ROS-responsive biomimetic nanosystem camouflaged by hybrid membranes of platelet-exosomes engineered with neuronal targeting peptide for TBI therapy.

Recovery and survival following traumatic brain injury (TBI) depends on optimal amelioration of secondary injuries at lesion site. Delivering mitochondria-protecting drugs to neurons may revive damaged neurons at sites secondarily traumatized by TBI. Pioglitazone (PGZ) is a promising candidate for TBI treatment, limited by its low brain accumulation and poor targetability to neurons. Herein, we report a ROS-responsive nanosystem, camouflaged by hybrid membranes of platelets and engineered extracellular vesicles (EVs) (C3-EPm-|TKNPs|), that can be used for targeted delivery of PGZ for TBI therapy. Inspired by intrinsic ability of macrophages for inflammatory chemotaxis, engineered M2-like macrophage-derived EVs were constructed by fusing C3 peptide to EVs membrane integrator protein, Lamp2b, to confer them with ability to target neurons in inflamed lesions. Platelets provided hybridized EPm with capabilities to target hemorrhagic area caused by trauma via surface proteins. Consequently, C3-EPm-|PGZ-TKNPs| were orientedly delivered to neurons located in the traumatized hemisphere after intravenous administration, and triggered the release of PGZ from TKNPs via oxidative stress. The current work demonstrate that C3-EPm-|TKNPs| can effectively deliver PGZ to alleviate mitochondrial damage via mitoNEET for neuroprotection, further reversing behavioral deficits in TBI mice. Our findings provide proof-of-concept evidence of C3-EPm-|TKNPs|-derived nanodrugs as potential clinical approaches against neuroinflammation-related intracranial diseases.

The hypoxia-inducible factor 1 inhibitor LW6 mediates the HIF-1α/PD-L1 axis and suppresses tumor growth of hepatocellular carcinoma in vitro and in vivo.

The low survival rate of hepatocellular carcinoma (HCC) remains a major challenge for clinicians and patients, and its progression may be related to hypoxia-inducible factor (HIF) and PD-L1. LW6 is a drug that inhibits hypoxia by reducing HIF-1α accumulation and gene transcriptional activity. However, its effect and regulatory mechanism in HCC remain to be revealed, especially under hypoxic conditions. The HIF-1α and PD-L1 expression in HCC specimens and paracarcinoma tissues was evaluated by a tissue microarray (TMA). The effects of LW6 were evaluated by cell viability, colony formation, and Transwell assays and xenografted nude mice. Cell cycle and apoptosis of HCC cells were detected by flow cytometry. The effects of LW6 on HIF-1α signaling and its targets PD-L1 and VEGF were evaluated through qRT-PCR, Western blots, Cell transfection, Transwell migration and invasion assays, immunohistochemistry, immunofluorescence and luciferase assays. In this study, we found that LW6 had antiproliferative effects on HCC and promoted HCC cell apoptosis, inhibited their migration and invasion, and affected their cell cycle. LW6 dramatically decreased HIF-1α expression through the VHL-dependent proteasome system pathway, inhibited HIF-1α transcriptional activation, and reduced PD-L1 expression by inhibiting EGFR pathway activation. These results suggest that LW6 can promote apoptosis of HCC cells by inhibiting HIF-1α, inhibit tumor angiogenesis, and downregulate the expression of PD-L1, which is an effective choice for the treatment of HCC. Moreover, inhibiting the hypoxic microenvironment combined with immunotherapy is expected to be a potentially effective strategy.

Red blood cell-hitchhiking mediated pulmonary delivery of ivermectin: Effects of nanoparticle properties.

