Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity.

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

ACE2 Receptor-Targeted Inhaled Nanoemulsions Inhibit SARS-CoV-2 and Attenuate Inflammatory Responses.

Three kinds of coronaviruses are highly pathogenic to humans, and two of them mainly infect humans through Angiotensin-converting enzyme 2 （ACE2）receptors. Therefore, specifically blocking ACE2 binding at the interface with the receptor-binding domain is promising to achieve both preventive and therapeutic effects of coronaviruses. Alternatively, drug-targeted delivery based on ACE2 receptors can further improve the efficacy and safety of inhalation drugs. Here, these two approaches are innovatively combined by designing a nanoemulsion (NE) drug delivery system (termed NE-AYQ) for inhalation that targets binding to ACE2 receptors. This inhalation-delivered remdesivir nanoemulsion (termed RDSV-NE-AYQ) effectively inhibits the infection of target cells by both wild-type and mutant viruses. The RDSV-NE-AYQ strongly inhibits Severe acute respiratory syndrome coronavirus 2 at two dimensions: they not only block the binding of the virus to host cells at the cell surface but also restrict virus replication intracellularly. Furthermore, in the mouse model of acute lung injury, the inhaled drug delivery system loaded with anti-inflammatory drugs (TPCA-1-NE-AYQ) can significantly alleviate the lung tissue injury of mice. This smart combination provides a new choice for dealing with possible emergencies in the future and for the rapid development of inhaled drugs for the treatment of respiratory diseases.

Co-delivery of oxaliplatin prodrug liposomes with Bacillus Calmette-Guérin for chemo-immunotherapy of orthotopic bladder cancer.

To reduce recurrence rate after transurethral resection of bladder tumor, long-term intravesical instillations of Bacillus Calmette-Guérin (BCG) and/or chemotherapeutic drugs is the standard treatment for non-muscle invasive bladder carcinoma. However, the main challenges of intravesical therapy, such as short retention time and poor permeability of drugs in the bladder, often require frequent and high-dose administrations, leading to significant adverse effects and financial burden for patients. Aiming at addressing these challenges, we developed a novel approach, in which the cell-penetrating peptide modified oxaliplatin prodrug liposomes and a low-dose BCG were co-delivered via a viscous chitosan solution (LRO-BCG/CS). LRO-BCG/CS addressed these challenges by significantly improving the retention capability and permeability of chemotherapy agents across the bladder wall. Then, oxaliplatin triggered the immunogenic cell death, and the combination of BCG simultaneously further activated the systemic anti-tumor immune response in the MB49 orthotopic bladder tumor model. As a result, LRO-BCG/CS demonstrated superior anti-tumor efficacy and prolonged the survival time of tumor-bearing mice significantly, even at relatively low doses of oxaliplatin and BCG. Importantly, this combinational chemo-immunotherapy showed negligible side effects, offering a promising and well-tolerated therapeutic strategy for bladder cancer patients.

Single-shot AAV-vectored vaccine against SARS-CoV-2 with fast and long-lasting immunity.

Due to the insufficient long-term protection and significant efficacy reduction to new variants of current COVID-19 vaccines, the epidemic prevention and control are still challenging. Here, we employ a capsid and antigen structure engineering (CASE) strategy to manufacture an adeno-associated viral serotype 6-based vaccine (S663V-RBD), which expresses trimeric receptor binding domain (RBD) of spike protein fused with a biological adjuvant RS09. Impressively, the engineered S663V-RBD could rapidly induce a satisfactory RBD-specific IgG titer within 2 weeks and maintain the titer for more than 4 months. Compared to the licensed BBIBP-CorV (Sinopharm, China), a single-dose S663V-RBD induced more endurable and robust immune responses in mice and elicited superior neutralizing antibodies against three typical SARS-CoV-2 pseudoviruses including wild type, C.37 (Lambda) and B.1.617.2 (Delta). More interestingly, the intramuscular injection of S663V-RBD could overcome pre-existing immunity against the capsid. Given its effectiveness, the CASE-based S663V-RBD may provide a new solution for the current and next pandemic.

