Favorable effects of open surgery on patients with extensive skull base osteoradionecrosis through a personalized sequential approach: A case series.

The present study aimed to investigate outcomes following open surgery for extensive skull base ORN. Open surgery through a personalized sequential approach was employed to deal with five cases of extensive skull base ORN. Two patients with mild cases underwent regional debridement and sequestrectomy, and three patients with severe cases underwent extensive resection with reconstruction using free anterolateral thigh (ALT) flap. Biological glues and vascularized flaps were used for obturation of the skull base bony defect to prevent postoperative cerebrospinal fluid (CSF) leakage. The infections were controlled by antibiotic administrations which strictly followed the principles of antimicrobial stewardship (AMS). As results, both regional debridement plus sequestrectomy and extensive resection achieved satisfied outcomes in all patients. No severe complications and delayed hospitalization occurred. During the follow-up period (8-19 months), all patients were alive, pain free, without crusting or purulent discharge, and no sequestration or CSF leakage occurred. In conclusion, a personalized sequential approach including open surgery, pedicled/vascularized free flap reconstruction and AMS was advocated for patients with extensive skull base ORN.

A Lactate-Depleting metal organic framework-based nanocatalyst reinforces intratumoral T cell response to boost anti-PD1 immunotherapy.

Infiltration and activation of intratumoral T lymphocytes are critical for immune checkpoint blockade (ICB) therapy. Unfortunately, the low tumor immunogenicity and immunosuppressive tumor microenvironment (TME) induced by tumor metabolic reprogramming cooperatively hinder the ICB efficacy. Herein, we engineered a lactate-depleting MOF-based catalytic nanoplatform (LOX@ZIF-8@MPN), encapsulating lactate oxidase (LOX) within zeolitic imidazolate framework-8 (ZIF-8) coupled with a coating of metal polyphenol network (MPN) to reinforce T cell response based on a "two birds with one stone" strategy. LOX could catalyze the degradation of the immunosuppressive lactate to promote vascular normalization, facilitating T cell infiltration. On the other hand, hydrogen peroxide (H2O2) produced during lactate depletion can be transformed into anti-tumor hydroxyl radical (•OH) by the autocatalytic MPN-based Fenton nanosystem to trigger immunogenic cell death (ICD), which largely improved the tumor immunogenicity. The combination of ICD and vascular normalization presents a better synergistic immunopotentiation with anti-PD1, inducing robust anti-tumor immunity in primary tumors and recurrent malignancies. Collectively, our results demonstrate that the concurrent depletion of lactate to reverse the immunosuppressive TME and utilization of the by-product from lactate degradation via cascade catalysis promotes T cell response and thus improves the effectiveness of ICB therapy.

An Immunocompetent Hafnium Oxide-Based STING Nanoagonist for Cancer Radio-immunotherapy.

cGAS-STING signaling plays a critical role in radiotherapy (RT)-mediated immunomodulation. However, RT alone is insufficient to sustain STING activation in tumors under a safe X-ray dose. Here, we propose a radiosensitization cooperated with cGAS stimulation strategy by engineering a core-shell structured nanosized radiosensitizer-based cGAS-STING agonist, which is constituted with the hafnium oxide (HfO2) core and the manganese oxide (MnO2) shell. HfO2-mediated radiosensitization enhances immunogenic cell death to afford tumor associated antigens and adequate cytosolic dsDNA, while the GSH-degradable MnO2 sustainably releases Mn2+ in tumors to improve the recognition sensitization of cGAS. The synchronization of sustained Mn2+ supply with cumulative cytosolic dsDNA damage synergistically augments the cGAS-STING activation in irradiated tumors, thereby enhancing RT-triggered local and system effects when combined with an immune checkpoint inhibitor. Therefore, the synchronous radiosensitization with sustained STING activation is demonstrated as a potent immunostimulation strategy to optimize cancer radio-immuotherapy.

Effects of Tai Chi on depression of middle-aged and older adults: an updated systematic review and meta-analysis.

