Smart Phototheranostics based on Carbon Nanohorns for Precise Imaging-Guided Post-PDT toward Residual Tumor Cells after Initial Phototherapy.

As promising photonic material, phototheranostics can be activated in the laser irradiation range of tumor with sensitivity and spatiotemporal precision. However, it is difficult to completely eradicate solid tumors due to their irregularity and limited laser irradiation area. Herein, multi-stimulus responsive HA-Ce6@SWNHs were constructed with single-walled carbon nanohorns (SWNHs) and chlorine e6 (Ce6) modified hyaluronic acid (HA) via non-covalent binding. This SWNHs-based phototheranostics not only exhibited water dispersion but also could target tumor and be activated by near-infrared light for photodynamic therapy (PDT) and photothermal therapy (PTT). Additionally, HA-Ce6@SWNHs could be degraded by hyaluronidase in residual tumor cells, causing HA-Ce6 to fall off the SWNHs surfaces to restore autofluorescence, thus precisely guiding the programmed photodynamic treatments for residual tumor cells after the initial phototherapy. Thus, this work provides a rationally designed multiple-stimulus-response strategy to develop smart SWNHs-based phototheranostics for precise PDT/PTT and post-treatment imaging-guided PDT of residual tumor cells.

Hydrophilic Silica Nanoparticles in O/W Emulsion: Insights from Molecular Dynamics Simulation.

Previous studies have been carried out on the effect of silica nanoparticles (SNPs) on the stability of oil-water emulsions. However, the combining configuration of SNPs and oil droplets at the molecular level and the effect of SNP content on the coalescence behavior of oil droplets cannot be obtained through experiments. In this paper, molecular dynamics (MD) simulation was performed to investigate the adsorption configuration of hydrophilic SNPs in an O/W emulsion system, and the effect of adsorption of SNPs on coalescence of oil droplets. The simulation results showed: (i) SNPs adsorbed on the surface of oil droplets, and excessive SNPs self-aggregated and connected by hydrogen bonds. (ii) Partially hydrophilic asphaltene and resin molecules formed adsorption configurations with SNPs, which changed the distribution of oil droplet components. Furthermore, compared with hydrophobic asphaltene, the hydrophilic asphaltene was easier to combine with SNPs. (iii) SNPs would extend the oil droplet coalescence time, and the π-π stacking structures were formed between asphaltene and asphaltene or resin molecules to enhance the connection between oil droplets during the oil droplet contact process. (iv) Enough SNPs tightly wrapped around the oil droplet, similar to the formation of a rigid film on the surface of an oil droplet, which hindered the contact and coalescence of components between oil droplets.

Immunogenicity and safety of an inactivated COVID-19 vaccine (CoronaVac®) co-administered with an inactivated enterovirus type 71 vaccine (Inlive®): A phase 4, randomized, controlled trial.

TRIAL REGISTRATION NUMBER: NCT04993365 (ClinicalTrials.gov).

Efficacy, immunogenicity and safety of CoronaVac® in children and adolescents aged 6 months to 17 years: a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial.

Safe and effective vaccines against COVID-19 for children and adolescents are needed. This international multicenter, randomized, double-blind, placebo-controlled, phase III clinical trial assessed the efficacy, immunogenicity, and safety of CoronaVac® in children and adolescents (NCT04992260). The study was carried out in Chile, South Africa, Malaysia, and the Philippines. The enrollment ran from September 10, 2021 to March 25, 2022. For efficacy assessment, the median follow-up duration from 14 days after the second dose was 169 days. A total of 11,349 subjects were enrolled. Two 3-µg injections of CoronaVac® or placebo were given 28 days apart. The primary endpoint was the efficacy of the CoronaVac®. The secondary endpoints were the immunogenicity and safety. The vaccine efficacy was 21.02% (95% CI: 1.65, 36.67). The level of neutralizing antibody in the vaccine group was significantly higher than that in the placebo group (GMT: 390.80 vs. 62.20, P <0.0001). Most adverse reactions were mild or moderate. All the severe adverse events were determined to be unrelated to the investigational products. In conclusion, in the Omicron-dominate period, a two-dose schedule of 3 µg CoronaVac® was found to be safe and immunogenic, and showed potential against symptomatic COVID-19 in healthy children and adolescents.

Algorithm of automatic identification of diabetic retinopathy foci based on ultra-widefield scanning laser ophthalmoscopy.