Recent studies have demonstrated that ivermectin (IVM) exhibits antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of coronavirus disease 2019 (COVID-19). However, the repurposing of IVM for the treatment of COVID-19 has presented challenges primarily due to the low IVM plasma concentration after oral administration, which was well below IC50. Here, a red blood cell (RBC)-hitchhiking strategy was used for the targeted delivery of IVM-loaded nanoparticles (NPs) to the lung. IVM-loaded poly (lactic-co-glycolic acid) (PLGA) NPs (IVM-PNPs) and chitosan-coating IVM-PNPs (IVM-CSPNPs) were prepared and adsorbed onto RBCs. Both RBC-hitchhiked IVM-PNPs and IVM-CSPNPs could significantly enhance IVM delivery to lungs, improve IVM accumulation in lung tissue, inhibit the inflammatory responses and finally significantly alleviate the progression of acute lung injury. Specifically, the redistribution and circulation effects were related to the properties of NPs. RBC-hitchhiked cationic IVM-CSPNPs showed a longer circulation time, slower accumulation and elimination rates, and higher anti-inflammatory activities than RBC-hitchhiked anionic IVM-PNPs. Therefore, RBC-hitchhiking provides an alternative strategy to improve IVM pharmacokinetics and bioavailability for repurposing of IVM to treat COVID-19. Furthermore, according to different redistribution effects of different NPs, RBC-hitchhiked NPs may achieve various accumulation rates and circulation times for different requirements of drug delivery.

Design of robust cubature fission particle filter algorithm in multi-source cooperative navigation.

As a part of the multi-source cooperative navigation scheme, data fusion has a significant impact on the quality of state estimation. Particle filtering has gradually become the focus of many fusion methods due to its unique theoretical advantages in nonlinear non-Gaussian systems. However, the particle degradation and the resulting sample impoverishment restrict its application in complex engineering scenarios. In this paper, a robust cubature fission particle filter (RCFPF) is proposed to deal with these problems. First, in the framework of cubature rule, Huber function is used to combine the L2 norm and L1 norm to improve the importance density function(IDF), suppress the observation noise. Meanwhile, the proposed distribution(PD) is further optimized by combining the Gaussian distribution with Laplace distribution to alleviate particle degradation. Second, the particle swarm is fissioned before resampling, and the particle weight is reconstructed by fission of high weight particles and covering low weight particles to inhibit sample impoverishment. The vehicle experiments of multi-source cooperative navigation show that the proposed algorithm achieves better test results in accuracy and robustness than extended Kalman filter (EKF), strong tracking particle filter (STPF), and cubature particle filter (CPF).

A Case Study of Community-based, Cross-sectoral Crisis Response to the COVID-19 Pandemic: Serving Racialized Immigrant Communities.

Crises-such as the COVID-19 pandemic-bring about myriad problems in magnitude (severity), dynamism (quality), and urgency (timing). Collaborative models that bring together actors from both the public and private sector have thus emerged for institutionalized and community-based crisis response. Such models aim particularly to reach vulnerable, hard-to-reach communities, such as racialized immigrant communities that are among those disproportionately impacted at times of crisis. This paper presents a case study of a community-based, cross-sectoral collaborative formed to respond to the COVID-19 pandemic and specifically targeting immigrant communities. Findings inform a conceptual framework that illustrates the integration of two spheres of service: crisis supports, characterized by a short-term approach, broad-based reach and general objectives; and settlement supports, characterized by their long-term approach, trust relations and targeted objectives, such as language supports and culturally appropriate outreach.

Antimicrobial and Aging Properties of Ag-, Ag/Cu-, and Ag Cluster-Doped Amorphous Carbon Coatings Produced by Magnetron Sputtering for Space Applications.

Inside a spacecraft, the temperature and humidity, suitable for the human crew onboard, also creates an ideal breeding environment for the proliferation of bacteria and fungi; this can present a hazard to human health and create issues for the safe running of equipment. To address this issue, wear-resistant antimicrobial thin films prepared by magnetron sputtering were developed, with the aim to coat key internal components within spacecrafts. Silver and copper are among the most studied active bactericidal materials, thus this work investigated the antibacterial properties of amorphous carbon coatings, doped with either silver, silver and copper, or with silver clusters. The longevity of these antimicrobial coatings, which is heavily influenced by metal diffusion within the coating, was also investigated. With a conventional approach, amorphous carbon coatings were prepared by cosputtering, to generate coatings that contained a range of silver and copper concentrations. In addition, coatings containing silver clusters were prepared using a separate cluster source to better control the metal particle size distribution in the amorphous carbon matrix. The particle size distributions were characterized by grazing-incidence small-angle X-ray scattering (GISAXS). Antibacterial tests were performed under both terrestrial gravity and microgravity conditions, to simulate the condition in space. Results show that although silver-doped coatings possess extremely high levels of antimicrobial activity, silver cluster-doped coatings are equally effective, while being more long-lived, despite containing a lower absolute silver concentration.

