International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Functional and Physical Interaction Between the Mismatch Repair and the FA-BRCA Pathways.

Abstract Abstract 3370 Introduction: Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, an increased risk for cancer and leukemia, and congenital abnormalities. Thirteen FA genes have been identified that when mutated result in hypersensitivity to DNA crosslinking agents. Therefore, components of the FA-BRCA pathway are thought to function in the repair of DNA interstrand crosslinks (ICLs). The monoubiquitylation and chromatin localization of two FA proteins, FANCD2 and FANCI, is considered the hallmark of FA pathway activation. It has been reported that FANCJ interacts with the mismatch repair (MMR) complex MutLα and we have previously shown that FANCD2 binds several mismatch repair proteins in vivo and that MSH2 is required for the monoubiquitylation of FANCD2 and FANCI. Interestingly, mismatch repair deficiency is also associated with leukemia in humans and a defect in hematopoietic repopulation in mouse models, suggesting a possible functional overlap between the FA-BRCA and MMR pathways. Methods: Cell lines used: HeLa, FA-A cell line GM6914 and corrected cell line GM6914 + Flag-FANCA, FA-D2 cell line PD20 and corrected cell lines PD20+Flag-FANCD2 and PD20+FANCD2 K561R, human endometrial adenocarcinoma cell line HEC59 (MSH2-deficient) and corrected cell line HEC59+Ch2, and human colon carcinoma cell line HCT116 (MLH1-deficient) and corrected cell line HCT116+Ch3. Cells were treated with the crosslinking agents mitomycin C (MMC), cisplatin (CDDP), or the alkylating agent temozolomide (TMZ). FANCD2 foci formation was assessed using immunofluorescence. Immunoprecipitation was used to demonstrate interactions between FANCD2, MSH2, and MLH1. Survival assays were performed by crystal violet staining and extraction. Chromosome breakage analysis was performed using metaphase spreads. FANCD2 RNAi flies, spel1-/- flies (MSH2-deficient), and double mutants were treated with diepoxybutane (DEB) and assessed for survival and mutagenicity. Mismatch binding EMSAs were performed using Cy5-labeled matched and mismatched 29-mers. Result: FANCD2 foci formation and chromatin loading is greatly diminished in MSH2-deficient cells, while cells lacking MLH1 show no effect, indicating a requirement for MSH2 in the activation of the FA-BRCA pathway and a possible downstream role for MLH1 in ICL repair. Human and mouse cells lacking MSH2 or human cells lacking MLH1 display increased sensitivity to mitomycin C and cisplatin as compared to their corrected counterparts as well as increased radial formation upon treatment with MMC. Studies in both human cell lines and Drosophila mutants indicate an epistatic relationship between FANCD2 and MSH2 with regards to survival, chromosome breakage, and mutagenicity after treatment with crosslinking agents. MSH2 is required for the interaction between FANCD2 and MLH1, but surprisingly, presence of MLH1 appears to enhance the interaction between FANCD2 and MSH2. Furthermore, the interaction between MSH2 and MLH1 after treatment with MMC is reduced in multiple FA cell lines. FA cell lines also display hypersensitivity to alkylating agents such as temozolomide. These results have led us to examine FA cell lines for a defect in mismatch repair through mismatch binding EMSAs and plasmid-based assays. Conclusion: These data suggest that mismatch repair proteins play a key role in the activation of the FA-BRCA pathway. Conversely, FA proteins appear to be required for interactions between mismatch repair factors and may also be involved in the repair of DNA mismatches, suggesting significant crosstalk between the FA and MMR pathways. Understanding this complex interplay could lead to the development of new therapies for the treatment of patients both with FA and cancer. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Allergies and Eosinophilic Esophagitis—Current Updates for the Pediatric Gastroenterologist

Purpose of reviewThe purpose of this article is to review recent developments demonstrating the role of allergies, the utility of allergy testing, and the role of the allergist in eosinophilic esophagitis (EoE) management.Recent findingsThe majority of patients with EoE have concurrent atopic disorders including food anaphylaxis, asthma, allergic rhinitis, and eczema. An atopic population likely is at greater risk for EoE. Delayed type hypersensitivity to food antigens is the most common pathogenic mechanism. Aeroallergens and pollen-food cross-reactivity also can trigger EoE. Th2 cell-mediated adaptive and innate immunity in response to epithelial damage occurs via IL-13- and IL-4-producing T cells and innate lymphoid cells. While IgE testing for foods is insufficient to build an elimination diet, IgE-mediated allergy may play a role in EoE severity and clinical course. There is strong evidence that Th2 immunity drives EoE. Optimal EoE management should include elucidating and managing EoE triggers and concurrent atopic diatheses