A Telomerase-Activated Magnetic Resonance Imaging Probe for Consecutively Monitoring Tumor Growth Kinetics and In Situ Screening Inhibitors.

Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. In this study, using the principle of distance-dependent magnetic resonance tuning, we constructed a telomerase-activated magnetic resonance imaging probe (TAMP) by connecting superparamagnetic ferroferric oxide nanoparticles (SPFONs) and paramagnetic Gd-DOTA (Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) complexes via telomerase-responsive DNA motifs. Upon telomerase-catalyzed extension of the primer in TAMP, Gd-DOTA-conjugated oligonucleotides can be liberated from the surface of SPFONs through a DNA strand displacement reaction, restoring the T1 signal of the Gd-DOTA for a direct readout of the telomerase activity. Here we show that, by tracking telomerase activity, this probe provides consistent monitoring of tumor growth kinetics during progression and in response to drug treatment and enables in situ screening of telomerase inhibitors in whole-animal models. This study provides an alternative toolkit for cancer diagnosis, treatment response assessment, and anticancer drug screening.

Magnetothermally Triggered Free-Radical Generation for Deep-Seated Tumor Treatment.

Tumor hypoxia and the tissue penetration limitation of excitation light hamper the widespread clinical use of photodynamic therapy. The development of new therapeutic strategies that can generate oxygen-independent free radicals without penetration depth limitation is of great demand. Herein, a novel magnetothermodynamic strategy for deep-seated tumor therapy is reported. In this system, a radical initiator (AIPH) was loaded into porous hollow iron oxide nanoparticles (PHIONs). Under the induction of an alternating magnetic field (AMF), PHIONs can generate heat to trigger the release and decomposition of AIPH, resulting in the generation of oxygen-independent alkyl radicals. The resulting alkyl radicals can effectively kill cancer cells under hypoxic conditions. More importantly, this magnetothermally triggered free-radical generator exhibits significant therapeutic efficacy for orthotopic liver tumors in a rat model. This magnetothermodynamic therapy strategy with the advantages of oxygen independence and no limitation of penetration depth holds great promise in deep-seated solid tumor treatment.

Black Phosphorus Quantum Dots with Renal Clearance Property for Efficient Photodynamic Therapy.

Black phosphorus (BP) nanomaterials have emerged as rapidly rising stars in the field of nanomedicine. In this work, BP quantum dots (BPQDs) are synthesized and their potential as photosensitizers is investigated for the first time. The BPQDs present good stability in physiological medium and no appreciable cytotoxicity. More importantly, the BPQDs can be rapidly eliminated from the body in their intact form via renal clearance due to their ultrasmall hydrodynamic diameter (5.4 nm). Both in vitro and in vivo studies indicate that the BPQDs have excellent photodynamic effect under light irradiation that can effectively generate reactive oxygen species to kill cancer cells. The BPQDs thus can serve as biocompatible and powerful photosensitizers for efficient photodynamic therapy.

Polyphenol-Inspired Facile Construction of Smart Assemblies for ATP- and pH-Responsive Tumor MR/Optical Imaging and Photothermal Therapy.

Smart assemblies have attracted increased interest in various areas, especially in developing novel stimuli-responsive theranostics. Herein, commercially available, natural tannic acid (TA) and iron oxide nanoparticles (Fe3 O4 NPs) are utilized as models to construct smart magnetic assemblies based on polyphenol-inspired NPs-phenolic self-assembly between NPs and TA. Interestingly, the magnetic assemblies can be specially disassembled by adenosine triphosphate, which shows a stronger affinity to Fe3 O4 NPs than that of TA and partly replaces the surface coordinated TA. The disassembly can further be facilitated by the acidic environment hence causing the remarkable change of the transverse relaxivity and potent "turn-on" of fluorescence (FL) signals. Therefore, the assemblies for specific and sensitive tumor magnetic resonance and FL dual-modal imaging and photothermal therapy after intravenous injection of the assemblies are successfully employed. This work not only provides understandings on the self-assembly between NPs and polyphenols, but also will open new insights for facilely constructing versatile assemblies and extending their biomedical applications.

