Immunogenicity and safety of boosting with a recombinant two-component SARS-CoV-2 vaccine: two randomized, parallel-controlled, phase 2 studies.

BACKGROUND: Recombinant protein vaccines are vital for broad protection against SARS-CoV-2 variants. This study assessed ReCOV as a booster in two Phase 2 trials. RESEARCH DESIGN AND METHODS: Study-1 involved subjects were randomized (1:1:1) to receive 20 µg ReCOV, 40 µg ReCOV, or an inactivated vaccine (COVILO®) in the United Arab Emirates. Study-2 participating individuals were randomized (1:1:1) to receive 20 µg ReCOV (pilot batch, ReCOV HA), 20 µg ReCOV (commercial batch, ReCOV TC), or 30 µg BNT162b2 (COMIRNATY®) in the Philippines. The primary immunogenicity objectives was to compare the geometric mean titer (GMT) and seroconversion rate (SCR) of neutralizing antibodies induced by one ReCOV booster dose with those of inactivated vaccine and BNT162b2, respectively, at 14 days post-booster. RESULTS: Heterologous ReCOV booster doses were safe and induced comparable immune responses to inactivated vaccines and BNT162b2 against Omicron variants and the prototype. They showed significant advantages in cross-neutralization against multiple SARS-CoV-2 variants, surpassing inactivated vaccines and BNT162b2, with good immune persistence. CONCLUSIONS: Heterologous ReCOV boosting was safe and effective, showing promise in combating COVID-19. The study highlights ReCOV's potential for enhanced protection, supported by strong cross-neutralization and immune persistence. CLINICAL TRIAL REGISTRATION: Study-1, www.clinicaltrials.gov, identifier is NCT05323435; Study-2, www.clinicaltrials.gov, identifier is NCT05084989.

Charge Transfer Complex-Enabled Synthesis of (Hetero)arylated m-Carboranes from m-Carborane Phosphonium Salts.

A photoinduced charge transfer complex (CTC)-enabled photoreduction of carborane phosphonium salts for the cage carbon (hetero)arylation of carboranes was developed. It offers a convenient approach for introducing a wide range of aryl and heteroaryl groups, such as pyrroles, thiophenes, indoles, thianaphthenes, benzofurans, pyridines, and benzenes, into carboranes. This strategy offers operational simplicity, mild reaction conditions, and a broad substrate scope, making it highly advantageous.

'Internet+' comprehensive nursing training course in the post-epidemic era-an exploration of the mixed teaching mode: a randomized trial.

Objective: To explore the effect of the application of the 'Internet+' nursing teaching mode on the comprehensive teaching 'Fundamentals of Nursing'. Trial design: Parallel design and convenient sampling were used to select vocational nursing students from the Nursing College of Capital Medical University. Methods: Selected students were randomly divided into two groups. The control group consisted of 30 students in Grade 2020 higher vocational nursing education (traditional teaching mode). The observation group consisted of 30 students in Grade 2021 higher vocational nursing education (Internet+ mixed teaching mode). Training assessment results, automatic learning ability, professional identity, and satisfaction were compared between the two groups. Results: Compared with the control group, the students in the observation group scored higher in the following operation practices: venous blood sampling, intradermal injection, cardiopulmonary resuscitation (CPR), sputum aspiration, and putting on and taking off robes (84.01 ± 0.87 vs. 92.14 ± 1.23; 91.41 ± 0.82 vs. 96.86 ± 0.27; 87.56 ± 0.31 vs. 93.91 ± 2.79; 88.11 ± 0.51 vs. 93.75 ± 0.29; and 82.29 ± 0.29 vs. 90.96 ± 0.34, respectively, with p < 0.05 for all scores). The total scores for autonomous learning ability and subjective satisfaction were also higher in the observation group compared with the control group (82.98 ± 4.72 vs. 93.17 ± 5.01 and 96.67% vs. 90.00%, respectively, with p < 0.05 for all scores). Conclusion: In the post-epidemic era, the 'Internet+ hybrid teaching mode' was applied to comprehensive nursing teaching. This changed the traditional education mode, which focuses only on professional knowledge. The 'Internet+' teaching mode results showed that the professional, ideological, and political courses exhibited the same value guidance, which improved students' independent learning ability, practical operation ability, professional identity, and satisfaction.

