Mast cell stabilizer, an anti-allergic drug, reduces ventricular arrhythmia risk via modulation of neuroimmune interaction.

Mast cells (MCs) are important intermediates between the nervous and immune systems. The cardiac autonomic nervous system (CANS) crucially modulates cardiac electrophysiology and arrhythmogenesis, but whether and how MC-CANS neuroimmune interaction influences arrhythmia remain unclear. Our clinical data showed a close relationship between serum levels of MC markers and CANS activity, and then we use mast cell stabilizers (MCSs) to alter this MC-CANS communication. MCSs, which are well-known anti-allergic agents, could reduce the risk of ventricular arrhythmia (VA) after myocardial infarction (MI). RNA-sequencing (RNA-seq) analysis to investigate the underlying mechanism by which MCSs could affect the left stellate ganglion (LSG), a key therapeutic target for modulating CANS, showed that the IL-6 and γ-aminobutyric acid (GABA)-ergic system may be involved in this process. Our findings demonstrated that MCSs reduce VA risk along with revealing the potential underlying antiarrhythmic mechanisms.

Melatonin improves cardiac remodeling and brain-heart sympathetic hyperactivation aggravated by light disruption after myocardial infarction.

Light in the external environment might affect cardiovascular function. The light disruption seems to be related to changes in cardiovascular physiological functions, and disturbing light may be a risk factor for cardiovascular diseases. Prior studies have found that light disruption after myocardial infarction (MI) exacerbates cardiac remodeling, and the brain-heart sympathetic nervous system may be one of the key mechanisms. However, how to improve light-disrupted cardiac remodeling remains unclear. Melatonin is an indoleamine secreted by the pineal gland and controlled by endogenous circadian oscillators within the suprachiasmatic nucleus, which is closely associated with light/dark cycle. This study aimed to explore whether melatonin could improve light-disrupted cardiac remodeling and modulate the brain-heart sympathetic nervous system. Our study revealed that light disruption reduced serum melatonin levels, aggravated cardiac sympathetic remodeling, caused overactivation of the brain-heart sympathetic nervous system, exacerbated cardiac dysfunction, and increased cardiac fibrosis after MI, while melatonin treatment improved light disruption-exacerbated cardiac remodeling and brain-heart sympathetic hyperactivation after MI. Furthermore, RNA-Seq results revealed the significant changes at the cardiac transcription level. In conclusion, melatonin may be a potential therapy for light-disrupted cardiac remodeling.

Rigid metal/liquid metal nanoparticles: Synthesis and application for locally ablative therapy.

Locally ablative therapy, as the main therapy for advanced tumors, has fallen into a bottleneck in recent years. The breakthrough of metal nanoparticles provides a novel approach for ablative therapy. Previous studies have mostly focused on the combined field of rigid metal nanoparticles and ablation. However, with the maturity of the preparation process of liquid metal nanoparticles, liquid metal nanoparticles not only have metallic properties but also have fluid properties, showing the potential to be combined with ablation. At present, there is no review on the combination of liquid metal nanoparticles and ablation. In this article, we first review the preparation, characterization and application characteristics of rigid metal and liquid metal nanoparticles in ablation applications, and then summarize the advantages, disadvantages and possible future development trends of rigid and liquid metal nanoparticles.

Deblurring Ghost Imaging Reconstruction Based on Underwater Dataset Generated by Few-Shot Learning.

Underwater ghost imaging based on deep learning can effectively reduce the influence of forward scattering and back scattering of water. With the help of data-driven methods, high-quality results can be reconstructed. However, the training of the underwater ghost imaging requires enormous paired underwater datasets, which are difficult to obtain directly. Although the Cycle-GAN method solves the problem to some extent, the blurring degree of the fuzzy class of the paired underwater datasets generated by Cycle-GAN is relatively unitary. To solve this problem, a few-shot underwater image generative network method is proposed. Utilizing the proposed few-shot learning image generative method, the generated paired underwater datasets are better than those obtained by the Cycle-GAN method, especially under the condition of few real underwater datasets. In addition, to reconstruct high-quality results, an underwater deblurring ghost imaging method is proposed. The reconstruction method consists of two parts: reconstruction and deblurring. The experimental and simulation results show that the proposed reconstruction method has better performance in deblurring at a low sampling rate, compared with existing underwater ghost imaging methods based on deep learning. The proposed reconstruction method can effectively increase the clarity degree of the underwater reconstruction target at a low sampling rate and promotes the further applications of underwater ghost imaging.

Underwater ghost imaging based on generative adversarial networks with high imaging quality.

