Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer.

BACKGROUND & AIMS: Activation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings. METHODS: We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-κB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. RESULTS: In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. CONCLUSIONS: Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.

Bevacizumab as Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Literature Review.

BACKGROUND: Severe, recurring epistaxis is the most common symptom of hereditary hemorrhagic telangiectasias (HHT). Current treatment modalities range from noninvasive treatments that frequently fail to achieve even short-term control to surgeries and systemic therapies that carry significant risk of complications. Recently, bevacizumab, a VEGF inhibitor, has been proposed as an alternative option to alleviate epistaxis symptoms in HHT. OBJECTIVE: To review the current literature regarding the use of bevacizumab for the treatment of epistaxis in patients with HHT and provide guidance on its usage for this indication. METHODS: A narrative literature review was performed to analyze various methods and dosages of bevacizumab administration for the treatment of HHT-related epistaxis, along with a review of current treatment modalities and their drawbacks. RESULTS: The current standard of care for HHT-related epistaxis consists of treatments that are largely ineffective or invasive with significant potential complications. Submucosal bevacizumab has demonstrated efficacy in reducing frequency, duration, and severity of epistaxis in those with HHT. CONCLUSION: Given the inadequacies and potential drawbacks of current treatments for epistaxis in HHT, there is a need for new therapeutic options. Submucosal bevacizumab has been effective with a limited risk profile in a number of studies and should now be considered as a treatment option for refractory epistaxis. Controlled studies are recommended to quantify optimal dosing, treatment schedule, and specific subpopulations that will respond best to this treatment.