Effect of pneumatic tourniquet on muscle oxygen tension.

Science.gov (United States)

Santavirta, S; Höckerstedt, K; Niinikoski, J

1978-10-01

Recent investigations suggest that circulation in a limb can be reduced with a tourniquet to less than 1 per cent of the control limb, or even completely occluded. The development of tissue oxygen tonometry with implanted silastic tubes has provided new possibilities for assessing muscle tissue oxygen tension. In the present work, this method was employed to register the effect of tourniquet blackade on the lower limb muscle PO2 in rabbits. The duration of the tourniquet blockade was 60, 120 and 180 minutes. The baseline muscle PO2 in the tibialis anterior muscle was 22.6 +/- 0.6 mmHg. During the tourniquet blockade the oxygen tension dropped to minimal values between 9.2 +/- 0.5 and 10.7 +/- 0.6 mmHg in these experimental groups, but the tissue microclimate never reached fully anoxic conditions. The rapid response of muscle PO2 to oxygen breathing after release of the blockade suggests that limb microcirculation tolerates tourniquet occlusion well.

Differential oxygen dynamics in two diverse Dunning prostate R3327 rat tumor sublines (MAT-Lu and HI) with respect to growth and respiratory challenge

International Nuclear Information System (INIS)

Zhao Dawen; Constantinescu, Anca; Hahn, Eric W.; Mason, Ralph P.

2002-01-01

Purpose: Since hypoxia may influence tumor response to therapy and prognosis, we have compared oxygenation of tumors known to exhibit differential growth rate and tissue differentiation. Methods and Materials: Regional tumor oxygen tension was measured using 19 F nuclear magnetic resonance echo planar imaging relaxometry of hexafluorobenzene, which provided dynamic maps with respect to respiratory intervention. Investigations used two Dunning prostate R3327 rat tumor sublines: the fast growing, highly metastatic MAT-Lu and the moderately well-differentiated, slower growing HI. Results: Both sublines showed significantly higher oxygen tension in smaller tumors ( 3 ) than in larger tumors (>3.5 cm 3 ). Pooled data showed that MAT-Lu tumors exhibited greater hypoxia compared with the size-matched HI tumors (p 2 for tumors of both sublines (p 2 , while those in the MAT-Lu tumors showed little response to respiratory intervention. Conclusions: These results concur with hypotheses that hypoxia is related to tumor growth rate and degree of differentiation. Under baseline conditions, the differences were subtle. However, response to respiratory intervention revealed highly significant differences, which, if held valid in the clinic, could have prognostic value

Fluctuations in pO2 in poorly and well-oxygenated spontaneous canine tumors before and during fractionated radiation therapy.

Science.gov (United States)

Brurberg, Kjetil G; Skogmo, Hege K; Graff, Bjørn A; Olsen, Dag R; Rofstad, Einar K

2005-11-01

The spatial heterogeneity in oxygen tension (pO2) in tumor tissue has been studied extensively, whereas, the information about the temporal heterogeneity is sparse. The purpose of the present study was to search for pO2 fluctuations in untreated and irradiated spontaneous canine tumors, and to investigate whether there is a relationship between overall tumor oxygenation status and pO2 fluctuation pattern. Six dogs scheduled for radiation therapy of head and neck cancer were included in the study. The primary tumors were irradiated with 18 fractions of 3 Gy. Eppendorf polarographic electrodes and OxyLite fluorescence probes were used to measure overall oxygenation status and pO2 fluctuation pattern, respectively. Tissue pO2 was recorded at three subsequent days prior to treatment, and immediately before radiation fraction 4, 7, and 10. Overall oxygenation status differed substantially among the tumors. Radiation therapy had no consistent effect on overall oxygenation status. Fluctuations in pO2 were detected in untreated as well as irradiated tumors, and independent of whether the tumors were poorly or well oxygenated. Fluctuations in pO2 can occur in untreated and irradiated spontaneous canine tumors. There is no correlation between pO2 fluctuation pattern and overall tumor oxygenation status.

Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension

NARCIS (Netherlands)

Papazova, Diana A.; Friederich-Persson, Malou; Joles, Jaap A.; Verhaar, Marianne C.

2015-01-01

Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (PO2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney

Transcutaneous oxygen tension in imminent foot gangrene

DEFF Research Database (Denmark)

Tønnesen, K H

1978-01-01

Transcutaneous oxygen tension at 44 degree C and maximal isotope clearance (90m Tc-pretechnetate + histramine) just proximal to the 1st toe and systolic toe blood pressure (strain gauge) were studied on a tilt table in patients with various degrees of obstructive arteriosclerotic disease. In legs...

Optic nerve oxygen tension in pigs and the effect of carbonic anhydrase inhibitors

DEFF Research Database (Denmark)

Stefánsson, E; Jensen, P K; Eysteinsson, T

1999-01-01

To evaluate how the oxygen tension of the optic nerve (ONP(O)2) is affected by the administration of the carbonic anhydrase inhibitors dorzolamide and acetazolamide and by alterations in oxygen and carbon dioxide in the breathing mixture.......To evaluate how the oxygen tension of the optic nerve (ONP(O)2) is affected by the administration of the carbonic anhydrase inhibitors dorzolamide and acetazolamide and by alterations in oxygen and carbon dioxide in the breathing mixture....

Oxygen distribution in tumors: A qualitative analysis and modeling study providing a novel Monte Carlo approach

International Nuclear Information System (INIS)

Lagerlöf, Jakob H.; Kindblom, Jon; Bernhardt, Peter

2014-01-01

Purpose: To construct a Monte Carlo (MC)-based simulation model for analyzing the dependence of tumor oxygen distribution on different variables related to tumor vasculature [blood velocity, vessel-to-vessel proximity (vessel proximity), and inflowing oxygen partial pressure (pO 2 )]. Methods: A voxel-based tissue model containing parallel capillaries with square cross-sections (sides of 10 μm) was constructed. Green's function was used for diffusion calculations and Michaelis-Menten's kinetics to manage oxygen consumption. The model was tuned to approximately reproduce the oxygenational status of a renal carcinoma; the depth oxygenation curves (DOC) were fitted with an analytical expression to facilitate rapid MC simulations of tumor oxygen distribution. DOCs were simulated with three variables at three settings each (blood velocity, vessel proximity, and inflowing pO 2 ), which resulted in 27 combinations of conditions. To create a model that simulated variable oxygen distributions, the oxygen tension at a specific point was randomly sampled with trilinear interpolation in the dataset from the first simulation. Six correlations between blood velocity, vessel proximity, and inflowing pO 2 were hypothesized. Variable models with correlated parameters were compared to each other and to a nonvariable, DOC-based model to evaluate the differences in simulated oxygen distributions and tumor radiosensitivities for different tumor sizes. Results: For tumors with radii ranging from 5 to 30 mm, the nonvariable DOC model tended to generate normal or log-normal oxygen distributions, with a cut-off at zero. The pO 2 distributions simulated with the six-variable DOC models were quite different from the distributions generated with the nonvariable DOC model; in the former case the variable models simulated oxygen distributions that were more similar to in vivo results found in the literature. For larger tumors, the oxygen distributions became truncated in the lower

Changes in transcutaneous oxygen tension during exercise in pulmonary emphysema.

OpenAIRE

Hughes, J A; Gray, B J; Hutchison, D C

1984-01-01

Continuous measurements of transcutaneous oxygen tension (tcPO2) were made in 23 patients with radiological evidence of emphysema, at rest and during a maximal progressive exercise test. tcPO2 during the final phase of exercise was compared with tcPO2 at rest; the mean change (exercising minus resting value) in tcPO2 (delta tcPO2) was -0.8 mm Hg (SD 10.5, range -18 to +25) (-0.1 kPa (SD 1.4, range -2.4 to +3.3]. delta tcPO2 was correlated with: resting arterial oxygen tension (PaO2) (r = 0.60...

Oxygen Tension in the Aqueous Humor of Human Eyes under Different Oxygenation Conditions

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Farideh Sharifipour

2013-01-01

Full Text Available Purpose: To measure oxygen tension in the aqueous humor of human eyes under different oxygenation conditions. Methods: This prospective comparative interventional case series consisted of two parts. In the first part, 120 consecutive patients scheduled for cataract surgery were randomized into group I (control group in which surgery was performed under local anesthesia inhaling 21% oxygen; group II in whom general anesthesia using 50% oxygen was employed; and group III receiving general anesthesia with 100% oxygen. After aspirating 0.2 ml aqueous humor under sterile conditions, the aqueous sample and a simultaneously drawn arterial blood sample were immediately analyzed using a blood gas analyzer. In part II the same procedures were performed in 10 patients after fitting a contact lens and patching the eye for 20 minutes (group IV and in 10 patients after transcorneal delivery of oxygen at a flow rate of 5 L/min (group V. Results: Mean aqueous PO2 in groups I, II and III was 112.3±6.2, 141.1±20.4, and 170.1±27 mmHg, respectively (P values <0.001 and mean arterial PO2 was 85.7±7.9, 184.6±46, and 379.1±75.9 mmHg, respectively (P values <0.001. Aqueous PO2 was 77.2±9.2 mmHg in group IV and 152.3±10.9 mmHg in group V (P values <0.001. There was a significant correlation between aqueous and blood PO2 (r=0.537, P<0.001. The contribution of atmospheric oxygen to aqueous PO2 was 23.7%. Conclusion: Aqueous oxygen tension is mostly dependent on the systemic circulation and in part on the atmosphere. Increasing inspiratory oxygen and transcorneal oxygen delivery both increase aqueous PO2 levels.

Hemodynamic parameters change earlier than tissue oxygen tension in hemorrhage.

Science.gov (United States)

Pestel, Gunther J; Fukui, Kimiko; Kimberger, Oliver; Hager, Helmut; Kurz, Andrea; Hiltebrand, Luzius B

2010-05-15

Untreated hypovolemia results in impaired outcome. This study tests our hypothesis whether general hemodynamic parameters detect acute blood loss earlier than monitoring parameters of regional tissue beds. Eight pigs (23-25 kg) were anesthetized and mechanically ventilated. A pulmonary artery catheter and an arterial catheter were inserted. Tissue oxygen tension was measured with Clark-type electrodes in the jejunal and colonic wall, in the liver, and subcutaneously. Jejunal microcirculation was assessed by laser Doppler flowmetry (LDF). Intravascular volume was optimized using difference in pulse pressure (dPP) to keep dPP below 13%. Sixty minutes after preparation, baseline measurements were taken. At first, 5% of total blood volume was withdrawn, followed by another 5% increment, and then in 10% increments until death. After withdrawal of 5% of estimated blood volume, dPP increased from 6.1% +/- 3.0% to 20.8% +/- 2.7% (P < 0.01). Mean arterial pressure (MAP), mean pulmonary artery pressure (PAP) and pulmonary artery occlusion pressure (PAOP) decreased with a blood loss of 10% (P < 0.01). Cardiac output (CO) changed after a blood loss of 20% (P < 0.05). Tissue oxygen tension in central organs, and blood flow in the jejunal muscularis decreased (P < 0.05) after a blood loss of 20%. Tissue oxygen tension in the skin, and jejunal mucosa blood flow decreased (P < 0.05) after a blood loss of 40% and 50%, respectively. In this hemorrhagic pig model systemic hemodynamic parameters were more sensitive to detect acute hypovolemia than tissue oxygen tension measurements or jejunal LDF measurements. Acute blood loss was detected first by dPP. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Low physiologic oxygen tensions reduce proliferation and differentiation of human multipotent mesenchymal stromal cells

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Handgretinger Rupert

2010-01-01

Full Text Available Abstract Background Human multipotent mesenchymal stromal cells (MSC can be isolated from various tissues including bone marrow. Here, MSC participate as bone lining cells in the formation of the hematopoietic stem cell niche. In this compartment, the oxygen tension is low and oxygen partial pressure is estimated to range from 1% to 7%. We analyzed the effect of low oxygen tensions on human MSC cultured with platelet-lysate supplemented media and assessed proliferation, morphology, chromosomal stability, immunophenotype and plasticity. Results After transferring MSC from atmospheric oxygen levels of 21% to 1%, HIF-1α expression was induced, indicating efficient oxygen reduction. Simultaneously, MSC exhibited a significantly different morphology with shorter extensions and broader cell bodies. MSC did not proliferate as rapidly as under 21% oxygen and accumulated in G1 phase. The immunophenotype, however, was unaffected. Hypoxic stress as well as free oxygen radicals may affect chromosomal stability. However, no chromosomal abnormalities in human MSC under either culture condition were detected using high-resolution matrix-based comparative genomic hybridization. Reduced oxygen tension severely impaired adipogenic and osteogenic differentiation of human MSC. Elevation of oxygen from 1% to 3% restored osteogenic differentiation. Conclusion Physiologic oxygen tension during in vitro culture of human MSC slows down cell cycle progression and differentiation. Under physiological conditions this may keep a proportion of MSC in a resting state. Further studies are needed to analyze these aspects of MSC in tissue regeneration.

A Method for Combined Retinal Vascular and Tissue Oxygen Tension Imaging.

Science.gov (United States)

Felder, Anthony E; Wanek, Justin; Tan, Michael R; Blair, Norman P; Shahidi, Mahnaz

2017-09-06

The retina requires adequate oxygenation to maintain cellular metabolism and visual function. Inner retinal oxygen metabolism is directly related to retinal vascular oxygen tension (PO 2 ) and inner retinal oxygen extraction fraction (OEF), whereas outer retinal oxygen consumption (QO 2 ) relies on oxygen availability by the choroid and is contingent upon retinal tissue oxygen tension (tPO 2 ) gradients across the retinal depth. Thus far, these oxygenation and metabolic parameters have been measured independently by different techniques in separate animals, precluding a comprehensive and correlative assessment of retinal oxygenation and metabolism dynamics. The purpose of the current study is to report an innovative optical system for dual oxyphor phosphorescence lifetime imaging to near-simultaneously measure retinal vascular PO 2 and tPO 2 in rats. The use of a new oxyphor with different spectral characteristics allowed differentiation of phosphorescence signals from the retinal vasculature and tissue. Concurrent measurements of retinal arterial and venous PO 2 , tPO 2 through the retinal depth, inner retinal OEF, and outer retinal QO 2 were demonstrated, permitting a correlative assessment of retinal oxygenation and metabolism. Future application of this method can be used to investigate the relations among retinal oxygen content, extraction and metabolism under pathologic conditions and thus advance knowledge of retinal hypoxia pathophysiology.

In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique

NARCIS (Netherlands)

Mik, Egbert G.; Johannes, Tanja; Zuurbier, Coert J.; Heinen, Andre; Houben-Weerts, Judith H. P. M.; Balestra, Gianmarco M.; Stap, Jan; Beek, Johan F.; Ince, Can

2008-01-01

Mitochondrial oxygen tension (mitoPO(2)) is a key parameter for cellular function, which is considered to be affected under various pathophysiological circumstances. Although many techniques for assessing in vivo oxygenation are available, no technique for measuring mitoPO(2) in vivo exists. Here we

Simultaneous administration of glucose and hyperoxic gas achieves greater improvement in tumor oxygenation than hyperoxic gas alone

International Nuclear Information System (INIS)

Snyder, Stacey A.; Lanzen, Jennifer L.; Braun, Rod D.; Rosner, Gary; Secomb, Timothy W.; Biaglow, John; Brizel, David M.; Dewhirst, Mark W.

2001-01-01

Purpose: To test the feasibility of hyperglycemic reduction of oxygen consumption combined with oxygen breathing (O 2 ), to improve tumor oxygenation. Methods and Materials: Fischer-344 rats bearing 1 cm R3230Ac flank tumors were anesthetized with Nembutal. Mean arterial pressure, heart rate, tumor blood flow ([TBF], laser Doppler flowmetry), pH, and pO 2 were measured before, during, and after glucose (1 or 4 g/kg) and/or O 2 . Results: Mean arterial pressure and heart rate were unaffected by treatment. Glucose at 1 g/kg yielded maximum blood glucose of 400 mg/dL, no change in TBF, reduced tumor pH (0.17 unit), and 3 mm Hg pO 2 rise. Glucose at 4 g/kg yielded maximum blood glucose of 900 mg/dL, pH drop of 0.6 unit, no pO 2 change, and reduced TBF (31%). Oxygen tension increased by 5 mm Hg with O 2 . Glucose (1 g/Kg) + O 2 yielded the largest change in pO 2 (27 mm Hg); this is highly significant relative to baseline or either treatment alone. The effect was positively correlated with baseline pO 2 , but 6 of 7 experiments with baseline pO 2 2 to improve tumor oxygenation. However, some cell lines are not susceptible to the Crabtree effect, and the magnitude is dependent on baseline pO 2 . Additional or alternative manipulations may be necessary to achieve more uniform improvement in pO 2

Oxygen tension and oocyte density during in vitro maturation affect the in vitro fertilization of bovine oocytes

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Angelo Bertani Giotto

2015-12-01

Full Text Available Oocyte maturation is the key factor affecting the fertilization and embryonic development. Factors such as oocyte density and oxygen tension can directly influence the IMV. Thus, the objective of this study was to evaluate the effect of the association of oxygen tensions (5% or 20% with different oocyte densities (1:10?l or 1:20?l in the in vitro maturation (IVM of bovine oocytes on maturation and fertilization rates, ROS production and antioxidant activity. Three experiments were performed with bovine oocytes that were obtained from slaughterhouse ovaries. After selection, the oocytes were randomly distributed in four treatments: 1:10/5%; 1:10/20%; 1:20/5%and 1:20/20% for each experiment. In experiment I, nuclear maturation status and cytoplasmic maturation were evaluated through detection of the first polar body by immunofluorescence and the mitochondrial reorganization assay. In experiment II, ROS production and antioxidant activity were analyzed in oocytes and IVM medium after 24 h of maturation through detection of ROS, reduced glutathione (GSH and Superoxide dismutase activity by spectrofluorimetric methods. In experiment III, fertilization was evaluated through pronucleus formation, sperm penetration with or without decondensation and polyspermy rates by immunofluorescence. In experiment I, the nuclear maturation and cytoplasmic maturation were similar among treatments (P>0.05. In experiment II, reactive oxygen species in oocytes were elevated in treatments with low oxygen tension which was independent of oocyte density (P<0.05. Additionally, ROS levels in IVM medium were higher in treatments with high oocyte density by volume of medium, which was independent of oxygen tension (P<0.05. In Experiment III, the fertilization and penetration rates were higher in the treatment with 20% oxygen tension and high oocyte density (P<0.05. Furthermore, a high incidence of polyspermy was observed in groups with high oxygen tension and low oocyte

Impact of low oxygen tension on stemness, proliferation and differentiation potential of human adipose-derived stem cells

Energy Technology Data Exchange (ETDEWEB)

Choi, Jane Ru; Pingguan-Murphy, Belinda; Wan Abas, Wan Abu Bakar [Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur (Malaysia); Noor Azmi, Mat Adenan; Omar, Siti Zawiah [Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur (Malaysia); Chua, Kien Hui [Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia); Wan Safwani, Wan Kamarul Zaman, E-mail: wansafwani@um.edu.my [Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur (Malaysia)

2014-05-30

Highlights: • Hypoxia maintains the stemness of adipose-derived stem cells (ASCs). • ASCs show an increased proliferation rate under low oxygen tension. • Oxygen level as low as 2% enhances the chondrogenic differentiation potential of ASCs. • HIF-1α may regulate the proliferation and differentiation activities of ASCs under hypoxia. - Abstract: Adipose-derived stem cells (ASCs) have been found adapted to a specific niche with low oxygen tension (hypoxia) in the body. As an important component of this niche, oxygen tension has been known to play a critical role in the maintenance of stem cell characteristics. However, the effect of O{sub 2} tension on their functional properties has not been well determined. In this study, we investigated the effects of O{sub 2} tension on ASCs stemness, differentiation and proliferation ability. Human ASCs were cultured under normoxia (21% O{sub 2}) and hypoxia (2% O{sub 2}). We found that hypoxia increased ASC stemness marker expression and proliferation rate without altering their morphology and surface markers. Low oxygen tension further enhances the chondrogenic differentiation ability, but reduces both adipogenic and osteogenic differentiation potential. These results might be correlated with the increased expression of HIF-1α under hypoxia. Taken together, we suggest that growing ASCs under 2% O{sub 2} tension may be important in expanding ASCs effectively while maintaining their functional properties for clinical therapy, particularly for the treatment of cartilage defects.

[Long-term expansion of multipotent mesenchymal stromal cells under reduced oxygen tension].

Science.gov (United States)

Rylova, Iu V; Buravkova, L B

2013-01-01

We have shown that the decrease in oxygen tension in the culture medium of multipotent mesenchymal stromal cells (MMSCs) results in a short-term reduction in the proportion of CD73(+)-cells in the population, without effecting the number of cells expressing other constitutive surface markers (CD90 and CD105). In this case, the heterogeneity of the cell population declined: large spread cells disappeared. The proliferative activity of MMSCs significantly increased and remained stable in conditions in which the oxygen content was close to the tissue oxygen levels (5% O2). At lower oxygen concentration, proliferative activity of the cells gradually reduced from passages 3-4. The increase in proliferative activity was not accompanied by increased expression of telomerase gene indicateding the alsance of cell transformation. However, genome-wide analysis of MMSC gene expression level revealed changes in expression of cyclins (CCND2 and PCNA), regulatory subunit cyclin-dependent kinase (CKS2) and an inhibitor of cyclin-dependent kinase (CDKN2C), regulating the cell cycle, which is obviously facilitated the increase in the proliferative capacity of cells at lower oxygen tension.

Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems.

Science.gov (United States)

Lee-Montiel, Felipe T; George, Subin M; Gough, Albert H; Sharma, Anup D; Wu, Juanfang; DeBiasio, Richard; Vernetti, Lawrence A; Taylor, D Lansing

2017-10-01

This article describes our next generation human Liver Acinus MicroPhysiology System (LAMPS). The key demonstration of this study was that Zone 1 and Zone 3 microenvironments can be established by controlling the oxygen tension in individual devices over the range of ca. 3 to 13%. The oxygen tension was computationally modeled using input on the microfluidic device dimensions, numbers of cells, oxygen consumption rates of hepatocytes, the diffusion coefficients of oxygen in different materials and the flow rate of media in the MicroPhysiology System (MPS). In addition, the oxygen tension was measured using a ratiometric imaging method with the oxygen sensitive dye, Tris(2,2'-bipyridyl) dichlororuthenium(II) hexahydrate (RTDP) and the oxygen insensitive dye, Alexa 488. The Zone 1 biased functions of oxidative phosphorylation, albumin and urea secretion and Zone 3 biased functions of glycolysis, α1AT secretion, Cyp2E1 expression and acetaminophen toxicity were demonstrated in the respective Zone 1 and Zone 3 MicroPhysiology System. Further improvements in the Liver Acinus MicroPhysiology System included improved performance of selected nonparenchymal cells, the inclusion of a porcine liver extracellular matrix to model the Space of Disse, as well as an improved media to support both hepatocytes and non-parenchymal cells. In its current form, the Liver Acinus MicroPhysiology System is most amenable to low to medium throughput, acute through chronic studies, including liver disease models, prioritizing compounds for preclinical studies, optimizing chemistry in structure activity relationship (SAR) projects, as well as in rising dose studies for initial dose ranging. Impact statement Oxygen zonation is a critical aspect of liver functions. A human microphysiology system is needed to investigate the impact of zonation on a wide range of liver functions that can be experimentally manipulated. Because oxygen zonation has such diverse physiological effects in the liver, we

Oxygen Tension Regulates Human Mesenchymal Stem Cell Paracrine Functions.

Science.gov (United States)

Paquet, Joseph; Deschepper, Mickael; Moya, Adrien; Logeart-Avramoglou, Delphine; Boisson-Vidal, Catherine; Petite, Hervé

2015-07-01

: Mesenchymal stem cells (MSCs) have captured the attention and research endeavors of the scientific world because of their differentiation potential. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly due to the multitude of bioactive mediators secreted by these cells. Because the paracrine potential of MSCs is closely related to their microenvironment, the present study investigated and characterized select aspects of the human MSC (hMSC) secretome and assessed its in vitro and in vivo bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. In contrast to supernatant conditioned media (CM) obtained from hMSCs cultured at either 5% or 21% of O2, CM from hMSCs cultured under near anoxia exhibited significantly (p mesenchymal stem cell (hMSC) secretome and assessed its in vitro and in vivo biological bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. The present study provided the first evidence of a shift of the hMSC cytokine signature induced by oxygen tension, particularly near anoxia (0.1% O2). Conditioned media obtained from hMSCs cultured under near anoxia exhibited significantly enhanced chemotactic and proangiogenic properties and a significant decrease in the inflammatory mediator content. These findings provide new evidence that elucidates aspects of great importance for the use of MSCs in regenerative medicine, could contribute to improving the efficacy of such therapies, and most importantly highlighted the interest in using conditioned media in therapeutic modalities. ©AlphaMed Press.

Oxygen tension during biofilm growth influences the efficacy antimicrobial agents

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Raquel Pippi ANTONIAZZI

Full Text Available Abstract Objective To compare the antimicrobial efficacy of a 0.12% chlorhexidine (CHX and herbal green tea (Camellia sinensis solution on established biofilms formed at different oxygen tensions in an in situ model. Method Twenty-five dental students were eligible for the study. In situ devices with standardized enamel specimens (ES facing the palatal and buccal sides were inserted in the mouths of volunteers for a 7 day period. No agent was applied during the first four days. From the fifth day onward, both agents were applied to the test ES group and no agent was applied to the control ES group. After 7 days the ES fragments were removed from the devices, sonicated, plated on agar, and incubated for 24 h at 37 °C to determine and quantify the colony forming units (CFUs. Result CHX had significantly higher efficacy compared to green tea on the buccal (1330 vs. 2170 CFU/µL and palatal (2250 vs. 2520 CFU/µL ES. In addition, intragroup comparisons showed significantly higher efficacy in buccal ES over palatal ES (1330 vs. 2250 CFU/µL for CHX and 2170 vs, 2520 CFU/µL for CV for both solutions. Analysis of the ES controls showed significantly higher biofilm formation in palatal ES compared to buccal ES. Conclusion CHX has higher efficacy than green tea on 4-day biofilms. The efficacy of both agents was reduced for biofilms grown in a low oxygen tension environment. Therefore, the oxygen tension environment seems to influence the efficacy of the tested agents.

Evaluation of multi-exponential curve fitting analysis of oxygen-quenched phosphorescence decay traces for recovering microvascular oxygen tension histograms

NARCIS (Netherlands)

Bezemer, Rick; Faber, Dirk J.; Almac, Emre; Kalkman, Jeroen; Legrand, Matthieu; Heger, Michal; Ince, Can

2010-01-01

Although it is generally accepted that oxygen-quenched phosphorescence decay traces can be analyzed using the exponential series method (ESM), its application until now has been limited to a few (patho)physiological studies, probably because the reliability of the recovered oxygen tension (pO(2))

Tension pneumoventricle after excision of third ventricular tumor in sitting position

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Nidhi Gupta

2011-01-01

Full Text Available Occurrence of tension pneumoventricle (symptomatic intraventricular air can result in rapid clinical deterioration in an otherwise stable patient. It is a rare clinical entity, mentioned in relation to cerebrospinal fluid (CSF diversion procedures, during the late postoperative period. We present a patient with posterior third ventricular tumor who underwent excision by midline suboccipital craniotomy in sitting position. Neurological status of the patient deteriorated rapidly in the immediate postoperative period owing to development of tension pneumoventricle. The condition improved after twist-drill burr-hole evacuation of air under water-seal. Pre-existing gross hydrocephalus, exploration of third ventricle in sitting position, and residual tumor in third ventricle were possibly the factors responsible for this complication.

Low Oxygen Tension Enhances Expression of Myogenic Genes When Human Myoblasts Are Activated from G0 Arrest

DEFF Research Database (Denmark)

Sellathurai, Jeeva; Nielsen, Joachim; Hejbøl, Eva Kildall

2016-01-01

-PCR, immunocytochemistry and western blot. RESULTS AND CONCLUSIONS: We found an increase in proliferation rate of myoblasts when activated at a low oxygen tension (1% O2) compared to 21% O2. In addition, the gene expression studies showed up regulation of the myogenesis related genes PAX3, PAX7, MYOD, MYOG (myogenin), MET......, NCAM, DES (desmin), MEF2A, MEF2C and CDH15 (M-cadherin), however, the fraction of DES and MYOD positive cells was not increased by low oxygen tension, indicating that 1% O2 may not have a functional effect on the myogenic response. Furthermore, the expression of genes involved in the TGFβ, Notch...... and Wnt signaling pathways were also up regulated in low oxygen tension. The differences in gene expression were most pronounced at day one after activation from G0-arrest, thus the initial activation of myoblasts seemed most sensitive to changes in oxygen tension. Protein expression of HES1 and β...

A theoretical model for the effects of reduced hemoglobin-oxygen affinity on tumor oxygenation

International Nuclear Information System (INIS)

Kavanagh, Brian D.; Secomb, Timothy W.; Hsu, Richard; Lin, P.-S.; Venitz, Jurgen; Dewhirst, Mark W.

2002-01-01

Purpose: To develop a theoretical model for oxygen delivery to tumors, and to use the model to simulate the effects of changing the affinity of hemoglobin for oxygen on tumor oxygenation. Methods and Materials: Hemoglobin affinity is expressed in terms of P 50 , the partial pressure of oxygen (Po 2 ) at half saturation. Effects of changing P 50 on arterial Po 2 are predicted using an effective vessel approach to describe diffusive oxygen transport in the lungs, assuming fixed systemic oxygen demand and fixed blood flow rate. The decline in oxygen content of blood as it flows through normal tissue before entering the tumor region is assumed fixed. The hypoxic fraction of the tumor region is predicted using a three-dimensional simulation of diffusion from a network of vessels whose geometry is derived from observations of tumor microvasculature in the rat. Results: In air-breathing rats, predicted hypoxic fraction decreases with moderate increases in P 50 , but increases with further increases of P 50 , in agreement with previous experimental results. In rats breathing hyperoxic gases, and in humans breathing either normoxic or hyperoxic gases, increased P 50 is predicted to improve tumor oxygenation. Conclusions: The results support the administration of synthetic agents to increase P 50 during radiation treatment of tumors

Should direct measurements of tumor oxygenation relate to the radiobiological hypoxic fraction of a tumor?

International Nuclear Information System (INIS)

Fenton, Bruce M.; Kiani, Mohammad F.; Siemann, Dietmar W.

1995-01-01

Purpose: Numerous previous studies have attempted to relate the radiobiological hypoxic fraction (HF) to direct measures of tumor oxygenation such as HbO 2 saturations, tumor pO 2 levels, or hypoxic cell labeling. Although correlations have been found within tumor lines, no overall relationships were seen across tumor lines. The current objective was to examine the effect on HF of changes in the fractions of the oxygenated and anoxic tumor cells that remain clonogenic. Methods and Materials: A mathematical model was developed that relates the HF to direct measures of tumor oxygenation. The primary assumptions were that: (a) the tumor is divided into distinct compartments of either fully oxygenated or fully anoxic cells, and (b) the survival of the oxygenated cells is negligible compared to that of the anoxic cells. Based on these assumptions, the HF is plotted as a function of the fractions of clonogenic or nonclonogenic, and oxygenated or anoxic cells. Results: If all cells are clonogenic, then the HF equals the fraction of anoxic cells. If a higher fraction of anoxic than oxygenated cells are nonclonogenic, then the HF will be overestimated by the fraction of the tumor measured to be anoxic using direct measuring techniques. If a higher fraction of the oxygenated than anoxic cells are nonclonogenic, the HF will be underestimated by the fraction of anoxic cells. Conclusion: Correlations between the HF and direct measures of tumor oxygenation have been described within tumor lines evaluated under different physiological condition. However, such relationships can be totally unpredictable between different tumors if the fraction of the anoxic cells that is clonogenic varies substantially. Clearly, if tumor anoxia cannot be detected using direct measures, this is an accurate indication that the tumor is well oxygenated. When tumor anoxia is present, however, the conclusions are ambiguous. Even when a small fraction of the tumor is measured as anoxic, direct measures

"Tissue oxygen tension, a determinant of resistance to infection and ...

African Journals Online (AJOL)

"Tissue oxygen tension, a determinant of resistance to infection and healing" - An Inaugural Lecture. K Jönsson. Abstract. An Inaugural Lecture Given in the University of Zimbabwe on 21 June 2001. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT.

Effect of carbogen on tumor oxygenation: combined fluorine-19 and proton MRI measurements

International Nuclear Information System (INIS)

Fan Xiaobing; River, Jonathan N.; Zamora, Marta; Al-Hallaq, Hania A.; Karczmar, Gregory S.

2002-01-01

Purpose: Blood oxygen level dependent (BOLD) contrast in magnetic resonance imaging (MRI) has been widely used for noninvasive evaluation of the effects of tumor-oxygenating agents. However, there have been few tests of the validity of this method. The goal of the present work was to use the T 1 of fluorine-19 in perfluorocarbon (PFC) emulsions as a 'gold standard' for comparison with BOLD MRI. Methods and Materials: Rats bearing R3230AC tumors implanted in the hind limb were injected with an emulsion of perfluoro-15-crown-5-ether for 2-3 days before experiments, which ensured that the PFC emulsion concentrated in the tumors. We correlated changes in tumor oxygenation caused by carbogen inhalation measured by 1 H BOLD MRI with quantitative 19 F measurements. The 19 F spin-lattice relaxation rate R 1 (= 1/T 1 ) was measured to determine initial oxygen tension (pO 2 ) in each image pixel containing the PFC, and changes in pO 2 during carbogen (95% O 2 , 5% CO 2 ) breathing. In a second carbogen breathing period, changes in water signal linewidth were measured using high spectral and spatial resolution imaging. 19 F and 1 H measurements were used to classify pixels as responders to carbogen (pixels where oxygen increased significantly) or nonresponders (no significant change in tumor oxygenation). Results: The 19 F and 1 H measurements agreed in 65% ± 11% of pixels (n = 14). Agreement was even stronger among pixels where 1 H showed increased oxygenation; 19 F measurements agreed with 1 H measurements in over 79% ± 11% of these pixels. Similarly, there was strong agreement between the two modalities in pixels where 19 F reported no change in pO 2 ; 1 H also showed no changes in 76% ± 18% of these pixels. Quantitative correlation of changes T 2 * (ΔT 2 *) in 1 H and changes R 1 (ΔR 1 ) in 19 F was weak during carbogen breathing, and averaged over the whole tumor was ∼0.40 for 14 experiments. However, the spatial patterns of 1 H and 19 F changes were qualitatively

Cerebral interstitial tissue oxygen tension, pH, HCO3, CO2.

Science.gov (United States)

Charbel, F T; Hoffman, W E; Misra, M; Hannigan, K; Ausman, J I

1997-10-01

There are many techniques for monitoring the injured brain following trauma, subarachnoid hemorrhage, or surgery. It is thought that the major determinants for recovery of injured cerebral tissue are oxygen, glucose delivery, and the clearance of metabolites. These factors, at optimal levels, are probably responsible for the regaining of neuronal functions. These parameters are in turn dependent on the tissue's blood flow and metabolism. We have been using a single, compact, polyethylene sensor, the Paratrend 7 for the measurement of cerebral oxygen tension, CO2, pH, and temperature. This sensor is designed for continuous blood gas analysis to aid in monitoring neurosurgical patients, both during surgery and in the intensive care unit. Using the Paratrend 7 sensor, we found the normal range of values to be: PO2 33 +/- 11 mm Hg; PCO2 48 +/- 7 mm Hg; pH 7.19 +/- 0.11. Critical measurements are considered to be tissue PO2 60 mm Hg, and pH effective method of measuring tissue cerebral oxygen tension, along with carbon dioxide levels, pH, and temperature.

Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: experimental and modeling studies

OpenAIRE

Sgouralis, Ioannis; Kett, Michelle M.; Ow, Connie P. C.; Abdelkader, Amany; Layton, Anita T.; Gardiner, Bruce S.; Smith, David W.; Lankadeva, Yugeesh R.; Evans, Roger G.

2016-01-01

Oxygen tension (Po2) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po2. Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po2 from bladder urine Po2. Both intravenous infusion of [Phe2,Ile3,Orn8]-vasopressin and infusion of NG-nitro-l-arginine reduced urinary Po2 and medullary Po2 (8–1...

Increase in tumor oxygen tension and radiosensitivity after administration of pentoxifylline

International Nuclear Information System (INIS)

Hasegawa, Takeo; Gu, Yeun Hwa; Nagao, Takashi; Miyata, Katsuyuki; Song, Chang W.; Tanake, Yoshimasa; Hasegawa, Takashi

1999-01-01

The effects of pentoxifylline (PTX) on the pO2 and radioresponse in SCK tumors of A/J mice were investigated. When the mice were injected intraperitoneally with 5 mg/kg of PTX, the tumor pO2 increased slowly, peaked 20-50 min postinjection, and returned to its original level in 70-90 min. The magnitude of the changes in tumor pO2 after on ip injection of 25 or 50 mg/kg PTX was similar to that caused by 5 mg/kg PTX. When the A/J mice bearing SCK tumors in the legs were injected ip with 50 mg/kg PTX and the tumors were X ray irradiated 20 min later, the tumor growth delay was greater than that of radiation alone

Oxygen Tension Regulates Human Mesenchymal Stem Cell Paracrine Functions

OpenAIRE

Paquet, Joseph; Deschepper, Mickael; Moya, Adrien; Logeart-Avramoglou, Delphine; Boisson-Vidal, Catherine; Petite, Hervé

2015-01-01

This study examined the shift of the human mesenchymal stem cell (hMSC) cytokine signature induced by oxygen tension. Conditioned media obtained from hMSCs cultured under near anoxia exhibited significantly enhanced chemotactic and proangiogenic properties and a significant decrease in the inflammatory mediator content. These results elucidate important aspects of using MSCs in regenerative medicine, contribute to improving the efficacy of such therapies, and highlight the interest in using c...

Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor

International Nuclear Information System (INIS)

Bourke, Vincent A.; Zhao Dawen; Gilio, Joseph; Chang, C.-H.; Jiang Lan; Hahn, Eric W.; Mason, Ralph P.

2007-01-01

Purpose: To investigate the application of pretreatment oxygenation to the AT1 subline of the Dunning R3327 prostate tumor, which is more hypoxic and faster growing than the H1 subline previously studied. Methods and Materials: Dunning prostate R3327-AT1 tumors growing on Copenhagen rats were administered 30 Gy of X-ray radiation either with or without oxygen inhalation. Tumor oxygenation was sampled by 19 F nuclear magnetic resonance echo planar imaging relaxometry of the reporter molecule hexafluorobenzene, no more than 24 h before irradiation. Results: Large tumors (>3.0 cm 3 ) exhibited significantly greater hypoxic fractions and lower mean partial pressure of oxygen (pO 2 ) than their smaller counterparts ( 3 ). However, unlike the R3327-HI subline, large AT1 tumors generally did not respond to oxygen inhalation in terms of altered hypoxic fraction or response to irradiation. Although the tumors did not respond to oxygen inhalation, each tumor had a different pO 2 , and there was a clear trend between level of oxygenation at time of irradiation and tumor growth delay, with considerably better outcome when mean pO 2 > 10 mm Hg. The comparatively small baseline hypoxic fraction in the group of small tumors was virtually eliminated by breathing oxygen, and the growth rate was significantly reduced for tumors on rats breathing oxygen during irradiation. Conclusions: These results further validate the usefulness of nuclear magnetic resonance oximetry as a predictor of response to radiation therapy

Nuclear medicine markers of tumor oxygenation and radioresistance

International Nuclear Information System (INIS)

Chapman, J. Donald; Schneider, R.H.; Stobbe, C.C.; Kim, E.; Engelhardt, E.L.; Coia, L.

1996-01-01

Purpose/Objective: The objective of this research project was to synthesize, purify, radiolabel and characterize second-generation nuclear medicine markers of tissue oxygenation with properties superior to iodoazomycin arabinoside (IAZA) and to validate the hypoxia-marking activity of optimal compounds by independent measurements of tumor oxygenation and tumor radioresistance. Materials and Methods: Six hypoxic markers of the iodoazomycin nucleoside class with water solubilities greater than IAZA were synthesized by published procedures. The markers were purified, chemically characterized and labeled with Iodine-125 or Iodine-131. Absolute rates of marker ligation to the macromolecules of hypoxic EMT-6 tumor cells in vitro were determined as a function of marker concentration and used to establish relative marker effectiveness. Hypoxic marking activity in tumors was determined from tumor/blood (T/B) and tumor/muscle (T/M) ratios of radiolabelled marker in EMT-6 tumor-bearing C.B17/Icr scid mice. The optimal marker was administered to R3327-H and R3327-AT tumor-bearing Fischer X Copenhagen rats for estimates of tumor oxygenation by T/B and T/M ratios. Oxygen distributions in the same tumors were obtained with the Eppendorf pO 2 Histograph. The radioresistance of individual tumors was determined from in vitro plating efficiencies of cells released from tumors which had been irradiated in vivo with 20 Gy Cs-137 γ-rays. Results: Of the six iodinated azomycin nucleosides investigated, five were novel markers and all had water solubilities higher than IAZA. Iodinated azomycin xylopyranoside (β-D-IAZXP) was selected as the optimal marker of this class since it 1) exhibited the highest absolute rate of ligation to hypoxic tumor cells in vitro, 2) had the fastest plasma clearance rate in tumor-bearing mice and 3) yielded high T/B ratios in both the mouse and rat tumor models employed in this study. Planar nuclear medicine images of (I-131) β-D-IAZXP in tumor-bearing rats

Localized increase of tissue oxygen tension by magnetic targeted drug delivery

Science.gov (United States)

Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

2014-07-01

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to

Radioprotection of mouse skin by WR-2721: the critical influence of oxygen tension

International Nuclear Information System (INIS)

Denekamp, J.; Michael, B.D.; Rojas, A.; Stewart, F.A.

1982-01-01

The epidermal clone assay has been used to study the radioprotective effect of WR-2721 on mouse skin under different conditions of oxygenation and under anoxia. The skin has shown a progressive decrease in sensitivity as the inspired gas has changed from 100% oxygen towards 0% oxygen. Compared with mice breathning 100% oxygen, those breathing air are partially protected. The inspired oxygen concentration to give half the full oxygen effect is 10-12%. The radioprotecton observed with 400 mg/kg WR-2721 is markedly dependent on the ambient oxygen concentration. The protection factor is 1.1 or less in mice breathing 5%, 1% or 0% oxygen. Protection is maximal (1.95) in air and in 50% oxygen and diminishes to 1.6 at higher oxygen tensions

Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor

Energy Technology Data Exchange (ETDEWEB)

Bourke, Vincent A [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Dawen, Zhao [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Gilio, Joseph [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Chang, C -H [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Lan, Jiang [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Hahn, Eric W [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Mason, Ralph P [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States)

2007-03-15

Purpose: To investigate the application of pretreatment oxygenation to the AT1 subline of the Dunning R3327 prostate tumor, which is more hypoxic and faster growing than the H1 subline previously studied. Methods and Materials: Dunning prostate R3327-AT1 tumors growing on Copenhagen rats were administered 30 Gy of X-ray radiation either with or without oxygen inhalation. Tumor oxygenation was sampled by {sup 19}F nuclear magnetic resonance echo planar imaging relaxometry of the reporter molecule hexafluorobenzene, no more than 24 h before irradiation. Results: Large tumors (>3.0 cm{sup 3}) exhibited significantly greater hypoxic fractions and lower mean partial pressure of oxygen (pO{sub 2}) than their smaller counterparts (<1.5 cm{sup 3}). However, unlike the R3327-HI subline, large AT1 tumors generally did not respond to oxygen inhalation in terms of altered hypoxic fraction or response to irradiation. Although the tumors did not respond to oxygen inhalation, each tumor had a different pO{sub 2}, and there was a clear trend between level of oxygenation at time of irradiation and tumor growth delay, with considerably better outcome when mean pO{sub 2} > 10 mm Hg. The comparatively small baseline hypoxic fraction in the group of small tumors was virtually eliminated by breathing oxygen, and the growth rate was significantly reduced for tumors on rats breathing oxygen during irradiation. Conclusions: These results further validate the usefulness of nuclear magnetic resonance oximetry as a predictor of response to radiation therapy.

Enhanced proliferation and dopaminergic differentiation of ventral mesencephalic precursor cells by synergistic effect of FGF2 and reduced oxygen tension

DEFF Research Database (Denmark)

Jensen, Pia; Gramsbergen, Jan-Bert; Zimmer, Jens

2011-01-01

Effective numerical expansion of dopaminergic precursors might overcome the limited availability of transplantable cells in replacement strategies for Parkinson's disease. Here we investigated the effect of fibroblast growth factor-2 (FGF2) and FGF8 on expansion and dopaminergic differentiation o...... enzyme activity, which may explain the elevated dopamine levels. Our findings demonstrate that modulation of oxygen tension is a recognizable factor for in vitro expansion and dopaminergic differentiation of rat embryonic midbrain precursor cells....... of rat embryonic ventral mesencephalic neuroblasts cultured at high (20%) and low (3%) oxygen tension. More cells incorporated bromodeoxyuridine in cultures expanded at low as compared to high oxygen tension, and after 6 days of differentiation there were significantly more neuronal cells in low than......, switching FGF2-expanded cultures from low to high oxygen tension during the last two days of differentiation significantly enhanced dopamine release and intracellular dopamine levels as compared to all other treatment groups. In addition, the short-term exposure to high oxygen enhanced in situ assessed TH...

Discrepancies between measured changes of radiobiological hypoxic fraction and oxygen tension monitoring using two assay systems

International Nuclear Information System (INIS)

Sasai, K.; Brown, J.M.

1994-01-01

This study was conducted to assess the ability of computerized pO 2 histography to measure changes in tumor oxygenation produced by low oxygen breathing. Female syngeneic C3H/Km mice bearing SCC VII/St carcinomas were used in these experiments. Changes in tumor oxygenation produced by the mice breathing 10% oxygen were assessed with computerized pO2 histography, 3 H-misonidazole binding, and the paired survival curve assay of radiosensitivity. The hypoxic cell fraction of the tumors in mice breathing 10% oxygen was 3.1 times higher than that of tumors in mice breathing normal air determined by an in vivo-in vitro clonogenic assay. Binding of radiolabeled misonidazole to the tumors in mice breathing 10% oxygen was also significantly higher than that to tumors in mice breathing normal air (p 2 value for the tumor. The number of pO 2 readings lower than 5 mmHg in the tumor was not affected by the 10% oxygen breathing. These findings indicate that increases in radiobiological hypoxic fraction produced by lower blood oxygen levels may not correlate well with the results of polarographic measurements of tumor pO 2 levels. 29 refs., 4 figs., 1 tab

The Role of Oxygen Tension in Penile Erection and Its Relationship to Erectile Dysfunction

Directory of Open Access Journals (Sweden)

Jong-Kwan Park

2004-01-01

Full Text Available The corpus cavernosum of the penis is one of the few vascular beds in which there is a change in oxygen tension with function (blood PO2 25-40mm Hg in the flaccid state, and 90-100mm Hg in the erect state. This change in oxygen tension exposes the components of the corpus cavernosum to a variety of cytokines, humoral, vasoactive, and growth factors which may affect the structure and function of the endothelial cells, smooth muscle cells, neurons and extracellular matrix. Among these cell types, endothelial cells are the first line of defense to blood-borne stress and can affect the underlying smooth muscle via paracrine mechanisms. Impotence is defined as the inability to obtain or sustain an erection sufficient for vaginal penetration and can result from a variety of pathological conditions, vascular disease, endocrine disease, neurological disease, and psychogenic disorders. The penis is a vascular organ and as such is susceptible to the effects of vascular diseases. This review will discuss the basic etiology of erection and vasculogenic erectile dysfunction and explore the role oxygen tension in regulating various cellular and humoral factors as well as trabecular structure and function.

Hypoxyradiotherapy: lack of experimental evidence for a preferential radioprotective effect on normal versus tumor tissue as shown by direct oxygenation measurements in experimental sarcomas

International Nuclear Information System (INIS)

Kelleher, Debra K.; Thews, Oliver; Vaupel, Peter

1997-01-01

Aim: In order to investigate possible pathophysiological mechanisms underlying the postulated preferential protective effect of hypoxia on normal tissue during radiotherapy, the impact of acute respiratory hypoxia (8.2% O 2 + 91.8% N 2 ) on tissue oxygenation was assessed. Methods: Tumor and normal tissue oxygenation was directly determined using O 2 -sensitive electrodes in two experimental rat tumors (DS and Yoshida sarcomas) and in the normal subcutis of the hind foot dorsum. Results: During respiratory hypoxia, arterial blood O 2 tension (pO 2 ), oxyhemoglobin saturation and mean arterial blood pressure decreased. Changes in the arterial blood gas status were accompanied by a reflex hyperventilation leading to hypocapnia and respiratory alkalosis. In the subcutis, tissue oxygenation worsened during acute hypoxia, with decreases in the mean and median pO 2 . Significant increases in the hypoxic fractions were, however, not seen. In tumor tissues, oxygenation also worsened upon hypoxic hypoxia with significant decreases in the mean and median pO 2 and increases in the size of the hypoxic fractions for both sarcomas. Conclusion: These results suggest that during respiratory hypoxia, radiobiologically relevant reductions in the oxygenation (and a subsequent selective radioprotection) of normal tissue may not be achieved. In addition, in the tumor models studied, a worsening of tumor oxygenation was seen which could result in an increased radioresistance

Multiple oxygen tension environments reveal diverse patterns of transcriptional regulation in primary astrocytes.

Directory of Open Access Journals (Sweden)

Wayne Chadwick

Full Text Available The central nervous system normally functions at O(2 levels which would be regarded as hypoxic by most other tissues. However, most in vitro studies of neurons and astrocytes are conducted under hyperoxic conditions without consideration of O(2-dependent cellular adaptation. We analyzed the reactivity of astrocytes to 1, 4 and 9% O(2 tensions compared to the cell culture standard of 20% O(2, to investigate their ability to sense and translate this O(2 information to transcriptional activity. Variance of ambient O(2 tension for rat astrocytes resulted in profound changes in ribosomal activity, cytoskeletal and energy-regulatory mechanisms and cytokine-related signaling. Clustering of transcriptional regulation patterns revealed four distinct response pattern groups that directionally pivoted around the 4% O(2 tension, or demonstrated coherent ascending/decreasing gene expression patterns in response to diverse oxygen tensions. Immune response and cell cycle/cancer-related signaling pathway transcriptomic subsets were significantly activated with increasing hypoxia, whilst hemostatic and cardiovascular signaling mechanisms were attenuated with increasing hypoxia. Our data indicate that variant O(2 tensions induce specific and physiologically-focused transcript regulation patterns that may underpin important physiological mechanisms that connect higher neurological activity to astrocytic function and ambient oxygen environments. These strongly defined patterns demonstrate a strong bias for physiological transcript programs to pivot around the 4% O(2 tension, while uni-modal programs that do not, appear more related to pathological actions. The functional interaction of these transcriptional 'programs' may serve to regulate the dynamic vascular responsivity of the central nervous system during periods of stress or heightened activity.

Cerebral Microcirculation and Oxygen Tension in the Human Secondary Cortex

Science.gov (United States)

Linninger, A. A.; Gould, I. G.; Marinnan, T.; Hsu, C.-Y.; Chojecki, M.; Alaraj, A.

2013-01-01

The three-dimensional spatial arrangement of the cortical microcirculatory system is critical for understanding oxygen exchange between blood vessels and brain cells. A three-dimensional computer model of a 3 × 3 × 3 mm3 subsection of the human secondary cortex was constructed to quantify oxygen advection in the microcirculation, tissue oxygen perfusion, and consumption in the human cortex. This computer model accounts for all arterial, capillary and venous blood vessels of the cerebral microvascular bed as well as brain tissue occupying the extravascular space. Microvessels were assembled with optimization algorithms emulating angiogenic growth; a realistic capillary bed was built with space filling procedures. The extravascular tissue was modeled as a porous medium supplied with oxygen by advection–diffusion to match normal metabolic oxygen demand. The resulting synthetic computer generated network matches prior measured morphometrics and fractal patterns of the cortical microvasculature. This morphologically accurate, physiologically consistent, multi-scale computer network of the cerebral microcirculation predicts the oxygen exchange of cortical blood vessels with the surrounding gray matter. Oxygen tension subject to blood pressure and flow conditions were computed and validated for the blood as well as brain tissue. Oxygen gradients along arterioles, capillaries and veins agreed with in vivo trends observed recently in imaging studies within experimental tolerances and uncertainty. PMID:23842693

A method for volumetric retinal tissue oxygen tension imaging.

Science.gov (United States)

Felder, Anthony E; Wanek, Justin; Teng, Pang-Yu; Blair, Norman P; Shahidi, Mahnaz

2018-01-01

Inadequate retinal oxygenation occurs in many vision-threatening retinal diseases, including diabetic retinopathy, retinal vascular occlusions, and age-related macular degeneration. Therefore, techniques that assess retinal oxygenation are necessary to understand retinal physiology in health and disease. The purpose of the current study is to report a method for the three-dimensional (3D) imaging of retinal tissue oxygen tension (tPO 2 ) in rats. Imaging was performed in Long Evans pigmented rats under systemic normoxia (N = 6) or hypoxia (N = 3). A vertical laser line was horizontally scanned on the retina and a series of optical section phase-delayed phosphorescence images were acquired. From these images, phosphorescence volumes at each phase delay were constructed and a 3D retinal tPO 2 volume was generated. Retinal tPO 2 volumes were quantitatively analyzed by generating retinal depth profiles of mean tPO 2 (M tPO2 ) and the spatial variation of tPO 2 (SV tPO2 ). The effects of systemic condition (normoxia/hypoxia) and retinal depth on M tPO2 and SV tPO2 were determined by mixed linear model. Each 3D retinal tPO 2 volume was approximately 500 × 750 × 200 μm (horizontal × vertical × depth) and consisted of 45 en face tPO 2 images through the retinal depth. M tPO2 at the chorioretinal interface was significantly correlated with systemic arterial oxygen tension (P = 0.007; N = 9). There were significant effects of both systemic condition and retinal depth on M tPO2 and SV tPO2 , such that both were lower under hypoxia than normoxia and higher in the outer retina than inner retina (P < 0.001). For the first time, 3D imaging of retinal tPO 2 was demonstrated, with potential future application for assessment of physiological alterations in animal models of retinal diseases.

Enhanced dopaminergic differentiation of human neural stem cells by synergistic effect of Bcl-xL and reduced oxygen tension

DEFF Research Database (Denmark)

Krabbe, Christina; Courtois, Elise; Jensen, Pia

2009-01-01

Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic different......Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic...... days at 20% oxygen, hVMbcl-x(L) cultures contained proportionally more tyrosine hydroxylase(TH)-positive cells than hVM1 control cultures. This difference was significantly potentiated from 11 +/- 0.8% to 17.2 +/- 0.2% of total cells when the oxygen tension was lowered to 3%. Immunocytochemistry and Q...

Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes

DEFF Research Database (Denmark)

Antonovic, Laura; Lindblom, Emely; Dasu, Alexandru

2014-01-01

, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER...... was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related...... to LOCs did not compensate for the increase in total dose required for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high...

Preliminary Study of Oxygen-Enhanced Longitudinal Relaxation in MRI: A Potential Novel Biomarker of Oxygenation Changes in Solid Tumors

International Nuclear Information System (INIS)

O'Connor, James P.B.; Naish, Josephine H.; Parker, Geoff J.M.; Waterton, John C.; Watson, Yvonne; Jayson, Gordon C.; Buonaccorsi, Giovanni A.; Cheung, Sue; Buckley, David L.; McGrath, Deirdre M.; West, Catharine M.L.; Davidson, Susan E.; Roberts, Caleb; Mills, Samantha J.; Mitchell, Claire L.; Hope, Lynn; Ton, N. Chan; Jackson, Alan

2009-01-01

Purpose: There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R 1 ). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. Methods and materials: Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R 1 while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced ΔR 1 . Results: ΔR 1 showed significant increases of 0.021 to 0.058 s -1 in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the ΔR 1 curve (consistent with minimal increase in oxygen concentration). Conclusions: These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.

Influence of hyperoxia on the number of nucleated cells and oxygen tension in rat bone marrow after whole-body irradiation

International Nuclear Information System (INIS)

Zima, M.; Vodicka, I.

1987-01-01

The cell number in the femur bone marrow of rats determined three days after X-ray or gamma irradiation is inversely proportional to the dose while oxygen tension in the marrow shows direct dependence on the dose. With fractionation of the lethal dose of gamma radiation (9 Gy) into two doses with different time intervals between them, a greater number of bone marrow cells and a smaller oxygen tension are reached on the 3rd day after the second dose, reflecting the extent of bone marrow repair. A short-term hyperoxia (95% O 2 + 5% CO 2 ) lasting 20 min from the end of exposure compared with the euoxic conditions induced, on the 3rd day after the second fraction, a nonsignificant but reproducible increase in the marrow cell number and a decrease in partial oxygen tension in the distal part of femur marrow. The results obtained testify that immediate short-term hyperoxia facilitates regeneration of the marrow and that a greater number of cells accompanied by greater metabolic activity and oxygen consumption decrease the partial oxygen tension measured on the 3rd day following the last exposure. (author). 7 figs., 16 refs

Indomethacin lowers optic nerve oxygen tension and reduces the effect of carbonic anhydrase inhibition and carbon dioxide breathing

DEFF Research Database (Denmark)

Pedersen, D B; Eysteinsson, T; Stefánsson, E

2004-01-01

Prostaglandins are important in blood flow regulation. Carbon dioxide (CO(2)) breathing and carbonic anhydrase inhibition increase the oxygen tension in the retina and optic nerve. To study the mechanism of this effect and the role of cyclo-oxygenase in the regulation of optic nerve oxygen tension...... (ONPO(2)), the authors investigated how indomethacin affects ONPO(2) and the ONPO(2) increases caused by CO(2) breathing and carbonic anhydrase inhibition in the pig....

Oxygenation of spontaneous canine tumors during fractionated radiation therapy

International Nuclear Information System (INIS)

Achermann, R.E.; Ohlerth, S.M.; Bley, C.R.; Inteeworn, N.; Schaerz, M.; Wergin, M.C.; Kaser-Hotz, B.; Gassmann, M.; Roos, M.

2004-01-01

Background and purpose: tumor oxygenation predicts treatment outcome, and reoxygenation is considered important in the efficacy of fractionated radiation therapy. Therefore, the purpose of this study was to document the changes of the oxygenation status in spontaneous canine tumors during fractionated radiation therapy using polarographic needle electrodes. Material and methods: tumor oxygen partial pressure (pO 2 ) measurements were performed with the eppendorf-pO 2 -Histograph. The measurements were done under general anesthesia, and probe tracks were guided with ultrasound. pO 2 was measured before radiation therapy in all dogs. In patients treated with curative intent, measurements were done sequentially up to eight times (total dose: 45-59.5 Gy). Oxygenation status of the palliative patient group was examined before each fraction of radiation therapy up to five times (total dose: 24-30 Gy). Results: 15/26 tumors had a pretreatment median pO 2 ≤ 10 mmHg. The pO 2 values appeared to be quite variable in individual tumors during fractionated radiation therapy. The pO 2 of initially hypoxic tumors (pretreatment median pO 2 ≤ 10 mmHg) remained unchanged during fractionated radiotherapy, whereas in initially normoxic tumors the pO 2 decreased. Conclusion: hypoxia is common in spontaneous canine tumors, as 57.7% of the recorded values were ≥ 10 mmHg. The data of this study showed that initially hypoxic tumors remained hypoxic, whereas normoxic tumors became more hypoxic. (orig.)

Microcomputer-based system for registration of oxygen tension in peripheral muscle.

Science.gov (United States)

Odman, S; Bratt, H; Erlandsson, I; Sjögren, L

1986-01-01

For registration of oxygen tension fields in peripheral muscle a microcomputer based system was designed on the M6800 microprocessor. The system was designed to record the signals from a multiwire oxygen electrode, MDO, which is a multiwire electrode for measuring oxygen on the surface of an organ. The system contained patient safety isolation unit built on optocopplers and the upper frequency limit was 0.64 Hz. Collected data were corrected for drift and temperature changes during the measurement by using pre- and after calibrations and a linear compensation technique. Measure drift of the electrodes were proved to be linear and thus the drift could be compensated for. The system was tested in an experiment on pig. To study the distribution of oxygen statistically mean, standard deviation, skewness and curtosis were calculated. To see changes or differences between histograms a Kolmogorv-Smirnov test was used.

Tumor radiation responses and tumor oxygenation in aging mice

International Nuclear Information System (INIS)

Rockwell, S.

1989-01-01

EMT6 mouse mammary tumors transplanted into aging mice are less sensitive to radiation than tumors growing in young adult animals. The experiments reported here compare the radiation dose-response curves defining the survivals of tumor cells in aging mice and in young adult mice. Cell survival curves were assessed in normal air-breathing mice and in mice asphyxiated with N 2 to produce uniform hypoxia throughout the tumors. Analyses of survival curves revealed that 41% of viable malignant cells were severely hypoxic in tumors in aging mice, while only 19% of the tumor cells in young adult animals were radiobiologically hypoxic. This did not appear to reflect anaemia in the old animals. Treatment of aging animals with a perfluorochemical emulsion plus carbogen (95% O 2 /5% CO 2 ) increased radiation response of the tumors, apparently by improving tumor oxygenation and decreasing the number of severely hypoxic, radiation resistant cells in the tumors. (author)

[Effect of different oxygen tension on the cytoskeleton remodeling of goat temporomandibular joint disc cells].

Science.gov (United States)

Xiaolan, He; Guangjie, Bao; Linglu, Sun; Xue, Zhang; Shanying, Bao; Hong, Kang

2017-08-01

Objective The effect of different oxygen tensions on the cytoskeleton remodeling of goat temporomandibular joint (TMJ) disc cells were investigated. Methods Goat TMJ disc cells were cultured under normoxia (21% O₂) and hypoxia (2%, 4%, and 8% O₂). Toluidine blue, picrosirius red, and type Ⅰ collagen immunocytochemical staining were performed to observe the changes in cell phenotype under different oxygen levels. Immunofluorescent staining and real-time reverse transcription-polymerase chain reaction analysis were then performed to identify actin, tubulin, and vimentin in the cultured disc cells. Results TMJ disc cells still displayed fibroblast characteristics under different oxygen levels and their cytoskeletons had regular arrangement. The fluorescence intensities of actin and vimentin were lowest at 4% O₂(P0.05). Actin mRNA levels were considerably decreased at 2% O₂ and 4% O₂ in hypoxic conditions, while actin mRNA expression was highest in 21% O₂. Tubulin mRNA levels considerably increased at 2% O₂, while tubulin mRNA expression was lowest in 8% O₂ (Plevels among these oxygen levels (Poxygen tensions, and 2% O₂ may be the optimal oxygen level required to proliferate TMJ disc cells.

The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study

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Ju, Julia A.; Baek, Jin Hyen; Yalamanoglu, Ayla; Buehler, Paul W.; Gilkes, Daniele M.; Palmer, Andre F.

2018-01-01

A major constraint in the treatment of cancer is inadequate oxygenation of the tumor mass, which can reduce chemotherapeutic efficacy. We hypothesize that polymerized human hemoglobin (PolyhHb) can be transfused into the systemic circulation to increase solid tumor oxygenation, and improve chemotherapeutic outcomes. By locking PolyhHb in the relaxed (R) quaternary state, oxygen (O2) offloading at low O2 tensions (20 mm Hg) is facilitated with tense (T) state PolyhHb. Therefore, R-state PolyhHb may deliver significantly more O2 to hypoxic tissues. Biophysical parameters of T and R-state PolyhHb were used to populate a modified Krogh tissue cylinder model to assess O2 transport in a tumor. In general, we found that increasing the volume of transfused PolyhHb decreased the apparent viscosity of blood in the arteriole. In addition, we found that PolyhHb transfusion decreased the wall shear stress at large arteriole diameters (>20 μm), but increased wall shear stress for small arteriole diameters (state PolyhHb may be more effective than T-state PolyhHb for O2 delivery at similar transfusion volumes. Reduction in the apparent viscosity resulting from PolyhHb transfusion may result in significant changes in flow distributions throughout the tumor microcirculatory network. The difference in wall shear stress implies that PolyhHb may have a more significant effect in capillary beds through mechano-transduction. Periodic top-load transfusions of PolyhHb into mice bearing breast tumors confirmed the oxygenation potential of both PolyhHbs via reduced hypoxic volume, vascular density, tumor growth, and increased expression of hypoxia inducible genes. Tissue section analysis demonstrated primary PolyhHb clearance occurred in the liver and spleen indicating a minimal risk for renal damage. PMID:29414985

The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas

International Nuclear Information System (INIS)

Nordsmark, Marianne; Hoeyer, Morten; Keller, Johnny; Nielsen, Ole Steen; Jensen, Oluf Myhre; Overgaard, Jens

1996-01-01

Purpose: In malignant tumors the oxygenation status and tumor cell proliferation are known to influence local tumor control after radiotherapy. However, the relationship between oxygenation status and tumor cell kinetics in human tumors has not yet been described. Newly developed clinically applicable techniques such as oxygen electrode measurements and assessment of tumor cell proliferation rates have been suggested as promising predictive assays. The purpose of the present study was to characterize tumor oxygenation status in soft tissue sarcomas and to compare this with tumor cell kinetics and clinical parameters. Methods and Materials: Pretreatment tumor oxygenation status was measured by polarographic oxygen needle electrodes and evaluated as the median pO 2 and the percentage of pO 2 values ≤ 5 mmHg and ≤ 2.5 mmHg in 22 patients with primary soft tissue sarcomas. All tumors were characterized by histology, grade of malignancy, the level of microscopic necrosis, the level of effective hemoglobin, and magnetic resonance imaging estimation of tumor volume. The tumor cell potential doubling time and labeling index were measured by flow cytometric and immunohistochemical analysis of tumor biopsy specimens after in vivo incorporation of iododeoxyuridine. Results: There was a significant correlation between the median pO 2 and the tumor cell potential doubling time (p = 0.041), whereas no correlation was found between the level of hypoxia expressed by the percentage of pO 2 values ≤ 2.5 and ≤ 5 mmHg, respectively, and tumor cell potential doubling time. Furthermore, no correlation was found between either of the three tumor oxygenation parameters and labeling index. The material represented large intertumor heterogeneity in oxygenation status, cell kinetics, and tumor volume, and no correlation was found between oxygenation status and either volume, histopathology, grade of malignancy, or effective hemoglobin. Conclusion: This report is the first to suggest

Effects of carbogen plus fractionated irradiation on KHT tumor oxygenation

International Nuclear Information System (INIS)

Fenton, Bruce M.

1997-01-01

Background and purpose: Numerous studies have demonstrated improvements in the oxygenation of tumor cells following both irradiation and carbogen breathing. The current studies were initiated to measure the combined effects of carbogen inhalation plus single and multi-dose irradiation on tumor oxygen availability, to better define the underlying physiological relationships. Materials and methods: Using KHT murine sarcomas, radiation was delivered to the tumor-bearing legs of non-anesthetized mice. Tumors were quick-frozen prior to or following single or multifraction irradiation and carbogen breathing, and intravascular HbO 2 saturation profiles were determined cryospectrophotometrically. Results: HbO 2 levels for blood vessels located near the tumor surface initially decreased following 10 Gy irradiation, then increased and remained elevated. Interior HbO 2 levels remained unchanged. Following 2.5 Gy, HbO 2 changes were minimal. At 24 h following 10 Gy, HbO 2 levels were significantly increased compared to non-irradiated controls, and carbogen breathing produced no additional benefit. At 24 h following five fractions of 2 Gy, HbO 2 levels throughout the tumor volume were significantly higher in carbogen breathing animals than in air breathing controls. Conclusions: Although peripheral blood vessels demonstrated substantial improvements in oxygenation following irradiation, oxygen availability nearer the tumor center remained at very low levels. The utility of carbogen in enhancing tumor oxygen availability was maintained following five clinically relevant fractions. At higher doses, radiation-induced enhancements in HbO 2 levels overshadowed the carbogen effect. For either air or carbogen breathing, a decrease in the percentage of vessels with very low oxygen content did not appear to be a major factor in the reoxygenation of the KHT tumor

Radiosensitivity of Hela cells in various O2 concentrations and consideration of oxygen effect in radiotherapy

International Nuclear Information System (INIS)

Kuroda, Yoshikazu; Nyunoya, Koichiro

1979-01-01

The aim of this paper is the study of the radiosensitivity of HeLa cells in vitro in various oxygen concentrations and the consideration of the utilization of oxygen effect in radiation therapy, based on the data of HeLa cells and tumor oxygen tension. Survival curves of HeLa cells are found to be exponential as a function of radiation dose and the radiosensitivity is dependent on oxygen tension of culture medium. Relative radiosensitivity decreases remarkably at low level of oxygen, especially under 9 mmHg pO 2 . The utilization of oxygen effect in radiation may be useful in hyperbaric oxygen inhalation and not useful under local tissue hypoxia induced by tourniquet application. Reoxygenation occurs with shrinkage of tumor after irradiation and this phenomenon will diminish the value of hyperbaric oxygen in radiation therapy. (author)

Oxidative stress under ambient and physiological oxygen tension in tissue culture

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Jagannathan, Lakshmanan; Cuddapah, Suresh; Costa, Max

2016-01-01

Oxygen (O2) levels range from 2–9% in vivo. However, cell culture experiments are performed at atmospheric O2 levels (21%). Oxidative stress due to generation of reactive oxygen species (ROS) in cells cultured at higher than physiological levels is implicated in multitude of deleterious effects including DNA damage, genomic instability and senescence. In addition, oxidative stress activates redox sensitive transcription factors related to inflammatory signaling and apoptotic signaling. Furthermore, several chromatin-modifying enzymes are affected by ROS, potentially impacting epigenetic regulation of gene expression. While primary cells are cultured at lower O2 levels due to their inability to grow at higher O2, the immortalized cells, which display no such apparent growth difficulties, are typically cultured at 21% O2. This review will provide an overview of issues associated with increased oxygen levels in in vitro cell culture and point out the benefits of using lower levels of oxygen tension even for immortalized cells. PMID:27034917

Tumor oxygenation in a transplanted rat rhabdomyosarcoma during fractionated irradiation

International Nuclear Information System (INIS)

Zywietz, Friedrich; Reeker, Wolfram; Kochs, Eberhard

1995-01-01

Purpose: To quantify the changes in tumor oxygenation in the course of a fractionated radiation treatment extending over 4 weeks. Methods and Materials: Rhabdomyosarcomas R1H of the rat were irradiated with 60 Co-γ-rays with a total dose of 60 Gy, given in 20 fractions over 4 weeks. Oxygen partial pressure (pO 2 ) in tumors was measured at weekly intervals using polarographic needle probes in combination with a microprocessor-controlled device (pO 2 -Histograph/KIMOC). The pO 2 measurements were carried out in anesthetized animals under mechanical ventilation and in respiratory and hemodynamic steady state. Tumor pO 2 values were correlated to the arterial oxygen pressure p a O 2 , arterial pCO 2 , and pH determined with a blood gas analyzer. Results: Tumor oxygenation did not change significantly during the 3 weeks of irradiation (up to 45 Gy), from a median pO 2 of 23 ± 2 mmHg in untreated controls to 19 ± 4 mmHg after the third week. The decrease of the number of pO 2 values between 0 and 5 mmHg indicated that an improved oxygenation in the tumors occurred. However, with increasing radiation dose (fourth week, 60 Gy) a significant decrease in tumor oxygenation to a median pO 2 of 8 ± 2 mmHg and a rapid increase in the frequency of pO 2 values (35 ± 4%) between 0 and 5 mmHg was found. Conclusion: Improved oxygenation in rhabdomyosarcomas R1H was only present in the early phase of the fractionated irradiation. Radiation doses above 45 Gy led to a considerable decrease of tumor oxygenation in the later phase of irradiation

Oxygen tension regulates the osteogenic, chondrogenic and endochondral phenotype of bone marrow derived mesenchymal stem cells

Energy Technology Data Exchange (ETDEWEB)

Sheehy, Eamon J.; Buckley, Conor T. [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin, Dublin 2 (Ireland); Kelly, Daniel J., E-mail: kellyd9@tcd.ie [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin, Dublin 2 (Ireland)

2012-01-06

Highlights: Black-Right-Pointing-Pointer Expansion in low oxygen enhances MSC proliferation and osteogenesis. Black-Right-Pointing-Pointer Differentiation in low oxygen enhances chondrogenesis and suppresses hypertrophy. Black-Right-Pointing-Pointer Oxygen can regulate the MSC phenotype for use in tissue engineering applications. -- Abstract: The local oxygen tension is a key regulator of the fate of mesenchymal stem cells (MSCs). The objective of this study was to investigate the effect of a low oxygen tension during expansion and differentiation on the proliferation kinetics as well as the subsequent osteogenic and chondrogenic potential of MSCs. We first hypothesised that expansion in a low oxygen tension (5% pO{sub 2}) would improve both the subsequent osteogenic and chondrogenic potential of MSCs compared to expansion in a normoxic environment (20% pO{sub 2}). Furthermore, we hypothesised that chondrogenic differentiation in a low oxygen environment would suppress hypertrophy of MSCs cultured in both pellets and hydrogels used in tissue engineering strategies. MSCs expanded at 5% pO{sub 2} proliferated faster forming larger colonies, resulting in higher cell yields. Expansion at 5% pO{sub 2} also enhanced subsequent osteogenesis of MSCs, whereas differentiation at 5% pO{sub 2} was found to be a more potent promoter of chondrogenesis than expansion at 5% pO{sub 2}. Greater collagen accumulation, and more intense staining for collagen types I and X, was observed in pellets maintained at 20% pO{sub 2} compared to 5% pO{sub 2}. Both pellets and hydrogels stained more intensely for type II collagen when undergoing chondrogenesis in a low oxygen environment. Differentiation at 5% pO{sub 2} also appeared to inhibit hypertrophy in both pellets and hydrogels, as demonstrated by reduced collagen type X and Alizarin Red staining and alkaline phosphatase activity. This study demonstrates that the local oxygen environment can be manipulated in vitro to either stabilise a

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

DEFF Research Database (Denmark)

Laklai, Hanane; Miroshnikova, Yekaterina A.; Pickup, Michael W.

