ABSTRACT
The role of glial scar after intracerebral hemorrhage(ICH)remains unclear.This study aimed to inves-tigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar.We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation.Spatial transcriptomics(ST)analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods.During the early stage,sustained microglial depletion induced disorganized astrocytic scar,enhanced neutrophil infiltration,and impaired tissue repair.ST analysis indicated that microglia-derived insulin like growth factor 1(IGF1)modulated astrocytic scar formation via mechanistic target of rapamycin(mTOR)signaling activation.Moreover,repopulating microglia(RM)more strongly activated mTOR signaling,facilitating a more protective scar formation.The combination of IGF1 and osteopontin(OPN)was necessary and sufficient for RM function,rather than IGF1 or OPN alone.At the chronic stage of ICH,the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this.The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH.Inversely,early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy.This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes,and develop elaborate treatment strategies at precise time points after ICH.
ABSTRACT
Purpose: This study investigated the outcome of elderly patients (≥65 years) with thoracic esophageal squamous cell carcinoma (TESCC) treated with esophagectomy and postoperative radiotherapy (PORT) or definitive radiotherapy (DRT). Patients and Methods: One hundred and ninety patients (median age of 72 years) who received PORT (n = 68) or DRT (n = 122) for TESCC were analyzed. Majority of them showed locally advanced disease (T3/4: 70.5%, N+: 70.5%, Stage III: 51.6%). Compared to patients who received DRT, those who received PORT had lower Age-Adjusted Charlson Comorbidity Index (AACCI) scores (2.49 ± 0.61 vs. 3.73 ± 1.28, χ2 = 7.283; P = 0.000) and higher Karnofsky Performance Scale (KPS) (χ2 = 9.016; P = 0.003) and were of younger ages (68.90 ± 3.00 vs. 75.17 ± 5.71, χ2 = 9.925; P = 0.000). Results: Overall survival (OS) was significantly higher in the PORT group (median, 61.2 months; 95% confidence interval [CI], 46.04–76.36) than in the DRT group (median, 24.37 months; 95% CI, 15.43–33.31). Multivariate analysis showed that treatment method (hazard ratio [HR]: 2.38, 95% CI, 1.46–3.90; P = 0.001), clinical T stage (HR: 0.57, 95% CI, 0.34–0.95; P = 0.031), and lymph node metastasis (HR: 0.51, 95% CI, 0.31–0.84; P = 0.008) were independent prognostic factors. Regarding subgroup analysis, OS of patients receiving PORT was significantly higher than that of DRT in the T3–4 group (HR: 2.98, 95% CI, 1.80–4.92; P = 0.000) and the N+ group (HR: 2.20, 95% CI, 1.26–3.83; P = 0.006). Conclusions: The efficacy of PORT for the treatment of elderly TESCC patients was superior to DRT. With regard to AACCI, KPS, and age, DRT is still a treatment option for elderly TESCC patients, especially for those >75 years of age