The positive effects of postbiotic (SWF concentration®) supplemented diet on skin mucus, liver, gut health, the structure and function of gut microbiota of common carp (Cyprinus carpio) fed with high-fat diet.

Postbiotics are an emerging research interest in recent years, which shows that metabolites, lysate extracts, cell wall components and even culture supernatants of probiotics can also exhibit significant prebiotic effects. In this study postbiotic stress worry free concentration® (SWFC) were prepared from the composition of culture supernatant of Cetobacterium somerae and Lactococcus lactis. The positive effects of SWFC supplemented diets on the growth performance, skin mucus, liver and gut health, and intestinal microbiota profile of Cyprinus carpio fed with high fat diets were investigated. 180 C. carpio with an average body weight of (3.01 ± 0.01) g were selected and randomly divided into three groups. They were fed with one of the three experimental diets supplemented with SWFC of 0 (control), 0.2 and 0.3 g/kg for 98 days, afterwards indexes were detected. The results revealed that, addition of SWFC had no significant effect on growth performance of C. carpio, while it can improve the health of the fish remarkably. In addition, SWFC improved mucosal C3, T-AOC, SOD activities, and decreased lipid peroxidation product MDA level, which were notably better than those in the control group (P < 0.05). In terms of the liver health systems, C. carpio fed on the diet supplemented with 0.2 g/kg of SWFC, showed significant improvement of the liver injured by HFD and reduce the contents of serum ALT and AST, and liver TAG (P < 0.05; P < 0.01). The expression of inflammation-related and lipid synthesis genes revealed that SWFC0.2 group could noteworthy enhance antioxidant capacity, reduced the expression of pro-inflammatory factors (TNF-α, IL-1ß) and lipid synthesis genes (ACC, FAS, PPAR-ß, PPAR-γ), and up-regulated the expression of anti-inflammatory factors (TGF-ß). Additionally, intestinal morphology arose inflammatory cell infiltration, while intestinal integrity was better in SWFC groups compared with the control. Furthermore, the contents of serum LPS and LBP were remarkably lower in the SWFC0.2 group compared with the control (P < 0.01). The mRNA expression of genes related to gut health indicated that SWFC supplementation noteworthy up-regulated the expression of antioxidant (Nrf2, CAT, GPX), immune (Hepcidin, IL-10) and tight junction protein-related (ZO-1, Occludin). Simultaneously, the results of GF-zebrafish showed that the relative expression of anti-inflammatory genes (IL-1ß, TGF-ß) and antioxidant related genes (Nrf2, HO-1) were significantly up-regulated in SWFC groups. Data on intestinal microbiota profile verified that, at the phylum level, the abundance of Fusobacteria was remarkably elevated in the SWFC groups (P < 0.05), whereas the abundance of Firmicutes was declined noteworthy in SWFC0.2 and SWFC0.3 compared to the control group (P < 0.05; P < 0.01) respectively. At the genus level, the abundance of Cetobacterium in the SWFC groups were notably higher than those in the control group (P < 0.05), while the Vibrio content in the SWFC groups was significantly decreased (P < 0.05). PCoA result indicated that the intestinal microflora of SWFC0.2 group was abundant and diverse. Our results elucidate that dietary supplementation of SWFC protects C. carpio from HFD induced inflammatory response and oxidative stress, ameliorate skin mucus, liver and gut health, and improve the gut microbiota balance. Therefore, SWFC could be considered as an improving-fish-health additive, when supplemented to aquatic animal feed. With regards to how SWFC regulates the immunity and inflammatory responses and which signal transductions are involved remains unclear and more scientific evidences are needed to address these issues.

A dendrite-free and anticaustic Zn anode enabled by high current-induced reconstruction of the electrical double layer.

Aqueous Zn-based batteries deliver thousands of cycles at high rates but poor recyclability at low rates. Herein, we reveal that this illogical phenomenon is attributed to the reconstructed electrode/electrolyte interface at high rates, wherein the condensed electrical double layer (EDL) and the tightly absorbed Zn2+ ions on the Zn electrode surface afford compact and corrosion-resistant Zn deposits.

Effect of Probiotic Lactobacillus plantarum on Streptococcus mutans and Candida albicans Clinical Isolates from Children with Early Childhood Caries.

