Browsing by Author "Chen, Rong"

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    Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.
    (Cancers, 2022-05) Zhu, Liang; Ji, Juntao; Ma, Jianjia; Wang, Dan; Liu, Muyun; Du, James Xianxing; Chen, Rong; Hou, Wei; Abbruzzese, James L; Logsdon, Craig D; Yang, Vincent W; Luo, Yongde; Lu, Weiqin
    KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain unclear. In this study, we compared the differential effects of a high-carbohydrate diet (HCD), an HFD, and a high-protein diet (HPD) in PDAC development using a mouse model expressing an endogenous level of mutant KRASG12D specifically in pancreatic acinar cells. Our study showed that although with a lower tumorigenic capacity than chronic HFD, chronic HCD promoted acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions with increased inflammation, fibrosis, and cell proliferation compared to the normal diet (ND) in KrasG12D/+ mice. By contrast, chronic HPD showed no significant adverse effects compared to the ND. Furthermore, ablation of pancreatic acinar cell cyclooxygenase 2 (Cox-2) in KrasG12D/+ mice abrogated the adverse effects induced by HCD, suggesting that diet-induced pancreatic inflammation is critical for promoting oncogenic KRAS-mediated neoplasia. These results indicate that diets rich in different macronutrients have differential effects on pancreatic tumorigenesis in which the ensuing inflammation exacerbates the process. Management of macronutrient intake aimed at thwarting inflammation is thus an important preventive strategy for patients harboring oncogenic KRAS.
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    Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.
    (Genet Med, 2014-10) Enns, Gregory M; Shashi, Vandana; Bainbridge, Matthew; Gambello, Michael J; Zahir, Farah R; Bast, Thomas; Crimian, Rebecca; Schoch, Kelly; Platt, Julia; Cox, Rachel; Bernstein, Jonathan A; Scavina, Mena; Walter, Rhonda S; Bibb, Audrey; Jones, Melanie; Hegde, Madhuri; Graham, Brett H; Need, Anna C; Oviedo, Angelica; Schaaf, Christian P; Boyle, Sean; Butte, Atul J; Chen, Rui; Chen, Rong; Clark, Michael J; Haraksingh, Rajini; FORGE Canada Consortium; Cowan, Tina M; He, Ping; Langlois, Sylvie; Zoghbi, Huda Y; Snyder, Michael; Gibbs, Richard A; Freeze, Hudson H; Goldstein, David B
    PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.