Research Progress of Long Non-Coding RNA GAS5 in Malignant Tumors.

With completing the whole genome sequencing project, awareness of lncRNA further deepened. The growth arrest-specific transcript 5 (GAS5) was initially identified in growth-inhibiting cells. GAS5 is a lncRNA (long non-coding RNA), and it plays a crucial role in various human cancers. There are small ORFs (open reading frames) in the exons of the GAS5 gene sequence, but they do not encode functional proteins. In addition, GAS5 is also the host gene of several small nucleolar RNAs (snoRNA). These snoRNAs are believed to play a suppressive role during tumor progression by methylating ribosomal RNA (rRNA). As a result, GAS5 expression levels in tumor tissues are significantly reduced, leading to increased malignancy, poor prognosis, and drug resistance. Recent studies have demonstrated that GAS5 can interact with miRNAs by base-pairing and other functional proteins to inhibit their biological functions, impacting signaling pathways and changing the level of intracellular autophagy, oxidative stress, and immune cell function in vivo. In addition, GAS5 participates in regulating proliferation, invasion, and apoptosis through the above molecular mechanisms. This article reviews the recent discoveries on GAS5, including its expression levels in different tumors, its biological behavior, and its molecular regulation mechanism in human cancers. The value of GAS5 as a molecular marker in the prevention and treatment of cancers is also discussed.

Methodology for forecast and control of coastal harmful algal blooms by embedding a compound eutrophication index into the ecological risk index.

Harmful algae bloom (HAB) is a major global ecological hazard and is a serious problem in the Bohai Sea. There have been few successful controls of HABs associated with HAB accurate predictions due to a lack of link between ecological risks and control measures. A methodology is proposed that embeds the compound eutrophication index (CEI) into an ecological risk index (ERI) for HAB prediction, which can define critical factors associated with measures of HAB control. CEI can be calculated by means of a function with 15 control elements. These are multiplied with the occurrence probability and ecosystem vulnerability to HAB events to calculate the ERI of HAB. Based on the results of CEI and ERI, it has experienced eutrophication and has been at a high-risk state since 1989 in the Bohai Sea. There is good correlation between CEI and chlorophyll a concentration, and HAB risk evaluation in accordance with ERI embedded CEI is considerable reliability in both location and time in the Bohai Sea. The ERI value averages 24% ± 35% with peak values (73% ± 4.3%) in summer, and high values (at the level of grade III of ERI, 6%) are mostly in Bohai Bay, Laizhou Bay, Liaodong Bay and the coastal sea waters of Qinhuangdao city. The contribution of terrigenous pollutant emission and concentration effects to the ERI is 63%, with reclamation and hydrodynamic effects accounting for 22%, and runoff and sediment effects accounting for 15%. Thus, actions associated with terrigenous pollutant emission/concentration would be more effective than other measures in prevention and control of HAB.

Compound eutrophication index: An integrated approach for assessing ecological risk and identifying the critical element controlling harmful algal blooms in coastal seas.

Current ecological risk assessment and controlling element identification methods of harmful algal blooms (HABs) are not connected. Here, we identified the controlling elements by correlation and principal component analyses, and the analytic hierarchy process. A compound eutrophication index (CEI) integrating risk assessment with controlling element identification was constructed and verified using data collected from Jiaozhou Bay, China. The CEI results agreed with the chlorophyll-a concentration and the main eutrophication assessment results. The HAB risk assessment of the CEI was more efficient than that of the nutrient quality index and Assessment of Estuarine Trophic Status. The contribution ratio of the loads and concentrations of nutrients (nitrogen, phosphorus, and chemical oxygen demand) to HABs in Jiaozhou Bay was 70%. In the high-risk areas, the contribution ratio of nutrients to HABs was 77%. Therefore, terrestrial nutrient inputs must be reduced to prevent and control HABs in the north-eastern areas of Jiaozhou Bay.

Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells.

Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-α (sTNF-α) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-α (tmTNF-α) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-α at high levels in breast cancer tissues and tmTNF-α expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-α expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-α, a mutant form with intact intracellular domain of tmTNF-α to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-α/NTF-ERK-GST-π axis and tmTNF-α/NTF-NF-κB-mediated anti-apoptotic functions were required for tmTNF-α-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-α suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-α mediates DOX-resistance through reverse signaling and targeting tmTNF-α may be beneficial for the treatment of DOX-resistant breast cancer.

