Cross-linked hyaluronic acid hydrogel (cHA gel) and dexamethasone (Dex) have been used to treat knee osteoarthritis (OA) in clinical practice owing to their chondroprotective and anti-inflammatory effects, respectively. The aim of the present study was to compare the treatment effects of the cHA gel pre-mixed with/without Dex in a surgery-induced osteoarthritis model in rats. Anterior cruciate ligament transection (ACLT) surgery was performed on the right knee of rats to induce OA. Male 2-month-old Sprague-Dawley rats were randomly divided into five groups (n = 10/per group): (1) ACLT + saline; (2) ACLT + cHA gel; (3) ACLT + cHA-Dex (0.2 mg/mL) gel; (4) ACLT + cHA-Dex (0.5 mg/mL) gel; (5) Sham + saline. Intra-joint injections were performed four weeks after ACLT in the right knee. All animals were euthanized at 12 weeks post-surgery. Cartilage damage and changes in the synovial membrane were assessed by micro X-ray, Indian ink articular surface staining, Safranin-O/Fast Green staining, immunohistochemistry, hematoxylin and eosin staining of the synovial membrane, and quantitative reverse transcription-polymerase chain reaction for changes in gene expression. Micro X-ray revealed that the knee joint treated with the cHA-Dex gel was wider than those treated with cHA gel alone or saline. The cHA-Dex gel group had less Indian ink staining (indicator of cartilage fibrillation) than the cHA gel or saline injection groups. Safranin-O/Fast Green staining indicated that increased proteoglycan staining and less cartilage damage were found in the cHA-Dex gel group compared with the cHA gel or saline injection groups. Quantification of histology findings from saline, cHA gel, cHA-Dex (0.2 mg/mL) gel, cHA-Dex (0.5 mg/mL) gel, and sham groups were 5.84 ± 0.29, 4.50 ± 0.87, 3.00 ± 1.00, 2.00 ± 0.48, and 0.30 ± 0.58 (p < 0.05), respectively. A strong staining of type II collagen was found in both the cHA-Dex gel groups compared with saline group or cHA alone group. Similar result was found for the mRNA level of aggrecan and opposite result for type X collagen. Hematoxylin and eosin staining in the synovial membrane showed less synovial lining cell layers and reduced inflammatory cell infiltration in cHA-Dex gel-treated animals compared with saline or cHA only groups. Altogether, cHA-Dex gel has better chondroprotective and anti-inflammatory effects in rat surgery-induced osteoarthritis than cHA alone.

Rationale: Sonographic septations are assumed to be important clinical predictors of outcome in pleural infection, but the evidence for this is sparse. The inflammatory and fibrinolysis-associated intrapleural pathway(s) leading to septation formation have not been studied in a large cohort of pleural fluid (PF) samples with confirmed pleural infection matched with ultrasound and clinical outcome data. Objectives: To assess the presence and severity of septations against baseline PF PAI-1 (Plasminogen-Activator Inhibitor-1) and other inflammatory and fibrinolysis-associated proteins as well as to correlate these with clinically important outcomes. Methods: We analyzed 214 pleural fluid samples from PILOT (Pleural Infection Longitudinal Outcome Study), a prospective observational pleural infection study, for inflammatory and fibrinolysis-associated proteins using the Luminex platform. Multivariate regression analyses were used to assess the association of pleural biological markers with septation presence and severity (on ultrasound) and clinical outcomes. Measurements and Main Results: PF PAI-1 was the only protein independently associated with septation presence (P < 0.001) and septation severity (P = 0.003). PF PAI-1 concentrations were associated with increased length of stay (P = 0.048) and increased 12-month mortality (P = 0.003). Sonographic septations alone had no relation to clinical outcomes. Conclusions: In a large and well-characterized cohort, this is the first study to associate pleural biological parameters with a validated sonographic septation outcome in pleural infection. PF PAI-1 is the first biomarker to demonstrate an independent association with mortality. Although PF PAI-1 plays an integral role in driving septation formation, septations themselves are not associated with clinically important outcomes. These novel findings now require prospective validation.

Glioblastoma (GBM) is a common primary brain tumor with poor clinical prognosis. Although CAR-T therapy has been trialed for treatment of GBM, the outcomes are sub-optimal possibly due to exhaustion of T cells and life-threatening neurotoxicity. To address these issues, a combined therapeutic strategy was tested in the current study using GD2 CAR-T together with Nivolumab - an anti-PD-1 monoclonal antibody. An effector-to-target co-culture system was established to evaluate the short-term and long-term cytotoxicity of CAR-T, as well as to investigate the inhibitory activity and T cell exhaustion associated with the PD-1/PD-L1 signaling pathway. Orthotopic NOD/SCID GBM animal models were generated to evaluate the safety and efficacy of the combined therapeutic strategy at various dosages of GD2 CAR-T with Nivolumab. GD2 CAR-T exhibited significant antigen-specific cytotoxicity in a dose-dependent manner in vitro. The persistence of cytotoxicity of GD2 CAR-T could be enhanced by addition of Nivolumab in the co-culture system. Animal studies suggested that GD2 CAR-T effectively infiltrated into tumor tissue and significantly hampered tumor progression. The optimal therapeutic outcome was obtained via using the medium dosage of CAR-T with Nivolumab, which displayed the highest efficacy in extending the survival up to 60 days. Further investigation of toxicity revealed that high-dosage of GD2 CAR-T could induce tumor apoptosis through p53/caspase-3/PARP signaling pathway. This study suggests that GD2 CAR-T in combination with Nivolumab may offer an improved therapeutic strategy for treatment of GBM.