The role of terminations and coordination atoms on the pseudocapacitance of titanium carbonitride monolayers.

Nowadays, MXenes have received extensive concern as a prominent electrode material of electrochemical capacitors. As two important factors to the capacitance, the influence of the intrinsical terminations (F, O and OH) and coordination atoms (C and N) is investigated using first-principles calculations. According to the density of states aligned with the standard hydrogen electrode, it turns out that a Ti3CNO2 monolayer is proven to show an obvious pseudocapacitive behavior, while the bare, F and OH terminated Ti3CN monolayers may only present electrochemical double layer characters in an aqueous electrolyte. Moreover, the illustration of molecular orbitals over the Fermi level are mainly contributed by the d-orbitals of Ti atoms coordinated with O and N atoms, indicating that the redox pseudocapacitance of the Ti3CNO2 monolayer is promoted by the coordination N atoms. Then the superiority of N bonded Ti atoms in accepting charges can be visualized through the charge population. Further, the larger ratio of C/N in the coordination environment of Ti atoms indicates that more electrons can be stored. Our investigation can give an instructional advice in the MXenes-electrode production.

Facile Phase Transfer and Surface Biofunctionalization of Hydrophobic Nanoparticles Using Janus DNA Tetrahedron Nanostructures.

Hydrophobic nanoparticles have shown substantial potential for bioanalysis and biomedical applications. However, their use is hindered by complex phase transfer and inefficient surface modification. This paper reports a facile and universal strategy for phase transfer and surface biofunctionalization of hydrophobic nanomaterials using aptamer-pendant DNA tetrahedron nanostructures (Apt-tet). The Janus DNA tetrahedron nanostructures are constructed by three carboxyl group modified DNA strands and one aptamer sequence. The pendant linear sequence is an aptamer, in this case AS1411, known to specifically bind nucleolin, typically overexpressed on the plasma membranes of tumor cells. The incorporation of the aptamers adds targeting ability and also enhances intracellular uptake. Phase-transfer efficiency using Apt-tet is much higher than that achieved using single-stranded DNA. In addition, the DNA tetrahedron nanostructures can be programmed to permit the incorporation of other functional nucleic acids, such as DNAzymes, siRNA, or antisense DNA, allowing, in turn, the construction of promising theranostic nanoagents for bioanalysis and biomedical applications. Given these unique features, we believe that our strategy of surface modification and functionalization may become a new paradigm in phase-transfer-agent design and further expand biomedical applications of hydrophobic nanomaterials.

Association between heme oxygenase 1 gene promoter polymorphisms and susceptibility to coronary artery disease: a HuGE review and meta-analysis.

We performed a systematic review and meta-analysis of heme oxygenase 1 gene (HO-1) promoter polymorphisms and susceptibility to coronary artery disease (CAD) based on eligible studies retrieved from electronic databases from 2002 to 2013. Eleven studies, involving 10,170 patients with CAD and 6,868 controls, were included. Overall, no significantly decreased risk of CAD was found in persons with the SS genotype of the HO-1 (GT)n repeat length polymorphism compared with those with the LL + SL genotype. However, decreased risks of CAD were observed in the Asian subgroup, the coronary-artery-narrowing ≥50% subgroup, the myocardial infarction subgroup, the age- and sex-matched subgroup, and the good-quality-reports subgroup. The primary heterogeneity in the studies came from age and sex matching and the extent of coronary stenosis. CAD risk was significantly decreased for persons with the AA genotype of the T(-413)A single-nucleotide polymorphism versus those with the TT genotype, but most of the studies showed that the allele distribution was inconsistent with Hardy-Weinberg equilibrium. In this meta-analysis, we found that the (GT)n SS genotype was associated with decreased risk of CAD after controlling for biases due to age and sex matching, extent of coronary stenosis, ethnicity, and study quality. The relationship between the T(-413)A single-nucleotide polymorphism and CAD should be interpreted more cautiously.

Magnetotactic Bacteria AMB-1 with Active Deep Tumor Penetrability for NIR-II Photothermal Tumor Therapy.

