Injection Of Cells Research Articles

Mucosal-associated invariant T cells modulate innate immune cells and inhibit colon cancer growth.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of invivo-expanded MAIT cells into RAG1-/- mice with MC38-derived tumours inhibits tumour growth compared to control. Multiplex cytokine analyses showed that tumours from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co-culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.

442O A phase I clinical trial of intrathecal injection of allogeneic CAR-γδT cells targeting B7H3 for the treatment of patients with recurrent glioblastoma

442O A phase I clinical trial of intrathecal injection of allogeneic CAR-γδT cells targeting B7H3 for the treatment of patients with recurrent glioblastoma

Emerging alternatives to keratoplasty for corneal endothelial cell dysfunction.

While effective for treating endothelial dysfunction, keratoplasty has shortcomings including limited access to donor tissue for much of the world. Thus, alternative strategies are under development. This review explores the main advancements achieved in this field during 2022-2023. Recent publications further support the validity of intracameral cultivated allogeneic endothelial cell injection and Descemet stripping only, while emphasizing the benefits of adjunctive Rho-associated kinase inhibitor (ROCKi) therapy. New donor-independent artificial implants, such as EndoArt, show favorable results. Multiple pharmacologic agents, especially ROCKi, show promise as monotherapies, yet none are currently approved for human treatment. Multiple regenerative and genetic therapies are being investigated but all are still in preclinical stages. A plethora of innovative alternatives to keratoplasty for endothelial disease is in development. Among these, surgical methods are still the mainstay of treatment and closest to clinical application, though further studies to establish their benefits over keratoplasty are needed. Albeit promising, pharmacologic, regenerative, and genetic approaches require validation and are farther from clinical application.

Efficacy and safety of mesenchymal stem cell injections for knee osteoarthritis: A systematic review and meta-analysis

Background: There have not been any clear studies on the use of mesenchymal stem cells (MSCs) to treat osteoarthritis (OA) in the knee. Materials and Methods: This study investigates the effects of different MSC dosages on pain alleviation in individuals with OA in the knee by conducting a meta-analysis of existing randomized controlled trials. Electronic resources such as Google Scholar, PubMed, Cochrane Library, and Web of Science were searched up until June 2023. Treatment effect sizes were computed using the knee osteoarthritis outcome score (KOOS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Knee Society Score (KSS). Random or fixed effect models were applied to aggregate the data. We performed a subgroup analysis according to dosage level. The heterogeneity of the research was investigated using the Chi-square test and the I2 index. Results: The meta-analysis included 26 studies with a total sample size of 739 patients. A significant reduction in pain was observed 1 year and 2 years following the injection of MSCs into the injured joint, as indicated by the Visual Analogue Scale, WOMAC, KOOS, and KSS indexes (P < 0.05). Patients on MSCs reported much reduced pain after 1 and 2 years compared to the control group (P < 0.05). Subgroup and meta-regression analyses revealed no statistically significant variations in the effectiveness of MSC dosage (P < 0.05). The studies did not report any adverse effects. Conclusion: Different dosages of MSCs had the same pain-relieving effects on patients with OA in the knee. MSC injections were safe and beneficial in such cases.

Epigenetic Regulation of RNF135 by LSD1 Promotes Stemness Maintenance and Brain Metastasis in LungAdenocarcinoma.

RING finger protein 135 (RNF135) is identified as a regulator in certain cancer types. However, its role and molecular mechanisms in lung adenocarcinoma (LUAD) are still unclear. Herein, we investigated the level of RNF135 in tumor tissues of LUAD patients using the UALCAN database and confirmed the data by real-time PCR and western blot analysis. The effects of RNF135 on stemness maintenance and migration/invasion capability of LUAD cells were investigated by sphere formation, flow cytometry, wound healing, and transwell assay. Limiting dilution xenograft assay and intracardiac injection of LUAD cells were applied to assess the implications of RNF135 in tumorigenesis and brain metastasis. Our results revealed that RNF135 was upregulated in tumor tissues of LUAD patients and was positively correlated with poor prognosis. Knockdown of RNF135 suppressed cancer stem cells (CSCs)-like properties, and migration/invasion capability of A549 and NCI-H1975 cells. Conversely, overexpression of RNF135 augmented CSCs-like traits and migration/invasion ability of LUAD cells. Limiting dilution xenograft assay demonstrated that RNF135 was required for the self-renewal of CSCs to initiate LUAD development. Overexpression of RNF135 in A549 cells increased their ability to metastasize to the brain in vivo. Mechanistically, the transcriptional activation of RNF135 by LSD1 involved H3K9me2 demethylation at the promoter region of RNF135. Reexpression of RNF135 in LSD1-silenced A549 cells was able to reverse LSD1-mediated stemness maintenance and migration/invasion capability. Overall, our results implied that targeting of LSD1/RNF135 axis might be a feasible method to suppress tumorigenesis and brain metastasis of LUAD patients.

