Flower-like ZIF-8 enhance the peroxidase-like activity of nanoenzymes at neutral pH for detection of heparin and protamine.

The peroxide-like catalytic activity of gold nanoclusters (Au-NCs) is very low under physiological conditions (pH 7.4), which greatly limits its biological detection applications. A new nanoenzyme platform was constructed by self-assembly of Au-NCs and ZIF-8/CQDs. It was found that heparin can significantly promote the peroxidase-like activity of Au-NCs on the nanoenzyme platform at pH 7.4. In the presence of H2O2, the catalytic activity of Au-NCs on the nanoenzyme platform for TMB increased nearly 50 times. Based on this phenomenon, a colorimetric method was developed to determine heparin in the range of 0.0185-9.25 U/mL, with a detection limit of 0.0027 U/mL. When protamine is introduced, heparin and protamine take the lead in specific binding due to antagonism, which makes heparin unable to adsorb on the surface of ZIF-8/CQDS, thus inhibiting the enhancement of the catalytic activity of Au-NCs. Based on this phenomenon, a colorimetric method was developed to determine protamine in the range of 0.01-0.5 µg/mL, with a detection limit of 0.003 µg/mL. Therefore, this method provides a new idea for the visual detection of heparin and protamine under physiological conditions.

Efficacy and Safety of a Pegasparaginase-Based Chemotherapy Regimen vs an L-asparaginase-Based Chemotherapy Regimen for Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized Clinical Trial.

Importance: The L-asparaginase-based SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen has shown higher response rates and survival benefit over an anthracycline-containing regimen. However, the safety profile was not satisfied. A well-tolerated regimen with promising efficacy is lacking. Objective: To compare the efficacy and safety of the DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) regimen with the SMILE regimen in newly diagnosed advanced-stage (III/IV) extranodal natural killer/T-cell lymphoma (ENKL). Design, Setting, and Participants: This was an open-label, multicenter, randomized clinical trial that took place across 12 participating hospitals in China from January 2011 to February 2019. Patients were eligible if they were 14 to 70 years old with newly diagnosed ENKL in stages III/IV and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Eligible patients were evenly randomized to either the DDGP or SMILE group. Interventions: Patients in each group were treated with the assigned regimen every 21 days for 6 cycles. Main Outcomes and Measures: The primary end point was progression-free survival (PFS), and secondary end points included overall response rate and overall survival (OS). The adverse events between the DDGP and SMILE groups were compared. Results: Among the 87 randomized patients, 80 received treatment (40 in the DDGP group and 40 in the SMILE group); the median (IQR) age was 43 (12) years, and 51 (64%) were male. The baseline characteristics were similar between the groups. At a median follow-up of 41.5 months, the median PFS was not reached in the DDGP group vs 6.8 months in the SMILE group (HR, 0.42; 95% CI, 0.23-0.77; P = .004), and the median OS was not reached in the DDGP group vs 75.2 months in the SMILE group (HR, 0.41; 95% CI, 0.19-0.89, P = .02). The PFS rate at 3 years and OS rate at 5 years were higher in the DDGP group vs the SMILE group (3-year PFS, 56.6% vs 41.8%; 5-year OS, 74.3% vs 51.7%). The overall response rate was higher in the DDGP group than in the SMILE group (90.0% vs 60.0%; P = .002). Grade 3 and 4 hematologic toxic effects were more frequently reported in the SMILE group vs the DDGP group (leukopenia, 85.0% vs 62.5%; neutropenia, 85.0% vs 65.0%). Conclusions and Relevance: In this randomized clinical trial, the DDGP regimen showed promising preliminary results for patients with newly diagnosed local advanced ENKL. A confirmation trial based on larger population is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01501149.

LncRNA MEG3 regulates breast cancer proliferation and apoptosis through miR-141-3p/RBMS3 axis.

Maternally expressed 3 (MEG3) and RNA binding motif single stranded interacting protein 3 (RBMS3) are abnormally expressed in breast cancer susceptibility genes (BRCA), but the mechanism of the two in breast cancer (BC) is unclear. By performing in vivo and in vitro experiments, we found that MEG3 and RBMS3 were low-expressed, negatively correlated with high-expressed miR-141-3p, were positively correlated with each other in BC. MEG3 targeted miR-141-3p, and miR-141-3p targeted RBMS3. MEG3, which was mainly distributed in BC cytoplasm, could down-regulate miR-141-3p and up-regulate RBMS3, and reverse effect of miR-141-3p on related gene expressions and on promoting cancer development. Overexpressed MEG3 inhibited growth of xenografts, promoted cell apoptosis via regulating apoptosis related factors, and up-regulated RBMS3 expression but down-regulated miR-141-3p. The findings of this study showed that MEG3 inhibited proliferation and promoted apoptosis of BC cells through the miR-141-3p/RBMS3 axis, and MEG3 inhibited growth of xenografts through miR-141-3p.

Magnetic organic porous polymer as a solid-phase extraction adsorbent for enrichment and quantitation of gastric cancer biomarkers (P-cresol and 4-hydroxybenzoic acid) in urine samples by UPLC.

