A scaffold vaccine to promote tumor antigen cross-presentation via sustained toll-like receptor-2 (TLR2) activation.

Cancer vaccination holds great promise for cancer treatment, but its effectiveness is hindered by suboptimal activation of CD8+ cytotoxic T lymphocytes, which are potent effectors to mediate anti-tumor immune responses. A possible solution is to switch antigen-presenting cells to present tumor antigens via the major histocompatibility complex class I (MHC-I) to CD8+ T cells - a process known as cross-presentation. To achieve this goal, we develop a three-dimensional (3D) scaffold vaccine to promote antigen cross-presentation by persisted toll-like receptor-2 (TLR2) activation after one injection. This vaccine comprises polysaccharide frameworks that "hook" TLR2 agonist (acGM) via tunable hydrophobic interactions and forms a 3D macroporous scaffold via click chemistry upon subcutaneous injection. Its retention-and-release of acGM enables sustained TLR2 activation in abundantly recruited dendritic cells in situ, inducing intracellular production of reactive oxygen species (ROS) in optimal kinetics that crucially promotes efficient antigen cross-presentation. The scaffold loaded with model antigen ovalbumin (OVA) or tumor specific antigen can generate potent immune responses against lung metastasis in B16-OVA-innoculated wild-type mice or spontaneous colorectal cancer in transgenic ApcMin/+ mice, respectively. Notably, it requires neither additional adjuvants nor external stimulation to function and can be adjusted to accommodate different antigens. The developed scaffold vaccine may represent a new, competent tool for next-generation personalized cancer vaccination.

Relationship between primary caregivers' social support function, anxiety, and depression after interventional therapy for acute myocardial infarction patients.

BACKGROUND: An acute myocardial infarction (AMI) is often treated with direct coronary intervention and requires home-based rehabilitation. Caregivers of patients with AMI need adequate social support to maintain high-quality care; however, their social support function is low, and relevant indicators for intervention must be identified. AIM: To analyze the correlation between social support for primary caregivers, their anxiety, and depression, when caring for patients with AMI after interventional therapy. METHODS: Using convenience sampling, we selected 300 primary caregivers of patients with AMI who had undergone interventional therapy. The Social Support Rating Scale (SSRS), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS) were used to assess the primary caregivers. A Pearson's correlation analysis was used to analyze the correlations between the SSRS, SAS, and SDS, and a multiple logistic regression analysis was used to analyze the factors influencing the low social support function of primary caregivers. The receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the pre-dictive ability of the SAS and SDS for low social support function in primary caregivers. RESULTS: Considering the norm among Chinese people, AMI caregivers' objective support, subjective support, support utilization, and SSRS scores were lower, while their SAS and SDS scores were higher. The SSRS scores of female caregivers were higher than those of the male caregivers (t = 2.123, P = 0.035). The Pearson correlation analysis showed that objective support, subjective support, support utilization, and SSRS total scores were significantly correlated with both SAS (r = -0.414, -0.460, -0.416, -0.535) and SDS scores (r = -0.463, -0.379, -0.349, -0.472). Among the 300 AMI caregivers, 56 cases (18.67%) had a low level of support function (SSRS ≤ 22 points). Logistic regression model analysis showed that SAS and SDS were independent risk factors for low social support function of AMI caregivers, regardless of adjustment for other variables (P < 0.05). SAS and SDS predicted that the AUC of AMI caregivers with low support function was 0.84, sensitivity was 67.9 and 71.4, and specificity was 84.0 and 70.9, respectively. CONCLUSION: The social support function of the primary caregiver of patients with AMI after interventional therapy was lower and negatively correlated with anxiety and depression in the primary caregiver.

Design, Synthesis and Molecular Docking of 1,3,4-Oxadiazole-2(3H)-thione Derivatives Containing 1,4-Benzodioxane Skeleton as Potential FabH Inhibitors.

Fatty acid biosynthesis is essential for bacterial survival. Of these promising targets, ß-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target. A series of novel 1,3,4-oxadiazole-2(3H)-thione derivatives containing 1,4-benzodioxane skeleton targeting FabH were designed and synthesized. These compounds were determined by 1 H-NMR, 13 C-NMR, MS and further confirmed by crystallographic diffraction study for compound 7m and 7n. Most of the compounds exhibited good inhibitory activity against bacteria by computer-assisted screening, antibacterial activity test and E. coli FabH inhibitory activity test, wherein compounds 7e and 7q exhibited the most significant inhibitory activities. Besides, compound 7q showed the best E. coli FabH inhibitory activity (IC50 =2.45 µΜ). Computational docking studies also showed that compound 7q interacts with FabH critical residues in the active site.

