Dissecting positive selection events and immunological drives during the evolution of adeno-associated virus lineages.

Adeno-associated virus (AAV) serotypes from primates are being developed and clinically used as vectors for human gene therapy. However, the evolutionary mechanism of AAV variants is far from being understood, except that genetic recombination plays an important role. Furthermore, little is known about the interaction between AAV and its natural hosts, human and nonhuman primates. In this study, natural AAV capsid genes were subjected to systemic evolutionary analysis with a focus on selection drives during the diversification of AAV lineages. A number of positively selected sites were identified from these AAV lineages with functional relevance implied by their localization on the AAV structures. The selection drives of the two AAV2 capsid sites were further investigated in a series of biological experiments. These observations did not support the evolution of the site 410 of the AAV2 capsid driven by selection pressure from the human CD4+ T-cell response. However, positive selection on site 548 of the AAV2 capsid was directly related to host humoral immunity because of the profound effects of mutations at this site on the immune evasion of AAV variants from human neutralizing antibodies at both the individual and population levels. Overall, this work provides a novel interpretation of the genetic diversity and evolution of AAV lineages in their natural hosts, which may contribute to their further engineering and application in human gene therapy.

[Development of A Nomogram for Predicting Survival of Patients 
with Primary Mediastinal Germ Cell Tumor Based on SEER Database].

BACKGROUND: Primary mediastinal germ cell tumor (PMGCT) is a rare but occasionally highly invasive mediastinal tumor. At present, there are few related disease special survival (DSS) studies on PMGCT, rare large data analysis, and uncommon DSS prognostic models. This study was to investigate the prognostic factors of DSS of the PMGCT patients, and build a simple and effective nomogram to predict the DSS prognosis in patients with PMGCT. METHODS: Retrospective clinicopathological data of 325 patients with PMGCT from 1975 to 2019 were extracted from Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method along with the Log-rank test were utilized to estimate the DSS. Cox proportional hazard regression model was used to screen the independent risk factors affecting prognosis, from which an individualized nomogram was constructed to predict 3-yr, 5-yr and 8-yr DSS of patients with PMGCT. The prediction accuracy of the model is evaluated by receiver operating characteristic (ROC) curve, correction curve and decision curve analysis (DCA) curve. RESULTS: The 3-yr, 5-yr and 8-yr survival rates of PMGCT were 84.6%, 83.6% and 83.3%, respectively. Univariate analysis showed that histology, surgery, age, tumor size, metastasis and stage could affect the prognosis of PMGCT. Multivariate analysis showed that histology, surgery, age and tumor size were independent risk factors for the prognosis of PMGCT patients, and the nomogram was constructed using these independent risk factors. The area under the curve (AUC) of ROC curve was 0.824. The results of the correction curves of 3-yr, 5-yr and 8-yr survival time and DCA, indicated that there was a good consistency between the predicted results of the nomogram evaluation and the real results. CONCLUSIONS: Patients with histological classification of seminoma in PMGCT have a better prognosis than patients with non-seminoma. The prognosis of patients with over the age of 40 yr, tumor size ≥15 cm and without surgical treatment was even worse. The nomogram model can accurately and intuitively predict the DSS of patients with PMGCT.