Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Diagnostic accuracy of salivary active matrix metalloproteinase (aMMP)-8 point-of-care test for detecting periodontitis in adults: A systematic review and meta-analysis.

OBJECTIVE: To determine the accuracy of salivary active matrix metalloproteinase (aMMP)-8 point-of-care test (POCT) for detecting periodontitis in adults, through meta-analysis. MATERIALS AND METHODS: Diagnostic studies evaluating the accuracy of salivary/oral rinse aMMP-8 POCT for detecting periodontitis in adults, when compared with clinical examination, were considered eligible. A comprehensive search was performed up to 31 August 2023 through five databases. Quality Assessment of Diagnostic Accuracy Studies 2 was utilized to evaluate the methodological quality of the included articles. Meta-analysis was performed using Bayesian bivariate hierarchical model and subgroup analysis. RESULTS: From 368 screened studies, 6 studies (4 cross-sectional and 2 longitudinal studies) were included in the meta-analysis. Overall, the pooled sensitivity and specificity of salivary aMMP-8-POCT for detecting periodontitis were 0.63 (95% CI: 0.41-0.82) and 0.84 (95% CI: 0.65-0.95), respectively. Subgroup analyses revealed that the 95% CI for oral fluid types, predefined diagnostic thresholds and the POCT systems largely overlapped, indicating that the differences between them may not be significant. CONCLUSION: Salivary aMMP-8 POCT shows fair accuracy for detecting periodontitis. The diagnostic accuracy cannot be significantly influenced by the types of oral fluids, predefined diagnostic thresholds or the specific POCT systems used. More research is needed to confirm the clinical utility and implementation of aMMP-8 POCT in the diagnosis of periodontitis.

Effect of zirconia surface modification using dopamine polymerisation on the shear bond strength of resin cement.

This study evaluated the influence of polydopamine treatment on the surface properties and bond strength of yttria-stabilised tetragonal zirconia polycrystal (Y-TZP). Sixty-three zirconia blocks (10 × 10 × 2 mm) were randomly divided into three groups defined by surface treatment: (i) control group (C), (ii) grit-blasted with 110 µm alumina particles (GB), and (iii) polydopamine (PDA) coating. The surfaces of specimens subjected to different treatments were investigated by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and water contact angle measurements. After the surface treatments, the specimens were cemented to resin composite cylinders. After bonding, the shear bond strength of the ceramic to the resin was measured, and the failure mode of each specimen was analysed using a stereomicroscope. The results indicated that the shear bond strength is highest for the GB treatment and lowest for the controls. However, the difference between groups GB and PDA was not statistically significant. In the control group, adhesive failure was predominant, whereas in the treatment groups, mixed mode failure was predominant. The pre-treatment of Y-TZP ceramic with the polydopamine coating might improve the bond strength of the resin cement to the zirconia ceramic.

Nuclear-targeting TAT-PEG-Asp8-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer.

AIM: Drug efflux-associated multidrug resistance (MDR) is a main obstacle to effective cancer chemotherapy. Large molecule drugs are not the substrates of P-glycoprotein, and can circumvent drug efflux and be retained inside cells. In this article we report a polymer-drug conjugate nanoparticulate system that can overcome MDR based on size-related exclusion effect. METHODS: Doxorubicin was coupled with the triblock polymeric material cell-penetrating TAT-PEG-poly(aspartic acid). The amphiphilic macromolecules (termed TAT-PEG-Asp8-Dox) could self-assemble into nanoparticles (NPs) in water. The antitumor activity was evaluated in drug-resistant human colon cancer HCT8/ADR cells in vitro and in nude mice bearing HCT8/ADR tumor. RESULTS: The self-assembling TAT-PEG-Asp8-Dox NPs were approximately 150 nm with a narrow particle size distribution, which not only increased the cellular uptake efficiency, but also bypassed P-glycoprotein-mediated drug efflux and improved the intracellular drug retention, thus yielding an enhanced efficacy for killing drug-resistant HCT8/ADR colon cancer cells in vitro. Importantly, the TAT-PEG-Asp8-Dox NPs enhanced the intranuclear disposition of drugs for grater inhibition of DNA/RNA biosynthesis. In nude mice bearing xenografted HCT8/ADR colon cancers, intravenous or peritumoral injection of TAT-PEG-Asp8-Dox NPs for 22 d effectively inhibited tumor growth. CONCLUSION: TAT-PEG-Asp8-Dox NPs can increase cellular drug uptake and intranuclear drug delivery and retain effective drug accumulation inside the cells, thus exhibiting enhanced anticancer activity toward the drug-resistant human colon cancer HCT8/ADR cells.