Design, Synthesis and Molecular Docking of Novel Quinazolinone Hydrazide Derivatives as EGFR Inhibitors.

A series of novel quinazolinone hydrazide derivatives were designed and synthesized as EGFR inhibitors. The results indicated that most of the aimed compounds had potential anti-tumor cell proliferation and EGFR inhibitory activities. In the comprehensive analysis of all the tested compounds, the target compound 9c showed the best anti-tumor cell proliferation activity, (IC50 =1.31 µM for MCF-7, IC50 =1.89 µM for HepG2, IC50 =2.10 µM for SGC), and IC50 =0.59 µM for the EGFR inhibitory activity. Docking results showed that compound 9c could ideally insert the active site and interact with the critical amino acid residues (Val702, Lys721, Met769, Asp831) in the active site.

Preparation of Oral Core-Shell Zein Nanoparticles to Improve the Bioavailability of Glycyrrhizic Acid for the Treatment of Ulcerative Colitis.

In this study, oral colon-targeted adhesion core-shell nanoparticles were designed by applying FA-Zein as the core and using pectin as the shell to enhance the low bioavailability exhibited by glycyrrhizic acid (GA) and the anti-inflammatory effect in specific parts of the intestine. As indicated by the results, the nanoparticles (NPs) remained stable in the stomach and small intestine, while pectins began to degrade and release GA in considerable amounts in the colon with the abundant flora. Subsequently, folate-acid targeting was further assessed with Raw 264.7 and NCM 460 cells. Lastly, NPs were reported to exhibit high adhesion on the colon by using the DSS-induced ulcerative colitis mouse model. Moreover, as indicated by in vitro and in vivo studies, nanoparticles could decrease the levels of MPO and TNF-α by reducing macrophages and neutrophils. In brief, this study provides an ideal loaded natural anti-inflammatory drug delivery system to treat ulcerative colitis.

Strategy for osteoarthritis therapy: Improved the delivery of triptolide using liposome-loaded dissolving microneedle arrays.

Osteoarthritis (OA) is a chronic disease that seriously impairs people's physical function and quality of life. Triptolide (TP), as a promising anti-inflammatory drug for the treatment of OA, has limited clinical application due to its severe systemic toxicity, poor solubility and rapid elimination in the body. To extend its application prospect for OA treatment. We have developed a liposome-loaded dissolving microneedle (DMN) system, which can effectively deliver poorly water-soluble TP and improve OA symptoms. To incorporate TP into DMNs, triptolide liposome (TP-Lipo) with entrapment efficiency of 90.25% was prepared by ethanol injection. Subsequently, TP-Lipo was concentrated by ultrafiltration tube and mixed with hyaluronic acid solution to prepare DMNs, TP-Lipo-loaded DMNs (TP-Lipo@DMNs) showed sufficient mechanical and insertion properties to penetrate about 200 µm of rat skin. The drug distribution in vivo showed that TP-Lipo@DMNs had a slow-release effect compared with intra-articular injection. In vivo pharmacodynamic research showed that TP-Lipo@DMNs significantly reduced knee joint swelling and the level of inflammatory cytokines (TNF-α, IL-1ß, IL-6). Micro-CT and histological evaluation showed that TP-Lipo@DMNs effectively reduced cartilage destruction and alleviated OA symptoms. These results support that TP@Lipo@DMNs may be a promising option for OA treatment.

Photothermal-promoted multi-functional dual network polysaccharide hydrogel adhesive for infected and susceptible wound healing.

A low-cost wound dressing with efficient sterilization and exhibiting long-term antimicrobial activity is required for the absence of antibiotics, particularly for the wound healing of patients with chronic wounds or long-term activities under low sanitary conditions (e.g., battlefield and poverty-stricken areas). Here, a dual dynamic crosslinking hydrogel was introduced. The hydrogel was supported by gallic acid grafted chitosan and oxidized Bletilla striata polysaccharide as the scaffold and formed by two types of dynamic crosslinking: Schiff base, pyrogallol-Fe3+. It exhibited its adhesion, self-healing, good biocompatibility, great intrinsic antibacterial, and near-infrared photothermal conversion activity. In addition, the use of two types of polysaccharides, and the existence of the photothermal effect, making the hydrogel has the functions of accelerating gelation, degradation on-demand, and rapid sterilization. In brief, such cost-effective multifunctional hydrogel could support wound healing in patients prone to bacterial infection, and it has a promising application in the care of infected wounds.

CosG: A Graph-Based Contrastive Learning Method for Fact Verification.

