Detection of OG:A Lesion Mispairs by MutY Relies on a Single His Residue and the 2-Amino Group of 8-Oxoguanine.

MutY glycosylase excises adenines misincorporated opposite the oxidatively damaged lesion, 8-oxo-7,8-dihydroguanine (OG), to initiate base excision repair and prevent G to T transversion mutations. Successful repair requires MutY recognition of the OG:A mispair amidst highly abundant and structurally similar undamaged DNA base pairs. Herein we use a combination of in vitro and bacterial cell repair assays with single-molecule fluorescence microscopy to demonstrate that both a C-terminal domain histidine residue and the 2-amino group of OG base are critical for MutY detection of OG:A sites. These studies are the first to directly link deficiencies in MutY lesion detection with incomplete cellular repair. These results suggest that defects in lesion detection of human MutY (MUTYH) variants may prove predictive of early-onset colorectal cancer known an MUTYH-associated polyposis. Furthermore, unveiling these specific molecular determinants for repair makes it possible to envision new MUTYH-specific cancer therapies.

Clinical features and outcomes of dogs with attempted medical management for discrete gastrointestinal foreign material: 68 cases (2018-2023).

OBJECTIVE: To retrospectively describe clinical characteristics of canine gastrointestinal foreign bodies (GIFB) that were successfully and unsuccessfully managed conservatively. ANIMALS: 68 client-owned dogs presented to the Texas A&M Small Animal Teaching Hospital between January 1, 2018, and October 1, 2023, for GIFB where medical management was attempted. CLINICAL PRESENTATION: Medical records were reviewed for signalment, history, physical examination, bloodwork, diagnostic imaging, foreign body type, location, treatments, and outcome. Success was defined as the passage of the foreign body through the colon, while failure was defined as requiring surgery, endoscopy, or euthanasia. RESULTS: Medical management was successful in 32 cases (47%; 95% CI, 0.32 to 0.66). Gastric dilation resolved in all success cases (n = 5 [100%]; 95% CI, 0.32 to 2.3) but did not resolve in any failure cases (13 [0%]). Small intestinal dilation resolved in all success cases (n = 13 [100%]; 95% CI, 0.53 to 1.7) but progressed in most failure cases (9 [75%]; 95% CI, 0.34 to 1.4). In the success group, 31 GIFB were nonlinear (96.9%; 95% CI, 0.66 to 1.4), while 1 was linear (3.1%; 95% CI, 0.001 to 0.17). In the failure group, 29 GIFB were nonlinear (80.6%; 95% CI, 0.54 to 1.16), while 7 were linear (19.4%; 95% CI, 0.08 to 0.4). Of the cases that elected surgery (n = 29 [42.7%]; 95% CI, 0.29 to 0.61), resection and anastomosis was performed in 3 cases (10.3%; 95% CI, 0.02 to 0.3). All cases that required resection and anastomosis were nonlinear GIFB. CLINICAL RELEVANCE: Conservative management of GIFB provides a feasible treatment option and may be considered based on presentation, foreign body location, hemodynamic stability of the patient, diagnostic imaging, and type of foreign body.