Tumor-overexpressed enzyme responsive amphiphiles small molecular self-assembly nano-prodrug for the chemo-phototherapy against non-small-cell lung cancer.

Rational design of self-assembly drug amphiphiles can provide a promising strategy for constructing nano-prodrug with high drug loading, smart stimuli-responsive drug release and high tumor selectivity. Herein, we report a small molecular amphiphile prodrug that can self-assemble into multifunctional nano-prodrug for enhanced anticancer effect by the combination of chemotherapy and phototherapy (PDT/PTT). In this prodrug, the simple insertion of quinone propionate into hydrophilic drug Irinotecan (Ir) generates suitable amphiphiles that endow a good self-assembly behavior of the prodrug and transform it into a stable and uniform nanoparticle. Interestingly, this excellent self-assembly behavior can load phototherapy agent ICG to form a multifunctional nano-prodrug, thereby enhancing the chemotherapeutic effect with PDT/PTT. Importantly, the quinone propionic acid moiety in the prodrug showed a high sensitivity to the overexpressed NAD(P)H:quinone oxidoreductase-1 (NQO1) in non-small cell lung cancer (NSCLC) cells, and this sensitivity enables the disassembly of nano-prodrug and efficient NQO1-responsive drug release. To further enhance the drug accumulation on tumor tissue and migrate the blood clearance, a biomimetic nano-prodrug has been successfully explored by coating hybrid membrane on the above nano-prodrug, which displays high selective inhibition of tumor growth and metastasis on NSCLC mice model. Our findings provide new insights into the rational design of tumor-overexpressed enzyme responsive nano-prodrug for cancer combinational therapy.

Bilateral inferior venae cava combined with the persistent left superior vena cava and hemiazygos continuation of left inferior vena cava with drainage into right atrium: A case report.

The persistent left superior vena cava (PLSVC) is a common venous abnormality. However, malformation of the bilateral inferior venae cava (IVC) is extremely rare, with an incidence rate of .3%. IVC malformation is associated most frequently with heart defects and isomerism and often has a poor prognosis. We presented a case of vascular malformations in the fetus of bilateral caval veins with the interruption of the left-sided venous return with hemiazygos continuation in presence of a right-sided inferior caval vein. Also noted were the PLSVC and a dilated right heart with a widened pulmonary trunk. In this case, there were no heart defects or chromosomal abnormalities, and the newborn postpartum was in a good condition.

Rational N,P-Codoped pH-Activatable Red Carbon Dot for In Vitro and In Vivo Tumor Imaging.

Tumor detection and imaging via tumor microenvironmental indicators can have practical value. Here, a low-pH-responsive red carbon dot (CD) was prepared via a hydrothermal reaction for specific tumor imaging in vitro and in vivo. The probe responded to the acidic tumor microenvironment. The CDs are codoped by nitrogen and phosphorene and contain anilines on the surface. These anilines are efficient electron donors and modulate the pH response: Fluorescence is undetectable at common physical pH (>7.0), but red fluorescence (600-720 nm) increases with decreasing pH. The inactivation of fluorescence is due to three aspects: photoinduced electron transfer from anilines, deprotonation-induced energy states changing, and particle aggregation-induced quenching. It is believed that this pH-responsive character of CD is better than other reported CDs. Thus, in vitro images of HeLa cells show strong fluorescence that is 4-fold higher than normal cells. Subsequently, the CDs are used for in vivo imaging of tumors in mice. Tumors can be clearly observed within 1 h, and clearance of CDs will be finished within 24 h due to the small size of the CDs. The CDs offer excellent tumor-to-normal tissue (T/N) ratios and have great potential for biomedical research and disease diagnosis.

Spontaneous perirenal hemorrhage (Wunderlich syndrome) in the fetus: a case report.

BACKGROUND: Spontaneous perirenal hemorrhage (Wunderlich syndrome) in the fetus is a rare urinary system disease. Prenatal ultrasound diagnosis presents challenges due to the lack of specific clinical features. CASE PRESENTATION: A 27-year-old Chinese woman gravida 2 para 0 found her fetus with the left Wunderlich syndrome accompanying bilateral hydronephroses and bladder dysfunction with an early diagnosis through prenatal ultrasound and postnatal magnetic resonance imaging. After a timely emergency cesarean section, the infant was administrated antimicrobial prophylaxis and an indwelling catheter treatment. Ultrasound follow-up showed his urinary system gradually developed normally. CONCLUSION: A fetus with bilateral hydronephroses accompanying bladder dysfunction should be observed because of the risk of spontaneous renal rupture with hemorrhage formation. Ultrasound and magnetic resonance imaging play a vital role in the diagnosis and follow-up of Wunderlich syndrome. Early diagnosis facilitates better pregnancy planning and appropriate care of newborns.