Targeted delivery of PARP inhibitors to neuronal mitochondria via biomimetic engineered nanosystems in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co-modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. STATEMENT OF SIGNIFICANCE: TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane-coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo.

RBC-hitchhiking chitosan nanoparticles loading methylprednisolone for lung-targeting delivery.

Hyper-inflammation associated with cytokine storm syndrome causes high mortality in patients with COVID-19. Glucocorticoids, such as methylprednisolone sodium succinate (MPSS), effectively inhibit this inflammatory response. However, frequent and chronic administration of glucocorticoids at high doses leads to hormone dependence and serious side effects. The aim of the present study was to combine nanoparticles with erythrocytes for the targeted delivery of MPSS to the lungs. Chitosan nanoparticles loading MPSS (MPSS-CSNPs) were prepared and adsorbed on the surface of red blood cells (RBC-MPSS-CSNPs) by non-covalent interaction. In vivo pharmacokinetic study indicated that RBC-hitchhiking could significantly reduce the plasma concentration of the drug and prolong the circulation time. The mean residence time (MRT) and area under the curve (AUC) of the RBC-MPSS-CSNPs group were significantly higher than those of the MPSS-CSNPs group and the MPSS injection group. Moreover, in vivo imaging and tissue distribution indicated that RBC-hitchhiking facilitated the accumulation of nanoparticles loading fluorescein in the lung, preventing uptake of these nanoparticles by the liver. Furthermore, compared with the MPSS-CSNPs and MPSS treatment groups, treatment with RBC-MPSS-CSNPs considerably inhibited the production of inflammatory cytokines such as TNF-α and IL-6, and consequently attenuated lung injury induced by lipopolysaccharide in rats. Therefore, RBC-hitchhiking is a potentially effective strategy for the delivery of nanoparticles to the lungs for the treatment of acute lung injury and acute respiratory distress syndrome.

The Role of Aldehyde Oxidase in the Metabolic Clearance of Substituted Benzothiazoles.

BACKGROUND: A group of substituted benzothiazoles from a research project was found to have low microsomal clearance. However, these compounds had very high clearance in vivo. METHODS: In the present study, the clearance mechanism of two of the structural analogs, was investigated in vitro and in vivo. RESULTS: In vitro studies showed the formation of corresponding non-P450 dependent oxidative metabolites in S9, cytosol, and hepatocytes. The in vitro formation of these metabolites was observed in mice, rats, non-human primates, and humans. The dog did not form the corresponding metabolites in any of the matrices. Inhibition studies with S9 fraction and incubation with human recombinant aldehyde oxidase (AO) showed that the formation of the corresponding metabolites was AO dependent. To investigate the role of this pathway in vivo, mice were dosed with compound A and bile and plasma were analyzed. Most of the metabolites in bile contained the AO-dependent oxidized benzothiazole moiety, indicating that metabolism involving AO was probably the main pathway for clearance. The same metabolites were also observed circulating in plasma. Mass spectrometric analysis of the metabolite showed that the oxidation was on the benzothiazole moiety, but the exact position could not be identified. Isolation of the metabolite of compound A and analysis by NMR confirmed the structure of the metabolite as C2 carbon oxidation of the thiazole ring resulting in carboxamide moiety. Further comparison of both metabolites with corresponding authentic standards confirmed the structures. CONCLUSION: To our knowledge, such an observation of in vitro and in vivo oxidation of substituted benzothiazole by AO has not been reported before. The results helped the medicinal chemists design compounds that avoid AO-mediated metabolism and with better ADME property.

Overweight with HBV infection limited the efficacy of TACE in hepatocellular carcinoma by inhibiting the upregulated HMGB1.