Probiotics interfere with pathogenic microorganisms or reinstate the natural microbiome. Streptococcus mutans and Candida albicans are well-known emerging pathogenic bacteria/fungi for dental caries. In this study, three probiotic Lactobacilli strains (Lactobacillus plantarum 8014, L. plantarum 14917, and Lactobacillus salivarius 11741) were tested on S. mutans and C. albicans clinical isolates using a multispecies biofilm model simulating clinical cariogenic conditions. The ten pairs of clinical isolates of S. mutans and C. albicans were obtained from children with severe early childhood caries. Our study findings show a remarkable inhibitory effect of L. plantarum 14917 on S. mutans and C. albicans clinical isolates, resulting in significantly reduced growth of S. mutans and C. albicans, a compromised biofilm structure with a significantly smaller microbial and extracellular matrix and a less virulent microcolony structure. FurTre, plantaricin, an antimicrobial peptide produced by L. plantarum, inhibited the growth of S. mutans and C. albicans. The mechanistic assessment indicated that L. plantarum 14917 had a positive inhibitory impact on the expression of S. mutans and C. albicans virulence genes and virulent structure, such as C. albicans hypha formation. Future utilization of L. plantarum 14917 and/or its antimicrobial peptide plantaricin could lead to a new paradigm shift in dental caries prevention.

Causes of Death in Long-Term Nasopharyngeal Carcinoma Survivors.

Purpose: To assess the causes of death (COD) and long-term survival after nasopharyngeal carcinoma (NPC) diagnosis. Methods: Using linked data from the Surveillance, Epidemiology, and End Results program, patients with NPC diagnosed from 1990 to 2010 and followed up >5 years were identified. Chi-squared test, the Kaplan-Meier method, and the Cox proportional hazard model were used for analyses. Results: Among the 3,036 long-term NPC survivors, 1,432 survived for >5-10 years and 1,604 survived for >10 years. The most common COD was primary NPC (36.9%), followed by other causes (28.7%), other cancers (15.3%), cardiac disease (12.9%), and non-malignant pulmonary disease (6.2%). With a median follow-up of 125 months, deaths from NPC decreased with increasing time from diagnosis, while death because of cardiac disease and other causes increased. In those aged <50 years, death due to NPC remained the main COD over time, while cardiopulmonary disease-related death was the leading COD in patients aged ≥50 years. In White patients, death due to NPC decreased, and death due to cardiac disease increased over time. Death from NPC remained significant in Black and Asian patients even 15 years after the diagnosis of NPC, while death due to cardiac disease significantly increased after 9 years of diagnosis in Black patients. Multivariate analyses showed that the independent factors associated with inferior NPC-specific survival were older age, Asians, American Indian/Alaska Native, regional stage, distant stage, and diagnosis in the early years. Conclusions: The probability of death from primary NPC remains significant even 15 years after the NPC diagnosis. Our study advocates continued surveillance for NPC survivors beyond the traditional 5 years. Individualized follow-up strategies are required for patients with NPC of different ages and races.

Quenching the Macroporous Collapse of Polyelectrolyte Multilayer Films for Repeated Drug Loading.

Macroporous structures can be developed within polyelectrolyte multilayer films for efficient drug loading, but these structures tend to collapse or fracture during conventional drying procedures. Herein, a facile dehydrating method for macroporous polyelectrolyte multilayer films is proposed using solvent exchange to ethanol and then spontaneous evaporation. During these processes, the collapse of the macroporous structures can be effectively avoided, which can be ascribed to a combined effect of two factors. On one hand, capillary pressure during ethanol evaporation is relatively small since the surface tension of ethanol is much lower than that of water. On the other hand, solvent exchange suppresses the interdiffusion of polyelectrolytes and substantially increases the mechanical strength of the macroporous films, more than three orders of magnitude, making the pore walls highly tolerant of the capillary pressure. The stability of macroporous polyelectrolyte films to ethanol enables the repeated wicking from the ethanol solution of drugs, leading to a higher loading beyond previous studies. Such a high loading is favorable for the long-term release of drugs from the surfaces of modified substrates and maintaining a local drug concentration above the minimum effective concentration.

Lactobacillus plantarum Disrupts S. mutans-C. albicans Cross-Kingdom Biofilms.

