimulus coherence weakly increased local responses to both coherent motion and Glass patterns. These results suggest that visual attention differentially modulates the activity of early visual areas at both local and global levels of structural encoding

Subitizing capacities as a function of viewing eccentricity were generally flat for unscaled (Experiment 1) and scaled (Experiment 2) stimulus sizes.

<p>Subitizing capacities as a function of viewing eccentricity were generally flat for unscaled (Experiment 1) and scaled (Experiment 2) stimulus sizes.</p