ABSTRACT
The SARS-CoV-2 Omicron variant with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the spike (S) from Omicron reveals amino acid substitutions forging interactions that stably maintain an active conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of the viral fusion step. Alterations in local conformation, charge, and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Structure of the Omicron S bound with human ACE2, together with the analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members, as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies, sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.
Subject(s)
Immune Evasion/physiology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/immunology , Binding Sites , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cryoelectron Microscopy , Humans , Mutagenesis, Site-Directed , Neutralization Tests , Protein Binding , Protein Domains/immunology , Protein Structure, Quaternary , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Surface Plasmon Resonance , Virus AttachmentABSTRACT
The natural history and optimal treatment of pleomorphic (PLCIS) and florid (FLCIS) lobular carcinoma in situ variants remains uncertain. We reviewed the clinicopathologic features and management of LCIS variants at our institution over a 20-year period. Of 85 cases (61 PLCIS, 24 FLCIS), 77% were associated with invasive carcinoma (84% lobular, 13% ductal/lobular, 3% ductal) and only 17% (9 PLCIS, 5 FLCIS) were pure. Most (81%) invasive carcinomas were grade 2, with all grade 3/pleomorphic invasive lobular carcinomas (ILC) associated with PLCIS, and all grade 1 tumors associated with FLCIS. PLCIS-associated invasive carcinomas were more often ER- (21%) or HER2+ (14%) than FLCIS-associated tumors (100% ER+, 6% HER2+). LCIS variants were unifocal and co-localized with invasive carcinoma in 20/20 selected spatially mapped cases, whereas classic LCIS (CLCIS) was multifocal with wider distribution (10/17). Of 21 pure LCIS variants on core biopsy, all represented the radiographic (95%) or palpable (5%) target. The excisional upgrade rate was similar for PLCIS (38%) and FLCIS (33%). Pure LCIS variants on core biopsy were often (20%) HER2+ and had a higher Ki-67-index than synchronous CLCIS (P=0.002). Lower ER expression in LCIS variants versus CLCIS was due to ER- apocrine PLCIS. ER and HER2 were consistently concordant between LCIS variants and upgraded ILC but discordant between synchronous CLCIS and LCIS variants in 5/14 (36%). Pure LCIS variants were excised to negative margins and frequently (58%) treated with endocrine but not radiation therapy without recurrences. In summary, PLCIS and FLCIS demonstrate features of direct precursor lesions warranting surgical excision.