Downregulation of malic enzyme 3 facilitates progression of gastric carcinoma via regulating intracellular oxidative stress and hypoxia-inducible factor-1α stabilization

BackgroundGastric cancer (GC) is one of the most malignant cancers worldwide. Metabolism disorder is a critical characteristic of malignant tumors related to tumor progression and metastasis. However, the expression and molecular mechanism of malic enzyme 3 (ME3) in GC are rarely reported. In this study, we aim to investigate the molecular mechanism of ME3 in the development of GC and to explore its potential value as a prognostic and therapeutic target in GC.MethodME3 mRNA and protein expression were evaluated in patients with GC using RT-qPCR, WB, and immunohistochemistry, as well as their correlation with clinicopathological indicators. The effect of ME3 on proliferation and metastasis was evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU) assay, transwell assay, wound healing assay, and subcutaneous injection or tail vein injection of tumor cells in mice model. The effects of ME3 knockdown on the level of metabolites and hypoxia-inducible factor-1α (HIF-1α) protein were determined in GC cells. Oxidative phosphorylation was measured to evaluate adenosine triphosphate (ATP) production.ResultsME3 was downregulated in human GC tissues (P < 0.001). The decreased ME3 mRNA expression was associated with younger age (P = 0.02), pathological staging (P = 0.049), and lymph node metastasis (P = 0.001), while low ME3 expression was associated with tumor size (P = 0.048), tumor invasion depth (P < 0.001), lymph node metastasis (P = 0.018), TNM staging (P < 0.001), and poor prognosis (OS, P = 0.0206; PFS P = 0.0453). ME3 knockdown promoted GC cell malignancy phenotypes. Moreover, α-ketoglutarate (α-KG) and NADPH/NADP+ ratios were reduced while malate was increased in the ME3 knockdown group under normoxia. When cells were incubated under hypoxia, the NADPH/NADP+ ratio and α-KG decreased while intracellular reactive oxygen species (ROS) increased significantly. The ME3 knockdown group exhibited an increase in ATP production and while ME3 overexpression group exhibited oppositely. We discovered that ME3 and HIF-1α expression were negatively correlated in GC cells and tissues, and proposed the hypothesis: downregulation of ME3 promotes GC progression via regulating intracellular oxidative stress and HIF-1α.ConclusionWe provide evidence that ME3 downregulation is associated with poor prognosis in GC patients and propose a hypothesis for the ME3 regulatory mechanism in GC progression. The present study is of great scientific significance and clinical value for exploring the prognostic and therapeutic targets of GC, evaluating and improving the clinical efficacy of patients, reducing recurrence and metastasis, and improving the prognosis and quality of life of patients.

Tissue-engineered sub-urethral sling with muscle-derived cells for urethral sphincter regeneration in an animal model of stress urinary incontinence.

Stress urinary incontinence (SUI) is a widespread condition affecting more than 200 million people worldwide. Common treatments for this condition include retropubic colposuspension, and pelvic sling methods, which use autologous grafts or synthetic materials to support the bladder neck and urethral sphincter. Although these treatments have a cure rate of over 80%, adverse effects and recurrence may still occur. Several studies have focused on the potential of cell therapy. Muscle-derived cells (MDCs) can be easily obtained from small biopsied striated muscular tissues and possess superior multi-lineage differentiation and self-renewal capacity. Based on the unique characteristics of MDCs and previous favorable results in muscle regeneration, we fabricated a chitosan-gelatin hydrogel sling loaded with MDCs in a rat model of SUI. Leak point pressure and histological indices regarding inflammation, muscular atrophy, and collagen density were assessed to compare the effectiveness of cell injection and cell-laden sling. The level of LPP was significantly reduced in the MODEL group versus the control animals. The LPP level was considerably higher in CELL INJECTION, SLING, and CELL/SLING groups compared to the MODEL group but did not reach the significance threshold. The inflammation rate was significantly lower in the CELL/SLING group compared to the SLING group. The CELL/SLING group showed less atrophy compared to the other experimental groups, indicating that the cells may have higher viability on SLING than through injection. This also suggests that in long-term studies, as the degradation rate of hydrogels increases, the function of cells will become more apparent.