Dental caries, an ecological dysbiosis of oral microflora, initiates from the virulent biofilms formed on tooth surfaces where cariogenic microorganisms metabolize dietary carbohydrates, producing acid that demineralizes tooth enamel. Forming cariogenic biofilms, Streptococcus mutans and Candida albicans are well-recognized and emerging pathogens for dental caries. Recently, probiotics have demonstrated their potential in treating biofilm-related diseases, including caries. However, limited studies have assessed their effect on cariogenic bacteria-fungi cross-kingdom biofilm formation and their underlying interactions. Here, we assessed the effect of four probiotic Lactobacillus strains (Lactobacillus rhamnosus ATCC 2836, Lactobacillus plantarum ATCC 8014, Lactobacillus plantarum ATCC 14917, and Lactobacillus salivarius ATCC 11741) on S. mutans and C. albicans using a comprehensive multispecies biofilm model that mimicked high caries risk clinical conditions. Among the tested probiotic species, L. plantarum demonstrated superior inhibition on the growth of C. albicans and S. mutans, disruption of virulent biofilm formation with reduced bacteria and exopolysaccharide (EPS) components, and formation of virulent microcolonies structures. Transcriptome analysis (RNA sequencing) further revealed disruption of S. mutans and C. albicans cross-kingdom interactions with added L. plantarum. Genes of S. mutans and C. albicans involved in metabolic pathways (e.g., EPS formation, carbohydrate metabolism, glycan biosynthesis, and metabolism) were significantly downregulated. More significantly, genes related to C. albicans resistance to antifungal medication (ERG4), fungal cell wall chitin remodeling (CHT2), and resistance to oxidative stress (CAT1) were also significantly downregulated. In contrast, Lactobacillus genes plnD, plnG, and plnN that contribute to antimicrobial peptide plantaricin production were significantly upregulated. Our novel study findings support further assessment of the potential role of probiotic L. plantarum for cariogenic biofilm control.

Influences of dietary Eucommia ulmoides leaf extract on the hepatic lipid metabolism, inflammation response, intestinal antioxidant capacity, intestinal microbiota, and disease resistance of the channel catfish (Ictalurus punctatus).

The purpose of the study was to investigate the effects of Eucommia ulmoides leaf extract (ELE) on the common occurrence of liver steatosis, chronic inflammation, oxidative stress, disturbance of gut microbiota, and disease susceptibility in high-fat diet-fed channel catfish. Channel catfish fed three diets, including a high-fat diet (11% crude fat) and ELE-supplemented diets containing 1‰ or 2‰ ELE for 4 weeks. The results showed the contents of liver triacylglycerol of 1‰ and 2‰ ELE groups were reduced, and ELE treatments decreased the expression of lipogenesis related genes (srebp-1c, pparγ, and acc-1), and increased the expression of lipolysis related genes (pparα). In addition, the supplementation of ELE improved the inflammatory response of the liver and intestine. ELE could improve the destruction of intestinal morphology structure and increase the expression level of hif-1a and tight junction proteins (Occludin, Claudin2, Claudin15). 2‰ ELE significantly enhanced the antioxidant capacity of intestine by increasing the activity of SOD enzyme. Moreover, the supplement of ELE significantly increased the abundance of Cetobacterium and Romboutsia (p < 0.05). Compared with the control group, the expression of immune factor nf-κb had a significant decrease, and il-1ß showed a tendency to decrease in the ELE supplement groups after pathogenic bacteria challenge. In conclusion, the ELE alleviated fatty liver disease and inflammation response, improved the oxidative capacity and physiological structure of intestine, and improved the structure of intestinal microbiota and disease resistance in HFD-fed channel catfish.

Development and internal validation of a Wasp Sting Severity Score to assess severity and indicate blood purification in persons with Asian wasp stings.

