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Advanced Science (Weinheim,... Jun 2024The unique physical tumor microenvironment (TME) and aberrant immune metabolic status are two obstacles that must be overcome in cancer immunotherapy to improve clinical...
The unique physical tumor microenvironment (TME) and aberrant immune metabolic status are two obstacles that must be overcome in cancer immunotherapy to improve clinical outcomes. Here, an in situ mechano-immunometabolic therapy involving the injection of a biomimetic hydrogel is presented with sequential release of the anti-fibrotic agent pirfenidone, which softens the stiff extracellular matrix, and small interfering RNA IDO1, which disrupts kynurenine-mediated immunosuppressive metabolic pathways, together with the multi-kinase inhibitor sorafenib, which induces immunogenic cell death. This combination synergistically augmented tumor immunogenicity and induced anti-tumor immunity. In mouse models of clear cell renal cell carcinoma, a single-dose peritumoral injection of a biomimetic hydrogel facilitated the perioperative TME toward a more immunostimulatory landscape, which prevented tumor relapse post-surgery and prolonged mouse survival. Additionally, the systemic anti-tumor surveillance effect induced by local treatment decreased lung metastasis by inhibiting epithelial-mesenchymal transition conversion. The versatile localized mechano-immunometabolic therapy can serve as a universal strategy for conferring efficient tumoricidal immunity in "cold" tumor postoperative interventions.
PubMed: 38884220
DOI: 10.1002/advs.202308734 -
Cureus May 2024Tenosynovial giant cell tumor (TGCT) is a monoarticular fibrohistiocytic benign or locally aggressive soft tissue tumor that originates from the synovium of joints,...
BACKGROUND
Tenosynovial giant cell tumor (TGCT) is a monoarticular fibrohistiocytic benign or locally aggressive soft tissue tumor that originates from the synovium of joints, bursae, and tendon sheaths. It has an inflammatory neoplastic nature, with a clinical presentation ranging from pain, swelling, stiffness, and limited range of movement to joint instability and blockage. Its uncommon incidence leads to a poorly understood pathogenesis. Localized forms of TGCT (LTGCT) can cause significant morbidity, interfere with daily patient activities, and decrease the patient's quality of life in challenging cases. This study aimed to investigate the immunohistochemical expression of PPARγ (peroxisome proliferator-activated receptor gamma) and P53 in LTGCT to understand the disease better and offer potential therapeutic targets.
METHODS
The study is cross-sectional, in which 27 LTGCT cases were collected from the Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Solitary and multiple LTGCT cases retrieved between January 2018 and December 2022 were included, and immunohistochemically stained with anti-PPARγ and P53 antibodies. The TGCT samples were excluded if they were insufficient for sectioning, processing, and interpretation, over-fixed, had process artifacts, or were of the diffuse TGCT type. Scoring of stain expression was performed by ImageJ (National Institutes of Health, Bethesda, MD) analysis using the threshold method and was expressed in percent area/high power field. Clinicopathological correlations were analyzed.
RESULTS
All the 27 collected LTGCT cases were located in the small joints of patients' hands. Cases with solitary LGTCTs constituted 55.6% (n = 15), while 44.4% (n = 12) had multiple LTGCTs related to one affected site/case (e.g., multiple tumors in one finger). PPARγ was expressed in the cytoplasm of mononuclear and multinucleated tumor cells and foamy histiocytes, while P53 expression was mainly in mononuclear cells' nuclei. PPARγ significantly correlated with P53 expression (r = 0.9 and P = 0.000). PPARγ (r = 0.4 and P = 0.02) and P53 (r = 0.5 and P = 0.01) were positively correlated with tumor size. Only P53 expression was positively correlated with tumor multiplicity (r = 0.4 and P = 0.03). Using the receiver operating characteristic curve test, the P53 cutoff score detecting the multiplicity of TGCTs was ≥20.5%, with a 75% sensitivity and 80% specificity.
CONCLUSION
PPARγ and P53 have a significant role in LTGCT growth, while P53 plays a role in tumor multiplicity. They can be possible targets in LTGCTs unfit for excision.
PubMed: 38882990
DOI: 10.7759/cureus.60377 -
Stem Cells International 2024Joint articular injection of mesenchymal stem cells (MSCs) has emerged as a novel treatment approach for osteoarthritis (OA). However, the effectiveness of MSCs derived... (Review)
Review
BACKGROUND
Joint articular injection of mesenchymal stem cells (MSCs) has emerged as a novel treatment approach for osteoarthritis (OA). However, the effectiveness of MSCs derived from different sources in treating OA patients remains unclear. Therefore, this study aimed to explore the differences between the effectiveness and safety of different sources of MSCs.