AIM: To propose an algorithm for automatic detection of diabetic retinopathy (DR) lesions based on ultra-widefield scanning laser ophthalmoscopy (SLO). METHODS: The algorithm utilized the FasterRCNN (Faster Regions with CNN features)+ResNet50 (Residua Network 50)+FPN (Feature Pyramid Networks) method for detecting hemorrhagic spots, cotton wool spots, exudates, and microaneurysms in DR ultra-widefield SLO. Subimage segmentation combined with a deeper residual network FasterRCNN+ResNet50 was employed for feature extraction to enhance intelligent learning rate. Feature fusion was carried out by the feature pyramid network FPN, which significantly improved lesion detection rates in SLO fundus images. RESULTS: By analyzing 1076 ultra-widefield SLO images provided by our hospital, with a resolution of 2600×2048 dpi, the accuracy rates for hemorrhagic spots, cotton wool spots, exudates, and microaneurysms were found to be 87.23%, 83.57%, 86.75%, and 54.94%, respectively. CONCLUSION: The proposed algorithm demonstrates intelligent detection of DR lesions in ultra-widefield SLO, providing significant advantages over traditional fundus color imaging intelligent diagnosis algorithms.

Warthin-like papillary renal cell carcinoma: A case report.

BACKGROUND: Warthin-like papillary renal cell carcinoma (WPRCC) has been described as a rare pathological subtype of papillary renal cell carcinoma in the 2022 World Health Organization Classification of the Urinary and Male Reproductive System. Herein we report a case of WPRCC in the left kidney. CASE SUMMARY: Physical examination of a previously healthy 47-year-old woman revealed a lump in her left kidney, 4.5 cm × 3.5 cm × 3.5 cm in size. Based on the clinical information, imaging data, histmorphological features, and immunohistochemistry results, the pathological diagnosis was WPRCC in left kidney. CONCLUSION: Resection of the mass in the left kidney was performed and her postoperative course was uneventful.

Molecular insights into the uptake of SiO2 nanoparticles on phospholipid membrane: Effect of surface properties and particle size.

Silica (SiO2) nanoparticles (NPs) have attracted much attention due to the potential for a wide range of applications and they have been confirmed to be hazardous to humans. Partitioning to phospholipid bilayers is an important way for their bioaccumulation. However, the detailed mechanism of SiO2 NPs uptake by membrane phospholipids remains uncertain. In this work, molecular dynamics (MD) simulations were employed to study the uptake process of SiO2 NPs into DPPC bilayers. Results show that these SiO2 NPs uptake onto DPPC bilayer surface is favorable from the viewpoint of thermodynamics. During the uptake process, the SiO2 NP needed to adjust the angle of interaction with the DPPC surface until the most stable adsorption configuration was reached. After incorporating into DPPC bilayers, the interaction between PO4- group and SiO2 particle is stronger than -N+(CH3)3 group and SiO2. Small SiO2 NP was found to adsorb to the surface of DPPC bilayer without disturbing the morphology or membrane. In contract, bioaccumulation of large SiO2 NP to DPPC induced a strong local membrane deformation. In addition, the effect of SiO2 NP surface functionalization on its interaction with DPPC was also investigated. This molecular-level study reports a complete description of the interaction between SiO2 NPs and DPPC bilayer, aiming to provide some insights for the further work on the bioaccumulation and hemolytic activity of SiO2 NPs.

A Novel circRNA hsa_circRNA_002178 as a Diagnostic Marker in Hepatocellular Carcinoma Enhances Cell Proliferation, Invasion, and Tumor Growth by Stabilizing SRSF1 Expression.

Background: Previous research studies have shown that the elevation of circular RNA (circRNA), hsa_circRNA_002178, was associated with the poor prognosis of breast cancer and colorectal cancer, while its molecular mechanisms underlying the effects on hepatocellular carcinoma (HCC) are still elusive. Methods: The microarray dataset GSE97332 was obtained from the Gene Expression Omnibus (GEO) database and calculated by using the GEO2R tool to identify differentially expressed circRNAs. Differentially expressed hsa_circRNA_002178, in 7 HCC tissue samples and paracancerous tissues, as well as in HCC cell lines and normal hepatocytes, was checked by RT-qPCR. Cell proliferation, invasion, migration, and epithelial-to-mesenchymal transition (EMT)-related proteins were tested in hsa_circRNA_002178-overexpressed or hsa_circRNA_002178-knocked down HCC cells. Subsequently, we identified whether hsa_circRNA_002178 binds to serine- and arginine-rich splicing factor 1 (SRSF1) and then analyzed their function in regulating HCC cell behavior. The effect on HCC cell xenograft tumor growth was observed by the knockdown of hsa_circRNA_002178 in vivo. Results: GEO2R-based analysis displayed that hsa_circRNA_002178 was upregulated in HCC tissues. Overexpression or knockdown of hsa_circRNA_002178 encouraged or impeded HCC cell proliferation, migration, invasion, and EMT program. Mechanically, hsa_circRNA_002178 bound to SRSF1 3'-untranslated region (UTR) and stabilized its expression. SRSF1 weakening eliminated the effects of pcDNA-hsa_circRNA_002178 on cell malignant behavior. Finally, the knockdown of hsa_circRNA_002178 was confirmed to prevent xenograft tumor growth. Conclusions: hsa_circRNA_002178 overexpression encouraged the stability of SRSF1 mRNA expression, and it may serve as an upstream factor of SRSF1 for the diagnosis of HCC.