BACKGROUND: In recent years, the incidence of wasp sting has increased annually in China. Organ damage and high mortality due to mass wasp envenomation remain major challenges. Timely and appropriate medical intervention can improve survival. However, there are currently no normalized tools for early assessment of severity. METHODS: The clinical data of wasp sting patients hospitalized from 2011 to 2019 were used as a training set. Logistic regression was used to explore major risk factors for the development of a severe case of wasp sting (SC). The Wasp Sting Severity Score (WSS) was determined considering these risk factors to identify SCs and was tested in a validation dataset that was prospectively collected in 2020. RESULTS: The data of 1131 wasp sting patients from 2011 to 2019 were included in the training set. Logistic regression analysis showed that tea-colored urine, number of stings, and lactate dehydrogenase and total bilirubin levels were risk factors for developing an SC. The WSS was developed considering these four risk factors, and the total possible WSS was 20 points. The WSS was tested using the validation dataset, comprising the data of 153 patients, in 2020, and we found that a WSS ≥3 points was an important indication for blood purification, with a sensitivity of 71.9%, specificity of 92.6% and an area under the curve of 0.918 (95% confidence interval 0.873-0.962). Among patients with more than 30 stings, mortality in those who underwent plasma exchange (PE) within 24 h after admission was significantly lower than that in those who did not receive PE treatment (14.3% versus 46.9%, P = 0.003). However, continuous venovenous hemofiltration (CVVH) (P = 0.317) and hemoperfusion (HP) (P = 0.869) did not significantly reduce mortality. CONCLUSIONS: Patients with WSS scores ≥3 should be considered for blood purification as early as possible in addition to routine treatment. In addition, PE is better than CVVH and HP at reducing mortality in patients suffering from severe wasp stings.

Macrophage-tumor chimeric exosomes accumulate in lymph node and tumor to activate the immune response and the tumor microenvironment.

Despite multiple immunotherapeutic technologies that achieve potent T cell activation, effector T cells still lack efficiency because of the highly immunosuppressive conditions in the tumor microenvironment. Inspired by recent advances in nano-sized secreted vesicles known as exosomes as therapeutic agents and research revealing that circulating cancer cells have a "homing" capacity to return to the main tumor sites, we generated macrophage-tumor hybrid cells. We introduced nuclei isolated from tumor cells into activated M1-like macrophages to produce chimeric exosomes (aMT-exos). The aMT-exos were able to accumulate in both lymph nodes and diverse tumors of xenograft mice. They entered lymph nodes and primed T cell activation in both the classical antigen-presenting cell­induced immunostimulatory manner and a unique "direct exosome interaction" manner. aMT-exos also had strong "homing behavior" to tumor sites, where they ameliorated immunosuppression. They were effective in inducing tumor regression and extending survival in primary mouse models of lymphoma and breast and melanoma cancers. In addition, when combined with anti­programmed death 1 (a-PD1) treatment, aMT-exos were able to extend survival of metastatic and postsurgical tumor recurrence mouse models. Such a coactivation of the immune response and the tumor microenvironment enabled aMT-exos to confer efficient inhibition of primary tumors, tumor metastases, and postoperative tumor recurrence for personalized immunotherapy, which warrants further exploration in the clinical setting.

Prognostic Value of an Autophagy-Related Five-Gene Signature for Lower-Grade Glioma Patients.

Background: Molecular characteristics can be good indicators of tumor prognosis and have been introduced into the classification of gliomas. The prognosis of patients with newly classified lower-grade gliomas (LGGs, including grade 2 and grade 3 gliomas) is highly heterogeneous, and new molecular markers are urgently needed. Methods: Autophagy related genes (ATGs) were obtained from Human Autophagy Database (HADb). From the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), gene expression profiles including ATG expression information and patient clinical data were downloaded. Cox regression analysis, receiver operating characteristic (ROC) analysis, Kaplan-Meier analysis, random survival forest algorithm (RSFVH) and stratification analysis were performed. Results: Through univariate Cox regression analysis, we found a total of 127 ATGs associated with the prognosis of LGG patients from TCGA dataset and a total of 131 survival-related ATGs from CGGA dataset. Using TCGA dataset as the training group (n = 524), we constructed a five-ATG signature (including BAG1, BID, MAP1LC3C, NRG3, PTK6), which could divide LGG patients into two risk groups with significantly different overall survival (Log Rank P < 0.001). Then we confirmed in the independent CGGA dataset that the five-ATG signature had the ability to predict prognosis (n = 431, Log Rank P < 0.001). We further discovered that the predictive ability of the five-ATG signature was better than the existing clinical indicators and IDH mutation status. In addition, the five-ATG signature could further classify patients after receiving radiotherapy or chemotherapy into groups with different prognosis. Conclusions: We identified a five-ATG signature that could be a reliable prognostic marker and might be therapeutic targets for autophagy therapy for LGG patients.