Ghost imaging is widely used in underwater active optical imaging because of its simple structure, long distance, and non-local imaging. However, the complexity of the underwater environment will greatly reduce the imaging quality of ghost imaging. To solve this problem, an underwater ghost imaging method based on the generative adversarial networks is proposed in the study. The generator of the proposed network adopts U-Net with the double skip connections and the attention module to improve the reconstruction quality. In the network training process, the total loss function is the sum of the weighted adversarial loss, perceptual loss, and pixel loss. The experiment and simulation results show that the proposed method effectively improves the target reconstruction performance of underwater ghost imaging. The proposed method promotes the further development of active optical imaging of underwater targets based on ghost imaging technology.

PEG10 as an oncogene: expression regulatory mechanisms and role in tumor progression.

Cancer is a major public health problem as one of the leading causes of death worldwide. Deciphering the molecular regulation mechanisms of tumor progression can make way for tumor diagnosis and therapy. Paternally expressed gene 10 (PEG10), located on human chromosome 7q21.3, has turned out to be an oncogene implicated in the proliferation, apoptosis and metastasis of tumors. PEG10 has been found to be positively expressed in a variety of cancers with seemingly complex expression regulation mechanisms. In this review, we focus on the most vital factors influencing PEG10 expression and recapitulate some of the currently known and potential mechanisms of PEG10 affecting tumor progression, as understanding the molecular regulatory mechanisms of tumor progression can provide potential PEG10 related diagnosis and biomarker specific targeted therapies.

Damage and failure of underground subway stations under different soil constraint conditions.

Investigations from past earthquakes have shown that underground subway stations can suffer excessive deformation under strong seismic loads, leading to the damage of critical components and the collapse of structures. This study presents the results of finite element analyses on the seismic damage of underground subway stations installed under different soil constraint conditions. The plastic hinge distribution and damage characteristics of cut and cover double-storey and three-storey subway stations are analyzed using the finite element method software ABAQUS. Combined with the static analysis results of the column sections, a discriminant method for bending plastic hinges is presented. The numerical results show that the collapse of the subway stations begins with the failure of the bottom columns' bottom sections, which leads to the bending of the plates and the destruction of the whole structure. The bending deformation at the end section of columns has an approximatively linear relationship with the inter-storey drift ratio, and the change in soil conditions shows no apparent influence. The sidewall deformation behavior varies significantly under different soil conditions, and the bending deformation at the bottom section of sidewalls increases along with an increase in the soil-structure stiffness ratio at the same inter-storey drift deformation level. The sidewall bending ductility ratio of the double-storey and three-storey stations at the elastic-plastic drift ratio limit increases by 61.6% and 26.7%, respectively. In addition, the fitting curves between the component bending ductility ratio and inter-storey drift ratio based on the analysis results are also presented. The findings may provide a helpful reference for the seismic performance evaluation and design of underground subway stations.

Liquid Metal Nanoplatform Based Autologous Cancer Vaccines.

Therapeutic cancer vaccines have been vigorously sought to bolster host adaptive immunity against metastatic cancers, but tumor heterogeneity, ineffective antigen utilization, and immunosuppressive tumor microenvironment hinder their clinical applications. Autologous antigen adsorbability and stimulus-release carrier coupling with immunoadjuvant capacity are urgent for personalized cancer vaccines. Here, we propose a perspective strategy of using a multipotent gallium-based liquid metal (LM) nanoplatform for personalized in situ cancer vaccines (ISCVs). The antigen-capturing and immunostimulatory LM nanoplatform can not only effectively destroy orthotopic tumors to generate multifarious autologous antigens upon external energy stimulation (photothermal/photodynamic effect) but also capture and transport antigens into dendritic cells (DCs) to enhance antigen utilization (adequate DCs uptake, antigen-endo/lysosomal escape) and facilitate DCs activation (mimic alum immunoadjuvant capacity), which ultimately awaken systemic antitumor immunity (expand cytotoxic T lymphocytes and modulate tumor microenvironment). With immune checkpoint blockade (anti-PD-L1) to further relieve the immunosuppressive tumor microenvironment, the positive tumoricidal immunity feedback loop was established to effectively eliminate orthotopic tumors, inhibit abscopal tumor growth, relapse, and metastasis as well as tumor-specific prevention. Collectively, this study demonstrates the potential of a multipotent LM nanoplatform for personalized ISCVs, which will open frontier exploration of LM-based immunostimulatory biomaterials and may encourage further investigation of precise individualized immunotherapy.

Autologous-cancer-cryoablation-mediated nanovaccine augments systematic immunotherapy.

