A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB.

The non-canonical NF-κB signalling cascade is essential for lymphoid organogenesis, B cell maturation, osteoclast differentiation, and inflammation in mammals1,2; dysfunction of this system is associated with human diseases, including immunological disorders and cancer3-6. Although expression of NF-κB-inducing kinase (NIK, also known as MAP3K14) is the rate-limiting step in non-canonical NF-κB pathway activation2,7, the mechanisms by which transcriptional responses are regulated remain largely unknown. Here we show that the sine oculis homeobox (SIX) homologue family transcription factors SIX1 and SIX2 are integral components of the non-canonical NF-κB signalling cascade. The developmentally silenced SIX proteins are reactivated in differentiated macrophages by NIK-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 target a subset of inflammatory gene promoters and directly inhibit the trans-activation function of the transcription factors RELA and RELB in a negative feedback circuit. In support of a physiologically pivotal role for SIX proteins in host immunity, a human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS/P53-driven non-small-cell lung carcinomas from inflammatory cell death induced by SMAC-mimetic chemotherapeutic agents (small-molecule activators of the non-canonical NF-κB pathway). Our findings identify a NIK-SIX signalling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.

The increased expression and aberrant methylation of SHC1 in non-small cell lung cancer: Integrative analysis of clinical and bioinformatics databases.

Despite the previous evidence showing that SHC adaptor protein 1 (SHC1) could encode three distinct isoforms (p46SHC, p52SHC and p66SHC) that function in different activities such as regulating life span and Ras activation, the precise underlying role of SHC1 in lung cancer also remains obscure. In this study, we firstly found that SHC1 expression was up-regulated both in lung adenocarcinoma (LUAD) and in lung squamous cell carcinoma (LUSC) tissues. Furthermore, compared to patients with lower SHC1 expression, LUAD patients with higher expression of SHC1 had poorer overall survival (OS). Moreover, higher expression of SHC1 was also associated with worse OS in patients with stages 1 and 2 but not stage 3 lung cancer. Significantly, the analysis showed that SHC1 methylation level was associated with OS in lung cancer patients. It seemed that the methylation level at specific probes within SHC1 showed negative correlations with SHC1 expression both in LUAD and in LUSC tissues. The LUAD and LUSC patients with hypermethylated SHC1 at cg12473916 and cg19356022 probes had a longer OS. Therefore, it is reasonable to conclude that SHC1 has a potential clinical significance in LUAD and LUSC patients.

Cell-based high-throughput screening of polysaccharide biosynthesis hosts.

Valuable polysaccharides are usually produced using wild-type or metabolically-engineered host microbial strains through fermentation. These hosts act as cell factories that convert carbohydrates, such as monosaccharides or starch, into bioactive polysaccharides. It is desirable to develop effective in vivo high-throughput approaches to screen cells that display high-level synthesis of the desired polysaccharides. Uses of single or dual fluorophore labeling, fluorescence quenching, or biosensors are effective strategies for cell sorting of a library that can be applied during the domestication of industrial engineered strains and metabolic pathway optimization of polysaccharide synthesis in engineered cells. Meanwhile, high-throughput screening strategies using each individual whole cell as a sorting section are playing growing roles in the discovery and directed evolution of enzymes involved in polysaccharide biosynthesis, such as glycosyltransferases. These enzymes and their mutants are in high demand as tool catalysts for synthesis of saccharides in vitro and in vivo. This review provides an introduction to the methodologies of using cell-based high-throughput screening for desired polysaccharide-biosynthesizing cells, followed by a brief discussion of potential applications of these approaches in glycoengineering.

Hydrophilic and Electroneutral Nanoparticles to Overcome Mucus Trapping and Enhance Oral Delivery of Insulin.

