The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia ...The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.展开更多
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The prognosis for patients who present with inoperable primary liver tumors is poor with median survival times of 12 months or less. Tumor-re...Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The prognosis for patients who present with inoperable primary liver tumors is poor with median survival times of 12 months or less. Tumor-related liver failure is a common cause of mortality, underscoring the importance of local control. Recent advancements in external beam radiation therapy delivery techniques have enabled dose escalation that in turn has significantly improved local control and has allowed radiation therapy to emerge as an effective modality in this setting. In this review, we outline the critical practical aspects of treating liver tumors with radiation including choice of fractionation, motion management, image guidance and use of intensity-modulated radiation therapy vs. proton beam therapy. We review our approach to ablative radiation therapy for HCC with consideration of underlying cirrhosis and provide a brief overview of the current literature.展开更多
基金the Arizona Biomedical Research Commission(ABRC)young investigator awardthe Fred Hutchinson Cancer Research Center(0000917241)Tulane University Startup fund。
文摘The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.
文摘Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The prognosis for patients who present with inoperable primary liver tumors is poor with median survival times of 12 months or less. Tumor-related liver failure is a common cause of mortality, underscoring the importance of local control. Recent advancements in external beam radiation therapy delivery techniques have enabled dose escalation that in turn has significantly improved local control and has allowed radiation therapy to emerge as an effective modality in this setting. In this review, we outline the critical practical aspects of treating liver tumors with radiation including choice of fractionation, motion management, image guidance and use of intensity-modulated radiation therapy vs. proton beam therapy. We review our approach to ablative radiation therapy for HCC with consideration of underlying cirrhosis and provide a brief overview of the current literature.
