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Yasunori, O.

Publications and source records attributed to Yasunori, O..

2 recordsLinked to original sources

Band-selective IR PRESS for brain tumor spectroscopy allows robust detection of lactate

Lactate plays a critical role in the tumor microenvironment, driving tumor progression, metastasis, and immune evasion. Despite its importance, in vivo quantification of lactate using magnetic resonance spectroscopy (MRS) has faced challenges, primarily due to the overlapping lipid signal at 1.3 ppm. Current clinical practice employs a long echo time to exploit differences in T2 relaxation between lactate and lipids; however, this approach significantly suppresses signals from other metabolites. Lipid has a notably different T1 relaxation time than lactate and other metabolites, which may be exploited by an inversion recovery sequence to better distinguish them. However, this method has not found wide use because of the loss of signal in other metabolites. Here we introduce a selective inversion pulse with a short echo time MRS method (SPIR-PRESS), which mitigates this issue. In phantom experiments, SPIR-PRESS successfully suppressed lipid signals that could be misinterpreted as lactate in short TE PRESS spectra, while maintaining sensitivity to the full metabolite profile. SPIR-PRESS demonstrated superior performance in quantifying lactate compared to long echo time PRESS, with [~] 60 % increase in sensitivity for lactate detection compared to conventional PRESS with a 288 ms TE. In a mouse glioma model, SPIR-PRESS clearly detected lactate and other key tumor metabolites (choline, creatine, NAA) in the tumor, which were not detectable in conventional long TE PRESS. These findings highlight SPIR-PRESS as a promising technique for improved lactate quantification and comprehensive metabolite profiling in tumor environments.

biochemistry↗

Pharmacological Ascorbate Induces Transient Hypoxia Sensitizing Pancreatic Ductal Adenocarcinoma to a Hypoxia Activated Prodrug

Hypoxic tumor microenvironments pose a significant challenge in cancer treatment. Hypoxia-activated prodrugs like evofosfamide aim to specifically target and eliminate these resistant cells. However, their effectiveness is often limited by reoxygenation after cell death. We hypothesized that ascorbates pro-oxidant properties could be harnessed to induce transient hypoxia, enhancing the efficacy of evofosfamide by overcoming reoxygenation. To test this hypothesis, we investigated the sensitivity of MIA Paca-2 and A549 cancer cells to ascorbate in vitro and in vivo. Ascorbate induced a cytotoxic effect at 5 mM that could be alleviated by endogenous administration of catalase, suggesting a role for hydrogen peroxide in its cytotoxic mechanism. In vitro, Seahorse experiments indicated generation of hydrogen peroxide consumes oxygen, which is offset at later time points by a reduction in oxygen consumption due to hydrogen peroxides cytotoxic effect. In vivo, photoacoustic imaging showed ascorbate treatment at sublethal levels triggered a complex, multi-phasic response in tumor oxygenation across both cell lines. Initially, ascorbate generated transient hypoxia within minutes through hydrogen peroxide production, via reactions that consume oxygen. This initial hypoxic phase peaked at around 150 seconds and then gradually subsided. However, at longer time scales (approximately 300 seconds) a vasodilation effect triggered by ascorbate resulted in increased blood flow and subsequent reoxygenation. Combining sublethal levels of ascorbate with evofosfamide significantly prolonged tumor doubling time in MIA Paca-2 and A549b xenografts compared to either treatment alone. This improvement, however, was only observed in a subpopulation of tumors, highlighting the complexity of the oxygenation response.

cancer biology↗