Signal "on-off-off" strategy for improving the sensitivity of BRCA1 electrochemical detection by combining gold substrate amplification, DNA conformational transformation and DSN enzymatic hydrolysis dual reduction.

In this article we proposed a new signal amplification strategy based on signal "on-off-off" for improving the detection sensitivity of breast cancer 1 (BRCA1) electrochemical sensor. First, the stem-loop structured captured DNA (C-DNA) modified by 5' sulfhydryl group and 3' methylene blue (MB), was self-assembled on electrodeposited nanoAu surface through Au-S reaction. Electrodeposition of nanoAu increased electrode area and strengthened MB electrochemical signal, which indicated "signal on". Then, BRCA1 hybridization with C-DNA made MB away from nanoAu surface, and reduced the MB signal due to the formation of stiff C-DNA/BRCA1 hybridized structure, which indicated "signal off". Finally, the double strand specific nuclease (DSN) was used to cleave C-DNA/BRCA1, and led to the further decrease of MB signal, which also indicated "signal off". Results showed that the designed sensor based on signal "on-off-off" had excellent detection sensitivity for BRCA1. The relative percentage change of MB reduction peak current was linear with BRCA1 concentration from 5 nM to 70 nM, and a low detection limit of 52 pM was achieved. The proposed sensor could distinguish single base mismatch BRCA1, two base mismatch BRCA1, and non-complementary DNA well. In addition, the sensor showed good reproducibility and stability.

The clinical application of PIVKA-II in hepatocellular carcinoma and chronic liver diseases: A multi-center study in China.

BACKGROUND: Due to the absence of specific symptoms and low survival rate, efficient biomarkers for hepatocellular carcinoma (HCC) diagnosis are urgently required. The purpose of this study was to evaluate the diagnostic performance of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and to determine the optimal cutoff values for HBV infection-related HCC. METHODS: We conducted a cross-sectional, multi-center study in China to ascertain the cutoff value for HCC patients in the context of CHB- and HBV-related cirrhosis. The receiver operating characteristic curve (ROC) and the area under the curve (AUC) were used to evaluate the diagnostic performance of PIVKA-II. RESULTS: This study enrolled 784 subjects and demonstrated that PIVKA-II had a sensitivity of 84.08% and a specificity of 90.43% in diagnosis HCC from chronic liver diseases. PIVKA-II at a cutoff of 37.5 mAU/mL yielded an AUC of 0.9737 (sensitivity 91.78% and specificity 96.30%) in discriminating HCC from chronic hepatitis B (CHB) patients. PIVKA-II at a cutoff of 45 mAU/mL yielded an AUC of 0.9419 (sensitivity 77.46% and specificity 95.12%) in discriminating HCC- from HBV-related cirrhosis patients. Furthermore, using a cutoff value of 40 mAU/mL for PIVKA-II as an HCC marker, only 4.81% (15/312) was positive in chronic hepatitis and 12.80% (37/289) in cirrhosis patients, revealing the satisfactory specificity of PIVKA-II in chronic liver disease of different etiologies. CONCLUSION: Our data indicated that PIVKA-II had satisfactory diagnostic efficiencies and could be used as a screening or surveillance biomarker in HCC high-risk population.

Levels of serum IgG subclasses in patients with liver disease: A retrospective study.

Viral and alcoholic liver disease, drug induced liver disease (DILD), primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are among the most common liver diseases observed in clinical practice. These diseases lack unique clinical characteristics at the beginning of pathogenesis, which renders specific diagnosis difficult. Immunoglobulin G (IgG) subclasses are the main isoform of antibodies that can be found in the serum that serve important protective roles in immunity. The present study aimed to investigate the serum IgG subclass distribution in patients with the five common liver diseases aforementioned. The present study retrospectively recorded and analyzed the serum IgG subclass levels of different patients, who were grouped according to their clinical diagnosis. Serum IgG subclass levels were measured using immunonephelometric assays. IgG3 levels were found to be significantly increased whereas IgG4 levels were significantly decreased in patients with PBC. In patients with AIH, IgG1 levels were significantly increased. By contrast, IgG1/IgG level ratios in patients with viral liver disease were significantly increased. No clear pattern in the distribution characteristics of IgG subclasses could be observed in cohorts with alcoholic liver disease and DILD in the present study. Additionally, model for end-stage liver disease scores regarding IgG1 in patients with AIH shared a synergistic relationship. Anti-mitochondrial antibody subtype M2 (AMA-M2) and IgG3 in patients with PBC demonstrated a synergistic relationship. These results suggested that IgG subclasses may be used as biomarkers to further the understanding of liver disease, which could allow for early diagnosis.