Intravenous injection of allogenic canine mesenchymal stem cells in 40 client-owned dogs: a safety assessment in veterinary clinical trials

BackgroundThe aim of this study was to evaluate the adverse effects of allogeneic mesenchymal stem cells (MSCs) transplanted via intravenous infusion in dogs and examine their safety. We performed a retrospective analysis of various clinical assessments, including physical examination, blood tests, and radiographs, and monitored the formation of neoplasms during a 6-month follow-up period in 40 client-owned dogs that received intravenous infusion of adipose tissue-derived MSCs (AT-MSCs) for the treatment of various underlying diseases between 2012 and 2018.ResultsNo significant adverse effects of MSC therapy were detected by clinical assessment, blood tests, or radiographic examination in the 6-month follow-up period after the first MSC treatment. Additionally no new neoplasms were observed during this period.ConclusionsTo our knowledge, this study is the first to evaluate the safety aspects (≥ 6 months) associated with intravenous allogeneic AT-MSC infusion. These results suggest that allogenic AT-MSC infusion could be a useful and relatively safe therapeutic approach in canines.

Curcumin suppresses copper accumulation in non-small cell lung cancer by binding ATOX1

BackgroundNon-small cell lung cancer (NSCLC) is associated with intracellular copper accumulation. Antioxidant 1 (ATOX1) is a copper chaperone. This study aimed to analyze the anti-cancer effects of curcumin on the ATOX1-mediated copper pathway in NSCLC.MethodsA binding activity between curcumin and ATOX1 was measured using molecular docking. NSCLC cells, A549 and H1299, were treated with different doses of curcumin (10, 20, 40 µM) or DC-AC50 (5, 10, 20 µM) for 24 h. The cell viability and levels of ATOX1, ATP7A and COX17 proteins were observed in cells. Overexpressing ATOX1 in cells was established by pcDNA3.1-ATOX1 transfection for 24 h. The ATOX1 overexpressing cells were treated with 40 µM curcumin or 20 µM DC-AC50 for 24 h to analyze the mechanism of curcumin in NSCLC treatment. Cell viability was measured by CCK-8, and levels of proteins were measured by western blotting. The copper level in cells was labeled by copper sensor-1. Moreover, nude mice models were induced by injection of A549 cells and treated with 20 mg/kg/d DC-AC50 or 40 mg/kg/d curcumin. Tumor growth was observed by measuring tumor volume and tumor weight. The levels of ATOX1, ATP7A and COX17 in tumors were measured by immunohistochemistry and western blotting.ResultsCurcumin bound to ATOX1 (score = −6.1 kcal/mol) and decreased the levels of ATOX1, ATP7A and COX17 proteins in NSCLC cells. The curcumin or DC-AC50 treatment suppressed cell viability by inhibiting the ATOX1-mediated copper signaling in NSCLC cells. The ATOX1 overexpression in cells significantly weakened the effects of curcumin on suppressing copper accumulation and the ATOX1-mediated copper pathway (p < 0.05). In mice models, curcumin or DC-AC50 treatment also suppressed tumor growth by suppressing the ATOX1-mediated copper pathway in tumors.ConclusionThis study demonstrated that curcumin bound ATOX1 to suppress copper accumulation in NSCLC cells, providing a new mechanism of curcumin for NSCLC treatment.

New Endoscopic Devices and Techniques for the Management of Post-Sleeve Gastrectomy Fistula and Gastric Band Migration.