2016-01-01

by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were......Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop...... stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression...

Effect of oxygen tension on bioenergetics and proteostasis in young and old myoblast precursor cells.

Science.gov (United States)

Konigsberg, M; Pérez, V I; Ríos, C; Liu, Y; Lee, S; Shi, Y; Van Remmen, H

2013-01-01

In the majority of studies using primary cultures of myoblasts, the cells are maintained at ambient oxygen tension (21% O2), despite the fact that physiological O2 at the tissue level in vivo is much lower (~1-5% O2). We hypothesized that the cellular response in presence of high oxygen concentration might be particularly important in studies comparing energetic function or oxidative stress in cells isolated from young versus old animals. To test this, we asked whether oxygen tension plays a role in mitochondrial bioenergetics (oxygen consumption, glycolysis and fatty acid oxidation) or oxidative damage to proteins (protein disulfides, carbonyls and aggregates) in myoblast precursor cells (MPCs) isolated from young (3-4 m) and old (29-30 m) C57BL/6 mice. MPCs were grown under physiological (3%) or ambient (21%) O2 for two weeks prior to exposure to an acute oxidative insult (H2O2). Our results show significantly higher basal mitochondrial respiration in young versus old MPCs, an increase in basal respiration in young MPCs maintained at 3% O2 compared to cells maintained at 21% O2, and a shift toward glycolytic metabolism in old MPCs grown at 21% O2. H2O2 treatment significantly reduced respiration in old MPCs grown at 3% O2 but did not further repress respiration at 21% O2 in old MPCs. Oxidative damage to protein was higher in cells maintained at 21% O2 and increased in response to H2O2 in old MPCs. These data underscore the importance of understanding the effect of ambient oxygen tension in cell culture studies, in particular studies measuring oxidative damage and mitochondrial function.

Effect of body position and oxygen tension on foramen ovale recruitment.

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Moses, Kayla L; Beshish, Arij G; Heinowski, Nicole; Baker, Kim R; Pegelow, David F; Eldridge, Marlowe W; Bates, Melissa L

2015-01-01

While there is an increased prevalence of stroke at altitude in individuals who are considered to be low risk for thrombotic events, it is uncertain how venous thrombi reach the brain. The patent foramen ovale (PFO) is a recruitable intracardiac shunt between the right and left atrium. We aimed to determine whether body position and oxygen tension affect blood flow through the PFO in healthy adults. We hypothesized that hypoxia and body positions that promote right atrial filling would independently recruit the PFO. Subjects with a PFO (n = 11) performed 11 trials, combining four different fractions of inhaled oxygen (FiO₂) (1.0, 0.21, 0.15, and 0.10) and three positions (upright, supine, and 45° head down), with the exception of FiO₂ = 0.10, while 45° head down. After 5 min in each position, breathing the prescribed oxygen tension, saline bubbles were injected into an antecubital vein and a four-chamber echocardiogram was obtained to evaluate PFO recruitment. We observed a high incidence of PFO recruitment in all conditions, with increased recruitment in response to severe hypoxia and some contribution of body position at moderate levels of hypoxia. We suspect that increased pulmonary vascular pressure, secondary to hypoxia-induced pulmonary vasoconstriction, increased right atrial pressure enough to recruit the PFO. Additionally, we hypothesize that the minor increase in breathing resistance that was added by the mouthpiece, used during experimental trials, affected intrathoracic pressure and venous return sufficiently to recruit the PFO. Copyright © 2015 the American Physiological Society.

Methyl sterol and cyclopropane fatty acid composition of Methylococcus capsulatus grown at low oxygen tensions

Science.gov (United States)

Jahnke, L. L.; Nichols, P. D.

1986-01-01

The sterol and fatty acid concentrations for M. capsulatus grown in fed-batch cultures over a wide range of oxygen tensions (0.1-10.6 percent) and at a constant methane level are evaluated. The analyses reveal that the biomass decreases as oxygen levels are lowered; the sterol concentration increases when the oxygen range is between 0.5-1.1 percent and decreases when the oxygen range is below 0.5 percent; and the amount of monounsaturated C16 decreases and the concentration of cyclopropane fatty acids increases after oxygen is reduced. It is noted that growth and membrane synthesis occur at low oxygen concentrations and that the synthesis of membrane lipids responds to growth conditions.

Optical imaging of tumor hypoxia dynamics

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Palmer, Gregory M.; Fontanella, Andrew N.; Zhang, Guoqing; Hanna, Gabi; Fraser, Cassandra L.; Dewhirst, Mark W.

2010-11-01

The influence of the tumor microenvironment and hypoxia plays a significant role in determining cancer progression, treatment response, and treatment resistance. That the tumor microenvironment is highly heterogeneous with significant intratumor and intertumor variability presents a significant challenge in developing effective cancer therapies. Critical to understanding the role of the tumor microenvironment is the ability to dynamically quantify oxygen levels in the vasculature and tissue in order to elucidate the roles of oxygen supply and consumption, spatially and temporally. To this end, we describe the use of hyperspectral imaging to characterize hemoglobin absorption to quantify hemoglobin content and oxygen saturation, as well as dual emissive fluorescent/phosphorescent boron nanoparticles, which serve as ratiometric indicators of tissue oxygen tension. Applying these techniques to a window-chamber tumor model illustrates the role of fluctuations in hemoglobin saturation in driving changes in tissue oxygenation, the two being significantly correlated (r = 0.77). Finally, a green-fluorescence-protein reporter for hypoxia inducible factor-1 (HIF-1) provides an endpoint for hypoxic stress in the tumor, which is used to demonstrate a significant association between tumor hypoxia dynamics and HIF-1 activity in an in vivo demonstration of the technique.

Indomethacin decreases optic nerve oxygen tension by a mechanism other than cyclo-oxygenase inhibition

DEFF Research Database (Denmark)

Noergaard, M Hove; Pedersen, D Bach; Bang, K

2008-01-01

We investigated the effect of several Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), on the preoptic nerve oxygen tension (ONPO2), as indomethacin previously has demonstrated a strong decreasing effect on ONPO2. We tested whether these NSAIDs, like indomethacin, also reduce the increasing effect...

Matrix forming characteristics of inner and outer human meniscus cells on 3D collagen scaffolds under normal and low oxygen tensions.

Science.gov (United States)

Croutze, Roger; Jomha, Nadr; Uludag, Hasan; Adesida, Adetola

2013-12-13

Limited intrinsic healing potential of the meniscus and a strong correlation between meniscal injury and osteoarthritis have prompted investigation of surgical repair options, including the implantation of functional bioengineered constructs. Cell-based constructs appear promising, however the generation of meniscal constructs is complicated by the presence of diverse cell populations within this heterogeneous tissue and gaps in the information concerning their response to manipulation of oxygen tension during cell culture. Four human lateral menisci were harvested from patients undergoing total knee replacement. Inner and outer meniscal fibrochondrocytes (MFCs) were expanded to passage 3 in growth medium supplemented with basic fibroblast growth factor (FGF-2), then embedded in porous collagen type I scaffolds and chondrogenically stimulated with transforming growth factor β3 (TGF-β3) under 21% (normal or normoxic) or 3% (hypoxic) oxygen tension for 21 days. Following scaffold culture, constructs were analyzed biochemically for glycosaminoglycan production, histologically for deposition of extracellular matrix (ECM), as well as at the molecular level for expression of characteristic mRNA transcripts. Constructs cultured under normal oxygen tension expressed higher levels of collagen type II (p = 0.05), aggrecan (p oxygen tension. There was no significant difference in expression of these genes between scaffolds seeded with MFCs isolated from inner or outer regions of the tissue following 21 days chondrogenic stimulation (p > 0.05). Cells isolated from inner and outer regions of the human meniscus demonstrated equivalent differentiation potential toward chondrogenic phenotype and ECM production. Oxygen tension played a key role in modulating the redifferentiation of meniscal fibrochondrocytes on a 3D collagen scaffold in vitro.

Interplay of tumor vascular oxygenation and tumor pO2 observed using near-infrared spectroscopy, an oxygen needle electrode, and 19F MR pO2 mapping.

Science.gov (United States)

Kim, Jae G; Zhao, Dawen; Song, Yulin; Constantinescu, Anca; Mason, Ralph P; Liu, Hanli

2003-01-01

This study investigates the correlation of tumor blood oxygenation and tumor pO(2) with respect to carbogen inhalation. After having refined and validated the algorithms for calculating hemoglobin concentrations, we used near-infrared spectroscopy (NIRS) to measure changes of oxygenated hemoglobin concentration (delta[HbO(2)]) and used an oxygen needle electrode and (19)F MRI for pO(2) measurements in tumors. The measurements were taken from Dunning prostate R3327 tumors implanted in rats, while the anesthetized rats breathed air or carbogen. The NIRS results from tumor measurements showed significant changes in tumor vascular oxygenation in response to carbogen inhalation, while the pO(2) electrode results showed an apparent heterogeneity for tumor pO(2) response to carbogen inhalation, which was also confirmed by (19)F MR pO(2) mapping. Furthermore, we developed algorithms to estimate hemoglobin oxygen saturation, sO(2), during gas intervention based on the measured values of delta[HbO(2)] and pO(2). The algorithms have been validated through a tissue-simulating phantom and used to estimate the values of sO(2) in the animal tumor measurement based on the NIRS and global mean pO(2) values. This study demonstrates that the NIRS technology can provide an efficient, real-time, noninvasive approach to monitoring tumor physiology and is complementary to other techniques, while it also demonstrates the need for an NIR imaging technique to study spatial heterogeneity of tumor vasculature under therapeutic interventions. Copyright 2003 Society of Photo-Optical Instrumentation Engineers

Oxygen Exposure Resulting in Arterial Oxygen Tensions Above the Protocol Goal Was Associated With Worse Clinical Outcomes in Acute Respiratory Distress Syndrome.

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Aggarwal, Neil R; Brower, Roy G; Hager, David N; Thompson, B Taylor; Netzer, Giora; Shanholtz, Carl; Lagakos, Adrian; Checkley, William

2018-04-01

High fractions of inspired oxygen may augment lung damage to exacerbate lung injury in patients with acute respiratory distress syndrome. Participants enrolled in Acute Respiratory Distress Syndrome Network trials had a goal partial pressure of oxygen in arterial blood range of 55-80 mm Hg, yet the effect of oxygen exposure above this arterial oxygen tension range on clinical outcomes is unknown. We sought to determine if oxygen exposure that resulted in a partial pressure of oxygen in arterial blood above goal (> 80 mm Hg) was associated with worse outcomes in patients with acute respiratory distress syndrome. Longitudinal analysis of data collected in these trials. Ten clinical trials conducted at Acute Respiratory Distress Syndrome Network hospitals between 1996 and 2013. Critically ill patients with acute respiratory distress syndrome. None. We defined above goal oxygen exposure as the difference between the fraction of inspired oxygen and 0.5 whenever the fraction of inspired oxygen was above 0.5 and when the partial pressure of oxygen in arterial blood was above 80 mm Hg. We then summed above goal oxygen exposures in the first five days to calculate a cumulative above goal oxygen exposure. We determined the effect of a cumulative 5-day above goal oxygen exposure on mortality prior to discharge home at 90 days. Among 2,994 participants (mean age, 51.3 yr; 54% male) with a study-entry partial pressure of oxygen in arterial blood/fraction of inspired oxygen that met acute respiratory distress syndrome criteria, average cumulative above goal oxygen exposure was 0.24 fraction of inspired oxygen-days (interquartile range, 0-0.38). Participants with above goal oxygen exposure were more likely to die (adjusted interquartile range odds ratio, 1.20; 95% CI, 1.11-1.31) and have lower ventilator-free days (adjusted interquartile range mean difference of -0.83; 95% CI, -1.18 to -0.48) and lower hospital-free days (adjusted interquartile range mean difference of -1.38; 95

Mapping In Vivo Tumor Oxygenation within Viable Tumor by 19F-MRI and Multispectral Analysis

Directory of Open Access Journals (Sweden)

Yunzhou Shi

2013-11-01

Full Text Available Quantifying oxygenation in viable tumor remains a major obstacle toward a better understanding of the tumor microenvironment and improving treatment strategies. Current techniques are often complicated by tumor heterogeneity. Herein, a novel in vivo approach that combines 19F magnetic resonance imaging (19F-MRIR1 mapping with diffusionbased multispectral (MS analysis is introduced. This approach restricts the partial pressure of oxygen (pO2 measurements to viable tumor, the tissue of therapeutic interest. The technique exhibited sufficient sensitivity to detect a breathing gas challenge in a xenograft tumor model, and the hypoxic region measured by MS 19F-MRI was strongly correlated with histologic estimates of hypoxia. This approach was then applied to address the effects of antivascular agents on tumor oxygenation, which is a research question that is still under debate. The technique was used to monitor longitudinal pO2 changes in response to an antibody to vascular endothelial growth factor (B20.4.1.1 and a selective dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor (GDC-0980. GDC-0980 reduced viable tumor pO2 during a 3-day treatment period, and a significant reduction was also produced by B20.4.1.1. Overall, this method provides an unprecedented view of viable tumor pO2 and contributes to a greater understanding of the effects of antivascular therapies on the tumor's microenvironment.

Multibreath alveolar oxygen tension imaging.

Science.gov (United States)

Clapp, Justin; Hamedani, Hooman; Kadlecek, Stephen; Xin, Yi; Shaghaghi, Hoora; Siddiqui, Sarmad; Rossman, Milton D; Rizi, Rahim R

2016-10-01

This study tested the ability of a multibreath hyperpolarized HP (3) He MRI protocol to increase the accuracy of regional alveolar oxygen tension (PA O2 ) measurements by lessening the influence of gas-flow artifacts. Conventional single-breath PA O2 measurement has been susceptible to error induced by intervoxel gas flow, particularly when used to study subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD). Both single-breath and multibreath PA O2 imaging schemes were implemented in seven human subjects (one healthy, three asymptomatic smokers, and three COPD). The number and location of voxels with nonphysiologic PA O2 values generated by intervoxel gas flow were compared between the two protocols. The multibreath scheme resulted in a significantly lower total percentage of nonphysiologic PA O2 values (6.0%) than the single-breath scheme (13.7%) (P = 0.006). PA O2 maps showed several patterns of gas-flow artifacts that were present in the single-breath protocol but mitigated by the multibreath approach. Multibreath imaging also allowed for the analysis of slow-filling areas that presented no signal after a single breath. A multibreath approach enhances the accuracy and completeness of noninvasive PA O2 measurement by significantly lessening the proportion of nonphysiologic values generated by intervoxel gas flow. Magn Reson Med 76:1092-1101, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Additive influence of extracellular pH, oxygen tension, and pressure on invasiveness and survival of human osteosarcoma cells

Directory of Open Access Journals (Sweden)

Takao eMatsubara

2013-07-01

Full Text Available BACKGROUND/PURPOSE:The effects of chemical and physical interactions in the microenvironment of solid tumors have not been fully elucidated. We hypothesized that acidosis, hypoxia, and elevated interstitial fluid pressure (eIFP have additive effects on tumor cell biology and lead to more aggressive behavior during tumor progression. We investigated this phenomenon using 3 human osteosarcoma cell lines and a novel in vitro cell culture apparatus. MATERIALS AND METHODS:U2OS, SaOS, and MG63 cell lines were cultured in media adjusted to various pH levels, oxygen tension (hypoxia 2% O2, normoxia 20% O2, and hydrostatic gauge pressure (0 or 50 mm Hg. Growth rate, apoptosis, cell cycle parameters, and expression of mRNA for proteins associated with invasiveness and tumor microenvironment (CA IX, VEGF-A, HIF-1A, MMP-9, and TIMP-2 were analyzed. Levels of CA IX, HIF-1α, and MMP-9 were measured using immunofluorescence. The effect of pH on invasiveness was evaluated in a Matrigel chamber assay.RESULTS: Within the acidic–hypoxic–pressurized conditions that simulate the microenvironment at a tumor’s center, invasive genes were upregulated, but the cell cycle was downregulated. The combined influence of acidosis, hypoxia, and IFP promoted invasiveness and angiogenesis to a greater extent than did pH, pO2, or eIFP individually. Significant cell death after brief exposure to acidic conditions occurred in each cell line during acclimation to acidic media, while prolonged exposure to acidic media resulted in reduced cell death. Furthermore, 48-hour exposure to acidic conditions promoted tumor invasiveness in the Matrigel assay. CONCLUSION: Our findings demonstrate that tumor microenvironmental parameters—particularly pH, pO2, and eIFP—additively influence tumor proliferation, invasion, metabolism, and viability to enhance cell survival.

Thioredoxin and Cancer: A Role for Thioredoxin in all States of Tumor Oxygenation

International Nuclear Information System (INIS)

Karlenius, Therese Christina; Tonissen, Kathryn Fay

2010-01-01

Thioredoxin is a small redox-regulating protein, which plays crucial roles in maintaining cellular redox homeostasis and cell survival and is highly expressed in many cancers. The tumor environment is usually under either oxidative or hypoxic stress and both stresses are known up-regulators of thioredoxin expression. These environments exist in tumors because their abnormal vascular networks result in an unstable oxygen delivery. Therefore, the oxygenation patterns in human tumors are complex, leading to hypoxia/re-oxygenation cycling. During carcinogenesis, tumor cells often become more resistant to hypoxia or oxidative stress-induced cell death and most studies on tumor oxygenation have focused on these two tumor environments. However, recent investigations suggest that the hypoxic cycling occurring within tumors plays a larger role in the contribution to tumor cell survival than either oxidative stress or hypoxia alone. Thioredoxin is known to have important roles in both these cellular responses and several studies implicate thioredoxin as a contributor to cancer progression. However, only a few studies exist that investigate the regulation of thioredoxin in the hypoxic and cycling hypoxic response in cancers. This review focuses on the role of thioredoxin in the various states of tumor oxygenation

Singlet oxygen treatment of tumor cells triggers extracellular singlet oxygen generation, catalase inactivation and reactivation of intercellular apoptosis-inducing signaling☆

Science.gov (United States)

Riethmüller, Michaela; Burger, Nils; Bauer, Georg

2015-01-01

Intracellular singlet oxygen generation in photofrin-loaded cells caused cell death without discrimination between nonmalignant and malignant cells. In contrast, extracellular singlet oxygen generation caused apoptosis induction selectively in tumor cells through singlet oxygen-mediated inactivation of tumor cell protective catalase and subsequent reactivation of intercellular ROS-mediated apoptosis signaling through the HOCl and the NO/peroxynitrite signaling pathway. Singlet oxygen generation by extracellular photofrin alone was, however, not sufficient for optimal direct inactivation of catalase, but needed to trigger the generation of cell-derived extracellular singlet oxygen through the interaction between H2O2 and peroxynitrite. Thereby, formation of peroxynitrous acid, generation of hydroxyl radicals and formation of perhydroxyl radicals (HO2.) through hydroxyl radical/H2O2 interaction seemed to be required as intermediate steps. This amplificatory mechanism led to the formation of singlet oxygen at a sufficiently high concentration for optimal inactivation of membrane-associated catalase. At low initial concentrations of singlet oxygen, an additional amplification step needed to be activated. It depended on singlet oxygen-dependent activation of the FAS receptor and caspase-8, followed by caspase-8-mediated enhancement of NOX activity. The biochemical mechanisms described here might be considered as promising principle for the development of novel approaches in tumor therapy that specifically direct membrane-associated catalase of tumor cells and thus utilize tumor cell-specific apoptosis-inducing ROS signaling. PMID:26225731

Oxygen Tension Beneath Scleral Lenses of Different Clearances.

Science.gov (United States)

Giasson, Claude J; Morency, Jeanne; Melillo, Marc; Michaud, Langis

2017-04-01

To evaluate the relative partial pressure in oxygen (pO2) at the corneal surface under Boston XO2 scleral lenses (SL) fitted with targeted clearances of 200 and 400 μm (SL200 and SL400). During this prospective study, the right eyes of eight normal subjects were fitted with SL200 and SL400. Clearance, validated after 5 minutes of wear with an optical coherence tomograph, was used with lens thicknesses to calculate transmissibility and estimate pO2. Corneal pO2s were measured with an oxygen electrode after 5 minutes of (1) corneal exposure to calibrating gases with various pO2 or of (2) SL wear. Decays in pO2 were modeled to an exponential. Linear regression between exponent k of these decays and calibrating gas pO2s allowed for the calculation of corneal pO2 under SL. Differences between pO2s beneath SL200 and SL400 were tested with a mixed ANOVA. The estimated transmissibility based on thicknesses and clearances (239.7 ± 34.7; 434.5 ± 33.2 μm) predicted a corneal pO2 of 8.52 ± 0.51 and 6.37 ± 0.28% for SL200 and SL400. These values were close to measured pO2: 9.07 ± 0.86 and 6.19 ± 0.87% (mean ± SEM) (P time, an 18-mm scleral lens fitted with a 400-μm clearance reduces the oxygen tension available to the cornea by 30% compared to a similar lens fitted with a 200-μm clearance after 5 minutes of wear.

Singlet oxygen treatment of tumor cells triggers extracellular singlet oxygen generation, catalase inactivation and reactivation of intercellular apoptosis-inducing signaling.

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Riethmüller, Michaela; Burger, Nils; Bauer, Georg

2015-12-01

Intracellular singlet oxygen generation in photofrin-loaded cells caused cell death without discrimination between nonmalignant and malignant cells. In contrast, extracellular singlet oxygen generation caused apoptosis induction selectively in tumor cells through singlet oxygen-mediated inactivation of tumor cell protective catalase and subsequent reactivation of intercellular ROS-mediated apoptosis signaling through the HOCl and the NO/peroxynitrite signaling pathway. Singlet oxygen generation by extracellular photofrin alone was, however, not sufficient for optimal direct inactivation of catalase, but needed to trigger the generation of cell-derived extracellular singlet oxygen through the interaction between H2O2 and peroxynitrite. Thereby, formation of peroxynitrous acid, generation of hydroxyl radicals and formation of perhydroxyl radicals (HO2(.)) through hydroxyl radical/H2O2 interaction seemed to be required as intermediate steps. This amplificatory mechanism led to the formation of singlet oxygen at a sufficiently high concentration for optimal inactivation of membrane-associated catalase. At low initial concentrations of singlet oxygen, an additional amplification step needed to be activated. It depended on singlet oxygen-dependent activation of the FAS receptor and caspase-8, followed by caspase-8-mediated enhancement of NOX activity. The biochemical mechanisms described here might be considered as promising principle for the development of novel approaches in tumor therapy that specifically direct membrane-associated catalase of tumor cells and thus utilize tumor cell-specific apoptosis-inducing ROS signaling. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Unusual Growth Phase and Oxygen Tension Regulation of Oxidative Stress Protection Enzymes, Catalase and Superoxide Dismutase, in the Phytopathogen Xanthomonas oryzae pv. oryzae

OpenAIRE

Chamnongpol, S.; Mongkolsuk, S.; Vattanaviboon, P.; Fuangthong, M.

1995-01-01

The enzymes catalase and superoxide dismutase play major roles in protecting phytopathogenic bacteria from oxidative stress. In Xanthomonas species, these enzymes are regulated by both growth phase and oxygen tension. The highest enzyme levels were detected within 1 h of growth. Continued growth resulted in a decline of both enzyme activities. High oxygen tension was an inducing signal for both enzyme activities. An 80,000-Da monofunctional catalase and a manganese superoxide dismutase were t...

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

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Yoichi Takakusagi

Full Text Available BACKGROUND: TH-302 is a hypoxia-activated prodrug (HAP of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. METHODOLOGY/RESULTS: The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2, with minimal effect under aerobic conditions (21% O2. Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3. Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3, significantly delayed tumor growth. CONCLUSIONS/SIGNIFICANCE: Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

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Takakusagi, Yoichi; Matsumoto, Shingo; Saito, Keita; Matsuo, Masayuki; Kishimoto, Shun; Wojtkowiak, Jonathan W; DeGraff, William; Kesarwala, Aparna H; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Munasinghe, Jeeva P; Gillies, Robert J; Mitchell, James B; Hart, Charles P; Krishna, Murali C

2014-01-01

TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3). Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3)), significantly delayed tumor growth. Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.

Quantifying oxygen in paper-based cell cultures with luminescent thin film sensors.

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Boyce, Matthew W; Kenney, Rachael M; Truong, Andrew S; Lockett, Matthew R

2016-04-01

Paper-based scaffolds are an attractive material for generating 3D tissue-like cultures because paper is readily available and does not require specialized equipment to pattern, cut, or use. By controlling the exchange of fresh culture medium with the paper-based scaffolds, we can engineer diffusion-dominated environments similar to those found in spheroids or solid tumors. Oxygen tension directly regulates cellular phenotype and invasiveness through hypoxia-inducible transcription factors and also has chemotactic properties. To date, gradients of oxygen generated in the paper-based cultures have relied on cellular response-based readouts. In this work, we prepared a luminescent thin film capable of quantifying oxygen tensions in apposed cell-containing paper-based scaffolds. The oxygen sensors, which are polystyrene films containing a Pd(II) tetrakis(pentafluorophenyl)porphyrin dye, are photostable, stable in culture conditions, and not cytotoxic. They have a linear response for oxygen tensions ranging from 0 to 160 mmHg O2, and a Stern-Volmer constant (K sv) of 0.239 ± 0.003 mmHg O2 (-1). We used these oxygen-sensing films to measure the spatial and temporal changes in oxygen tension for paper-based cultures containing a breast cancer line that was engineered to constitutively express a fluorescent protein. By acquiring images of the oxygen-sensing film and the fluorescently labeled cells, we were able to approximate the oxygen consumption rates of the cells in our cultures.

Experimental studies on radiation effects under high pressure oxygen

Energy Technology Data Exchange (ETDEWEB)

Fujimura, E [Osaka Univ. (Japan). School of Dentistry

1974-06-01

The effect of oxygen tension on the radiosensitivity of tumor cells is well known, but its clinical application for radiotherapy is not yet established. Rabbits with V x 2 carcinoma in the maxilla were irradiated by /sup 60/Co under high pressure oxygen (experimental group), and compared with those treated in air (control group). For the purpose of examining the clinical effects of high pressure oxygen, an experiment was made in vivo. The following items were compared respectively: a) Tumor regression effect b) Tumor clearance rate c) Survival days d) Half size reduction time e) Inhibition of DNA synthesis in the tumor tissue. Results obtained were as follows: a) 56 per cent of animals showed tumor regression in the experimental group, whereas it occured 26 per cent in the control group. b) 53 per cent of animals showed tumor disappearance in the experimental group, while it was observed only in 13 per cent in the control group. c) Only 2 of 30 rabbits irradiated in air survived over 180 days, whereas 11 of 30 rabbits survived meanwhile in the group irradiated under high pressure oxygen. d) About 11 days were necessary to reduce the tumor size by half after irradiation in the group under high pressure oxygen, while it took 17 days in the group treated in normal air. e) DNA synthesis was inhibited more prominently in the group irradiated under high pressure oxygen in normal air.

Comparison between model-predicted tumor oxygenation dynamics and vascular-/flow-related Doppler indices.

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Belfatto, Antonella; Vidal Urbinati, Ailyn M; Ciardo, Delia; Franchi, Dorella; Cattani, Federica; Lazzari, Roberta; Jereczek-Fossa, Barbara A; Orecchia, Roberto; Baroni, Guido; Cerveri, Pietro

2017-05-01

Mathematical modeling is a powerful and flexible method to investigate complex phenomena. It discloses the possibility of reproducing expensive as well as invasive experiments in a safe environment with limited costs. This makes it suitable to mimic tumor evolution and response to radiotherapy although the reliability of the results remains an issue. Complexity reduction is therefore a critical aspect in order to be able to compare model outcomes to clinical data. Among the factors affecting treatment efficacy, tumor oxygenation is known to play a key role in radiotherapy response. In this work, we aim at relating the oxygenation dynamics, predicted by a macroscale model trained on tumor volumetric data of uterine cervical cancer patients, to vascularization and blood flux indices assessed on Ultrasound Doppler images. We propose a macroscale model of tumor evolution based on three dynamics, namely active portion, necrotic portion, and oxygenation. The model parameters were assessed on the volume size of seven cervical cancer patients administered with 28 fractions of intensity modulated radiation therapy (IMRT) (1.8 Gy/fraction). For each patient, five Doppler ultrasound tests were acquired before, during, and after the treatment. The lesion was manually contoured by an expert physician using 4D View ® (General Electric Company - Fairfield, Connecticut, United States), which automatically provided the overall tumor volume size along with three vascularization and/or blood flow indices. Volume data only were fed to the model for training purpose, while the predicted oxygenation was compared a posteriori to the measured Doppler indices. The model was able to fit the tumor volume evolution within 8% error (range: 3-8%). A strong correlation between the intrapatient longitudinal indices from Doppler measurements and oxygen predicted by the model (about 90% or above) was found in three cases. Two patients showed an average correlation value (50-70%) and the remaining

Is oxygen important in the radiocurability of human tumors

International Nuclear Information System (INIS)

Withers, H.R.; Suit, H.D.

1974-01-01

It is quite likely that untreated human tumors contain hypoxic cells. Frequently, perhaps usually, the presence of these hypoxic cells does not influence radiocurability. If hypoxia limits radiocurability, it is more likely to do so in the treatment of large tumors and maybe with greater likelihood in tumors in certain sites. Hypoxia would also be more likely to affect response to a small number of fractions, since reoxygenation would need to be more complete in order that cell killing by the larger dose fractions used would not be prejudiced by the hypoxia of a small proportion of cells. Hyperbaric oxygen is disappointing as an adjuvant to radiotherapy. Results obtained are not better than those obtained using the best conventional fractionation regimes in air. This does not prove, however, that hypoxia is not a cause of failure to control tumors locally, since physiological adaptive mechanisms against HPO such as vasoconstriction may prevent better oxygenation of the tumor. If other methods such as high LET beams are to be used to reduce any effect hypoxia may have on radiocurability, their greatest benefit would be expected in the local control of late-stage disease and this benefit may be greater in some tumor sites than others. (U.S.)

Endoscopic Resection of Tracheal Tumor in an Elderly Woman Under Extracorporeal Membrane Oxygenation

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Yi-Ying Chiang

2011-03-01

Full Text Available Anesthetic management of patients with difficult airway is challenging, especially in patients who present with near total occlusion of the airway. Tracheal tumors occur more frequently in elderly patients who are more prone to hypoxic injury. Reliable ventilation and oxygenation are mandatory for a safe and sound intervention. Herein, we report on a 71-year-old woman with a large tracheal tumor occluding approximately 90% of the tracheal lumen. Extracorporeal membrane oxygenation under local anesthesia was used during electrocautery resection of the tumor because of the possibility of fatal airway collapse due to the degree of occlusion and location of the tumor. After the tumor had been successfully resected by means of bronchoscopy, an endotracheal tube was inserted, and the patient was weaned from extracorporeal membrane oxygenation.

Adverse effects of reduced oxygen tension on the proliferative capacity of rat kidney and insulin-secreting cell lines involve DNA damage and stress responses

International Nuclear Information System (INIS)

Chen Jianhua; Jones, R. Huw; Tarry-Adkins, Jane; Smith, Noel H.; Ozanne, Susan E.

2008-01-01

Standard cell culture conditions do not reflect the physiological environment in terms of oxygen tension (20% vs 3%). The effects of lowering oxygen tension on cell proliferation in culture can be beneficial as well as detrimental depending on the cell line studied, but the molecular mechanism underlying such effects is not fully understood. We observed that the proliferative capacity of the rat cell lines NRK and INS-1 was inhibited when cultured under 3% oxygen as compared to 20% oxygen. Suppression of proliferation in NRK cells was accompanied by induction of DNA double strand breaks whereas in INS-1 cells it was accompanied by up-regulation of p53 and p27. Although Sirt1 was up-regulated in both cell lines by 3% oxygen the effects on antioxidant enzymes (MnSOD, CuZnSOD and catalase) were cell line specific. Marked up-regulation of heme oxygenase-1 (HO-1) was detected in both NRK and INS-1 cells when cultured in 3% oxygen. HO-1 expression can be readily induced by exposure to hydrogen peroxide in culture. These results suggest that reduced oxygen tension suppresses the proliferative capacity of these two cell lines through a stress response that is similar to an oxidative stress response but the molecular events that lead to the reduced cell proliferation are cell line specific

Electron Paramagnetic Resonance pO2 Image Tumor Oxygen-Guided Radiation Therapy Optimization.