AIM: The objective of this study was to evaluate the efficacy of Tai Chi, a mind-body movement therapy originating from China, on depression in middle-aged and older adults. METHODS: A systematic search was conducted in seven databases (Embase, Cochrane, Medline, Wanfang, SinoMed, Weipu date, CNKI) for Randomized Controlled Trials (RCTs) published until Apr 16, 2023. The quality assessment, heterogeneity analysis, subgroup analysis, and sensitivity analysis of 12 RCTs selected from the literature were performed. Meta-analyses were conducted using RevMan 5.4 software. RESULTS: The study included 12 trials comprising 731 participants that met the inclusion criteria. The findings revealed that Tai Chi significantly improved depression in middle-aged and older adults [SMD = -1.21, 95% CI (-1.59, -0.83), I2 = 87.6%, P < 0.001]. Subgroup analysis revealed that the number of exercise weeks within the specified range, the total duration of exercise, and Tai Chi maneuvers had the greatest benefits on depression in middle-aged and elderly people. The results demonstrated that interventions lasting more than 24 weeks were more effective [SMD = -1.66, 95% CI (-2.28, -1.04), P < 0.05] than those lasting only 12 weeks [SMD = -0.73, 95% CI (-1.08, -0.38), P < 0.05]. The effect size was more significant when the total duration of the intervention was more than 2400 min [SMD = -1.31, 95% CI (-1.71, -0.92), P < 0.001], and when the 24-style Tai Chi exercise was selected [SMD = -1.06, 95% CI (-1.37, -0.75), P < 0.001], the difference was also statistically significant. Funnel plots combined with sensitivity analyses, Begg's and Egger's tests indicated no publication bias. CONCLUSION: The study suggests that Tai Chi can be an alternative therapy for reducing depression in middle-aged and older adults. It is recommended to prolong the Tai Chi exercise period to more than 24 weeks, with a total exercise duration of more than 2400 min, and 24-style Tai Chi should be selected to achieve the best therapeutic effect in middle-aged and older adults with depression. It should be noted that there may be lower-quality studies in the RCT literature analyzed, which may limit the general applicability and credibility of the conclusions.

The effect of internet use on depressive symptoms in middle-aged and older adults with functional disability: the mediating role of social isolation.

Objective: The popularization of the internet provides the possibility to improve the depressive symptoms (DS) and social isolation of middle-aged and older adults with functional disability. There was a significant correlation between internet use and DS in middle-aged and older adults with functional disability, but the relationship between internet use, social isolation, and DS remains to be confirmed. Methods: Data were obtained from 7,955 middle-aged and older adults aged 45 years and older from the 2018 China Health and Retirement Longitudinal Study (CHARLS). Multiple linear regression models were used to analyze the association between internet use and DS, and the Sobel test was used to explore mediating models. Results: Results showed that internet use was negatively associated with DS among Chinese middle-aged and older adults. Among them, social needs (B = -0.770, p = 0.041), and information reception (B = -1.067, p = 0.007) were significantly related to DS in middle-aged and older adults. Only information reception (B = -3.161, p = 0.031) was significantly related to DS among middle-aged and older adults with functional disability. Social isolation partially mediated the association between internet use and DS in middle-aged and older adults without functional disability, whereas it was fully mediated in middle-aged and older adults with functional disability. Conclusion: This study indicates that when formulating health policies to promote the mental health of Chinese middle-aged and older adults, the use of the internet should not be overlooked.

A MOF-Based Potent Ferroptosis Inducer for Enhanced Radiotherapy of Triple Negative Breast Cancer.

Radiotherapy (RT) is one of the important clinical treatments for local control of triple-negative breast cancer (TNBC), but radioresistance still exists. Ferroptosis has been recognized as a natural barrier for cancer progression and represents a significant role of RT-mediated anticancer effects, while the simultaneous activation of ferroptosis defensive system during RT limits the synergistic effect between RT and ferroptosis. Herein, we engineered a tumor microenvironment (TME) degradable nanohybrid with a dual radiosensitization manner to combine ferroptosis induction and high-Z effect based on metal-organic frameworks for ferroptosis-augmented RT of TNBC. The encapsulated l-buthionine-sulfoximine (BSO) could inhibit glutathione (GSH) biosynthesis for glutathione peroxidase 4 (GPX4) inactivation to break down the ferroptosis defensive system, and the delivered ferrous ions could act as a powerful ferroptosis executor via triggering the Fenton reaction; the combination of them induces potent ferroptosis, which could synergize with the surface decorated Gold (Au) NPs-mediated radiosensitization to improve RT efficacy. In vivo antitumor results revealed that the nanohybrid could significantly improve the therapeutic efficacy and antimetastasis efficiency based on the combinational mechanism between ferroptosis and RT. This work thus demonstrated that combining RT with efficient ferroptosis induction through nanotechnology was a feasible and promising strategy for TNBC treatment.

