High-Sensitivity Dual-Probe Detection of Urinary miR-141 in Cancer Patients via a Modified Screen-Printed Carbon Electrode-Based Electrochemical Biosensor.

The screening and diagnosis of cancer are hallmarks of medicine in the aging population. Recently, microRNAs have shown potential for use as biomarkers, which could advance the field of diagnostics. The presence of miRNA-141 in the serum has been well described in several malignancies. However, the invasive approach used for sampling represents the major limitation for its practical application and, hence, its notable absence as a method for screening the general population. In light of this, we aimed to develop a high-sensitivity microRNA (miR) biosensor for application in the diagnosis of all miR-141-associated cancers, such as colorectal cancer (CRC) and breast cancer (BC). The novelty lies in our dual-probe design, which is reliant on the hybridization of the fluorescein isothiocyanate (FITC) targeting probe onto an existing sample of urinary miR-141 in the first step, followed by complementary binding with a biotinylated probe that has been coated on a modified screen-printed carbon electrode (SPCE). The hybridization of the probe and sensor produces signals via the catalytic reduction of H2O2 at HRP-modified SPCEs in the presence of H2O, which was measured by either cyclic voltammetry or chronoamperometry (CA) currents. In our study, the detection and expression of miR-141 in a cohort of colorectal cancer (n = 6) and breast cancer (n = 4) samples showed that its levels were significantly higher than in a healthy cohort (n = 9) (p < 0.004). Moreover, our miR sensor demonstrated high stability, reliability, and sensitivity (p < 0.0001). This work hopefully provides new information for the detection and monitoring of de novo and existing cancers.

Increased Internet Searches for Insomnia as an Indicator of Global Mental Health During the COVID-19 Pandemic: Multinational Longitudinal Study.

BACKGROUND: Real-time global mental health surveillance is urgently needed for tracking the long-term impact of the COVID-19 pandemic. OBJECTIVE: This study aimed to use Google Trends data to investigate the impact of the pandemic on global mental health by analyzing three keywords indicative of mental distress: "insomnia," "depression," and "suicide." METHODS: We examined increases in search queries for 19 countries. Significant increases were defined as the actual daily search value (from March 20 to April 19, 2020) being higher than the 95% CIs of the forecast from the 3-month baseline via ARIMA (autoregressive integrated moving average) modeling. We examined the correlation between increases in COVID-19-related deaths and the number of days with significant increases in search volumes for insomnia, depression, and suicide across multiple nations. RESULTS: The countries with the greatest increases in searches for insomnia were Iran, Spain, the United States, and Italy; these countries exhibited a significant increase in insomnia searches on more than 10 of the 31 days observed. The number of COVID-19-related deaths was positively correlated to the number of days with an increase in searches for insomnia in the 19 countries (ρ=0.64, P=.003). By contrast, there was no significant correlation between the number of deaths and increases in searches for depression (ρ=-0.12, P=.63) or suicide (ρ=-0.07, P=.79). CONCLUSIONS: Our analysis suggests that insomnia could be a part of routine mental health screening during the COVID-19 pandemic.

In silico discovery and validation of potent small-molecule inhibitors targeting the activation function 2 site of human oestrogen receptor α.

INTRODUCTION: Current approaches to inhibit oestrogen receptor-alpha (ERα) are focused on targeting its hormone-binding pocket and have limitations. Thus, we propose that inhibitors that bind to a coactivator-binding pocket on ERα, called activation function 2 (AF2), might overcome some of these limitations. METHODS: In silico virtual screening was used to identify small-molecule ERα AF2 inhibitors. These compounds were screened for inhibition of ERα transcriptional activity using stably transfected T47D-KBluc cell line. A direct physical interaction between the AF2 binders and the ERα protein was measured using biolayer interferometry (BLI) and an ERα coactivator displacement assay. Cell viability was assessed by MTS assay in ERα-positive MCF7 cells, tamoxifen-resistant (TamR) cell lines TamR3 and TamR6, and ERα-negative MDA-MB-453 and HeLa cell lines. In addition, ERα inhibition in TamR cells and the effect of compounds on mRNA and protein expression of oestrogen-dependent genes, pS2, cathepsin D and cell division cycle 2 (CDC2) were determined. RESULTS: Fifteen inhibitors from two chemical classes, derivatives of pyrazolidine-3,5-dione and carbohydrazide, were identified. In a series of in vitro assays, VPC-16230 of the carbohydrazide chemical class emerged as a lead ERα AF2 inhibitor that significantly downregulated ERα transcriptional activity (half-maximal inhibitory concentration = 5.81 µM). By directly binding to the ERα protein, as confirmed by BLI, VPC-16230 effectively displaced coactivator peptides from the AF2 pocket, confirming its site-specific action. VPC-16230 selectively suppressed the growth of ERα-positive breast cancer cells. Furthermore, it significantly inhibited ERα mediated transcription in TamR cells. More importantly, it reduced mRNA and protein levels of pS2, cathepsin D and CDC2, validating its ER-directed activity. CONCLUSION: We identified VPC-16230 as an ERα AF2-specific inhibitor that demonstrated promising antiproliferative effects in breast cancer cell lines, including TamR cells. VPC-16230 reduced the expression of ERα-inducible genes, including CDC2, which is involved in cell division. We anticipate that the application of ERα AF2 inhibitors will provide a novel approach that can act as a complementary therapeutic to treat ERα-positive, tamoxifen-resistant and metastatic breast cancers.