Cancer vaccines developed from autologous tumors hold tremendous promise for individualized cancer immunotherapy. Cryoablation-induced in situ autologous antigens are capable of activating systemic immunity with low damage. However, the dissipation of cancer fragments after cryoablation induces poor immunogenicity and short-time maintenance of immunological memory. To solve this challenge, a nanovaccine with functional grippers is proposed to largely enhance the in situ grasping of tumor fragments, combined with an immune adjuvant to further strengthen the immune-therapeutic effect. Herein, maleimide-modified Pluronic F127-chitosan nanoparticles encapsulating Astragalus polysaccharide (AMNPs) are developed. The AMNPs can capture multifarious and immunogenic tumor antigens generated through cryoablation, specifically target lymph nodes and facilitate lysosome escape to activate remote dendritic cells, and modulate T cell differentiation through cross-presentation, thereby breaking the immunosuppressive microenvironment to achieve durable and robust tumor-specific immunity. In the bilateral Lewis lung cancer tumor model, AMNP-mediated cryoablation can significantly regress primary tumors (with a tumor growth inhibition rate of 100%, and a recurrence rate of 0% (30 days) and 16.67% (60 days)), inhibit untreated abscopal tumor growth (a decrease of about 3.84-fold compared with the saline group), and ultimately improve the long-term survival rate (83.33%). Collectively, the development of a lymph-node-targeted in situ cancer-cryoablation-mediated nanovaccine provides a promising approach for personalized cancer immunotherapy against metastatic cancers.

Prognostic significance of pyroptosis-related factors in lung adenocarcinoma.

Background: Numerous studies have revealed that the abnormal expression of pyroptosis-related genes is closely related to the prognosis of lung adenocarcinoma (LUAD); however, a comprehensive analysis has yet to be conducted. This study aimed to reveal the influence of pyroptosis-related genes on the prognosis of LUAD and establish a prognostic model based on those genes, in order to evaluate the prognosis of LUAD. Methods: The data of tumor and normal samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differential analysis was used to identify pyroptosis-related genes (obtained from the GeneCards database) that were differentially expressed (DE) in TCGA database. Univariate and stepwise multivariate Cox proportional hazards regression analyses were used to screen feature genes related to LUAD overall survival (OS) and construct gene signature. Gene set enrichment analysis (GSEA) was then performed to reveal potential functions related to gene signature. Finally, the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to reveal distinctions in each cell-subtype groups in the immune landscape of LUAD. Results: Overall, 26 DE genes (DEGs) associated with pyroptosis were obtained. Among them, 4 (MKI67, BTK, MST1, and TUBB6) were selected as prognostic genes and a 4-gene signature with a good prognostic performance in the TCGA and GEO was constructed. The gene signature was shown to be an independent prognostic factor of LUAD in subsequent analysis. Functional enrichment indicated that the 4-gene signature may participate in the tumorigenesis and development of LUAD through various pathways related to tumor progression to play a prognostic role in LUAD. Additionally, the results of the immune landscape indicated that the 4-gene signature may affect the prognosis of LUAD via cooperating with changes in the immune microenvironment. Conclusions: The key biomarkers and pathways identified in this study would deepen the comprehension of the molecular mechanism of pyroptosis in LUAD. More importantly, the 4-gene signature may serve as a novel potential prognostic model for LUAD.

Bmal1 knockdown in the left stellate ganglion inhibits neural activity and prevents ventricular arrhythmias after myocardial ischemia.

Objectives: The neural activity of the left stellate ganglion (LSG) is closely related to the occurrence of ventricular arrhythmias (VAs). Bmal1 modulates genes associated with neural activity in the central nervous system. However, few studies indicated the role of Bmal1 in the LSG and the subsequent effect on the heart. Therefore, we aimed to investigate the influence of Bmal1 knockdown in the LSG on its neural activity and cardiac electrophysiology and to explore the mechanisms. Materials and methods: We used adeno-associated virus (AAV) to knock down Bmal1 in the LSG. Male beagles were randomized into the Bmal1 knockdown group and the control group. After 4 weeks of injection, the LSG function, neural activity, left ventricular effective refractory period (ERP), and action potential duration (APD) were measured. Electrocardiography for 1 h was recorded for VAs analysis after myocardial ischemia. Nerve growth factor (NGF) and c-fos in the LSG were quantified by immunofluorescence. Transcriptomic analysis was performed to assess the gene expression in the LSG. Results: Bmal1 was sufficiently knocked down by AAV. Compared with the control group, heart rate variability (HRV) in the knockdown group was altered. Bmal1 knockdown inhibited neural activity and function of LSG. It also prolonged ERP as well as APD90. Ischemia-induced VAs were significantly reduced. Nerve growth factor (NGF) and c-fos in the LSG were reduced. Bmal1 knockdown led to the expression changes of genes associated with neural activity in the LSG. Conclusion: Bmal1 knockdown in the LSG suppresses neural activity and prevents ventricular arrhythmias after myocardial ischemia.