Development and validation of a genomic nomogram based on a ceRNA network for comprehensive analysis of obstructive sleep apnea.

Objectives: Some ceRNA associated with lncRNA have been considered as possible diagnostic and therapeutic biomarkers for obstructive sleep apnea (OSA). We intend to identify the potential hub genes for the development of OSA, which will provide a foundation for the study of the molecular mechanism underlying OSA and for the diagnosis and treatment of OSA. Methods: We collected plasma samples from OSA patients and healthy controls for the detection of ceRNA using a chip. Based on the differential expression of lncRNA, we identified the target genes of miRNA that bind to lncRNAs. We then constructed lncRNA-related ceRNA networks, performed functional enrichment analysis and protein-protein interaction analysis, and performed internal and external validation of the expression levels of stable hub genes. Then, we conducted LASSO regression analysis on the stable hub genes, selected relatively significant genes to construct a simple and easy-to-use nomogram, validated the nomogram, and constructed the core ceRNA sub-network of key genes. Results: We successfully identified 282 DElncRNAs and 380 DEmRNAs through differential analysis, and we constructed an OSA-related ceRNA network consisting of 292 miRNA-lncRNAs and 41 miRNA-mRNAs. Through PPI and hub gene selection, we obtained 7 additional robust hub genes, CCND2, WT1, E2F2, IRF1, BAZ2A, LAMC1, and DAB2. Using LASSO regression analysis, we created a nomogram with four predictors (CCND2, WT1, E2F2, and IRF1), and its area under the curve (AUC) is 1. Finally, we constructed a core ceRNA sub-network composed of 74 miRNA-lncRNA and 7 miRNA-mRNA nodes. Conclusion: Our study provides a new foundation for elucidating the molecular mechanism of lncRNA in OSA and for diagnosing and treating OSA.

Analysis of long noncoding RNAs and messenger RNAs expression profiles in the hearts of mice with acute viral myocarditis.

Acute viral myocarditis (AVMC) is a common acute myocardial inflammation caused by viral infections, which can lead to severe cardiac dysfunction. Several long noncoding RNAs (lncRNAs) with aberrant expression have been identified in the pathogenesis of AVMC. However, the expression profiles and functions of lncRNAs in AVMC have not been fully elucidated. In the present study, we constructed AVMC mouse models by intraperitoneal injection of coxsackievirus B3 (CVB3) and performed RNA sequencing (RNA-seq) on heart tissues to investigate the differences in lncRNAs and messenger RNAs (mRNAs) expression profiles. Based on the cutoff criteria of adjusted p-values (padj) <0.05 and |log2FoldChange| >1, a total of 1122 differentially expressed lncRNAs (DElncRNAs) and 3186 differentially expressed mRNAs (DEmRNAs) were screened, including 734 upregulated and 388 downregulated lncRNAs, 1821 upregulated and 1365 downregulated mRNAs. RT-qPCR analysis validated that the expression patterns of 12 randomly selected genes (6 DElncRNAs and 6 DEmRNAs) were highly consistent with those in RNA-seq, proving the reliability of the RNA-seq data. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that differentially expressed genes were mainly involved in metabolic and immune-related processes. Furthermore, co-expression networks between DElncRNAs and DEmRNAs in cytokine-cytokine receptor interaction, MAPK signaling pathway, and PI3K-Akt signaling pathway were constructed to study the molecular interactions of these molecules. Our study, for the first time, reveals the expression profiles of lncRNAs and mRNAs associated with AVMC, which may shed light on the roles of lncRNAs in disease pathogenesis and aid in discovering new therapeutic targets.

Modified internal curvilinear distraction device with a pre-embedding guide rail, drive screw, and universal joint for curvilinear lengthening of the mandible: A finite element analysis and animal experiment.

