The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.

SCD1 promotes the stemness of gastric cancer stem cells by inhibiting ferroptosis through the SQLE/cholesterol/mTOR signalling pathway.

Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs.

NIR Absorbing Organic Chromophores Combination with NSAIDs for Remodeling of the Inflammatory Microenvironment to Amplify Tumor Ferroptosis-Photothermal Synergistic Therapy.

Photothermal therapy has emerged as a promising approach for cancer treatment, which can cause ferroptosis to enhance immunotherapeutic efficacy. However, excessively generated immunogenicity will induce serious inflammatory response syndrome, resulting in a discounted therapeutic effect. Herein, a kind of NIR absorption small organic chromophore nanoparticles (TTHM NPs) with high photothermal conversion efficiency (68.33%) is developed, which can induce mitochondria dysfunction, generate mitochondrial superoxide, and following ferroptosis. TTHM NPs-based photothermal therapy is combined with Sulfasalazine (SUZ), a kind of nonsteroidal anti-inflammatory drugs, to weaken inflammation and promote ferroptosis through suppressing glutamate/cystine (Glu/Cys) antiporter system Xc- (xCT). Additionally, the combination of SUZ with PTT can induce immunogenic cell death (ICD), followed by promoting the maturation of DCs and the attraction of CD8+ T cell, which will secrete IFN-γ and trigger self-amplified ferroptosis via inhibiting xCT and simulating Acyl-CoA synthetase long-chain family member 4 (ACSL4). Moreover, the in vivo results demonstrate that this combination therapy can suppress the expression of inflammatory factors, enhance dendritic cell activation, facilitate T-cell infiltration, and realize effective thermal elimination of primary tumors and distant tumors. In general, this work provides an excellent example of combined medication and stimulates new thinking about onco-therapy and inflammatory response.

FPR3 reprograms glycolytic metabolism and stemness in gastric cancer via calcium-NFATc1 pathway.

Aerobic glycolysis accelerates tumor proliferation and progression, and inhibitors or drugs targeting abnormal cancer metabolism have been developing. Cancer stem-like cells (CSCs) significantly contribute to tumor initiation, metastasis, therapy resistance, and recurrence. Formyl peptide receptor 3 (FPR3), a member of FPR family, involves in inflammation, tissue repair, and angiogenesis. However, studies in exploring the regulatory mechanisms of aerobic glycolysis and CSCs by FPR3 in gastric cancer (GC) remain unknown. Here, we demonstrated that overexpressed FPR3 suppressed glycolytic capacity and stemness of tumor cells, then inhibited GC cells proliferation. Mechanistically, FPR3 impeded cytoplasmic calcium ion flux and hindered nuclear factor of activated T cells 1 (NFATc1) nuclear translocation, leading to the transcriptional inactivation of NFATc1-binding neurogenic locus notch homolog protein 3 (NOTCH3) promoter, subsequently obstructing NOTCH3 expression and the AKT/mTORC1 signaling pathway, and ultimately downregulating glycolysis. Additionally, NFATc1 directly binds to the sex determining region Y-box 2 (SOX2) promoter and modifies stemness in GC. In conclusion, our work illustrated that FPR3 played a negative role in GC progression by modulating NFATc1-mediated glycolysis and stemness in a calcium-dependent manner, providing potential insights into cancer therapy.

Reconstruction of medial meniscus posterior portion deficiency in pigs with an autologous patellar tendon graft: an experimental study.