MATERIALS AND METHODS
For inclusion consideration, we searched trial registries and published databases, including PubMed, Cochrane Library, Embase, and Web of Science databases. Revman (V5.3), STATA (V16.0), and R (V4.0) were utilized for conducting data analysis, while the Cochrane Risk of Bias Tool was employed for assessing the quality of the studies. We derived outcome measures at 6 and 12 months based on the duration of study follow-up, including visual analog scale (VAS) score, WOMAC score, WOMAC pain, WOMAC Functional Limitation, and WOMAC stiffness. The evaluation time for short-term effectiveness is set at 6 months, while 12 months is utilized as the longest follow-up time for most studies to assess long-term effectiveness.
RESULTS
The evaluation of literature quality showed that the included studies had excellent methodological quality. A meta-analysis revealed that different sources of MSCs improved knee function and pain more effectively among patients suffering from knee OA (KOA) than controls. The results of the network meta-analysis showed the following: short-term functional improvement (the indexes were evaluated after 6 months of follow-up) (WOMAC total score: bone marrow-derived MSC (BMMSC) vs. adipose-derived MSC (ADMSC) (mean difference (MD) = -20.12, 95% confidence interval (CI) -125.24 to 42.88), umbilical cord-derived MSC (UCMSC) (MD = -7.81, 95% CI -158.13 to 74.99); WOMAC stiffness: BMMSC vs. ADMSC (MD = -0.51, 95% CI -7.27 to 4.29), UCMSC (MD = -0.75, 95% CI -9.74 to 6.63); WOMAC functional limitation: BMMSC vs. ADMSC (MD = -12.22, 95% CI -35.05 to 18.86), UCMSC (MD = -9.31, 95% CI -44.26 to 35.27)). Long-term functional improvement (the indexes were evaluated after 12 months of follow-up) (WOMAC total: BMMSC vs. ADMSC (MD = -176.77, 95% CI -757.1 to 378.25), UCMSC (MD = -181.55, 95% CI -937.83 to 541.13); WOMAC stiffness: BMMSC vs. ADMSC (MD = -0.5, 95% CI -26.05 to 18.61), UCMSC (MD = -1.03, 95% CI -30.44 to 21.69); WOMAC functional limitation: BMMSC vs. ADMSC (MD = -5.18, 95% CI -316.72 to 177.1), UCMSC (MD = -8.33, 95% CI -358.78 to 218.76)). Short-term pain relief (the indexes were evaluated after 6 months of follow-up) (VAS score: UCMSC vs. BMMSC (MD = -10.92, 95% CI -31.79 to 12.03), ADMSC (MD = -14.02, 95% CI -36.01 to 9.81), PLMSC (MD = -17.09, 95% CI -46.31 to 13.17); WOMAC pain relief: BMMSC vs. ADMSC (MD = -11.42, 95% CI -39.52 to 11.77), UCMSC (MD = -6.73, 95% CI -47.36 to 29.15)). Long-term pain relief (the indexes were evaluated after 12 months of follow-up) (VAS score: BMMSC vs. UCMSC (MD = -4.33, 95% CI -36.81 to 27.08), ADMSC (MD = -11.43, 95% CI -37.5 to 13.42); WOMAC pain relief: UCMSC vs. ADMSC (MD = 0.23, 95% CI -37.87 to 38.11), BMMSC (MD = 5.89, 95% CI -25.39 to 51.41)). According to the GRADE scoring system, WOMAC, VAS, and AE scores were of low quality.
CONCLUSION
Meta-analysis suggests MSCs can effectively treat KOA by improving pain and knee function compared to control groups. In terms of functional improvement in KOA patients, both short-term (6-month follow-up) and long-term (12-month follow-up) results indicated that while the differences between most treatments were not statistically significant, bone marrow-derived MSCs may have some advantages over other sources of MSCs. Additionally, BM-MSCs and UC-MSCs may offer certain benefits over ADMSCs in terms of pain relief for KOA patients, although the variances between most studies were not statistically significant. Therefore, this study suggests that BM-MSCs may present clinical advantages over other sources of MSCs.
PubMed: 38882598
DOI: 10.1155/2024/2741681 -
International Journal of Nanomedicine 2024Rheumatoid Arthritis (RA) involves prolonged inflammation of the synovium, damaging joints and causing stiffness and deformity. Celastrol (Cel), derived from the Chinese...