Science.gov (United States)

Epel, Boris; Maggio, Matt; Pelizzari, Charles; Halpern, Howard J

2017-01-01

Modern standards for radiation treatment do not take into account tumor oxygenation for radiation treatment planning. Strong correlation between tumor oxygenation and radiation treatment success suggests that oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. We have developed an OGRT protocol for rodents. Electron paramagnetic resonance (EPR) imaging is used for recording oxygen maps with high spatial resolution and excellent accuracy better than 1 torr. Radiation is delivered with an animal intensity modulated radiation therapy (IMRT) XRAD225Cx micro-CT/ therapy system. The radiation plan is delivered in two steps. First, a uniform 15% tumor control dose (TCD 15 ) is delivered to the whole tumor. In the second step, an additional booster dose amounting to the difference between TCD 98 and TCD 15 is delivered to radio-resistant, hypoxic tumor regions. Delivery of the booster dose is performed using a multiport conformal beam protocol. For radiation beam shaping we used individual radiation blocks 3D-printed from tungsten infused ABS polymer. Calculation of beam geometry and the production of blocks is performed next to the EPR imager, immediately after oxygen imaging. Preliminary results demonstrate the sub-millimeter precision of the radiation delivery and high dose accuracy. The efficacy of the radiation treatment is currently being tested on syngeneic FSa fibrosarcoma tumors grown in the legs of C3H mice.

Experimental studies on the effect of perfluorochemicals in tumor irradiation

International Nuclear Information System (INIS)

Shinoda, Jun; Iwai, Tomohiko; Hattori, Tatsuaki; Kondo, Hiroaki; Sakai, Noboru; Yamada, Hiroshi

1984-01-01

The effects of radiation therapy with Fluosol-DA on rat mammary tumors were studied. The tissue oxygen tension values of tumors in breathing mixed gas (5% carbon dioxide and 95% oxygen) with Fluosol-DA (25 ml/kg, i.v.) were significantly higher than those in room air without Fluosol-DA. The rats were divided into three groups: Group I received Fluosol-DA but no irradiation, Group II was treated with 1000 rads of irradiation using 60 Co without Fluosol-DA in room air and Group III received the same irradiation and Fluosol-DA in breathig mixed gas. In the latter group we observed a prolongation of the survival time and suppression of the tumor growth. (author)

Oxygen tension is a determinant of the matrix-forming phenotype of cultured human meniscal fibrochondrocytes.

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Adetola B Adesida

Full Text Available BACKGROUND: Meniscal cartilage displays a poor repair capacity, especially when injury is located in the avascular region of the tissue. Cell-based tissue engineering strategies to generate functional meniscus substitutes is a promising approach to treat meniscus injuries. Meniscus fibrochondrocytes (MFC can be used in this approach. However, MFC are unable to retain their phenotype when expanded in culture. In this study, we explored the effect of oxygen tension on MFC expansion and on their matrix-forming phenotype. METHODOLOGY/PRINCIPAL FINDINGS: MFC were isolated from human menisci followed by basic fibroblast growth factor (FGF-2 mediated cell expansion in monolayer culture under normoxia (21%O(2 or hypoxia (3%O(2. Normoxia and hypoxia expanded MFC were seeded on to a collagen scaffold. The MFC seeded scaffolds (constructs were cultured in a serum free chondrogenic medium for 3 weeks under normoxia and hypoxia. Constructs containing normoxia-expanded MFC were subsequently cultured under normoxia while those formed from hypoxia-expanded MFC were subsequently cultured under hypoxia. After 3 weeks of in vitro culture, the constructs were assessed biochemically, histologically and for gene expression via real-time reverse transcription-PCR assays. The results showed that constructs under normoxia produced a matrix with enhanced mRNA ratio (3.5-fold higher; p<0.001 of collagen type II to I. This was confirmed by enhanced deposition of collagen II using immuno-histochemistry. Furthermore, the constructs under hypoxia produced a matrix with higher mRNA ratio of aggrecan to versican (3.5-fold, p<0.05. However, both constructs had the same capacity to produce a glycosaminoglycan (GAG -specific extracellular matrix. CONCLUSIONS: Our data provide evidence that oxygen tension is a key player in determining the matrix phenotype of cultured MFC. These findings suggest that the use of normal and low oxygen tension during MFC expansion and subsequent neo

Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

NARCIS (Netherlands)

Emans, Tonja W.; Janssen, Ben J.; Pinkham, Maximilian I.; Ow, Connie P. C.; Evans, Roger G.; Joles, Jaap A.; Malpas, Simon C.; Krediet, C. T. Paul; Koeners, Maarten P.

2016-01-01

Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary. We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats. This method provides stable and continuous

Regional perfusion and oxygenation of tumors upon methylxanthine derivative administration

International Nuclear Information System (INIS)

Kelleher, Debra K.; Thews, Oliver; Vaupel, Peter

1998-01-01

Purpose: The use of methylxanthine derivatives has been postulated as a means of increasing tumor perfusion and thus ameliorating tumor hypoxia. The aim of this study was to quantify and compare the effects of three methylxanthine derivatives: pentoxifylline (PX), torbafylline (TB), and HWA 138 (HW) on tumor perfusion and oxygenation. Methods and Materials: Anesthetized Sprague Dawley rats with DS-sarcomas implanted subcutaneously onto the hind foot dorsum were used in this study. Mean arterial blood pressure (MABP) was measured throughout experiments. Regional red blood cell (RBC) flux was monitored using a multichannel laser Doppler device and tumor oxygenation on a more global level was assessed polarographically using an O 2 -sensitive catheter electrode. The methylxanthine derivatives were administered as a single dose intraperitoneally (for PX 50 mg/kg; for TB and HW 75 mg/kg). Results: Following drug administration, initial decreases in MABP down to 75% of baseline values were observed for all three substances. PX, HW, and TB caused initial transient reductions in mean RBC flux followed by gradual increases to values of 137 ± 27 %, 139 ± 14 %, and 122 ± 14 % respectively at t = 60 min. Following a small initial decrease upon drug administration, O 2 partial pressure (pO 2 ) rose to 160 ± 31 %, 153 ± 34 %, and 121 ± 11 % for PX, HW, and TB, respectively at t = 60 min. At the end of the observation period (t = 90 min), increases in RBC flux and pO 2 were still evident. When individual tumors were considered, a variety of patterns (including opposing effects) for changes in RBC flux were seen, not necessarily reflected in the mean values. Thus, while the methylxanthine derivatives caused an increased average tumor perfusion, there is evidence suggesting that a redistribution of tumor blood flow occurs which may amplify preexisting heterogeneity. Conclusions: Substantial improvements in tumor oxygenation and perfusion were observed after administration of

Temporal variation in the response of tumors to hyperoxia with breathing carbogen and oxygen

Science.gov (United States)

Hou, Hua-gang; Khan, Nadeem; Du, Gai-xin; Hodge, Sassan; Swartz, Harold M.

2016-01-01

The effect of hyperoxygenation with carbogen (95% O2 + 5% CO2) and 100% oxygen inhalation on partial pressure of oxygen (pO2) of radiation-induced fibrosarcoma (RIF-1) tumor was investigated. RIF-1 tumors were innoculated in C3H mice, and aggregates of oximetry probe, lithium phthalocyanine (LiPc), was implanted in each tumor. A baseline tumor pO2 was measured by electron paramagnetic resonance (EPR) oximetry for 20 minutes in anesthetized mice breathing 30% O2 and then the gas was switched to carbogen or 100 % oxygen for 60 minutes. These experiments were repeated for 10 days. RIF-1 tumors were hypoxic with a baseline tissue pO2 of 6.2–8.3 mmHg in mice breathing 30% O2. Carbogen and 100% oxygen significantly increased tumor pO2 on days 1 to 5, with a maximal increase at approximately 32–45 minutes on each day. However, the extent of increase in pO2 from the baseline declined significantly on day 5 and day 10. The results provide quantitative information on the effect of hyperoxic gas inhalation on tumor pO2 over the course of 10 days. EPR oximetry can be effectively used to repeatedly monitor tumor pO2 and test hyperoxic methods for potential clinical applications. PMID:27867481

Temporal variation in the response of tumors to hyperoxia with breathing carbogen and oxygen

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Hua-gang Hou

2016-01-01

Full Text Available The effect of hyperoxygenation with carbogen (95% O 2 + 5% CO 2 and 100% oxygen inhalation on partial pressure of oxygen (pO 2 of radiation-induced fibrosarcoma (RIF-1 tumor was investigated. RIF-1 tumors were innoculated in C3H mice, and aggregates of oximetry probe, lithium phthalocyanine (LiPc, was implanted in each tumor. A baseline tumor pO 2 was measured by electron paramagnetic resonance (EPR oximetry for 20 minutes in anesthetized mice breathing 30% O 2 and then the gas was switched to carbogen or 100 % oxygen for 60 minutes. These experiments were repeated for 10 days. RIF-1 tumors were hypoxic with a baseline tissue pO 2 of 6.2-8.3 mmHg in mice breathing 30% O 2 . Carbogen and 100% oxygen significantly increased tumor pO 2 on days 1 to 5, with a maximal increase at approximately 32-45 minutes on each day. However, the extent of increase in pO 2 from the baseline declined significantly on day 5 and day 10. The results provide quantitative information on the effect of hyperoxic gas inhalation on tumor pO 2 over the course of 10 days. EPR oximetry can be effectively used to repeatedly monitor tumor pO 2 and test hyperoxic methods for potential clinical applications.

Oxygenation level and hemoglobin concentration in experimental tumor estimated by diffuse optical spectroscopy

Science.gov (United States)

Orlova, A. G.; Kirillin, M. Yu.; Volovetsky, A. B.; Shilyagina, N. Yu.; Sergeeva, E. A.; Golubiatnikov, G. Yu.; Turchin, I. V.

2017-07-01

Using diffuse optical spectroscopy the level of oxygenation and hemoglobin concentration in experimental tumor in comparison with normal muscle tissue of mice have been studied. Subcutaneously growing SKBR-3 was used as a tumor model. Continuous wave fiber probe diffuse optical spectroscopy system was employed. Optical properties extraction approach was based on diffusion approximation. Decreased blood oxygen saturation level and increased total hemoglobin content were demonstrated in the neoplasm. The main reason of such differences between tumor and norm was significant elevation of deoxyhemoglobin concentration in SKBR-3. The method can be useful for diagnosis of tumors as well as for study of blood flow parameters of tumor models with different angiogenic properties.

BIOELECTRIC POTENTIALS IN HALICYSTIS : VII. THE EFFECTS OF LOW OXYGEN TENSION.

Science.gov (United States)

Blinks, L R; Darsie, M L; Skow, R K

1938-11-20

The potential difference across the protoplasm of impaled cells of Halicystis is not affected by increase of oxygen tension in equilibrium with the sea water, nor with decrease down to about 1/10 its tension in the air (2 per cent O(2) in N(2)). When bubbling of 2 per cent O(2) is stopped, the P.D. drifts downward, to be restored on stirring the sea water, or rebubbling the gas. Bubbling 0.2 per cent O(2) causes the P.D. to drop to 20 mv. or less; 1.1 per cent O(2) to about 50 mv. Restoration of 2 per cent or higher O(2) causes recovery to 70 or 80 mv. often with a preliminary cusp which decreases the P.D. before it rises. Perfusion of aerated sea water through the vacuole is just as effective in restoring the P.D. as external aeration, indicating that the direction of the oxygen gradient is not significant. Low O(2) tension also inhibits the reversed, negative P.D. produced by adding NH(4)Cl to sea water, 0.2 per cent O(2) bringing this P.D. back to the same low positive values found without ammonia. Restoration of 2 per cent O(2) or air, restores this latent negativity. At slightly below the threshold for ammonia reversal, low O(2) may induce a temporary negativity when first bubbled, and a negative cusp may occur on aeration before positive P.D. is regained. This may be due to a decreased consumption of ammonia, or to intermediate pH changes. The locus of the P.D. alteration was tested by applying increased KCl concentrations to the cell exterior; the large cusps produced in aerated solutions become greatly decreased when the P.D. has fallen in 0.2 per cent O(2). This indicates that the originally high relative mobility or concentration of K(+) ion has approached that of Na(+) in the external protoplasmic surface under reduced O(2) tension. Results obtained with sulfate sea water indicate that Na(+) mobility approaches that of SO(4) (-) in 0.2 per cent O(2). P.D. measurements alone cannot tell whether this is due to an increase of the slower ion or a decrease of

Hyperbaric oxygen and radiotherapy

International Nuclear Information System (INIS)

Mayer, R.; Hamilton-Farrell, M.R.; Kleij, A.J. van der

2005-01-01

Background: Hyperbaric oxygen (HBO) therapy is the inhalation of 100% oxygen at a pressure of at least 1.5 atmospheres absolute (150 kPa). It uses oxygen as a drug by dissolving it in the plasma and delivering it to the tissues independent of hemoglobin. For a variety of organ systems, HBO is known to promote new vessel growth into areas with reduced oxygen tension due to poor vascularity, and therewith promotes wound healing and recovery of radiation-injured tissue. Furthermore, tumors may be sensitized to irradiation by raising intratumoral oxygen tensions. Methods: A network of hyperbaric facilities exists in Europe, and a number of clinical studies are ongoing. The intergovernmental framework COST B14 action 'Hyperbaric Oxygen Therapy' started in 1999. The main goal of the Working Group Oncology is preparation and actual implementation of prospective study protocols in the field of HBO and radiation oncology in Europe. Results: In this paper a short overview on HBO is given and the following randomized clinical studies are presented: (a) reirradiation of recurrent squamous cell carcinoma of the head and neck after HBO sensitization; (b) role of HBO in enhancing radiosensitivity on glioblastoma multiforme; (c) osseointegration in irradiated patients; adjunctive HBO to prevent implant failures; (d) the role of HBO in the treatment of late irradiation sequelae in the pelvic region. The two radiosensitization protocols (a, b) allow a time interval between HBO and subsequent irradiation of 10-20 min. Conclusion: Recruitment of centers and patients is being strongly encouraged, detailed information is given on www.oxynet.org. (orig.)

Effect of supplemental oxygen versus dobutamine administration on liver oxygen tension in dPP-guided normovolemic pigs.

Science.gov (United States)

Pestel, G; Fukui, K; Hager, H; Kurz, A; Hiltebrand, L

2009-01-01

Difference in pulse pressure (dPP) confirms adequate intravascular filling as a prerequisite for tissue perfusion. We hypothesized that both oxygen and dobutamine increase liver tissue oxygen tension (ptO(2)). Eight anesthetized pigs received dPP-guided fluid management. Hepatic pO(2) was measured with Clark-type electrodes placed subcapsularly, and on the liver surface. Pigs received: (1) supplemental oxygen (F(i)O(2) 1.0); (2) dobutamine 2.5 microg/kg/min, and (3) dobutamine 5 microg/kg/min. Data were analyzed using repeated-measures ANOVA followed by a Tukey post-test for multiple comparisons. ptO(2 )measured subcapsularly and at the liver surface were compared using the Bland-Altman plot. Variation in F(i)O(2) changed local hepatic tissue ptO(2) [subcapsular measurement: 39 +/- 12 (F(i)O(2) 0.3), 89 +/- 35 mm Hg (F(i)O(2) 1.0, p = 0.01 vs. F(i)O(2) 0.3), 44 +/- 10 mm Hg (F(i)O(2) 0.3, p = 0.05 vs. F(i)O(2) 1.0); surface measurement: 52 +/- 35 (F(i)O(2) 0.3), 112 +/- 24 mm Hg (F(i)O(2) 1.0, p = 0.001 vs. F(i)O(2) 0.3), 54 +/- 24 mm Hg (F(i)O(2) 0.3, p = 0.001 vs. F(i)O(2) 1.0)]. Surface measurements were widely scattered compared to subcapsular measurements (bias: -15 mm Hg, precision: 76.3 mm Hg). Dobutamine did not affect hepatic oxygenation. Supplemental oxygen increased hepatic tissue pO(2) while dobutamine did not. Although less invasive, the use of surface measurements is discouraged. Copyright 2009 S. Karger AG, Basel.

Oxygen-boosted immunogenic photodynamic therapy with gold nanocages@manganese dioxide to inhibit tumor growth and metastases.

Science.gov (United States)

Liang, Ruijing; Liu, Lanlan; He, Huamei; Chen, Zhikuan; Han, Zhiqun; Luo, Zhenyu; Wu, Zhihao; Zheng, Mingbin; Ma, Yifan; Cai, Lintao

2018-09-01

Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease among women worldwide, characterized by high mortality and poor prognosis despite systemic therapy with radiation and chemotherapies. Photodynamic therapy (PDT) is an important strategy to eliminate the primary tumor, however its therapeutic efficacy against metastases and recurrence is still limited. Here, we employed a template method to develop the core-shell gold nanocage@manganese dioxide (AuNC@MnO 2 , AM) nanoparticles as tumor microenvironment responsive oxygen producers and near-infrared (NIR)-triggered reactive oxygen species (ROS) generators for oxygen-boosted immunogenic PDT against mTNBC. In this platform, MnO 2 shell degrades in acidic tumor microenvironment pH/H 2 O 2 conditions and generates massive oxygen to boost PDT effect of AM nanoparticles under laser irradiation. Fluorescence (FL)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging confirms the effective accumulation of AM nanoparticles with sufficient oxygenation in tumor site to ameliorate local hypoxia. Moreover, the oxygen-boosted PDT effect of AM not only destroys primary tumor effectively but also elicits immunogenic cell death (ICD) with damage-associated molecular patterns (DAMPs) release, which subsequently induces DC maturation and effector cells activation, thereby robustly evoking systematic antitumor immune responses against mTNBC. Hence, this oxygen-boosted immunogenic PDT nanosystem offers a promising approach to ablate primary tumor and simultaneously prevent tumor metastases via immunogenic abscopal effects. Copyright © 2018 Elsevier Ltd. All rights reserved.

Interrogation of metabolic and oxygen states of tumors with fiber-based luminescence lifetime spectroscopy.

Science.gov (United States)

Lukina, Maria; Orlova, Anna; Shirmanova, Marina; Shirokov, Daniil; Pavlikov, Anton; Neubauer, Antje; Studier, Hauke; Becker, Wolfgang; Zagaynova, Elena; Yoshihara, Toshitada; Tobita, Seiji; Shcheslavskiy, Vladislav

2017-02-15

The study of metabolic and oxygen states of cells in a tumor in vivo is crucial for understanding of the mechanisms responsible for tumor development and provides background for the relevant tumor's treatment. Here, we show that a specially designed implantable fiber-optic probe provides a promising tool for optical interrogation of metabolic and oxygen states of a tumor in vivo. In our experiments, the excitation light from a ps diode laser source is delivered to the sample through an exchangeable tip via a multimode fiber, and the emission light is transferred to the detector by another multimode fiber. Fluorescence lifetime of a nicotinamid adenine dinucleotide (NAD(P)H) and phosphorescence lifetime of an oxygen sensor based on an iridium (III) complex of enzothienylpyridine (BTPDM1) are explored both in model experiment in solutions and in living mice.

Reactive oxygen species-driven HIF1α triggers accelerated glycolysis in endothelial cells exposed to low oxygen tension

International Nuclear Information System (INIS)

Paik, Jin-Young; Jung, Kyung-Ho; Lee, Jin-Hee; Park, Jin-Won; Lee, Kyung-Han

2017-01-01

Endothelial cells and their metabolic state regulate glucose transport into underlying tissues. Here, we show that low oxygen tension stimulates human umbilical vein endothelial cell 18 F–fluorodeoxyglucose ( 18 F–FDG) uptake and lactate production. This was accompanied by augmented hexokinase activity and membrane Glut-1, and increased accumulation of hypoxia-inducible factor-1α (HIF1α). Restoration of oxygen reversed the metabolic effect, but this was blocked by HIF1α stabilization. Hypoxia-stimulated 18 F–FDG uptake was completely abrogated by silencing of HIF1α expression or by a specific inhibitor. There was a rapid and marked increase of reactive oxygen species (ROS) by hypoxia, and ROS scavenging or NADPH oxidase inhibition completely abolished hypoxia-stimulated HIF1α and 18 F–FDG accumulation, placing ROS production upstream of HIF1α signaling. Hypoxia-stimulated HIF1α and 18 F–FDG accumulation was blocked by the protein kinase C (PKC) inhibitor, staurosporine. The phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, blocked hypoxia-stimulated 18 F–FDG uptake and attenuated hypoxia-responsive element binding of HIF1α without influencing its accumulation. Thus, ROS-driven HIF1α accumulation, along with PKC and PI3K signaling, play a key role in triggering accelerated glycolysis in endothelial cells under hypoxia, thereby contributing to 18 F–FDG transport.

Modulation of the tumor vasculature and oxygenation to improve therapy

DEFF Research Database (Denmark)

Siemann, Dietmar W; Horsman, Michael R

2015-01-01

The tumor microenvironment is increasingly recognized as a major factor influencing the success of therapeutic treatments and has become a key focus for cancer research. The progressive growth of a tumor results in an inability of normal tissue blood vessels to oxygenate and provide sufficient...... important are the functional consequences experienced by the tumor cells residing in such environments: adaptation to hypoxia, cell quiescence, modulation of transporters and critical signaling molecules, immune escape, and enhanced metastatic potential. Together these factors lead to therapeutic barriers...

Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: experimental and modeling studies

Science.gov (United States)

Sgouralis, Ioannis; Kett, Michelle M.; Ow, Connie P. C.; Abdelkader, Amany; Layton, Anita T.; Gardiner, Bruce S.; Smith, David W.; Lankadeva, Yugeesh R.

2016-01-01

Oxygen tension (Po2) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po2. Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po2 from bladder urine Po2. Both intravenous infusion of [Phe2,Ile3,Orn8]-vasopressin and infusion of NG-nitro-l-arginine reduced urinary Po2 and medullary Po2 (8–17%), yet had opposite effects on renal blood flow and urine flow. Changes in bladder urine Po2 during these stimuli correlated strongly with changes in medullary Po2 (within-rabbit r2 = 0.87–0.90). Differences in the Po2 of saline infused into the ureter close to the kidney could be detected in the bladder, although this was diminished at lesser ureteric flow. Diffusion of oxygen across the wall of the bladder was very slow, so it was not considered in the computational model. The model predicts Po2 in the pelvic ureter (presumed to reflect medullary Po2) from known values of bladder urine Po2, urine flow, and arterial Po2. Simulations suggest that, across a physiological range of urine flow in anesthetized rabbits (0.1–0.5 ml/min for a single kidney), a change in bladder urine Po2 explains 10–50% of the change in pelvic urine/medullary Po2. Thus, it is possible to infer changes in medullary Po2 from changes in urinary Po2, so urinary Po2 may have utility as a real-time biomarker of risk of acute kidney injury. PMID:27385734

Oxygen microenvironment affects the uptake of nanoparticles in head and neck tumor cells

Science.gov (United States)

Chen, Eunice Y.; Hodge, Sasson; Tai, Katherine; Hou, Huagang; Khan, Nadeem; Hoopes, P. Jack; Samkoe, Kimberley S.

2013-02-01

Survival of head and neck cancer patients has not improved in several decades despite advances in diagnostic and therapeutic techniques. Tumor hypoxia in head and neck cancers is a critical factor that leads to poor prognosis, resistance to radiation and chemotherapies, and increased metastatic potential. Magnetic nanoparticle hyperthermia (mNPHT) is a promising therapy for hypoxic tumors because nanoparticles (NP) can be directly injected into, or targeted to, hypoxic tumor cells and exposed to alternating magnetic fields (AMF) to induce hyperthermia. Magnetic NPHT can improve therapeutic effectiveness by two modes of action: 1) direct killing of hypoxic tumor cells; and 2) increase in tumor oxygenation, which has the potential to make the tumor more susceptible to adjuvant therapies such as radiation and chemotherapy. Prior studies in breast cancer cells demonstrated that a hypoxic microenvironment diminished NP uptake in vitro; however, mNPHT with intratumoral NP injection in hypoxic tumors increased tumor oxygenation and delayed tumor growth. In this study, head and neck squamous cell carcinoma (HNSCC) cell lines were incubated in normoxic, hypoxic, and hyperoxic conditions with iron oxide NP for 4-72 hours. After incubation, the cells were analyzed for iron uptake by mass spectrometry, Prussian blue staining, and electron microscopy. In contrast to breast cancer cells, uptake of NPs was increased in hypoxic microenvironments as compared to normoxic conditions in HNSCC cells. In future studies, we will confirm the effect of the oxygen microenvironment on NP uptake and efficacy of mNPHT both in vitro and in vivo.

Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas

International Nuclear Information System (INIS)

Becker, Axel; Stadler, Peter; Lavey, Robert S.; Haensgen, Gabriele; Kuhnt, Thomas; Lautenschlaeger, Christine; Feldmann, Horst Juergen; Molls, Michael; Dunst, Juergen

2000-01-01

Purpose: To investigate the relationship between tumor oxygenation and the blood hemoglobin (Hb) concentration in patients with squamous cell carcinoma of the head and neck (SCCHN). Methods and Materials: A total of 133 patients with SCCHN underwent pretreatment polarographic pO 2 measurements of their tumors. In 66 patients measurements were also made in sternocleidomastoid muscles. The patients were divided into three groups according to their Hb concentration--severe anemia (Hb 2 . Conclusion: Our data suggest that a low Hb concentration and cigarette smoking contribute to inadequate oxygenation of SCCHN and thus for increased radioresistance. Consequently, Hb correction and abstinence from smoking may significantly improve tumor oxygenation

Postnatal follow-up of the oxygenation index, arterial to alveolar oxygen tension ratio and alveolar arterial oxygen tension difference values in neonates with the respiratory distress syndrome treated with conventional ventilatory support.

Science.gov (United States)

Atanasov, A; Despotova-Toleva, L

1997-01-01

Recent development of sophisticated intensive care technique for use in newborn infants with the respiratory distress syndrome (RDS) has resulted in changes in the therapeutic strategies and moved the problem of neonatal survival into the realm of new therapeutic realities. At present, the mechanical ventilation methods form an integral part of the intensive care strategy of infants with RDS. They have come to the forefront of infant care because of their successful use in ventilatory support and children survival where other therapeutic modalities have failed. The present prospective observational longitudinal study was designed to assess the real-time convenience, reliability and accuracy of the changes in the oxygenation index (OI), arterial-to-alveolar oxygen tension ratio (a/A PO2) and alveolar-arterial oxygen gradient (A-a)DO2 in ventilator-dependent neonates with RDS, to analyze their feasibility and potential information yield in oxygen inhalation therapy as well as their prognostic implications and predictive value. Twenty neonates with RDS, heralded by respiratory failure which necessitated the initiation of oxygen inhalation therapy and ventilatory support within 24 hours of birth, were enrolled in the study. Ten of the infants survived and the remaining ten died. OI, (a/A PO2) and (A-a)DO2 were followed up sequentially and thoroughly analyzed as the primary outcome measures of the study. The indices were calculated on the basis of the complete monitoring of the ventilatory equipment parameters and acid-base status carried out on an hourly basis. Our results show that: 1. The combination of three indexes (OI, (a/A)PO2 and (A-a)DO2 we propose is a useful discriminating predictor of neonatal lung maturity reflecting arterial blood gas status in ventilator-dependent neonates with RDS. 2. The indices detect the efficacy of the modern conventional ventilatory support with real-time convenience and reliable accuracy forming the cornerstone of clinical decision

The relationship between alveolar oxygen tension and the single-breath carbon monoxide diffusing capacity.

Science.gov (United States)

Kanner, R E; Crapo, R O

1986-04-01

The effects of alveolar oxygen tension (PAO2) on the single-breath carbon monoxide diffusing capacity (DLCO) were quantified and a factor was derived to accommodate for differences in PAO2 over commonly encountered altitudes and/or varying concentrations of oxygen in the test gas mixture (FIO2) We performed duplicate measurements of DLCO in 7 normal subjects with 6 different oxygen fractions (0.176, 0.196, 0.211, 0.22, 0.25, and 0.27). The PAO2 for each test was measured as the PO2 in the alveolar gas sample bag. DLCO varied inversely with PAO2 and changed by 0.35% for each mmHg change in PAO2 (r = -0.62, p less than 0.001). At an FIO2 of 0.25, PAO2 varied between subjects and was highly correlated with each subject's residual volume to total lung capacity ratio (r = -0.84, p less than 0.001). We suggest that laboratories can adjust the measured DLCO when PAO2 is not congruent to 120 mmHg by the following formula: DLCO (corrected = DLCO (measured) x [1.0 + 0.0035 (PAO2 - 120)].

Towards a quantitative understanding of oxygen tension and cell density evolution in fibrin hydrogels.

Science.gov (United States)

Demol, Jan; Lambrechts, Dennis; Geris, Liesbet; Schrooten, Jan; Van Oosterwyck, Hans

2011-01-01

The in vitro culture of hydrogel-based constructs above a critical size is accompanied by problems of unequal cell distribution when diffusion is the primary mode of oxygen transfer. In this study, an experimentally-informed mathematical model was developed to relate cell proliferation and death inside fibrin hydrogels to the local oxygen tension in a quantitative manner. The predictive capacity of the resulting model was tested by comparing its outcomes to the density, distribution and viability of human periosteum derived cells (hPDCs) that were cultured inside fibrin hydrogels in vitro. The model was able to reproduce important experimental findings, such as the formation of a multilayered cell sheet at the hydrogel periphery and the occurrence of a cell density gradient throughout the hydrogel. In addition, the model demonstrated that cell culture in fibrin hydrogels can lead to complete anoxia in the centre of the hydrogel for realistic values of oxygen diffusion and consumption. A sensitivity analysis also identified these two parameters, together with the proliferation parameters of the encapsulated cells, as the governing parameters for the occurrence of anoxia. In conclusion, this study indicates that mathematical models can help to better understand oxygen transport limitations and its influence on cell behaviour during the in vitro culture of cell-seeded hydrogels. Copyright © 2010 Elsevier Ltd. All rights reserved.

Exogenous and endogenous angiotensin‐II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

Science.gov (United States)

Emans, Tonja W.; Janssen, Ben J.; Pinkham, Maximilian I.; Ow, Connie P. C.; Evans, Roger G.; Joles, Jaap A.; Malpas, Simon C.; Krediet, C. T. Paul

2016-01-01

Key points Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary.We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats.This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation.Exogenous angiotensin‐II reduced renal cortical tissue PO2 more than equi‐pressor doses of phenylephrine, probably because it reduced renal oxygen delivery more than did phenylephrine.Activation of the endogenous renin–angiotensin system in transgenic Cyp1a1Ren2 rats reduced cortical tissue PO2; in this model renal hypoxia precedes the development of structural pathology and can be reversed acutely by an angiotensin‐II receptor type 1 antagonist.Angiotensin‐II promotes renal hypoxia, which may in turn contribute to its pathological effects during development of chronic kidney disease. Abstract We hypothesised that both exogenous and endogenous angiotensin‐II (AngII) can decrease the partial pressure of oxygen (PO2) in the renal cortex of unrestrained rats, which might in turn contribute to the progression of chronic kidney disease. Rats were instrumented with telemeters equipped with a carbon paste electrode for continuous measurement of renal cortical tissue PO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PO2 was dose‐dependently reduced by intravenous AngII. Reductions in PO2 were significantly greater than those induced by equi‐pressor doses of phenylephrine. In anaesthetised rats, renal oxygen consumption was not affected, and filtration fraction was increased only in the AngII infused animals. Oxygen delivery decreased by 50% after infusion of AngII and renal blood flow (RBF) fell by 3.3 ml min−1

3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

Energy Technology Data Exchange (ETDEWEB)

Lagerloef, Jakob H.; Kindblom, Jon; Bernhardt, Peter [Department of Radiation Physics, Goeteborg University, Goeteborg 41345 (Sweden); Department of Oncology, Sahlgrenska University Hospital, Goeteborg 41345 (Sweden); Department of Radiation Physics, Goeteborg University, Goeteborg, Sweden and Department of Nuclear Medicine, Sahlgrenska University Hospital, Goeteborg 41345 (Sweden)

2011-08-15

Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2

Perfluorocarbon-Loaded Lipid Nanocapsules to Assess the Dependence of U87-Human Glioblastoma Tumor pO2 on In Vitro Expansion Conditions.

Science.gov (United States)

Lemaire, Laurent; Nel, Janske; Franconi, Florence; Bastiat, Guillaume; Saulnier, Patrick

2016-01-01

Growing tumor cell lines, such as U87-MG glioma cells, under mild hypoxia (3% O2) leads to a ca. 40% reduction in growth rate once implanted in the brain of nude mice, as compared to normoxia (21% O2) grown cells, wherein the former over-express HIF-1 and VEGF-A. Despite developing differently, the tumors have similar: blood perfusion, oxygen consumption, and vascular surface area parameters, whereas the number of blood vessels is nearly doubled in the tumor arising from normoxia cultured cells. Interestingly, tumor oxygen tension, measured using 19F-oximetry, showed that the normoxia grown cells led to tumors characterized by mild hypoxic environment (approximately 4%) conditions, whilst the hypoxia grown cells led to tumors characterized by physioxic environment (approximately 6%) conditions. This reversal in oxygen concentration may be responsible for the apparent paradoxical growth profiles.

An Automatic Occlusion Device for Remote Control of Tumor Tissue Ischemia

Science.gov (United States)

El-Dahdah, Hamid; Wang, Bei; He, Guanglong; Xu, Ronald X.

2015-01-01

We developed an automatic occlusion device for remote control of tumor tissue ischemia. The device consists of a flexible cannula encasing a shape memory alloy wire with its distal end connected to surgical suture. Regional tissue occlusion was tested on both the benchtop and the animal models. In the benchtop test, the occlusion device introduced quantitative and reproducible changes of blood flow in a tissue simulating phantom embedding a vessel simulator. In the animal test, the device generated a cyclic pattern of reversible ischemia in the right hinder leg tissue of a black male C57BL/6 mouse. We also developed a multimodal detector that integrates near infrared spectroscopy and electron paramagnetic resonance spectroscopy for continuous monitoring of tumor tissue oxygenation, blood content, and oxygen tension changes. The multimodal detector was tested on a cancer xenograft nude mouse undergoing reversible tumor ischemia. The automatic occlusion device and the multi-modal detector can be potentially integrated for closed-loop feedback control of tumor tissue ischemia. Such an integrated occlusion device may be used in multiple clinical applications such as regional hypoperfusion control in tumor resection surgeries and thermal ablation processes. In addition, the proposed occlusion device can also be used as a research tool to understand tumor oxygen transport and hemodynamic characteristics. PMID:20082532

Oxygen, nitric oxide and articular cartilage

Directory of Open Access Journals (Sweden)

B Fermor

2007-04-01

Full Text Available Molecular oxygen is required for the production of nitric oxide (NO, a pro-inflammatory mediator that is associated with osteoarthritis and rheumatoid arthritis. To date there has been little consideration of the role of oxygen tension in the regulation of nitric oxide production associated with arthritis. Oxygen tension may be particularly relevant to articular cartilage since it is avascular and therefore exists at a reduced oxygen tension. The superficial zone exists at approximately 6% O2, while the deep zone exists at less than 1% O2. Furthermore, oxygen tension can alter matrix synthesis, and the material properties of articular cartilage in vitro.The increase in nitric oxide associated with arthritis can be caused by pro-inflammatory cytokines and mechanical stress. Oxygen tension significantly alters endogenous NO production in articular cartilage, as well as the stimulation of NO in response to both mechanical loading and pro-inflammatory cytokines. Mechanical loading and pro-inflammatory cytokines also increase the production of prostaglandin E2 (PGE2. There is a complex interaction between NO and PGE2, and oxygen tension can alter this interaction. These findings suggest that the relatively low levels of oxygen within the joint may have significant influences on the metabolic activity, and inflammatory response of cartilage as compared to ambient levels. A better understanding of the role of oxygen in the production of inflammatory mediators in response to mechanical loading, or pro-inflammatory cytokines, may aid in the development of strategies for therapeutic intervention in arthritis.