The oral delivery of macromolecules using nanoparticles is limited by secreted mucus, resulting in low contact or internalization via intestinal cells and, thus, both mucus trapping and further low cellular uptake need to be overcome. Here, hydrophilic and electroneutral nanoparticles were developed to overcome mucus trapping and enhance the oral delivery of macromolecules. Mesoporous silica nanoparticles (MSNs) were synthesized and modified with a hydrophilic block polymer (poly(lactic acid)-methoxy poly(ethylene glycol), PLA-PEG), and then an overall electroneutrality and promoted cellular uptake were achieved by sequential modification with cell-penetrating peptides (CPPs). Reduced hydrophobic and electrostatic interactions of MSN@PLA-PEG-CPP with mucus decreased mucus trapping by 36.0%, increased the cellular uptake of MSN@PLA-PEG-CPP by 2.3-folds in mucous conditions via active heparan sulfate proteoglycan receptor (HSPG)-mediated and caveolae-mediated endocytosis and electrostatic interactions. Furthermore, insulin, a model macromolecular drug, was successfully loaded into the nanoparticles (INS@MSN@PLA-PEG-CPP). Compared with insulin solution, in vitro cellular uptake in mucous conditions and in vivo pharmacodynamic effects were significantly increased by 9.1- and 14.2-folds, respectively. As well, all nanoparticles with or without insulin loading presented negligible in vitro and in vivo toxicity. Herein, hydrophilic and electroneutral nanoparticles with sequential PEG and CPP modification could promote cellular uptake against mucus trapping and finally show good prospects for oral insulin delivery.

Integration of RNA-seq and RNAi provides a novel insight into the immune responses of Epinephelus coioides to the impB gene of Pseudomonas plecoglossicida.

Pseudomonas plecoglossicida is a Gram-negative bacterium that causes visceral white spot disease in Epinephelus coioides and leads to severe aquatic economic losses. The RNA-seq results of a previous study showed that the expression of the impB gene in P. plecoglossicida was significantly upregulated during infection. Four shRNAs were designed and synthesized to silence the impB gene in P. plecoglossicida, and the maximum silencing efficiency was 95.2%. Intraperitoneal injection of the impB-RNAi strain of P. plecoglossicida did not cause E. coioides death, and the spleens of infected fish did not show significant clinical symptoms. Although the injection of the mutant strain increased the antibody titer in E. coioides serum, it could not effectively protect E. coioides against wild strain infection. Compared with E. coioides infected with the wild type strain, the RNA-seq results for E. coioides infected with the impB-RNAi strain differed greatly. The KEGG enrichment analysis showed that key genes of the chemokine signalling pathway of E. coioides were downregulated by the silencing of impB in P. plecoglossicida. Infection with the impB-RNAi strain of P. plecoglossicida through injection did not produce good immune protection against E. coioides. The present study provides a novel insight into the immune responses of E. coioides to the impB gene of P. plecoglossicida.

Imaging Features and Clinical Decision Analysis of 110 Cases of Intrapulmonary Lymph Nodes.

OBJECTIVE: Through the summary and analysis of large samples, the characteristic imaging manifestations of intrapulmonary lymph nodes (IPLNs) were quantified, and two corresponding rating tables were developed. These rating tables could be used to distinguish the IPLNs from primary lung cancer, so as to improve the diagnostic accuracy and help clinicians make correct judgments and decisions. METHODS: A total of 82 patients with 110 IPLNs and 35 patients with primary lung cancer lesions were collected from June 2017 to December 2018. All lesions were solid nodules of less than 12 mm in diameter, which were confirmed by pathology. Observation indicators included location, size, shape, density, border and internal vacuoles of nodules, linear high-density shadow around the nodules, distance from the pleura, pleural indentation, and so on. RESULTS: There were statistically significant differences in the location, size, shape, internal vacuole of the nodules, and distance from the pleura (p < 0.05). The diagnostic scoring table of the nature of solid nodules and the malignant risk table were drawn. The nodule corresponding to Level A was most likely the primary lung cancer, and surgical resection was recommended. The nodule corresponding to Level C was most likely IPLNs, and it was better to receive no treatment currently. The positive predictive value was 81% (23/28), the negative predictive value was 97% (89/92), the sensitivity was 63% (23/35), and the specificity was 81% (89/110). CONCLUSION: For the pulmonary solid nodules of less than 12 mm in diameter and unknown nature, the evaluation in accordance with the Score Table and the Risk Level Table of this study can be more accurate and faster than the original judgment, which will help clinicians in diagnosis and treatment decisions.

Prophylactic ligation of the thoracic duct branch prevents chylothorax after pulmonary resection for right lung cancer.