BACKGROUND: Transarterial chemoembolization (TACE) is an effective treatment for patients with hepatocellular carcinoma (HCC). However, the impact of hepatitis B viral (HBV) infection and body mass index (BMI) on TACE is controversial. The present study aimed to compare the influence of HBV and high BMI on TACE outcomes in advanced HCC. METHODS: Based on HBV infection history and BMI, patients were assigned to different subgroups. Blood samples were collected and analyzed by an enzyme-linked immunosorbent assay (ELISA) kit. The primary endpoint was progression-free survival (PFS) and the overall survival (OS) in the population. RESULTS: Compared to overweight combined HBV patients who received TACE, people with normal weight or no viral infection had significantly better OS and PFS. Sex, age, portal vein tumor thrombus, BCLC, ECOG, and tumor diameter are the main risk factors affecting PFS and OS. Except for the postoperative fever, no significant difference was detected in adverse reactions. Irrespective of TACE, the average expression of HMGB1 in hepatitis or obesity patients was higher than that in normal individuals and did not show upregulation after TACE. Patients without overweight or HBV infection had a low expression of serum HMGB1 that was substantially upregulated after TACE. CONCLUSIONS: In this study, overweight combined HBV infection patients had shorter PFS and OS than other HCC patients. Thus, HBV and BMI maybe two factors affecting the efficacy of TACE via upregulated HMGB1.

Transcatheter Arterial Infusion Combined With Radioactive Particles in the Treatment of Advanced Body/Tail Pancreatic Cancer: A Retrospective Cohort Study.

OBJECTIVES: This retrospective cohort study investigated the efficacy of routine intravenous chemotherapy (the control group), transcatheter arterial infusion (TAI) chemotherapy, and TAI combined with radioactive particles as therapeutic methods for advanced body/tail pancreatic cancer by assessing the short-term and overall survival rates. METHODS: We screened our prospective database for patients with advanced body/tail pancreatic cancer, which tumor deemed unresectable, and no other confirmed malignant tumors, patients were assigned into 3 groups according to their treatment: routine intravenous chemotherapy, TAI, and TAI combined with radioactive particles. RESULTS: The median survival time was 6 months in the control group, 10 months in the TAI group, and 13 months in the TAI combined group. The Kaplan-Meier estimates of the overall survival among the 3 groups, indicating that there is significant difference among 3 groups (P < 0.000). The clinical remission rates were 17.5% in the control group, 41.5% in the TAI group, and 48.0% in the TAI combined group. Covariates analyzed showed that different treatment methods and times affected the results significantly (P < 0.002). CONCLUSIONS: In the treatment of advanced body/tail pancreatic cancer, TAI and TAI combined with radioactive particles significantly improved the clinical outcomes in patients compared with routine intravenous chemotherapy.

Aging erythrocyte membranes as biomimetic nanometer carriers of liver-targeting chromium poisoning treatment.

Chromium poisoning has become one of the most common heavy metal poisoning occupational diseases with high morbidity and mortality. However, most antidotes detoxify the whole body and are highly toxic. To achieve hepato-targeted chromium poisoning detoxification, a novel hepato-targeted strategy was developed using aging erythrocyte membranes (AEMs) as biomimetic material coated with a dimercaptosuccinic acid (DMSA) nanostructured lipid carrier to construct a biomimetic nano-drug delivery system. The particle size, potential, drug loading, encapsulation rate, in vitro release, and stability of the nanoparticles (NPs) were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be phagocytized by RAW264.7 macrophage cells. The efficacy of AEM-DMSA-NPs for targeted liver detoxification was evaluated by in vitro MTT analysis and an in vivo model of chromium poisoning. The results showed that the NPs could safely and efficiently achieve targeted liver chromium poisoning detoxification. All the results indicated that the biomimetic nano-drug delivery system mediated by aging erythrocyte membranes and containing DMSA nanoparticles could be used as a novel therapeutic drug delivery system potentially targeting liver detoxification.

HMGB1, the Next Predictor of Transcatheter Arterial Chemoembolization for Liver Metastasis of Colorectal Cancer?

HMGB1 is an important mediator of inflammation during ischemia-reperfusion injury on organs. The serum expression of HMGB1 was increased significantly on the 1st day after TACE and decreased significantly which was lower on the 30th day after TACE. Tumor markers of post-DEB-TACE decreased significantly. The correlational analysis showed that patients with low HMGB1 expression had lower risks of fever and liver injury compared those with the higher expression, while the ORR is relatively worse. Patients with lower expression of HMGB1 had longer PFS, better efficacy, and higher quality of life. With the high post-expression, the low expression had lower incidence of fever and liver injury too. There was no statistical difference in the one-year survival among the different groups. The quality of life of all patients was improved significantly. The over-expression of HMGB1 in LMCRC is an adverse prognostic feature and a positive predictor of response to TACE.

Endpoint of embolization: A study of transarterial chemoembolization in patients with large hepatocellular carcinoma.

