Nirushan Narendran

Beclin-1 has a central role in the regulation of autophagy. Barrett's esophagus (BE) is associated with a significantly increased risk for the development of esophageal adenocarcinoma (EAC). In the current study, we evaluated the role of Beclin-1 and autophagy in the EAC. Biopsies obtained from patients with BE and EAC, tissues from a rat model of BE and EAC, and esophageal cell lines were evaluated for the expression of Beclin-1 by immunohistochemistry, immunoblotting, or RT-PCR. Since reflux of bile acids is important in EAC, we also evaluated the effect of exposure to deoxycholic acid (DCA) on autophagy and Beclin-1 expression. Beclin-1 expression was high in squamous epithelium and nondysplastic BE, whereas its expression was low in dysplastic BE and EAC. The same pattern of expression was observed in rat tissues and in esophageal cell lines. Normal esophageal epithelium and HET-1A cells (derived from normal squamous epithelium) show high levels of Beclin-1, but lower levels of Beclin-1 were found in BE and EAC cell lines (CP-A, CP-C, and OE33). Acute exposure to DCA led to increased Beclin-1 expression and increased autophagy as evaluated by electron microscopy and counting percentage of GFP-LC3-positive BE cells with punctate pattern. In contrast, chronic exposure to DCA did not result in the alteration of Beclin-1 levels or autophagy. In summary, these data suggest that autophagy is initially activated in response to bile acids, but chronic exposure to bile acids leads to decreased Beclin-1 expression and autophagy resistance.

BACKGROUND: Acute exacerbations of chronic rhinosinusitis (AECRS) are thought to arise from common viral infections progressing to secondary bacterial infections. However, the pathophysiology of AECRS remains poorly understood due to a lack of prospective longitudinal studies. METHODS: We conducted a one-year prospective longitudinal study involving chronic rhinosinusitis (CRS) adults. At baseline, we assessed subjective symptom scores using a validated upper respiratory infection questionnaire (WURSS), sinonasal outcome testing scores (SNOT-22), and endoscopic scores (modified Lund-Kennedy score). Every 2 weeks, we contacted subjects to collect WURSS and SNOT-22 scores. If WURSS scores were ≥1 and SNOT-22 scores were ≥ 8.9 compared with baseline, subjects underwent an AECRS assessment. We identified rhinovirus (RV) incidence through viral nasal brushings at each visit and bacterial infection through bacterial swabs if mucus scores were ≥1. RESULTS: Thiry-five of 80 CRS subjects reported at least one AECRS episode during the year, predominantly occurring in the fall and winter seasons. RV infections were detected in 8 of 35 cases, bacterial infections in 17 of 35, and co-occurring infections in 7 of 35. All subjects with AECRS visits exhibited significantly higher endoscopic scores compared with baseline. Subjects with co-occurring RV and bacterial infections demonstrated higher disease severity compared with those with either RV or bacterial infection, or no infection. CONCLUSIONS: In a one-year prospective longitudinal study involving CRS adults, we identified significant risk factors for AECRS including seasonality and the presence of RV and bacterial infections. These data suggest a standard definition of AECRS and the need to target RV and bacterial infections if we are to help reduce disease severity.

Objective: Chronic rhinosinusitis with nasal polyps (CRSwNP) presents with nasal obstruction, facial pressure, smell alterations, and post-nasal drainage. Endoscopic sinus surgery (ESS) is indicated when medical treatments fail, however some patients’ nasal polyps can recur. Biologic therapies targeting type-2 inflammation have been shown to improve sinonasal symptoms in CRSwNP. Few studies compare ESS to biologic outcomes longitudinally. To review and compare the efficacy of ESS to biologics in managing CRSwNP using standardized outcome measures longitudinally. Data Sources: We searched electronic databases, including MEDLINE, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov from inception through August 2024. Review Methods: Primary outcome included changes in symptom scores (SNOT-22). Secondary analyses included change in nasal polyp score (NPS) and olfactory function scores. The mean differences and 95% CI were synthesized using a random-effects meta-analysis with heterogeneity assessed using I² statistics. Results: Although there was significant heterogeneity between and within groups, we performed a meta-analysis of SNOT-22 outcomes from both biologic and ESS studies (n = 27). SNOT-22 significantly improved at 6/12 months in biologic and ESS studies with no differences between groups. Secondary analysis of NPS and olfactory function were limited by the small number of studies. Both treatments improved outcomes from baseline, with biologics showing improved olfaction at 6 months compared to ESS. Conclusion: Significant heterogeneity in patient selection, testing methods, and longitudinal data collection was identified. Future comparative studies should incorporate individual complete data with consistent follow-up to reduce heterogeneity and synthesize the best evidence comparing biologic to ESS outcomes in CRSwNP.