Fine particulate matter results in hemodynamic changes in subjects with blunted nocturnal blood pressure dipping.

Particulate matter with aerodynamic diameter of <2.5 µm (PM2.5) is associated with blood pressure and hemodynamic changes. Blunted nocturnal blood pressure dipping is a major risk factor for cardiovascular events; limited information is available on whether PM2.5 exposure-related hemodynamic changes vary with day-night blood pressure circadian rhythms. In this study, we enrolled 161 subjects and monitored the changes in ambulatory blood pressure and hemodynamics for 24h. The day-night blood pressure and cardiovascular metrics were calculated according to the sleep-wake cycles logged in the subject׳s diary. The effects of PM2.5 exposure on blood pressure and hemodynamic changes were analyzed using generalized linear mixed-effect model. After adjusting for potential confounders, a 10-µg/m(3) increase in PM2.5 was associated with 1.0 mmHg [95% confidence interval (CI): 0.2-1.8 mmHg] narrowing in the pulse pressure, 3.1% (95% CI: 1.4-4.8%) decrease in the maximum rate of left ventricular pressure rise, and 3.6% (95% CI: 1.6-5.7%) increase in systemic vascular resistance among 79 subjects with nocturnal blood pressure dip of <10%. In contrast, PM2.5 was not associated with any changes in cardiovascular metrics among 82 subjects with nocturnal blood pressure dip of ≥10%. Our findings demonstrate that short-term exposure to PM2.5 contributes to pulse pressure narrowing along with cardiac and vasomotor dysfunctions in subjects with nocturnal blood pressure dip of <10%.

Short-term effects of air pollution on pulse pressure among nonsmoking adults.

BACKGROUND: Previous studies on the effects of acute air pollution have focused primarily on blood pressure (BP). METHODS: Our study enrolled 9238 nonsmoking adults over 30 years of age from 6 townships in Taiwan: 1 seaport, 1 urban, 1 industrial, and 3 rural. Using generalized additive models, we evaluated the associations between brachial BP and short-term exposure to 5 air pollutants: particulate matter with diameter <10 µm (PM(10)), sulfur dioxide (SO(2)), nitrogen dioxide (NO(2)), carbon monoxide (CO), and ozone (O(3)). RESULTS: After adjusting for individual and meteorologic factors, the systolic BP was decreased by all 5 pollutants, whereas the diastolic BP was increased by SO(2), NO(2), and O(3). The pulse pressure was consistently decreased by all 5 pollutants, with changes of -1.5 (95% confidence interval = -2.0 to -1.1), -0.6 (-0.9 to -0.4), -2.4 (-3.0 to -1.8), -1.2 (-1.6 to -0.9), and -1.4 (-1.8 to -0.9) mm Hg for interquartile range increases in 3-day lagged PM(10), SO(2), NO(2), carbon monoxide, and O(3), respectively. PM(10) exposure was more strongly associated with reduction of pulse pressure among men, persons >60 years of age, those with hypertension, and those living in the industrial township. CONCLUSIONS: Short-term exposure to air pollution reduces pulse pressure. PM(10) in industrial emissions may contribute to pulse pressure changes. Age, sex, and hypertensive status may modify the effects of PM(10) on pulse pressure.

Urinary MicroRNA Sensing Using Electrochemical Biosensor to Evaluate Colorectal Cancer Progression.