Utility of Natural Sitting Lateral Radiograph in the Diagnosis of Segmental Instability for Patients with Degenerative Lumbar Spondylolisthesis.

BACKGROUND: Segmental instability in patients with degenerative lumbar spondylolisthesis is an indication for surgical intervention. The most common method to evaluate segmental mobility is lumbar standing flexion-extension radiographs. Meanwhile, other simple radiographs, such as standing upright radiograph, a supine sagittal magnetic resonance imaging (MRI) or supine lateral radiograph, or a slump or natural sitting lateral radiograph, have been reported to diagnose segmental instability. However, those common posture radiographs have not been well characterized in one group of patients. Therefore, we measured slip percentage in a group of patients with degenerative lumbar spondylolisthesis using radiographs of patients in standing upright, natural sitting, standing flexion, and standing extension positions as well as supine MRI. QUESTIONS/PURPOSES: We asked: (1) Does the natural sitting radiograph have a larger slip percentage than the standing upright or standing flexion radiograph? (2) Does the supine sagittal MRI reveal a lower slip percentage than the standing extension radiograph? (3) Does the combination of the natural sitting radiograph and the supine sagittal MRI have a higher translational range of motion (ROM) and positive detection rate of translational instability than traditional flexion-extension mobility using translational instability criteria of greater than or equal to 8%? METHODS: We retrospectively performed a study of 62 patients (18 men and 44 women) with symptomatic degenerative lumbar spondylolisthesis at L4 who planned to undergo a surgical intervention at our institution between September 2018 and June 2019. Each patient underwent radiography in the standing upright, standing flexion, standing extension, and natural sitting positions, as well as MRI in the supine position. The slip percentage was measured three times by single observer on these five radiographs using Meyerding's technique (intraclass correlation coefficient 0.88 [95% CI 0.86 to 0.90]). Translational ROM was calculated by absolute values of difference between two radiograph positions. Based on the results of comparison of slip percentage and translational ROM, we developed the diagnostic algorithm to evaluate segmental instability. Also, the positive rate of translational instability using our diagnostic algorithms was compared with traditional flexion-extension radiographs. RESULTS: The natural sitting radiograph revealed a larger mean slip percentage than the standing upright radiograph (21% ± 7.4% versus 17.7% ± 8.2%; p < 0.001) and the standing flexion radiograph (21% ±7.4% versus 18% ± 8.4%; p = 0.002). The supine sagittal MRI revealed a lower slip percentage than the standing extension radiograph (95% CI 0.49% to 2.8%; p = 0.006). The combination of natural sitting radiograph and the supine sagittal MRI had higher translational ROM than the standing flexion and extension radiographs (10% ± 4.8% versus 5.4% ± 3.7%; p < 0.001). More patients were diagnosed with translational instability using the combination of natural sitting radiograph and supine sagittal MRI than the standing flexion and extension radiographs (61% [38 of 62] versus 19% [12 of 62]; odds ratio 3.9; p < 0.001). CONCLUSION: Our results indicate that a sitting radiograph reveals high slip percentage, and supine sagittal MRI demonstrated a reduction in anterolisthesis. The combination of natural sitting and supine sagittal MRI was suitable to the traditional flexion-extension modality for assessing translational instability in patients with degenerative lumbar spondylolisthesis. LEVEL OF EVIDENCE: Level III, diagnostic study.

Choice of Nanovaccine Delivery Mode Has Profound Impacts on the Intralymph Node Spatiotemporal Distribution and Immunotherapy Efficacy.

Nanovaccines have attracted booming interests in vaccinology studies, but the profound impacts of their delivery mode on immune response remain unrealized. Herein, immunostimulatory CpG-modified tumor-derived nanovesicles (CNVs) are used as a nanovaccine testbed to initially evaluate the impacts of three distinct delivery modes, including mono-pulse CNVs, staggered-pulse CNVs, and gel-confined CNVs. Fundamentally, delivery mode has enormous impacts on the immunomodulatory effects, altering the spatiotemporal distribution of nanovaccine residence and dendritic cell-T cell interaction in lymph nodes, and finally affecting subsequent T cell-mediated immune performance. As a result, the gel-confined delivery mode offers the best therapeutic performance in multiple tumor models. When extending evaluation to examine how the various delivery modes impact the performance of liposome-based nanovaccines, similar trends in intralymph node distribution and antitumor effect are observed. This work provides a strong empirical foundation that nanovaccine researchers should position delivery mode near the top of their considerations for the experimental design, which should speed up nanovaccine development and facilitate efficient selection of appropriate delivery modes in the clinic.