Recent advance in biosensing applications based on two-dimensional transition metal oxide nanomaterials.

In recent years, two-dimensional transition metal oxide nanomaterials (2D TMONs) have drawn increasing attention due to their various functionalization, tunable electronic characteristics, unique optical properties, excellent chemical and thermal stabilities, large surface area and strong oxidation ability. The metal ions of 2D TMONs usually possessed the unfilled d-orbital. Furthermore, 2D TMONs contained oxygen ion in comparison with other 2D nanomaterials. Thus, 2D TMONs has a series of features which included reactive electronic transitions, high dielectric constants, wide bandgaps and excellent electrical property. They could act as quencher to quench the fluorescence intensity of fluorescent sensor or electrochemiluminescence. Recently, they have been demonstrated both excellent biological compatibility and good dispersion for the oxygen ions. These properties endow 2D TMONs could be used in optic, electronic, catalytic, energy technology, biosensing to biomedical diagnosis and therapy. In this review, we provide a brief overview regarding the progress of 2D TMONs based biosensors that function through various analytical methods including fluorescence, chemiluminescence, electrochemical and colorimetric in recent five years. The review may do some help to the researchers who are interested in 2D TMONs based biosensors.

A metal-organic framework/aptamer system as a fluorescent biosensor for determination of aflatoxin B1 in food samples.

The demand of simple, sensitive, selective and reliable assay for aflatoxin B1 (AFB1) detection is ubiquitous in food safety, due to its high toxic. Herein, a novel fluorescent aptasensor using metal-organic frameworks (UiO-66-NH2) and TAMRA label aptamer as sensing platform for AFB1 detection was developed. The TAMRA aptamer adsorbed on the surface of UiO-66-NH2 via van der Waals force and its fluorescence was quenched for the charge transfer from fluorescence dye TAMRA to metal ions of UiO-66-NH2. After introducing AFB1 to the system, the TAMRA aptamer binded to AFB1 and formed TAMRA aptamer/AFB1complex, making its conformation change and resulting in fluorescence recovery. Thus, the quantity of AFB1 could be analyzed according to the fluorescence signal change. Under optimize experimental conditions, the assay exhibited high sensitivity toward AFB1 in range of 0-180 ng mL-1 with low limit of detection of 0.35 ng mL-1 and good specificity against other toxins. Moreover, the aptamer/metal-organic frameworks sensing platform could be utilized to determine AFB1 content in food samples such as corn, rice and milk. It provided a reasonable method for other mycotoxin detection by changing the sequence of aptamer.

Nitrogen-sulfur co-doped pH-insensitive fluorescent carbon dots for high sensitive and selective hypochlorite detection.

Carbon dots (CDs) are novel fluorescent carbon nanomaterial with exceptional properties and have drawn great attention in recent years. However, the preparation and applications of high-quality carbon dots remain challenging. Here, we describe a simple hydrothermal synthesis route using citric acid as a carbon source for stable fluorescent CDs. The CDs are modified with glutathione and exhibit high fluorescent quantum yields (30.2%) and excellent photo-stability. In addition, the fluorescence intensity of CDs remains stable over a wide range of pH values (3-12). Hypochlorite (ClO-) can effectively quench the fluorescence of the CDs by destroying the pyrrolic ring and conjugate structure of the CDs. Thus, the CDs can be used to detect ClO-. Under optimized conditions, the fluorescence intensity changes of CDs correspond selectively to ClO- in the range of 100-800 nmol/L with a LOD of 16 nmol/L. Practical applications of the proposed method for free chlorine detection in tap water show similar results and recovery compared to the standard DPD-based method. These results suggest that the pH-insensitive CDs prepared via this facile procedure are a promising chemosensor for free chlorine and have great potential in analytical applications.

One Step Preparation of Peptide-Coated Gold Nanoparticles with Tunable Size.

Gold nanoparticles (AuNPs) made from self-assembling peptides have been used in many research fields and attracted a great deal of attention due to their high stability, biocompatibility and functionality. However, existing preparation methods for peptide-coated AuNPs are post-synthesis processes, which are complicated and time consuming. Therefore, a one-step preparation method for peptide-coated AuNPs is proposed here. The AuNPs obtained by this method exhibit good stability. Importantly, peptide-coated AuNPs with precise different sizes can be prepared by this method through pH control of reducing reagent tyrosine in range of 10.0~12.7. Thus, the one-step preparation method proposed here provides a significant tool for the research in different fields concerning NP size, stability and biocompatibility.