Research in cancer diagnostics has recently established its footing and significance in the biosensor sphere, emphasizing the idea of a unique probe design used as a sensor and actuator, to identify the presence of protein, DNA, RNA, or miRNA. The fluorescein isothiocyanate (FITC) probe and biotinylated probe are designed for a two-pronged approach to the detection of the urinary miR-21 and miR-141, both of which have demonstrated significance in the development and progression of colorectal cancer, a leading cause of mortality and morbidity. The remainder of the apparatus is composed of a modified screen-printed carbon electrode (SPCE), to which the probes adhere, that transduces signals via the redox reaction between H2O2 and HRP, measured with chronoamperometry and cyclic voltammetry. The precise nature of our ultra-non-invasive biosensor makes for a highly sensitive and practical cancer detector, concluded by the significance when establishing disease presence (miR-21 p-value = 0.0176, miR-141 p-value = 0.0032), disease follow-up (miR-21 p-value = 0.00154, miR141 p-value < 0.0005), and even disease severity. This article hopes to emphasize the potential of an additional clinical tool for the management of colorectal cancer.

An Effective SARS-CoV-2 Electrochemical Biosensor with Modifiable Dual Probes Using a Modified Screen-Printed Carbon Electrode.

Due to the severe acute respiratory syndrome coronavirus (SARS-CoV-2, also called coronavirus disease 2019 (COVID-19)) pandemic starting in early 2020, all social activities ceased in order to combat its high transmission rate. Since vaccination combats one aspect for halting the spread of the virus, the biosensor community has looked at another aspect of reducing the burden of the COVID-19 pandemic on society by developing biosensors that incorporate point-of-care (POC) testing and the rapid identification of those affected in order to deploy appropriate measures. In this study, we aim first to propose a screen-printed carbon electrode (SPCE)-based electrochemical biosensor that meets the ASSURED criteria (i.e., affordable, sensitive, specific, user-friendly, rapid, equipment-free, and deliverable) for POC testing, but more importantly, we describe the novelty of our biosensor's modifiability that uses custom dual probes made from target nucleic acid sequences. Additionally, regarding the sensitivity of the biosensor, the lowest sample concentration was 10 pM (p = 0.0257) without amplification, which might challenge the traditional technique of reverse transcriptase-polymerase chain reaction (RT-PCR). The purpose of this study is to develop a means of diagnostics for the current pandemic as well as to provide an established POC platform for future epidemics.

Significant elevation of antiviral activity of strictinin from Pu'er tea after thermal degradation to ellagic acid and gallic acid.

Compared with abundant catechins, strictinin is a minor constituent in teas and has been demonstrated to possess inhibitory potency on influenza virus. In this study, strictinin was found as the major phenolic compound in Pu'er teas produced from leaves and buds of wild trees. Due to its thermal instability, strictinin, in tea infusion or in an isolated form, was completely decomposed to ellagic acid and gallic acid after being autoclaved for 7 minutes. A plaque reduction assay was employed to compare the relative inhibitory potency between strictinin and its thermally degraded products against human influenza virus A/Puerto Rico/8/34. The results showed that the antiviral activity of ellagic acid regardless of the presence or absence of gallic acid was significantly higher than that of strictinin. Thermal degradation of strictinin to ellagic acid and gallic acid seems to be beneficial for the preparation of Pu'er teas in terms of enhancing antiviral activity.

Increasing emergency room visits for stroke by elevated levels of fine particulate constituents.

The associations between fine particulate matter (PM2.5) and stroke remain inconsistent. We conducted a time-series study to evaluate emergency room (ER) visits for ischemic and hemorrhagic strokes in relation to PM2.5 and its constituents. Generalized additive models were used to model the counts of daily ER visits for ischemic and hemorrhagic strokes among patients admitted to the National Taiwan University Hospital from 1 January 2004 to 31 August 2008. Exposure variables included PM2.5 and the four constituents, nitrate, sulfate, organic carbon (OC), and elemental carbon (EC). 12,982 ischemic stroke and 3362 hemorrhagic stroke cases were identified during the study period. For hemorrhagic stroke, the strongest relative risks (RRs) of ER visits were 1.19 [95% confidence interval (CI), 1.07-1.32] and 1.08 (95% CI, 1.02-1.15) for an interquartile range (IQR) increase in 3-day average nitrate and EC. For ischemic stroke, increased RRs of ER visits of 1.21 (95% CI, 1.07-1.36) and 1.18 (95% CI, 1.06-1.31) were observed in the warm season for an IQR increase in 3-day average of OC and EC, respectively. PM2.5 and OC were associated with increased RRs of ER visits for ischemic stroke among patients aged 65 years or older and female patients. In conclusion, PM2.5 constituents, rather than PM2.5 mass, are more closely related to ER visits for hemorrhagic stroke. Both PM2.5 mass and its chemical constituents are associated with ER visits for ischemic stroke in the warm season, among patients older than 65 years, and female patients.