Self-Referenced Smartphone-Based Nanoplasmonic Imaging Platform for Colorimetric Biochemical Sensing.

Colorimetric sensors usually suffer due to errors from variation in light source intensity, the type of light source, the Bayer filter algorithm, and the sensitivity of the camera to incoming light. Here, we demonstrate a self-referenced portable smartphone-based plasmonic sensing platform integrated with an internal reference sample along with an image processing method to perform colorimetric sensing. Two sensing principles based on unique nanoplasmonics enabled phenomena from a nanostructured plasmonic sensor, named as nanoLCA (nano Lycurgus cup array), were demonstrated here for colorimetric biochemical sensing: liquid refractive index sensing and optical absorbance enhancement sensing. Refractive indices of colorless liquids were measured by simple smartphone imaging and color analysis. Optical absorbance enhancement in the colorimetric biochemical assay was achieved by matching the plasmon resonance wavelength with the chromophore's absorbance peak wavelength. Such a sensing mechanism improved the limit of detection (LoD) by 100 times in a microplate reader format. Compared with a traditional colorimetric assay such as urine testing strips, a smartphone plasmon enhanced colorimetric sensing system provided 30 times improvement in the LoD. The platform was applied for simulated urine testing to precisely identify the samples with higher protein concentration, which showed potential point-of-care and early detection of kidney disease with the smartphone plasmonic resonance sensing system.

White blood cell counting on smartphone paper electrochemical sensor.

White blood cell (WBC) analysis provides rich information in rapid diagnosis of acute bacterial and viral infections as well as chronic disease management. For patients with immune deficiency or leukemia WBC should be persistently monitored. Current WBC counting method relies on bulky instrument and trained personnel and is time consuming. Rapid, low-cost and portable solution is in highly demand for point of care test. Here we demonstrate a label-free smartphone based electrochemical WBC counting device on microporous paper with patterned gold microelectrodes. WBC separated from whole blood was trapped by the paper with microelectrodes. WBC trapped on the paper leads to the ion diffusion blockage on microelectrodes, therefore cell concentration is determined by peak current on the microelectrodes measured by a differential pulse voltammeter and the quantitative results are collected by a smartphone wirelessly within 1min. We are able to rapidly quantify WBC concentrations covering the common physiological and pathological range (200-20000µL-1) with only 10µL sample and high repeatability as low as 10% in CoV (Coefficient of Variation). The unique smartphone paper electrochemical sensor ensures fast cell quantification to achieve rapid and low-cost WBC analysis at the point-of-care under resource limited conditions.

A coastal three-dimensional water quality model of nitrogen in Jiaozhou Bay linking field experiments with modelling.

With anthropogenic changes, the structure and quantity of nitrogen nutrients have changed in coastal ocean, which has dramatically influenced the water quality. Water quality modeling can contribute to the necessary scientific grounding of coastal management. In this paper, some of the dynamic functions and parameters of nitrogen were calibrated based on coastal field experiments covering the dynamic nitrogen processes in Jiaozhou Bay (JZB), including phytoplankton growth, respiration, and mortality; particulate nitrogen degradation; and dissolved organic nitrogen remineralization. The results of the field experiments and box model simulations showed good agreement (RSD=20%±2% and SI=0.77±0.04). A three-dimensional water quality model of nitrogen (3DWQMN) in JZB was improved and the dynamic parameters were updated according to field experiments. The 3DWQMN was validated based on observed data from 2012 to 2013, with good agreement (RSD=27±4%, SI=0.68±0.06, and K=0.48±0.04), which testifies to the model's credibility.

Large-area, lithography-free, low-cost SERS sensor with good flexibility and high performance.