OBJECTIVES: The semiburied design of the traditional internal distractor has a relatively high risk of infection and aesthetic problems. To reduce these potential risks, a modified internal distractor with design of pre-embedding curvilinear rail, drive screw, and universal joint was invented. Its stress distribution characteristics and the effect on curvilinear distraction osteogenesis (DO) in vivo were further tested. MATERIALS AND METHODS: Finite element analysis (FEA) was performed on a model of the human mandible and distraction device to measure the stress distribution during curvilinear DO. Six beagles underwent curvilinear DO and consolidation using the new device. Radiological and histological examinations were performed on the new bone. RESULTS: On FEA, the stress was concentrated in the condyle (128.6 MPa) and curved guide rails (324.8 MPa). Four of the six animals completed the DO period and were consolidated for 12 weeks. Secondary infections were not observed. Radiography showed that a new fan-shaped bone-15.5 ± 5.5 mm in length and 4.6 ± 1.6 mm in height-was formed in the bone gap. Micro-computed tomography and histological examinations of specimens indicated that the structure of the new bone was similar to that of the normal bone. CONCLUSIONS: The modified internal curvilinear distraction device meets the mechanical strength requirement and achieve curvilinear DO in animal experiments.

The Data and Safety Monitoring Board: The Toughest Job in Clinical Trials.

The DSMB: The Toughest Job in Clinical TrialsIn this review article, the authors discuss methods that DSMBs can use to compare the absolute and relative risks of benefits and adverse effects between trial interventions and illustrate how the DSMB can use this approach to evaluate the balance of these competing risks. Two approaches are discussed - the win ratio and the DOOR probability on one treatment relative to another.

Preparation and Characterization of Cyclodextrin Coated Red Phosphorus Double-Shell Microcapsules and Its Application in Flame Retardant Polyamide6.

Using the melamine borate and crosslinked ß-cyclodextrin as shell materials, the double-shell microcapsules (Mic-DP) of red phosphorus (RP) was prepared, and its flame-retardant effect on polyamide 6 (PA6) was investigated. Compared with RP, Mic-DP showed lower hygroscopic and better inoxidizability. The limiting oxygen index (LOI) of PA6/13%Mic-DP was 27.8%, and PA6/13%Mic-DP reached V-0 rating. After the addition of 13% Mic-DP, the total exothermic (THR), peak exothermic (PK-HRR), and average effective thermal combustion (AV-EHC) rates of PA6 decreased. In addition, in order to investigate its flame-retardant mechanism, the pyrolysis gas chromatography-mass spectrometry (Py-GC-MS), scanning electron microscopy (SEM), and Fourier transform infrared (FT-IR) methods were used, and the results showed that mic DP acted as a flame retardant in the gas and condensed phases. The Mic-DP exhibited good compatibility and dispersibility in PA6.

LncGBP9 knockdown alleviates myocardial inflammation and apoptosis in mice with acute viral myocarditis via suppressing NF-κB signaling pathway.

BACKGROUND: Myocardial inflammation and apoptosis are key processes in coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC). Accumulating evidence reveals the essential roles of long noncoding RNAs (lncRNAs) in the pathogenesis of AVMC. Here, we aimed to evaluate the biological functions of a novel lncRNA guanylate-binding protein 9 (lncGBP9) in AVMC progression and further explore its underlying mechanisms. METHODS: Initially, mouse models of AVMC were constructed by CVB3 infection. The expression and localization of lncGBP9 in heart tissues were analyzed using RT-qPCR and FISH. Adeno-associated virus serotype 9 (AAV9)-mediated lncGBP9 knockdown was then employed to clarify its roles in survival, cardiac function, and myocardial inflammation and apoptosis. Moreover, the mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) were detected by RT-qPCR and ELISA, and the regulation of lncGBP9 knockdown on the NF-κB signaling pathway was investigated by Western blotting. Using an in vitro model of HL-1 cardiomyocytes exposed to CVB3 infection, the effects of lncGBP9 knockdown on cell viability, inflammation, and apoptosis were further evaluated in vitro. RESULTS: Increased lncGBP9 expression was detected in the heart tissues of AVMC mice and CVB3-infected HL-1 cells, and was mainly located in the cytoplasm. Knockdown of lncGBP9 remarkably alleviated the severity of AVMC in CVB3-infected mice, as verified by improved cardiac function, and reduced myocardial inflammation and apoptosis. Additionally, lncGBP9 knockdown suppressed the NF-κB signaling pathway and consequently reduced productions of pro-inflammatory cytokines in vivo. In vitro functional assays further confirmed that lncGBP9 knockdown promoted cell viability, inhibited cell apoptosis, and reduced pro-inflammatory cytokines release in CVB3-infected HL-1 cells through suppressing NF-κB activation. CONCLUSIONS: Collectively, lncGBP9 knockdown exerts anti-inflammatory and anti-apoptotic effects in CVB3-induced AVMC, which may be mediated in part via NF-κB signaling pathway. These findings highlight lncGBP9 as an attractive target for therapeutic interventions.