Lot-to-lot consistency, immunogenicity, and safety of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults: A randomized, double-blind, phase IV trial.

Previous phase I to III clinical trials have shown that the inactivated SARS-CoV-2 vaccine namely CoronaVac has good efficacy, safety, and immunogenicity. This phase IV trial aims to evaluate the lot-to-lot consistency, immunogenicity, and safety on a commercial scale in healthy adults, which could provide data to support stable manufacturing. In this single-center, randomized, double-blind study, 1,080 healthy adults aged 26-45 years were randomly assigned into three groups to receive one of three lots of vaccines. All subjects received two doses of CoronaVac with an interval of 28 days. Serum samples were collected before the first dose and 28 days after the second dose to assess the immunogenicity. Solicited local and systemic adverse events (AEs) within 7 days and unsolicited AEs within 28 days after each dose of vaccination were recorded. A total of 1,039 participants completed the study and were included in the per-protocol set (PPS). The GMTs were 75.2 (68.5,82.6), 65.0 (59.0,71.7), and 65.3 (59.4,71.8), respectively, and the seroconversion rates of neutralizing antibody were all higher than 98%. The GMT ratios of each pair of lots were 1.16 (1.01,1.32), 1.15 (1.01, 1.32), and 0.99 (0.87, 1.14), respectively, meeting the immunological equivalence criteria. The incidence rates of adverse reactions (ARs) were 19.17%, 13.89%, and 18.33%, with no statistical difference. The ARs were all in grade 1 and grade 2, with incidences of 15.46% and 2.50%. Non-vaccine-related serious adverse events (SAEs) were reported. These results showed robust lot-to-lot consistency, immunogenicity, and safety. The stable production indicated that CoronaVac is suitable for large-scale use.Trial registration number: NCT04894227 (ClinicalTrials.gov).

Safety and immunogenicity following a homologous booster dose of CoronaVac in children and adolescents.

Data on safety and immunity elicited by a third booster dose of inactivated COVID-19 vaccine in children and adolescents are scarce. Here we conducted a study based on a double-blind, randomised, placebo-controlled phase 2 clinical trial (NCT04551547) to assess the safety and immunogenicity of a third dose of CoronaVac. In this study, 384 participants in the vaccine group were assigned to two cohorts. One received the third dose at a 10-months interval (cohort 1) and the other one at a 12-months interval (cohort 2). The primary endpoint is safety and immunogenicity following a third dose of CoronaVac. The secondary endpoint is antibody persistence following the primary two-dose schedule. Severities of local and systemic adverse reactions reported within 28 days after dose 3 were mild and moderate in both cohorts. A third dose of CoronaVac increased GMTs to 681.0 (95%CI: 545.2-850.7) in cohort 1 and 745.2 (95%CI: 577.0-962.3) in cohort 2. Seropositivity rates against the prototype were 100% on day 28 after dose 3. Seropositivity rates against the Omicron variant were 90.6% (cohort 1) and 91.5% (cohort 2). A homologous booster dose of CoronaVac is safe and induces a significant neutralising antibody levels increase in children and adolescents.

Effect of Different Filler Wires on Mechanical Property and Conductivity of Aluminum-Copper Joints.

The 1060 aluminum and T2 copper were joined by the pulsed double electrode gas metal arc welding (DE-GMAW) brazing method by using four types of filler wires, namely pure aluminum (Al) ER1100, aluminum-magnesium (Al-Mg) ER5356, aluminum-silicon (Al-Si) ER4043, and Al-Si ER4047, respectively. The effects of different types of filler wires on intermetallic compounds, microhardness tensile strength, and conductivity of joints were investigated. The results showed that a lot of brittle intermetallic compounds laying in the copper side brazing interface zone were generated using pure Al, Al-Mg, and Al-Si filler wires, which caused the change of microhardness, tensile strength, and the conductivity of joints. Meanwhile, with the increase in Si elements contents for Al-Sifiller wires, the thickness of the intermetallic compound layers decreased obviously, which was only up to 3 µm and the conductivity of the joints decreased. In addition, the microhardness, tensile strength, and the conductivity of the joints, when using Al-Sifiller wires, was higher than that using pure Al and Al-Mg filler wires. Hence, in comparison to the pure filler wires and Al-Mg filler wires, the Al-Si filler wires were more suitable for Al-Cu joints by DE-GMAW as Si element content was lower.