PURPOSE: Chylothorax is a rare and challenging complication of thoracic surgery. Whereas most current studies focus on postoperative treatment and preventative measures for esophageal cancer surgery, the current study investigates the impact of prophylactic ligation of the thoracic duct branch on postoperative chylothorax after pulmonary resection for right lung cancer. METHODS: The subjects of this retrospective study were 1165 patients who underwent right pulmonary resection and mediastinal lymph-node dissection in our department between January 2015 and August 2019. Those who underwent prophylactic ligation of the thoracic duct branch after 4R lymph-node dissection were assigned to group A (n = 475), and those who did not were assigned to group B (n = 690). The incidence of postoperative chylothorax, the success rate of conservative treatment, the postoperative hospital stay, and the chest drainage volume were recorded and compared statistically between the two groups. RESULTS: The incidence of postoperative chylothorax was significantly lower in group A than in group B (0.84% vs. 2.90%, p = 0.015). Patients who had a chylothorax in group A had a significantly shorter postoperative hospital stay, less mean drainage volume per day, and less total drainage than those in group B (7.25 ± 0.50 days vs. 11.00 ± 2.81 days, p = 0.003; 0.64 ± 0.04 L vs. 0.80 ± 0.09 L, p = 0.003; 4.64 ± 0.40 L vs. 8.82 ± 2.84 L; p = 0.002). The success rate of conservative treatment was higher in group A than in group B, but the difference was not significant (100% vs. 75.0%, p = 0.544). CONCLUSION: Performing prophylactic ligation of the thoracic duct branch during right pulmonary resection and mediastinal lymph-node dissection is an effective and safe method of preventing postoperative chylothorax.

BIK1 interacts with PEPRs to mediate ethylene-induced immunity.

Plants have evolved intricate immune mechanisms to combat pathogen infection. Upon perception of pathogen-derived signals, plants accumulate defense hormones such as ethylene (ET), jasmonate, salicylate, and damage-associated molecular patterns to amplify immune responses. In particular, the Arabidopsis peptide Pep1 and its family members are thought to be damage-associated molecular patterns that trigger immunity through Pep1 receptor kinases PEPR1 and PEPR2. Here we show that PEPR1 specifically interacts with receptor-like cytoplasmic kinases botrytis-induced kinase 1 (BIK1) and PBS1-like 1 (PBL1) to mediate Pep1-induced defenses. In vitro and in vivo studies suggested that PEPR1, and likely PEPR2, directly phosphorylates BIK1 in response to Pep1 treatment. Surprisingly, the pepr1/pepr2 double-mutant seedlings displayed reduced in sensitivity to ET, as indicated by the elongated hypocotyls. ET-induced expression of defense genes and resistance to Botrytis cinerea were compromised in pepr1/pepr2 and bik1 mutants, reenforcing an important role of PEPRs and BIK1 in ET-mediated defense signaling. Pep treatment partially mimicked ET-induced seedling growth inhibition in a PEPR- and BIK1-dependent manner. Furthermore, both ET and Pep1 treatments induced BIK1 phosphorylation in a PEPR-dependent manner. However, the Pep1-induced BIK1 phosphorylation, seedling growth inhibition, and defense gene expression were independent of canonical ET signaling components. Together our results illustrate a mechanism by which ET and PEPR signaling pathways act in concert to amplify immune responses.

Perfluoropolyether-incorporated polyurethane with enhanced antibacterial and anti-adhesive activities for combating catheter-induced infection.

To avoid the undesired bacterial attachment on polyurethane-based biomedical devices, we designed a class of novel perfluoropolyether-incorporated polyurethanes (PFPU) containing different contents of perfluoropolyether (PFPE) segments. After blending with Ag nanoparticles (AgNPs), a series of bifunctional PFPU/AgNPs composites with bactericidal and anti-adhesion abilities were obtained and correspondingly made into PFPU/AgNPs films (PFPU/Ag-F) using a simple solvent-casting method. Due to its highest hydrophobicity and suitable mechanical properties, PFPU8/Ag-F containing 8 mol% of PFPE content was chosen as the optimized one for the next antibacterial assessment. The PFPU8/Ag-F can effectively deactivate over 99.9% of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) cells at 106 CFU mL-1 within 30 min. Furthermore, the PFPU8/AgNPs composite was used as painting material to form a protective coating for the commercial polyurethane (PU) catheter. The as-prepared PFPU8/Ag coating exhibits high resistance to bacterial adhesion in a continuous-flow artificial urine model in an 8 day exposure. Therefore, it can be expected that the proposed PFPE-containing films and coatings can effectively prevent bacterial colonization and biofilm formation on catheters or other implants, thereby reducing the risk of postoperative catheter-induced infection.