Fact verification aims to verify the authenticity of a given claim based on the retrieved evidence from Wikipedia articles. Existing works mainly focus on enhancing the semantic representation of evidence, e.g., introducing the graph structure to model the evidence relation. However, previous methods can't well distinguish semantic-similar claims and evidences with distinct authenticity labels. In addition, the performances of graph-based models are limited by the over-smoothing problem of graph neural networks. To this end, we propose a graph-based contrastive learning method for fact verification abbreviated as CosG, which introduces a contrastive label-supervised task to help the encoder learn the discriminative representations for different-label claim-evidence pairs, as well as an unsupervised graph-contrast task, to alleviate the unique node features loss in the graph propagation. We conduct experiments on FEVER, a large benchmark dataset for fact verification. Experimental results show the superiority of our proposal against comparable baselines, especially for the claims that need multiple-evidences to verify. In addition, CosG presents better model robustness on the low-resource scenario.

3-Year Outcomes of the ULTIMATE Trial Comparing Intravascular Ultrasound Versus Angiography-Guided Drug-Eluting Stent Implantation.

OBJECTIVES: The aim of this study was to explore the difference in target vessel failure (TVF) 3 years after intravascular ultrasound (IVUS) guidance versus angiographic guidance among all comers undergoing second-generation drug-eluting stent (DES) implantation. BACKGROUND: The multicenter randomized ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions) trial showed a lower incidence of 1-year TVF after IVUS-guided DES implantation among all comers compared with angiographic guidance. However, the 3-year clinical outcomes of the ULTIMATE trial remain unknown. METHODS: A total of 1,448 all comers undergoing DES implantation who were randomly assigned to either IVUS guidance or angiographic guidance in the ULTIMATE trial were followed for 3 years. The primary endpoint was the risk for TVF at 3 years. The safety endpoint was definite or probable stent thrombosis (ST). RESULTS: At 3 years, TVF occurred in 47 patients (6.6%) in the IVUS-guided group and in 76 patients (10.7%) in the angiography-guided group (p = 0.01), driven mainly by the decrease in clinically driven target vessel revascularization (4.5% vs. 6.9%; p = 0.05). The rate of definite or probable ST was 0.1% in the IVUS-guided group and 1.1% in the angiography-guided group (p = 0.02). Notably, the IVUS-defined optimal procedure was associated with a significant reduction in 3-year TVF relative to that with the suboptimal procedure. CONCLUSIONS: IVUS-guided DES implantation was associated with significantly lower rates of TVF and ST during 3-year follow-up among all comers, particularly those who underwent the IVUS-defined optimal procedure compared with those with angiographic guidance. (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions; NCT02215915).

Novel probiotic-bound oxidized Bletilla striata polysaccharide-chitosan composite hydrogel.

As a new strategy for wound management, probiotics are highly sensitive to the external environment during use. In this study, an attempt is made to apply oxidized Bletilla striata polysaccharide (OBSP) hydrogel as a delivery system to put up a physical barrier to probiotics. Bletilla striata, as a famous traditional Chinese medicine, has been widely used for over 1500 years to promote wound healing. Firstly, probiotic-bound OBSP-Chitosan composite hydrogel (OBSP-CS-LP hydrogel) was prepared by a simple and environmentally friendly approach. Subsequently, the SEM image, swelling and rheological properties of the OBSP-CS-LP hydrogel were investigated. Notably, composite probiotics to wounds are an attractive novel intervention that significantly improves the antibacterial properties of the hydrogel and avoids the pitfalls of many antibiotic therapies. Furthermore, the full-thickness skin defect model in vivo indicated an outstanding wound healing efficacy. Therefore, OBSP-CS-LP hydrogel could be applied as a promising dressing in the wound healing.

Imaging endogenous HClO in atherosclerosis using a novel fast-response fluorescence probe.

A novel pyrene-based naked-eye colorimetric and fluorescent turn-on probe (S-ClO) was developed. Besides, imaging in living RAW264.7 cells, an arterial vessel inflammation nude mouse model and human serum using S-ClO indicates that S-ClO could serve as a potential tool for early diagnosing and monitoring inflammatory diseases.

Impact of intravascular ultrasound-guided drug-eluting stent implantation on patients with chronic kidney disease: Results from ULTIMATE trial.