Live Macrophage-Delivered Doxorubicin-Loaded Liposomes Effectively Treat Triple-Negative Breast Cancer.

Triple-negative breast cancer is often aggressive and resistant to various cancer therapies, especially corresponding targeted drugs. It is shown that targeted delivery of chemotherapeutic drugs to tumor sites could enhance treatment outcome against triple-negative breast cancer. In this study, we exploited the active tumor-targeting capability of macrophages by loading doxorubicin-carrying liposomes on their surfaces via biotin-avidin interactions. Compared with conventional liposomes, this macrophage-liposome (MA-Lip) system further increased doxorubicin accumulation in tumor sites, penetrated deeper into tumor tissue, and enhanced antitumor immune response. As a result, the MA-Lip system significantly lengthened the survival rate of 4T1 cell-bearing mice with low toxicity. Besides, the MA-Lip system used highly biocompatible and widely approved materials, which ensured its long-term safety. This study provides a system for triple-negative breast cancer treatment and offers another macrophage-based strategy for tumor delivery.

Dynamic Auxiliary Soft Labels for decoupled learning.

The long-tailed distribution in the dataset is one of the major challenges of deep learning. Convolutional Neural Networks have poor performance in identifying classes with only a few samples. For this problem, it has been proved that separating the feature learning stage and the classifier learning stage improves the performance of models effectively, which is called decoupled learning. We use soft labels to improve the performance of the decoupled learning framework by proposing a Dynamic Auxiliary Soft Labels (DaSL) method. Specifically, we design a dedicated auxiliary network to generate auxiliary soft labels for the two different training stages. In the feature learning stage, it helps to learn features with smaller variance within the class, and in the classifier learning stage it helps to alleviate the overconfidence of the model prediction. We also introduce a feature-level distillation method for the feature learning, and improve the learning of general features through multi-scale feature fusion. We conduct extensive experiments on three long-tailed recognition benchmark datasets to demonstrate the effectiveness of our DaSL.

Design and implementation of a highly integrated dual hemisphere capsule robot.

To achieve cancer screening in any appointed position in 3D regions of the gastrointestinal (GI) tract such as esophagus, stomach and colon, a highly integrated dual hemisphere capsule robot (DHCR) with a novel three-layer nested structure is proposed. Based on tracking effect, in which the robotic axis is likely to be approximately coincident with the orientation of the space universal rotating magnetic field (SURMF) using the gyroscope dynamic balance, the dual hemisphere structure realizes the observation at a fixed-point in the passive mode and the rolling locomotion in the active mode by the dynamic posture control of the SURMF manipulation. The image acquisition module, wireless transmission module and driving actuator are tuned in a spherical structure, making the DHCR more compact and less invasive. To verify the maneuverability of the innovative DHCR both for observation at a fixed-point and navigation in curved intestine by aid of image, experiments are conducted in the simulated GI tract environment. The results show that the DHCR achieves effective conversion between posture adjustment and rolling locomotion, which lays a foundation for all-over inspection and medical operation inside 3D regions of the GI tract of human body.

A Lightweight Encoder-Decoder Path for Deep Residual Networks.

In this article, we present a novel lightweight path for deep residual neural networks. The proposed method integrates a simple plug-and-play module, i.e., a convolutional encoder-decoder (ED), as an augmented path to the original residual building block. Due to the abstract design and ability of the encoding stage, the decoder part tends to generate feature maps where highly semantically relevant responses are activated, while irrelevant responses are restrained. By a simple elementwise addition operation, the learned representations derived from the identity shortcut and original transformation branch are enhanced by our ED path. Furthermore, we exploit lightweight counterparts by removing a portion of channels in the original transformation branch. Fortunately, our lightweight processing does not cause an obvious performance drop but brings a computational economy. By conducting comprehensive experiments on ImageNet, MS-COCO, CUB200-2011, and CIFAR, we demonstrate the consistent accuracy gain obtained by our ED path for various residual architectures, with comparable or even lower model complexity. Concretely, it decreases the top-1 error of ResNet-50 and ResNet-101 by 1.22% and 0.91% on the task of ImageNet classification and increases the mmAP of Faster R-CNN with ResNet-101 by 2.5% on the MS-COCO object detection task. The code is available at https://github.com/Megvii-Nanjing/ED-Net.