Post-sleeve gastrectomy fistulas are a rare but possibly severe life-threatening complication. Besides early reoperation and drainage, endoscopy is the main treatment option. According to the clinical setting, endoscopic treatment options comprise stent or clip placement. New endoscopic therapies have recently gained attention, including endoscopic vacuum therapy, VacStent therapy, endoscopic internal drainage with pigtail stents, endoscopic suturing and stem cell injection. In this narrative review, we shed light on recent literature, developments, indications and contraindications of these treatments. Intragastric gastric band migration is a rare complication after gastric band positioning. Reoperation can sometimes be difficult, especially when a gastric band has already migrated far into the stomach. Endoscopic retrieval can be a valid, non-invasive therapeutic solution. We reviewed the current literature on this matter.

Management of Red Cell Alloimmunization in Pregnancy.

Rhesus immune globulin has resulted in a marked decrease in the prevalence of RhD alloimmunization in pregnancy; however, antibody formation to other red cell antigens continues to occur. Evaluation for the presence of anti-red cell antibodies should be routinely undertaken at the first prenatal visit. If anti-red cell antibodies are detected, consideration of a consultation or referral to a maternal-fetal medicine specialist with experience in the monitoring and treatment of these patients is warranted. Cell-free DNA can be used to determine fetal red cell antigen status to determine whether the pregnancy is at risk of complications from the red cell antibodies. First-time sensitized pregnancies are followed up with serial maternal titers, and, when indicated, serial Doppler assessment of the peak systolic velocity in the middle cerebral artery should be initiated by 16 weeks of gestation. When there is a history of an affected fetus or neonate, maternal titers are less predictive of fetal risk; if the fetus is antigen positive, serial peak systolic velocity in the middle cerebral artery measurements should be initiated by 15 weeks of gestation because intraperitoneal intrauterine blood transfusions can be used at this gestation if needed. The mainstay of fetal therapy involves intrauterine transfusion through ultrasound-directed puncture of the umbilical cord with the direct intravascular injection of red cells. A perinatal survival rate exceeding 95% can be expected at experienced centers. Neonatal phototherapy and "top-up" transfusions attributable to suppressed reticulocytosis often are still required for therapy after delivery.

Does rAj-Tspin, a novel peptide from A. japonicus, exert antihepatocellular carcinoma effects via the ITGB1/ZYX/FAK/AKT signaling pathway?

rAj-Tspin, a soluble recombinant peptide from Apostichopus japonicus, can inhibit the integrin β1 (ITGB1)/FAK/AKT signaling pathway in hepatocellular carcinoma (HCC) via cell epithelial–mesenchymal transition (EMT) and apoptosis. Zyxin (ZYX) is a focal adhesion protein that is considered a novel mediator of EMT and apoptosis. However, the inhibitory mechanisms of rAj-Tspin in HCC and whether it is related to ZYX are unclear. We examined the antitumor effect of rAj-Tspin on the Huh7 human HCC cell line and on a nude mouse model generated via subcutaneous injection or orthotopic intrahepatic transplantation of Huh7 cells. Our results revealed that rAj-Tspin strikingly reduced the viability and promoted the apoptosis of Huh7 cells and inhibited HCC tumor growth in nude mice. rAj-Tspin inhibited ITGB1 and ZYX protein expression in vivo and in vitro in a dose-dependent manner. Mechanistically, the FAK/AKT signaling pathway and the proliferation and invasion of HCC cells were suppressed upon ITGB1 and ZYX knockdown. Moreover, the effect of ITGB1 overexpression on the growth of HCC cells was inhibited by rAj-Tspin. In contrast, the promoting effect of ITGB1 overexpression could be inhibited by ZYX knockdown. ZYX knockdown had no effect on ITGB1 expression. These findings suggest that ZYX is required for the indispensable role of ITGB1 in rAj-Tspin‐alleviated HCC and provide an important therapeutic target for HCC. In summary, the anti-HCC effect of rAj-Tspin potentially involves the regulation of the ITGB1/ZYX/FAK/AKT pathway, which in turn impacts EMT and apoptosis.Graphical

MicroRNA-based engineered mesenchymal stem cell extracellular vesicles to treat visual deficits after blast-induced trauma