OBJECTIVES: This study aimed to investigate the impacts of intravascular ultrasound (IVUS)-guided drug-eluting stent (DES) implantation on patients with chronic kidney disease (CKD) based on the ULTIMATE trial. BACKGROUND: IVUS-guided DES implantation improves clinical outcomes in complex lesions. However, routine IVUS guidance in patients with CKD remains controversial. METHODS: CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL min-1 1.73 m-2 . The primary end point was target vessel failure (TVF) at 12 months, including cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization. RESULTS: eGFR was available in 1,443 patients, of whom 723 were in the IVUS guidance group, and 720 were in the angiography guidance group. Finally, CKD was present in 349 (24.2%) patients. At 12 months, TVF in the CKD group was 7.2%, which was significantly higher than 3.2% in the non-CKD group (p = .001). Moreover, there were 25 TVFs in the CKD patients, with 7 (3.9%) TVFs in the IVUS group and 18 (10.7%) TVFs in the angiography group (hazard ratio [HR]: 0.35; 95% confidence interval [CI]: 0.15-0.84; p = .01), whereas 35 TVFs occurred in patients without CKD, with 14 (2.6%) TVFs in the IVUS group and 21 (3.8%) TVFs in the angiography group (HR: 0.67; 95% CI: 0.34-1.32; p = .25; p for interaction = .24). CONCLUSIONS: This study demonstrated that CKD patients undergoing DES implantations were associated with a higher risk of TVF at 12 months. More importantly, the risk of TVF in the CKD patients could be significantly decreased through IVUS guidance. CLINICAL TRIAL: NCT02215915.

Intravascular Ultrasound Versus Angiography-Guided Drug-Eluting Stent Implantation: The ULTIMATE Trial.

BACKGROUND: Intravascular ultrasound (IVUS)-guided drug-eluting stent (DES) implantation is associated with fewer major adverse cardiovascular events compared with angiography guidance for patients with individual lesion subset. However, the beneficial effect on major adverse cardiovascular event outcome of IVUS guidance over angiography guidance in all-comers who undergo DES implantation still remains understudied. OBJECTIVES: This study aimed to determine the benefits of IVUS guidance over angiography guidance during DES implantation in all-comer patients. METHODS: A total of 1,448 all-comer patients who required DES implantation were randomly assigned (1:1 ratio) to either an IVUS guidance or angiography guidance group. The primary endpoint was target-vessel failure (TVF) at 12 months, including cardiac death, target-vessel myocardial infarction, and clinically driven target-vessel revascularization (TVR). The procedure was defined as a success if all IVUS-defined optimal criteria were met. RESULTS: At 12 months follow-up, 60 TVFs (4.2%) occurred, with 21 (2.9%) in the IVUS group and 39 (5.4%) in the angiography group (hazard ratio [HR]: 0.530; 95% confidence interval [CI]: 0.312 to 0.901; p = 0.019). In the IVUS group, TVF was recorded in 1.6% of patients with successful procedures, compared with 4.4% in patients who failed to achieve all optimal criteria (HR: 0.349; 95% CI: 0.135 to 0.898; p = 0.029). The significant reduction of clinically driven target-lesion revascularization or definite stent thrombosis (HR: 0.407; 95% CI: 0.188 to 0.880; p = 0.018) based on lesion-level analysis by IVUS guidance was not achieved when the patient-level analysis was performed. CONCLUSIONS: The present study demonstrates that IVUS-guided DES implantation significantly improved clinical outcome in all-comers, particularly for patients who had an IVUS-defined optimal procedure, compared with angiography guidance. (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions [ULTIMATE]; NCT02215915).

Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) patients with early repolarization (ER) pattern are at higher risk of ventricular arrhythmia, yet the genetic background of this situation has not been well investigated. Here we report novel trigenic mutations detected in a Chinese family of obstructive HCM with ER and short QT syndrome (SQTS). METHODS: Proband and family members underwent detailed medical assessments. DNAs were extracted from peripheral blood leukocytes for genetic screening with next generation method. The functional characterization of the mutation was conducted in TSA201 cells with patch-clamp experiment. RESULTS: The proband was a 52-year-old male who had a ER pattern ECG in inferioral-lateral leads with atrioventricular block and QTc of 356 ms. He also suffered from severe left ventricular hypertrophy and dysfunction. Targeted sequencing revealed trigenic mutations: c.700G>A/p.E234K in DES, c.2966G>A/p.R989H in MYPN, and c.5918G>C/p.R1973P in CACNA1C. All mutations were also detected in his daughter with ER and mild myocardium hypertrophy. The CACNA1C-R1973P mutation caused significant reduction (68.4%) of ICa compared to CACNA1C-WT (n = 14 and 14, P < 0.05). The computer modeling showed that all 3 mutations were highly disease-causing. The proband received the CRT-D (cardiac resynchronizing therapy) implantation, which lowered the left ventricular outflow tract gradient (LVOTG, 124 mmHg pre vs. 27 mmHg post) and restored the LV function (LVEF 40% pre vs. 63% post). CONCLUSIONS: The study reveals a novel CACNA1C mutation underlying the unique ER pattern ECGs with SQTS. It also shows the rare trigenic mutations are the pathogenic substrates for the complicated clinical manifestation in HCM patients.