Safety and tolerability of Evusheld in patients with CVID: The Mayo Clinic experience

Background: The past 2 years of the COVID-19 pandemic brought with it many unknowns for patients with immunodeficiency. Because of the concern for severe infection in those with immunocompromise, patients have been eager for effective prevention, vaccination, and treatment strategies. Preexposure prophylaxis provides another means of prevention in those with immunocompromise. A combination of tixagevimab and cilgavimab (Evusheld [AstraZeneca Cambridge, United Kingdom]) was granted emergency use authorization for preexposure prophylaxis at the end of 2021, but questions remained regarding how this would be tolerated and the side effects associated with its use. Objectives: Our aim was to evaluate the safety and tolerability of Evusheld in patients with CVID from our tri-site institution. Methods: We performed an institutional review board–approved, retrospective chart review of patients with common variable immunodeficiency (CVID) who received Evusheld before March 26, 2022. Results: Of the 45 patients with CVID who received Evusheld, 41 (91%) received the recommended full dose of 600 mg. The majority of patients (39 of 45 [87%]) tolerated Evusheld without adverse events. The adverse events reported included immediate injection site pain, fatigue and cough, an episode of shingles, and chest pain. Conclusions: This is an initial report on the safety and tolerability of Evusheld injections in patients with CVID. The majority of patients tolerated the injections without adverse events. For patients with reported chest pain, the results of a subsequent cardiac workup were negative. The efficacy of Evusheld could not be evaluated owing to the short median follow-up of this study (19 days)

Statistical Mechanics Metrics in Pairing and Parsing In Silico and Phenotypic Data of a Novel Genetic NFκB1 (c.T638A) Variant

(1) Background: Mutations in NFκB1, a transcriptional regulator of immunomodulating proteins, are a known cause of inborn errors of immunity. Our proband is a 22-year-old male with a diagnosis of common variable immunodeficiency (CVID), cytopenias with massive splenomegaly, and nodular regenerative hyperplasia of the liver. Genetic studies identified a novel, single-point mutation variant in NFκB1, c. T638A p. V213E. (2) Methods: Next-generation panel sequencing of the patient uncovered a novel single-point mutation in the NFκB1 gene that was modeled using the I-TASSER homology-modeling software, and molecular dynamics were assessed using the YASARA2 software (version 20.14.24). (3) Results: This variant replaces valine with glutamic acid at position 213 in the NFκB1 sequence. Molecular modeling and molecular dynamic studies showed altered dynamics in and around the rel homology domain, ankyrin regions, and death domain of the protein. We postulate that these changes alter overall protein function. (4) Conclusions: This case suggests the pathogenicity of a novel variant using protein-modeling techniques and molecular dynamic simulations

A novel retinoblastoma therapy from genomic and epigenetic analyses

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of the RB1 gene. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated RB1’s role in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. Here we show that the retinoblastoma genome is stable, but multiple cancer pathways can be epigenetically deregulated. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, RB1 inactivation may allow preneoplastic cells to acquire multiple hallmarks of cancer through epigenetic mechanisms, resulting directly or indirectly from RB1 loss. These data provide novel targets for chemotherapeutic interventions of retinoblastoma