ONSET-1 Phase 2b Randomized Trial to Evaluate the Safety and Efficacy of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease.

PURPOSE: The purpose of this trial was to evaluate the safety and efficacy of OC-01 (varenicline solution), a nicotinic acetylcholine receptor agonist nasal spray, on signs and symptoms of dry eye disease. METHODS: A phase 2b, multicenter, randomized, double-masked, vehicle-controlled trial (ONSET-1; NCT03636061) was performed. Patients were aged 22 years or older with a physician's diagnosis of dry eye disease and previous use of artificial tears were randomized 1:1:1:1 to control (vehicle nasal spray twice daily [BID]), OC-01 0.006 mg BID, OC-01 0.03 mg BID, and OC-01 0.06 mg BID. The primary end point was the change in the anesthetized Schirmer test score from baseline to day 28 in the study eye. The secondary end points included the change in the eye dryness score from baseline to day 28. RESULTS: One hundred eighty-two patients were randomized. After 28 days, patients who received OC-01 0.03 or 0.06 mg showed a statistically significant improvement in tear film production relative to vehicle, with least squares mean differences from vehicle of 7.7 mm [95% confidence interval, 3.8-11.7; P < 0.001] with OC-01 0.03 mg and 7.5 mm (95% confidence interval, 3.4-11.6; P < 0.001) with OC-01 0.06 mg. Patients receiving OC-01 0.03 mg showed a significant reduction in the eye dryness score by day 28 versus vehicle (P = 0.021); those receiving the OC-01 0.06 mg dose showed a nonsignificant reduction versus vehicle. OC-01 administration was associated with sneezing (62%-84%) and cough (9%-25%); these were transient and predominantly mild in severity. CONCLUSIONS: OC-01 nasal spray administered BID at 0.03 and 0.06 mg resulted in significant improvements in signs and symptoms of dry eye disease, was well tolerated, and warrants further clinical investigation.

Nursing of acute graft-versus-host disease after simultaneous pancreas-kidney transplantation: a case series study.

Background: This paper aimed to summarize our experience in the nursing of acute graft-versus-host disease (aGVHD) after simultaneous pancreas-kidney transplantation (SPK). Methods: We retrospectively collected and analyzed the demographic characteristics, preoperative evaluation, donor evaluation, screening, and surgical methods of patients with aGVHD after SPK in our center from September 2016 to September 2019. Results: One patient developed intractable diarrhea with decline in platelet (PLT), white blood cell (WBC), and red blood cell (RBC) counts. Meanwhile, the other two patients experienced facial and trunk rashes, hepatic impairment, as well as decreased PLT, WBC, and RBC counts. We took the following nursing interventions: establishing an intensive care team and close monitoring of changes in the condition; protective isolation to minimize exogenous infections; nursing of pulmonary infections; and nutritional support. However, despite careful treatment and nursing, the conditions of the three patients subsequently worsened rapidly and became uncontrollable, and all died. Conclusions: aGVHD is extremely rare after SPK, and no literature exists concerning nursing care or management related to this condition. Clinical manifestations and histopathology are helpful for diagnosis; however, treatment outcomes might be unsatisfactory and the prognosis is poor. Early detection, diagnosis, and intervention have a positive impact on the prognosis of aGVHD, and proper nursing can benefit patients.