BACKGROUND
Rheumatoid Arthritis (RA) involves prolonged inflammation of the synovium, damaging joints and causing stiffness and deformity. Celastrol (Cel), derived from the Chinese herbal medicine Hook F, offers immunosuppressive effects for RA treatment but is limited by poor solubility and bioavailability.
PURPOSE
In this study, long-circulating Cel-loaded liposomes (Cel-LPs) were used to increase the pharmacokinetics of Cel, thereby improving drug delivery and efficacy for the treatment of RA.
METHODS
Cel-LPs were prepared and administered orally and intravenously to compare the elimination half-life of drugs and bioavailability of Cel. Cel-LPs were prepared using the lipid thin-layer-hydration-extrusion method. Human rheumatoid arthritis synovial (MH7A) cells were used to investigate the compatibility of Cel-LPs. The pharmacokinetic studies were performed on male Sprague-Dawley (SD) rats.
RESULTS
The Cel-LPs had an average size of 72.20 ± 27.99 nm, a PDI of 0.267, a zeta potential of -31.60 ± 6.81 mV, 78.77 ± 5.69% drug entrapment efficiency and sustained release (5.83 ± 0.42% drug loading). The cytotoxicity test showed that liposomes had excellent biocompatibility and the fluorescence microscope diagram indicated that liposome entrapment increased intracellular accumulation of Rhodamine B by MH7A cells. Furthermore, the results exhibited that Cel-LPs improved the pharmacokinetics of Cel by increasing the elimination half-life (t) to 11.71 hr, mean residence time (MRT) to 7.98 hr and apparent volume of distribution (Vz/F) to 44.63 L/kg in rats, compared to the Cel solution.
CONCLUSION
In this study, liposomes were demonstrated to be effective in optimizing the delivery of Cel, enabling the formulation of Cel-LPs with prolonged blood circulation and sustained release characteristics. This formulation enhanced the intravenous solubility and bioavailability of Cel, developing a foundation for its clinical application in RA and providing insights on poorly soluble drug management.
Topics: Pentacyclic Triterpenes; Animals; Liposomes; Triterpenes; Male; Rats, Sprague-Dawley; Humans; Administration, Intravenous; Rats; Biological Availability; Cell Line; Arthritis, Rheumatoid; Particle Size; Cell Survival; Drug Delivery Systems
PubMed: 38882540
DOI: 10.2147/IJN.S461624 -
Matrix Biology Plus Aug 2024Cardiac fibrosis is characterized by excessive accumulation and deposition of ECM proteins. Cardiac fibrosis is commonly implicated in a variety of cardiovascular...
Cardiac fibrosis is characterized by excessive accumulation and deposition of ECM proteins. Cardiac fibrosis is commonly implicated in a variety of cardiovascular diseases, including post-myocardial infarction (MI). We have previously developed a dual-delivery nanogel therapeutic to deliver tissue plasminogen activator (tPA) and Y-27632 (a ROCK inhibitor) to address MI-associated coronary artery occlusion and downregulate cell-contractility mediated fibrotic responses. Initial studies were conducted on glass substrates. The study presented here employs the use of polyacrylamide (PA) gels and microgel thin films to mimic healthy and fibrotic cardiac tissue mechanics. Soft and stiff polyacrylamide substrates or high and low loss tangent microgel thin films were utilized to examine the influence of cell-substrate interactions on dual-loaded nanogel therapeutic efficacy. In the presence of Y-27632 containing nanogels, a reduction of fibrotic marker expression was noted on traditional PA gels mimicking healthy and fibrotic cardiac tissue mechanics. These findings differed on more physiologically relevant microgel thin films, where early treatment with the ROCK inhibitor intensified the fibrotic related responses.
PubMed: 38882395
DOI: 10.1016/j.mbplus.2024.100150 -
Medical Science Monitor : International... Jun 2024BACKGROUND Over the past decades, total knee arthroplasty (TKA) in China has increased substantially. Owing to a lack of a joint registry, there is restricted...