Structural Design and Preliminary Tests of a Novel Patient Transfer Apparatus for Medical Scenarios.

Patient transfer has always been a difficult problem, usually requiring multiple caregivers to work together, which is time consuming and can easily cause secondary injuries to the patient. In addition, with the crisis of COVID-19, the issue of patient transfer is even more critical, as caregivers are at a high risk of infection, causing significant damage to healthcare resources. In this paper, a patient transfer assist system named E-pat-plus (Easy Patient Transfer plus) has been proposed; it can assist caregivers in transferring patients, reduce direct contact between them, and avoid secondary injuries. In the mechanical structure of this apparatus, a novel five-gear assembly module and a synchronous belt pulley set are proposed; they are the key points to the basic functional realization of the device and can reduce the cost of the prototype. Furthermore, a fuzzy (proportion-integration-differentiation) PID-based cross-coupling control strategy is applied to the apparatus to ensure the stability and safety of the operation. Finally, some preliminary experiments, including current experiments and error experiments, are carried out to verify the reliability of the device and lay the foundation for clinical tests.

Posture Dynamic Modeling and Stability Analysis of a Magnetic Driven Dual-Spin Spherical Capsule Robot.

In order to realize the intervention operation in the unstructured and ample environments such as stomach and colon, a dual-spin spherical capsule robot (DSCR) driven by pure magnetic torque generated by the universal rotating magnetic field (URMF) is proposed. The coupled magnetic torque, the viscoelastic friction torque, and the gravity torque were analyzed. Furthermore, the posture dynamic model describing the electric-magnetic-mechanical-liquid coupling dynamic behavior of the DSCR in the gastrointestinal (GI) tract was established. This model is a second-order periodic variable coefficient dynamics equation, which should be regarded as an extension of the Lagrange case for the dual-spin body system under the fixed-point motion, since the external torques were applied. Based on the Floquet-Lyapunov theory, the stability domain of the DSCR for the asymptotically stable motion and periodic motion were obtained by investigating the influence of the angular velocity of the URMF, the magnetic induction intensity, and the centroid deviation. Research results show that the DSCR can realize three kinds of motion, which are asymptotically stable motion, periodic motion, and chaotic motion, according to the distribution of the system characteristic multipliers. Moreover, the posture stability of the DSCR can be improved by increasing the angular velocity of the URMF and reducing the magnetic induction intensity.

ESPRIT-Like Two-Dimensional DOA Estimation for Monostatic MIMO Radar with Electromagnetic Vector Received Sensors under the Condition of Gain and Phase Uncertainties and Mutual Coupling.

In this paper, we focus on the problem of two-dimensional direction of arrival (2D-DOA) estimation for monostatic MIMO Radar with electromagnetic vector received sensors (MIMO-EMVSs) under the condition of gain and phase uncertainties (GPU) and mutual coupling (MC). GPU would spoil the invariance property of the EMVSs in MIMO-EMVSs, thus the effective ESPRIT algorithm unable to be used directly. Then we put forward a C-SPD ESPRIT-like algorithm. It estimates the 2D-DOA and polarization station angle (PSA) based on the instrumental sensors method (ISM). The C-SPD ESPRIT-like algorithm can obtain good angle estimation accuracy without knowing the GPU. Furthermore, it can be applied to arbitrary array configuration and has low complexity for avoiding the angle searching procedure. When MC and GPU exist together between the elements of EMVSs, in order to make our algorithm feasible, we derive a class of separated electromagnetic vector receiver and give the S-SPD ESPRIT-like algorithm. It can solve the problem of GPU and MC efficiently. And the array configuration can be arbitrary. The effectiveness of our proposed algorithms is verified by the simulation result.

