Superhydrophobic Nanoparticles: An Efficiently Selective Adsorbent for Surfactant-Like Contaminants from Complex Wastewater Matrices.

Surfactant-like contaminants (SLCs) with distinctive amphiphilic structures have become a global concern in wastewater due to their toxicity and persistency. Despite extensive efforts, achieving efficient and selective SLCs removal remains challenging because of their wide range of molecular weights and complex functional group compositions. Superhydrophobic nanoparticles can potentially tackle this challenge by targeting the long oleophilic chains of SLCs. However, conventional contact angle measurements hinder hydrophobicity characterization and corresponding selectivity research because of the powder morphology of nanoparticles. Herein, the authors offered information regarding the distribution of water molecular probes in surfaces and proposed a quantitative characterization approach based on low-field nuclear magnetic resonance. Through synthesizing superhydrophobic and hydrophilic polydopamine nanospheres with similar morphologies, the selective adsorption potential of superhydrophobic nanoparticles for SLCs is systematically demonstrated. As revealed by the interaction mechanisms, the superhydrophobic surface of nanospheres increased its affinity and selectivity for SLCs adsorption by enhancing hydrophobic interactions. Superhydrophobic modification achieved ten times the adsorption capacity of sodium dodecyl benzene sulfonate, an exemplified surfactant, compared with pristine nanoparticles. By regulated self-polymerization, the superhydrophobic nanospheres are coated onto the surface of a 3D sponge and enable efficient selective SLCs adsorption from highly polluted leachate matrices with long-term stability and reusability.

Engineering Synthetic CopT/A-Based Genetic Biosensors for miRNA Imaging and Functional Gene Regulation.

Synthetic genetic biosensors that can operate at the transcriptional and translation levels have been widely applied in the control of cellular behaviors and functions. However, the regulation of genetic circuits is often accompanied by the introduction of exogenous substances or the endogenous generation of inhibitory products, which would bring uncontrollable hazards to biological safety and reduce the efficiency of the system. Here, we described a miRNA-responsive CopT-CopA (miCop) genetic biosensor system to realize real-time monitoring of the intracellular expression of miRNA-124a during neurogenesis or miRNA-122 under the stimulation of extracellular drugs in living cells and animals. Furthermore, to prove the modularity of the system, we engineered this miCop to tune the expression of the DTA (diphtheria toxin A) gene and showed its powerful capacity to kill cancer cells by inducing apoptosis and cell cycle arrest based on miRNA response. This study provides an effective means to couple miRNA sensing with miRNA-responsive gene modulation, which may open up new diagnostic or therapeutic applications.

Harnessing PUF-Based Reporters for Noninvasive Imaging of the MicroRNA Dynamics in Differentiation.

Precise characterization of miRNA expression patterns is critical to exploit the complexity of miRNA regulation in biology. Herein, we developed a Pumilio/FBF (PUF) protein-based engineering luciferase reporter system, PUF/miR, to quantitatively and non-invasively sense miRNA activity in living cells and animal models. We verified the feasibility of this reporter by monitoring the expression of several types of miRNAs (miRNA-9, 124a, 1, and 133a) in neural and muscle differentiated cells as well as subcutaneous or tibial anterior muscles in mice. The quantitative RT-PCR also validated the reliability and quantitative consistency of bioluminescence imaging in detecting miRNA expression. We further effectively employed this reporter system to visualize the expression of miRNA-1 and miRNA-133a in mouse models of skeletal muscle injury. As a non-invasive and convenient innovative approach, our results have realized the positive bioluminescence imaging of endogenous miRNAs in vitro and in vivo using the PUF/miR system. We believe that this approach would provide a potential means for noninvasive monitoring of disease-related miRNAs and could facilitate a deeper understanding of miRNA biology.

A ratiometric dual luciferase reporter for quantitative monitoring of pre-mRNA splicing efficiency in vivo.

Precursor messenger RNA (pre-mRNA) splicing is critical for cell growth and development, and errors in RNA splicing frequently cause cellular dysfunction, abnormal gene expression, and a variety of human diseases. However, there is currently a lack of reliable systems to noninvasively monitor the mRNA splicing efficiency in cells and animals. Here, we described the design of a genetically engineered ratiometric dual luciferase reporter to continuously quantify the changes in mRNA splice variants in vivo. This reporter system is encoded within a single polypeptide but on separate exons, thus generating two distinct luciferase signals derived from spliced and unspliced mRNAs. With this reporter, the two kinds of luciferase in the same individual can minimize the influence of indirect factors on splicing, and the ratio of these two luciferase intensities represents the dynamic splicing efficiency of pre-mRNA. Our study offers a convenient and robust tool for the screening and identification of small molecules or trans-acting factors that affect the efficiency of specific splicing reactions.