Tumor-Tropic Adipose-Derived Mesenchymal Stromal Cell Mediated Bi2 Se3 Nano-Radiosensitizers Delivery for Targeted Radiotherapy of Non-Small Cell Lung Cancer.

With the successful marriage between nanotechnology and oncology, various high-Z element containing nanoparticles (NPs) are approved as radiosensitizers to overcome radiation resistance for enhanced radiotherapy (RT). Unfortunately, NPs themselves lack specificity to tumors. Due to the inherent tropism nature of malignant cells, mesenchymal stem cells (MSCs) emerge as cell-mediated delivery vehicles for functional NPs to improve their therapeutic index. Herein, radiosensitive bismuth selenide (Bi2 Se3 ) NPs-laden adipose-derived mesenchymal stromal cells (AD-MSCs/Bi2 Se3 ) are engineered for targeted RT of non-small cell lung cancer (NSCLC). The results reveal that the optimized intracellular loading strategy hardly affects cell viability, specific surface markers, or migration capability of AD-MSCs, and Bi2 Se3  NPs can be efficiently transported from AD-MSCs to tumor cells. In vivo biodistribution test shows that the Bi2 Se3 NPs accumulation in tumor is increased 20 times via AD-MSCs-mediated delivery. Therefore, AD-MSCs/Bi2 Se3 administration synchronized with X-ray irradiation controls the tumor progress well in orthotopic A549 tumor bearing mice. Considering that MSCs migrate better to irradiated tumor cells in comparison to nonirradiated ones and MSCs preferentially accumulate within lung tissues after systemic administration into accounts, the tumor-tropic MSCs/NPs system is feasible and promising for targeted RT treatment of NSCLC.

Uptake pathways of phthalates (PAEs) into Chinese flowering cabbage grown in plastic greenhouses and lowering PAE accumulation by spraying PAE-degrading bacterial strain.

Uptake pathway and accumulation variation of soil and airborne phthalates (PAEs) in plastic greenhouses by vegetables remains unclear. Here, pot experiments of Chinese flowering cabbage were designed to distinguish root or leaf uptake pathways of PAEs, and investigate the mitigation of spraying PAE-degrading strain in PAE accumulation by vegetables. The results showed that leaves of Chinese flowering cabbage grown in plastic greenhouses absorbed more PAEs from air than those of outside greenhouses. Airborne PAEs were mainly stored in leaf surfaces of vegetables grown inside greenhouse, while PAEs absorbed by roots from soil were translocated and mainly stored in mesophyll, especially in cell walls and organelles. PAE concentrations in mesophyll elevated with increasing soil PAE levels, whereas those in leaf surfaces were not influenced by soil PAE levels. The values of bioconcentration factors for leaves inside greenhouses were significantly (1.39-3.47 fold) higher than those outside. PAE-degrading strain (Rhodococcus pyridinivorans XB) sprayed on leaf surfaces could grow well and Rhodococcus was the dominant genus as confirmed by Illumina high-throughput sequencing. PAE-degrading strain effectively reduced PAEs by 12.9%-34.9% in leaf surface, but not those in vegetables grown in high-PAE soil. This study demonstrated mitigation of spraying PAE-degrading strain in PAE accumulation by vegetable leaves from air of plastic greenhouse.

Anti-VEGFR2-labeled enzyme-immobilized metal-organic frameworks for tumor vasculature targeted catalytic therapy.