A High-Performance Self-Supporting Electrochemical Biosensor to Detect Aflatoxin B1.

High-performance electrochemical biosensors for the rapid detection of aflatoxin B1 (AFB1) are urgently required in the food industry. Herein, a multi-scaled electrochemical biosensor was fabricated by assembling carboxylated polystyrene nanospheres, an aptamer and horseradish peroxidase into a free-standing carbon nanofiber/carbon felt support. The resulting electrochemical biosensor possessed an exceptional performance, owing to the unique structures as well as the synergistic effects of the components. The 3D porous carbon nanofiber/carbon felt support served as an ideal substrate, owing to the excellent conductivity and facile diffusion of the reactants. The integration of carboxylated polystyrene nanospheres with horseradish peroxidase was employed as a signal amplification probe to enhance the electrochemical responses via catalyzing the decomposition of hydrogen peroxide. With the aid of the aptamer, the prepared sensors could quantitatively detect AFB1 in wine and soy sauce samples via differential pulse voltammetry. The recovery rates of AFB1 in the samples were between 87.53% and 106.71%. The limit of detection of the biosensors was 0.016 pg mL-1. The electrochemical biosensors also had excellent sensitivity, reproducibility, specificity and stability. The synthetic strategy reported in this work could pave a new route to fabricate high-performance electrochemical biosensors for the detection of mycotoxins.

Treatment of inflammatory bone loss in periodontitis by stem cell-derived exosomes.

Periodontitis is the primary cause of tooth loss, but there is no effective treatment to repair inflammatory bone loss in periodontitis. Exosomes emerge as essential paracrine factors of mesenchymal stem cells (MSCs) that mediated tissue regeneration. Here, we investigated the potential of exosomes secreted by periodontal ligament stem cells (PDLSCs) as therapeutics for the bone defect in periodontitis. Exosomes secreted from PDLSCs derived from healthy periodontal ligaments (h-PDLSCs) and their function were evaluated on PDLSCs isolated from the inflammatory periodontal ligament of periodontitis patients (i-PDLSCs). Treatment of exosomes of h-PDLSCs led to an increase in the formation of mineralized nodules and the expressions of osteogenic genes and proteins in i-PDLSCs. Mechanistically, h-PDLSCs-exosomes suppressed the over-activation of canonical Wnt signaling to recover the osteogenic differentiation capacity of i-PDLSCs. To evaluate the therapeutic of exosomes on inflammatory bone loss, h-PDLSCs-exosomes loaded with Matrigel or ß-TCP were employed to repair bone defects in rat models of periodontitis. Compared to the vehicle-treated control group, h-PDLSCs-exosomes-treated rats resulted in more bone formation in the defect of alveolar bone. In conclusion, these results demonstrated that exosomes derived from healthy PDLSCs could rescue the osteogenesis capacity of endogenous stem cells under an inflammatory environment and promote regeneration of alveolar bone. Our findings suggest that MSCs-derived exosome is an effective and practical cell-free MSC therapeutic for the treatment of periodontitis. STATEMENT OF SIGNIFICANCE: There is no effective treatment to repair inflammatory bone loss in periodontitis. As essential paracrine factors of PDLSCs, exosomes might mediate tissue regeneration during stem cell therapy. Here, we reported that exosomes secreted from healthy PDLSCs promoted the osteogenic differentiation of PDLSCs derived from periodontitis tissue. Healthy PDLSCs-exosomes treatment resulted in accelerated bone formation in the defect of alveolar bone in rat models of periodontitis. Mechanistically, h-PDLSCs-exosomes suppressed the over-activation of canonical Wnt signaling to recover the osteogenic differentiation capacity of inflammatory PDLSCs. These findings suggest that MSCs-derived exosome is an effective and practical cell-free MSC therapeutic for the treatment of periodontitis.

