Browsing by Author "Wang, Xiaojie"

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    A model of tension-induced fiber growth predicts white matter organization during brain folding
    (Springer Nature, 2021-11-18) Garcia, Kara E.; Wang, Xiaojie; Kroenke, Christopher D.; Radiology and Imaging Sciences, School of Medicine
    The past decade has experienced renewed interest in the physical processes that fold the developing cerebral cortex. Biomechanical models and experiments suggest that growth of the cortex, outpacing growth of underlying subcortical tissue (prospective white matter), is sufficient to induce folding. However, current models do not explain the well-established links between white matter organization and fold morphology, nor do they consider subcortical remodeling that occurs during the period of folding. Here we propose a framework by which cortical folding may induce subcortical fiber growth and organization. Simulations incorporating stress-induced fiber elongation indicate that subcortical stresses resulting from folding are sufficient to induce stereotyped fiber organization beneath gyri and sulci. Model predictions are supported by high-resolution ex vivo diffusion tensor imaging of the developing rhesus macaque brain. Together, results provide support for the theory of cortical growth-induced folding and indicate that mechanical feedback plays a significant role in brain connectivity.
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    Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet
    (Elsevier, 2019-11) Luo, Yongde; Yang, Yaying; Liu, Muyun; Wang, Dan; Wang, Feng; Bi, Yawei; Ji, Juntao; Li, Suyun; Liu, Yan; Chen, Rong; Huang, Haojie; Wang, Xiaojie; Swidnicka-Siergiejko, Agnieszka K.; Janowitz, Tobias; Beyaz, Semir; Wang, Guoqiang; Xu, Sulan; Bialkowska, Agnieszka B.; Luo, Catherine K.; Pin, Christoph L.; Liang, Guang; Lu, Xiongbin; Wu, Maoxin; Shroyer, Kenneth R.; Wolff, Robert A.; Plunkett, William; Ji, Baoan; Li, Zhaoshen; Li, Ellen; Li, Xiaokun; Yang, Vincent W.; Logsdon, Craig D.; Abbruzzese, James L.; Lu, Weiqin; Medical and Molecular Genetics, School of Medicine
    Background & Aims Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. Methods We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. Results Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression—a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival—only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. Conclusions Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.