Novel fluorescent GLUT1 inhibitor for precision detection and fluorescence image-guided surgery in oral squamous cell carcinoma.

Early detection and complete resection of oral squamous cell carcinoma (OSCC) are crucial to improving patient survival and prognosis. However, specifically targeted imaging probes for OSCC detection are limited. Our study aimed to synthesize a novel near-infrared fluorescence (NIRF) probe for precision detection and fluorescence image-guided surgery in OSCC. Bioinformatics data indicated that glucose transporter 1 (GLUT1) is highly expressed in patients with OSCC. We demonstrated high and specific GLUT1 expression upon immunohistochemical staining of samples from 20 patients with OSCC. The specific expression of GLUT1 was further validated in both human OSCC cell lines and OSCC tumor xenografts. Based on these findings, the GLUT1 inhibitor WZB117 was utilized to synthesize a novel NIRF imaging probe, WZB117-IR820. The fluorescence molecular imaging data revealed that WZB117-IR820 could specifically bind to the tumor areas in an orthotopic OSCC mouse model after intravenous injection and could be further applied for precision fluorescence image-guided surgery with no residual tumor in the orthotopic CAL27-fLUC mouse tumor model. For further clinical translational application in patients with OSCC, precise delineation of OSCC tumor areas was achieved after topical application of the WZB117-IR820 imaging probe and was validated by histopathological and immunohistochemical analyses. In conclusion, we synthesized a novel fluorescent imaging probe, WZB117-IR820, which has potential clinical applications for early detection and fluorescence image-guided surgery in OSCC with no observable toxicity.

Robust ERα-Targeted Near-Infrared Fluorescence Probe for Selective Hydrazine Imaging in Breast Cancer.

Breast cancer is the most common malignancy in women and may become worse when a high concentration of hydrazine is absorbed from the environment or drug metabolite. Therefore, rapid and sensitive detection of hydrazine in vivo is beneficial for people's health. In this work, a novel estrogen receptor α (ERα)-targeted near-infrared fluorescence probe was designed to detect hydrazine levels. The probe showed good ERα affinity and an excellent fluorescence response toward hydrazine. Selectivity experiments demonstrated that the probe had a strong anti-interference ability. Mechanistic studies, including mass spectrometry (MS) and density functional theory (DFT) calculation, indicated that intermolecular charge transfer (ICT) progress was hindered when the probe reacted with hydrazine, resulting in fluorescent quenching. In addition, the probe could selectively bind to MCF-7 breast cancer cells with excellent biocompatibility. The in vivo and ex vivo imaging studies demonstrated that the probe could rapidly visualize hydrazine with high contrast in MCF-7 xenograft tumors. Therefore, this probe can serve as a potential tool to robustly monitor hydrazine levels in vivo.

Laser ablation of anal fistulae: a 6-year experience in a tertiary teaching hospital in Malaysia.

BACKGROUND: Several studies have investigated the role of laser ablation of anal fistulae in the European setting. However, long-term follow-up results following laser fistula ablations are not widely investigated and no study was performed in the Asia-Pacific, a region with a distinctive prevalence of tuberculosis. The primary objective of this study is to report a single-centre experience with laser ablation of anal fistulae in Malaysia over a period of 6 years. METHOD: This was a retrospective observational study assessing the outcomes following 70 laser ablations of anal fistulae from February 2014 till December 2019. All cases were assessed using endoanal ultrasound. The laser ablation procedures were performed using laser systems and fibres from Endoteq Medizinische Laser GmBH, Germany, and Biolitec AG, Jena, Germany. Laser fibres were introduced into the fistula tract and laser energy was emitted radially in continuous mode when activated during the procedure. Pre-defined post-procedural outcomes (primary healing, healing failure or recurrence) were recorded as either present or absent during subsequent follow-up appointments and the data was analysed. RESULTS: Over a median follow-up period of 10 months, primary healing was reported following 42 procedures (60.0%). Healing failure was reported following 28 procedures (40.0%) whilst recurrence was seen after 16 procedures (22.86%). No new cases of incontinence were reported following the procedure. CONCLUSION: The reported primary healing rate following laser ablation of anal fistulae in this study appears consistent with existing literature published by other international centres. The most apparent clinical advantage of this procedure is sphincter-function preservation. However, the primary healing rate after isolated laser fistula ablation is still suboptimal. Judicious patient selection and application in anal fistulae with suitable characteristics could potentially improve the post-procedural outcomes.