Development of an inactivated vaccine candidate for SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. Because of the novelty of the virus, there are currently no SARS-CoV-2-specific treatments or vaccines available. Therefore, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here, we developed a pilot-scale production of PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats, and nonhuman primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against other strains. Three immunizations using two different doses, 3 or 6 micrograms per dose, provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support the clinical development and testing of PiCoVacc for use in humans.

Characterization of the radical scavenging and antioxidant activities of danshensu and salvianolic acid B.

Danshensu (3-(3,4-dihydroxyphenyl) lactic acid) and salvianolic acid B, two natural phenolic acids of caffeic acid derivatives isolated from Salvia miltiorrhiza root of the most widely used traditional Chinese medicine for the treatment of various cardiovascular diseases, have been reported to have potential protective effects from oxidative injury. To better understand their biological functions, the in vitro radical scavenging and antioxidant activities of danshensu and salvianolic acid B were evaluated along with vitamin C. Both danshensu and salvianolic acid B exhibited higher scavenging activities against free hydroxyl radicals (HO()), superoxide anion radicals (O(2)(-)), 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals and 2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radicals than vitamin C. In contrary, danshensu and salvianolic acid B showed weaker iron chelating and hydrogen peroxide (H(2)O(2)) scavenging activities than vitamin C. As expressed as vitamin C equivalent capacity (VCEAC), the relative VCEAC values (mg/100ml) were in the order of salvianolic acid B (18.59) > danshensu (12.89) > vitamin C (10.00) by ABTS radical assay. The protective efficiencies against hydrogen peroxide induced human vein vascular endothelial cell damage were correlated with their antioxidant activities. Analysis of structure-activity relationship of these two compounds showed that the condensation and conjugation of danshensu and caffeic acid appears important for antioxidant activity. These results indicated that danshensu and salvianolic acid B are efficient radical scavengers and antioxidants, and salvianolic acid B is superior to danshensu. Their radical scavenging and antioxidant properties might have potential applications in food and healthcare industry.

Profiling of alternative polyadenylation sites in luminal B breast cancer using the SAPAS method.

Breast cancer (BC) is a leading cause of cancer-related mortality in females and is recognized as a molecularly heterogeneous disease. Previous studies have suggested that alternative messenger RNA (mRNA) processing, particularly alternative polyadenylation [poly(A)] (APA), can be a powerful molecular biomarker with prognostic potential. Therefore, in the present study, we profiled APA sites in the luminal B subtype of BC by sequencing APA sites (SAPAS) method, in order to assess the relation of these APA site-switching events to the recognized molecular subtypes of BC, and to discover novel candidate genes and pathways in BC. Through comprehensive analysis, the trend of APA site-switching events in the 3' untranslated regions (3'UTRs) in the luminal B subtype of BC were found to be the same as that in MCF7 cell lines. Among the genes involved in the events, a significantly greater number of genes was found with shortened 3'UTRs in the samples, which were samples of primary cancer with relatively low proliferation. These findings may provide novel information for the clinical diagnosis and prognosis on a molecular level. Several potential biomarkers with significantly differential tandem 3'UTRs and expression were found and validated. The related biological progresses and pathways involved were partly confirmed by other studies. In conclusion, this study provides new insight into the diagnosis and prognosis of BC from the APA site profile aspect.

Proteomic analysis of enamel matrix using a two-dimensional protein fractionation system.

Our objectives in this study were to perform separate proteomic analyses of porcine soft and hard enamel matrices, using the ProteomeLab PF-2D System, to compare the contents of the hard and soft enamel and to identify matrix constituents that are absent from the early maturation stage. Developing first permanent molars were dissected from 6-month-old pigs. Both immature and mature enamel samples were obtained by scraping the secretory-stage (soft) and maturation-stage (hard) enamel, respectively. Enamel matrix samples were sequentially extracted and fractionated with 50 mM phosphate buffer (pH 7.4) and then with 50 mM carbonate buffer (pH 10.8). The neutral enamel extract was separated into four fractions by successive ammonium sulfate precipitations. The alkaline enamel extract was separated into four fractions by ion-exchange chromatography. These eight extracts from both the soft and hard enamel were injected for chromatofocusing. Soft enamel fractions containing constituents absent from the hard enamel were further separated by reverse-phase high-performance liquid chromatography. The major soft enamel constituents absent from the hard enamel were acidic glycoproteins, corresponding to the 32-kDa enamelin, and the 29-, 27-, 15-, 13-, 8- and 6-kDa C-terminal fragments of ameloblastin. Loss of these glycoproteins is associated with a post-transition increase in enamel mineralization.