OBJECTIVE: This study was performed to investigate the effectiveness of two surgical procedures, autologous patellar tendon graft reconstruction and trans-tibial plateau pull-out repair, using a pig model. The primary focus was to assess the repair capability of medial meniscus posterior portion (MMPP) deficiency, the overall structural integrity of the meniscus, and protection of the femoral and tibial cartilage between the two surgical groups. The overall aim was to provide experimental guidelines for clinical research using these findings. METHODS: Twelve pigs were selected to establish a model of injury to the MMPP 10 mm from the insertion point of the tibial plateau. They were randomly divided into three groups of four animals each: reconstruction (autologous tendon graft reconstruction of the MMPP), pull-out repair (suture repair of the MMPP via a trans-tibial plateau bone tunnel), and control (use of a normal medial meniscus as the negative control). The animals were euthanized 12 weeks postoperatively for evaluation of the meniscus, assessment of tendon bone healing, and gross observation of knee joint cartilage. The tibial and femoral cartilage injuries were evaluated using the International Society for Cartilage Repair (ICRS) grade and Mankin score. Histological and immunohistochemical staining was conducted on the meniscus-tendon junction area, primary meniscus, and tendons. The Ishida score was used to evaluate the regenerated meniscus in the reconstruction group. Magnetic resonance imaging (MRI) was used to evaluate meniscal healing. RESULTS: All 12 pigs recovered well after surgery; all incisions healed without infection, and no obvious complications occurred. Gross observation revealed superior results in the reconstruction and pull-out repair groups compared with the control group. In the tibial cartilage, the reconstruction group had ICRS grade I injury whereas the pull-out repair and control groups had ICRS grade II and III injury, respectively. The Mankin score was significantly different between the reconstruction and control groups; histological staining showed that the structure of the regenerated meniscus in the reconstruction group was similar to that of the original meniscus. Immunohistochemical staining showed that the degree of type I and II collagen staining was similar between the regenerated meniscus and the original meniscus in the reconstruction group. The Ishida score was not significantly different between the regenerated meniscus and the normal primary meniscus in the reconstruction group. MRI showed that the MMPP in the reconstruction and pull-out repair groups had fully healed, whereas that in the control group had not healed. CONCLUSION: Autologous patellar tendon graft reconstruction of the MMPP can generate a fibrocartilage-like regenerative meniscus. Both reconstruction and pull-out repair can preserve the structural integrity of the meniscus, promote healing of the MMPP, delay meniscal degeneration, and protect the knee cartilage.

HWJMSC-EVs promote cartilage regeneration and repair via the ITGB1/TGF-ß/Smad2/3 axis mediated by microfractures.

The current first-line treatment for repairing cartilage defects in clinical practice is the creation of microfractures (MF) to stimulate the release of mesenchymal stem cells (MSCs); however, this method has many limitations. Recent studies have found that MSC-derived extracellular vesicles (MSC-EVs) play an important role in tissue regeneration. This study aimed to verify whether MSC-EVs promote cartilage damage repair mediated by MFs and to explore the repair mechanisms. In vitro experiments showed that human umbilical cord Wharton's jelly MSC-EVs (hWJMSC-EVs) promoted the vitality of chondrocytes and the proliferation and differentiation ability of bone marrow-derived MSCs. This was mainly because hWJMSC-EVs carry integrin beta-1 (ITGB1), and cartilage and bone marrow-derived MSCs overexpress ITGB1 after absorbing EVs, thereby activating the transforming growth factor-ß/Smad2/3 axis. In a rabbit knee joint model of osteochondral defect repair, the injection of different concentrations of hWJMSC-EVs into the joint cavity showed that a concentration of 50 µg/ml significantly improved the formation of transparent cartilage after MF surgery. Extraction of regenerated cartilage revealed that the changes in ITGB1, transforming growth factor-ß, and Smad2/3 were directly proportional to the repair of regenerated cartilage. In summary, this study showed that hWJMSC-EVs promoted cartilage repair after MF surgery.

Misperception of peer beliefs reinforces inequitable gender norms among Tanzanian men.