Uniportal Endoscopic Vein Harvest Using the Three-Step Haemostatic Technique-A Modified Approach.

Endoscopic venous harvest (EVH) has become widely adopted in routine elective coronary artery bypass graft operations given it reduces surgical-site infections and improves wound cosmesis. The conventional EVH involves a 'stab and grab' incision at the inguinal crease, which is a hard-to-reach area for routine wound care. This paper describes the steps of the uniportal EVH, which transects the venous conduit, omitting the need for a stab incision at the groin.

Integration of TaOx with Bi2S3 for Targeted Multimodality Breast Cancer Theranostics.

Early identification and treatment of breast cancer is very important for breast conserving therapy and to improve the prognosis and survival rates of patients. Multifunctional nanotheranostic agents are of particular importance in the field of precise nanomedicine, since they can augment the visualization and treatment of cancer. We developed a novel Bi2S3 nanoparticle coated with a hyaluronic acid (HA)-modified tantalum oxide (TaOx) nanoshell (Bi2S3@TaOx-HA). The as-prepared core/shell nanoparticles exhibited a high Bi2S3 nanoparticle loading efficiency of (67 wt %). The TaOx nanoshell exhibited excellent biocompatibility and computed tomography imaging capacity, and the Bi2S3 nanoparticles exhibited an excellent photothermal transducing performance and computed tomography (CT) and photoacoustic imaging capacity. As a result of these merits, the Bi2S3@TaOx core-shell nanoparticles can act as a theranostic agent for CT/photoacoustically monitored enhanced photothermal therapy. These findings will evoke new interest in future cancer therapeutic strategies based on biocompatible functional nanomaterials.

Novel hybrid conjugates with dual estrogen receptor α degradation and histone deacetylase inhibitory activities for breast cancer therapy.

Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. On the other hand, double- or multi-target conjugates, which are able to synergize antitumor activity by different pathways, thus may enhance therapeutic effect in comparison with single targeted therapy. In this study, we designed and synthesized a series of novel dual-functional conjugates targeting both ERα degradation and histone deacetylase inhibiton by combining a privileged SERD skeleton 7-oxabicyclo[2.2.1]heptane sulfonamide (OBHSA) with a histone deacetylase inhibitor side chain. We found that substituents on both the sulfonamide nitrogen and phenyl group of OBHSA unit had significant effect on biological activities. Among them, conjugate 16i with N-methyl and naphthyl groups exhibited potent antiproliferative activity against MCF-7 cells, and excellent ERα degradation activity and HDACs inhibitory ability. A further molecular docking study indicated the interaction patterns of these conjugates with ERα, which may provide guidance to design novel SERDs or PROTAC-like SERDs for breast cancer therapy.

A Secreted Reporter for Blood Monitoring of Pyroptotic Cell Death.

Pyroptotic cell death is a phenomenon that runs through all life activities and plays an important role in physiological and pathological processes of the body's metabolism. It is of big biological significance to understand the phenomenon and nature of cell pyroptosis. In the process of cell pyroptosis, the pore-forming effector gasdermin D (GSDMD) is cleaved to form oligomers, which are inserted into the cell membrane, causing rapid cell death. However, the effective cell death induced by GSDMD complicates our ability to understand the behavior of pyroptosis. In this work, we performed molecular mutagenesis to develop a genetically encoded pyroptotic reporter, where a secreted Gaussia luciferase (Gluc) was strategically placed in the p30-p20 tolerated junction of GSDMD to support natural pyrophosphorylation and promote live imaging of cell pyroptosis. In addition, we demonstrated that this fused Gluc-GSDMD reporter executed inflammatory body-dependent pyroptosis in response to extracellular stimuli, and that the lysed p30-GSDMD can be secreted out of the cell and can be detected in the culture medium and animal blood. Therefore, our study provides a valuable tool that not only noninvasive and real-time monitoring of cell pyroptosis, but also affords a high-throughput functional screening of pyroptosis-targeted compounds in cultured cells and animal models.