Modelling of L-valine Repeated Fed-batch Fermentation Process Taking into Account the Dissolved Oxygen Tension

Directory of Open Access Journals (Sweden)

Tzanko Georgiev

2009-03-01

Full Text Available This article deals with synthesis of dynamic unstructured model of variable volume fed-batch fermentation process with intensive droppings for L-valine production. The presented approach of the investigation includes the following main procedures: description of the process by generalized stoichiometric equations; preliminary data processing and calculation of specific rates for main kinetic variables; identification of the specific rates takes into account the dissolved oxygen tension; establishment and optimisation of dynamic model of the process; simulation researches. MATLAB is used as a research environment.

Comparing CT perfusion with oxygen partial pressure in a rabbit VX2 soft-tissue tumor model

International Nuclear Information System (INIS)

Sun Changjin; Li Chao; Lv Haibo

2014-01-01

The aim of this study was to evaluate the oxygen partial pressure of the rabbit model of the VX2 tumor using a 64-slice perfusion CT and to compare the results with that obtained using the oxygen microelectrode method. Perfusion CT was performed for 45 successfully constructed rabbit models of a VX2 brain tumor. The perfusion values of the brain tumor region of interest, the blood volume (BV), the time to peak (TTP) and the peak enhancement intensity (PEI) were measured. The results were compared with the partial pressure of oxygen (PO2) of that region of interest obtained using the oxygen microelectrode method. The perfusion values of the brain tumor region of interest in 45 successfully constructed rabbit models of a VX2 brain tumor ranged from 1.3–127.0 (average, 21.1 ± 26.7 ml/min/ml); BV ranged from 1.2–53.5 ml/100g (average, 22.2 ± 13.7 ml/100g); PEI ranged from 8.7–124.6 HU (average, 43.5 ± 28.7 HU); and TTP ranged from 8.2–62.3 s (average, 38.8 ± 14.8 s). The PO2 in the corresponding region ranged from 0.14–47 mmHg (average, 16 ± 14.8 mmHg). The perfusion CT positively correlated with the tumor PO2, which can be used for evaluating the tumor hypoxia in clinical practice. (author)

Comparing CT perfusion with oxygen partial pressure in a rabbit VX2 soft-tissue tumor model.

Science.gov (United States)

Sun, Chang-Jin; Li, Chao; Lv, Hai-Bo; Zhao, Cong; Yu, Jin-Ming; Wang, Guang-Hui; Luo, Yun-Xiu; Li, Yan; Xiao, Mingyong; Yin, Jun; Lang, Jin-Yi

2014-01-01

The aim of this study was to evaluate the oxygen partial pressure of the rabbit model of the VX2 tumor using a 64-slice perfusion CT and to compare the results with that obtained using the oxygen microelectrode method. Perfusion CT was performed for 45 successfully constructed rabbit models of a VX2 brain tumor. The perfusion values of the brain tumor region of interest, the blood volume (BV), the time to peak (TTP) and the peak enhancement intensity (PEI) were measured. The results were compared with the partial pressure of oxygen (PO2) of that region of interest obtained using the oxygen microelectrode method. The perfusion values of the brain tumor region of interest in 45 successfully constructed rabbit models of a VX2 brain tumor ranged from 1.3-127.0 (average, 21.1 ± 26.7 ml/min/ml); BV ranged from 1.2-53.5 ml/100g (average, 22.2 ± 13.7 ml/100g); PEI ranged from 8.7-124.6 HU (average, 43.5 ± 28.7 HU); and TTP ranged from 8.2-62.3 s (average, 38.8 ± 14.8 s). The PO2 in the corresponding region ranged from 0.14-47 mmHg (average, 16 ± 14.8 mmHg). The perfusion CT positively correlated with the tumor PO2, which can be used for evaluating the tumor hypoxia in clinical practice.

Optic nerve oxygenation

DEFF Research Database (Denmark)

Stefánsson, Einar; Pedersen, Daniella Bach; Jensen, Peter Koch

2005-01-01

The oxygen tension of the optic nerve is regulated by the intraocular pressure and systemic blood pressure, the resistance in the blood vessels and oxygen consumption of the tissue. The oxygen tension is autoregulated and moderate changes in intraocular pressure or blood pressure do not affect...... the optic nerve oxygen tension. If the intraocular pressure is increased above 40 mmHg or the ocular perfusion pressure decreased below 50 mmHg the autoregulation is overwhelmed and the optic nerve becomes hypoxic. A disturbance in oxidative metabolism in the cytochromes of the optic nerve can be seen...... at similar levels of perfusion pressure. The levels of perfusion pressure that lead to optic nerve hypoxia in the laboratory correspond remarkably well to the levels that increase the risk of glaucomatous optic nerve atrophy in human glaucoma patients. The risk for progressive optic nerve atrophy in human...

Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow.

Science.gov (United States)

Emans, Tonja W; Janssen, Ben J; Pinkham, Maximilian I; Ow, Connie P C; Evans, Roger G; Joles, Jaap A; Malpas, Simon C; Krediet, C T Paul; Koeners, Maarten P

2016-11-01

Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary. We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats. This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation. Exogenous angiotensin-II reduced renal cortical tissue PO2 more than equi-pressor doses of phenylephrine, probably because it reduced renal oxygen delivery more than did phenylephrine. Activation of the endogenous renin-angiotensin system in transgenic Cyp1a1Ren2 rats reduced cortical tissue PO2; in this model renal hypoxia precedes the development of structural pathology and can be reversed acutely by an angiotensin-II receptor type 1 antagonist. Angiotensin-II promotes renal hypoxia, which may in turn contribute to its pathological effects during development of chronic kidney disease. We hypothesised that both exogenous and endogenous angiotensin-II (AngII) can decrease the partial pressure of oxygen (PO2) in the renal cortex of unrestrained rats, which might in turn contribute to the progression of chronic kidney disease. Rats were instrumented with telemeters equipped with a carbon paste electrode for continuous measurement of renal cortical tissue PO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PO2 was dose-dependently reduced by intravenous AngII. Reductions in PO2 were significantly greater than those induced by equi-pressor doses of phenylephrine. In anaesthetised rats, renal oxygen consumption was not affected, and filtration fraction was increased only in the AngII infused animals. Oxygen delivery decreased by 50% after infusion of AngII and renal blood flow (RBF) fell by 3.3 ml min -1 . Equi-pressor infusion of

Changes in tumor oxygenation during a combined treatment with fractionated irradiation and hyperthermia: an experimental study.

Science.gov (United States)

Zywietz, F; Reeker, W; Kochs, E

1997-01-01

To determine the influence of adjuvant hyperthermia on the oxygenation status of fractionated irradiated tumors. Oxygen partial pressure (pO2) in rat rhabdomyosarcomas (R1H) was measured sequentially at weekly intervals during a fractionated irradiation with 60Co-gamma-rays (60 Gy/20f/4 weeks) in combination with local hyperthermia (8 f(HT) at 43 degrees C, 1 h/4 weeks). Tumors were heated twice weekly with a 2450 MHz microwave device at 43 degrees C, 1 h starting 10 min after irradiation. The pO2 measurements (pO2-histograph, Eppendorf, Germany) were performed in anesthetized animals during mechanical ventilation and in hemodynamic steady state. All tumor pO2 measurements were correlated to measurements of the arterial oxygen partial pressure (paO2) determined by a blood gas analyzer. The oxygenation status of R1H tumors decreased continuously from the start of the combined treatment, with increasing radiation dose and number of heat fractions. In untreated controls a median tumor pO2 of 23 +/- 2 mmHg (mean +/- SEM) was measured. Tumor pO2 decreased to 11 +/- 2 mmHg after 30 Gy + 4 HT (2 weeks), and to 6 +/- 2 mmHg after 60 Gy + 8HT (4 weeks). The increase in the frequency of pO2-values below 5 mmHg and the decrease in the range of the pO2 histograms [delta p(10/90)] further indicated that tumor hypoxia increased relatively rapidly from the start of combined treatment. After 60 Gy + 8HT 48 +/- 5% (mean +/- SEM) of the pO2-values recorded were below 5 mmHg. These findings suggest that adjuvant hyperthermia to radiotherapy induces greater changes in tumor oxygenation than radiation alone [cf. (39)]. This might be of importance for the temporary application of hyperthermia in the course of a conventional radiation treatment.

Development of bovine embryos cultured in CR1aa and IVD101 media using different oxygen tensions and culture systems.

Science.gov (United States)

Somfai, Tamás; Inaba, Yasushi; Aikawa, Yoshio; Ohtake, Masaki; Kobayashi, Shuji; Konishi, Kazuyuki; Nagai, Takashi; Imai, Kei

2010-12-01

The aim of the present study was to optimise the culture conditions for the in vitro production of bovine embryos. The development of in vitro fertilised bovine oocytes in CR1aa supplemented with 5% calf serum and IVD101 culture media were compared using traditional microdrops and Well of the Well (WOW) culture systems either under 5% or 20% oxygen tension. After 7 days of culture, a significantly higher blastocyst formation rate was obtained for embryos cultured in CR1aa medium compared to those cultured in IVD101, irrespective of O2 tensions and culture systems. The blastocyst formation in IVD101 was suppressed under 20% O2 compared to 5% O2 . Despite their similar total cell numbers, higher rates of inner cell mass (ICM) cells were observed in blastocysts developed in IVD101 medium than in those developed in CR1aa, irrespective of O2 tensions. There was no significant difference in blastocyst formation, total, ICM and trophectoderm (TE) cell numbers between embryos obtained by microdrop and WOW culture systems irrespective of the culture media and O2 tensions used. In conclusion, CR1aa resulted in higher blastocyst formation rates irrespective of O2 tension, whereas IVD101 supported blastocyst formation only under low O2 levels but enhanced the proliferation of ICM cells.

Manipulation of tumor oxygenation and radiosensitivity through modification of cell respiration. A critical review of approaches and imaging biomarkers for therapeutic guidance.

Science.gov (United States)

Gallez, Bernard; Neveu, Marie-Aline; Danhier, Pierre; Jordan, Bénédicte F

2017-08-01

Tumor hypoxia has long been considered as a detrimental factor for the response to irradiation. In order to improve the sensitivity of tumors cells to radiation therapy, tumor hypoxia may theoretically be alleviated by increasing the oxygen delivery or by decreasing the oxygen consumption by tumor cells. Mathematical modelling suggested that decreasing the oxygen consumption should be more efficient than increasing oxygen delivery in order to alleviate tumor hypoxia. In this paper, we review several promising strategies targeting the mitochondrial respiration for which alleviation of tumor hypoxia and increase in sensitivity to irradiation have been demonstrated. Because the translation of these approaches into the clinical arena requires the use of pharmacodynamics biomarkers able to identify shift in oxygen consumption and tumor oxygenation, we also discuss the relative merits of imaging biomarkers (Positron Emission Tomography and Magnetic Resonance) that may be used for therapeutic guidance. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. Copyright © 2017 Elsevier B.V. All rights reserved.

Diet-induced weight loss decreases adipose tissue oxygen tension with parallel changes in adipose tissue phenotype and insulin sensitivity in overweight humans

NARCIS (Netherlands)

Vink, R.G.; Roumans, N.J.; Čajlaković, M.; Cleutjens, J.P.M.; Boekschoten, M.V.; Fazelzadeh, P.; Vogel, M.A.A.; Blaak, E.E.; Mariman, E.C.; Baak, van M.A.; Goossens, G.H.

2017-01-01

Background/objectives: Although adipose tissue (AT) hypoxia is present in rodent models of obesity, evidence for this in humans is limited. Here, we investigated the effects of diet-induced weight loss (WL) on abdominal subcutaneous AT oxygen tension (pO 2), AT blood flow (ATBF), AT capillary

Comparison of Preterm and Term Wharton's Jelly-Derived Mesenchymal Stem Cell Properties in Different Oxygen Tensions.

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Balgi-Agarwal, Saloni; Winter, Caitlyn; Corral, Alexis; Mustafa, Shamimunisa B; Hornsby, Peter; Moreira, Alvaro

2018-06-27

Mesenchymal stem cells (MSCs) have shown promise as therapeutic agents in treating morbidities associated with premature birth. MSCs derived from the human umbilical cord are easy to isolate and have low immunogenicity and a robust ability to secrete paracrine factors. To date, there are no studies evaluating preterm versus term umbilical cord tissue-derived MSCs. Therefore, our aim was twofold: (1) to compare stem cell properties in preterm versus term MSCs and (2) to examine the impact of oxygen tension on stem cell behavior. Umbilical cord tissue was obtained from 5 preterm and 5 term neonates. The cells were isolated and characterized as MSCs in accordance with the International Society for Cellular Therapy. We exposed MSCs to different oxygen tensions to examine the impact of environmental factors on cell performance. We studied the following stem cell properties: (i) motility, (ii) proliferation, (iii) senescence, (iv) cell viability, (v) colony-forming unit efficiency, and (vi) inflammatory cytokine expression. Under normoxia (21% O2), cells from preterm and term infants had similar properties. Under hypoxic conditions (1% O2), term MSCs had better cell proliferation; however, cells exposed to hyperoxia (90% O2) had the slowest motility and lowest cell viability (p cytokine expression between the groups. The term cells demonstrated more colony-forming efficiency than the preterm cells. In sum, our preliminary findings suggest that MSCs derived from term and preterm umbilical cords have similar characteristics, offering the potential of future autologous/allogeneic MSC transplants in neonates. © 2018 S. Karger AG, Basel.

Noninvasive diffuse optical monitoring of head and neck tumor blood flow and oxygenation during radiation delivery

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Dong, Lixin; Kudrimoti, Mahesh; Cheng, Ran; Shang, Yu; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

2012-01-01

This study explored using a novel diffuse correlation spectroscopy (DCS) flow-oximeter to noninvasively monitor blood flow and oxygenation changes in head and neck tumors during radiation delivery. A fiber-optic probe connected to the DCS flow-oximeter was placed on the surface of the radiologically/clinically involved cervical lymph node. The DCS flow-oximeter in the treatment room was remotely operated by a computer in the control room. From the early measurements, abnormal signals were observed when the optical device was placed in close proximity to the radiation beams. Through phantom tests, the artifacts were shown to be caused by scattered x rays and consequentially avoided by moving the optical device away from the x-ray beams. Eleven patients with head and neck tumors were continually measured once a week over a treatment period of seven weeks, although there were some missing data due to the patient related events. Large inter-patient variations in tumor hemodynamic responses were observed during radiation delivery. A significant increase in tumor blood flow was observed at the first week of treatment, which may be a physiologic response to hypoxia created by radiation oxygen consumption. Only small and insignificant changes were found in tumor blood oxygenation, suggesting that oxygen utilizations in tumors during the short period of fractional radiation deliveries were either minimal or balanced by other effects such as blood flow regulation. Further investigations in a large patient population are needed to correlate the individual hemodynamic responses with the clinical outcomes for determining the prognostic value of optical measurements. PMID:22312579

Regional tumor oximetry: 19F NMR spectroscopy of hexafluorobenzene

International Nuclear Information System (INIS)

Hunjan, Sandeep; Mason, Ralph P.; Constantinescu, Anca; Peschke, Peter; Hahn, Eric W.; Antich, Peter P.

1998-01-01

Purpose: An accurate method for monitoring oxygen tension (pO 2 ) of individual tumors could be valuable for optimizing treatment plans. We have recently shown that 19 F nuclear magnetic resonance (NMR) spin-lattice relaxometry of hexafluorobenzene (HFB) provides a highly sensitive indicator of tumor oxygenation. We have now refined the methodology to provide enhanced precision, and applied the method to investigate dynamic changes in tumor oxygenation. Methods and Materials: Dunning prostate adenocarcinoma R3327-AT1 was grown in the form of pedicles on the foreback of male Copenhagen rats. When the tumors reached ≅1 cm diameter, HFB (20 μl) was administered, either centrally or peripherally, by direct intratumoral (IT) injection. Local pO 2 was determined using pulse-burst saturation recovery (PBSR) 19 F NMR spectroscopy on the basis of the spin-lattice relaxation rate, R1. Results: Interrogation of the central region of tumors provided typical values in the range pO 2 = 1.4-6.4 mmHg, with a typical stability of ±2 mmHg over a period of 20 min, when rats breathed 33% O 2 . Altering the inhaled gas to oxygen or carbogen (95% O 2 /5% CO 2 ) produced no significant change. In contrast, interrogation of tumor periphery indicated baseline pO 2 in the range 7.9-78.9 mmHg. Altering inspired gas produced significant changes (p 2 or carbogen, although the change was generally greater with carbogen. In each case, pO 2 returned to baseline within 16 min of returning the inhaled gas to baseline. Conclusion: We believe this method provides a valuable new approach with the requisite precision and accuracy to investigate tumor pO 2

Hemoglobin as a factor in the control of tumor oxygenation

International Nuclear Information System (INIS)

Hirst, D.G.

1987-01-01

The concentration of hemoglobin in the blood has been shown to have a market effect on the radiosensitivity of human and animal tumors. Experimental studies in mice indicate that radiosensitivity is influenced by a change in the hemoglobin level rather than by the absolute concentration. This dependence may be exploited to therapeutic advantage. Recent studies of hemoglobin/oxygen affinity have shown that the concentration of 2,3 diphosphoglycerate (2,3 DPG) affects tumor sensitivity to X-rays. Increased 2,3 DPG levels increase radiosensitivity in several mouse tumors. The time dependence of this effect remains to be established. The effective application of these effects in man may depend on the development of drugs which produce changes in hemoglobin affinity without the need for blood transfusions. Several drugs are currently being investigated

Measurements of partial oxygen pressure pO2 using the OxyLite system in R3327-AT tumors under isoflurane anesthesia.

Science.gov (United States)

Wen, Bixiu; Urano, Muneyasu; O'Donoghue, Joseph A; Ling, C Clifton

2006-09-01

The presence of oxygen-deficient tumor cells is a critical issue in cancer therapy. To identify tumor hypoxia, tissue partial oxygen pressure (pO2) can be measured directly. The OxyLite system allows determination of pO2 in tumors and permits continuous measurements of pO2 at a fixed point. In this study, this system was used to continuously measure pO2 in R3327-AT tumors in animals anesthetized with isoflurane. In addition, continuous pO2 measurement was performed in the muscle in non-tumor-bearing animals. In animals breathing isoflurane balanced by air, tumor pO2 at fixed positions decreased rapidly within 1-2 min of probe positioning but remained stable thereafter. In animals breathing isoflurane balanced by pure oxygen, tumor pO2 was higher and remained high. We also measured pO2 values at multiple positions in R3327-AT tumors of various sizes, with anesthetized animals breathing either air or pure oxygen. Our data showed that the frequency of pO2 measurements below 2.5 or 5.0 mmHg was significantly higher in animals breathing air than in animals breathing pure oxygen. Measurements in different-sized tumors showed that the mean pO2 value decreased as tumor volume increased, with the largest change occurring between tumor volumes of 100 and 200 mm3. Our data demonstrate that the OxyLite system, when used with isoflurane anesthesia, is a valuable tool in the study of tumor hypoxia.

Tumor reoxygenation by aqueous oxygen solutions and its role in cancer treatment with chemotherapy and radiation therapy

International Nuclear Information System (INIS)

Calderwood, S.K.

2003-01-01

Many tumors contain significant areas of hypoxia which cause resistance to tumor radiation therapy and chemotherapy. We have used perfusion into afferent arteries with super saturated aqueous oxygen solutions (AO) to re-oxygenate the hypoxic areas of experimental tumors with the aim of restoring sensitivity to treatment and enhancing cancer therapy. We first concentrated on examining the ability of AO infusion to reoxygenate the MAT B III 13762 rat carcinoma growing in the thighs of rats. In experiments on 33 AO infused tumors using Eppendorf microelectrode monitoring, we consistently observed a significant decrease in the fraction of tumor domains with O 2 less than 5mmHg before and after AO infusion. Significant tumor reoxygenation was observed in most tumors with a volume less than 2.5 cm 3 . We next examined 15 New Zealand white rabbits transplanted with the VX2 carcinoma. Tissue oxygen studies indicated that intramuscular rabbit VX-2 tumor has a consistently lower hypoxic fraction (O 2 2 <5mm Hg). Significant reoxygenation did occur in these infused tumors although the degree of reoxygenation was slightly less than in the rat MAT B III 13762 perhaps reflecting the lower hypoxic fraction. Further studies showed that AO could also be infused directly into tumors with a reduction of hypoxic fraction of between 60-90% Overall, the experiments show that AO infusion into either arterial or intratumor sites is a viable approach to tumor reoxygenation and preliminary studies indicate increase effectiveness in treatment with cyclophosphamide / AO combination

Closed Loop Control of Oxygen Delivery and Oxygen Generation

Science.gov (United States)

2017-08-01

were used for this study and were connected via a USB cable to allow communication. The ventilator was modified to allow closed loop control of oxygen...connected via a USB cable to allow communication. The ventilator was modified to allow closed loop control of oxygen based on the oxygen saturation...2017-4119, 28 Aug 2017. oximetry (SpO2) and intermittent arterial blood sampling for arterial oxygen tension (partial pressure of oxygen [PaO2]) and

Effects of breathing a hyperoxic hypercapnic gas mixture on blood oxygenation and vascularity of head-and-neck tumors as measured by magnetic resonance imaging

International Nuclear Information System (INIS)

Rijpkema, Mark; Kaanders, Johannes H.A.M.; Joosten, Frank; Kogel, Albert J. van der; Heerschap, Arend

2002-01-01

Purpose: For head-and-neck tumors, breathing a hyperoxic hypercapnic gas mixture and administration of nicotinamide has been shown to result in a significantly improved tumor response to accelerated radiotherapy (ARCON, Accelerated Radiotherapy with CarbOgen and Nicotinamide). This may be caused by improved tumor oxygenation, possibly mediated by vascular effects. In this study, both blood oxygenation and vascular effects of breathing a hyperoxic hypercapnic gas mixture (98% O 2 +2% CO 2 ) were assessed by magnetic resonance imaging (MRI) in patients with head-and-neck tumors. Methods and Materials: Tumor vascularity and oxygenation were investigated by dynamic gadolinium contrast-enhanced MRI and blood oxygen level dependent (BOLD) MRI, respectively. Eleven patients with primary head-and-neck tumors were each measured twice; with and without breathing the hyperoxic hypercapnic gas mixture. Results: BOLD MR imaging revealed a significant increase of the MRI time constant of transverse magnetization decay (T 2 *) in the tumor during hypercapnic hyperoxygenation, which correlates to a decrease of the deoxyhemoglobin concentration. No changes in overall tumor vascularity were observed, as measured by the gadolinium contrast uptake rate in the tumor. Conclusion: Breathing a hyperoxic hypercapnic gas mixture improves tumor blood oxygenation in patients with head-and-neck tumors, which may contribute to the success of the ARCON therapy

Singlet oxygen explicit dosimetry to predict long-term local tumor control for Photofrin-mediated photodynamic therapy

Science.gov (United States)

Penjweini, Rozhin; Kim, Michele M.; Ong, Yi Hong; Zhu, Timothy C.

2017-02-01

Although photodynamic therapy (PDT) is an established modality for the treatment of cancer, current dosimetric quantities do not account for the variations in PDT oxygen consumption for different fluence rates (φ). In this study we examine the efficacy of reacted singlet oxygen concentration ([1O2]rx) to predict long-term local control rate (LCR) for Photofrin-mediated PDT. Radiation-induced fibrosarcoma (RIF) tumors in the right shoulders of female C3H mice are treated with different in-air fluences of 225-540 J/cm2 and in-air fluence rate (φair) of 50 and 75 mW/cm2 at 5 mg/kg Photofrin and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 630 nm wavelength. [1O2]rx is calculated by using a macroscopic model based on explicit dosimetry of Photofrin concentration, tissue optical properties, tissue oxygenation and blood flow changes during PDT. The tumor volume of each mouse is tracked for 90 days after PDT and Kaplan-Meier analyses for LCR are performed based on a tumor volume defined as a temporal integral of photosensitizer concentration and Φ at a 3 mm tumor depth. φ is calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. Our preliminary studies show that [1O2]rx is the best dosimetric quantity that can predict tumor response and correlate with LCR. Moreover, [1O2]rx calculated using the blood flow changes was in agreement with [1O2]rx calculated based on the actual tissue oxygenation.

IVF/ICSI outcomes after culture of human embryos at low oxygen tension: a meta-analysis

Directory of Open Access Journals (Sweden)

Gomes Sobrinho David B

2011-11-01

Full Text Available Abstract Background Improved pregnancy, implantation, and birth rates have been reported after the use of reduced O2 concentration during embryo culture, mainly due to a reduction of the cumulative detrimental effects of reactive oxygen species. However, some studies have failed to report any positive effects. The objective of this meta-analysis was to evaluate the effect of a low-O2 environment on IVF/intracytoplasmic sperm injection (ICSI outcomes. Methods All available published and ongoing randomised trials that compared the effects of low (~5%; OC~5 and atmospheric (~20%; OC~20 oxygen concentrations on IVF/ICSI outcomes were included. Search strategies included online surveys of databases from 1980 to 2011. The outcomes measured were fertilisation rate, implantation rate and ongoing pregnancy rates. The fixed effects model was used to calculate the odds ratio. Results Seven studies were included in this analysis. The pooled fertilisation rate did not differ significantly (P = 0.54 between the group of oocytes cultured at low O2 tension and the group at atmospheric O2 tension. Concerning all cycles, the implantation (P = 0.06 and ongoing pregnancy (P = 0.051 rates were not significantly different between the group receiving transferred sets containing only OC~5 embryos and the group receiving transferred sets with only OC~20 embryos. In a meta-analysis performed for only those trials in which embryos were transferred on day 2/3, implantation (P = 0.63 and ongoing pregnancy (P = 0.19 rates were not significantly different between the groups. In contrast, when a meta-analysis was performed using only trials in which embryos were transferred on days 5 and 6 (at the blastocyst stage, the group with transferred sets of only OC~5 embryos showed a statistically significantly higher implantation rate (P = 0.006 than the group receiving transferred sets with only OC~20 embryos, although the ongoing pregnancy (P = 0.19 rates were not significantly

Oxygen tension regulates the miRNA profile and bioactivity of exosomes released from extravillous trophoblast cells - Liquid biopsies for monitoring complications of pregnancy.

Directory of Open Access Journals (Sweden)

Grace Truong

Full Text Available Our understanding of how cells communicate has undergone a paradigm shift since the recent recognition of the role of exosomes in intercellular signaling. In this study, we investigated whether oxygen tension alters the exosome release and miRNA profile from extravillous trophoblast (EVT cells, modifying their bioactivity on endothelial cells (EC. Furthermore, we have established the exosomal miRNA profile at early gestation in women who develop pre-eclampsia (PE and spontaneous preterm birth (SPTB. HTR-8/SVneo cells were used as an EVT model. The effect of oxygen tension (i.e. 8% and 1% oxygen on exosome release was quantified using nanocrystals (Qdot® coupled to CD63 by fluorescence NTA. A real-time, live-cell imaging system (Incucyte™ was used to establish the effect of exosomes on EC. Plasma samples were obtained at early gestation (<18 weeks and classified according to pregnancy outcomes. An Illumina TrueSeq Small RNA kit was used to construct a small RNA library from exosomal RNA obtained from EVT and plasma samples. The number of exosomes was significantly higher in EVT cultured under 1% compared to 8% oxygen. In total, 741 miRNA were identified in exosomes from EVT. Bioinformatic analysis revealed that these miRNA were associated with cell migration and cytokine production. Interestingly, exosomes isolated from EVT cultured at 8% oxygen increased EC migration, whilst exosomes cultured at 1% oxygen decreased EC migration. These changes were inversely proportional to TNF-α released from EC. Finally, we have identified a set of unique miRNAs in exosomes from EVT cultured at 1% oxygen and exosomes isolated from the circulation of mothers at early gestation, who later developed PE and SPTB. We suggest that aberrant exosomal signalling by placental cells is a common aetiological factor in pregnancy complications characterised by incomplete SpA remodeling and is therefore a clinically relevant biomarker of pregnancy complications.

Injectable LiNc-BuO loaded microspheres as in vivo EPR oxygen sensors after co-implantation with tumor cells.

Science.gov (United States)

Frank, Juliane; Gündel, Daniel; Drescher, Simon; Thews, Oliver; Mäder, Karsten

2015-12-01

Electron paramagnetic resonance (EPR) oximetry is a technique which allows accurate and repeatable oxygen measurements. We encapsulated a highly oxygen sensitive particulate EPR spin probe into microparticles to improve its dispersibility and, hence, facilitate the administration. These biocompatible, non-toxic microspheres contained 5-10 % (w/w) spin probe and had an oxygen sensitivity of 0.60 ± 0.01 µT/mmHg. To evaluate the performance of the microparticles as oxygen sensors, they were co-implanted with syngeneic tumor cells in 2 different rat strains. Thus, tissue injury was avoided and the microparticles were distributed all over the tumor tissue. Dynamic changes of the intratumoral oxygen partial pressure during inhalation of 8 %, 21 %, or 100 % oxygen were monitored in vivo by EPR spectroscopy and quantified. Values were verified in vivo by invasive fluorometric measurements using Oxylite probes and ex vivo by pimonidazole adduct accumulation. There were no hints that the tumor physiology or tissue oxygenation had been altered by the microparticles. Hence, these microprobes offer great potential as oxygen sensors in preclinical research, not only for EPR spectroscopy but also for EPR imaging. For instance, the assessment of tissue oxygenation during therapeutic interventions might help understanding pathophysiological processes and lead to an individualized treatment planning or the use of formulations with hypoxia triggered release of active agents. Copyright © 2015 Elsevier Inc. All rights reserved.

Oxygen dependency of porfiromycin cytotoxicity

International Nuclear Information System (INIS)

Marshall, R.S.; Rauth, A.M.

1987-01-01

The authors determined the oxygen dependency of toxicity for the bioreductive alkylating agents mitomycin C (MMC) and porfiromycin (PM) to investigate whether the toxicities of these agents increase in the range of oxygen tensions over which cells become increasingly radioresistant. In the present work the oxygen dependency of PM in CHO cells was determined by assaying survival as a function of time of exposure to 1.0 μg/ml PM under various known levels of oxygen. While PM demonstrated preferential hypoxic cell toxicity, aerobic cell survival was reduced ten-fold after five hours of exposure. Conversely, PM toxicity after a five hour hypoxic exposure to <0.001% oxygen appeared to be greater than that observed for similar MMC exposures, suggesting that PM may be more selective than MMC in killing hypoxic rather than aerobic cells. The authors are currently investigating this preferential toxicity in two human cell lines, one of which is resistant to these agents. At present, these observations suggest that PM may be more effective than MMC at destroying tumour cells in regions of intermediate and low oxygen tensions which may survive radiotherapy, though the range of oxygen tensions which mediate toxicity is similar for both agents

Radiobiological studies on the importance of tumor oxygenation for anti-neoplastic therapy

International Nuclear Information System (INIS)

Grau, C.

1994-01-01

The aim of the twelve studies included in the present thesis was to determine the importance of hypoxia for various anti-neoplastic treatment modalities, and to evaluate possible ways of overcoming the hypoxia problem by combined modality therapy. The murine tumor systems were the C3H mammary carcinoma with 5-12% hypoxic cells, and the SCCVII squamous cell carcinoma with 2% hypoxic cells. The radiation response was significantly improved by the use of hypoxic cell radiosensitizers such as nimorazole or misonidazole, or by allowing the mice to breathe oxygen or carbogen during irradiation. In contrast, the radiation response was significantly impaired by carbon monoxide breathing at a level comparable to what has been observed in heavy smokers. The clamped TCD 50 assay was used to classify cancer chemotherapeutic drugs according to their preferential cytotoxicity towards the different tumor subpopulations. Methotrexate had no effect on hypoxic cells and was only borderline toxic towards aerobic cells. Three drugs had significant effect against oxic cells only (5-fluorouracil, bleomycin and cisplatin). Similarly, three drugs were toxic towards hypoxic cells only (etoposide, carmustine, and mitomycin c). Three drugs were effective towards both cell types (vincristine, adriamycin, cyclophosphamide). Hypoxic cells in areas with insufficient blood supply, poor nutrition and increased acidity is known to be highly sensitive to hyperthermia. In a study where cisplatin, heat and x-rays were given together, the local tumor control was not improved when compared to radiation + heat, apparently due to a lack of enhancement in the killing of hypoxic cells. These studies have demonstrated the influence of tumor oxygenation on tumor response to treatment with drugs, hyperthermia and irradiation. New strategies targeted also against perfusion-limited hypoxia is needed. One of the most important conclusions from the present thesis can be implemented without expensive trials or

The role of tissue oxygen tension in the control of local blood flow in the microcirculation of skeletal muscles

DEFF Research Database (Denmark)

Ngo, Thuc Anh

2010-01-01

In the microcirculation blood flow is highly regulated dependent on the metabolic activity of the tissues. Among several mechanisms, mechanisms involved in the coupling of changes in tissue oxygen tension due to changes in the metabolic activity of the tissue play an important role. In the systemic...... (inhibitor of KATP channels) in the superfusate abolished both vasodilatation and constriction to low and high oxygen superfusate, indicating that KATP channels are involved in both hypoxic vasodilatation and hyperoxic vasoconstriction. Red blood cells (RBCs) have been proposed to release ATP and...... as in the intact blood-perfused arteriole. This indicates that RBCs are not essential for hypoxic vasodilatation. In addition several potential pathways were evaluated. Application of DPCPX (inhibitor of adenosine A1 and A2 receptors) and L-NAME (inhibitor of NO-synthase) did not affect vasomotor responses to low...

Paradox between angiogenesis and oxygen effect in the treatment of tumor

International Nuclear Information System (INIS)

Hayashi, Masanobu

2008-01-01

The paradox in the title is described on recent findings concerning the effects of anti-angiogenetic drugs on possible radiation resistance and sensitivity of tumor tissue. Suppression of angiogenesis leads to inhibition of tumor growth, based on which anti-tumor drugs like anti- vascular endotherial growth factor (VEGF) antibody bevacizumab to suppress the genesis have been developed and clinically used, but they conceivably increase the population of hypoxic tumor cells. Those drugs are essentially used in combination with other chemotherapeutic agents and/or radiation. Hypoxic tumor cells present in the tissue are generally radioresistant. There are reported findings, however, that the drugs sometimes elevate the efficacy of radiotherapy, which hypothesizes that the drugs induces a proangiogenetic state, where increased level of growth factors in the tissue is reduced to normalize the vasculature and thereby reoxygenation occurs, the oxygen effect. Because copper is a cofactor of growth factors like VEGF and basic fibroblast growth factor (bFGF) and essential for angiogenesis, authors have studied the effect of a Cu-chelator, trientine, on transplanted mouse tumors which has been shown to induce apoptosis of the target cells. Combination of the chelator with X-ray irradiation is found effective in tumor growth inhibition and in survival increase. For more effective combination therapy, the interaction occurring in combinations of regimen should be elucidated. (R.T.)