BACKGROUND Over the past decades, total knee arthroplasty (TKA) in China has increased substantially. Owing to a lack of a joint registry, there is restricted information concerning the epidemiology of TKA failures in China. We aimed to (1) investigate the etiology of TKA failures in a cohort of Chinese patients and (2) determine the related demographic and anthropometric risk factors in Jilin, China, to have a look at the actual situation. MATERIAL AND METHODS A total of 1927 primary and 109 revision TKAs performed between April 2014 and May 2022 were analyzed in this retrospective study. Patient demographics and anthropometric measures, the interval from primary TKA to revision procedures, and the mechanisms for primary TKA failure were evaluated. A chi-square test, unpaired t test, and multivariate logistic regression were used to investigate the relationships between different factors and TKA failures. RESULTS The leading failure mechanism was infection (53.3%), followed by aseptic loosening (21.5%), stiffness (15.0%), instability (3.7%), malposition (2.8%), periprosthetic fractures (2.8%), and extensor mechanism disruption (0.9%). Infection (59.7%) was the main reason for early revision. Aseptic loosening (43.3%) was the leading cause of late revision. The male ratio in infection patients was higher (35.1% vs 20.6%). The smoking rate in patients with revision and infection was higher (18.9%, 23.9% vs 7%) than in primary patients. There was no difference in BMI between groups. CONCLUSIONS The leading cause of revision TKA in Jilin, China, was infection, followed by aseptic loosening and stiffness. Sex and smoking history were associated with TKA failures in this region.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Arthroplasty, Replacement, Knee; China; East Asian People; Knee Prosthesis; Prosthesis Failure; Reoperation; Retrospective Studies; Risk Factors
PubMed: 38881074
DOI: 10.12659/MSM.943681 -
Histochemistry and Cell Biology Jun 2024Förster resonance energy transfer (FRET) serves as a tool for measuring protein-protein interactions using various sensor molecules. The tension sensor module relies on...
Förster resonance energy transfer (FRET) serves as a tool for measuring protein-protein interactions using various sensor molecules. The tension sensor module relies on FRET technology. In our study, this module was inserted within the actinin molecule to measure the surface tension of the cells. Given that the decay curve of FRET efficiency correlates with surface tension increase, precise and accurate efficiency measurement becomes crucial. Among the methods of FRET measurements, FRET efficiency remains the most accurate if sample fixation is successful. However, when cells were fixed with 4% paraformaldehyde (PFA), the actinin-FRET sensor diffused across the cytoplasm; this prompted us to explore fixation method enhancements. Glyoxal fixative has been reported to improve cytoskeletal morphologies compared to PFA. However, it was not known whether glyoxal fits FRET measurements. Glyoxal necessitates an acetic acid solution for fixation; however, acidic conditions could compromise fluorescence stability. We observed that the pH working range of glyoxal fixative aligns closely with MES (methyl-ethylene sulfonic acid) Good's buffer. Initially, we switched the acidic solution for MES buffer and optimized the fixation procedure for in vitro and in vivo FRET imaging. By comparing FRET measurements on hydrogels with known stiffness to tumor nodules in mouse lung, we estimated in vivo stiffness. The estimated stiffness of cancerous tissue was harder than the reported stiffness of smooth muscle. This discovery shed lights on how cancer cells perceive environmental stiffness during metastasis.
PubMed: 38880796
DOI: 10.1007/s00418-024-02304-x -
International Orthopaedics Jun 2024To compare the efficacy and safety of MAKO robot-assisted total knee arthroplasty (MA-TKA) with conventional manual total knee arthroplasty (CM-TKA) in patients with...
Comparison of the efficacy and safety of MAKO robot-assisted total knee arthroplasty versus conventional manual total knee arthroplasty in uncomplicated unilateral total knee arthroplasty a single-centre retrospective analysis.
PURPOSE
To compare the efficacy and safety of MAKO robot-assisted total knee arthroplasty (MA-TKA) with conventional manual total knee arthroplasty (CM-TKA) in patients with end-stage knee osteoarthritis (KOA) during the early postoperative period.
METHOD
A retrospective analysis was conducted on 22 patients with KOA who underwent MA-TKA and 26 patients who underwent CM-TKA from April 2023 to July 2023. Hip-knee-ankle angle (HKA), lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), American Knee Society Score (AKSS), Forgotten Joint Score-12 (FJS-12), visual analogue scale (VAS), and postoperative complications were recorded and compared between the two groups.