Cost-effective, sensitive and bio-compatible surface-enhanced Raman spectroscopy (SERS) substrate has been in high demand since the Raman spectrum was designated as a significant tool for analyzing the composition of liquids, gases and solids in 1998 [1]. In this research, we presented the design, fabrication and characterization of an improved gold-based SERS substrate. With fine tuning of the SiO2 thickness we achieved a 3.391 times improvement and achieved an enhancement factor of 1.55 * 10(7) which is 15 times better than the current gold-standard Klarite substrate. Such improvement is ascribed to the localized surface plasmon resonance (SPR) and propagating SPR, which is proved by full-wave finite-difference time-domain simulations.

Transmembrane TNF-α promotes suppressive activities of myeloid-derived suppressor cells via TNFR2.

It has been reported that TNFR2 is involved in regulatory T cell induction and myeloid-derived suppressor cell (MDSC) accumulation, two kinds of immunosuppressive cells contributing to tumor immune evasion. Because transmembrane TNF-α (tmTNF-α) is the primary ligand for TNFR2, we hypothesized that tmTNF-α is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF-α, rather than secretory TNF-α (sTNF-α), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-ß, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF-α was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-α-induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF-α caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-α-mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF-α mutant by 4T1 cells significantly promoted tumor progression and angiogenesis, accompanied with more accumulation of MDSCs and regulatory T cells in the tumor site, increased production of NO, IL-10, and TGF-ß, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF-α mutant by 4T1 cells that only released sTNF-α without expression of surface tmTNF-α markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF-α acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.

Targeting transmembrane TNF-α suppresses breast cancer growth.

TNF antagonists may offer therapeutic potential in solid tumors, but patients who have high serum levels of TNF-α fail to respond to infliximab, suggesting consumption of the circulating antibody and loss of transmembrane TNF-α (tmTNF-α) on tumors by ectodomain shedding. Addressing this possibility, we developed a monoclonal antibody (mAb) that binds both full-length tmTNF-α and its N-terminal truncated fragment on the membrane after tmTNF-α processing but does not cross-react with soluble TNF-α. We documented high levels of tmTNF-α expression in primary breast cancers, lower levels in atypical hyperplasia or hyperplasia, but undetectable levels in normal breast tissue, consistent with the notion that tmTNF-α is a potential therapeutic target. Evaluations in vitro and in vivo further supported this assertion. tmTNF-α mAb triggered antibody-dependent cell-mediated cytotoxicity against tmTNF-α-expressing cells but not to tmTNF-α-negative cells. In tumor-bearing mice, tmTNF-α mAb delayed tumor growth, eliciting complete tumor regressions in some mice. Moreover, tmTNF-α mAb inhibited metastasis and expression of CD44v6, a prometastatic molecule. However, the antibody did not activate tmTNF-α-mediated reverse signaling, which facilitates tumor survival and resistance to apoptosis, but instead inhibited NF-κB activation and Bcl-2 expression by decreasing tmTNF-α-positive cells. Overall, our results established that tmTNF-α mAb exerts effective antitumor activities and offers a promising candidate to treat tmTNF-α-positive tumors, particularly in patients that are nonresponders to TNF antagonists.

Implementation of a portable electronic system for providing pain relief to patellofemoral pain syndrome patients.

In this study, a portable electromyogram (EMG) system and a stimulator are developed for patellofemoral pain syndrome patients, with the objective of reducing the pain experienced by these patients; the patellar pain is caused by an imbalance between the vastus medialis obliquus (VMO) and the vastus lateralis (VL). The EMG measurement circuit and the electrical stimulation device proposed in this study are specifically designed for the VMO and the VL; they are capable of real-time waveform recording, possess analyzing functions, and can upload their measurement data to a computer for storage and analysis. The system can calculate and record the time difference between the EMGs of the VMO and the VL, as well as the signal strengths of both the EMGs. As soon as the system detects the generation of the EMG of the VL, it quickly calculates and processes the event and stimulates the VMO as feedback through electrical stimulation units, in order to induce its contraction. The system can adjust the signal strength, time length, and the sequence of the electrical stimulation, both manually and automatically. The output waveform of the electrical stimulation circuit is a dual-phase asymmetrical pulse waveform. The primary function of the electrical simulation circuit is to ensure that the muscles contract effectively. The performance of the device can be seen that the width of each pulse is 20-1000 µs, the frequency of each pulse is 10-100 Hz, and current strength is 10-60 mA.