Dual-Targeted Self-Adjuvant Heterocyclic Lipidoid@Polyester Hybrid Nanovaccines for Boosting Cancer Immunotherapy.

Tumor vaccines have demonstrated a modest response rate, primarily attributed to their inefficient delivery to dendritic cells (DCs), low cross-presentation, DC-intrinsic immunosuppressive signals, and an immunosuppressive tumor microenvironment (TME). Here, draining lymph node (DLN)-targeted and tumor-targeted nanovaccines were proposed to address these limitations, and heterocyclic lipidoid (A18) and polyester (BR647) were synthesized to achieve dual-targeted cancer immunotherapy. Meanwhile, oligo hyaluronic acid (HA) and DMG-PEG2000-Mannose were incorporated to prepare dual-targeted nanovaccines encapsulated with STAT3 siRNA and model antigens. The nanovaccines were designed to target the DLN and the tumor, facilitating the delivery of cargo into the cytoplasm. These dual-targeted nanovaccines improved antigen presentation and DC maturation, activated the stimulator of interferon genes (STING) pathway, enhanced the pro-apoptotic effect, and stimulated antitumor immune responses. Additionally, these dual-targeted nanovaccines overcame immunosuppressive TME, reduced immunosuppressive cells, and promoted the polarization of tumor-associated neutrophils from N2 to N1. Among the four dual-targeted nanovaccines that induced robust antitumor responses, the heterocyclic lipidoid@polyester hybrid nanovaccines (MALO@HBNS) demonstrated the most promising results. Furthermore, a combination strategy involving MALO@HBNS and an anti-PD-L1 antibody exhibited an immensely powerful anticancer role. This work introduced a dual-targeted nanovaccine platform for antitumor treatment, suggesting its potential combination with an immune checkpoint blockade as a comprehensive anticancer strategy.

Research on the loading and release kinetics of the vincristine sulfate liposomes and its anti-breast cancer activity.

Vincristine (VCR), as a cytotoxic drug, is used clinically to treat acute lymphatic leukemia and breast cancer, and commonly used clinically as vincristine sulfate (VCRS). However, its clinical use is limited by unpredictable pharmacologic characteristics, a narrow therapeutic index, and neurotoxicity. The pH gradient method was used for active drug loading of VCRS, and the process route mainly includes the preparation of blank liposomes and drug-loaded liposomes. VCRS liposomes had suitable particle size, high encapsulation efficiency and good stability. The loading and release kinetics of VCRS liposomes were explored. By calculating the changes of encapsulation efficiency with time at different temperatures, it was confirmed that the drug-loading process of liposomes exhibited a first-order kinetic feature, and the activation energy required for the reaction was determined as 20.6 kcal/mol. The release behavior at different pH was also investigated, and it was demonstrated that the release behavior conformed to the first-order model, suggesting that the release mechanism of VCRS was simple transmembrane diffusion. VCRS liposomes also enhanced in vitro and in vivo antitumor activity. Thus, VCRS liposomes showed great potential for VCRS delivery, and the loading and release kinetics were well researched to provide a reference for investigating active drug loading liposomes.

Plasma metabolomics study in screening and differential diagnosis of multiple primary lung cancer.