The complex tumor structure and microenvironment such as abnormal tumor vasculature, dense tumor matrix, and elevated interstitial fluid pressure greatly hinder the penetration and retention of therapeutic agents in solid tumors. The development of an advanced method for robust penetration and retention of therapeutic agents in tumors is of great significance for efficient tumor treatments. In this work, we demonstrated that magnetotactic bacteria AMB-1 with hypoxic metabolism characteristics can actively penetrate the tumor to selectively colonize deep hypoxic regions, which emerge as a promising intelligent drug carrier. Furthermore, AMB-1 presents intrinsic second near-infrared (NIR-II) photothermal performance that can efficiently convert a 1064 nm laser into heat for tumor thermal ablation. We believe that our investigations not only develop a novel bacteria-based photothermal agent but also provide useful insights for the development of advanced tumor microbial therapies.

An adaptive collision avoidance strategy for autonomous vehicle under various road friction and speed.

When the autonomous vehicle (AV) is under various road friction and speed, emergency collision avoidance is extremely difficult. In this situation, the AV may encounter severe understeering problem, so it is hard to achieve collision avoidance, even under the control of active safety system. To tackle this problem, an adaptive collision avoidance strategy (ACAS) is proposed for AV under various road friction and speed. The adaptive performance of the ACAS is realized via three aspects. (1) An adaptive reference path planning method is proposed to provide desired evasive speed and reference path for the AV according to various road friction and reduces the turning burden of AV. (2) A predictive-based fuzzy controller is designed to realize the speed control, and it improves the tracking accuracy of various desired evasive speed. (3) A novel turning enhanced method built with a direct yaw turning controller and a torque distribution method can enhance the turning capability of AV. Finally, the proposed strategy is verified on AV via simulation experiments. The code can be found online here: https://github.com/wangjinlei-hnu/ACAS.

Switchable ROS Scavenger/Generator for MRI-Guided Anti-Inflammation and Anti-Tumor Therapy with Enhanced Therapeutic Efficacy and Reduced Side Effects.

Photosensitizer in photodynamic therapy (PDT)  accumulates in both tumor and adjacent normal tissue due to low selective biodistribution, results in undesirable side effect with limited clinic application. Herein, an intelligent nanoplatform is reported that selectively acts as reactive oxygen species (ROS) scavenger in normal tissue but as ROS generator in tumor microenvironment (TME) to differentially control ROS level in tumor and surrounding normal tissue during PDT. By down-regulating the produced ROS with dampened cytokine wave in normal tissue after PDT, the nanoplatform reduces the inflammatory response of normal tissue in PDT, minimizing the side effect and tumor metastasis in PDT. Alternatively, the nanoplatform switches from ROS scavenger to generator through the glutathione (GSH) responsive degradation in TME, which effectively improves the PDT efficacy with reduced GSH level and amplified oxidative stress in tumor. Simultaneously, the released Mn ions provide real-time and in situ signal change of magnetic resonance imaging (MRI) to monitor the reversal process of catalysis activity and achieve accurate tumor diagnosis. This TME-responsive ROS scavenger/generator with activable MRI contrast may provide a new dimension for design of next-generation PDT agents with precise diagnosis, high therapeutic efficacy, and low side effect.

Dual-Responsive Turn-On T1 Imaging-Guided Mild Photothermia for Precise Apoptotic Cancer Therapy.