Maternal exposure to polystyrene nanoplastics during gestation and lactation induces hepatic and testicular toxicity in male mouse offspring.

Nanoplastics have raised considerable concerns since their ubiquity in the environment and potential hazard to health. It has been proven that polystyrene nanoparticles (PS-NPs) can be maternally transferred to the offspring. In this study, mice were exposed gestationally and lactationally to PS-NPs (size 100 nm) at different doses (0.1, 1 and 10 mg/L) to investigate the trans-generational poisonousness. Our data illustrated that maternal PS-NPs exposure in pregnancy and lactation resulted in a decline in birth and postnatal body weight in offspring mice. Furthermore, high-dose PS-NPs reduced liver weight, triggered oxidative stress, caused inflammatory cell infiltration, up-regulated proinflammatory cytokine expression, and disturbed glycometabolism in the liver of male offspring mice. In addition, pre- and postnatal PS-NPs exposure diminished testis weight, disrupted seminiferous epithelium and decreased sperm count in mouse offspring. Moreover, PS-NPs induced testicular oxidative injury, as presented by increased malondialdehyde generation and altered superoxide dismutase and catalase activities in the testis of offspring mice. These findings declared that maternal exposure to PS-NPs in pregnancy and lactation can cause hepatic and testicular toxicity in male mouse pups, which put forward new understanding into the detrimental effects of nanoplastics on mammalian offspring.

[The ophthalmic applications of nanotechnology].

This paper briefly reviews the researches and applications of nanotechnology in ophthalmological field recent years. Nanotechnology is the production of modern science and advanced engineering. In ophthalmological field it is generally applied on foundational investigation, medicine carrying agent, biomaterial, diagnosis and therapy. It helps us observe and control physiological and pathological phenomenon at nanometer level precisely. As new drug carriers, drug-loaded nanoparticles have lots of advantages with its targeting options and sustained drug release. As biomaterial it also has better biocompatible. It is a promising material in clinical application. The diagnosis and treatment level would be improved definitely by nanotechnology.

[Effect of sintering temperature on mechanical properties of dental zirconia toughened alumina ceramics].

PURPOSE: To investigate the effect of sintering temperature on mechanical properties of dental zirconia toughened alumina (ZTA) ceramics prepared by gel-casting technique. METHODS: The samples prepared by gel-casting were sintered at 1100, 1200, 1250, 1300 and 1400degrees centigrade for each group. The flexural strength, fracture toughness, Vickers hardness and brittleness index were obtained and microscopic morphology of each group was observed under scanning electron microscope (SEM). The data were statistically analyzed using SPSS 19.0 software package. RESULTS: The flexural strength, fracture toughness and Vickers hardness increased with the increasing sintering temperature during 1100~1400degrees centigrade. The lowest brittleness index (0.74±0.16) µm-1/2 was observed in group sintered at 1200degrees centigrade and the highest (2.76±0.14) µm-1/2 was at 1400degrees centigrade (P<0.05), while the flexural strength of these two groups was (46.89±3.24) MPa and (349.64±54.72) MPa, respectively. CONCLUSIONS: The ZTA dental ceramics exhibit good machinability with proper sintering temperature (1200degrees centigrade) and the strength meets the requirement of clinical application.