Tumor vasculature-targeting therapy either using angiogenesis inhibitors or vascular disrupting agents offers an important new avenue for cancer therapy. In this work, a tumor-specific catalytic nanomedicine for enhanced tumor ablation accompanied with tumor vasculature disruption and angiogenesis inhibition was developed through a cascade reaction with enzyme glucose oxidase (GOD) modified on Fe-based metal organic framework (Fe-MOF) coupled with anti-VEGFR2.The GOD enzyme could catalyze the intratumoral glucose decomposition to trigger tumor starvation and yet provide abundant hydrogen peroxide as the substrate for Fenton-like reaction catalyzed by Fe-MOF to produce sufficient highly toxic hydroxyl radicals for enhanced chemodynamic therapy and instantly attacked tumor vascular endothelial cells to destroy the existing vasculature, while the anti-VEGFR2 antibody guided the nanohybrids to target blood vessels and block the VEGF-VEGFR2 connection to prevent angiogenesis. Both in vitro and in vivo results demonstrated the smart nanohybrids could cause the tumor cell apoptosis and vasculature disruption, and exhibited enhanced tumor regression in A549 xenograft tumor-bearing mice model. This study suggested that synergistic targeting tumor growth and its vasculature network would be more promising for curing solid tumors. STATEMENT OF SIGNIFICANCE: Cooperative destruction of tumor cells and tumor vasculature offers a potential avenue for cancer therapy. Under this premise, a tumor-specific catalytic nanomedicine for enhanced tumor ablation accompanied with tumor vasculature disruption and new angiogenesis inhibition was developed through a cascade reaction with glucose oxidase modified on the surface of iron-based metal organic framework coupled with VEGFR2 antibody. The resulting data demonstrated that a therapeutic regimen targeting tumor growth as well as its vasculature with both existing vasculature disruption and neovasculature inhibition would be more potential for complete eradication of tumors.

Influencing factors and drug application of iontophoresis in transdermal drug delivery: an overview of recent progress.

Transdermal drug delivery is limited by the stratum corneum of skin, which blocks most molecules, and thus, only few molecules with specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) are able to penetrate the skin. Recently, various technologies have been developed to overcome the strong barrier properties of stratum corneum. Iontophoresis technology, which uses a small current to improve drug permeation through skin, is one of the effective ways to circumvent the stratum corneum. This approach not only provides a more efficient, noninvasive, and patient-friendly method of drug delivery but also widens the scope of drugs for transdermal delivery. In this review, the mechanisms underlying iontophoresis and affecting factors are outlined. The focus will be on the latest advancements in iontophoretic transdermal drug delivery and application of iontophoresis with other enhancing technologies. The challenges of this technology for drug administration have also been highlighted, and some iontophoretic systems approved for clinical use are described.

Molecular perspective of efficiency and safety problems of chemical enhancers: bottlenecks and recent advances.

Chemical penetration enhancer (CPE) is a preferred approach to improve drug permeability through the skin, due to its unique advantages of simple use and high compatibility. However, CPEs efficiency and safety problems frequently arise, which greatly restrains the further application in transdermal drug delivery systems (TDDS). To get access to the root of problems, the efficiency and safety of CPEs are reviewed especially from molecular perspectives, which include (1) the possible factors of CPEs low efficiency; (2) the possible contribution of CPEs in the evolution of safety problems such as skin irritation and allergic reaction; (3) the interactive relationship between CPEs efficiency and safety, as well as the bottlenecks of achieving their balance. More importantly, based on these, recent advances are summarized in improving efficiency or safety of CPEs, which offers a guidance of rationally selecting CPEs in future research.

Reeducating Tumor-Associated Macrophages Using CpG@Au Nanocomposites to Modulate Immunosuppressive Microenvironment for Improved Radio-Immunotherapy.

With the recent success of immune checkpoint blockade (ICB) in cancer immunotherapy, there has been renewed interest in evaluating the combination of ICB inhibitors with radiotherapy (RT) in clinical trials in view of the localized RT-initiated vaccination effect, which can be augmented further by systemic immune-stimulating agents. Unfortunately, traditional RT/ICB accompanies severe toxicity from high-dose ionizing irradiation and low response rate from RT-aggravated immunosuppression, among which M2-type tumor-associated macrophages (TAMs) play an important role. Herein, CpG-decorated gold (Au) nanoparticles (CpG@Au NPs) were fabricated to improve the RT/ICB efficacy by immune modulation under low-dose X-ray exposure, where Au NPs served as radioenhancers to minimize the radiotoxicity, and yet acted as nanocarriers to deliver CpG, a toll-like receptor 9 agonist, to re-educate immunosuppressive M2 TAMs to immunostimulatory M1 counterparts, thus arousing innate immunity and meanwhile priming T cell activation. When combined with an anti-programmed death 1 antibody, irradiated CpG@Au led to consistent abscopal responses that efficiently suppressed distant tumors in a bilateral GL261 tumor-bearing model. This work thus demonstrates that CpG@Au-mediated macrophage reeducation could efficiently modulate the tumor-immune microenvironment for synergistic RT/ICB.