Apoptosis has gained increasing attention in cancer therapy as an intrinsic signaling pathway, which leads to minimal leakage of waste products from a dying cell to neighboring normal cells. Among various stimuli to trigger apoptosis, mild hyperthermia is attractive but confronts limitations of non-specific heating and acquired resistance from elevated expression of heat shock proteins. Here, a dual-stimulation activated turn-on T1 imaging-based nanoparticulate system (DAS) is developed for mild photothermia (≈43 °C)-mediated precise apoptotic cancer therapy. In the DAS, a superparamagnetic quencher (ferroferric oxide nanoparticles, Fe3 O4 NPs) and a paramagnetic enhancer (Gd-DOTA complexes) are connected via the N6-methyladenine (m6 A)-caged, Zn2+ -dependent DNAzyme molecular device. The substrate strand of the DNAzyme contains one segment of Gd-DOTA complex-labeled sequence and another one of HSP70 antisense oligonucleotide. When the DAS is taken up by cancer cells, overexpressed fat mass and obesity-associated protein (FTO) specifically demethylates the m6 A group, thereby activating DNAzymes to cleave the substrate strand and simultaneously releasing Gd-DOTA complex-labeled oligonucleotides. The restored T1 signal from the liberated Gd-DOTA complexes lights up the tumor to guide the location and time of deploying 808 nm laser irradiation. Afterward, locally generated mild photothermia works in concert with HSP70 antisense oligonucleotides to promote apoptosis of tumor cells. This highly integrated design provides an alternative strategy for mild hyperthermia-mediated precise apoptotic cancer therapy.

Graphene enhances the specificity of the polymerase chain reaction.

Graphene can inhibit non-specific DNA fragments, and the specificity of the polymerase chain reaction (PCR) can be retained even after eight rounds of repeated amplification in the presence of graphene in the form of reduced graphene oxide (RGO). In the figure, the numbers at the top give the number of rounds of PCR; lanes marked with C correspond to controls (no RGO), and the concentration of RGO in the other samples is 12 µg mL(-1) .

[Non-compaction cardiomyopathy in a 5-generation Chinese family].

OBJECTIVE: Familial left ventricular noncompaction(LVNC) is quite rare. We screened for the presence of LVNC and related clinical characteristics in a 5-generation Chinese family. METHODS: Comprehensive medical history was obtained from 40 members in a 5-generation Chinese family. Systemic clinical investigations including echocardiography (UCG), routine and ambulatory electrocardiogram (ECG), X-rays were performed in 33 family members. Cardiovascular magnetic resonance image (MRI) was carried out in 2 family members. RESULTS: Sudden cardiac death (including 1 occurred while following-up) was reported in 7 family members (17.5%, 7/40). LVNC was diagnosed in 10 out of the 33 family members (30.3%) and heart enlargement was evidenced in 3, heart failure in 2, complete left branch conductive block in 3, serious sick sinus syndrome (SSS) treated with permanent pacemaker implantation in 1 and paroxysmal supraventricular tachycardia treated with radiofrequency ablation procedure in 1 out of these 10 LVNC patients. Primary pedigree analysis revealed that offspring from female patients were at the highest risk to be affected by LVNC (15/18, 83.3%) while LVNC was absent in offspring of male LVNC patients (0/8). Moreover, clinical heart failure symptoms and arrhythmias were more severe in female LVNC patients than in male LVNC patients. CONCLUSION: Primary familial investigation reveals the matrilineal inheritance of familial LVNC in this 5-generation Chinese family, further investigations are warranted to explore the potential mutations in the mitochondrial genome responsible for LVNC in this family.

Magnetotactic bacteria AMB-1 with active deep tumor penetrability for magnetic hyperthermia of hypoxic tumors.

Tumor hypoxia is a great physiological barrier for tumor treatment. The development of efficient detection and treatment methods for tumor hypoxia has great scientific and clinical significance. In this work, we investigated the potential of magnetotactic bacteria AMB-1 for magnetic resonance imaging (MRI)-guided magnetic hyperthermia treatment of hypoxic tumors. Our investigations reveal that AMB-1 bacteria can selectively migrate to the hypoxic regions of solid tumors due to their anaerobic characteristics, showing active deep tumor penetrability. Moreover, AMB-1 bacteria exhibit high MRI contrast and magnetic heating performances because of the excellent magnetic performance of their magnetosomes. In vivo studies demonstrate that AMB-1 can not only generate T2-weighted contrast signals in tumor tissue, but also efficiently ablate hypoxic solid tumors through the magnetic hyperthermia effect. We believe that this novel microbial therapy can be a potential weapon for hypoxic tumor treatment.

Engineering manganese ferrite shell on iron oxide nanoparticles for enhanced T1 magnetic resonance imaging.

