ABSTRACT
BACKGROUND: Gastric cancer significantly contributes to cancer mortality globally. Gastric intestinal metaplasia (GIM) is a stage in the Correa cascade and a premalignant lesion of gastric cancer. The natural history of GIM formation and progression over time is not fully understood. Currently, there are no clear guidelines on GIM surveillance or management in the United States. AIM: To investigate factors associated with GIM development over time in African American-predominant study population. METHODS: This is a retrospective longitudinal study in a single tertiary hospital in Washington DC. We retrieved upper esophagogastroduodenoscopies (EGDs) with gastric biopsies from the pathology department database from January 2015 to December 2020. Patients included in the study had undergone two or more EGDs with gastric biopsy. Patients with no GIM at baseline were followed up until they developed GIM or until the last available EGD. Exclusion criteria consisted of patients age < 18, pregnancy, previous diagnosis of gastric cancer, and missing data including pathology results or endoscopy reports. The study population was divided into two groups based on GIM status. Univariate and multivariate Cox regression was used to estimate the hazard induced by patient demographics, EGD findings, and Helicobacter pylori (H. pylori) status on the GIM status. RESULTS: Of 2375 patients who had at least 1 EGD with gastric biopsy, 579 patients were included in the study. 138 patients developed GIM during the study follow-up period of 1087 d on average, compared to 857 d in patients without GIM (P = 0.247). The average age of GIM group was 64 years compared to 56 years in the non-GIM group (P < 0.001). In the GIM group, adding one year to the age increases the risk for GIM formation by 4% (P < 0.001). Over time, African Americans, Hispanic, and other ethnicities/races had an increased risk of GIM compared to Caucasians with a hazard ratio (HR) of 2.12 (1.16, 3.87), 2.79 (1.09, 7.13), and 3.19 (1.5, 6.76) respectively. No gender difference was observed between the study populations. Gastritis was associated with an increased risk for GIM development with an HR of 1.62 (1.07, 2.44). On the other hand, H. pylori infection did not increase the risk for GIM. CONCLUSION: An increase in age and non-Caucasian race/ethnicity are associated with an increased risk of GIM formation. The effect of H. pylori on GIM is limited in low prevalence areas.
ABSTRACT
In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3-GEF-Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.