Our previous studies have shown the benefit of intravitreal injection of a mesenchymal stem cell (MSC)- derived secretome to treat visual deficits in a mild traumatic brain injury (mTBI) mouse model. In this study, we have addressed whether MSC-derived extracellular vesicles (EV) overexpressing miR424, which particularly targets neuroinflammation, show similar benefits in the mTBI model. Adult C57BL/6 mice were subjected to a 50-psi air pulse on the left side, overlying the forebrain, resulting in mTBI. Sham-blast mice were controls. Within an hour of blast injury, 3 μl (∼7.5 × 108 particles) of miR424-EVs, native-EVs, or saline was delivered intravitreally. One month later, retinal morphology was observed through optical coherence tomography (OCT); visual function was assessed using optokinetic nystagmus (OKN) and electroretinogram (ERG), followed by immunohistological analysis. A separate study in adult mice tested the dose-response of EVs for safety. Blast injury mice with saline showed decreased visual acuity compared with the sham group (0.30 ± 0.03 vs. 0.39 ± 0.01 c/d, p < 0.02), improved with miR424-EVs (0.39 ± 0.02 c/d, p < 0.01) but not native-EVs (0.33 ± 0.04 c/d, p > 0.05). Contrast sensitivity thresholds of blast mice receiving saline increased compared with the sham group (85.3 ± 5.9 vs. 19.9 ± 4.8, %, p < 0.001), rescued by miR424-EVs (23.6 ± 7.3 %, p < 0.001) and native-EVs (45.6 ± 10.7 %, p < 0.01). Blast injury decreased “b” wave amplitude compared to sham mice (94.6 ± 24.0 vs. 279.2 ± 25.3 μV, p < 0.001), improved with miR424-EVs (173.0 ± 27.2 μV, p < 0.03) and native-EVs (230.2 ± 37.2 μV, p < 0.01) with a similar decrease in a-wave amplitude in blast mice improved with both miR424-EVs and native-EVs. Immunohistology showed increased GFAP and IBA1 in blast mice with saline compared with sham (GFAP: 11.9 ± 1.49 vs. 9.1 ± 0.8, mean intensity/100,000 μm2 area, p < 0.03; IBA1: 36.08 ± 4.3 vs. 24.0 ± 1.54, mean intensity/100,000 μm2 area, p < 0.01), with no changes with native-EVs (GFAP: 12.6 ± 0.79, p > 0.05; IBA1: 32.8 ± 2.9, p > 0.05), and miR424-EV (GFAP: 13.14 ± 0.76, p > 0.05; IBA1: 31.4 ± 2.7, p > 0.05). Both native-EVs and miR424-EVs exhibited vitreous aggregation, as evidenced by particulates in the vitreous by OCT, and increased vascular structures, as evidenced by αSMA and CD31 immunostainings. The number of capillary lumens in the ganglion cell layer increased with increased particles in the eye, with native EVs showing the worst effects. In conclusion, our study highlights the promise of EV-based therapies for treating visual dysfunction caused by mTBI, with miR424-EVs showing particularly strong neuroprotective benefits. Both miR424-EVs and native-EVs provided similar protection, but issues with EV aggregation and astrogliosis or microglial/macrophage activation at the current dosage call for improved delivery methods and dosage adjustments. Future research should investigate the mechanisms behind EVs' effects and optimize miR424 delivery strategies to enhance therapeutic outcomes and reduce complications.

Immunotherapy for children with malignant brain tumors

The incidence of high-grade malignant gliomas (MG) ranges from 35 to 46% of all central nervous system tumors. Despite combined therapy including surgery, radiation treatment and chemotherapy, overall five-year survival does not exceed 10%. The advent of novel immunotherapeutic strategies has promoted a renewed hopes for the treatment of MG. The aim of the present study was to improve the survival rates of glioma patients. Our study included 5 pediatric patients at the median age of 7.6 years (2-16). Three pts had anaplastic astrocytoma (AA) (1st relapse, 1 pt; 2nd relapse, in 2 pts), One patient was diagnosed with glioblastoma multiforme (GBM) (3rd recurrence), and 1 child had diffuse brainstem glioma (BSG). The median time to the first relapse was 12 months (4 to 16), the second relapse occurred at a median of 5 months (1 to 8). The protocol of immunotherapy included combined administration of autologous dendritic cell-based vaccine (DV) and repeated intrathecal/intraventricular injections of donor allogeneic immunocompetent cells (alloIC) for at least 2 years. Two of 3 pts with AA experienced a progression-free interval of 67 and 71 months. One patient with 3rd GBM relapse is alive without any treatment for 13.3 years after starting the immunotherapy. The median time of follow-up was 67 months, with the 2-year overall survival rate of 58%. Two pts died from the disease progression within 6 and 7 months from the beginning of immunotherapy. Over the period of treatment, the patients received a median of 20 alloIC injections (8 to 60), and 18 DV administrations (8 to 44). No serious side-effects were observed. Immunotherapy could be an promising option for treating patients with high-grade malignant gliomas refractory to conventional therapy and, therefore, deserves further investigations.