Doping Mn (II) ions into iron oxide (IO) as manganese ferrite (MnIO) has been proved to be an effective strategy to improve T1 relaxivity of IO nanoparticle in recent years; however, the high T2 relaxivity of MnIO nanoparticle hampers its T1 contrast efficiency and remains a hurdle when developing contrast agent for early and accurate diagnosis. Herein, we engineered the interfacial structure of IO nanoparticle coated with manganese ferrite shell (IO@MnIO) with tunable thicknesses. The Mn-doped shell significantly improve the T1 contrast of IO nanoparticle, especially with the thickness of ∼0.8 nm. Compared to pristine IO nanoparticle, IO@MnIO nanoparticle with thickness of ∼0.8 nm exhibits nearly 2 times higher T1 relaxivity of 9.1 mM-1s-1 at 3 T magnetic field. Moreover, exclusive engineering the interfacial structure significantly lower the T2 enhancing effect caused by doped Mn (II) ions, which further limits the impairing of increased T2 relaxivity to T1 contrast imaging. IO@MnIO nanoparticles with different shell thicknesses reveal comparable T1 relaxation rates but obvious lower T2 relaxivities and r2/r1 ratios to MnIO nanoparticles with similar sizes. The desirable T1 contrast endows IO@MnIO nanoparticle to provide sufficient signal difference between normal and tumor tissue in vivo. This work provides a detailed instance of interfacial engineering to improve IO-based T1 contrast and a new guidance for designing effective high-performance T1 contrast agent for early cancer diagnosis.

Practically acquired and modified cone-beam computed tomography images for accurate dose calculation in head and neck cancer.

BACKGROUND: On-line cone-beam computed tomography (CBCT) may be used to reconstruct the dose for geometric changes of patients and tumors during radiotherapy course. This study is to establish a practical method to modify the CBCT for accurate dose calculation in head and neck cancer. PATIENTS AND METHODS: Fan-beam CT (FBCT) and Elekta's CBCT were used to acquire images. The CT numbers for different materials on CBCT were mathematically modified to match them with FBCT. Three phantoms were scanned by FBCT and CBCT for image uniformity, spatial resolution, and CT numbers, and to compare the dose distribution from orthogonal beams. A Rando phantom was scanned and planned with intensity-modulated radiation therapy (IMRT). Finally, two nasopharyngeal cancer patients treated with IMRT had their CBCT image sets calculated for dose comparison. RESULTS: With 360° acquisition of CBCT and high-resolution reconstruction, the uniformity of CT number distribution was improved and the otherwise large variations for background and high-density materials were reduced significantly. The dose difference between FBCT and CBCT was < 2% in phantoms. In the Rando phantom and the patients, the dose-volume histograms were similar. The corresponding isodose curves covering ≥ 90% of prescribed dose on FBCT and CBCT were close to each other (within 2 mm). Most dosimetric differences were from the setup errors related to the interval changes in body shape and tumor response. CONCLUSION: The specific CBCT acquisition, reconstruction, and CT number modification can generate accurate dose calculation for the potential use in adaptive radiotherapy.

Two potential fields fused adaptive path planning system for autonomous vehicle under different velocities.

Path planning is a basic function for autonomous vehicle (AV). However, it is difficult to adapt to different velocities and different types of obstacles including dynamic obstacle and static obstacle (such as road boundary) for AV. To solve the problem of path planning under different velocities and different types of obstacles, a two potential fields fused adaptive path planning system (TPFF-APPS) which includes two parts, a potential field fusion controller and an adaptive weight assignment unit, is presented in this work. In the potential field fusion controller, a novel potential velocity field is built by velocity information and fused with a traditional artificial potential field for adapting various velocities. The adaptive weight assignment unit is designed to distribute adaptively the weights of two potential fields for adapting different types of obstacles at the same time, including road boundary and dynamic obstacles. The simulation is carried on the Carsim-Matlab co-simulation platform, and the simulation results indicate that the proposed TPFF-APPS has excellent performance for path planning adapting to different velocities and different types of obstacles.