Dynamic Liquid Surface Enhanced Raman Scattering Platform Based on Soft Tubular Microfluidics for Label-Free Cell Detection.

Cell detection is of great significance for biomedical research. Surface enhanced Raman scattering (SERS) has been widely applied to the detection of cells. However, there is still a lack of a general, low-cost, rapid, and sensitive SERS method for cell detection. Herein, a dynamic liquid SERS platform, which combines label-free SERS technique with soft tubular microfluidics for cell detection, is proposed. Compared with common static solid and static liquid measurement, the dynamic liquid SERS platform can present dynamical mixing, precise control of the mixing time, and continuous spectra collection. By characterizing the model molecules, the proposed dynamic liquid SERS platform has successfully demonstrated good stability and repeatability with 1.90% and 4.98% relative standard deviation (RSD), respectively. Three cell lines including one normal breast cell line (MCF-10A) and two breast cancer cell lines (MCF-7 and MDA-MB-231) were investigated in this platform. 270 cell spectra were selected as the training set for the classification of the models based on the K-Nearest Neighbor (K-NN) algorithm. In three independent experiments, three types of cells were identified by a test set containing 180 cell spectra with sensitivities above 83.3% and specificities above 91.6%. The accuracy was 94.1 ± 1.14% among three independent cell identifications. The dynamic liquid SERS platform has shown higher signal intensity, better repeatability, less pretreatment, and obtainment of more spectra with less time consumption. It will be a powerful detection tool in the area of cell research, clinical diagnosis, and food safety.

Simultaneously Enhanced Singlet Oxygen and Fluorescence Production of Nanoplatform by Surface Plasmon Resonance Coupling for Biomedical Applications.

Photodynamic therapy (PDT) and fluorescence imaging offer the possibility of precise and personalized treatment of cancer, but low singlet oxygen production of a commercial photosensitizer and the quenching effect of fluorescent dyes limit the further application of PDT treatment and fluorescence imaging. In addition, the single nanoplatform that simultaneously achieved singlet oxygen and fluorescence enhancement is rare. In this paper, a novel simultaneously enhanced singlet oxygen and fluorescence production nanoplatform of AuNR@mSiO2-Ce6-Cy5.5 has been successfully designed and synthesized by surface plasmon resonance coupling. The as-synthesized nanoplatform achieved a 1.8-fold enhancement of the singlet oxygen production of Ce6 and a 5.0-fold enhancement of the fluorescence production of Cy5.5 by surface plasmon resonance coupling. The as-synthesized nanoplatform simultaneously enhances the photodynamic therapy and fluorescence imaging of cancer, which will have great potential in biomedical applications.

A Novel Estrogen Receptor α-Targeted Near-Infrared Fluorescent Probe for in Vivo Detection of Breast Tumor.

The ability to detect breast cancer early in its progression is essential to improve patient survival and quality of life. The noninvasive and dynamic imaging and functional assessments of estrogen receptor-alpha (ERα), which is commonly expressed at high levels in breast cancer, are important for effective diagnosis and treatment. Hence, the development of a specific ERα-targeted probe is a major research goal. To that end, in the present study, we created a novel near-infrared (NIR) fluorescent probe, IRDye800CW-E2, for targeted ERα imaging in breast-tumor-bearing mice. IRDye800CW-E2 consisted of a cyanine dye IRDye800CW as the NIR fluorophore and the E2 analogue ethinyl estradiol amine as an ERα targeting ligand. The ethinyl estradiol amine was initially labeled with fluorescein isothiocyanate (FITC) to evaluate the binding specificity to human breast-tumor cells in vitro. Flow chamber and in vitro confocal laser endomicroscopy imaging experiments demonstrated that FITC-E2 was specifically taken up by MCF-7 cells. Furthermore, NIR fluorescence imaging revealed the ability of IRDye800CW-E2 to rapidly target tumors and to achieve good contrast between tumors and background signal 4-48 h postinjection. The fluorescent signal of IRDye800CW-E2 in tumors was successfully blocked by the coinjection of the endogenous ERα-ligand 17ß-estradiol (E2) and the probe. Ex vivo fluorescent imaging further confirmed high uptake of the probe by tumors. These results indicated that IRDye800CW-E2 has great potential as an ERα-targeted imaging probe for early breast-tumor detection and has potential for clinical translation.