RESULT
Both groups successfully completed the surgeries. In terms of radiographic parameters, postoperative one month LDFA and HKA in the MA-TKA group were significantly lower than those in the CM-TKA group (P < 0.05). At the one month follow-up, 19 patients (86.4%) in the MA-TKA group had an HKA less than 3°, compared to 20 patients (76.9%) in the CM-TKA group. Clinically, VAS scores at 24 h, 48 h, and 72 h postoperatively were lower in the MA-TKA group both at rest and during activity. At one month and three months postoperatively, AKSS Function Scores and FJS-12 scores in the MA-TKA group were significantly higher than those in the CM-TKA group (P < 0.05). Regarding postoperative complications, no complications occurred in the MA-TKA group, while one patient in the CM-TKA group experienced postoperative knee stiffness, which resolved after physical therapy, with no statistically significant difference (P > 0.05).
CONCLUSION
Compared with conventional manual total knee arthroplasty, MAKO robot-assisted TKA demonstrates better short-term clinical efficacy, achieves better alignment planning, and maintains good safety.
PubMed: 38874668
DOI: 10.1007/s00264-024-06234-0 -
Journal of Sports Sciences May 2024The primary objective of this study was to investigate the relationship between metatarsophalangeal joint (MTPj) flexion torque and sprint acceleration, cutting and...
The primary objective of this study was to investigate the relationship between metatarsophalangeal joint (MTPj) flexion torque and sprint acceleration, cutting and jumping performance, and kinetics. A secondary aim was to explore this relationship when MTP flexion strength was associated with other foot and lower limb neuromuscular outputs. After an initial MTPj flexion torque assessment using a custom-built dynamometer, 52 high-level athletes performed the following tasks on a force platform system: maximal sprint acceleration, 90-degree cutting, vertical and horizontal jumps, and foot-ankle hops. Their foot posture, foot passive stiffness and foot-ankle reactive strength were assessed using the Foot Posture Index, the Arch Height Index Measurement System and the Foot-Ankle Rebound Jump Test. Ankle plantarflexion and knee extension isometric torque were assessed using an isokinetic dynamometer. During maximal speed sprinting, multiple linear regressions suggested a major contribution of MTPj flexion torque, foot passive stiffness and foot-ankle reactive strength to explain 28% and 35% of the total variance in the effective vertical impulse and contact time. Ankle plantarflexor and quadriceps isometric torques were aggregately contributors of acceleration performance and separate contributors of cutting and jumping performance. In conclusion, MTPj flexion torque was more strongly associated with sprinting performance kinetics especially at high-speed.
Topics: Humans; Muscle Strength; Torque; Acceleration; Running; Athletic Performance; Foot; Young Adult; Male; Biomechanical Phenomena; Metatarsophalangeal Joint; Kinetics; Female; Ankle; Muscle, Skeletal; Adolescent; Adult; Posture
PubMed: 38874271
DOI: 10.1080/02640414.2024.2367365 -
Journal of Cellular Immunology 2024Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes arthralgias and arthritis that may last for years. The objective of this study was to describe...
BACKGROUND
Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes arthralgias and arthritis that may last for years. The objective of this study was to describe the arthritis progression and T cell immunology over a two-year period.
METHODS
A cohort of 40 cases of serologically confirmed CHIKV from Magdalena and Atlántico, Colombia were followed in 2019 and again in 2021. Arthritis disease severity, disability, pain, stiffness, physical function, mobility, fatigue, anxiety, sleep disturbances and depression were assessed. Serum cytokines and T-cell subsets were measured and tested for change. Correlations within each of the 2 time periods for laboratory parameters were also examined.
RESULTS
Although, arthritis disease severity, as measured by the Disease Activity Score-28 (DAS-28) did not change significantly over a two-year period, a new metric- the Chikungunya Disease Activity Score (CHIK-DAS)- was more sensitive to detect changes in disease severity than the Disease Activity Score-28 (DAS-28) and showed some improvement in average disease severity from moderate to mild over two years. Cases were characterized by moderate disability, pain, and stiffness with mild alterations of physical function, mobility, fatigue, anxiety, sleep disturbances and depression that did not change significantly over time. Small joints including the fingers and wrists were most affected without significant change over time. The percentage of effector T cells (Teffs) and regulatory T cells (Tregs) of CD4 T cells both decreased over time. Teff percentages decreased more significantly resulting in a halving of the Teff/Treg ratio two years later. Furthermore, markers of Treg immunosuppressive function such as CTLA4, Helios, CD28, CD45RA and 41bb decreased over time. Cytokines did not change significantly over time.
CONCLUSIONS
The presented data suggest that arthritis persists almost seven years after chikungunya infection in some patients with waning Teff and Treg numbers and activation markers over time. Treg activation may be a promising therapeutic target for further investigation.
PubMed: 38873035
DOI: 10.33696/immunology.6.191