Ultrasound-guided injection of botulinum toxin type A blocks cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic myocardial infarction.

BACKGROUND: Strategies to improve various cardiovascular diseases by blocking cardiac sympathetic ganglion have been increasingly available currently. Botulinum toxin type A (BTA), a typical neurotoxin, has been shown to block neural transmission in a safe and long-lasting manner. OBJECTIVE: The aim of the present preclinical study was to assess the efficacy of BTA microinjection to alleviate cardiac remodeling after chronic myocardial infarction (MI) by blocking cardiac sympathetic ganglion in a canine model. METHODS: Beagles were randomly divided into a control group (saline microinjection with sham surgery), an MI group (saline microinjection with MI), and an MI + BTA group (BTA microinjection with MI). Ultrasound-guided percutaneous BTA or saline injection into the left stellate ganglion (LSG) was performed followed by MI induction via left anterior descending artery occlusion (LADO) or sham surgery. After 30 days, electrocardiography, Doppler echocardiography, LSG function, neural activity, and ventricular electrophysiological detection were performed in all experimental dogs. At the end, LSG and ventricular tissues were collected for further detection. RESULTS: BTA treatment significantly inhibited LSG function and neural activity and improved heart rate variability. Additionally, BTA application alleviated ventricular remodeling, ameliorated cardiac function, and prevented ventricular arrhythmias after 30-day chronic LADO-induced MI. CONCLUSION: Ultrasound-guided percutaneous microinjection of BTA can block cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic LADO-induced MI. Ultrasound-guided BTA microinjection has potential for clinical application as a novel cardiac sympathetic ganglion blockade strategy for MI.

Nanoparticles: A New Approach to Upgrade Cancer Diagnosis and Treatment.

Traditional cancer therapeutics have been criticized due to various adverse effects and insufficient damage to targeted tumors. The breakthrough of nanoparticles provides a novel approach for upgrading traditional treatments and diagnosis. Actually, nanoparticles can not only solve the shortcomings of traditional cancer diagnosis and treatment, but also create brand-new perspectives and cutting-edge devices for tumor diagnosis and treatment. However, most of the research about nanoparticles stays in vivo and in vitro stage, and only few clinical researches about nanoparticles have been reported. In this review, we first summarize the current applications of nanoparticles in cancer diagnosis and treatment. After that, we propose the challenges that hinder the clinical applications of NPs and provide feasible solutions in combination with the updated literature in the last two years. At the end, we will provide our opinions on the future developments of NPs in tumor diagnosis and treatment.

Novel Insights Into the Interaction Between the Autonomic Nervous System and Inflammation on Coronary Physiology: A Quantitative Flow Ratio Study.

Background: Heart rate variability (HRV) was proposed as a noninvasive biomarker to stratify the risk of cardiovascular disease. However, it remains to be determined if HRV can be used as a surrogate for coronary artery physiology as analyzed by quantitative flow ratio (QFR) in patients with new-onset unstable angina pectoris (UAP). Methods: A total of 129 consecutive patients with new-onset UAP who underwent 24-h long-range 12-channel electrocardiography from June 2020 to December 2020 were included in this study. HRV, coronary angiography, and QFR information was retrieved from patient medical records, the severity of coronary lesions was evaluated using the Gensini score (GS), and total atherosclerotic burden was assessed using the three-vessel contrast QFR (3V-cQFR) calculated as the sum of cQFR in three vessels. Results: Multivariate logistic analysis showed that low-frequency power (LF) and high-sensitivity C-reactive protein (hs-CRP) were directly correlated with functional ischemia of target vessel, which were inversely correlated with total atherosclerotic burden as assessed by 3V-cQFR. Moreover, incorporation of the increase in LF into the existing model that uses clinical risk factors, GS, and hs-CRP significantly increased the discriminatory ability for evaluating coronary artery physiology of target vessel. Conclusions: LF and hs-CRP are independently associated with functional ischemia in patients with new-onset UAP. The relative increase of LF and hs-CRP could add value to the use of classical cardiovascular risk factors to predict the functional severity of coronary artery stenosis. Our results suggest a potential association between the autonomic nervous system, inflammation, and coronary artery physiology.

Clinical, inflammatory, and immune differences between COVID-19 patients with and without cancer: A protocol for systematic review and meta-analysis.

