Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer.

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C

Gastrointestinal tract pathology of the owl monkey (Aotus spp.).

Owl monkeys are small nocturnal new world primates in the genus Aotus that are most used in biomedical research for malaria. Cardiomyopathy and nephropathy are well-described common diseases contributing to their morbidity and mortality; less is known about lesions affecting the gastrointestinal tract. Records from a 14-year period (2008-2022) at the Keeling Center for Comparative Medicine and Research were queried to identify instances of spontaneous gastrointestinal disease that directly contributed to the cause of death from the 235 adult owl monkeys submitted for necropsy. Of the 235, 10.6% (25/235) had gastrointestinal disease listed as a significant factor that contributed to morbidity and mortality. Diagnoses included candidiasis (3/25), gastric bloat (4/25), and intestinal incarceration and ischemia secondary (11/25), which included intussusception (4/25), mesenteric rent (3/25), strangulating lipoma (2/25), intestinal torsion (1/25), and an inguinal hernia (1/25). Intestinal adenocarcinomas affecting the jejunum (4/25) were the most common neoplasia diagnosis. Oral squamous cell carcinoma (1/25) and intestinal lymphoma (2/25) were also diagnosed. This report provides evidence of spontaneous lesions in the species that contribute to morbidity and mortality.

Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production.

SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Patients have elevated manganese in the blood and brain and develop neurotoxicity. Liver manganese is increased in patients lacking SLC30A10 but not SLC39A14. These organ-specific changes in manganese were recently recapitulated in knockout mice. Surprisingly, Slc30a10 knockouts also had elevated thyroid manganese and developed hypothyroidism. To determine the mechanisms of manganese-induced hypothyroidism and understand how SLC30A10 and SLC39A14 cooperatively mediate manganese detoxification, here we produced Slc39a14 single and Slc30a10/Slc39a14 double knockout mice and compared their phenotypes with that of Slc30a10 single knockouts. Compared with wild-type controls, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had higher manganese levels in the blood and brain but not in the liver. In contrast, Slc30a10 single knockouts had elevated manganese levels in the liver as well as in the blood and brain. Furthermore, SLC30A10 and SLC39A14 localized to the canalicular and basolateral domains of polarized hepatic cells, respectively. Thus, transport activities of both SLC39A14 and SLC30A10 are required for hepatic manganese excretion. Compared with Slc30a10 single knockouts, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had lower thyroid manganese levels and normal thyroid function. Moreover, intrathyroid thyroxine levels of Slc30a10 single knockouts were lower than those of controls. Thus, the hypothyroidism phenotype of Slc30a10 single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. These findings provide new insights into the mechanisms of manganese detoxification and manganese-induced thyroid dysfunction.

Targeted Phage Display-based Pulmonary Vaccination in Mice and Non-human Primates.

BACKGROUND: The extensive alveolar capillary network of the lungs is an attractive route for administration of several agents. One key functional attribute is the rapid onset of systemic action due to the absence of first-pass metabolism. METHODS: Here we applied a combinatorial approach for ligand-directed pulmonary delivery as a unique route for systemic targeting in vaccination. FINDINGS: We screened a phage display random peptide library in vivo to select, identify, and validate a ligand (CAKSMGDIVC) that specifically targets and is internalized through its receptor, α3ß1 integrin, on the surface of cells lining the lung airways and alveoli and mediates CAKSMGDIVC-displaying phage binding and systemic delivery without compromising lung homeostasis. As a proof-of-concept, we show that the pulmonary delivery of targeted CAKSMGDIVC-displaying phage particles in mice and non-human primates elicit a systemic and specific humoral response. CONCLUSIONS: This broad methodology blueprint represents a robust and versatile platform tool enabling new ligand-receptor discovery with many potential translational applications. FUNDING: Cancer Center Support Grants to the University of Texas M.D. Anderson Cancer Center (CA016672), University of New Mexico Comprehensive Cancer Center (CA118100), Rutgers Cancer Institute of New Jersey (CA072720), research awards from the Gillson Longenbaugh Foundation, and National Institutes of Health (NIH) grant no. 1R01CA226537.

Mismatch repair gene mutations lead to lynch syndrome colorectal cancer in rhesus macaques.

Colorectal cancer accounts for a substantial number of deaths each year worldwide. Lynch Syndrome is a genetic form of colorectal cancer (CRC) caused by inherited mutations in DNA mismatch repair (MMR) genes. Although researchers have developed mouse models of Lynch Syndrome through targeted mutagenesis of MMR genes, the tumors that result differ in important ways from those in Lynch Syndrome patients. We identified 60 cases of CRC in rhesus macaques (Macaca mulatta) at our facility since 2001. The tumors occur at the ileocecal junction, cecum and proximal colon and display clinicopathologic features similar to human Lynch Syndrome. We conducted immunohistochemical analysis of CRC tumors from several rhesus macaques, finding they frequently lack expression of MLH1 and PMS2 proteins, both critical MMR proteins involved in Lynch Syndrome. We also found that most macaque cases we tested exhibit microsatellite instability, a defining feature of Lynch Syndrome. Whole genome sequencing of rhesus macaque CRC cases identified mutations in MLH1 and/or MSH6 that are predicted to disrupt protein function. We conclude that this population of rhesus macaques constitutes a spontaneous model of Lynch Syndrome, matching the human disease in several significant characteristics, including genetic risk factors that parallel human Lynch Syndrome.