A novel magnetic organic porous polymer (denoted as Fe3O4@PC-POP) was developed for magnetic solid-phase extraction (MSPE) of two gastric cancer biomarkers (P-cresol and 4-hydroxybenzoic acid) from urine samples prior to high-performance liquid chromatographic analysis. The adsorbent was characterized by scanning electron microscope, transmission electron microscope, FTIR, powder X-ray diffraction, and other techniques. The result of dynamic light scattering shows that the particle size of the adsorbent is mainly distributed around 400 nm. Based on the design concept of the Fe3O4@PC-POP, the proposed material can effectively capture the target analytes through electrostatic and hydrophobic interaction mechanism. Furthermore, the enrichment conditions were optimized by the response surface method, and the method was utilized for the determination of P-cresol and 4-hydroxybenzoic acid in real urine samples from health and gastric cancer patients with high enrichment factors (34.8 times for P-cresol and 38.7 times for 4-hydroxybenzoic acid), low limit of detection (0.9-5.0 µg L-1), wide linear ranges (3.0-1000 µg L-1), satisfactory relative standard deviation (2.5%-8.5%), and apparent recoveries (85.3-112% for healthy people's and 86.0-112% for gastric cancer patients' urine samples). This study provides a guided principle for design of the versatile polymer with specific capturing of the target compounds from complex biological samples. Graphical abstract.

Lysosome-targeted two-photon fluorescent probe for detection of hypobromous acid in vitro and in vivo.

It is found that hypobromous acid (HOBr) can affect the activity of type IV collagen. Herein, we synthesized a lysosome-targeted fluorescence probe NA-lyso based on Suzuki coupling reaction with naphthalimide as a fluorescent group. HOBr can oxidize the amino group and methylthio group, which increased the degree of conjugation of the probe, thereby affecting its optical properties. Accordingly, it can establish a method for the specific detection of HOBr. NA-lyso has the properties including fast response, high fluorescence quantum yield (Φ = 59.17%), high selectivity, low cytotoxicity and good membrane-permeability. The probe can locate to lysosome of cells. The potential of the probe as biosensor for HOBr was demonstrated by imaging of exogenous and endogenous HOBr in living cells and in mice. In consequence, NA-lyso is expected to be a powerful tool to detect HOBr in complex biosystem and provides a means of exploring physiological functions associated with HOBr in living organisms.

Co-delivery of paclitaxel and gemcitabine by methoxy poly(ethylene glycol)-poly(lactide-coglycolide)-polypeptide nanoparticles for effective breast cancer therapy.

Traditional chemotherapeutic drugs have shown limited clinical curative effects in antitumor therapy. The application of multidrug combination and adjuvant-drug carriers is a feasible strategy to overcome the limitations while minimizing the dosage of single drug and acquiring the synergistic effects in tumor therapy. However, the systemic toxicity, drug resistance, and tumor recurrence are still unavoidable. Here we develop core-shell nanoparticles (NPs) to encapsulate paclitaxel (PTX) and gemcitabine (GEM) for breast cancer therapy. We find that the NPs could encapsulate PTX and GEM, with an encapsulation efficiency of 96.3 and 95.13%, respectively. Moreover, the drug loading of these NPs is 2.71% (PTX) and 2.64% (GEM). Notably, the co-delivery of GEM and PTX performs enhanced anticancer effect compared with the PTX alone or GEM alone therapy at the same concentration, which indicates a synergistic effect. Moreover, encapsulation of PTX and GEM by methoxy poly(ethylene glycol)-poly(lactide-coglycolide) also shows enhanced anticancer effects (81.5% tumor inhibition) and reduced systemic toxicity in vivo compared with free drugs (65% tumor inhibition). Together with those results, co-delivery of PTX and GEM by methoxy poly(ethylene glycol)-poly(lactide-coglycolide) might have important potencies in clinical applications for breast cancer therapy.

Identification of novel mutations of PKD1 gene in Chinese patients with autosomal dominant polycystic kidney disease by targeted next-generation sequencing.

BACKGROUND: Mutations of PKD1 and PKD2 accounted for the most cases of autosomal dominant polycystic kidney disease (ADPKD). The presence of the large transcript, numerous exons and complex reiterated regions within the gene has significantly complicated the analysis of PKD1 with routine PCR-based approaches. METHODS: We developed a strategy to analyze both the PKD1/PKD2 genes simultaneously using targeted next-generation sequencing (NGS). All coding exons plus the flanking sequences of PKD1 and PKD2 genes from probands were captured, individually barcoded and followed by HiSeq2000 sequencing. The candidate variants were validated by using classic Sanger sequencing. PKD1-specific primers were designed to amplify the replicated areas of PKD1 gene. RESULTS: Five novel variations and one known mutation in PKD1 gene were detected in five familial and one sporadic Chinese ADPKD patients. Through pedigree and bioinformatic analysis, five of them were identified as pathogenic mutations (p.G1319R, p.Y3781*, p.W4122*, p.Val700Glyfs*14, and p.Leu3656Trpfs*28) and one was as polymorphism (p.T2420I). CONCLUSIONS: Our result showed that targeted capture and NGS technology were effective for the gene testing of ADPKD disorder. Mutation study of PKD1 and PKD2 genes in Chinese patients may contribute to better understanding of the genetic diversity between different ethnic groups and enrich the mutation database in Asian population.