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Understanding the mechanism of neutralizing antibodies (NAbs) against SARS-CoV-2 is critical for effective vaccines and therapeutics development. We recently reported an exceptionally potent NAb, BD-368-2, and revealed the existence of VH3-53/VH3-66 convergent NAbs in COVID-19. Here we report the 3.5-[A] cryo-EM structure of BD-368-2s Fabs in complex with a mutation-induced prefusion-state-stabilized spike trimer. Unlike VH3-53/VH3-66 NAbs, BD-368-2 fully blocks ACE2 binding by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their "up" and "down" positions. BD-368-2 also triggers fusogenic-like structural rearrangements of the spike trimer, which could impede viral entry. Moreover, BD-368-2 completely avoids the common epitope of VH3-53/VH3-66 NAbs, evidenced by multiple crystal structures of their Fabs in tripartite complexes with RBD, suggesting a new way of pairing potent NAbs to prevent neutralization escape. Together, these results rationalize a unique epitope that leads to exceptional neutralization potency, and provide guidance for NAb therapeutics and vaccine designs against SARS-CoV-2.
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Objective To investigate the status quo of utilization of chronic disease resources and quality of life in chronic obstructive pulmonary disease (COPD) patients,and explore the correlation between them.Methods A total of 394 patients with COPD were investigated by the general information question,the Chronic Illness Resources Survey and COPD Assessment Test (CAT).Results The CAT score of COPD patients was (21.33 ± 7.14) points.Among 394 COPD patients,63 patients (16.0％) had ideal utilization of chronic disease resources,and 331 patients (84.0％) did not,the highest dimension of each dimension score was 3.33 points for the health care team (interquartile range 2.67-3.67 points),and the lowest score was 1.67 points for the organization (interquartile range 1.00-2.00 points).Except media policy and quality of life were not relevant,all other dimensions were negatively correlated with CAT scores in COPD patients (r=-0.368--0.169,all P＜0.05).Linear regression analysis showed that the factors affecting the quality of life of COPD patients were:health care team,family and friends,individual coping (P＜0.05).Conclusions COPD patients with quality of life and chronic disease resources should be improved,medical staff should pay more attentions to patients in communication and guidance,and encourage the support of family and friends,in particular,pay attentions to patients with poor attitude,thus improving the quality of life of patients.
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We hypothesized that plasma-based EGFR mutation analysis for NSCLC may be feasible for monitoring treatment response to EGFR TKIs and also predict drug resistance.Clinically relevant mutations including exon 19 deletion (ex19del), L858R and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples (n = 367) from 81 NSCLC patients treated with EGFR TKI. Of a total 58 baseline cell-free DNA (cfDNA) samples available for ddPCR analysis, 43 (74.1%) had the same mutation in the matched tumors (clinical sensitivity: 70.8% [17/24] for L858R and 76.5% [26/34] for ex19del). The concordance rates of plasma with tissue-based results of EGFR mutations were 87.9% for L858R and 86.2% for ex19del. All 40 patients who were detected EGFR mutations at baseline showed a dramatic decrease of mutant copies (>50%) in plasma during the first two months after treatment. Median progression-free survival (PFS) was 10.1 months for patients with undetectable EGFR v 6.3 months for detectable EGFR mutations in blood after two-month treatment (HR 3.88, 95% CI 1.48-10.19, P = 0.006). We observed emerging resistance with early detection of T790M as a secondary mutation in 14 (28.6%) of 49 patients. Plasma-based EGFR mutation analysis using ddPCR can monitor treatment response to EGFR TKIs and can lead to early detection of EGFR TKIs resistance. Further studies confirming clinical implications of EGFR mutation in plasma are warranted to guide optimal therapeutic strategies upon knowledge of treatment response and resistance.