Gender role ideology, i.e. beliefs about how genders should behave, is shaped by social learning. Accordingly, if perceptions about the beliefs of others are inaccurate this may impact trajectories of cultural change. Consistent with this premise, recent studies report evidence of a tendency to overestimate peer support for inequitable gender norms, especially among men, and that correcting apparent 'norm misperception' promotes transitions to relatively egalitarian beliefs. However, supporting evidence largely relies on self-report measures vulnerable to social desirability bias. Consequently, observed patterns may reflect researcher measurement error rather than participant misperception. Addressing this shortcoming, we examine men's gender role ideology using both conventional self-reported and a novel wife-reported measure of men's beliefs in an urbanising community in Tanzania. We confirm that participants overestimate peer support for gender inequity. However, the latter measure, which we argue more accurately captures men's true beliefs, implies that this tendency is relatively modest in magnitude and scope. Overestimation was most pronounced among men holding relatively inequitable beliefs, consistent with misperception of peer beliefs reinforcing inequitable norms. Furthermore, older and poorly educated men overestimated peer support for gender inequity the most, suggesting that outdated and limited social information contribute to norm misperception in this context.

Bioinformatics integration reveals key genes associated with mitophagy in myocardial ischemia-reperfusion injury.

BACKGROUND: Myocardial ischemia is a prevalent cardiovascular disorder associated with significant morbidity and mortality. While prompt restoration of blood flow is essential for improving patient outcomes, the subsequent reperfusion process can result in myocardial ischemia-reperfusion injury (MIRI). Mitophagy, a specialized autophagic mechanism, has consistently been implicated in various cardiovascular disorders. However, the specific connection between ischemia-reperfusion and mitophagy remains elusive. This study aims to elucidate and validate central mitophagy-related genes associated with MIRI through comprehensive bioinformatics analysis. METHODS: We acquired the microarray expression profile dataset (GSE108940) from the Gene Expression Omnibus (GEO) and identified differentially expressed genes (DEGs) using GEO2R. Subsequently, these DEGs were cross-referenced with the mitophagy database, and differential nucleotide sequence analysis was performed through enrichment analysis. Protein-protein interaction (PPI) network analysis was employed to identify hub genes, followed by clustering of these hub genes using cytoHubba and MCODE within Cytoscape software. Gene set enrichment analysis (GSEA) was conducted on central genes. Additionally, Western blotting, immunofluorescence, and quantitative polymerase chain reaction (qPCR) analyses were conducted to validate the expression patterns of pivotal genes in MIRI rat model and H9C2 cardiomyocytes. RESULTS: A total of 2719 DEGs and 61 mitophagy-DEGs were identified, followed by enrichment analyses and the construction of a PPI network. HSP90AA1, RPS27A, EEF2, EIF4A1, EIF2S1, HIF-1α, and BNIP3 emerged as the seven hub genes identified by cytoHubba and MCODE of Cytoscape software. Functional clustering analysis of HIF-1α and BNIP3 yielded a score of 9.647, as determined by Cytoscape (MCODE). In our MIRI rat model, Western blot and immunofluorescence analyses confirmed a significant elevation in the expression of HIF-1α and BNIP3, accompanied by a notable increase in the ratio of LC3II to LC3I. Subsequently, qPCR confirmed a significant upregulation of HIF-1α, BNIP3, and LC3 mRNA in the MIRI group. Activation of the HIF-1α/BNIP3 pathway mediates the regulation of the degree of Mitophagy, thereby effectively reducing apoptosis in rat H9C2 cardiomyocytes. CONCLUSIONS: This study has identified seven central genes among mitophagy-related DEGs that may play a pivotal role in MIRI, suggesting a correlation between the HIF-1α/BNIP3 pathway of mitophagy and the pathogenesis of MIRI. The findings highlight the potential importance of mitophagy in MIRI and provide valuable insights into underlying mechanisms and potential therapeutic targets for further exploration in future studies.

A superior heterologous prime-boost vaccination strategy against COVID-19: A bivalent vaccine based on yeast-derived RBD proteins followed by a heterologous vaccine.