BACKGROUND: Multiple primary lung cancer (MPLC) is becoming increasingly common in clinical practice. Imaging examination is sometimes difficult to differentiate from intrapulmonary metastasis (IM) or single primary lung cancer (SPLC) before surgery. There is a lack of effective blood biomarkers as an auxiliary diagnostic method. PARTICIPANTS AND METHODS: A total of 179 patients who were hospitalized and operated in our department from January to June 2019 were collected, and they were divided into SPLC with 136 patients, MPLC with 24 patients, and IM with 19 patients. In total, 96 healthy people without lung cancer were enrolled. Medical history, imaging, and pathology data were assembled from all participants. Plasma metabolomics analysis was performed by quadrupole time-of-flight tandem mass spectrometry, and data were analyzed using SPSS19.0/Simca 14.1/MetaboAnalyst5.0 software. Significant metabolites were selected by variable importance in projection, P value, and fold change. The area under the receiver operating characteristic curve was used to evaluate their diagnostic ability. RESULTS: There were significant differences in plasma metabolite profiles between IM and MPLC. Seven metabolites were screened out. Two metabolites had higher levels in IM, and five metabolites had higher levels in MPLC. All had favorable discriminating capacity. Phosphatidyl ethanolamine (38:5) showed the highest sensitivity (0.95) and specificity (0.92). It was followed by l -histidine with sensitivity 0.92 and specificity 0.84. l -tyrosine can be used to identify SPLC and MPLC. The panel composed of related metabolites exhibited higher diagnostic ability. Eight principal metabolites caused remarkable differences between healthy people and MPLC, and five of them had area under the curves greater than 0.85, showing good discriminating power. CONCLUSION: Through the study of plasma metabolomics, it was found that there were obvious differences in the metabolite profiles of MPLC, IM, SPLC, and the healthy population. Some discovered metabolites possessed excellent diagnostic competence with high sensitivity and specificity. They had the potential to act as biomarkers for the screening and differential diagnosis of MPLCs.

Dual-responsive PEG-lipid polyester nanoparticles for siRNA and vaccine delivery elicit anti-cancer immune responses by modulating tumor microenvironment.

Cancer vaccine-based immunotherapy has great potential; however, the vaccines have been hindered by the immunosuppressive tumor microenvironment (TME). In this study, dual-responsive PEG-lipid polyester nanoparticles (PEG BR647-NPs) for tumor-targeted delivery were proposed. PEG BR647-NPs containing the model tumor-associated antigen (TAA) OVA and the signal transduction and activator of transcription 3 (STAT3) siRNA were delivered to the tumor. The PEG BR647-NPs were internalized by tumor-associated dendritic cells (TADCs), where the TAA and siRNA were released into the cytoplasm via the endo/lysosome escape effect. The released OVA was presented by the major histocompatibility complex class I to activate T cells, and the released STAT3 siRNA acted to relieve TADC dysfunction, promote TADC maturation, improve antigen-presenting ability, and enhance anticancer T cell immunity. Meanwhile, the PEG BR647-NPs were ingested by tumor cells, killing them by the pro-apoptosis effect of STAT3 siRNA. Moreover, PEG BR647-NPs could reduce the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumors and abrogate immunosuppression. The integration of relieved TADC dysfunction, promoted TADC maturation, enhanced antigen cross-presentation, abrogated immunosuppression, and improved pro-apoptosis effect boosted the vaccination for tumor immunotherapy. Thus, PEG BR647-NPs efficiently delivered the vaccine and STAT3 siRNA to the tumor and modulated immunosuppressive TME, thus providing better antitumor effects.

The treatment of hepatocellular carcinoma with SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC)2 nanoparticles facilitating Cu accumulation in the tumor.

BACKGROUND: Copper diethyldithiocarbamate (Cu(DDC)2) has been demonstrated to possess excellent antitumor activity. However, the extremely poor water solubility of Cu(DDC)2 bring difficulty for its formulation research. In this study, we aim to develop a novel nanocarrier for Cu(DDC)2 delivery to overcome this obstacle and enhance antitumor activity. METHODS: The SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC)2 nanoparticles (DCDP) was established by combining the method of inverse microemulsion aggregation and thin-film dispersion. In vitro cellular assays and in vivo tumor-xenograft experiments were conducted to evaluate the tumor chemotherapeutic effect of DCDP. And the vital role of copper ions played in DSF or DDC (DSF/DDC)-based cancer chemotherapy was also explored. RESULTS: DCDP with an encapsulation efficiency (EE%) of 74.0% were successfully prepared. SP94 modification facilitated cellular intake for DCDP, and promoted apoptosis to repress tumor cell proliferation (IC50, 200 nM). And DCDP effectively inhibited tumor growth with a high tumor inhibition rate of 74.84%. Furthermore, Cu(DDC)2 was found to facilitate the copper ion accumulation in tumor tissues, which is beneficial to therapy with high potency. CONCLUSION: DCDP exhibited high-efficient tumor chemotherapeutic efficacy and provided a novel strategy for investigating the anticancer mechanism of Cu(DDC)2.