Biomineralized Bacterial Outer Membrane Vesicles Potentiate Safe and Efficient Tumor Microenvironment Reprogramming for Anticancer Therapy.

The highly immunosuppressive tumor microenvironment (TME) in solid tumors often dampens the efficacy of immunotherapy. In this study, bacterial outer membrane vesicles (OMVs) are demonstrated as powerful immunostimulants for TME reprogramming. To overcome the obstacles of antibody-dependent clearance and high toxicity induced by OMVs upon intravenous injection (a classic clinically relevant delivery mode), calcium phosphate (CaP) shells are employed to cover the surface of OMVs, which enables potent OMV-based TME reprograming without side effects. Meanwhile, the pH-sensitive CaP shells facilitate the neutralization of acidic TME, leading to highly beneficial M2-to-M1 polarization of macrophages for improved antitumor effect. Moreover, the outer shells can be integrated with functional components like folic acid or photosensitizer agents, which facilitates the use of the OMV-based platform in combination therapies for a synergic therapeutic effect.

Biosynthesis of Self-Assembled Proteinaceous Nanoparticles for Vaccination.

Recent years have seen enormous advances in nanovaccines for both prophylactic and therapeutic applications, but most of these technologies employ chemical or hybrid semi-biosynthetic production methods. Thus, production of nanovaccines has to date failed to exploit biology-only processes like complex sequential post-translational biochemical modifications and scalability, limiting the realization of the initial promise for offering major performance advantages and improved therapeutic outcomes over conventional vaccines. A Nano-B5 platform for in vivo production of fully protein-based, self-assembling, stable nanovaccines bearing diverse antigens including peptides and polysaccharides is presented here. Combined with the self-assembly capacities of pentamer domains from the bacterial AB5 toxin and unnatural trimer peptides, diverse nanovaccine structures can be produced in common Escherichia coli strains and in attenuated pathogenic strains. Notably, the chassis of these nanovaccines functions as an immunostimulant. After showing excellent lymph node targeting and immunoresponse elicitation and safety performance in both mouse and monkey models, the strong prophylactic effects of these nanovaccines against infection, as well as their efficient therapeutic effects against tumors are further demonstrated. Thus, the Nano-B5 platform can efficiently combine diverse modular components and antigen cargos to efficiently generate a potentially very large diversity of nanovaccine structures using many bacterial species.

Self-healing microcapsules synergetically modulate immunization microenvironments for potent cancer vaccination.

Therapeutic cancer vaccines that harness the immune system to reject cancer cells have shown great promise for cancer treatment. Although a wave of efforts have spurred to improve the therapeutic effect, unfavorable immunization microenvironment along with a complicated preparation process and frequent vaccinations substantially compromise the performance. Here, we report a novel microcapsule-based formulation for high-performance cancer vaccinations. The special self-healing feature provides a mild and efficient paradigm for antigen microencapsulation. After vaccination, these microcapsules create a favorable immunization microenvironment in situ, wherein antigen release kinetics, recruited cell behavior, and acid surrounding work in a synergetic manner. In this case, we can effectively increase the antigen utilization, improve the antigen presentation, and activate antigen presenting cells. As a result, effective T cell response, potent tumor inhibition, antimetastatic effects, and prevention of postsurgical recurrence are achieved with various types of antigens, while neoantigen was encapsuled and evaluated in different tumor models.

[Encircling needling is superior to "Bangci"(focal center-side needling) in promoting wound healing in diabetic mice].