Boron Quantum Dots for Photoacoustic Imaging-Guided Photothermal Therapy.

Photothermal therapy is a new type of tumor therapy with great potential. An ideal photothermal therapy agent should have high photothermal conversion effect, low biological toxicity, and degradability. The development of novel photothermal therapy agents with these properties is of great demand. In this study, we synthesized boron quantum dots (BQDs) with an ultrasmall hydrodynamic diameter. Both in vitro and in vivo studies show that the as-synthesized BQDs have good biological safety, high photoacoustic imaging performance, and photothermal conversion ability, which can be used for photoacoustic imaging-guided photothermal agents for tumor treatment. Our investigations confirm that the BQDs hold great promise in tumor theranostic applications.

Improving the sensitivity of T1 contrast-enhanced MRI and sensitive diagnosing tumors with ultralow doses of MnO octahedrons.

Rationale: Sensitive and accurate imaging of cancer is essential for early diagnosis and appropriate treatment. For generally employed magnetic resonance imaging (MRI) in clinic, comprehending how to enhance the contrast effect of T1 imaging is crucial for improving the sensitivity of cancer diagnosis. However, there is no study ever to reveal the clear mechanism of how to enhance the effect of T1 imaging and accurate relationships of influencing factors. Herein, this study aims to figure out key factors that affect the sensitivity of T1 contrast-enhanced MRI (CE-MRI), thereby to realize sensitive detection of tumors with low dose of CAs. Methods: Manganese oxide (MnO) nanoparticles (NPs) with various sizes and shapes were prepared by thermal decomposition. Factors impacting T1 CE-MRI were investigated from geometric volume, surface area, crystal face to r2/r1 ratio. T1 CE-MR imaging of liver, hepatic and subcutaneous tumors were conducted with MnO NPs of different shapes. Results: The surface area and occupancy rate of manganese ions have positive impacts on the sensitivity of T1 CE-MRI, while volume and r2/r1 ratio have negative effects. MnO octahedrons have a high r1 value of 20.07 mM-1s-1 and exhibit an excellent enhanced effect in liver T1 imaging. ZDS coating facilitates tumor accumulation and cellular uptake, hepatic and subcutaneous tumors could be detected with MnO octahedrons at an ultralow dose of 0.4 mg [Mn]/kg, about 1/10 of clinical dose. Conclusions: This work is the first quantitative study of key factors affecting the sensitivity of T1 CE-MRI of MnO nanoparticles, which can serve as a guidance for rational design of high-performance positive MRI contrast agents. Moreover, these MnO octahedrons can detect hepatic and subcutaneous tumors with an ultralow dose, hold great potential for sensitive and accurate diagnosis of cancer with lower cost, less dosages and side effects in clinic.

Design and Fabrication of a Novel Dual-Frequency Confocal Ultrasound Transducer for Microvessels Super-Harmonic Imaging.

Recently, super-harmonic ultrasound imaging technology has caused much attention due to its capability of distinguishing microvessels from the tissues surrounding them. However, the fabrication of a dual-frequency confocal transducer is still a challenge. In this work, 270- [Formula: see text] PMN-PT single crystal 1-3 composite and 28- [Formula: see text] PVDF thick film, acting as transmission layer and receiving layer, respectively, are integrated in a novel co-focusing structure. To realize delicate wave propagation control, microwave transmission line theory is introduced to design such structure. Two acoustic filter layers, 13- [Formula: see text] copper layer and 39- [Formula: see text] Epoxy 301 layer, are indispensable and should be added between two piezoelectric layers. Therefore, an acoustic issue can be overcome via an electrical method and the successful achievement of a dual-frequency (5 MHz/30 MHz) ultrasound transducer with a confocal distance of 8 mm can be realized. The super-harmonic ultrasound imaging experiment is conducted using this kind of device. The 3-D image of 110- [Formula: see text]-diameter phantom tube injected with microbubbles can be obtained. These promising results demonstrate that this novel dual-frequency (5 MHz/30 MHz) confocal ultrasound transducer is potentially usable for microvascular medical imaging application in the future.