Codelivery of anti-CD47 antibody and chlorin e6 using a dual pH-sensitive nanodrug for photodynamic immunotherapy of osteosarcoma

Osteosarcoma is a malignant tumor originating from bone tissue that progresses rapidly and has a poor patient prognosis.Immunotherapy has shown great potential in the treatment of osteosarcoma.However,the immunosuppressive microenvironment severely limits the efficacy of osteosarcoma treatment.The dual pH-sensitive nanocarrier has emerged as an effective antitumor drug delivery system that can selectively release drugs into the acidic tumor microenvironment.Here,we prepared a dual pH-sensitive nanocarrier,loaded with the photosensitizer Chlorin e6(Ce6)and CD47 monoclonal antibodies(aCD47),to deliver synergistic photodynamic and immunotherapy of osteosarcoma.On laser irradiation,Ce6 can generate reactive oxygen species(ROS)to kill cancer cells directly and induces immunogenic tumor cell death(ICD),which further facilitates the dendritic cell maturation induced by blockade of CD47 by aCD47.Moreover,both calreticulin released during ICD and CD47 blockade can accelerate phagocytosis of tumor cells by macrophages,promote antigen presentation,and eventually induce T lymphocyte-mediated antitumor immunity.Overall,the dual pH-sensitive nanodrug loaded with Ce6 and aCD47 showed excellent immune-activating and anti-tumor effects in osteosarcoma,which may lay the theoretical foundation for a novel combination model of osteosarcoma treatment.

TP53-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer:a clinical next-generation sequencing study

Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast cancer.However,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear.Methods:Clinical next-generation sequencing(NGS)of both tumor and paired blood DNA from 119 breast cancer patients(BRCA-119 cohort)was performed with a 520-gene panel.Mutations,tumor mutation burden(TMB),and genomic HRD scores were assessed from NGS data.NGS data from 47 breast cancer patients in the HRD test cohort were analyzed for further verification.Results:All TP53 pathogenic mutations in patients had somatic origin,which was associated with the protein expression of estrogen receptor and progestogen receptor.Compared to patients without TP53 pathologic mutations,patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations.The frequency of TP53 pathologic mutation was higher in the HRDhigh group(HRD score≥42)relative to that in the HRD-low group(HRD score<42).TP53 has different mutational characteristics between the HRD-low and HRD-high groups.TP53-specific mutation subgroups had diverse genomic features and TMB.Notably,TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve(AUC)of 0.61.TP53-specific mutations,namely HRD-low mutation,HRD-high mutation,and HRD common mutation,predicted the HRD status of breast cancer patients with AUC values of 0.32,0.72,and 0.58,respectively.Interestingly,TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values(0.80)in predicting HRD status.Conclusions:TP53-specific mutation combinations predict the HRD status of patients,indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase(PARP)inhibitors in breast cancer patients.

弥散张量成像对于康复期COVID-19患者神经损害的初步研究

目的应用弥散张量成像(diffusion tensor imaging,DTI)评估康复期COVID-19患者可能存在的白质纤维结构的改变,探讨SARS-CoV2对中枢神经系统可能造成的潜在迟发性损害。方法回顾性分析27例康复期COVID-19患者(普通患者组17例,重症患者组10例)和39例健康对照组的临床及颅脑MRI影像学资料。结果重症患者组的炎症反应及凝血功能异常较普通患者组明显;DTI结果:重症患者组多个神经纤维束的平均扩散率(mean diffusivity,MD)增加(P<0.05,FDR校正),主要分布在小脑中脚、胼胝体体部、双侧前、上放射冠区、双侧内囊前肢、左侧皮质脊髓束、左侧外囊、左侧上额枕束、毯及右侧下额枕束、右侧勾束等;小脑中脚各向异性分数(fractional anisotropy,FA)值下降(P<0.05,FDR校正)。结论康复期COVID-19患者存在白质纤维结构的改变,SARS-CoV2可能对中枢神经系统造成持续性或迟发性损害。DTI可提供有效的神经系统病毒感染的证据,有助于疾病的早期诊断。