Assessment of Hypoxic Tissue Fraction and Prediction of Survival in Cervical Carcinoma by Dynamic Contrast-Enhanced MRI

Tumor hypoxia is a major cause of treatment resistance and poor survival in locally-advanced cervical carcinoma (LACC). It has been suggested that Ktrans and ve maps derived by dynamic contrast-enhanced magnetic resonance imaging can provide information on the oxygen supply and oxygen consumption of tumors, but it is not clear whether and how these maps can be combined to identify tumor hypoxia. The aim of the current study was to find the optimal strategy for calculating hypoxic fraction and predicting survival from Ktrans and ve maps in cervical carcinoma. Ktrans and ve maps of 98 tumors of four patient-derived xenograft models of cervical carcinoma as well as 80 patients with LACC were investigated. Hypoxic fraction calculated by using Ktrans maps correlated strongly (P < 0.0001) to hypoxic fraction assessed with immunohistochemistry using pimonidazole as a hypoxia marker and was associated with disease-free and overall survival in LACC patients. Maps of ve did not provide information on hypoxic fraction and patient outcome, and combinations of Ktrans and ve were not superior to Ktrans alone for calculating hypoxic fraction. These observations imply that Ktrans maps reflect oxygen supply and may be used to identify hypoxia and predict outcome in cervical carcinoma, whereas ve is a poor parameter of oxygen consumption and does not provide information on tumor oxygenation status.

Implication of O2 dynamics for both N2O and CH4 emissions from soil during biological soil disinfestation

Soil O2 dynamics have significant influences on greenhouse gas emissions during soil management practice. In this study, we deployed O2-specific planar optodes to visualize spatiotemporal distribution of O2 in soils treated with biological soil disinfestation (BSD). This study aimed to reveal the role of anoxia development on emissions of N2O and CH4 from soil amended with crop residues during BSD period. The incorporation of crop residues includes wheat straw only, wheat straw with biochar and early straw incorporation. The anoxia in soil developed very fast within 3 days, while the O2 in headspace decreased much slower and it became anaerobic after 5 days, which was significantly affected by straw and biochar additions. The N2O emissions were positively correlated with soil hypoxic fraction. The CH4 emissions were not significant until the anoxia dominated in both soil and headspace. The co-application of biochar with straw delayed the anoxia development and extended the hypoxic area in soil, resulting in lower emissions of N2O and CH4. Those results highlight that the soil O2 dynamic was the key variable triggering the N2O and CH4 productions. Therefore, detailed information of soil O2 availability could be highly beneficial for optimizing the strategies of organic amendments incorporation in the BSD technique.

Modelling the effects of cerebral microthrombi on tissue oxygenation and cell death

Thrombectomy, the mechanical removal of a clot, is the most common way to treat ischaemic stroke with large vessel occlusions. However, perfusion cannot always be restored after such an intervention. It has been hypothesised that the absence of reperfusion is due to the clot fragments that block the downstream vessels. In this paper, we present a new way of quantifying the effects of cerebral microthrombi on oxygen transport to tissue in terms of hypoxia and ischaemia. The oxygen transport was simulated with the Green’s function method on physiologically accurate microvascular cubes, which was found independent of both microvascular geometry and length scale. The microthrombi occlusions were then simulated in the microvasculature, which were extravasated over time with a new vessel extravasation model. The tissue hypoxic fraction was fitted as a sigmoidal function of vessel blockage fraction, which was then taken to be a function of time after the formation of microthrombi occlusions. A novel hypoxia-based 3-state cell death model was finally proposed to simulate the hypoxic tissue damage over time. Using the cell death model, the impact of a certain degree of microthrombi occlusions on tissue viability and microinfarct volume can be predicted over time. Quantifying the impact of microthrombi on oxygen transport and tissue death will play an important role in full brain models of ischaemic stroke and thrombectomy.

