Biology subjects

Miller, G. C.

Publications and source records attributed to Miller, G. C..

3 recordsLinked to original sources

bioRxiv2025

Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet-induced obesity

ObjectivesHistone deacetylase 7 (HDAC7), a classical HDAC family member, promotes LPS-inducible glycolysis and inflammatory mediator production in macrophages, innate immune cells that contribute to pathology in metabolic diseases. Here, we investigated myeloid HDAC7 functions in obesity-driven metabolic disease. MethodsWe used gain- and loss-of-function genetic approaches in mice to investigate myeloid HDAC7 functions in hepatic inflammation and metabolic disease, as well as associations with hepatic gene signatures characteristic of advanced chronic liver disease (CLD). ResultsTransgenic expression of Hdac7 in myeloid cells increased liver inflammation and liver mRNA levels of Ccl2 and Il1b, key inflammatory mediators linked to CLD. Liver glycogen levels were also decreased, another feature of CLD. Transgenic expression of Hdac7 in myeloid cells mimicked the hepatic inflammatory phenotype that was observed in mice fed a high fat, high cholesterol, and high sucrose (HFHCHS) diet, an obesity model that mimics some features of metabolic dysfunction-associated steatotic liver disease. In myeloid Hdac7 transgenic mice fed a HFHCHS diet, relative weight gain was increased, fasted glucose levels were elevated and glucose tolerance was dysregulated by comparison to control mice. Conversely, fasted blood glucose levels were reduced and glucose tolerance was improved in myeloid Hdac7-deleted mice on a HFHCHS diet. HDAC7 mRNA levels were also elevated in the livers of people with advanced CLD and spatial transcriptomics revealed that myeloid HDAC7 directs hepatic gene signatures characteristic of advanced CLD. ConclusionsMyeloid HDAC7 contributes to hepatic inflammation and systemic glucose dysregulation in a mouse model of obesity and liver inflammation.

immunology↗

bioRxiv2025

Efficient delivery of mRNA-LNPs in primary and secondary liver cancer

Primary liver cancer is the sixth most prevalent cancer globally and is often diagnosed late, when treatment options are limited. Secondary liver cancer, arising from metastasis of other cancers to the liver, is a common complication of advanced solid cancers and a significant cause of cancer-related morbidity and mortality. Existing treatment options for advanced primary and secondary liver tumours have limited efficacy and new treatment modalities have the potential to improve patient outcomes. mRNA therapeutics are readily delivered to the healthy liver after systemic administration, but their uptake and expression within liver tumours is unclear. Here we show that intravenous delivery of mRNA-LNPs efficiently transfects virtually all hepatocytes in healthy, fibrotic, and cirrhotic liver, and also many cells of spontaneous hepatocellular carcinomas in situ. Delivery of mRNA is also possible to xenograft models of both primary and secondary liver cancer, albeit with attenuated protein expression relative to the normal liver. These findings demonstrate the potential for systemically delivered mRNA-LNP therapies for liver disease and cancer.

molecular biology↗

bioRxiv2018

Yield of Universal Testing for DNA Mismatch Repair Protein Deficiency in Colorectal Carcinoma From an Australian Community-based Practice

Lynch syndrome is the most common cause of inherited colorectal carcinoma (CRC). Testing all newly diagnosed CRC for MMR protein deficiency, known as universal testing, has recently emerged as the preferred approach to identify potential Lynch syndrome individuals. All newly diagnosed CRCs were screened for MMR protein expression by immunohistochemistry. A 2-step approach was used: PMS2 and MSH6 testing followed by the testing of the respective MMR protein partner if one of the proteins is lost. We retrospectively searched our pathology database for MMR protein expression results across a 5-year period (2012-2016) when universal testing was performed. Clinical and pathological data were extracted from the pathology report. A total of 2077 consecutive CRCs were tested for MMR protein expression. Mean age at diagnosis was 68.4 years. MMR protein deficiency was identified in 399 cases (19.2%). The vast majority of CRC with MLH1/PMS2 loss were diagnosed in patients older than 70 years (84%), most of them are likely to be secondary to sporadic MLH1 methylation. MMR protein deficiency patterns suggestive of a defect in MSH2, MSH6 or PMS2 comprised 42 cases, of which 37 were found in individuals aged 50 years or older. CRCs with MSH2/MSH6 loss were most commonly found in patients older than 70 years (57%). In summary, universal testing for MMR protein deficiency in CRC identifies abnormal patterns of expression suggestive of Lynch syndrome in all age groups. Further studies are needed to demonstrate the actual rate of Lynch syndrome individuals identified from this initial screening.

pathology↗