Chelator-Free and Biocompatible Melanin Nanoplatform with Facile-Loading Gadolinium and Copper-64 for Bioimaging.

Development of a chelator-free and biocompatible platform for the facile construction of gadolinium3+ (Gd3+)-loaded nanoparticle based probes for in vivo magentic resonance imaging (MRI) is still challenging. Herein, biocompatible Gd3+-loading melanin dots (Gd-M-dots) have been easily prepared and have exhibited good loading efficiency for Gd3+, high stability, and higher T1 relaxivity compared to the commercial Gd-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) agent. Furthermore, Gd-M-dots showed unique photoacoustic (PA) properties, and a high PA imaging signal could be observed in vivo 1 h after injection. Compared to the traditional Gd3+-loaded nanoparticles for single-modal MRI, Gd-M-dots can also be radiolabeled with 64Cu2+ for positron emission tomography. Overall, these attractive properties of Gd-M-dots render them a promising imaging agent for various biomedical applications.

Dual functional small molecule fluorescent probes for image-guided estrogen receptor-specific targeting coupled potent antiproliferative potency for breast cancer therapy.

A strategy by integrating biological imaging into early stages of the drug discovery process can improve our understanding of drug activity during preclinical and clinical study. In this article, we designed and synthesized coumarin-based nonsteroidal type fluorescence ligands for drug-target binding imaging. Among these synthesized compounds, 3e, 3f and 3h showed potent ER binding affinity and 3e (IC50=0.012µM) exhibited excellent ERα antagonistic activity, its antiproliferative potency in breast cancer MCF-7 cells is equipotent to the approved drug tamoxifen. The fluorescence of compounds 3e and 3f depended on the solvent properties and showed significant changes when mixed with ERα or ERß in vitro. Furthermore, target molecule 3e could cross the cell membrane, localize and image drug-target interaction in real time without cell washing. Thus, the coumarin-based platform represents a promising new ER-targeted delivery vehicle with potential imaging and therapeutic properties.

Synthesis and structure-activity relationships of novel hybrid ferrocenyl compounds based on a bicyclic core skeleton for breast cancer therapy.

Breast cancer is the most frequent cancer in women worldwide, and incidence is increasing year by year. Although current selective estrogen receptor modulators (SERMs) have clear advantages in the treatment of hormone-responsive breast cancer, they are ineffective for ER(-). In this study, we describe the design and synthesis of a series of dual-acting estrogen receptor (ER) and histone deacetylase (HDAC) inhibitors with incorporation of the ferrocenyl moiety, leading to novel hybrid ferrocenyl complexes (FcOBHS-HDACis) for breast cancer therapy. It is worth to note that these ferrocenyl conjugates could not only potently inhibit HDACs and the proliferation of ERα positive (ER(+)) breast cancer cells (MCF-7), but also show significant antiproliferative effect on ER(-) breast cancer cells (MDA-MB-231). Thus, the FcOBHS-HDACi conjugates represent a novel approach to the development of efficiently dual-acting agents for treatment of breast cancer.

Anomalous left coronary artery arising from the pulmonary artery discovered beyond infancy.

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a congenital heart defect rarely diagnosed beyond infancy. We present a 9-year-old girl who had once been diagnosed as congenital coronary artery fistula. Echogenic mitral chordae tendineae, multiple coronary collaterals within the ventricular septum and free ventricular wall, and a shunting flow from the left coronary artery into the pulmonary artery were prominent echocardiographic features of ALCAPA. Reimplantation of the left coronary artery directly onto the aorta achieved a favorable outcome with regression of left ventricular size and alleviation of mitral regurgitation.

Glycosmisines A and B: isolation of two new carbazole-indole-type dimeric alkaloids from Glycosmis pentaphylla and an evaluation of their antiproliferative activities.

Two unique carbazole-indole-type dimeric alkaloids, glycosmisines A (1) and B (2), have been isolated from the stems of Glycosmis pentaphylla and their structures are elucidated by 1D and 2D NMR analyses, and their cytotoxicity against the growth of three cancer cell lines (A549, HepG-2 and Huh-7 cells) in culture was investigated using an MTT assay. Compounds 1 and 2 exhibited significant levels of cytotoxicity against three human cancer cell lines, and these two compounds also induced apoptosis in the same cell lines, as evidenced by changes in the morphological features of cells treated with these compounds and their dose-dependent accumulation of a sub-G1 population.