[Comparison of the shear bond strength by using nano silica sol to zirconia basement and veneer porcelain].

PURPOSE: To investigate the feasibility of using sol gel technique to produce thin layer nano silicon dioxide on zirconia ceramic surface and the effect of improving shear bond strength between zirconia and veneer porcelain. METHODS: The presintered zirconia specimen was cut into a rectangle block piece (15 mm×10 mm×2.5 mm), a total of 40 pieces were obtained and divided into 4 groups, each group had 10 pieces. Four different treatments were used in each group respectively. Pieces in group A (control group) were only sintered at 1450°C to crystallization; pieces in group B underwent 30% nano silica sol infiltration first and then were sintered at 1450°C to crystallization; piece in group C underwent crystallization first at 1450°C, then 30% nano silica sol infiltration and were sintered at 1450°C again; pieces in group D was coated by nano silica sol and then sintered at 1450°C to crystallization; ten rectangle block pieces (12 mm×8 mm×2 mm) in group E were made. Cylinder veneers 5 mm in diameter and 4 mm in height were produced in each group and the shear bond strength was tested. Data were statistically analyzed by SPSS 19.0 software package. RESULTS: The shear bond strength of the 5 group specimens were: (28.12±2.95) MPa in group A, (31.09±3.94) MPa in group B, (25.60±2.45) MPa in group C, (31.75±4.90) MPa in group D, (28.67±3.95) MPa in group E, respectively. Significant differences existed between the 5 groups, and group C had significant difference compared with group B and D. CONCLUSIONS：① Use of nano silicon sol gel on presintered zirconia surface to make thin layer of nano silicon dioxide can improve the shear bond strength between zirconia and veneer; ②Using nano silicon sol gel on crystallization zirconia surface to make thin layer of nano silicon dioxide will decrease the shear bond strength between zirconia and veneer; ③ Zirconia veneer bilayer ceramic has the same shear bond strength with porcelain fused to Ni Cr alloy; ④Use of sol gel technique to produce thin layer nano silicon dioxide on zirconia ceramic surface is feasible and can improve shear bond strength between zirconia and veneer porcelain.

Preparation and application of porous nitrogen-doped graphene obtained by co-pyrolysis of lignosulfonate and graphene oxide.

Nitrogen-doped graphene with in-plane porous structure was fabricated by simple co-pyrolysis of lignosulfonate and graphene oxide in the presence of urea. Lignosulfonate first performs as a dispersant adsorbed on the surface of graphene oxide to prevent the aggregation of graphene oxide sheets for preparing homogeneous nitrogen-containing precursor, and then acts as a porogen to render graphene sheets with nanopores in the pyrolysis process of the nitrogen-containing precursor. Urea was used as a nitrogen source to incorporate nitrogen atoms into graphene basal plane. The special nanoporous structure combined with nitrogen content of 7.41at.% endows the nitrogen-doped graphene electrode material with super capacitance up to 170Fg(-1), high rate performance, and excellent cycling stability.

The effect of implant shape and screw pitch on microdamage in mandibular bone.

PURPOSE: The aim of this study was to investigate the effect of implant shape and screw pitch on microdamage in bone during insertion of dental implants. MATERIALS AND METHODS: Thirty custom-made implants (length, 10 mm; diameters, 4.1 mm; cylindrical, tapered, and taper-cylindrical shapes; screw pitches, 1.25 and 0.8 mm; classified as 1.25C, 0.8C, 1.25T, 0.8T, 1.25TC, 0.8TC) were placed with a surgical device in the mandibles of eight goats. Two implant sites were prepared in the edentulous area on each side of the mandible. Implants were placed in a randomized order. Immediately after placement of the implants, the bone blocks with the implants were collected, bulk stained with basic fuchsin, embedded in methyl methacrylate, and sectioned. Histomorphometric quantification of the microcrack length (Cr.Le, µm); microcrack surface density (Cr.Le/B.Ar, µm/mm(2) ), and damaged bone area fraction (DB.Ar/B.Ar, %) were measured. RESULTS: The Cr.Le, Cr.Le/B.Ar, and DB.Ar/B.Ar values of 0.8TC group were 80.96 ± 17.55, 478.75 ± 51.85, and 4.40 ± 0.36, respectively. All these parameters of microdamage induced by 0.8TC were significantly lower than those induced by other five types of implants (p < .05). CONCLUSION: Taper-cylindrical implants with 0.8 mm screw pitch caused the least microdamage to the bone in comparison with the other five types of implants during placement of implants.