Abstract Mo010: Evidence for cardiomyocyte dysfunction in cancer-induced cachexia in mice

Background: There is currently no therapy targeting cancer-related cardiomyopathy and treatment of heart failure in the oncological setting is nonspecific. Moreover, cancer is often assocaited with cachexia and the pathophysiology of cancer-cachexia induced cardiac (dys)functions are not fully known. Methods: Colon-26 adenocarcinoma (C26; n=30) or shIL-6 (C26 shIL-6; n=30) cells were inoculated subcutaneously into the flank of syngeneic adult male BALB/cmice, meanwhile control mice were injected with PBS (n=25). Twenty days after the cells injection, cardiac function was assessed using transthoracic echocardiography, ex vivo isolated working heart methods. In addition, intracellular Ca 2+ transient and force-calcium relationships were assessed in isolated single ventricular cardiomyocytes (CMs). Cardiac inflammation, metabolism and fibrosis were also assessed. Results: Despite that tumor size was comparable between the cancer groups, C26 group showed a loss of subcutaneous fat and skeletal muscle confirming a cachectic phenotype in association with an elevation of serum IL-6 levels. Tumor-bearing mice groups show a tendecy towards to both LV systolic and diastolic dysfunction. Sarcomere dysfunction, including significantly reduced maximum calcium-activated tension (Tmax) and increased calcium sensitivity (decreased EC 50 ) was found in skinned cardiomyocyte preparation from both tumor-bearing mice in compared to controls (p&lt;0.05, respectively). Intracellular Ca 2+ transient was exclusively increased in CM isolated from cachectic mice, suggesting the SERCA2 upregulation. Infiltration of macrophage or T-cells, nor interstital fibrosis were difference. β-myosin heavy chain expression is upregulated in a cell autonomous fashion in C26 mice. Comprehensive energetic and metabolims analysis showed shift to a profound glucose metabolsim and reduction in fatty acid oxidation in LV samples. This was futher proven in h9c2 cells were incubated with C26 or shIL6 cell culture medium. Discussion: Our results suggest that LV dysfunction in cancer mice is associated with sarcomere dysfunction while additional abnormal intracellular Ca 2+ handling is solely present in mice with cachectic phenotype. These functional alterations are independent from changes in myocardial fibrosis and inflammation but may rely on the cardiac metabolism alterations. These data provide new insights into how cancer and cancer-cachexia impacts the cardiac performance even prior to cancer therapy treatments.

Denosumab Re-Challenge and Long-Term Efficacy for Aneurysmal Bone Cyst of the Spine: Enhanced Treatment Algorithm.

Background/Objective: Surgical treatment of aneurysmal bone cysts (ABCs) can be challenging, especially in the spine. Non-surgical treatments such as with denosumab have shown promising results in different osteolytic pathologies. This retrospective observational study aimed to evaluate the long-term clinical and radiologic response of patients with ABCs of the mobile spine treated with denosumab and propose an updated treatment algorithm. Methods: Six patients with relapsed and symptomatic ABCs of the mobile spine were treated with denosumab (120 mg subcutaneously on days 1, 8, 15, 29, and every 4 weeks thereafter) between 2012 and 2023. Disease assessments were conducted using CT and MRI at 3, 6, 9, and 12 months post-treatment. Clinical data, including pain levels, symptoms, and adverse events, were documented from patients' charts. Results: Patients underwent an initial phase of treatment with denosumab, receiving a mean of 22 administrations (range 13-42) over a median follow-up period of 41 months (range 15-98 months). Clinical improvement was observed in all patients after 4 weeks of treatment, and all patients demonstrated a radiological response after 12-24 weeks on denosumab. Three patients were progression-free after discontinuing denosumab following 13, 15, and 42 administrations, respectively. At the last follow-up, after 38, 43, and 98 months, these patients remained stable without relapse of the disease. Three patients had a relapse of disease after denosumab; two of them underwent denosumab re-challenge, while one patient received one mesenchymal stem cells (MSCs) injection. All patients showed clinical and radiological improvement and were resulted to be disease-free at the last follow-up. Conclusions: This study demonstrates the long-term efficacy and safety of denosumab in treating ABCs of the mobile spine, as well as the potential of re-challenge in managing recurrence. A treatment algorithm is proposed, positioning denosumab as a viable therapeutic option after other local treatments. Careful patient selection, monitoring, and further research are necessary to optimize denosumab use for ABCs.