Hypoxia Pathway Proteins As Central Mediators of Metabolism in the Tumor Cells and Their Microenvironment

Directory of Open Access Journals (Sweden)

Sundary Sormendi

2018-01-01

Full Text Available Low oxygen tension or hypoxia is a determining factor in the course of many different processes in animals, including when tissue expansion and cellular metabolism result in high oxygen demands that exceed its supply. This is mainly happening when cells actively proliferate and the proliferating mass becomes distant from the blood vessels, such as in growing tumors. Metabolic alterations in response to hypoxia can be triggered in a direct manner, such as the switch from oxidative phosphorylation to glycolysis or inhibition of fatty acid desaturation. However, as the modulated action of hypoxia-inducible factors or the oxygen sensors (prolyl hydroxylase domain-containing enzymes can also lead to changes in enzyme expression, these metabolic changes can also be indirect. With this review, we want to summarize our current knowledge of the hypoxia-induced changes in metabolism during cancer development, how they are affected in the tumor cells and in the cells of the microenvironment, most prominently in immune cells.

Method for the determination of oxygen consumption rates and diffusion coefficients in multicellular spheroids

OpenAIRE

Mueller-Klieser, W.

1984-01-01

A method has been developed for the quantitative evaluation of oxygen tension (PO2) distributions in multicellular spheroids measured with O2-sensitive microelectrodes. The experimental data showed that multicellular tumor spheroids in stirred growth media were characterized by a diffusion-depleted zone surrounding the spheroids. This zone was elicited by an unstirred layer of medium next to the spheroid leading to a continuous decrease in the PO2 values from the bulk medium towards the spher...

Near-simultaneous hemoglobin saturation and oxygen tension maps in mouse brain using an AOTF microscope.

Science.gov (United States)

Shonat, R D; Wachman, E S; Niu, W; Koretsky, A P; Farkas, D L

1997-09-01

A newly developed microscope using acousto-optic tunable filters (AOTFs) was used to generate in vivo hemoglobin saturation (SO2) and oxygen tension (PO2) maps in the cerebral cortex of mice. SO2 maps were generated from the spectral analysis of reflected absorbance images collected at different wavelengths, and PO2 maps were generated from the phosphorescence lifetimes of an injected palladium-porphyrin compound using a frequency-domain measurement. As the inspiratory O2 was stepped from hypoxia (10% O2), through normoxia (21% O2), to hyperoxia (60% O2), measured SO2 and PO2 levels rose accordingly and predictably throughout. A plot of SO2 versus PO2 in different arterial and venous regions of the pial vessels conformed to the sigmoidal shape of the oxygen-hemoglobin dissociation curve, providing further validation of the two mapping procedures. The study demonstrates the versatility of the AOTF microscope for in vivo physiologic investigation, allowing for the generation of nearly simultaneous SO2 and PO2 maps in the cerebral cortex, and the frequency-domain detection of phosphorescence lifetimes. This class of study opens up exciting new possibilities for investigating the dynamics of hemoglobin and O2 binding during functional activation of neuronal tissues.

Activated Macrophages as a Novel Determinant of Tumor Cell Radioresponse: The Role of Nitric Oxide-Mediated Inhibition of Cellular Respiration and Oxygen Sparing

International Nuclear Information System (INIS)

Jiang Heng; De Ridder, Mark; Verovski, Valeri N.; Sonveaux, Pierre; Jordan, Benedicte F.; Law, Kalun; Monsaert, Christinne; Van den Berge, Dirk L.; Verellen, Dirk; Feron, Olivier; Gallez, Bernard; Storme, Guy A.

2010-01-01

Purpose: Nitric oxide (NO), synthesized by the inducible nitric oxide synthase (iNOS), is known to inhibit metabolic oxygen consumption because of interference with mitochondrial respiratory activity. This study examined whether activation of iNOS (a) directly in tumor cells or (b) in bystander macrophages may improve radioresponse through sparing of oxygen. Methods and Materials: EMT-6 tumor cells and RAW 264.7 macrophages were exposed to bacterial lipopolysaccharide plus interferon-γ, and examined for iNOS expression by reverse transcription polymerase chain reaction, Western blotting and enzymatic activity. Tumor cells alone, or combined with macrophages were subjected to metabolic hypoxia and analyzed for radiosensitivity by clonogenic assay, and for oxygen consumption by electron paramagnetic resonance and a Clark-type electrode. Results: Both tumor cells and macrophages displayed a coherent picture of iNOS induction at transcriptional/translational levels and NO/nitrite production, whereas macrophages showed also co-induction of the inducible heme oxygenase-1, which is associated with carbon monoxide (CO) and bilirubin production. Activation of iNOS in tumor cells resulted in a profound oxygen sparing and a 2.3-fold radiosensitization. Bystander NO-producing, but not CO-producing, macrophages were able to block oxygen consumption by 1.9-fold and to radiosensitize tumor cells by 2.2-fold. Both effects could be neutralized by aminoguanidine, a metabolic iNOS inhibitor. An improved radioresponse was clearly observed at macrophages to tumor cells ratios ranging between 1:16 to 1:1. Conclusions: Our study is the first, as far as we are aware, to provide evidence that iNOS may induce radiosensitization through oxygen sparing, and illuminates NO-producing macrophages as a novel determinant of tumor cell radioresponse within the hypoxic tumor microenvironment.

Membrane culture and reduced oxygen tension enhances cartilage matrix formation from equine cord blood mesenchymal stromal cells in vitro.

Science.gov (United States)

Co, C; Vickaryous, M K; Koch, T G

2014-03-01

Ongoing research is aimed at increasing cartilage tissue yield and quality from multipotent mesenchymal stromal cells (MSC) for the purpose of treating cartilage damage in horses. Low oxygen culture has been shown to enhance chondrogenesis, and novel membrane culture has been proposed to increase tissue yield and homogeneity. The objective of this study was to evaluate and compare the effect of reduced oxygen and membrane culture during in vitro chondrogenesis of equine cord blood (CB) MSC. CB-MSC (n = 5 foals) were expanded at 21% oxygen prior to 3-week differentiation in membrane or pellet culture at 5% and 21% oxygen. Assessment included histological examination (H&E, toluidine Blue, immunohistochemistry (IHC) for collagen type I and II), protein quantification by hydroxyproline assay and dimethylmethylene assay, and mRNA analysis for collagen IA1, collagen IIA1, collagen XA1, HIF1α and Sox9. Among treatment groups, 5% membrane culture produced neocartilage most closely resembling hyaline cartilage. Membrane culture resulted in increased wet mass, homogenous matrix morphology and an increase in total collagen content, while 5% oxygen culture resulted in higher GAG and type II collagen content. No significant differences were observed for mRNA analysis. Membrane culture at 5% oxygen produces a comparatively larger amount of higher quality neocartilage. Matrix homogeneity is attributed to a uniform diffusion gradient and reduced surface tension. Membrane culture holds promise for scale-up for therapeutic purposes, for cellular preconditioning prior to cytotherapeutic applications, and for modeling system for gas-dependent chondrogenic differentiation studies. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Singlet oxygen explicit dosimetry to predict local tumor control for HPPH-mediated photodynamic therapy

Science.gov (United States)

Penjweini, Rozhin; Kim, Michele M.; Ong, Yi Hong; Zhu, Timothy C.

2017-02-01

This preclinical study examines four dosimetric quantities (light fluence, photosensitizer photobleaching ratio, PDT dose, and reacted singlet oxygen ([1O2]rx)) to predict local control rate (LCR) for 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH)-mediated photodynamic therapy (PDT). Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated with different in-air fluences (135, 250 and 350 J/cm2) and in-air fluence rates (50, 75 and 150 mW/cm2) at 0.25 mg/kg HPPH and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 665 nm wavelength. A macroscopic model was used to calculate ([1O2]rx)) based on in vivo explicit dosimetry of the initial tissue oxygenation, photosensitizer concentration, and tissue optical properties. PDT dose was defined as a temporal integral of drug concentration and fluence rate (φ) at a 3 mm tumor depth. Light fluence rate was calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. The tumor volume of each mouse was tracked for 30 days after PDT and Kaplan-Meier analyses for LCR were performed based on a tumor volume <=100 mm3, for four dose metrics: fluence, HPPH photobleaching rate, PDT dose, and ([1O2]rx)). The results of this study showed that ([1O2]rx)) is the best dosimetric quantity that can predict tumor response and correlate with LCR.

Critical oxygen tension and the effect of hypoxia on the oxygen consumption of the striped catfish, Pangasius hypophthaimos (Pangasiidae)

DEFF Research Database (Denmark)

Lefevre, S.; Bayley, Mark; Wang, Tobias

2008-01-01

The striped catfish (Pangasius hypophthalmus) is an air-breathing teleost that uses a modified swim bladder for aerial gas exchange. Pangasius is of enormous importance for aquaculture industry in the Mekong Delta(Vietnam), but little is known about its physiology. We have initiated a series...... consumption (VO2), measured with intermittent closed respirometry, was 67.8 ± 5.1 mLO2/kg/h when the fish were maintained without access to air at 27 °C. The critical oxygen tension (Pcrit) at these conditions was 57.9 ± 8.9 mmHg (N = 7). The metabolic response to aquatic hypoxia was studied in fish subjected....... The ontogenetic effect of environmental PO2 on metabolism is currently under investigation with fish being reared in 30%, 60% and 100% saturation. Data on resting VO2and Pcrit will be presented and discussed for these animals....

Oxygen Modulates Human Decidual Natural Killer Cell Surface Receptor Expression and Interactions with Trophoblasts1

Science.gov (United States)

Wallace, Alison E.; Goulwara, Sonu S.; Whitley, Guy S.; Cartwright, Judith E.

2014-01-01

Decidual natural killer (dNK) cells have been shown to both promote and inhibit trophoblast behavior important for decidual remodeling in pregnancy and have a distinct phenotype compared to peripheral blood NK cells. We investigated whether different levels of oxygen tension, mimicking the physiological conditions of the decidua in early pregnancy, altered cell surface receptor expression and activity of dNK cells and their interactions with trophoblast. dNK cells were isolated from terminated first-trimester pregnancies and cultured in oxygen tensions of 3%, 10%, and 21% for 24 h. Cell surface receptor expression was examined by flow cytometry, and the effects of secreted factors in conditioned medium (CM) on the trophoblast cell line SGHPL-4 were assessed in vitro. SGHPL-4 cells treated with dNK cell CM incubated in oxygen tensions of 10% were significantly more invasive (P cells treated with dNK cell CM incubated in oxygen tensions of 3% or 21%. After 24 h, a lower percentage of dNK cells expressed CD56 at 21% oxygen (P cells expressed NKG2D at 10% oxygen (P oxygen tensions, with large patient variation. This study demonstrates dNK cell phenotype and secreted factors are modulated by oxygen tension, which induces changes in trophoblast invasion and endovascular-like differentiation. Alterations in dNK cell surface receptor expression and secreted factors at different oxygen tensions may represent regulation of function within the decidua during the first trimester of pregnancy. PMID:25232021

Blood transfusion before radiation for malignancies

International Nuclear Information System (INIS)

Hunt, T.K.

1989-01-01

This editorial discusses the situation of administering blood to patients prior to radiotherapy in an attempt to increase tissue/tumor oxygen tension. The author believes that since the rate at which tumor cells consume oxygen is highly variable, the aim of achieving high cellular oxygen tension may be met better by maintaining a high blood perfusion rate. Blood volume can be maintained without relying on transfusion, and safer alternatives are available

First experience with a novel luminescence-based optical sensor for measurement of oxygenation in tumors

International Nuclear Information System (INIS)

Jarm, T.; Miklavcic, D.; Lesnicar, H.; Sersa, G.

2001-01-01

Background. The purpose of this preliminary study was to evaluate a novel luminescence-based fiber-optic sensor (OxyLite system) for the measurement of partial pressure of oxygen (pO 2 ) in tumors and for the detection of changes in pO 2 as a function of time. The new method was used simultaneously with the laser Doppler flowmetry method for the measurement of relative tissue perfusion. Materials and methods. Blood perfusion and pO 2 were measured continuously via fiber-optic sensors inserted into SA-1 tumors in anesthetized A/J mice. The changes in blood flow and oxygenation of tumors were induced by transient changes of the parameters of anesthesia and by injection of a vasoactive drug hydralazine. Results. Both optical methods used in the study successfully detected the induced changes in blood flow and pO 2 . The measurements of pO 2 were well correlated with measurements of microcirculatory blood perfusion. In the majority of pO 2 measurements, we observed an unexpected behavior of the signal during the stabilization process immediately after the insertion of the probe into tumor. This behaviour of the pO 2 signal was most probably caused by local tissue damage induced by the insertion of the probe. Conclusion. The novel luminescence-based optical oximetry can reliably detect local pO 2 changes in tumors as a function of time but some aspects of prolonged pO 2 measurement by this method require further investigation. (author)

Oxygen tension and riboflavin gradients cooperatively regulate the migration of Shewanella oneidensis MR-1 revealed by a hydrogel-based microfluidic device

Directory of Open Access Journals (Sweden)

Beum Jun Kim

2016-09-01

Full Text Available Shewanella oneidensis (S. oneidensis is a model bacterial strain for studies of bioelectrochemical systems (BESs. It has two extracellular electron transfer pathways: 1 shuttling electrons via an excreted mediator riboflavin; and 2 direct contact between the c-type cytochromes at the cell membrane and the electrode. Despite the extensive use of S. oneidensis in bioelectrochemical systems such as microbial fuel cells and biosensors, many basic microbiology questions about S. oneidensis in the context of BES remain unanswered. Here, we present studies of motility and chemotaxis of S. oneidensis under well controlled concentration gradients of two electron acceptors, oxygen and oxidized form of riboflavin (flavin+ using a newly developed microfluidic platform. Experimental results demonstrate that either oxygen or flavin+ is a chemoattractant to S. oneidensis. The chemotactic tendency of S. oneidensis in a flavin+ concentration gradient is significantly enhanced in an anaerobic in contrast to an aerobic condition. Furthermore, either a low oxygen tension or a high flavin+ concentration considerably enhances the speed of S. oneidensis. This work presents a robust microfluidic platform for generating oxygen and/or flavin+ gradients in an aqueous environment, and demonstrates that two important electron acceptors, oxygen and oxidized riboflavin, cooperatively regulate S. oneidensis migration patterns. The microfluidic tools presented as well as the knowledge gained in this work can be used to guide the future design of BESs for efficient electron production.

Singlet oxygen explicit dosimetry to predict long-term local tumor control for BPD-mediated photodynamic therapy

Science.gov (United States)

Kim, Michele M.; Penjweini, Rozhin; Ong, Yi Hong; Zhu, Timothy C.

2017-02-01

Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence, photosensitizer photobleaching rate, and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (Φ) effects are not accounted for, which has a large effect on the oxygen consumption rate. In this preclinical study, reacted singlet oxygen [1O2]rx was investigated as a dosimetric quantity for PDT outcome. The ability of [1O2]rx to predict the long-term local tumor control rate (LCR) for BPD-mediated PDT was examined. Mice bearing radioactivelyinduced fibrosarcoma (RIF) tumors were treated with different in-air fluences (250, 300, and 350 J/cm2) and in-air ϕ (75, 100, and150 mW/cm2) with a BPD dose of 1 mg/kg and a drug-light interval of 3 hours. Treatment was delivered with a collimated laser beam of 1 cm diameter at 690 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and BPD concentration was used to calculate [1O2]rx. Φ was calculated for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Kaplan-Meier analyses for LCR were done for an endpoint of tumor volume defined as the product of the timeintegral of photosensitizer concentration and Φ at a 3 mm tumor depth. Preliminary studies show that [1O2]rx better correlates with LCR and is an effective dosimetric quantity that can predict treatment outcome.

Oxygen sensing and conducted vasomotor responses in mouse cremaster arterioles in situ

DEFF Research Database (Denmark)

Ngo, Thuc Anh; Jensen, Lars Jørn; Riemann, Mads Achen

2010-01-01

.0 +/- 4.9 mum) when changing from high (PO(2) = 242.5 +/- 13.3 mm Hg) to low (PO(2) = 22.5 +/- 4.8 mm Hg) oxygen tension as seen in the intact cremaster circulation (DeltaD = 18.7 +/- 1.0 mum). Blockade of NO synthases by L: -NAME and adenosine receptors by DPCPX had no effects on vasomotor responses...... to low or high oxygen. Induction of localized low (PO(2) = 23.3 +/- 5.7 mmHg) or high (PO(2) = 300.0 +/- 25.7 mm Hg) oxygen tension caused vasodilatation or -constriction locally and at a site 1,000 mum upstream (distantly). Glibenclamide blocker of ATP-sensitive K(+) channels inhibited vasodilatation...... and -constriction to low (PO(2) = 16.0 +/- 6.4 mm Hg) and high (PO(2) = 337.4 +/- 12.8 mm Hg) oxygen tension. 1) ATP-sensitive K(+) channels seem to mediate, at least in part, vasodilatation and vasoconstriction to low and high oxygen tension; 2) Red blood cells are not necessary for inducing vasodilatation...

The treatment of tumors by the induction of anemia and irradiation in hyperbaric oxygen

International Nuclear Information System (INIS)

Sealy, R.; Jacobs, P.; Wood, L.; Levin, W.; Barry, L.; Boniaszczuk, J.; Blekkenhorst, G.

1989-01-01

Because increased effects have been achieved when murine tumors are irradiated after a period of hypoxia and because of anecdotal clinical experiences of an improved result after irradiation of previously anemic patients in hyperbaric oxygen, the relationship between irradiation and increased survival was investigated in seventy-two patients with advanced head and neck or cervical cancer. Anemia was achieved by means of a two-stage isovolemic venesection maintained for seventy-two hours, hemoglobin was returned to a normal level, and treatment in hyperbaric oxygen was started. Marked tumor shrinkage after the induction of anemia and before radiotherapy was seen and was probably disease, site, and hemoglobin level related. As a result, a possible new approach to cancer therapy is suggested. After completion of therapy, the 1-year disease-free survival for patients with head and neck and cervical cancer was not improved, but the 21-month survival for cervical cancer was improved. Further studies are strongly urged

Oxygenation measurement by multi-wavelength oxygen-dependent phosphorescence and delayed fluorescence: catchment depth and application in intact heart

NARCIS (Netherlands)

Balestra, Gianmarco M.; Aalders, Maurice C. G.; Specht, Patricia A. C.; Ince, Can; Mik, Egbert G.

2015-01-01

Oxygen delivery and metabolism represent key factors for organ function in health and disease. We describe the optical key characteristics of a technique to comprehensively measure oxygen tension (PO(2)) in myocardium, using oxygen-dependent quenching of phosphorescence and delayed fluorescence of

Development of pulmonary vascular response to oxygen

International Nuclear Information System (INIS)

Morin, F.C. III; Egan, E.A.; Ferguson, W.; Lundgren, C.E.

1988-01-01

The ability of the pulmonary circulation of the fetal lamb to respond to a rise in oxygen tension was studied from 94 to 146 days of gestation. The unanesthetized ewe breathed room air at normal atmospheric pressure, followed by 100% oxygen at three atmospheres absolute pressure in a hyperbaric chamber. In eleven near-term lambs, fetal arterial oxygen tension (Pa O 2 ) increased from 25 to 55 Torr, which increased the proportion or right ventricular output distributed to the fetal lungs from 8 to 59%. In five very immature lambs fetal Pa O 2 increased from 27 to 174 Torr, but the proportion of right ventricular output distributed to the lung did not change. In five of the near-term lambs, pulmonary blood flow was measured. For each measurement of the distribution of blood flow, approximately 8 x 10 5 spheres of 15-μm diameter, labeled with either 153 Gd, 113 Sn, 103 Ru, 95 Nb, or 46 Sc were injected. It increased from 34 to 298 ml · kg fetal wt -1 · min -1 , an 8.8-fold increase. The authors conclude that the pulmonary circulation of the fetal lamb does not respond to an increase in oxygen tension before 101 days of gestation; however, near term an increase in oxygen tension alone can induce the entire increase in pulmonary blood flow that normally occurs after the onset of breathing at birth

Measurement of brain oxygenation changes using dynamic T1-weighted imaging

DEFF Research Database (Denmark)

Haddock, Bryan; Larsson, Henrik B W; Hansen, Adam E

2013-01-01

Magnetic resonance imaging (MRI) has proven useful in evaluating oxygenation in several types of tissue and blood. This study evaluates brain tissue oxygenation changes between normoxia and hyperoxia in healthy subjects using dynamic T1 and T2*-weighted imaging sequences. The change in FiO2 induced...... by hyperoxia caused a significant decrease in T1. A model to determine changes in tissue oxygen tension from the T1-weighted MRI signal is presented based on previous findings that T1 is sensitive to oxygen tension whereas T2* is sensitive to blood saturation. The two sequences produce results with different...... regional and temporal dynamics. These differences combined with results from simulations of the T1 signal intensities, indicate an increase in extravascular oxygen tension during hyperoxia. This study concludes that T1 and T2* responses to FiO2 serve as independent biomarkers of oxygen physiology...

Assessment of tumor energy and oxygenation status by bioluminescence, nuclear magnetic resonance spectroscopy, and cryospectrophotometry.

Science.gov (United States)

Mueller-Klieser, W; Schaefer, C; Walenta, S; Rofstad, E K; Fenton, B M; Sutherland, R M

1990-03-15

The energy and oxygenation status of tumors from two murine sarcoma lines (KHT, RIF-1) and two human ovarian carcinoma xenograft lines (MLS, OWI) were assessed using three independent techniques. Tumor energy metabolism was investigated in vivo by 31P nuclear magnetic resonance spectroscopy. After nuclear magnetic resonance measurements, tumors were frozen in liquid nitrogen to determine the tissue ATP concentration by imaging bioluminescence and to register the intracapillary oxyhemoglobin (HbO2) saturation using the cryospectrophotometric method. There was a positive correlation between the nucleoside triphosphate beta/total resonance ratio or a negative correlation between the Pi/total resonance ratio and the model ATP concentration obtained by bioluminescence, respectively. This was true for small tumors with no extended necrosis irrespective of tumor type. Moreover, a positive correlation was obtained between the HbO2 saturations and the ATP concentration measured with bioluminescence. The results demonstrate the potential of combined studies using noninvasive, integrating methods and high-resolution imaging techniques for characterizing the metabolic milieu in tumors.

Intervention of oxygen-control ability to radiation sensitivity, cell aging and cell transformation

International Nuclear Information System (INIS)

Yoshii, Hanako; Watanabe, Masami

2009-01-01

Oxygen is essential for life, and cells have therefore developed numerous adaptive responses to oxygen change. Here, we examined the difference in oxygen-control functions of human (HE), mouse (ME), and Syrian hamster embryo (SHE) cells cultured under different oxygen conditions (0.5%, 2% and 20%), and also examined whether oxygen tensions contributed to cellular lifespan and transformation. HE cells had their replicative lifespan slightly extended under hypoxic (0.5% and 2% oxygen) conditions, but were not immortalized under any of the oxygen concentrations. On the other hand, although ME cells cultured under 20% oxygen tension decreased their proliferation potency temporarily at early stage, all rodent cells were immortalized and acquired anchorage-independency, regardless of oxygen tension. These results suggest that cellular oxygen control function is related to sensitivities cellular immortalization and transformation. To understand intervention of oxygen control ability on cellular immortalization and transformation, we examined the intracellular oxidative level, mitochondria functions and radiation sensitivity. Intracellular oxidative levels of hypoxically cultured rodent cells were significantly enhanced. Mitochondrial membrane potential was altered depend on oxygen tensions, but the change was not parallel to mitochondria number in rodent cells. ME cells were particularly sensitive to oxygen change, and showed a clear oxygen effect on the X-ray survival. However, there was no difference in frequency of radiation-induced micronuclei between HE and ME cells. These results suggest that the response to oxygen change differs markedly in HE and rodent cells. (author)

Increased Tumor Oxygenation and Drug Uptake During Anti-Angiogenic Weekly Low Dose Cyclophosphamide Enhances the Anti-Tumor Effect of Weekly Tirapazamine

Science.gov (United States)

Doloff, J.C.; Khan, N.; Ma, J.; Demidenko, E.; Swartz, H.M.; Jounaidi, Y.

2010-01-01

Metronomic cyclophosphamide treatment is associated with anti-angiogenic activity and is anticipated to generate exploitable hypoxia using hypoxia-activated prodrugs. Weekly administration of tirapazamine (TPZ; 5 mg/kg body weight i.p.) failed to inhibit the growth of 9L gliosarcoma tumors grown s.c. in scid mice. However, the anti-tumor effect of weekly cyclophosphamide (CPA) treatment (140 mg/kg BW i.p.) was substantially enhanced by weekly TPZ administration. An extended tumor free period and increased frequency of tumor eradication without overt toxicity were observed when TPZ was given 3, 4 or 5 days after each weekly CPA treatment. Following the 2nd CPA injection, Electron Paramagnetic Resonance (EPR) Oximetry indicated significant increases in tumor pO2, starting at 48 hr, which further increased after the 3rd CPA injection. pO2 levels were, however, stable in growing untreated tumors. A strong negative correlation (−0.81) between tumor pO2 and tumor volume during 21 days of weekly CPA chemotherapy was observed, indicating increasing tumor pO2 with decreasing tumor volume. Furthermore, CPA treatment resulted in increased tumor uptake of activated CPA. CPA induced increases in VEGF RNA, which reached a maximum on day 1, and in PLGF RNA which was sustained throughout the treatment, while anti-angiogenic host thrombospondin-1 increased dramatically through day 7 post-CPA treatment. Weekly cyclophosphamide treatment was anticipated to generate exploitable hypoxia. However, our findings suggest that weekly CPA treatment induces a functional improvement of tumor vasculature, which is characterized by increased tumor oxygenation and drug uptake in tumors, thus counter-intuitively, benefiting intratumoral activation of TPZ and perhaps other bioreductive drugs. PMID:19754361

Effect of low oxygen tension on the biological characteristics of human bone marrow mesenchymal stem cells.

Science.gov (United States)

Kim, Dae Seong; Ko, Young Jong; Lee, Myoung Woo; Park, Hyun Jin; Park, Yoo Jin; Kim, Dong-Ik; Sung, Ki Woong; Koo, Hong Hoe; Yoo, Keon Hee

2016-11-01

Culture of mesenchymal stem cells (MSCs) under ambient conditions does not replicate the low oxygen environment of normal physiological or pathological states and can result in cellular impairment during culture. To overcome these limitations, we explored the effect of hypoxia (1 % O 2 ) on the biological characteristics of MSCs over the course of different culture periods. The following biological characteristics were examined in human bone marrow-derived MSCs cultured under hypoxia for 8 weeks: proliferation rate, morphology, cell size, senescence, immunophenotypic characteristics, and the expression levels of stemness-associated factors and cytokine and chemokine genes. MSCs cultured under hypoxia for approximately 2 weeks showed increased proliferation and viability. During long-term culture, hypoxia delayed phenotypic changes in MSCs, such as increased cell volume, altered morphology, and the expression of senescence-associated-β-gal, without altering their characteristic immunophenotypic characteristics. Furthermore, hypoxia increased the expression of stemness and chemokine-related genes, including OCT4 and CXCR7, and did not decrease the expression of KLF4, C-MYC, CCL2, CXCL9, CXCL10, and CXCR4 compared with levels in cells cultured under normoxia. In conclusion, low oxygen tension improved the biological characteristics of MSCs during ex vivo expansion. These data suggest that hypoxic culture could be a useful method for increasing the efficacy of MSC cell therapies.

Variations in tumour oxygen tension (pO2) during accelerated radiotherapy of head and neck carcinoma

International Nuclear Information System (INIS)

Guichard, M.; Eschwege, F.; Luboinski, B.; Wibault, P.; Weeger, P.; Lusinchi, A.; Lartigau, E.

1998-01-01

The study was performed to assess the effect of accelerated radiotherapy on oxygenation of primary tumours and metastatic nodes in patients with advanced head and neck tumours. In 14 patients with head and neck tumour, oxygen tension (pO 2 ) was evaluated in normal tissues and tumours (primary tumour or metastatic neck node) before (0 Gy) and after 2 weeks (32 Gy) of accelerated radiotherapy (70 Gy in 3.5 weeks, with three daily fractions). Radiotherapy was combined with carbogen breathing in 5 patients. pO 2 was measured using a polarographic technique. For pooled normal tissues, median pO 2 was 38 mmHg before treatment and 46 mmHg after 2 weeks. For tumours, very low values ( 2 12 mmHg before treatment versus 26 mmHg after 2 weeks, P 2 was 44 mmHg at 2 weeks, compared with 13.5 mmHg before treatment (P=0.05). Very low pO 2 values, corresponding to tumour hypoxia, were found in the tumours (primary and metastatic neck nodes) prior to accelerated treatment. During the first 2 weeks of accelerated treatment, an increase in median pO 2 was found in nine of the 14 tumours, together with a decrease in the frequency of very low values. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

Doranidazole (PR-350), a hypoxic cell radiosensitizer, radiosensitizes human lung tumors (RERF-LC- AI) and causes changes in tumor oxygenation

International Nuclear Information System (INIS)

Kubota, N.; Griffin, R.J.; Williams, B.W.; Song, C.W.; Yahiro, T.

2003-01-01

Full text: We previously have reported the radiosensitizing capability of Doranidazole (PR-350) on SCCVII cells and tumors (Puerto Rico, 2001). In the present study, we have investigated the efficacy of PR-350 as a hypoxic cell radiosensitizer using human lung cancer cells (RERF-LC-AI) in vitro and also RERF-LC-AI tumors grown s.c. in Balb/c nude mice. Using the micronucleus assay method, we determined the effect of PR-350 on the response of RERF-LC-AI cells to radiation under hypoxic conditions and enhancement ratios (ER) of 1.45∼2.26 were obtained. The in vivo radiosensitizing effect was studied by irradiating RERF-LC-AI tumors with 15 Gy at 20 min. after i.v. injection of PR-350 (200mg/kg) and measuring the tumor growth delay. Significant growth delay occurred after i.v. injection of PR-350 before irradiation compared to radiation alone. We measured tumor pO 2 at 3, 7 and 14 days after treatment using an Eppendorf pO 2 histograph. The frequency of pO 2 values 2 in tumors treated with radiation plus PR-350 were higher than that in tumors treated with radiation plus saline. These data suggest that the O 2 consumption in tumors treated with radiation plus PR-350 was less than that in tumors treated with radiation plus saline due to greater drug and radiation-induced cell death. This hypothesis is supported by the fact that the tumor size in the combined treatment group was smaller than in radiation alone. These results suggest that PR-350 may improve the response of tumors to radiotherapy not only by increasing the radiosensitivity of hypoxic cells but also by improving tumor oxygenation over many days during fractionated radiotherapy

Radiation-induced DNA damage in tumors and normal tissues. II. Influence of dose, residual DNA damage and physiological factors in oxygenated cells

International Nuclear Information System (INIS)

Zhang, H.; Wheeler, K.T.

1994-01-01

Detection and quantification of hypoxic cells in solid tumors is important for many experimental and clinical situations. Several laboratories, including ours, have suggested that assays which measure radiation-induced DNA strand breaks and DNA-protein crosslinks (DPCs) might be used to detect or quantify hypoxic cells in tumors and normal tissues. Recently, we demonstrated the feasibility of using an alkaline elution assay that measures strand breaks and DPCs to detect and/or quantify hypoxic cells in tissues. For this approach to be valid, DPCs must not be formed to any great extent in irradiated oxygenated cells, and the formation and repair of strand breaks and DPCs in oxygenated cells must not be modified appreciably by physiological factors (e.g., temperature, pH and nutrient depletion) that are often found in solid tumors. To address these issues, two sets of experiments were performed. In one set of experiments, oxygenated 9L cells in tissue culture, subcutaneous 9L tumors and rat cerebella were irradiated with doses of 15 or 50 Gy and allowed to repair until the residual strand break damage was low enough to detect DPCs. In another set of experiments, oxygenated exponentially growing or plateau-phase 9L cells in tissue culture were irradiated with a dose of 15 Gy at 37 or 20 degrees C, while the cells were maintained at a pH of either 6.6 or 7.3. DNA-protein crosslinks were formed in oxygenated cells about 100 times less efficiently than in hypoxic cells. In addition, temperature, pH, nutrient depletion and growth phase did not appreciably alter the formation and repair of strand breaks or the formation of DPCs in oxygenated 9L cells. These results support the use of this DNA damage assay for the detection and quantification of hypoxic cells in solid tumors. 27 refs., 5 tabs

Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models.

Science.gov (United States)

Bobko, Andrey A; Evans, Jason; Denko, Nicholas C; Khramtsov, Valery V

2017-06-01

Tissue oxygenation, extracellular acidity, and tissue reducing capacity are among crucial parameters of tumor microenvironment (TME) of significant importance for tumor pathophysiology. In this paper, we demonstrate the complementary application of particulate lithium octa-n-butoxy-naphthalocyanine and soluble nitroxide paramagnetic probes for monitoring of these TME parameters using electron paramagnetic resonance (EPR) technique. Two different types of therapeutic interventions were studied: hypothermia and systemic administration of metabolically active drug. In summary, the results demonstrate the utility of EPR technique for non-invasive concurrent longitudinal monitoring of physiologically relevant chemical parameters of TME in mouse xenograft tumor models, including that under therapeutic intervention.

Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study

International Nuclear Information System (INIS)

Cao-Pham, Thanh-Trang; Tran, Ly-Binh-An; Colliez, Florence; Joudiou, Nicolas; El Bachiri, Sabrina; Grégoire, Vincent; Levêque, Philippe; Gallez, Bernard; Jordan, Bénédicte F.

2016-01-01

Purpose: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R_1, water R_1, lipids R_1, and R_2*. R_1 is sensitive to dissolved molecular oxygen, whereas R_2* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R_1, water R_1, lipids R_1, and R_2* with pO_2 assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). Methods and Materials: R_1, R_2*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O_2, 5% CO_2). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. Results: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO_2. Global and lipids R_1 were found to be correlated to pO_2 in the rhabdomyosarcoma model, whereas R_2* was found to be inversely correlated to pO_2 in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R_2* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. "1"8F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. Conclusion: This work illustrates the sensitivity of oxygen-sensitive R_1 and R_2* parameters to changes in tumor oxygenation. However, R_1 parameters showed limitations in terms of predicting the outcome of RT in the tumor models studied, whereas R_2* was found to be

Inadequate cerebral oxygen delivery and central fatigue during strenuous exercise

DEFF Research Database (Denmark)

Nybo, Lars; Rasmussen, Peter

2007-01-01

Under resting conditions, the brain is protected against hypoxia because cerebral blood flow increases when the arterial oxygen tension becomes low. However, during strenuous exercise, hyperventilation lowers the arterial carbon dioxide tension and blunts the increase in cerebral blood flow, which...... can lead to an inadequate oxygen delivery to the brain and contribute to the development of fatigue....