OBJECTIVE: To compare the therapeutic effects of "Bangci"(focal center-side needling) and encircling needling in promoting skin wound healing and local blood perfusion in diabetic mice. METHODS: Thirty-two male C57BL/6N mice were randomized into normal, diabetic model, focal center-side needling and encircling needling groups (n=8 in each group). The skin wound model was prepared by cutting a piece of full-thickness skin at the mouse's back by using a puncher. One hour after modeling, two acupuncture needles were respectively inserted into the center of the wound and the spot at the normal skin about 0.5 cm away from the edge of the wound for mice of the focal center-side needling group, followed by EA (0.5 mA, 0.5 Hz) for 30 min. For mice of the encircling needling group, 4 acupuncture needles were respectively inserted into the upper, lower, left and right normal marginal skin around the wound, followed by EA stimulation with the same parameters as those of the center-side needling group. The wound conditions, diameter and area of the wound were monitored, and the wound blood perfusion volume was measured by using a laser speckle flowmeter. RESULTS: The wound shrinkage rates were significantly higher at the time-points of 3, 5, 7, 9 and 11 d after modeling in both focal center-side needling and encircling needling groups than in the model group (P<0.05), and on day 3, 5, 7 and 9 in the encircling needling group than in the focal center-side needling group (P<0.05). The wound healing time was obviously earlier in both focal center-side needling and encircling needling groups than in the model group (P<0.05), and in the encircling needling group than in the focal center-side needling group (P<0.05). Following modeling, the volume of wound blood perfusion was considerably higher from day 1 to 9 and markedly lower on day 11 in the model group than in the normal group (P<0.01), and after the intervention, the blood perfusion volume was considerably decreased on day 3, 5, 7 and 9 in both the focal center-side needling and encircling needling groups(P<0.05, P<0.01), and obviously increased on day 11 in the encircling needling group relevant to the model group (P<0.01).Comparison between post- and pre-EA stimulation showed that the immediate blood perfusion volume was significantly increased from day 1 to 11 after EA stimulation in both the focal center-side needling and encircling needling groups (P<0.01, P<0.05). The therapeutic effect of the encircling needling group was significantly superior to that of the focal center-side needling group in lowering blood perfusion volume from day 3 to 7, and in increasing blood perfusion volume on day 9 and 11 (P<0.01). Under the naked eyes, the conditions of exudation and inflammatory reaction, and the scar and granulation tissue were relatively milder and better respectively in both the center-side needling and encircling needling groups than in the model group. CONCLUSION: Both focal center-side needling and encircling needling can promote the skin wound healing by increasing the blood perfusion in diabetic mice, and the therapeutic effect of the encircling needling method was significantly superior to that of the focal center-side needling method.

How does sagittal spinopelvic alignment of lumbar multisegmental spondylolysis differ from monosegmental spondylolysis?

OBJECTIVE: The aim of this study was to investigate sagittal alignment and compensatory mechanisms in patients with monosegmental spondylolysis (mono_lysis) and multisegmental spondylolysis (multi_lysis). METHODS: A total of 453 adult patients treated for symptomatic low-grade spondylolytic spondylolisthesis were retrospectively studied at a single center. Patients were divided into 2 subgroups, the mono_lysis group and the multi_lysis group, based on the number of spondylolysis segments. A total of 158 asymptomatic healthy volunteers were enrolled in this study as the control group. Radiographic parameters measured on standing sagittal radiographs and the ratios of L4-S1 segmental lordosis (SL) to lumbar lordosis (L4-S1 SL/LL) and pelvic tilt to pelvic incidence (PT/PI) were compared between all experimental groups. RESULTS: There were 51 patients (11.3%) with a diagnosis of multi_lysis in the spondylolysis group. When compared with the control group, the spondylolysis group exhibited larger PI (p < 0.001), PT (p < 0.001), LL (p < 0.001), and L4-S1 SL (p = 0.025) and a smaller L4-S1 SL/LL ratio (p < 0.001). When analyzing the specific spondylolysis subgroups, there were no significant differences in PI, but the multi_lysis group had a higher L5 incidence (p = 0.004), PT (p = 0.018), and PT/PI ratio (p = 0.039). The multi_lysis group also had a smaller L4-S1 SL/LL ratio (p = 0.012) and greater sagittal vertical axis (p < 0.001). CONCLUSIONS: A high-PI spinopelvic pattern was involved in the development of spondylolytic spondylolisthesis, and a larger L5 incidence might be associated with the occurrence of consecutive multi_lysis. Unlike patients with mono_lysis, individuals with multi_lysis were characterized by an anterior trunk, insufficiency of L4-S1 SL, and pelvic retroversion.