The impact of subdermal adipose derived stem cell injections and early excision on systemic oxidative stress and wound healing in rats with severe scald burns

AimThis study aims to develop an experimental treatment model effective against oxidative stress in the acute period of severe burns and to analyze the mechanisms of healing large wound defects. MethodsFive rats, including 2 females and 3 males, were used as donors to obtain adipose-derived stem cells (ADSC) from the inguinal fat pad. The stem cells were labeled with green fluorescent protein. The study included four groups of 17 rats, each with grade 3 scalding burns on 30 % of their body surface, and a control group of 10 rats with an equal number of males and females. After early excision, 106 ADSC-derived stem cells were administered subdermally to the burned wound and autografted to the stem cell group (n = 17). The early excision group (n = 17) received early excision and autograft, with 2 ml of normal saline injected subdermally into the burn wound edge. The PLM group (n = 17) was treated with a polylactic membrane (PLM) dressing after the burn. No treatment was given to the burn group (n = 17). Ten rats from all groups were sacrificed on the 4th day post-burn for oxidative stress evaluation. The control group (n = 10) was sacrificed on day 4. Blood and tissue samples were collected post-sacrifice. Oxidative stress and inflammation in the blood, as well as cell damage in the skin, liver, kidneys, and lungs, were investigated histopathologically and biochemically on the 4th day post-burn. On the 70th day after burn, wound healing was examined macroscopically and histopathologically. ResultsOn the 4th day, oxidative stress results showed that the levels of Total Oxidative Capacity (TOC) in the blood were lowest in the stem cell (7.4 [6–8.8]), control (6.7 [5.9–7.6]), and early excision (7.5 [6.6–8.5]) groups, with no significant difference between them. The burn group (14.7 [12.5–16.9]) had the highest TOC levels. The PLM group (9.7 [8.6–10.7]) had lower TOC levels than the burn group but higher levels than the other groups.Histopathological examination on the 4th day revealed low liver caspase-3 immunoreactivity in the stem cell and early excision groups among the burn groups. Caspase-3 immunoreactivity levels were as follows: stem cell group (20 [10–30]), early excision group (25 [15–50]), PLM group (70 [50–100]), control group (0), and burn group (80 [60–120]). Other oxidative stress and end-organ damage outcomes were consistent with these results.All rats in the stem cell group had burn wounds that healed completely by the 70th day. Examination of the skin and its appendages from the stem cell group with an immunofluorescence microscope demonstrated green coloration, indicating incorporation of stem cells. ConclusionStem cells may have the potential to form new skin and its appendages, providing better healing for large skin defects. Early excision treatment, by removing local necrotic tissues after extensive and deep burns, can prevent end-organ damage due to systemic oxidative stress and inflammation. We also believe that when these two treatments are used together, they can achieve the best results.

Mesenchymal Stem Cells Injection Is More Effective Than Hyaluronic Acid Injection in the Treatment of Knee Osteoarthritis With Similar Safety: A Systematic Review and Meta-Analysis