TH-AB-209-05: Validating Hemoglobin Saturation and Dissolved Oxygen in Tumors Using Photoacoustic Computed Tomographic Spectroscopic Imaging

Energy Technology Data Exchange (ETDEWEB)

Burnett, J; Sick, J; Liu, B [Purdue University, West Lafayette, IN (United States); Cao, N [University of Washington Medical Center, Seattle, WA (United States); Nakshatri, H; Mendonca, M [Indiana University - Purdue University Indianapolis, Indianapolis, IN (United States); Stantz, K [Purdue University, West Lafayette, IN (United States); Indiana University - Purdue University Indianapolis, Indianapolis, IN (United States)

2016-06-15

Purpose: Photoacoustic computed tomographic spectroscopy (PCT-S) provides intra-tumor measurements of oxygenation with high spatial resolution (0.2mm) and temporal fidelity (1–2 minutes) without the need for exogenous agents or ionizing radiation, thus providing a unique in vivo assay to measure SaO{sub 2} and investigate acute and chronic forms of hypoxia. The goal of this study is to validate in vivo SaO{sub 2} levels within tail artery of mice and the relationship between SaO{sub 2} and pO{sub 2} within subcutaneous breast tumors using PCT-S imaging, pulse oximetry and an OxyLite probe. Methods: A closed circuit phantom was fabricated to control blood oxygenation levels, where SaO{sub 2} was measured using a co-oximeter and pO{sub 2} using an Oxylite probe. Next, SaO{sub 2} levels within the tail arteries of mice (n=3) were measured using PCT-S and pulse oximetry while breathing high-to-low oxygen levels (6-cycles). Finally, PCT-S was used to measure SaO{sub 2} levels in MCF-7, MCF-7-VEGF165, and MDA-MB-231 xenograft breast tumors and compared to Oxylite pO{sub 2} levels values. Results: SaO{sub 2} and pO{sub 2} data obtained from the calibration phantom was fit to Hill’s equation: aO{sub 2} levels between 88 and 52% demonstrated a linear relationship (r2=0.96) and a 3.2% uncertainty between PCT-S values relative to pulse oximetry. Scatter plots of localized PCT-S measured SaO2 and Oxylite pO{sub 2} levels in MCF-7/MCF-7-VEGF165 and MDA-MD-231 breast tumors were fit to Hill’s equation: P50=17.2 and 20.7mmHg, and n=1.76 and 1.63. These results are consistent with sigmoidal form of Hill’s equation, where the lower P{sub 50} value is indicative of an acidic tumor microenvironment. Conclusion: The results demonstrate photoacoustic imaging can be used to measure SaO{sub 2} cycling and intra-tumor oxygenation, and provides a powerful in vivo assay to investigate the role of hypoxia in radiation, anti-angiogenic, and immunotherapies.

EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate.

Science.gov (United States)

Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu; Morris, H Douglas; Munasinghe, Jeeva P; Lizak, Martin; Merkle, Hellmut; Ardenkjaer-Larsen, Jan Henrik; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Koretsky, Alan P; Mitchell, James B; Krishna, Murali C

2013-05-01

The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation and promote glycolysis for energy production. Thereby, inhibition of glycolysis has the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate blocks glycolysis pathway by inhibiting hypoxia inducible enzymes and enhanced cytotoxicity of 3-bromopyruvate under hypoxic conditions has been reported in vitro. However, the efficacy of 3-bromopyruvate was substantially attenuated in hypoxic tumor regions (pO23-bromopyruvate in SCCVII tumor. The discrepant results between in vitro and in vivo data were attributed to biphasic oxygen dependent expression of monocarboxylate transporter-1 in vivo. Expression of monocarboxylate transporter-1 was enhanced in moderately hypoxic (8-15 mmHg) tumor regions but down regulated in severely hypoxic (<5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia-activated drugs. Copyright © 2012 Wiley Periodicals, Inc.

Dynamic changes in oxygenation of intracranial tumor and contralateral brain during tumor growth and carbogen breathing: A multisite EPR oximetry with implantable resonators

Science.gov (United States)

Hou, Huagang; Dong, Ruhong; Li, Hongbin; Williams, Benjamin; Lariviere, Jean P.; Hekmatyar, S.K.; Kauppinen, Risto A.; Khan, Nadeem; Swartz, Harold

2013-01-01

Introduction Several techniques currently exist for measuring tissue oxygen; however technical difficulties have limited their usefulness and general application. We report a recently developed electron paramagnetic resonance (EPR) oximetry approach with multiple probe implantable resonators (IRs) that allow repeated measurements of oxygen in tissue at depths of greater than 10 mm. Methods The EPR signal to noise (S/N) ratio of two probe IRs was compared with that of LiPc deposits. The feasibility of intracranial tissue pO2 measurements by EPR oximetry using IRs was tested in normal rats and rats bearing intracerebral F98 tumors. The dynamic changes in the tissue pO2 were assessed during repeated hyperoxia with carbogen breathing. Results A 6–10 times increase in the S/N ratio was observed with IRs as compared to LiPc deposits. The mean brain pO2 of normal rats was stable and increased significantly during carbogen inhalation in experiments repeated for 3 months. The pO2 of F98 glioma declined gradually, while the pO2 of contralateral brain essentially remained the same. Although a significant increase in the glioma pO2 was observed during carbogen inhalation, this effect declined in experiments repeated over days. Conclusion EPR oximetry with IRs provides a significant increase in S/N ratio. The ability to repeatedly assess orthotopic glioma pO2 is likely to play a vital role in understanding the dynamics of tissue pO2 during tumor growth and therapies designed to modulate tumor hypoxia. This information could then be used to optimize chemoradiation by scheduling treatments at times of increased glioma oxygenation. PMID:22033225

Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study

Energy Technology Data Exchange (ETDEWEB)

Cao-Pham, Thanh-Trang; Tran, Ly-Binh-An; Colliez, Florence; Joudiou, Nicolas [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium); El Bachiri, Sabrina [Université Catholique de Louvain, IMMAQ Technological Platform, Methodology and Statistical Support, Louvain-la-Neuve (Belgium); Grégoire, Vincent [Université Catholique de Louvain, Institute of Experimental and Clinical Research, Center for Molecular Imaging, Radiotherapy and Oncology, Brussels (Belgium); Levêque, Philippe; Gallez, Bernard [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium); Jordan, Bénédicte F., E-mail: benedicte.jordan@uclouvain.be [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium)

2016-09-01

Purpose: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}*. R{sub 1} is sensitive to dissolved molecular oxygen, whereas R{sub 2}* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}* with pO{sub 2} assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). Methods and Materials: R{sub 1}, R{sub 2}*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O{sub 2}, 5% CO{sub 2}). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. Results: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO{sub 2}. Global and lipids R{sub 1} were found to be correlated to pO{sub 2} in the rhabdomyosarcoma model, whereas R{sub 2}* was found to be inversely correlated to pO{sub 2} in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R{sub 2}* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. {sup 18}F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. Conclusion: This work illustrates the sensitivity of oxygen-sensitive R{sub 1} and R{sub 2}* parameters to changes in tumor oxygenation. However, R{sub 1

The Neuroprotection Effect of Oxygen Therapy: A Systematic Review ...

African Journals Online (AJOL)

2018-04-04

Apr 4, 2018 ... investigating the neuroprotective effect of oxygen, but the outcomes as well as ...... Neuroprotective gases – Fantasy or reality for clinical use? Prog .... of oxygen on brain tissue oxygen tension in children with severe traumatic ...

Oxygen-controlled automated neural differentiation of mouse embryonic stem cells.

Science.gov (United States)

Mondragon-Teran, Paul; Tostoes, Rui; Mason, Chris; Lye, Gary J; Veraitch, Farlan S

2013-03-01

Automation and oxygen tension control are two tools that provide significant improvements to the reproducibility and efficiency of stem cell production processes. the aim of this study was to establish a novel automation platform capable of controlling oxygen tension during both the cell-culture and liquid-handling steps of neural differentiation processes. We built a bespoke automation platform, which enclosed a liquid-handling platform in a sterile, oxygen-controlled environment. An airtight connection was used to transfer cell culture plates to and from an automated oxygen-controlled incubator. Our results demonstrate that our system yielded comparable cell numbers, viabilities, metabolism profiles and differentiation efficiencies when compared with traditional manual processes. Interestingly, eliminating exposure to ambient conditions during the liquid-handling stage resulted in significant improvements in the yield of MAP2-positive neural cells, indicating that this level of control can improve differentiation processes. This article describes, for the first time, an automation platform capable of maintaining oxygen tension control during both the cell-culture and liquid-handling stages of a 2D embryonic stem cell differentiation process.

Induction of Tca8113 tumor cell apoptosis by icotinib is associated with reactive oxygen species mediated p38-MAPK activation.

Science.gov (United States)

Yang, Cailing; Yan, Jianguo; Yuan, Guoyan; Zhang, Yinghua; Lu, Derong; Ren, Mingxin; Cui, Weigang

2014-08-01

Icotinib, a selective EGFR tyrosine kinase inhibitor (EGFR-TKI), has been shown to exhibit anti-tumor activity against several tumor cell lines. However, the exact molecular mechanism of icotinib's anti-tumor effect remains unknown. This study aims to examine the zytotoxic effect of icotinib on Tca8113 cells and its potential molecular mechanism. Icotinib significantly resulted in dose-dependent cell death as determined by MTT assay, accompanied by increased levels of Bax and DNA fragmentation. Icotinib could also induce Reactive Oxygen Species (ROS) generation. Further studies confirmed that scavenging of reactive oxygen species by N-acetyl-L-cysteine (NAC), and pharmacological inhibition of MAPK reversed icotinib-induced apoptosis in Tca8113 cells. Our data provide evidence that icotinib induces apoptosis, possibly via ROS-mediated MAPK pathway in Tca8113 cells.

Temporal changes in tumor oxygenation and perfusion upon normo- and hyperbaric inspiratory hyperoxia

Energy Technology Data Exchange (ETDEWEB)

Thews, Oliver [University of Halle, Institute of Physiology, Halle (Saale) (Germany); Vaupel, Peter [University Medical Center Mainz, Department of Radiooncology and Radiotherapy, Tumor Pathophysiology Section, Mainz (Germany)

2016-03-15

Inspiratory hyperoxia under hyperbaric conditions has been shown to effectively reduce tumor hypoxia and to improve radiosensitivity. However, applying irradiation (RT) under hyperbaric conditions is technically difficult in the clinical setting since RT after decompression may be effective only if tumor pO{sub 2} remains elevated for a certain period of time. The aim of the present study was to analyze the time course of tumor oxygenation and perfusion during and after hyperbaric hyperoxia. Tumor oxygenation, red blood cell (RBC) flux for perfusion monitoring, and vascular resistance were assessed continuously in experimental rat DS-sarcomas by polarographic catheter electrodes and laser Doppler flowmetry at 1 and 2 atm (bar) of environmental pressure during breathing of pure O{sub 2} or carbogen (95 % O{sub 2} + 5 % CO{sub 2}). During room air breathing, the tumor pO{sub 2} followed very rapidly within a few minutes the change of the ambient pressure during compression or decompression. With O{sub 2} breathing under hyperbaric conditions, the tumor pO{sub 2} increased more than expected based on the rise of the environmental pressure, although the time course was comparably rapid. Breathing carbogen, the tumor pO{sub 2} followed with a slight delay of the pressure change, and within 10 min after decompression the baseline values were reached again. RBC flux increased during carbogen breathing but remained almost constant with pure O{sub 2}, indicating a vasodilation (decrease in vascular resistance) with carbogen but a vasoconstriction (increase in vascular resistance) with O{sub 2} during hyperbaric conditions. Since the tumor pO{sub 2} directly followed the environmental pressure, teletherapy after hyperbaric conditions does not seem to be promising as the pO{sub 2} reaches baseline values again within 5-10 min after decompression. (orig.) [German] Inspiratorische Hyperoxie unter hyperbaren Bedingungen reduziert sehr effektiv die Tumorhypoxie und erhoeht die

Diffuse Reflectance Spectroscopy (DRS) of radiation-induced re-oxygenation in sensitive and resistant head and neck tumor xenografts

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Dadgar, Sina; Rodríguez Troncoso, Joel; Rajaram, Narasimhan

2018-02-01

Currently, anatomical assessment of tumor volume performed several weeks after completion of treatment is the clinical standard to determine whether a cancer patient has responded to a treatment. However, functional changes within the tumor could potentially provide information regarding treatment resistance or response much earlier than anatomical changes. We have used diffuse reflectance spectroscopy to assess the short and long-term re-oxygenation kinetics of a human head and neck squamous cell carcinoma xenografts in response to radiation therapy. First, we injected UM-SCC-22B cell line into the flank of 50 mice to grow xenografts. Once the tumor volume reached 200 mm3 (designated as Day 1), the mice were distributed into radiation and control groups. Members of radiation group underwent a clinical dose of radiation of 2 Gy/day on Days 1, 4, 7, and 10 for a cumulative dose of 8 Gy. DRS spectra of these tumors were collected for 14 days during and after therapy, and the collected spectra of each tumor were converted to its optical properties using a lookup table-base inverse model. We found statistically significant differences in tumor growth rate between two groups which is in indication of the sensitivity of this cell line to radiation. We further acquired significantly different contents of hemoglobin and scattering magnitude and size in two groups. The scattering has previously been associated with necrosis. We furthermore found significantly different time-dependent changes in vascular oxygenation and tumor hemoglobin concentration in post-radiation days.

Theoretical analysis of the dose dependence of the oxygen enhancement ratio and its relevance for clinical applications

International Nuclear Information System (INIS)

Wenzl, Tatiana; Wilkens, Jan J

2011-01-01

The increased resistance of hypoxic cells to ionizing radiation is usually believed to be the primary reason for treatment failure in tumors with oxygen-deficient areas. This oxygen effect can be expressed quantitatively by the oxygen enhancement ratio (OER). Here we investigate theoretically the dependence of the OER on the applied local dose for different types of ionizing irradiation and discuss its importance for clinical applications in radiotherapy for two scenarios: small dose variations during hypoxia-based dose painting and larger dose changes introduced by altered fractionation schemes. Using the widespread Alper-Howard-Flanders and standard linear-quadratic (LQ) models, OER calculations are performed for T1 human kidney and V79 Chinese hamster cells for various dose levels and various hypoxic oxygen partial pressures (pO2) between 0.01 and 20 mmHg as present in clinical situations in vivo. Our work comprises the analysis for both low linear energy transfer (LET) treatment with photons or protons and high-LET treatment with heavy ions. A detailed analysis of experimental data from the literature with respect to the dose dependence of the oxygen effect is performed, revealing controversial opinions whether the OER increases, decreases or stays constant with dose. The behavior of the OER with dose per fraction depends primarily on the ratios of the LQ parameters alpha and beta under hypoxic and aerobic conditions, which themselves depend on LET, pO2 and the cell or tissue type. According to our calculations, the OER variations with dose in vivo for low-LET treatments are moderate, with changes in the OER up to 11% for dose painting (1 or 3 Gy per fraction compared to 2 Gy) and up to 22% in hyper-/hypofractionation (0.5 or 20 Gy per fraction compared to 2 Gy) for oxygen tensions between 0.2 and 20 mmHg typically measured clinically in hypoxic tumors. For extremely hypoxic cells (0.01 mmHg), the dose dependence of the OER becomes more pronounced (up to 36

[Case of tension pneumothorax associated with asthma attack during general anesthesia].

Science.gov (United States)

Komasawa, Nobuyasu; Ueki, Ryusuke; Kusuyama, Kazuki; Okano, Yukari; Tatara, Tsuneo; Tashiro, Chikara

2010-05-01

We report a case of tension pneumothorax associated with asthma attack during general anesthesia. An 86-year-old woman with dementia underwent cataract surgery under general anesthesia. At 70 min after the start of operation, airway pressure suddenly increased from 19 to 28 cm HO2O. In spite of bag ventilation with 100% oxygen, Sp(O2) decreased to 81%. Chest-Xp showed typical image of tension pneumothorax. Chest drainage was immediately performed, after which Pa(O2) recovered soon. She was extubated on postoperative day 1 without any neurological disorder. Hyperinflation of fragile alveoli by mechanical ventilation was likely a cause of tension pneumothorax.

Intraoperative transfusion threshold and tissue oxygenation

DEFF Research Database (Denmark)

Nielsen, K; Dahl, B; Johansson, P I

2012-01-01

Transfusion with allogeneic red blood cells (RBCs) may be needed to maintain oxygen delivery during major surgery, but the appropriate haemoglobin (Hb) concentration threshold has not been well established. We hypothesised that a higher level of Hb would be associated with improved subcutaneous...... oxygen tension during major spinal surgery....

HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

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Kurosh Ameri

2015-02-01

Full Text Available Hypoxia-inducible gene domain family member 1A (HIGD1A is a survival factor induced by hypoxia-inducible factor 1 (HIF-1. HIF-1 regulates many responses to oxygen deprivation, but viable cells within hypoxic perinecrotic solid tumor regions frequently lack HIF-1α. HIGD1A is induced in these HIF-deficient extreme environments and interacts with the mitochondrial electron transport chain to repress oxygen consumption, enhance AMPK activity, and lower cellular ROS levels. Importantly, HIGD1A decreases tumor growth but promotes tumor cell survival in vivo. The human Higd1a gene is located on chromosome 3p22.1, where many tumor suppressor genes reside. Consistent with this, the Higd1a gene promoter is differentially methylated in human cancers, preventing its hypoxic induction. However, when hypoxic tumor cells are confronted with glucose deprivation, DNA methyltransferase activity is inhibited, enabling HIGD1A expression, metabolic adaptation, and possible dormancy induction. Our findings therefore reveal important new roles for this family of mitochondrial proteins in cancer biology.

Encouraging effects of a short-term, adapted Nordic diet intervention on skin microvascular function and skin oxygen tension in younger and older adults.

Science.gov (United States)

Rogerson, David; McNeill, Scott; Könönen, Heidi; Klonizakis, Markos

2018-05-01

The microvascular benefits of regional diets appear in the literature; however, little is known about Nordic-type diets. We investigated the effects of a short-term, adapted, Nordic diet on microvascular function in younger and older individuals at rest and during activity. Thirteen young (mean age: 28 y; standard deviation: 5 y) and 15 older (mean age: 68 y; standard deviation: 6 y) participants consumed a modified Nordic diet for 4 wk. Laser Doppler flowmetry and transcutaneous oxygen monitoring were used to assess cutaneous microvascular function and oxygen tension pre- and postintervention; blood pressure, body mass, body fat percentage, ratings of perceived exertion, and peak heart rate during activity were examined concurrently. Axon-mediated vasodilation improved in older participants (1.17 [0.30] to 1.30 [0.30]; P Nordic diet might improve microvascular health. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxygen tension in transplanted mouse osteosarcomas during fractionated high-LET- and low-LET radiotherapy - predictive aspects for choosing beam quality?

International Nuclear Information System (INIS)

Auberger, T.; Thuerriegel, B.; Freude, T.; Weissfloch, L.; Kneschaurek, P.; Molls, M.; Senekowitsch-Schmidtke, R.; Wagner, F.M.

1999-01-01

Murine OTS64 - osteosarcomas were tranplanted in 102 balb-C mice and irradiated by 36 Gy of photons in fractions of 3 Gy five times a week (group P-36/3) or by 12 Gy of reactor fission neutrons in fractions of 2 Gy two times a week (group N-12/2). Irradiations started at a tumor volume of 500 to 600 mm 3 . A third group received no radiotherapy, but all investigations (group CG). Tumor volume and tumor oxygenation were measured once a week under therapy and during three weeks after therapy. For in vivo-evaluation of oxygen status a computerized polarographic needle electrode system (KIMOC pO 2 histograph, Eppendorf) was used. The median pO 2 and the hypoxic fraction (pO 2 values 2 decreased from 20 mm to 8 mm Hg and the hypoxic fraction increased from 7% to 31%. After fractionated photon therapy a growth delay of three weeks was observed. Six weeks after beginning of the irradiation the median tumor volume had been doubled again. After fission neutron therapy growth delay continued until the end of the follow-up period. In both of the irradiated groups a significant decrease of median pO 2 values and an increase of the hypoxic fraction were observed under radiotherapy. Hypoxia was more intensive after neutrons with a decrease of the median pO 2 from 20 mm Hg to 1 mm Hg vs. 10 mm Hg after photon therapy and with an increase of the hypoxic fraction from 7% to 78% vs. 36% respectively. Two weeks after the end of therapy the median pO 2 and the hypoxic fraction of both treated groups reached the levels prior to irradiation indicating a complete reoxygenation. (orig.)

Measurement of pO2 in a Pre-clinical Model of Rabbit Tumor Using OxyChip, a Paramagnetic Oxygen Sensor.

Science.gov (United States)

Hou, H; Khan, N; Kuppusamy, P

2017-01-01

The objective of this work was to establish a novel and robust technology, based on electron paramagnetic resonance (EPR) oximetry, as a practical tool for measurement of tumor oxygen. Previously, we have reported on the development of oxygen-sensing paramagnetic crystals (LiNc-BuO) encapsulated in a biocompatible polymer, called OxyChip. In this report we present our recent data on the use of OxyChip for pO 2 measurements in the tumor of a pre-clinical, large-animal rabbit model. The results establish that OxyChip is capable of noninvasive and repeated measurement of pO 2 in a large animal model.

Front instabilities and invasiveness of simulated 3D avascular tumors.

Directory of Open Access Journals (Sweden)

Nikodem J Poplawski

2010-05-01

Full Text Available We use the Glazier-Graner-Hogeweg model to simulate three-dimensional (3D, single-phenotype, avascular tumors growing in an homogeneous tissue matrix (TM supplying a single limiting nutrient. We study the effects of two parameters on tumor morphology: a diffusion-limitation parameter defined as the ratio of the tumor-substrate consumption rate to the substrate-transport rate, and the tumor-TM surface tension. This initial model omits necrosis and oxidative/hypoxic metabolism effects, which can further influence tumor morphology, but our simplified model still shows significant parameter dependencies. The diffusion-limitation parameter determines whether the growing solid tumor develops a smooth (noninvasive or fingered (invasive interface, as in our earlier two-dimensional (2D simulations. The sensitivity of 3D tumor morphology to tumor-TM surface tension increases with the size of the diffusion-limitation parameter, as in 2D. The 3D results are unexpectedly close to those in 2D. Our results therefore may justify using simpler 2D simulations of tumor growth, instead of more realistic but more computationally expensive 3D simulations. While geometrical artifacts mean that 2D sections of connected 3D tumors may be disconnected, the morphologies of 3D simulated tumors nevertheless correlate with the morphologies of their 2D sections, especially for low-surface-tension tumors, allowing the use of 2D sections to partially reconstruct medically-important 3D-tumor structures.

Matrix stiffness and oxigen tension modulate epigenetic conversion of mouse dermal fibroblasts into insulin producing cells.

Directory of Open Access Journals (Sweden)

Alessandro Zenobi

2017-05-01

Full Text Available In vivo, cells are surrounded by a three-dimensional (3-D organization of supporting matrix, neighboring cells and a gradient of chemical and mechanical signals (Antoni, et al., 2015. However, the present understanding of many biological processes is mainly based on two-dimensional (2-D systems that typically provides a static environment. In the present study, we tested two different 3-D culture systems and apply them to the epigenetic conversion of mouse dermal fibroblasts into insulin producing-cells (Pennarossa, et al., 2013; Brevini, et al., 2015, combining also the use of two oxygen tensions. In particular, cells were differentiated using the Polytetrafluoroethylene micro-bioreactor (PTFE and the Polyacrylamide (PAA gels with different stiffness (1 kPa; 4 kPa, maintained either in the standard 20% or in the more physiological 5% oxygen tensions. Standard differentiation performed on plastic substrates was assessed as a control. Cell morphology (Fig.1A, insulin expression and release were analyzed to evaluate the role of both stiffness and oxygen tension in the process. The results obtained showed that 1 kPa PAA gel and PTFE system induced a significantly higher insulin expression and release than plastic and 4 kPa PAA gel, especially in low oxygen condition (Fig.1B. Furthermore, comparing the efficiency of the two systems tested, 1 kPa PAA gel ensured a higher insulin transcription than PTFE (Fig.1C. Recent studies show the direct influence of substrates on lineage commitment and cell differentiation (Engler, et al., 2006; Evans, et al., 2009. The evidence here presented confirm that the use of an appropriate stiffness (similar to the pancreatic tissue, combined with a physiological oxygen tension, promote β-cell differentiation, with beneficial effects on cell functional activity and insulin release. The present results highlight the importance of 3-D cell rearrangement and oxigen tension to promote in vitro epigenetic conversion of

Bilateral tension pneumothorax related to acupuncture.

Science.gov (United States)

Tagami, Rumi; Moriya, Takashi; Kinoshita, Kosaku; Tanjoh, Katsuhisa

2013-06-01

We report on a patient with a rare case of bilateral tension pneumothorax that occurred after acupuncture. A 69-year-old large-bodied man, who otherwise had no risk factors for spontaneous pneumothorax, presented with chest pressure, cold sweats and shortness of breath. Immediately after bilateral pneumothorax had been identified on a chest radiograph in the emergency room, his blood pressure and percutaneous oxygen saturation suddenly decreased to 78 mm Hg and 86%, respectively. We confirmed deterioration in his cardiopulmonary status and diagnosed bilateral tension pneumothorax. We punctured his chest bilaterally and inserted chest tubes for drainage. His vital signs promptly recovered. After the bilateral puncture and drainage, we learnt that he had been treated with acupuncture on his upper back. We finally diagnosed a bilateral tension pneumothorax based on the symptoms that appeared 8 h after the acupuncture. Because the patient had no risk factors for spontaneous pneumothorax, no alternative diagnosis was proposed. We recommend that patients receiving acupuncture around the chest wall must be adequately informed of the possibility of complications and expected symptoms, as a definitive diagnosis can be difficult without complete information.

Arterial oxygen tension and pulmonary ventilation in horses placed in the Anderson Sling suspension system after a period of lateral recumbency and anaesthetised with constant rate infusions of romifidine and ketamine.

Science.gov (United States)

François, I; Lalèyê, F-X; Micat, M; Benredouane, K; Portier, K

2014-09-01

Some controversy exists over whether or not horses' recovery and cardiopulmonary function are affected by suspension in slings. To measure arterial oxygen tension and pulmonary ventilation in anaesthetised horses placed in a standing position in an Anderson Sling (AS) after a period of right lateral recumbency (RLR). Randomised crossover experimental study. Six Standardbred horses were anaesthetised twice. Catheters were inserted into the right jugular vein and the left carotid artery. After premedication with romifidine, anaesthesia was induced with diazepam and ketamine. Following 50 min in RLR, horses were maintained in either RLR or AS for an additional 60 min through to recovery. Anaesthesia was maintained i.v. with a constant rate infusion of romifidine and ketamine. Heart rate, respiratory rate, mean arterial pressure, expiratory tidal volume, minute volumes and end tidal CO2 were monitored continuously. Venous and arterial bloods were sampled for lactate concentration, creatine kinase activity and blood gas analysis before premedication, after induction, every 20 min for 100 min, as soon as the horse was standing (TR), and 24 h later. The data were averaged within 2 anaesthetic periods: P1, 0-20 min; and P2, 40-100 min. During P2, horses in the RLR group had lower arterial oxygen tension (P = 0.001), higher alveolar-arterial oxygen tension gradient (P = 0.005), higher respiratory rate (P = 0.04) and higher minute volumes (P = 0.04) than horses in the AS group. Arterial CO2 tension and mean arterial pressure increased in the AS group during P2 (P = 0.01 and 0.02 respectively). The recoveries were judged better in the AS group than in the RLR group (P = 0.01). During TR, lactate were higher in the RLR group than in the AS group (P = 0.007). Creatine kinase activities were higher in the AS group at 24 h vs. TR (P = 0.02). Anderson Sling suspension after a period of recumbency improves cardiopulmonary function and recovery quality in horses and

Mixomics analysis of Bacillus subtilis: effect of oxygen availability on riboflavin production.

Science.gov (United States)

Hu, Junlang; Lei, Pan; Mohsin, Ali; Liu, Xiaoyun; Huang, Mingzhi; Li, Liang; Hu, Jianhua; Hang, Haifeng; Zhuang, Yingping; Guo, Meijin

2017-09-12

Riboflavin, an intermediate of primary metabolism, is one kind of important food additive with high economic value. The microbial cell factory Bacillus subtilis has already been proven to possess significant importance for the food industry and have become one of the most widely used riboflavin-producing strains. In the practical fermentation processes, a sharp decrease in riboflavin production is encountered along with a decrease in the dissolved oxygen (DO) tension. Influence of this oxygen availability on riboflavin biosynthesis through carbon central metabolic pathways in B. subtilis is unknown so far. Therefore the unveiled effective metabolic pathways were still an unaccomplished task till present research work. In this paper, the microscopic regulation mechanisms of B. subtilis grown under different dissolved oxygen tensions were studied by integrating 13 C metabolic flux analysis, metabolomics and transcriptomics. It was revealed that the glucose metabolic flux through pentose phosphate (PP) pathway was lower as being confirmed by smaller pool sizes of metabolites in PP pathway and lower expression amount of ykgB at transcriptional level. The latter encodes 6-phosphogluconolactonase (6-PGL) under low DO tension. In response to low DO tension in broth, the glucose metabolic flux through Embden-Meyerhof-Parnas (EMP) pathway was higher and the gene, alsS, encoding for acetolactate synthase was significantly activated that may result due to lower ATP concentration and higher NADH/NAD + ratio. Moreover, ResE, a membrane-anchored protein that is capable of oxygen regulated phosphorylase activity, and ResD, a regulatory protein that can be phosphorylated and dephosphorylated by ResE, were considered as DO tension sensor and transcriptional regulator respectively. This study shows that integration of transcriptomics, 13 C metabolic flux analysis and metabolomics analysis provides a comprehensive understanding of biosynthesized riboflavin's regulatory mechanisms in

Deleted in Malignant Brain Tumors 1 (DMBT1 is present in hyaline membranes and modulates surface tension of surfactant

Directory of Open Access Journals (Sweden)

Griese Matthias

2007-10-01

Full Text Available Abstract Background Deleted in Malignant Brain Tumors 1 (DMBT1 is a secreted scavenger receptor cysteine-rich protein that binds various bacteria and is thought to participate in innate pulmonary host defense. We hypothesized that pulmonary DMBT1 could contribute to respiratory distress syndrome in neonates by modulating surfactant function. Methods DMBT1 expression was studied by immunohistochemistry and mRNA in situ hybridization in post-mortem lungs of preterm and full-term neonates with pulmonary hyaline membranes. The effect of human recombinant DMBT1 on the function of bovine and porcine surfactant was measured by a capillary surfactometer. DMBT1-levels in tracheal aspirates of ventilated preterm and term infants were determined by ELISA. Results Pulmonary DMBT1 was localized in hyaline membranes during respiratory distress syndrome. In vitro addition of human recombinant DMBT1 to the surfactants increased surface tension in a dose-dependent manner. The DMBT1-mediated effect was reverted by the addition of calcium depending on the surfactant preparation. Conclusion Our data showed pulmonary DMBT1 expression in hyaline membranes during respiratory distress syndrome and demonstrated that DMBT1 increases lung surface tension in vitro. This raises the possibility that DMBT1 could antagonize surfactant supplementation in respiratory distress syndrome and could represent a candidate target molecule for therapeutic intervention in neonatal lung disease.

Radiosensitization of mouse skin by oxygen and depletion of glutathione

International Nuclear Information System (INIS)

Stevens, Graham; Joiner, Michael; Joiner, Barbara; Johns, Helen; Denekamp, Juliana

1995-01-01

Purpose: To determine the oxygen enhancement ratio (OER) and shape of the oxygen sensitization curve of mouse foot skin, the extent to which glutathione (GSH) depletion radiosensitized skin, and the dependence of such sensitization on the ambient oxygen tension. Methods and Materials: The feet of WHT mice were irradiated with single doses of 240 kVp x-rays while mice were exposed to carbogen or gases with oxygen/nitrogen mixtures containing 8-100% O 2 . The anoxic response was obtained by occluding the blood supply to the leg of anesthetized mice with a tourniquet, surrounding the foot with nitrogen, and allowing the mice to breathe 10% O 2 . Further experiments were performed to assess the efficacy of this method to obtain an anoxic response. Radiosensitivity of skin was assessed using the acute skin-reaction assay. Glutathione levels were modified using two schedules of dl-buthionine sulphoximine (BSO) and diethylmaleate (DEM), which were considered to produce extensive and intermediate levels of GSH depletion in the skin of the foot during irradiation. Results: Carbogen caused the greatest radiosensitization of skin, with a reproducible enhancement of 2.2 relative to the anoxic response. The OER of 2.2 is lower than other reports for mouse skin. This may indicate that the extremes of oxygenation were not produced, although there was no direct evidence for this. When skin radiosensitivity was plotted against the logarithm of the oxygen tension in the ambient gas, a sigmoid curve with a K value of 17-21% O 2 in the ambient gas was obtained. Depletion of GSH caused minimal radiosensitization when skin was irradiated under anoxic or well-oxygenated conditions. Radiosensitization by GSH depletion was maximal at intermediate oxygen tensions of 10-21% O 2 in the ambient gas. Increasing the extent of GSH depletion led to increasing radiosensitization, with sensitization enhancement ratios of 1.2 and 1.1, respectively, for extensive and intermediate levels of GSH

Oxygen transfer rate during the production of alginate by Azotobacter vinelandii under oxygen-limited and non oxygen-limited conditions

Directory of Open Access Journals (Sweden)

Peña Carlos F

2011-02-01

Full Text Available Abstract Background The oxygen transfer rate (OTR and dissolved oxygen tension (DOT play an important role in determining alginate production and its composition; however, no systematic study has been reported about the independent influence of the OTR and DOT. In this paper, we report a study about alginate production and the evolution of the molecular mass of the polymer produced by a wild-type A. vinelandii strain ATCC 9046, in terms of the maximum oxygen transfer rate (OTRmax in cultures where the dissolved oxygen tension (DOT was kept constant. Results The results revealed that in the two dissolved oxygen conditions evaluated, strictly controlled by gas blending at 0.5 and 5% DOT, an increase in the agitation rate (from 300 to 700 rpm caused a significant increase in the OTRmax (from 17 to 100 mmol L-1 h-1 for DOT of 5% and from 6 to 70 mmol L-1 h-1 for DOT of 0.5%. This increase in the OTRmax improved alginate production, as well as the specific alginate production rate (SAPR, reaching a maximal alginate concentration of 3.1 g L-1 and a SAPR of 0.031 g alg g biom-1 h-1 in the cultures at OTRmax of 100 mmol L-1 h-1. In contrast, the mean molecular mass (MMM of the alginate isolated from cultures developed under non-oxygen limited conditions increased by decreasing the OTRmax, reaching a maximal of 550 kDa at an OTRmax of 17 mmol L-1 h-1 . However, in the cultures developed under oxygen limitation (0.5% DOT, the MMM of the polymer was practically the same (around 200 kDa at 300 and 700 rpm, and this remained constant throughout the cultivation. Conclusions Overall, our results showed that under oxygen-limited and non oxygen-limited conditions, alginate production and its molecular mass are linked to the OTRmax, independently of the DOT of the culture.

Modification of the radiation response of pig skin by manipulation of tissue oxygen tension using anesthetics and administration of BW12C

International Nuclear Information System (INIS)

van den Aardweg, G.J.; Hopewell, J.W.; Barnes, D.W.; Sansom, J.M.; Nethersell, A.B.

1989-01-01

The importance of tissue oxygen tension on radiosensitivity was studied by examining modifications in the incidence of moist desquamation in pig skin after irradiation with strontium-90 plaques. The effects were analyzed using quantal dose-response data and comparisons were made using ED50 values for moist desquamation. Under standard anesthetic conditions of 2% halothane, approximately 70% oxygen, and approximately 30% nitrous oxide, the ED50 value (+/- SE) for moist desquamation was 27.32 +/- 0.52 Gy with no significant variation in radiosensitivity between dorsal, lateral, and ventral skin sites on the flank. Irradiation with 2% halothane and air increased the ED50 to 31.25 +/- 0.94 Gy, primarily due to an increased radioresistance of the dorsal sites. When combined with BW12C, a drug which binds oxygen selectively to hemoglobin and hence reduced the oxygen availability to tissues, a further increase in the ED50 values was observed. This was approximately 39 Gy with BW12C concentrations of 30 mg/kg and 50 mg/kg b.w. of BW12C, indicating a dose modification factor (DMF) of approximately 1.26. However, when animals were breathing the standard gas mixture, this DMF was reduced to 1.15 for 30 mg/kg of BW12C, indicating that a higher level of oxygen partly counteracted the effects of the drug in these studies with BW12C. The greatest variability in radiosensitivity was seen in the dorsal fields. This suggested complex physiological adaptation, a phenomenon that might also explain the absence of any modification of the radiation response when 100 mg/kg of BW12C was used

L-lysine escinat, thiotriazolin, gordox and mydocalm influence on oxygen tension in the intestinal wall and acid-base balance and limited proteolysis in intestinal venous blood in terms of intraabdominal hypertension modeling

Directory of Open Access Journals (Sweden)

Sapegin V.I.

