Abstract Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC cells to traditional chemotherapies, low drug accumulation, and limited drug residence time in the peritoneal cavity, the therapeutic effects of malignant ascites in HCC are not satisfactory. In this study, an injectable hydrogel drug delivery system based on chitosan hydrochloride and oxidized dextran (CH‐OD) is designed to load sulfasalazine (SSZ), an FDA‐approved drug with ferroptosis‐inducing ability, for effective tumor‐killing and activation of anti‐tumor immunity. Compared to free SSZ, SSZ‐loaded CH‐OD (CH‐OD‐SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH‐OD‐SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH‐OD‐SSZ hydrogel induces the repolarization of macrophages to an M1‐like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH‐OD‐SSZ hydrogel and anti‐programmed cell death protein 1 (PD‐1) immunotherapy achieves more than 50% ascites regression and generates long‐term immune memory. Collectively, CH‐OD‐SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti‐PD‐1 immunotherapy.
Abstract Background and Aim The benefits of deep disease healing need evaluation by long‐term clinical research in different populations. Confocal laser endomicroscopy (CLE) is a superior method for evaluating deep disease healing. Methods This prospective study enrolled ulcerative colitis (UC) patients in clinical remission who underwent colonoscopy, CLE, and histological assessment. Patients were monitored for relapse by patient‐reported outcomes and colonoscopy evaluation of mucosal healing. The ability of different methods of mucosal healing to predict long‐term disease recurrence was assessed using Kaplan–Meier estimation and Cox proportional hazard regression. Results Forty‐two patients in clinical remission were assessed by colonoscopy. Those with Mayo endoscopic subscores (MES) ≤ 1 were enrolled. The 48‐month recurrence rates in present healing group, assessed by CLE (colonic barrier assessment and ENHANCE index) and by histological examination (Geboes scale), were 20.0%, 26.7%, and 11.1%, respectively, and were significantly lower than absent healing group ( P < 0.05). Univariate Cox proportional risk regression analysis in absent of healing disease, determined by the ENHANCE index and Geboes scale, indicated an increased risk of recurrent events, with hazard ratios (HR) of 3.87 (95% CI: 1.18, 12.62) and 8.20 (95% CI: 1.06, 63.30), respectively. Multivariate Cox proportional hazard regression analysis adjusted for the extent of inflammation (E3 or not) showed a significant difference only for the ENHANCE index, with an HR of 3.53 (95% CI: 1.03, 12.10), P = 0.045. Conclusions Deep disease healing has a lower recurrence rate. The colonic barrier healing assessment, ENHANCE index, and histological Geboes scale have superior long‐term prognostic value for UC patients.
Radiotherapy (RT) serves as the primary treatment for solid tumors. Its potential to incite an immune response against tumors both locally and distally profoundly impacts clinical outcomes. However, RT may also promote the accumulation of immunosuppressive cytokines and immunosuppressive cells, greatly impeding the activation of antitumor immune responses and substantially limiting the effectiveness of RT. Therefore, regulating post-RT immunosuppression to steer the immune milieu toward heightened activation potentially enhances RT’s therapeutic potential. Cytokines, potent orchestrators of diverse cellular responses, play a pivotal role in regulating this immunosuppressive response. Identifying and promptly neutralizing early released immunosuppressive cytokines are a crucial development in augmenting RT’s immunomodulatory effects. To this end, we conducted a screen of immunosuppressive cytokines following RT and identified macrophage colony-stimulating factor (MCSF) as an early up-regulated and persistent immune suppressor. Single-cell sequencing revealed that the main source of up-regulated MCSF derived from tumor cells. Mechanistic exploration revealed that irradiation-dependent phosphorylation of the p65 protein facilitated its binding to the MCSF gene promoter, enhancing transcription. Knockdown and chemical inhibitor experiments conclusively demonstrated that suppressing tumor cell-derived MCSF amplifies RT’s immune-activating effects, with optimal results achieved by early MCSF blockade after irradiation. Additionally, we validated that MCSF acted on macrophages, inducing the secretion of a large number of inhibitory cytokines. In summary, we propose a novel approach to enhance the immune activation effects of RT by blocking the MCSF-CSF1R signaling pathway early after irradiation.
