Near-Infrared-II Nanoparticles for Vascular Normalization Combined with Immune Checkpoint Blockade via Photodynamic Immunotherapy Inhibit Uveal Melanoma Growth and Metastasis.

Photodynamic therapy (PDT) has been widely employed in tumor treatment due to its effectiveness. However, the tumor hypoxic microenvironment which is caused by abnormal vasculature severely limits the efficacy of PDT. Furthermore, the abnormal vasculature has been implicated in the failure of immunotherapy. In this study, a novel nanoparticle denoted as Combo-NP is introduced, composed of a biodegradable NIR II fluorescent pseudo-conjugate polymer featuring disulfide bonds within its main chain, designated as TPA-BD, and the vascular inhibitor Lenvatinib. Combo-NP exhibits dual functionality by not only inducing cytotoxic reactive oxygen species (ROS) to directly eliminate tumor cells but also eliciting immunogenic cell death (ICD). This ICD response, in turn, initiates a robust cascade of immune reactions, thereby augmenting the generation of cytotoxic T lymphocytes (CTLs). In addition, Combo-NP addresses the issue of tumor hypoxia by normalizing the tumor vasculature. This normalization process enhances the efficacy of PDT while concurrently fostering increased CTLs infiltration within the tumor microenvironment. These synergistic effects synergize to potentiate the photodynamic-immunotherapeutic properties of the nanoparticles. Furthermore, when combined with anti-programmed death-ligand 1 (PD-L1), they showcase notable inhibitory effects on tumor metastasis. The findings in this study introduce an innovative nanomedicine strategy aimed at triggering systemic anti-tumor immune responses for the treatment of Uveal melanoma.

The Role of Global Femoral Offset in Total Hip Arthroplasty with High Hip Center Technique.

OBJECTIVE: The high hip center (HHC) technique has been proposed for the treatment of patients with developmental dysplaisa of the hip (DDH) who have an acetabular bone defect. However, the importance of global femoral offset (FO) in the application of this technique has not been sufficiently appreciated. Our goals were to confirm that the HHC technique is feasible in the treatment of patients with DDH and to assess the function of global FO in this procedure. METHODS: We retrospectively analyzed 73 patients who underwent total hip arthroplasty using high hip center technique for unilateral DDH at our hospital between January 2014 and June 2019. According to global FO, the patients were split into three groups: increased FO group (increment greater than 5 mm), restored FO group (restoration within 5 mm) and decreased FO group (reduction greater than 5 mm). Patients' medical records and plain radiographs were reviewed. One-way ANOVA was used to compare radiographic outcomes and Harris hip score (HHS). Paired t-test was used to assess preoperative and postoperative HHS and leg length discrepancy. Trochanteric pain syndrome, Trendelenburg sign and postoperative limp was evaluated with Fisher's exact test. RESULTS: The average follow-up time was 7.5 ± 1.4 years. The patients' HHS and leg length discrepancy were significantly improved (p < 0.05). In terms of vertical acetabular height, abductor arm, postoperative leg length difference, and acetabular cup inclination, there was no statistically significant difference between the three groups. At the last follow-up, HHS was significantly higher in the restored FO group than in the decreased FO and increased FO groups. Trochanteric pain syndrome occurred in 15.0% and Trendelenburg sign and postoperative limp in 8.2% of all patients, respectively. Trochanteric pain syndrome, Trendelenburg sign and postoperative limp did not differ significantly across the three groups. One patient in increased FO group underwent revision for dislocation 6 years after surgery. CONCLUSION: The HHC technique is an alternative technique for total hip arthroplasty in patients with acetabular bone abnormalities, according to the results of the mid-term follow-up. Also, controlling the correction of the global femoral offset to within 5 mm may lead to better clinical outcomes.

Circular RNA CircSLC8A1 contributes to osteogenic differentiation in hBMSCs via CircSLC8A1/miR-144-3p/RUNX1 in periprosthetic osteolysis.

Circular RNAs (circRNAs) are often found in eukaryocyte and have a role in the pathogenesis of a variety of human disorders. Our related research has shown the differential expression of circRNAs in periprosthetic osteolysis (PPOL). However, the involvement of circRNAs in the exact process is yet unknown. CircSLC8A1 expression was evaluated in clinical samples and human bone marrow mesenchymal stem cells (hBMSCs) in this investigation using quantitative real-time PCR. In vitro and in vivo studies were conducted to explicate its functional role and pathway. We demonstrated CircSLC8A1 is involved in PPOL using gain- and loss-of-function methods. The association of CircSLC8A1 and miR-144-3p, along with miR-144-3p and RUNX1, was predicted using bioinformatics. RNA pull-down and luciferase assays confirmed it. The impact of CircSLC8A1 in the PPOL-mouse model was also investigated using adeno-associated virus. CircSLC8A1 was found to be downregulated in PPOL patients' periprosthetic tissues. Overexpression of CircSLC8A1 promoted osteogenic differentiation (OD) and inhibited apoptosis of hBMSCs in vitro. The osteogenic markers of RUNX1, osteopontin (OPN) and osteocalcin (OCN) were significantly upregulated in hBMSCs after miR-144-3p inhibitor was transferred. Mechanistic analysis demonstrated that CircSLC8A1 directly bound to miR-144-3p and participated in PPOL through the miR-144-3p/RUNX1 pathway in hBMSCs. Micro-CT and quantitative analysis showed that CircSLC8A1 markedly inhibited PPOL, and osteogenic markers (RUNX1, OPN and OCN) were significantly increased (P<0.05) in the mice model. Our findings prove that CircSLC8A1 exerted a regulatory role in promoting osteogenic differentiation in hBMSCs, and CircSLC8A1/miR-144-3p/RUNX1 pathway may provide a potential target for prevention of PPOL.

Material properties of degradable alloy Fe-30Mn-0.6N and its effect on ferroptosis in synoviocytes.

Ferroalloy has shown potential as implant materials, but little attention has been paid to their effects on synovial tissue ferroptosis. This study aimed to examine the mechanical properties, degradability and biocompatibility of Fe-30Mn-0.6N alloy and effects of it on synovial tissue ferroptosis. Tensile testing showed that Fe-30Mn-0.6N alloys exhibited tensile strength of 487 ± 18 MPa, yield strength of 221 ± 10 MPa, elongation of 16.9 ± 0.3% and Young's modulus of 37.7 ± 1.3 GPa. In vivo experiments, the cross-sectional area of the Fe-30Mn-0.6N alloys decreased by 73.32 ± 12.73% after 8 weeks of implantation. The results of scanning electron microscopy (SEM) and surface elemental analysis (EDS) showed that the Fe-30Mn-0.6N alloys had more Ca, O, C and P element deposition (p < .05). After 2, 4 and 8 weeks of implantation, no inflammatory response was observed in peri-implant synovial tissue of Fe-30Mn-0.6N and Ti-6Al-4V alloys, and Fe-30Mn-0.6N alloys did not affect the expression of the ferroptosis inhibitory gene Glutathione peroxidase 4 (GPX4). Compared with the control group, 30% Fe-30Mn-0.6N alloy extracts did not affect the cell viability (p > .05) in vitro, and intracellular Fe2+ and the reactive oxygen species (ROS) was significantly reduced (p < .05). WB and PCR results showed that the 30% extracts increased the protein activity and mRNA expression of GPX4, FTH1 and SLC7A11 in synoviocytes, but had no effect on PTGS2 and p53. It is concluded that Fe-30Mn-0.6N had degradability and biocompatibility in peri-implant synovial tissue, and did not induce significantly ferroptosis in synoviocytes.