1,6-Elimination reaction induced detection of fluoride ions in vitro and in vivo based on a NIR fluorescent probe.

Near-Infrared "turn on" type fluorescent probes are attractive and promising in the fields of chemical sensing and bioimaging. Here, a new dicyanomethylene-4H-pyran derivative (DCM-Si) NIR fluorescent probe was designed and synthesized for specific lighting up F- in living cells and bodies. SiO bond was used as F- trigger, and the release of fluorophore (DCM-NH2) occurred after substituent reaction and subsequent 1,6-elimination. This NIR probe displayed high sensitivity and selectivity for the sensing of F-, and the detection limit was calculated to be as low as 157 nM. Moreover, the "off-on" fluorescent signal changes can be realized by adding F- in living cells and zebrafish embryos.

A label-free fluorescent aptasensor for the detection of Aflatoxin B1 in food samples using AIEgens and graphene oxide.

The detection of Aflatoxin B1 (AFB1) has attracted extensive attention for food safety is a worldwide public health problem. Herein, a novel, simple and label-free fluorescent aptasensor, based on quaternized tetraphenylethene salt (TPE-Z), graphene oxide (GO) and AFB1 aptamer, has been constructed to detect AFB1. In the presence of AFB1, AFB1 aptamer undergoes a conformational switch from single stranded structure to the AFB1/AFB1 aptamer complex upon target binding, which induces the release of TPE-Z/AFB1 aptamer from the surface of GO. Thus, the fluorescence of TPE-Z/AFB1 aptamer is recovered. The assay can be performed by simply mixing TPE-Z, AFB1 aptamer, the GO and the AFB1 samples with a detection limit of 0.25 ng/mL. It is highly selective against other aflatoxins in foods and its performance has been verified in food samples (corn, milk and rice) with known concentration AFB1.

Integrated Solid-State Nanopore Electrochemistry Array for Sensitive, Specific, and Label-Free Biodetection.

Nanopore ionic current measurement is currently a prevailing readout and offers considerable opportunities for bioassays. Extending conventional electrochemistry to nanoscale space, albeit noteworthy, remains challenging. Here, we report a versatile electrochemistry array established on a nanofluidic platform by controllably depositing gold layers on the two outer sides of anodic aluminum oxide (AAO) nanopores, leading to form an electrochemical microdevice capable of performing amperometry in a label-free manner. Electroactive species ferricyanide ions passing through gold-decorated nanopores act as electrochemical indicator to generate electrolytic current signal. The electroactive species flux that dominates current signal response is closely related to the nanopore permeability. Such well-characteristic electrolytic current-species flux correlation lays a premise for quantitative electrochemical analysis. As a proof-of-concept demonstration, we preliminarily verify the analytical utility by detection of nucleic acid and protein at picomolar concentration levels. Universal surface modification and molecule assembly, specific target recognition and reliable signal output in nanopore enable direct electrochemical detection of biomolecules without the need of cumbersome probe labeling and signal amplification.

A highly sensitive and selective fluorescent probe without quencher for detection of Pb2+ ions based on aggregation-caused quenching phenomenon.

Lead is a highly toxic heavy metal, and various functional nucleic acid (FNA)-based biosensors have been developed for the detection of Pb2+ in environmental monitoring. However, most fluorescence biosensors that have been reported were designed on the basis of a double-labeled (fluorophore and quencher group) DNA sequence, which not only involved an inconvenient organic synthesis but also restricted their wider use in practical applications. Here, we utilized a G-rich DNA sequence as a recognition probe and conjugated fluorene (CF) to develop a fluorescence sensor without a quencher based on the aggregation-caused quenching (ACQ) effect. In the presence of Pb2+, the degree of aggregation of CF was reduced because Pb2+ induced the formation of a G-quadruplex structure of the CF-DNA probe, and the fluorescence signal increased with the concentration of Pb2+ (0-1 µM), with a limit of detection of 0.36 nM. This fluorescent probe without a quencher enables the sensitive and selective detection of Pb2+. On the basis of these advantages, the CF-DNA probe represents a promising analytical method for detecting Pb2+.

Facile Probe Design: Fluorescent Amphiphilic Nucleic Acid Probes without Quencher Providing Telomerase Activity Imaging Inside Living Cells.