PurposeTo evaluate the Efficacy and safety of intra-articular injection of mesenchymal stem cells (MSCs) versus Hyaluronic acid (HA) in the treatment of knee osteoarthritis (KOA). MethodsEligible randomized controlled trials (RCTs) were identified through a search of Pubmed, Embase, the Cochrane Library, Web of science, SinoMed and CNKI databases from inception to March 2024. For meta-analysis, data on clinical outcomes were measured using a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and data on cartilage repair were measured using the Whole-Organ Magnetic Resonance Imaging Score (WORMS); data on safety was evaluated by the incidence of adverse events. Two researchers independently read the included literatures, extracted data and evaluated the quality, and used Cochrane risk bias assessment tool for bias risk assessment, and RevMan5.3 software for Meta-analysis. Result：Ten RCTs involving 818 patients with KOA ranging from I-Ⅲ Kellgren – Lawrence grading scale were included in this meta-analysis. Meta results showed that compared with the HA control group, at 12months, the WOMAC total score [MD=-10.22, 95% CI (-14.86∼-5.59), P<0.0001, Z=4.32];VAS score[MD=-1.31, 95% CI (-1.90∼-0.73), P<0.0001, Z=4.40]; WORMS score [MD=-26.01,95% CI (-31.88∼-20.14),P<0.001,Z=8.69]of MSCs group all decreased significantly (P<0.05), and reached the minimum clinically important differences (MCID). Furthermore, there was no significant difference in the incidence of adverse events (RR=1.54, 95% CI= 0.85 ∼ 2.79, P=0.16, I2=0) between the two groups (P >0.05). ConclusionCompared to HA, intra-articular injection of MSCs therapy appears to effectively alleviate joint pain, improve clinical function of KOA patients. These benefits are observed to last for at least 12 months without an increase in adverse events. Due to limited, varied, and lacking MCID results in existing literature, further research is needed. Level of EvidenceLevel I, Meta-analysis of Level I studies.

Osteoarthritis year in review 2024: Epidemiology and therapy

This "Year in Review" presents a curated selection of research themes and individual studies within the clinical osteoarthritis (OA) field, focusing on epidemiology and therapy.The search was conducted in electronic database MEDLINE from March 4, 2023, to March 31, 2024, specifically targeting English-language articles involving human participants. Inclusions were based on perceived importance and relevance to identifying risk factors or advancing OA treatments. A total of 6,539 studies were screened by the 5 authors, resulting in 157 studies considered for potential inclusion. Ultimately, 44 studies were selected, uncovering six key OA-related themes: i) the burden of OA (mostly from Global Burden of Disease studies), ii) pain drivers and trajectories, iii) impacts of sex/gender, iv) OA risk factors, and treatments for v) hand and vi) knee OA. The prevalence of OA continues to rise, particularly affecting women, with unclear distinctions in risk factors and treatment responses between sex. Associations with atopy were demonstrated in two significant databases. Notably, the authors were particularly interested in recent high-quality methodology randomised controlled trials focusing on hand (methotrexate, denosumab, colchicine, topical bethamethasone) and knee OA with conflicting results about stem cells injection. These findings collectively contribute to show the growing burden of OA, but also to help the understanding of OA pathophysiology and inform ongoing efforts to enhance management for people with OA.

G-CSF induces neutrophil extracellular traps formation and promotes ovarian cancer peritoneal dissemination.

Epithelial ovarian cancer is characterized by aggressive peritoneal dissemination. Neutrophils are mobilized to peritoneal cavity in some patients with ovarian cancer dissemination; however, its pathological significance remains unknown. This study aimed to investigate the role of neutrophil extracellular traps (NETs) in ovarian cancer dissemination. We conducted a retrospective analysis of clinical data and samples from 340 patients with ovarian cancer who underwent primary surgery between 2007 and 2016 at the Osaka University Hospital. In vitro, NETs formation was induced by stimulating human peripheral neutrophils. The human ovarian cancer cell line, OVCAR8, was cocultured with NETs. For an ovarian cancer dissemination mouse model, we performed an intraperitoneal injection of OVCAR8 cells into nude mice. The association between NETs and peritoneal dissemination was explored, and model mice were treated with the PAD4 inhibitor GSK484 to assess antitumor efficacy. Neutrophilia (neutrophil count >7000/mm3) correlated with shorter survival, advanced peritoneal dissemination, elevated granulocyte colony-stimulating factor (G-CSF) levels, increased neutrophil count in ascites, and augmented NETs foci in peritoneal dissemination sites. In vitro assays revealed that G-CSF stimulated neutrophils to form NETs, promoting cancer cell adhesion. In vivo investigations revealed that G-CSF-producing tumor-bearing mice had accelerated peritoneal dissemination and poor prognosis. NETs formation was pathologically observed at the peritoneal dissemination sites. Inhibition of NETs formation by GSK484 significantly delayed peritoneal dissemination in vivo. In conclusion, G-CSF was associated with intra-abdominal NETs formation and increased peritoneal dissemination. NETs represent potential therapeutic targets for ovarian cancer, particularly in patients with neutrophilia.