Research on the preparation process of the cytarabine/daunorubicin dual-encapsulation liposome and its physicochemical properties and performances in vitro/vivo.

As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard chemotherapy treatment "DA 7 + 3″ in terms of clinical effectiveness. Although research on dual-loaded liposomes has increased in recent years, little attention has been paid to their preparation, which can affect their quality, efficacy, and safety. This study explored various preparation processes to create the cytarabine/daunorubicin co-loaded liposome (the Cyt/Daun liposome) and eventually settled on two methods: the sequential loading approach, thin film hydration-extrusion-copper ion gradient, and the simultaneous encapsulation technique, copper ion gradient-concentration gradient. Different preparation methods resulted in different particle sizes and encapsulation efficiencies; the two aforementioned preparation processes generated dual-loaded liposomes with comparable physicochemical properties. The sequential encapsulation technique was selected for the subsequent research owing to its higher encapsulation efficiency prior to purification; the prepared Cyt/Daun liposomes had small and uniform particle size (108.6 ± 1.02 nm, Polydispersity index (PDI) 0.139 ± 0.01), negative charge (-(60.2 ± 1.15) mV), high drug encapsulation efficiency (Cyt 88.2 ± 0.24 %, Duan 94.2 ± 0.45 %) and good plasma stability. To improve its storage stability, the Cyt/Daun liposome was lyophilized (-40 °C for 4 h, maintained for 130 min, and dried for 1200 min) using sucrose-raffinose (mass ratio 7:3; glycolipid ratio 4:1, w/w) as a lyoprotectant. The lyophilized liposomes were purple cakes, redissolved rapidly with insignificant alterations in particle size and encapsulation efficiency, and possessed well storage stability. The pharmacokinetic and tissue distribution studies demonstrated that the Cyt/Daun liposome could achieve long circulation and maintain synergic proportions of drugs within 24 h, increasing the accumulation of drugs at tumor sites. Furthermore, the in vitro/in vivo pharmacodynamic studies confirmed its good anti-tumor activity and safety.

Imaging of Escherichia coli K5 and glycosaminoglycan precursors via targeted metabolic labeling of capsular polysaccharides in bacteria.

The introduction of unnatural chemical moieties into glycosaminoglycans (GAGs) has enormous potential to facilitate studies of the mechanism and application of these critical, widespread molecules. Unnatural N-acetylhexosamine analogs were metabolically incorporated into the capsule polysaccharides of Escherichia coli and Bacillus subtilis via bacterial metabolism. Targeted metabolic labeled hyaluronan and the precursors of heparin and chondroitin sulfate were obtained. The azido-labeled polysaccharides (purified or in capsules) were reacted with dyes, via bioorthogonal chemistry, to enable detection and imaging. Site-specific introduction of fluorophores directly onto cell surfaces affords another choice for observing and quantifying bacteria in vivo and in vitro. Furthermore, azido-polysaccharides retain similar biological properties to their natural analogs, and reliable and predictable introduction of functionalities, such as fluorophores, onto azido-N-hexosamines in the disaccharide repeat units provides chemical tools for imaging and metabolic analysis of GAGs in vivo and in vitro.

Design of carboxymethylcellulose-conjugated polymeric prodrug micelles for enhanced in vivo performance of docetaxel.

Docetaxel (DTX) has become one of the most important cytotoxic drugs to treat cancer; nevertheless, its poor hydrophilicity and non-specific distribution of DTX lead to detrimental side effects. In this article, we devised carboxymethylcellulose (CMC)-conjugated polymeric prodrug micelles (mPEG-CMC-DTX PMs) for DTX delivery. The ester-bonded polymeric prodrug, mPEG-CMC-DTX, was synthesized and exhibited the capacity for self-assembling into polymeric micelles. The CMC is profusely substituted and acetylated to promote the coupling rate of DTX. Covalent binding of DTX and CMC through an ester bond can be hydrolyzed to dissociate the bond under the action of esterase in the tumor. The mPEG-CMC-DTX PMs displayed promoted drug loading (>50 %, wt), commendable stability, and sustained release behavior in vitro. The gradual release of the prodrug amplified the selectivity of cytotoxicity between normal cells and tumor cells, mitigating the systemic toxicity of mPEG-CMC-DTX PMs and enabling dose intensification. Notably, mPEG-CMC-DTX PMs demonstrated a superior antitumor efficacy and low systemic toxicity due to the elevated tolerance dosage (even at 40 mg/kg DTX). In summation, mPEG-CMC-DTX PMs harmonized the antitumor efficacy and toxicity of DTX. In essence, innovative perspectives for the rational design of CMC-conjugated polymeric prodrug micelles for the delivery of potently toxic drugs were proffered.