Various vaccines have been challenged by SARS-CoV-2 variants. Here, we reported a yeast-derived recombinant bivalent vaccine (Bivalent wild-type [Wt]+De) based on the wt and Delta receptor-binding domain (RBD). Yeast derived RBD proteins based on the wt and Delta mutant were used as the prime vaccine. It was found that, in the presence of aluminium hydroxide (Alum) and unmethylated CpG-oligodeoxynucleotides (CpG) adjuvants, more cross-protective immunity against SARS-CoV-2 prototype and variants were elicited by bivalent vaccine than monovalent wtRBD or Delta RBD. Furthermore, a heterologous boosting strategy consisting of two doses of bivalent vaccines followed by one dose adenovirus vectored vaccine exhibited cross-neutralization capacity and specific T cell responses against Delta and Omicron (BA.1 and BA.4/5) variants in mice, superior to a homologous vaccination strategy. This study suggested that heterologous prime-boost vaccination with yeast-derived bivalent protein vaccine could be a potential approach to address the challenge of emerging variants.

Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer.

Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8+T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.

Gut microbiota modulate CD8+ T cell immunity in gastric cancer through Butyrate/GPR109A/HOPX.

The gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A-/-mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

Intra-articular injection of ascorbic acid enhances microfracture-mediated cartilage repair.

Previous studies have confirmed that ascorbic acid (AA) can promote cartilage repair and improve cartilage differentiation in bone marrow mesenchymal stem cells. However, the use of microfracture (MFX) combined with AA to repair cartilage damage has not been studied. This study established a rabbit animal model and treated cartilage injury with different concentrations of AA combined with MFX. Macroscopic observations, histological analysis, immunohistochemical analysis and reverse transcription quantitative polymerase chain reaction analysis of TGF-ß, AKT/Nrf2, and VEGF mRNA expression were performed. The results showed that intra-articular injection of AA had a positive effect on cartilage repair mediated by microfractures. Moreover, 10 mg/ml AA was the most effective at promoting cartilage repair mediated by microfractures. Intra-articular injection of AA promoted the synthesis of type II collagen and the formation of glycosaminoglycans by downregulating the mRNA expression of TGF-ß and VEGF. In summary, this study confirmed that AA could promote cartilage repair after MFX surgery.

Efficacy of Antibiotic Bone Cement in the Treatment of Burkholderia cepacia Infection After Spinal Internal Fixation Surgery: Case Report and Literature Review.

BACKGROUND: In recent years, the number of spinal internal fixation operations has increased significantly, correlating with an elevated risk of postoperative surgical site infection and a rising incidence rate. While the conventional treatment approach involves surgical debridement combined with antibiotic administration, there is a notable gap in reported strategies for Burkholderia cepacia infection and patients exhibiting multidrug resistance. METHODS: Surgical site infection occurred in a patient following internal fixation surgery for thoracic vertebral fractures. Despite the application of systemic antibiotics and regular dressing changes, no improvement was observed. Bacterial culture and drug sensitivity experiments revealed a multidrug-resistant Burkholderia cepacia infection. Two comprehensive debridement procedures were performed along with continuous post-operative irrigation combined with antibiotic administration; however, no significant improvement was observed. The patient's infection was significantly controlled following treatment with vancomycin loaded bone cement. RESULTS: Following spinal internal fixation surgery, the management of a B. cepacian infection with multidrug resistance presented a significant challenge, despite the application of debridement procedures and systemic antibiotics. In this case, after 20 days of treatment with vancomycin-loaded bone cement, the patient's C-reactive protein level decreased to 54 mg/L, was normalized by February, and normal levels were maintained in the surgical area 1 month and 6 months after bone cement removal. CONCLUSIONS: The use of vancomycin-loaded bone cement proves effective in treating postoperative B. cepacian infection in a multidrug-resistant case following spinal internal fixation surgery.

Experimental study of a 3D-printing technique combined with biphasic calcium phosphates to treat osteonecrosis of the femoral head in a canine model.