INTRODUCTION: The World Health Organization announce that novel coronavirus (COVID-19) is pandemic worldwide on March 11, 2020. In this pandemic, cancer patients are prone to become critically ill after being infected with COVID-19 due to special immune conditions, and cannot effectively benefit from the treatment plan designed for normal people. However, only a few literatures report the differences between cancer patients and normal people after being infected with COVID-19. There is no systematic review to evaluate the clinical, inflammatory, and immune differences between COVID-19 patients with and without cancer. The systematic review aims to summarize and analyze the clinical, inflammatory, and immune differences between them. METHODS AND ANALYSIS: We plan to conduct a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines. Several databases (PubMed/MEDLINE, Embase, Web of Science, The Cochrane Library, CNKI, CBM, VIP, WanFang) were searched for relevant eligible observational studies on COVID-19 patients with cancer published from December 2019 to September 2020. Two researchers (Y.ZY and W.PP) will independently complete search strategy formulation, literature selecting, Information extraction, data collation, and quality assessment. The primary outcome will be the clinical characteristics differences between COVID-19 patients with and without cancer. Secondary outcomes will include immune function regulation characteristics such as T cell subset status, inflammation and other factors for COVID-19 patients with cancer. We intend to perform a meta-analysis of studies calculating odds ratio differences (Hedge g) for comparison in Forest plots and subgroup analysis after assessment of heterogeneity using I statistics based on compatibility on the basis of population and outcomes. ETHICS AND DISSEMINATION: We will use the information from published researches with no need for ethical assessment. Our findings will be published in a peer-reviewed journal according to the PRISMA guidelines. PROSPERO REGISTRATION NUMBER: CRD42020204417.

Triclosan Enhances the Clearing of Pathogenic Intracellular Salmonella or Candida albicans but Disturbs the Intestinal Microbiota through mTOR-Independent Autophagy.

Triclosan (TCS) is a broad-spectrum antimicrobial agent, whose well-known antibacterial mechanism is inhibiting lipid synthesis. Autophagy, an innate immune response, is an intracellular process that delivers the cargo including pathogens to lysosomes for degradation. In this study, we first demonstrated that TCS induced autophagy in a dose-dependent manner in non-phagocytic cells (HeLa) and in macrophages (Raw264.7) and in vivo. The western blot results also revealed that TCS induced autophagy via the AMPK/ULK1 and JNK/ERK/p38 pathways independent of mTOR. The immunofluorescence results indicated that TCS up-regulated the expression of the ubiquitin receptors NDP52 and p62 and strengthened the co-localization of these receptors with Salmonella enterica Typhimurium (S. typhimurium) or Candida albicans (C. albicans) in infected MΦ cells. In addition, sub-lethal concentrations of TCS enhanced the clearing of the pathogens S. typhimurium or C. albicans in infected MΦ and in corresponding mouse infection models in vivo. Specifically, we found that a sub-inhibitory concentration of TCS induced autophagy, leading to an imbalance of the intestinal microflora in mice through the analysis of 16s rRNA Sequencing. Together, these results demonstrated that TCS induced autophagy, which enhanced the killing against pathogenic S. typhimurium or C. albicans within mammal cells but broke the balance of the intestinal microflora.

Gefitinib induces lung cancer cell autophagy and apoptosis via blockade of the PI3K/AKT/mTOR pathway.

Gefitinib is a selective inhibitor of the tyrosine kinase epidermal growth factor receptor, which inhibits tumor pathogenesis, metastasis and angiogenesis, as well as promoting apoptosis. Therefore, gefitinib presents an effective drug for the targeted therapy of lung cancer. However, the underlying mechanisms by which gefitinib induces lung cancer cell death remain unclear. To investigate the effects of gefitinib on lung cancer cells and the mechanism of such, the present study analyzed the effect of gefitinib on the autophagy, apoptosis and proliferation of the A549 and A549-gefitinib-resistant (GR) cell lines GR. The regulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway was also investigated. Acridine orange staining revealed that gefitinib induced autophagy of A549 cells but not A549-GR cells. In addition, gefitinib promoted apoptosis and inhibited proliferation of A549 cells but not A549-GR cells. Furthermore, western blot analysis demonstrated that gefitinib treatment led to the downregulation of PI3K, AKT, pAKT, mTOR and phosphorylated-mTOR protein expression in A549 cells but not A549-GR cells. LY294002 blocked the PI3K/AKT/mTOR pathway and induced autophagy and apoptosis of A549 cells, however, no synergistic effect was observed following combined treatment with gefitinib and LY294002. In conclusion, the results of the present study indicate that gefitinib promotes autophagy and apoptosis of lung cancer cells via blockade of the PI3K/AKT/mTOR pathway, which leads to lung cancer cell death.