Hyaluronic acid fuels pancreatic cancer cell growth.

Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

The incidence of intraoperative gastric tube malposition verified by Point-of-Care Ultrasound.

BACKGROUND: Over a million gastric tubes are placed yearly for varying medical reasons including gastric decompression. In the operating room (OR), this is performed blindly, and position is confirmed by auscultation, aspiration, or palpation by a surgeon. Despite the known risks of malpositioned gastric tubes, there is limited data in anesthesia literature about the incidence of intraoperative malpositioned gastric tubes. In this study, we use Point-of-Care ultrasonography (POCUS) to confirm gastric tube placement in the OR. METHODS: Prospective observational study with a total of 149 subjects, all over 18 years of age, undergoing surgery with general endotracheal anesthesia and intraoperative blind placement of a gastric tube by an anesthesia provider. The primary objective of this study is to determine the incidence of malposition of blindly placed gastric tubes. RESULTS: In our analysis, we found that out of 149 patients 110 patients were successfully visualized; the incidence of malposition was 0.14 [95% CI: 0.08-0.21]. We did not find age, Body Mass Index, or sex to be associated with predisposing patients to intraoperative malposition of gastric tube. However, increasing years of experience of anesthesia provider correlated with higher malposition rates. CONCLUSIONS: In summary, we demonstrated that the incidence of malposition of blindly gastric tubes was 14%. Given the attendant risks of malpositioned gastric tubes, this data should inform decision algorithms for the blind placement of gastric tubes.

In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors.

The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1-13C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.

(13)C-labeled biochemical probes for the study of cancer metabolism with dynamic nuclear polarization-enhanced magnetic resonance imaging.

In recent years, advances in metabolic imaging have become dependable tools for the diagnosis and treatment assessment in cancer. Dynamic nuclear polarization (DNP) has recently emerged as a promising technology in hyperpolarized (HP) magnetic resonance imaging (MRI) and has reached clinical relevance with the successful visualization of [1-(13)C] pyruvate as a molecular imaging probe in human prostate cancer. This review focuses on introducing representative compounds relevant to metabolism that are characteristic of cancer tissue: aerobic glycolysis and pyruvate metabolism, glutamine addiction and glutamine/glutamate metabolism, and the redox state and ascorbate/dehydroascorbate metabolism. In addition, a brief introduction of probes that can be used to trace necrosis, pH changes, and other pathways relevant to cancer is presented to demonstrate the potential that HP MRI has to revolutionize the use of molecular imaging for diagnosis and assessment of treatments in cancer.