OBJECTIVE: This study was aimed to use a digital design of 3D-printing technology to create a surgical navigation template. At the same time, biphasic calcium phosphate (BCP) was applied to treat osteonecrosis of the femoral head (ONFH) in animal models, based on accurate positioning of necrotic lesions in the navigation templates and observation of its therapeutic effect. METHODS: Fifteen healthy adult male and female beagle dogs weighing 20 + 2 kg were randomly divided into three groups (n = 5) after establishing a model of ONFH using the liquid nitrogen freezing method. Each model underwent necrotic lesion creation and BPC implantations on one side of the femoral head and only necrotic lesion creation on the other side of the femoral head. Each group underwent CT examination, gross observation, histological examination and immunohistochemical staining at 6 weeks, 12 weeks and 18 weeks postoperatively. RESULTS: At weeks 6, 12, and 18, CT and gross examination showed that the necrotic area in the experimental group was basically intact and had been completely raised by BCP material. In the control group, there were signs of bone repair in the femoral head, but there were still large bone defects and cavities. At week 18, extensive collapse of the cartilage surface was observed. Through histological examination, in the experimental group at 12 and 18 weeks, a large number of new and reconstructed bone trabeculae containing a large amount of collagen fibres were observed (P < 0.05), while in the control group, there was extensive necrosis of the bone trabeculae without cellular structural areas. Immunohistochemical examination observation: A large number of CD31-positive cells were observed in the experimental group at 6 weeks, gradually decreasing at 12 and 18 weeks (P < 0.05), while a small number of CD31-positive cells were observed in the control group at 18 weeks. CONCLUSION: The 3D-printed navigation template can accurately locate ONFH lesions. Implantation of BCP material can effectively play a supporting role, prevent the collapse of the loading surface, and induce bone formation and angiogenesis to some extent.

[Progress and prospect of biological treatment for rotator cuff injury repair].

Objective: To review the research progress in biotherapy of rotator cuff injury in recent years, in order to provide help for clinical decision-making of rotator cuff injury treatment. Methods: The literature related to biotherapy of rotator cuff injury at home and abroad in recent years was widely reviewed, and the mechanism and efficacy of biotherapy for rotator cuff injury were summarized from the aspects of platelet-rich plasma (PRP), growth factors, stem cells, and exosomes. Results: In order to relieve patients' pain, improve upper limb function, and improve quality of life, the treatment of rotator cuff injury experienced an important change from conservative treatment to open surgery to arthroscopic rotator cuff repair. Arthroscopic rotator cuff repair plus a variety of biotherapy methods have become the mainstream of clinical treatment. All kinds of biotherapy methods have ideal mid- and long-term effectiveness in the repair of rotator cuff injury. The biotherapy method to promote the healing of rotator cuff injury is controversial and needs to be further studied. Conclusion: All kinds of biotherapy methods show a good effect on the repair of rotator cuff injury. It will be an important research direction to further develop new biotherapy technology and verify its effectiveness.

HOXA11 promotes lymphatic metastasis of gastric cancer via transcriptional activation of TGFß1.

Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a key target, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFß1 expression and activates the TGFß1/Smad2 pathway, which not only promotes EMT development but also induces VEGF-C secretion and lymphangiogenesis. These findings provide a plausible mechanism for HOXA11-modulated tumor in lymphatic metastasis and suggest that HOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.

Dual-tissue transplantation versus osteochondral autograft transplantation in the treatment of osteochondral defects: a porcine model study.

BACKGROUND: Osteochondral injury is a common sports injury, and hyaline cartilage does not regenerate spontaneously when injured. However, there is currently no gold standard for treating osteochondral defects. Osteochondral autograft transplantation (OAT) is widely used in clinical practice and is best used to treat small osteochondral lesions in the knee that are < 2 cm2 in size. Autologous dual-tissue transplantation (ADTT) is a promising method with wider indications for osteochondral injuries; however, ADTT has not been evaluated in many studies. This study aimed to compare the radiographic and histological results of ADTT and OAT for treating osteochondral defects in a porcine model. METHODS: Osteochondral defects were made in the bilateral medial condyles of the knees of 12 Dian-nan small-ear pigs. The 24 knees were divided into the ADTT group (n = 8), OAT group (n = 8), and empty control group (n = 8). At 2 and 4 months postoperatively, the knees underwent gross evaluation based on the International Cartilage Repair Society (ICRS) score, radiographic assessment based on CT findings and the magnetic resonance observation of cartilage repair tissue (MOCART) score, and histological evaluation based on the O'Driscoll histological score of the repair tissue. RESULTS: At 2 months postoperatively, the ICRS score, CT evaluation, MOCART score, and O'Driscoll histological score were significantly better in the OAT group than the ADTT group (all P < 0.05). At 4 months postoperatively, the ICRS score, CT evaluation, MOCART score, and O'Driscoll histological score tended to be better in the OAT group than the ADTT group, but these differences did not reach statistical significance (all P > 0.05). CONCLUSIONS: In a porcine model, ADTT and OAT are both effective treatments for osteochondral defects in weight bearing areas. ADTT may be useful as an alternative procedure to OAT for treating osteochondral defects.