Loss of FOXF2 Expression Predicts Poor Prognosis in Hepatocellular Carcinoma Patients.

BACKGROUND: FOXF2 is a member of the forkhead box (FOX) family of transcription factors. FOXF2 plays an important role in several tumors but its expression and role in hepatocellular carcinoma (HCC) remains unknown. METHODS: Using immunohistochemistry, western blot, and real-time polymerase chain reaction, we analyzed FOXF2 expression in 295 clinicopathologically characterized HCC cases. Using RNA interference (RNAi), we investigated the effects of FOXF2 depletion on tumor cell behavior in vitro. Statistical analyses were used to determine associations between FOXF2 levels, tumor features, and patient outcomes. RESULTS: FOXF2 downregulation was observed in HCC tissues (p < 0.001) compared with peritumorous tissues, and its expression levels were closely correlated with overall survival and recurrence-free survival (p = 0.023 and 0.006, respectively) in patients with HCC. RNAi-mediated silencing of the FOXF2 gene in the MHCC-97H cell line significantly promoted proliferation and anti-apoptosis. CONCLUSIONS: The results of the present study indicate that FOXF2 may serve as a prognostic biomarker for HCC and may be a promising target in the treatment of patients with HCC.

[An analysis of hypoglycemic agents used among patients with type 2 diabetes in Beijing communities].

OBJECTIVE: To compare the coverage rate of the hypoglycemic agents base on 2009 and 2012 versions of the national essential medicine list among patients with type 2 diabetes mellitus (T2DM) in Beijing communities. METHODS: A total of 900 patients with T2DM were enrolled in the study from four community health service centers in Beijing and followed up for one year. The following data were collected and analyzed, including patients characteristics, the proportion of patients with glycosylated hemoglobin A1c (HbA1c) less than 7% and the coverage rate of the hypoglycemic agents. RESULTS: (1) The coverage rate of using the hypoglycemic agents in 2012 version of the national essential medicine list was significantly higher than that in 2009 version (91.4% vs 42.9%, χ(2) = 481.09, P < 0.05). The coverage rates of the seven hypoglycemic agents in national essential medicine list were significantly different (χ(2) = 1519.65, P < 0.05) . The coverage rates of acarbose (48.9%), metformin(40.7%) and human insulin (31.1%) were higher than those of glimepiride (9.4%), glipizide (3.0%), glibenclamide (0.6%) and animal insulin (0.2%). (2) After one year follow-up, the proportion of the patients with HbA1c less than 7% was higher than that at the baseline(53.6% vs 32.3%, χ(2) = 77.26, P < 0.05). The coverage rate of using the hypoglycemic agents in 2012 version of the national essential medicine list was significantly higher than that in 2009 version (85.5% vs 37.4%, χ(2) = 376.367, P < 0.05). The coverage rates of acarbose (49.7%), metformin (36.3%) and insulin (30.4%) were still higher than those of glimepiride (6.3%), glipizide (2.2%) , glibenclamide (0.4%) and animal insulin(0.0%). CONCLUSION: The hypoglycemic agents in 2012 version of the national essential medicine list could meet the current need of the type 2 diabetes patients in Beijing communities better than those in 2009 version.

[Design of transdermal ultrasonophoresis equipment].

The recent fast development in biotechnology has resulted in a large number of therapeutic biologicals coming in the foreground for clinical application. Transdermal drug delivery (TDD) is designed for patching the drug on the skin, and then the drug molecules permeate through the skin into the subcutaneous capillary vessels. However,very few drugs can be administered transdermally at the therapeutic levels to pass through the barrier of stratum corneum. Several physical and chemical methods are applied to improve the permeability of skin. Research result shows that the low-frequency ultrasonic technique can extraordinarily increase the rate of permeation. As a result, it is becoming one of the potential methods that serve as the substitutes for traditional methods. In this paper is presented a type of equipment based on MSP430. The principle of design, the structure of hardware, and the applied function in this area are described.