A comparative study of dog models for osteotome sinus floor elevation and dental implants in posterior maxilla subjacent to the maxillary sinus.

OBJECTIVE: The objective of this study was to investigate the suitability of beagles and Labrador retrievers as animal models for osteotome sinus floor elevation (OSFE) and dental implants in posterior maxilla subjacent to sinus. STUDY DESIGN: Ten beagles and 8 Labrador retrievers were included. Their posterior maxillas subjacent to the sinus were studied by a gross survey, CT scan, and histologic analysis. RESULTS: In the posterior maxilla subjacent to sinus, the bone height was significantly higher for Labrador retrievers than for beagles (P < .05). There was no significant difference in sinus size from the coronal section and its location from the sagittal section (P > .05) between Labrador retrievers and beagles. CONCLUSIONS: As an animal model, the Labrador is more suitable for OSFE and dental implants in posterior maxilla subjacent to sinus. The midpoint of the maxillary fourth premolar is an ideal site for implantation.

[Experimental study of osseointegration of nHA/BG coating and Bio-Oss in implant defects].

PURPOSE: To evaluate bone regeneration in defects at titanium implants with nHA/BG coating in conjunction with Bio-Oss. METHODS: Four mandibular premolars were extracted in 6 Beagle dogs. After 3 months, buccal dehiscence-type defects (2.25 mm×3 mm×4 mm) were surgically created following implant site. The three treatment modalities were randomly allocated: nHA/BG implant/Bio-Oss, nHA/BG implant/blood clot, and mHA implant/Bio-Oss. After 8 and 16 weeks, the dogs were sacrificed respectively. A histomorphometric analysis was performed. The data was analyzed with SPSS 13.0 software package for Student's t test and ANOVA. RESULTS: At 8- and 16-week, nHA/BG implant group revealed comparable mean BIC (30% to 18% versus 61% to 53%). However, mHA implant/Bio-Oss group revealed significantly lower mean BIC (21% versus 46%) values than nHA/BG implant/Bio-Oss group.A significant difference was observed for the mean BIC and RA values at 8-week between nHA/BG implant/Bio-Oss group and mHA implant/Bio-Oss group. CONCLUSIONS: It is concluded that the application of Bio-Oss graft did not seem to interfere with the nHA/BG coating activity, but ensured a stabilization of the newly formed bone for defects.

Ab initio elasticity of poly(lactic acid) crystals.

We investigate the elastic properties of poly(lactic acid) crystals using a first-principles pseudopotential plane wave method within the generalized gradient approximation of the density functional theory. Stiffness and compliance matrices of poly(l-lactic acid) (PLLA) alpha- and beta-forms, and the stereocomplex (sc) between PLLA and poly(D-lactic acid) (PDLA) (50:50) sc-form are calculated using the finite strain technique. The results indicate that crystalline poly(lactic acid) is highly mechanical anisotropic. Contributions from the crystalline phase to the anisotropy of the elastic modulus in an uniaxially oriented poly(lactic acid) fiber are estimated on the basis of a cylindrically symmetric polycrystalline aggregate model. Both symmetry and orientation distribution of the crystals have been taken into account. Voigt and Reuss bounds of Young's moduli and shear moduli and Poisson's ratio are calculated from single crystal elastic properties.