Nowadays, the probe with fluorophore but no quencher is promising for its simple preparation, environmental friendliness, and wide application scope. This study designs a new amphiphilic nucleic acid probe (ANAP) based on aggregation-caused quenching (ACQ) effect without any quencher. Upon binding with targets, the dispersion of hydrophobic part (conjugated fluorene, CF) in ANAP is enhanced as a signal-on model for proteins, nucleic acids, and small molecules detection or the aggregation of CF is enhanced as a signal-off model for ion detection. Meanwhile, because of the high specificity of ANAP, a one-step method is developed powerfully for monitoring the telomerase activity not only from the cell extracts but also from 50 clinic urine samples (positive results from 45 patients with bladder cancer and negative results from 5 healthy people). ANAPs can also readily enter into cells and exhibit a good performance for distinguishing natural tumor cells from the tumor cells pretreated by telomerase-related drugs or normal cells. In contrast to our previous results ( Anal. Chem. 2015 , 87 , 3890 - 3894 ), the present CF is a monomer which is just the structure unit of the previous fluorescent polymer. Since the accurate molecular structure and high DNA/CF ratio of the present CF, these advanced experiments obtain an easier preparation of probes, an improved sensitivity and specificity, and broader detectable targets.

Nanopore-based analysis of biochemical species.

Biological nanochannels or nanopores play a crucial role in basic biochemical processes in cells. Artificial nanopores possessing dimensions comparable to the size of biological molecules and mimicking the function of biological ion channels are of particular interest with respect to the design of biosensors with a sensitivity that can go down to the fM level and even to single molecule detection. Nanopore-based analysis (NPA) is currently a new research field with fascinating prospects. This review (with 118 refs.) summarizes the progress made in this field in the recent 10 years. Following an introduction into the fundamentals of NPA, we demonstrate its potential by describing selected methods for sensing (a) proteins such as streptavidin, certain antibodies, or thrombin via aptamers; (b) oligomers, larger nucleic acids, or micro-RNA; (c) small molecules, (d) ions such as K(I) which is vital to the maintenance of life, or Hg(II) which is dangerous to health. We summarize the results and discuss the merits and limitations of the various methods at last. Graphical abstractSchematic of a signal-off system and a signal-on system in nanopore analysis. The effective diameter of nanopores decreases when targets undergo certain interactions with receptors attached on the inner surface of the nanopore. Correspondingly, the current will drop on appearance of the analyte. This is referred to as a "signal-off" system. Conversely, it is called a "signal-on" system.

Lab in a Tube: Sensitive Detection of MicroRNAs in Urine Samples from Bladder Cancer Patients Using a Single-Label DNA Probe with AIEgens.

We demonstrate an ultrasensitive microRNA detection method based on an extremely simple probe with only fluorogens but without quencher groups. It avoids complex and difficult steps to accurately design the relative distance between the fluorogens and quencher groups in the probes. Furthermore, the assay could accomplish various detection limits by tuning the reaction temperature due to the different activity of exonuclease III corresponding to the diverse temperature. Specifically, 1 pM miR-21 can be detected in 40 min at 37 °C, and 10 aM (about 300 molecules in 50 µL) miR-21 could be discriminated in 7 days at 4 °C. The great specificity of the assay guarantees that the real 21 urine samples from the bladder cancer patients are successfully detected by our method.

Real-Time, Quantitative Lighting-up Detection of Telomerase in Urines of Bladder Cancer Patients by AIEgens.

As a biomarker for early cancer diagnosis, telomerase are one of the promising targets for cancer therapeutics. Inspired by the fluorescent emission principle of aggregation-induced emission fluorogens, we creatively designed an AIE-based turn-on method to detect telomerase activity from cell extracts. A positively charged fluorogen (TPE-Z) is not fluorescent when freely diffused in solution. The fluorescence of TPE-Z is enhanced with the elongation of the DNA strand which could light up telomere elongation process. By exploitation of it, we can detect telomerase activity from different cell lines (E-J, HeLa, MCF-7, and HLF) with high sensitivity and specificity. Moreover, our method is successfully employed to demonstrate the applications in bladder cancer diagnosis (41 urine specimens from bladder cancer patients and 15 urine specimens from normal people are detected). The AIE-based method provides a simple one-pot technique for quantification and monitoring of the telomerase activity and shows great potential for future use in clinical tests.

Real-time monitoring of enzyme-free strand displacement cascades by colorimetric assays.

The enzyme-free toehold-mediated strand displacement reaction has shown potential for building programmable DNA circuits, biosensors, molecular machines and chemical reaction networks. Here we report a simple colorimetric method using gold nanoparticles as signal generators for the real-time detection of the product of the strand displacement cascade. During the process the assembled gold nanoparticles can be separated, resulting in a color change of the solution. This assay can also be applied in complex mixtures, fetal bovine serum, and to detect single-base mismatches. These results suggest that this method could be of general utility to monitor more complex enzyme-free strand displacement reaction-based programmable systems or for further low-cost diagnostic applications.