Intratumoral injection of norcantharidin liposome emulsion hybrid delivery system amplifies the cancer-fighting effects of oral sorafenib against hepatocellular carcinoma.

Interventional therapies are increasingly used in clinical trials for hepatocellular carcinoma (HCC). Sorafenib is the front-line remedy for HCC, however, chemoresistance occurs immutably and affects the effectiveness of treatment. In a previous study, a norcantharidin liposome emulsion hybrid (NLEH) delivery system for HCC was developed. This study aims to examine the therapeutic effects of the combination of intratumoral injection of NLEH and sorafenib in treating HCC. Sorafenib combined with NLEH activated the apoptosis pathway by synergistically upregulating caspase-9, promoting cytotoxicity, apoptosis (64.57%), and G2/M cell cycle arrest (48.96%). Norcantharidin could alleviate sorafenib resistance by counteracting sorafenib-induced phosphorylation of Akt. Additionally, intratumoral injection of NLEH exhibited a sustained accumulation in the tumor within 24 h and didn't distribute to other major organs. Intratumoral injection of NLEH in combination with oral sorafenib displayed the most potent tumor growth inhibitory effect (77.91%) in vivo. H&E staining results and the indicators of the renal and liver function tests demonstrated the safety of this combination therapy. Overall, these results showed that intratumoral injection of NLEH in combination with oral sorafenib treatment represented a rational potential therapeutic option for HCC.

Automatic stent struts detection in optical coherence tomography based on a multiple attention convolutional model.

Objective.Intravascular optical coherence tomography is a useful tool to assess stent adherence and dilation, thus guiding percutaneous coronary intervention and minimizing the risk of surgery. However, each pull-back OCT images may contain thousands of stent struts, which are tiny and dense, making manual stent labeling slow and costly for medical resources.Approach. This paper proposed a multiple attention convolutional model for automatic stent struts detection of OCT images. Multiple attention mechanisms were utilized to strengthen the feature extraction and feature fusion capabilities. In addition, to precisely detect tiny stent struts, the model integrated multiple anchor frames to predict targets in the output.Main results. The model was trained in 4625 frames OCT images of 37 patients and tested in 1156 frames OCT images of 9 patients, and achieved a precision of 0.9790 and a recall of 0.9541, which were significantly better than mainstream convolutional models. In terms of detection speed, the model achieved 25.2 ms per image. OCT images from different collection systems, collection times, and challenging scenarios were experimentally tested, and the model demonstrated stable robustness, achieving precision and recall higher than 0.9630. Meanwhile, clear 3D construction of the stent was achieved.Significance. In conclusion, the proposed model solves the problems of slow manual analysis and occupying a large amount of medical manpower resources. It enhances the detection efficiency of tiny and dense stent struts, thus facilitating the application of OCT quantitative analysis in real clinical scenarios.

Investigation of Negative Bias Temperature Instability Effect in Nano PDSOI PMOSFET.

The Negative Bias Temperature Instability (NBTI) effect of partially depleted silicon-on-insulator (PDSOI) PMOSFET based on 130 nm is investigated. First, the effect of NBTI on the IV characteristics and parameter degradation of T-Gate PDSOI PMOSFET was investigated by accelerated stress tests. The results show that NBTI leads to a threshold voltage negative shift, saturate drain current reduction and transconductance degradation of the PMOSFET. Next, the relationship between the threshold voltage shift and stress time, gate bias and temperature, and the channel length is investigated, and the NBTI lifetime prediction model is established. The results show that the NBTI lifetime of a 130 nm T-Gate PDSOI PMOSFET is approximately 18.7 years under the stress of VG = -1.2 V and T = 125 °C. Finally, the effect of the floating-body effect on NBTI of PDSOI PMOSFET is investigated. It is found that the NBTI degradation of T-Gate SOI devices is greater than that of the floating-body SOI devices, which indicates that the floating-body effect suppresses the NBTI degradation of SOI devices.