Combining imaging- and gene-based hypoxia biomarkers in cervical cancer improves prediction of chemoradiotherapy failure independent of intratumor heterogeneity

Purpose: Emerging biomarkers from medical imaging or molecular characterization of tumor biopsies open up for combining the two and exploiting their synergy in treatment planning. We compared pretreatment classification of locally advanced cervical cancer patients by two previously validated imaging- and gene-based hypoxia biomarkers, appraised the influence of intratumor heterogeneity, and investigated the benefit of combining them in prediction of chemoradiotherapy failure. Experimental Design: Hypoxic fraction, determined from dynamic contrast enhanced (DCE)-MR images, and an expression signature of 6 hypoxia-responsive genes were used as imaging- and gene-based biomarker, respectively, in 118 patients. Intratumor heterogeneity was assessed by variance analysis. The biomarkers were combined using a dimension reduction procedure. Results: The two biomarkers classified 75% of the patients with the same hypoxia status. Inconsistent classification in some cases was not related to imaging-defined intratumor heterogeneity in hypoxia, and hypoxia status of the slice covering the biopsy region was representative of the whole tumor. Hypoxia assessed by gene expression was independent on tumor cell fraction in the biopsies and showed minor heterogeneity across multiple samples in 9 tumors. Inconsistent classification was therefore rather caused by a difference in the hypoxia phenotype reflected by the biomarkers, providing a rational for combining them into a composite score. This score showed improved prediction of treatment failure (HR:7.3) compared to imaging (HR:3.8) and genes (HR:3.0) and significant prognostic impact in multivariate analysis with clinical variables. Conclusion: Combining our imaging- and gene-based biomarkers enables more precise and informative assessment of hypoxia-related chemoradiotherapy resistance in cervical cancer.

Hypoxia-Activated Pro-Drugs of the KDAC Inhibitor Vorinostat (SAHA)

<div><div><div><p>Hypoxia (lower than normal oxygen) is a characteristic of most solid tumours that results in poor cancer patient prognosis. The difference in cellular environment between normoxia (21% oxygen) or physoxia (4.5-7% oxygen) and hypoxia (<2.0% oxygen) causes increased resistance to radio- and chemotherapy, but also provides the opportunity to selectively release hypoxia-activated pro-drugs. This approach potentially allows targeting of chemotherapies, including lysine deacetylase (KDAC) inhibitors, to the hypoxic fraction of cells. Here, we report initial work on the development of KDAC inhibitors that are selectively released in hypoxic conditions. We have shown that the addition of a 4-nitrobenzyl (NB) or 1-methyl-2-nitroimidazole (NI) bioreductive group onto the hydroxamic acid moiety of SAHA, giving NB-SAHA and NI-SAHA, abolishes KDAC inhibition activity. Both NB-SAHA and NI-SAHA undergo enzyme-mediated bioreduction, in a hypoxia-dependent manner, to release SAHA selectively in <0.1% oxygen. This work provides an important foundation for further investigations into the targeted release of KDAC inhibitors in hypoxic tumours.</p></div></div></div>

Hypoxia-Activated Pro-Drugs of the KDAC Inhibitor Vorinostat (SAHA)

<div><div><div><p>Hypoxia (lower than normal oxygen) is a characteristic of most solid tumours that results in poor cancer patient prognosis. The difference in cellular environment between normoxia (21% oxygen) or physoxia (4.5-7% oxygen) and hypoxia (<2.0% oxygen) causes increased resistance to radio- and chemotherapy, but also provides the opportunity to selectively release hypoxia-activated pro-drugs. This approach potentially allows targeting of chemotherapies, including lysine deacetylase (KDAC) inhibitors, to the hypoxic fraction of cells. Here, we report initial work on the development of KDAC inhibitors that are selectively released in hypoxic conditions. We have shown that the addition of a 4-nitrobenzyl (NB) or 1-methyl-2-nitroimidazole (NI) bioreductive group onto the hydroxamic acid moiety of SAHA, giving NB-SAHA and NI-SAHA, abolishes KDAC inhibition activity. Both NB-SAHA and NI-SAHA undergo enzyme-mediated bioreduction, in a hypoxia-dependent manner, to release SAHA selectively in <0.1% oxygen. This work provides an important foundation for further investigations into the targeted release of KDAC inhibitors in hypoxic tumours.</p></div></div></div>