PURPOSE: To explore the degree of embolization and embolization endpoints in patients with large hepatocellular carcinoma (HCC) treated via transarterial chemoembolization (TACE). METHODS: Thirty-two HCC patients treated with TACE from 2015 to 2016 who met the enrollment criteria for this study were retrospectively analyzed. The experimental group was treated via complete embolization, with complete occlusion of the tumor blood supplying artery, while the control group underwent incomplete embolization of any blood supplying arteries, with limited residual visible blood flow detectable via angiography. Postoperative liver and kidney function, complications, prognosis, and survival for patients in these two groups were analyzed. RESULTS: There was no significant difference at baseline patient condition between the two treatment groups before treatment. After treatment, the alanine aminotransferase (ALT), aspartic aminotransferase (AST), and white blood cell (WBC) values in the experimental group were significantly higher than those in the control group (p=0.031, 0.038, and 0.034, respectively). There was also a significant increase in hepatic aseptic necrosis and acute liver function damage in the experimental group relative to the control group (p=0.015 and 0.023, respectively). Compared with the control group, the prognosis and survival of the experimental group was significantly decreased. Univariate and multivariate Cox regression analyses of overall survival revealed that the different treatment group and hepatitis B infection status were the main factors affecting patient prognosis and survival. CONCLUSIONS: For patients with large HCC tumors with a limited number of supporting arteries, careful attention should be paid to the use of embolic agents during the TACE procedure. Rather than proceeding to complete embolization of the artery root, embolization can be terminated when the main tumor feeding artery is still faintly visible on an angiogram in a structure reminiscent of a tree with dry branches, thereby reducing adverse outcomes in patients.

Analgesia of percutaneous thermal ablation plus cementoplasty for cancer bone metastases.

BACKGROUND: The purpose of this study was to review recent research related to the analgesic effect of ablation therapy combined with cementoplasty, as well as to identify the duration of analgesic effect and risk for cement leaks. METHODS: A systematic literature search using PubMed, Web of Science, and annual meeting proceedings of the oncology society and other organizations were conducted. RESULTS: Twelve retrospective studies met the inclusion criteria. Four of the studies included in the review assessed the changes immediately after treatment. Five studies were subjected to analyses of analgesic effect of combined percutaneous thermal ablation and Cementoplasty at 24 weeks after treatment. Incidences of leakage of bone cement during surgery were detected in 4 out of 12 studies. The change of mean pain scores at 1 days, at 1 week, and at 4 weeks, 12 weeks, and 24 weeks after treatment were -3.90 (95% CI: -4.80 to -3.00), -4.55 (95% CI:-5.46 to -3.64), -4.78 (95% CI: -5.70 to -3.86), -5.16 (95% CI: -6.39 to -3.92), and -5.91 (95% CI: -6.63 to -5.19). The relative risk of cement leakage was 0.10 (95% CI: -6.63 to -5.19). CONCLUSIONS: Our systematic review suggested that thermal ablation combined with cementoplasty could be a safe and effective intervention for the management of bone metastases-induced pain.

Efficacy of radiofrequency ablation and microwave ablation in the treatment of thoracic cancer: A systematic review and meta-analysis.

BACKGROUND: Radiofrequency ablation and microwave ablation are frequently prescribed for thoracic cancer. However, few writers have been able to draw on any systematic research into the differences between the two ablation methods. METHODS: A literature search was carried out using Embase, PUBMED, Web of Science, Cochrane Library, and CNKI databases, with additional searches carried out manually using terms associated with thoracic cancer and thermal ablation. Then we used Google Scholar for a complementary search. Data were extracted from studies of patients that underwent radiofrequency ablation or microwave ablation, and the investigator carried out efficacy evaluation and follow up. The data obtained from the literature were summarized and analyzed using Cochrane Revman software Version 5.3 and SPSS 22.0. RESULTS: There were seven comparative studies, but no randomized studies identified for data extraction; 246 patients received radiofrequency ablation therapy and 319 controls received microwave ablation. There was no significant difference in the six-month, one-year, two-year, and three-year survival rates, and adverse reactions were found in the two treatments. For patients' long-term survival rate, the two treatments can achieve a similar survival time. CONCLUSION: In the treatment of thoracic cancer, microwave ablation can achieve the same efficacy as radiofrequency ablation.

Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.

Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.

The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.