Mesenchymalstem cell (MSC)-based therapy is being increasingly explored in preclinical and clinical studies as a regenerative method for treating osteoarthritis (OA). However, the use of primary MSCs is hampered by a number of limitations, including donor heterogeneity and inconsistent cell quality. Here, we tested the therapeutic potential of embryonic stem cell-derived MSCs (ES-MSCs) in anOA rat model. ES-MSCs were generated and identified by morphology, trilineage differentiation and flow cytometry. Sprague Dawley rats were treated with either a single dose (10⁶ cells/rat) of ES-MSCs or with three doses spaced one week apart for each dose, starting at four weeks after anterior cruciate ligament transectionto induce OA. Cartilage quality was evaluated at 6 and 10 weeks after treatment with behavioral analysis, macroscopic examination, and histology. At sixweeks after treatment, the groups treated with both single and repeated doses of ES-MSCs had significantly better modified Mankin scores and International Cartilage Repair Society (ICRS) macroscopic scores in the femoral condyle compared to the control group. At 10 weeks after treatment, the repeated doses group had a significantly better ICRS macroscopic scores in the femoral condyle compared to the single dose and control groups. Histological analysis also showed more proteoglycan and less cartilage loss, along with lower Mankin scores in the repeated doses group. In conclusion, treatment with multiple injections of ES-MSCs can ameliorate OA in a rat model. TheES-MSCs have potential to be considered as a regenerative therapy for OA, and can provide an infinite cellular source.

In knee osteoarthritis (OA), there is more pronounced cartilage damage in the medial compartment (“lesion zone”) than the lateral compartment (“remote zone”). This study fills a gap in the literature by conducting a systematic comparison of cartilage and chondrocyte characteristics from these two zones. It also investigates whether chondrocytes from the different zones respond distinctly to changes in the physical and mechanical microenvironment using three-dimensional porous scaffolds by changing stiffness and pore size. Cartilage was harvested from patients with end-stage varus knee OA. Cartilage from the lesion and remote zones were compared through histological and biomechanical assessments, and through proteomic and gene transcription analyses of chondrocytes. Gelatin scaffolds with varied pore sizes and stiffness were used to investigate in vitro microenvironmental regulation of chondrocytes from the two zones. Cartilage from the lesion and remote zones differed significantly ( p < 0.05) in histological and biomechanical characteristics, as well as phenotype, protein, and gene expression of chondrocytes. Chondrocytes from both zones were sensitive to changes in the structural and mechanical properties of gelatin scaffolds. Of interest, although all chondrocytes better retained chondrocyte phenotype in stiffer scaffolds, those from the lesion and remote zones, respectively, preferred scaffolds with larger and smaller pores. Distinct variations exist in cartilage and chondrocyte characteristics in the lesion and remote zones of knee OA. Cells in these two zones respond differently to variations in the physical and mechanical microenvironment. Understanding and manipulating these differences will facilitate the development of more efficient and precise diagnostic and therapeutic approaches for knee OA.

Background: Continuous glucose monitoring (CGM) can help manage diabetes mellitus (DM) and prevent hypoglycemia. This study aimed to evaluate the performance and usability of a novel SiJoy GS1 CGM system. Methods: This multicenter trial enrolled participants with DM. Based on the comparison of glucose values measured by SiJoy GS1 CGM and venous blood glucose test, the 20/20% consistency and mean absolute relative difference (MARD%) were calculated, as well as Clarke and consensus error grid analysis. Product usability was evaluated by questionnaire completed by participants. Any occurrence of adverse events (AE) was documented. Results: Seventy participants were included in the study. The mean age of participants was 41.5 ± 13.2 years, among which 29 (42.0%) were male, with the DM course of 8.6 ± 7.5 years. A total of 39 (56.5%) of them had type 1 DM, 24 (34.8%) had type 2 DM, and 6 (8.7%) were others for DM. The 20/20% consistency achieved 91.82%, which was higher than the target 65%. The percentage of A + B zones of Clarke and consensus error grid was 99.22% and 99.90%, respectively. The MARD value was 8.83% ± 4.03%. The mean score of usability questionnaire was 86.59 ± 5.17 out of 90. AE were observed in only one participant (mild fever), and no severe AEs occurred. Conclusions: The SiJoy GS1 CGM system achieved satisfactory performance and usability. No severe AEs occurred and mild AE was reported in only one case.