Cancer Immunotherapy Based on Cell Membrane-Coated Nanocomposites Augmenting cGAS/STING Activation by Efferocytosis Blockade.

Innate immunity triggered by the cGAS/STING pathway has the potential to improve cancer immunotherapy. Previously, the authors reported that double-stranded DNA (dsDNA) released by dying tumor cells can trigger the cGAS/STING pathway. However, owing to efferocytosis, dying tumor cells are engulfed and cleared before the damaged dsDNA is released; hence, immunologic tolerance and immune escape occur. Herein, a cancer-cell-membrane biomimetic nanocomposites that exhibit tumor-immunotherapeutic effects are synthesized by augmenting the cGAS/STING pathway and suppressing efferocytosis. Once internalized by cancer cells, a combined chemo/chemodynamic therapy would be triggered, which damages their nuclear and mitochondrial DNA. Furthermore, the releasing Annexin A5 protein could inhibit efferocytosis effect and promote immunostimulatory secondary necrosis by preventing phosphatidylserine exposure, resulting in the burst release of dsDNA. These dsDNA fragments, as molecular patterns to immunogenic damage, escape from the cancer cells, activate the cGAS/STING pathway, enhance cross-presentation inside dendritic cells, and promote M1-polarization of tumor-associated macrophages. In vivo experiments suggest that the proposed nanocomposite could recruit cytotoxic T-cells and facilitate long-term immunological memory. Moreover, when combined with immune-checkpoint blockades, it could augment the immune response. Therefore, this novel biomimetic nanocomposite is a promising strategy for generating adaptive antitumor immune responses.

Radiosensitizing effects of pyrogallol-loaded mesoporous or-ganosilica nanoparticles on gastric cancer by amplified ferroptosis.

Radiotherapy (RT) incorporated multidisciplinary treatment is producing excellent clinical results, but its efficacy in treating late-stage gastric cancer is constrained by radioresistance and RT-related toxicity. Especially, since reactive oxygen species are the pivotal effectual molecules of ionizing radiation, improving ROS production by nanoparticles and other pharmacological modulation to amplify oxidation of polyunsaturated fatty acids and subsequent ferroptotic cell death is shown to enhance cancer cell radioresponse. Herein, we constructed a nanosystem by loading Pyrogallol (PG), a polyphenol compound and ROS generator, into mesoporous organosilica nanoparticles named as MON@pG. The nanoparticles exhibit proper size distribution with amplified ROS production and substantial glutathione depletion under X-ray radiation in gastric cancer cell line. Meanwhile, MON@PG enhanced radiosensitivity of gastric cancer in xenograft tumor model by ROS-mediated accumulation of DNA damage and apoptosis. Furthermore, this augmented oxidative process induced mitochondrial dysfunction and ferroptosis. In summary, MON@PG nanoparticles show the capacity to improve RT potency in gastric cancer by disrupting redox balance and augmenting ferroptosis.

Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation.

In antibody responses, mutated germinal center B (BGC) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of BGC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (TFH) cell-derived signals, in particular costimulation through CD40. Here, we demonstrate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BGC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. BGC cells, compared with non-BGC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in BGC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in BGC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.