As a chronic neurodegenerative disorder, Alzheimer's disease (AD) is the most common form of progressive dementia. The purpose of this study was to identify diagnostic signatures of AD and the effect of immune cell infiltration in this pathology.The expression profiles of GSE109887, GSE122063, GSE28146, and GSE1297 were downloaded from the Gene Expression Omnibus (GEO) database to obtain differentially expressed genes (DEGs) between AD and control brain samples. Functional enrichment analysis was performed to reveal AD-associated biological functions and key pathways. Besides, we applied the Least Absolute Shrinkage Selection Operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) analysis to screen potential diagnostic feature genes in AD, which were further tested in AD brains of the validation cohort (GSE5281). The discriminatory ability was then assessed by the area under the receiver operating characteristic curves (AUC). Finally, the CIBERSORT algorithm and immune cell infiltration analysis were employed to assess the inflammatory state of AD.A total of 49 DEGs were identified. The functional enrichment analysis revealed that leukocyte transendothelial migration, cytokine receptor interaction, and JAK-STAT signaling pathway were enriched in the AD group. MAF basic leucine zipper transcription factor F (MAFF), ADCYAP1, and ZFP36L1 were identified as the diagnostic biomarkers of AD with high discriminatory ability (AUC = 0.850) and validated in AD brains (AUC = 0.935). As indicated from the immune cell infiltration analysis, naive B cells, plasma cells, activated/resting NK cells, M0 macrophages, M1 macrophages, resting CD4+ T memory cells, resting mast cells, memory B cells, and resting/activated dendritic cells may participate in the development of AD. Additionally, all diagnostic signatures presented different degrees of correlation with different infiltrating immune cells.MAFF, ADCYAP1, and ZFP36L1 may become new candidate biomarkers of AD, which were closely related to the pathogenesis of AD. Moreover, the immune cells mentioned above may play crucial roles in disease occurrence and progression.
Radiotherapy could regulate systemic antitumor immunity, while the immune state in the tumor microenvironment (TME) also affects the efficacy of radiotherapy. We have found that higher CD8+ T cell infiltration is associated with longer overall survival of lung adenocarcinoma and melanoma patients receiving radiotherapy. 8-Gray radiation increased the transcriptional levels of chemokines in tumor cells in vitro. However, it was not sufficient to induce significant lymphocyte infiltration in vivo. Dipeptidyl peptidase 4 (DPP4) has been reported to inactivate chemokines via post-translational truncation. Single-cell sequencing revealed that dendritic cells (DCs) had a higher DPP4 expression among other cells in the TME and upregulated DPP4 expression after radiation. Combining a DPP4 inhibitor with radiotherapy could promote chemokines expression and T cell infiltration in the TME, enhancing the antitumor effect of radiotherapy. Moreover, this therapy further enhanced the therapeutic efficacy of anti-PD-1. In this study, we demonstrated the underlying mechanism of why radiotherapy failed to induce sufficient T cell infiltration and proposed an effective strategy to promote T cell infiltration and sensitize radiotherapy. These findings demonstrate the translational value of DPP4 inhibition as a complementary approach to enhance the efficacy of radiotherapy and the combination of radiotherapy with immunotherapy.
Retinoblastoma (RB) is a common intraocular malignant tumor of infants.It not only seriously threats children's eyesight, but also endangers their lives.RB develops from the immature cells of retina and its occurrence is closely related with the tumor suppressor gene RB1.The inactivation of two alleles of RB1 is the basis of RB occurrence and development.With the rapid development of biological technology, RB gene related research has made great progress.Researches showed that there are many changes in the chromosome level of RB.Many genes are also involved in the development and progression of RB, including oncogene MYCN, murine double minute 4 (MDM4, also known as MDMX), driver protein family members 14 (KIF14), DEK, E2F3, tumor suppressor gene calcium 11 (CDH11) and so on.This review summarizes the progress in gene research of RB, reveal pathogenesis of RB on DNA molecular level and provides a scientific basis for clinical doctors to formulate effective therapeutic plans.
Key words:
Retinoblastoma; RB1; MYCN; Gene
To explore an effective approach for the treatment of patients with uveal melanomas, we designed a strategy that combines HtrA2 gene therapy and radiation therapy.pIRES-Egr1-Omi/HtrA2 (pEgr1-HtrA2) recombinant plasmids were constructed and transfected into human uveal melanoma cells (OCM-1) in vitro. The transfected cells were exposed to irradiation. HtrA2 messenger RNA and protein level was detected by quantitative reverse transcription polymerase chain reaction and Western blot, respectively. Combined with radiation, assays that evaluated the apoptotic inducibility caused by HtrA2 gene therapy was performed by flow cytometry. Followingly, the effects of HtrA2 overexpression on the in vitro radiosensitivity of uveal melanoma cells were investigated by clonogenic formation assay. The in vivo effects of HtrA2 gene therapy combined with radiation therapy were evaluated in different groups.The recombinant plasmids could be successfully transferred into OCM-1 cells, and transfection of pEgr1-HtrA2 plasmids combined with radiotherapy caused dramatically elevation of HtrA2 compared with non-irradiated cells in messenger RNA and protein levels, which was associated with increased apoptosis. Furthermore, we observed that the transfection of pEgr1-HtrA2 could significantly enhance radiosensitivity of OCM-1 cell in vitro. In mice bearing xenograft tumours, pEgr1-HtrA2 combined with radiation therapy significantly inhibited tumour growth compared with the other treatment groups (P < 0.01).Our findings indicate that radiation-inducible gene therapy may have potential to be a more effective and specific therapy for uveal melanoma because the therapeutic gene can be spatially or temporally controlled by exogenous radiation.
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