2014-11-01

Full Text Available In acute experiments on rabbits there were studied changes in oxygen tension in the intestinal wall tissues, acid-base balance and limited proteolysis and its inhibitors in intestinal venous blood, protective action of L-lysine escinat (0,15 mg/kg / single dose, thiotriazolin (25 mg/kg / single dose, aprotinin (gordox (10,000 units/kg / single dose in sequential modeling of standard levels increasing of intra-abdominal hypertension (IAH — 50, 100, 150, 200, 250, 300, 350 m H2O, and also of tolperison (mydocalm (5 mg/kg / single dose on modeling of stable 3-hour IAH 200 m H2O. The IAH modeling was performed by means of stand of our construction. Under the influence of IAH the compensated metabolic acidosis in intestinal venous blood with a compensative hyperpnoe develops, decline of oxygen tension in tissues and activating of a limited proteolysis as well as decline of its inhibitors activity in intestinal venous blood occur. By the degree of metabolic acidosis prevention investigational preparations were distributed as follows gordox > thiotriazolin = L-lysine escinat = mydocalm, and by prevention of decline of oxygen tension in tissues — thiotriazolin > L-lysine escinat > mydocalm > gordox, it is is connected with different rate of methabolic products excretion into the blood, due to the influence on blood circulation and transcapilary exchange. By the degree of prevention of proteolytic activity and inhibitory potential changes, investigational preparations were distributed as follows: gordox > mydocalm > thiotriazolin > L-lysine escinat, this is connected with inhibition of proteolysis in gordox, and in other ones – with reduction of ischemic damage of tissues. Owing to different mechanism of action thiotriazolin, L-lysine escinat and mydocalm may be simultaneously recommended for a conservative treatment of patients with intraabdominal hypertension syndrome.

EPR oxygen imaging and hyperpolarized (13) C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate

DEFF Research Database (Denmark)

Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu

2013-01-01

The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation and promote glycolysis for energy production. Thereby, inhibition of glycolysis has...... the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate blocks glycolysis pathway by inhibiting hypoxia inducible enzymes and enhanced cytotoxicity of 3-bromopyruvate under...

EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as non-invasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate

Science.gov (United States)

Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu; Morris, H. Douglas; Munasinghe, Jeeva P.; Lizak, Martin; Merkle, Hellmut; Ardenkjaer-Larsen, Jan Henrik; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Koretsky, Alan P.; Mitchell, James B.; Krishna, Murali C.

2012-01-01

The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation, and promote glycolysis for energy production. Thereby, inhibition of glycolysis has the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate (3-BP) blocks glycolysis pathway by inhibiting hypoxia inducible enzymes, and enhanced cytotoxicity of 3-BP under hypoxic conditions has been reported in vitro. However, the efficacy of 3-BP was substantially attenuated in hypoxic tumor regions (pO2 < 10 mmHg) in vivo using squamous cell carcinoma (SCCVII)-bearing mouse model. Metabolic MRI studies using hyperpolarized 13C-labeled pyruvate showed that monocarboxylate transporter-1 (MCT1) is the major transporter for pyruvate and the analog 3-BP in SCCVII tumor. The discrepant results between in vitro and in vivo data were attributed to biphasic oxygen dependent expression of MCT1 in vivo. Expression of MCT1 was enhanced in moderately hypoxic (8–15 mmHg) tumor regions, but down regulated in severely hypoxic (< 5 mmHg) tumor regions. These results emphasize the importance of non-invasive imaging biomarkers to confirm the action of hypoxia-activated drugs. PMID:22692861

Optical Imaging of Tumor Response to Hyperbaric Oxygen Treatment and Irradiation in an Orthotopic Mouse Model of Head and Neck Squamous Cell Carcinoma

NARCIS (Netherlands)

J.A.M. Braks (Joanna); L. Spiegelberg (Linda); S. Koljenović (Senada); Y. Ridwan (Yanto); S. Keereweer (Stijn); R. Kanaar (Roland); E.B. Wolvius (Eppo); J. Essers (Jeroen)

2015-01-01

textabstractPurpose: Hyperbaric oxygen therapy (HBOT) is used in the treatment of radiation-induced tissue injury but its effect on (residual) tumor tissue is indistinct and therefore investigated in this study. Procedures: Orthotopic FaDu tumors were established in mice, and the response of the

Oxygenation measurements in head and neck cancers during hyperbaric oxygenation

International Nuclear Information System (INIS)

Becker, A.; Kuhnt, T.; Dunst, J.; Liedtke, H.; Krivokuca, A.; Bloching, M.

2002-01-01

Background: Tumor hypoxia has proven prognostic impact in head and neck cancers and is associated with poor response to radiotherapy. Hyperbaric oxygenation (HBO) offers an approach to overcome hypoxia. We have performed pO 2 measurements in selected patients with head and neck cancers under HBO to determine in how far changes in the oxygenation occur and whether a possible improvement of oxygenation parameters is maintained after HBO. Patients and Methods: Seven patients (five male, two female, age 51-63 years) with squamous cell cancers of the head and neck were investigated (six primaries, one local recurrence). The median pO 2 prior to HBO was determined with the Eppendorf histograph. Sites of measurement were enlarged cervical lymph nodes (n = 5), the primary tumor (n = 1) and local recurrence (n = 1). Patients then underwent HBO (100% O 2 at 240 kPa for 30 minutes) and the continuous changes in the oxygenation during HBO were determined with a Licox probe. Patients had HBO for 30 minutes (n = 6) to 40 minutes (n = 1). HBO was continued because the pO 2 had not reached a steady state after 30 minutes. After decompression, patients ventilated pure oxygen under normobaric conditions and the course of the pO 2 was further measured over about 15 minutes. Results: Prior to HBO, the median tumor pO 2 in the Eppendorf histography was 8.6 ± 5.4 mm Hg (range 3-19 mm Hg) and the pO 2 measured with the Licox probe was 17.3 ± 25.5 mm Hg (range 0-73 mm Hg). The pO 2 increased significantly during HBO to 550 ± 333 mm Hg (range 85-984 mm Hg, p = 0.018). All patients showed a marked increase irrespective of the oxygenation prior to HBO. The maximum pO 2 in the tumor was reached after 10-33 minutes (mean 17 minutes). After leaving the hyperbaric chamber, the pO 2 was 282 ± 196 mm Hg. All patients maintained an elevated pO 2 for further 5-25 minutes (138 ± 128 mm Hg, range 42-334 mm Hg, p = 0.028 vs the pO 2 prior to HBO). Conclusions: Hyperbaric oxygenation resulted in a

Prediction of inspired oxygen fraction for targeted arterial oxygen tension following open heart surgery in non-smoking and smoking patients.

Science.gov (United States)

Bou-Khalil, Pierre; Zeineldine, Salah; Chatburn, Robert; Ayyoub, Chakib; Elkhatib, Farouk; Bou-Akl, Imad; El-Khatib, Mohamad

2017-10-01

Simple and accurate expressions describing the P a O 2 -F i O 2 relationship in mechanically ventilated patients are lacking. The current study aims to validate a novel mathematical expression for accurate prediction of the fraction of inspired oxygen that will result in a targeted arterial oxygen tension in non-smoking and smoking patients receiving mechanical ventilation following open heart surgeries. One hundred P a O 2 -F i O 2 data pairs were obtained from 25 non-smoking patients mechanically ventilated following open heart surgeries. One data pair was collected at each of F i O 2 of 40, 60, 80, and 100% while maintaining same mechanical ventilation support settings. Similarly, another 100 hundred P a O 2 -F i O 2 data pairs were obtained from 25 smoking patients mechanically ventilated following open heart surgeries. The utility of the new mathematical expression in accurately describing the P a O 2 -F i O 2 relationship in these patients was assessed by the regression and Bland-Altman analyses. Significant correlations were seen between the true and estimated F i O 2 values in non-smoking (r 2  = 0.9424; p < 0.05) and smoking (r 2  = 0.9466; p < 0.05) patients. Tight biases between the true and estimated F i O 2 values for non-smoking (3.1%) and smoking (4.1%) patients were observed. Also, significant correlations were seen between the true and estimated P a O 2 /F i O 2 ratios in non-smoking (r 2  = 0.9530; p < 0.05) and smoking (r 2  = 0.9675; p < 0.05) patients. Tight biases between the true and estimated P a O 2 /F i O 2 ratios for non-smoking (-18 mmHg) and smoking (-16 mmHg) patients were also observed. The new mathematical expression for the description of the P a O 2 -F i O 2 relationship is valid and accurate in non-smoking and smoking patients who are receiving mechanical ventilation for post cardiac surgery.

Capillary-oxygenation-level-dependent near-infrared spectrometry in frontal lobe of humans

NARCIS (Netherlands)

Rasmussen, Peter; Dawson, Ellen A.; Nybo, Lars; van Lieshout, Johannes J.; Secher, Niels H.; Gjedde, Albert

2007-01-01

Brain function requires oxygen and maintenance of brain capillary oxygenation is important. We evaluated how faithfully frontal lobe near-infrared spectroscopy (NIRS) follows haemoglobin saturation (SCap) and how calculated mitochondrial oxygen tension (PMitoO2) influences motor performance. Twelve

Cerebral oxygenation is reduced during hyperthermic exercise in humans

DEFF Research Database (Denmark)

Rasmussen, Peter; Nybo, Lars; Volianitis, S.

2010-01-01

Abstract Aim: Cerebral mitochondrial oxygen tension (P(mito)O(2)) is elevated during moderate exercise, while it is reduced when exercise becomes strenuous, reflecting an elevated cerebral metabolic rate for oxygen (CMRO(2)) combined with hyperventilation-induced attenuation of cerebral blood flo...

Evaluation and Immunohistochemical Qualification of Carbogen-Induced ΔR{sub 2}* as a Noninvasive Imaging Biomarker of Improved Tumor Oxygenation

Energy Technology Data Exchange (ETDEWEB)

Baker, Lauren C.J., E-mail: lauren.baker@icr.ac.uk [Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey (United Kingdom); Boult, Jessica K.R.; Jamin, Yann; Gilmour, Lesley D.; Walker-Samuel, Simon; Burrell, Jake S. [Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey (United Kingdom); Ashcroft, Margaret [Division of Medicine, Centre for Cell Signalling and Molecular Genetics, University College London, London (United Kingdom); Howe, Franklyn A. [St. George' s, University of London, London (United Kingdom); Griffiths, John R. [Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Raleigh, James A. [Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina (United States); Kogel, Albert J. van der [University of Nijmegen Medical Centre, Nijmegen (Netherlands); Robinson, Simon P. [Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey (United Kingdom)

2013-09-01

Purpose: To evaluate and histologically qualify carbogen-induced ΔR{sub 2}* as a noninvasive magnetic resonance imaging biomarker of improved tumor oxygenation using a double 2-nitroimidazole hypoxia marker approach. Methods and Materials: Multigradient echo images were acquired from mice bearing GH3 prolactinomas, preadministered with the hypoxia marker CCI-103F, to quantify tumor R{sub 2}* during air breathing. With the mouse remaining positioned within the magnet bore, the gas supply was switched to carbogen (95% O{sub 2}, 5% CO{sub 2}), during which a second hypoxia marker, pimonidazole, was administered via an intraperitoneal line, and an additional set of identical multigradient echo images acquired to quantify any changes in tumor R{sub 2}*. Hypoxic fraction was quantified histologically using immunofluorescence detection of CCI-103F and pimonidazole adduct formation from the same whole tumor section. Carbogen-induced changes in tumor pO{sub 2} were further validated using the Oxylite fiberoptic probe. Results: Carbogen challenge significantly reduced mean tumor R{sub 2}* from 116 ± 13 s{sup −1} to 97 ± 9 s{sup −1} (P<.05). This was associated with a significantly lower pimonidazole adduct area (2.3 ± 1%), compared with CCI-103F (6.3 ± 2%) (P<.05). A significant correlation was observed between ΔR{sub 2}* and Δhypoxic fraction (r=0.55, P<.01). Mean tumor pO{sub 2} during carbogen breathing significantly increased from 6.3 ± 2.2 mm Hg to 36.0 ± 7.5 mm Hg (P<.01). Conclusions: The combined use of intrinsic susceptibility magnetic resonance imaging with a double hypoxia marker approach corroborates carbogen-induced ΔR{sub 2}* as a noninvasive imaging biomarker of increased tumor oxygenation.

Oxygen status during haemodialysis. The Cord-Group

DEFF Research Database (Denmark)

Nielsen, A L; Jensen, H Æ; Hegbrant, J

1995-01-01

Hypoxia during haemodialysis, mainly acetate, has been reported several times. In our study we have monitored oxygen status during 258 bicarbonate haemodialyses. A significant drop below 80 mmHg in mean oxygen tension occurred. Mean oxygen saturation reflected this drop but did not reach levels...... below 90%. The mean oxygen concentration was on the whole critical low, though slightly increasing during each haemodialysis session due to ultrafiltration. It is concluded that both hypoxia and hypoxaemia do occur during bicarbonate haemodialysis. To a group of patients generally having limited cardiac...... reserves, a poor oxygen status is a potentially serious complication to haemodialysis. Monitoring oxygen status is thus advisable....

Effect of epidural blockade and oxygen therapy on changes in subcutaneous oxygen tension after abdominal surgery

DEFF Research Database (Denmark)

Rosenberg, J; Pedersen, U; Erichsen, C J

1994-01-01

The effect of oxygen therapy (37% by face mask) and epidural local anesthetic blockade (9 ml 0.5% bupivacaine at Th9-11 level) on wound oxygenation was evaluated in eight otherwise healthy patients undergoing elective colorectal resection. The patients were monitored continuously for subcutaneous...... without epidural blockade and 15 (10-20) min with blockade (P surgery....

Tension Headache

Science.gov (United States)

... tight band around your head. A tension headache (tension-type headache) is the most common type of headache, and ... Headache after a head injury, especially if the headache gets worse ... tension or stress. But research suggests muscle contraction isn't the ...

Spontaneous calcium waves in Bergman glia increase with age and hypoxia and may reduce tissue oxygen.

Science.gov (United States)

Mathiesen, Claus; Brazhe, Alexey; Thomsen, Kirsten; Lauritzen, Martin

2013-02-01

Glial calcium (Ca(2+)) waves constitute a means to spread signals between glial cells and to neighboring neurons and blood vessels. These waves occur spontaneously in Bergmann glia (BG) of the mouse cerebellar cortex in vivo. Here, we tested three hypotheses: (1) aging and reduced blood oxygen saturation alters wave activity; (2) glial Ca(2+) waves change cerebral oxygen metabolism; and (3) neuronal and glial wave activity is correlated. We used two-photon microscopy in the cerebellar cortexes of adult (8- to 15-week-old) and aging (48- to 80-week-old) ketamine-anesthetized mice after bolus loading with OGB-1/AM and SR101. We report that the occurrence of spontaneous waves is 20 times more frequent in the cerebellar cortex of aging as compared with adult mice, which correlated with a reduction in resting brain oxygen tension. In adult mice, spontaneous glial wave activity increased on reducing resting brain oxygen tension, and ATP-evoked glial waves reduced the tissue O(2) tension. Finally, although spontaneous Purkinje cell (PC) activity was not associated with increased glia wave activity, spontaneous glial waves did affect intracellular Ca(2+) activity in PCs. The increased wave activity during aging, as well as low resting brain oxygen tension, suggests a relationship between glial waves, brain energy homeostasis, and pathology.

Ambient oxygen promotes tumorigenesis.

Directory of Open Access Journals (Sweden)

Ho Joong Sung

2011-05-01

Full Text Available Oxygen serves as an essential factor for oxidative stress, and it has been shown to be a mutagen in bacteria. While it is well established that ambient oxygen can also cause genomic instability in cultured mammalian cells, its effect on de novo tumorigenesis at the organismal level is unclear. Herein, by decreasing ambient oxygen exposure, we report a ∼50% increase in the median tumor-free survival time of p53-/- mice. In the thymus, reducing oxygen exposure decreased the levels of oxidative DNA damage and RAG recombinase, both of which are known to promote lymphomagenesis in p53-/- mice. Oxygen is further shown to be associated with genomic instability in two additional cancer models involving the APC tumor suppressor gene and chemical carcinogenesis. Together, these observations represent the first report directly testing the effect of ambient oxygen on de novo tumorigenesis and provide important physiologic evidence demonstrating its critical role in increasing genomic instability in vivo.

Galectin-1 Inhibitor OTX008 Induces Tumor Vessel Normalization and Tumor Growth Inhibition in Human Head and Neck Squamous Cell Carcinoma Models.

Science.gov (United States)

Koonce, Nathan A; Griffin, Robert J; Dings, Ruud P M

2017-12-09

Galectin-1 is a hypoxia-regulated protein and a prognostic marker in head and neck squamous cell carcinomas (HNSCC). Here we assessed the ability of non-peptidic galectin-1 inhibitor OTX008 to improve tumor oxygenation levels via tumor vessel normalization as well as tumor growth inhibition in two human HNSCC tumor models, the human laryngeal squamous carcinoma SQ20B and the human epithelial type 2 HEp-2. Tumor-bearing mice were treated with OTX008, Anginex, or Avastin and oxygen levels were determined by fiber-optics and molecular marker pimonidazole binding. Immuno-fluorescence was used to determine vessel normalization status. Continued OTX008 treatment caused a transient reoxygenation in SQ20B tumors peaking on day 14, while a steady increase in tumor oxygenation was observed over 21 days in the HEp-2 model. A >50% decrease in immunohistochemical staining for tumor hypoxia verified the oxygenation data measured using a partial pressure of oxygen (pO₂) probe. Additionally, OTX008 induced tumor vessel normalization as tumor pericyte coverage increased by approximately 40% without inducing any toxicity. Moreover, OTX008 inhibited tumor growth as effectively as Anginex and Avastin, except in the HEp-2 model where Avastin was found to suspend tumor growth. Galectin-1 inhibitor OTX008 transiently increased overall tumor oxygenation via vessel normalization to various degrees in both HNSCC models. These findings suggest that targeting galectin-1-e.g., by OTX008-may be an effective approach to treat cancer patients as stand-alone therapy or in combination with other standards of care.

Changes in the metabolic footprint of placental explant-conditioned medium cultured in different oxygen tensions from placentas of small for gestational age and normal pregnancies.

LENUS (Irish Health Repository)

Horgan, R P

2012-01-31

Being born small for gestational age (SGA) confers significantly increased risks of perinatal morbidity and mortality. Accumulating evidence suggests that an SGA fetus results from a poorly perfused and abnormally developed placenta. Some of the placental features seen in SGA, such as abnormal cell turnover and impaired nutrient transport, can be reproduced by culture of placental explants in hypoxic conditions. Metabolic footprinting offers a hypothesis-generating strategy to investigate factors absorbed by and released from this tissue in vitro. Previously, metabolic footprinting of the conditioned culture media has identified differences in placental explants cultured under normoxic and hypoxic conditions and between normal pregnancies and those complicated by pre-eclampsia. In this study we aimed to examine the differences in the metabolic footprint of placental villous explants cultured at different oxygen (O(2)) tensions between women who deliver an SGA baby (n = 9) and those from normal controls (n = 8). Placental villous explants from cases and controls were cultured for 96 h in 1% (hypoxic), 6% (normoxic) and 20% (hyperoxic) O(2). Metabolic footprints were analysed by Ultra Performance Liquid Chromatography coupled to an electrospray hybrid LTQ-Orbitrap Mass Spectrometry (UPLC-MS). 574 metabolite features showed significant difference between SGA and normal at one or more of the oxygen tensions. SGA explant media cultured under hypoxic conditions was observed, on a univariate level, to exhibit the same metabolic signature as controls cultured under normoxic conditions in 49% of the metabolites of interest, suggesting that SGA tissue is acclimatised to hypoxic conditions in vivo. No such behaviour was observed under hyperoxic culture conditions. Glycerophospholipid and tryptophan metabolism were highlighted as areas of particular interest.

Interstitial administration of perfluorochemical emulsions for reoxygenation of hypoxic tumor cells

International Nuclear Information System (INIS)

Woo, D.V.; Seegenschmiedt, H.; Schweighardt, F.K.; Emrich, J.; McGarvey, K.; Caridi, M.; Brady, L.W.

1987-01-01

Microparticulate perfluorochemical (PFC) emulsions have the capacity to solubilize significant quantities of oxygen compared to water. Although systemic administration of such emulsions may enhance oxygen delivery to some tissues, hypoxic tumor cells have marginal vascular supplies. The authors report studies which directly attempt to oxygenate hypoxic tumor cells by interstitial administration of oxygenated PFC emulsions followed by radiation therapy. Fortner MMI malignant melanomas (21 day old) grown in Syrian Golden hamsters were injected directly with either oxygenated PFC emulsions or Ringers solution. The volume of test substance administered was equal to 50% of the tumor volume. The tumors were immediately irradiated with 25 Gy of 10 MeV photons (Clinac 18). The tumor dimensions were measured daily post irradiation and the tumor doubling time determined. The results suggest that interstitial administration of oxygenated PFC emulsions directly into tumors followed by radiation therapy may increase the likelihood of killing hypoxic tumor cells

A preliminary study of murine walker-256 tumor hypoxia detected by blood oxygen level dependent-MR

International Nuclear Information System (INIS)

Zhang Shengjian; Mao Jian; Wu Bin; Peng Weijun

2013-01-01

Objective: To establish Walker-256 transplantation tumor model in SD Rats. To study of R_2"* signal changes on murine Walker-256 tumor after inhaling Carbogen by blood oxygen level dependent (BOLD)-MR, and to explore the feasibility of BOLD-MRI on detecting tumor hypoxia. Methods: Walker-256 tumor cell implanted subcutaneously in right lower abdomen of 95 female SD rats. MR was performed on the tumor-forming rats when the maximum diameter of tumor reached 1-3 cm, using a 3.0 T MR scanner equipped with a 3 inch animal surface coil. BOLD-MRI was done by using a multiecho SPGR sequence during inhaling air and at 10 minute after inhaling Carbogen, respectively. All images were transferred to GE ADW 4.3 workstation, then a baseline R_2"* (R_2"* a) and R_2"* (R_2"* b) after inhaling Carbogen of tumor was calculated using R_2 Star analysis software and ΔR_2"* was calculated through ΔR_2"* = R_2"* b -R_2"* a", meanwhile the volume of tumor were calculated as well. The difference of R_2"* signal pre and post-inhaling of Carbogen was compared with a paired t test, Pearson correlation was calculated between R_2"* a, ΔR_2"* and the volume of tumor, respectively. The correlation between ΔR_2"* and R_2"* a was also assessed by Pearson correlation. Results: Sixty-eight of ninety-five female SD rats formed the tumor (71.6%). The volume of tumor was from 352 to 13 173 mm"3. Mean ΔR_2"* decreased significantly (-2.26 ± 3.90) s"-"1 from (41.18 ± 22.29) s"-"1 during breathing air to (38.91 ± 21.35) s"-"1 10 min after inhaling Carbogen (t = 4.01, P 0.05). Conclusions: BOLD-MRI can detect the R_2"* signal change of murine Walker-256 tumor pre-and post-inhaling of Carbogen. The R_2"* signal showed significant decrease after inhaling Carbogen, however, the individual variation was remarkable. (authors)

Correlation of in vivo tumor response and singlet oxygen luminescence detection in mTHPC-mediated photodynamic therapy

Directory of Open Access Journals (Sweden)

Brian C. Wilson

2015-01-01

Full Text Available Excited-state singlet oxygen (1O2, generated during photodynamic therapy (PDT, is believed to be the primary cytotoxic agent with a number of clinically approved photosensitizers. Its relative concentration in cells or tissues can be measured directly through its near-infrared (NIR luminescence emission, which has correlated well with in vitro cell and in vivo normal skin treatment responses. Here, its correlation with the response of tumor tissue in vivo is examined, using the photosensitizer meso-tetrahydroxyphenylchlorin (mTHPC in an animal model comprising luciferase- and green fluorescent protein (GFP-transduced gliosarcoma grown in a dorsal window chamber. The change in the bioluminescence signal, imaged pretreatment and at 2, 5 and 9 d post treatment, was used as a quantitative measure of the tumor response, which was classified in individual tumors as "non", "moderate" and "strong" in order to reduce the variance in the data. Plotting the bioluminescence-based response vs the 1O2 counts demonstrated clear correlation, indicating that 1O2 luminescence provides a valid dosimetric technique for PDT in tumor tissue.

The effect of oxygen tension on porcine embryonic development is dependent on embryo type

DEFF Research Database (Denmark)

Booth, Paul; Holm, Peter; Callesen, Henrik

2005-01-01

of the embryos prior to culture--a study was performed to examine the effect of O2 tension during culture on three different types of porcine embryos, namely: in vivo flushed embryos, and in vitro matured oocytes either fertilized in vitro or parthenogenetically activated. In vivo embryos (n=208) were flushed...... supplemented with 10% calf serum until day 7. The gas environment for IVM/IVF was 5% CO2 in air, while that for IVC was either 5% CO2 in air or 5% O2, 5% CO2 and 90% N2. Low O2 tension increased both day 7 blastocyst rates (high versus low O2, respectively; 9.3+/-2.9%: 26/280; 23.9+/-4.2%: 71/293; P...

Radiosensitizers and the oxygen effects in mammalian cells

International Nuclear Information System (INIS)

Millar, B.C.; Fielden, E.M.; Steele, J.J.

1979-01-01

The survival curves for Chinese Hamster cells irradiated under various oxygen tensions have been determined. The variation in OER with oxygen concentration shows two distinct components. Between 1.4 and 7.0 μM the OER is constant with a value of 1.9. Experiments with nitroaromatic radiosensitizers in combination with low concentrations of oxygen show that they can all mimic the 'low concentration' oxygen effect. Of the compounds tested only misonidazole can apparently mimic the 'high concentration' oxygen effect although the full OER cannot be obtained with the authors cell line because of toxicity by the sensitizer. (Auth.)

A Comparative pO2 Probe and [18F]-Fluoro-Azomycinarabino-Furanoside ([18F]FAZA) PET Study Reveals Anesthesia-Induced Impairment of Oxygenation and Perfusion in Tumor and Muscle.

Science.gov (United States)

Mahling, Moritz; Fuchs, Kerstin; Thaiss, Wolfgang M; Maier, Florian C; Feger, Martina; Bukala, Daniel; Harant, Maren; Eichner, Martin; Reutershan, Jörg; Lang, Florian; Reischl, Gerald; Pichler, Bernd J; Kneilling, Manfred

2015-01-01

CT26 colon carcinoma-bearing mice were anesthetized with isoflurane (IF) or ketamine/xylazine (KX) while breathing air or oxygen (O2). We performed 10 min static PET scans 1 h, 2 h and 3 h after [18F]FAZA injection and calculated the [18F]FAZA-uptake and tumor-to-muscle ratios (T/M). In another experimental group, we placed a pO2 probe in the tumor as well as in the gastrocnemius muscle to measure the pO2 and perfusion. Ketamine/xylazine-anesthetized mice yielded up to 3.5-fold higher T/M-ratios compared to their isoflurane-anesthetized littermates 1 h, 2 h and 3 h after [18F]FAZA injection regardless of whether the mice breathed air or oxygen (3 h, KX-air: 7.1 vs. IF-air: 1.8, p = 0.0001, KX-O2: 4.4 vs. IF-O2: 1.4, p pO2 probe measurements yielded enhanced intra-tumoral pO2 values in air- and oxygen-breathing ketamine/xylazine-anesthetized mice compared to isoflurane-anesthetized mice (KX-air: 1.01 mmHg, IF-air: 0.45 mmHg; KX-O2 9.73 mmHg, IF-O2: 6.25 mmHg). Muscle oxygenation was significantly higher in air-breathing isoflurane-anesthetized (56.9 mmHg) than in ketamine/xylazine-anesthetized mice (33.8 mmHg, p = 0.0003). [18F]FAZA tumor uptake was highest in ketamine/xylazine-anesthetized mice regardless of whether the mice breathed air or oxygen. The generally lower [18F]FAZA whole-body uptake in isoflurane-anesthetized mice could be due to the higher muscle pO2-values in these mice compared to ketamine/xylazine-anesthetized mice. When performing preclinical in vivo hypoxia PET studies, oxygen should be avoided, and ketamine/xylazine-anesthesia might alleviate the identification of tumor hypoxia areals.

Tumor hypoxia and the positron data paradox

International Nuclear Information System (INIS)

De Schryver, A.; De Vis, K.; Schelstraete, K.

1991-01-01

It is possible using positron emission tomography (PET) techniques to obtain a fair estimate of both oxygen uptake and blood flow in human tumors. Oxygen uptake is measured by making use of tomographic recording during inhalation of oxygen 15, while blood flow can be determined either after injection of 13 N-ammonia or inhalation of 15 O-carbon dioxyde. A tomographic view is shown of a large sarcoma of right thigh, with ample oxygen concentration in its peripheral parts. Their oxygen concentration is higher than in surrounding normal tissues. The central core of the tumor, however, is clearly much less well provided with oxygen -this is what was expected. A similar picture emerges when blood flow is studied, f.ex, as in this case, using C 15 O 2 inhalation. Again, not surprising. There is, however, one more thing we can do: let the computer calculate the amount of oxygen extracted by the tumor as a function of blood flow (oxygen extraction ratio or OE x R) - pixel by pixel. If done so, it appears that those tumor parts where blood flow is low do not -as expected- extract more oxygen from whatever reduced flow is reaching them, than parts with normal flow do. Indeed, the resulting picture of the OE x R distribution denotes a remarkable homogeneity whether in the central or in the peripheral parts of the tumor. (author). 3 refs.; 1 tab

Study of cerebral blood flow and oxygen utilization in the edematous area and ipsilateral hemispheric gray matter using positron emission tomography in brain tumors

International Nuclear Information System (INIS)

Ikeda, Yusuke

1990-01-01

We measured the cerebral blood flow and oxygen utilization of the peritumoral white matter and ipsilateral hemispheric gray matter in 50 patients with brain tumors using Positron Emission Tomography (PET). The intraaxial tumors consisted of 34 cases (25 of gliomas, 6 of metastatic tumors, and 3 others), white the extraaxial tumors (all of meningiomas) were 16 cases. The cases were divided into 2 groups on the basis of the Xray CT scan findings. The cases of Edema (+) group showed moderate or large peritumoral edema in the white matter on the Xray CT scan, while Edema (-) group showed no or small edema. The method of PET study was the 15 O steady state inhalation technique by Frackoviak's method. ROIs (region of interest) were set on the peritumoral white matter and the ipsilateral hemispheric gray matter, and the mean CBF, OEF and CMRO2 values of the white and gray matter were calculated. In the Edema (+) group, the mean values of blood flow and oxygen utilization were low in the peritumoral white matter, and there were no obvious differences of values between intra and extraaxial tumors. But, the values in the ipsilateral hemispheric gray matter of intraaxial tumors were lower than those of extraaxial tumor. In the Edema (-) group, the mean values were almost normal in the white and gray matter, and there were no differences between intra and extraaxial tumors. The consideration about significance of the above stated results was discussed added with literature. (author)

Spin Lattice Relaxation EPR pO2 Images May Direct the Location of Radiation Tumor Boosts to Enhance Tumor Cure.

Science.gov (United States)

Epel, Boris; Krzykawska-Serda, Martyna; Tormyshev, Victor; Maggio, Matthew C; Barth, Eugene D; Pelizzari, Charles A; Halpern, Howard J

2017-12-01

Radiation treatment success and high tumor oxygenation and success have been known to be highly correlated. This suggests that radiation therapy guided by images of tumor regions with low oxygenation, oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. Before applying the technique to human subjects, OGRT needs to be tested in animals, most easily in rodents. Electron paramagnetic resonance imaging provides quantitative maps of tissue and tumor oxygen in rodents with 1 mm spatial resolution and 1 torr pO 2 resolution at low oxygen levels. The difficulty of using mouse models is their small size and that of their tumors. To overcome this we used XRAD225Cx micro-CT/ therapy system and 3D printed conformal blocks. Radiation is delivered first to a uniform 15% tumor control dose for the whole tumor and then a boost dose to either hypoxic tumor regions or equal volumes of well oxygenated tumor. Delivery of the booster dose used a multiple beam angles to deliver radiation beams whose shape conforms to that of all hypoxic regions or fully avoids those regions. To treat/avoid all hypoxic regions we used individual radiation blocks 3D-printed from acrylonitrile butadiene styrene polymer infused with tungsten particles fabricated immediately after imaging to determine regions with pO 2 less than 10 torr. Preliminary results demonstrate the efficacy of the radiation treatment with hypoxic boosts with syngeneic FSa fibrosarcoma tumors in the legs of C3H mice.

Diltiazem enhances tumor blood flow: MRI study in a murine tumor

International Nuclear Information System (INIS)

Muruganandham, M.; Kasiviswanathan, A.; Jagannathan, N.R.; Raghunathan, P.; Jain, P.C.; Jain, V.

1999-01-01

Purpose: Diltiazem, a calcium-channel blocker, is known to differentially influence the radiation responses of normal and murine tumor tissues. To elucidate the underlying mechanisms, the effects of diltiazem on the radiation response of Ehrlich ascites tumor (EAT) in mice have been investigated, and the hemodynamic changes induced by diltiazem in tumor and normal muscle have been studied using magnetic resonance imaging (MRI) techniques. Methods and Materials: Ehrlich ascites tumors were grown subcutaneously in Swiss albino strain A mice. Dynamic gadodiamide and blood oxygen level dependent (BOLD) contrast enhanced 1 H MR imaging studies of EAT and normal muscle were performed after administration of diltiazem in mice using a 4.7 Tesla MR scanner. Tumor radiotherapy experiments (total dose = 10 Gy, 0.4-0.5 Gy/min, single fraction) were carried out with 30 min preadministration of diltiazem (27.5 or 55 mg/kg i.p.) to EAT-bearing mice using a teletherapy machine. Results: The diltiazem+ radiation treated group showed significant tumor regression (in congruent with 65% of the animals) and enhanced animal survival. MR-gadodiamide contrast kinetics revealed a higher magnitude of signal enhancement in diltiazem treated groups as compared to the controls. The observed changes in the magnitude of kinetic parameters were the same for both tumor and normal muscle. BOLD-MR images at 30 min after diltiazem administration showed a 25% and 8% (average) intensity enhancement from their basal values in tumor and normal muscle regions, respectively. The control group showed no significant changes. Conclusion: The present studies demonstrate the radiosensitization potential of diltiazem in the mice EAT model. The enhanced radiation response observed with diltiazem correlates with the diltiazem-induced increase in tumor blood flow (TBF) and tumor oxygenation. The present results also demonstrate the applications of BOLD-MR measurements in investigating the alterations in tumor

Radiation-induced DNA damage in tumors and normal tissues. III. Oxygen dependence of the formation of strand breaks and DNA-protein crosslinks

International Nuclear Information System (INIS)

Zhang, H.; Wallen, C.A.; Wheeler, K.T.; Joch, C.J.

1995-01-01

Results from several laboratories, including ours, have suggested that measurements of radiation-induced DNA strand breaks and DNA-protein crosslinks (DPCs) may be used to estimate the hypoxic fraction or fractional hypoxic volume of tumors and normal tissues. This suggestion has been predicated on both published and nonpublished information that (1) the oxygen dependence of the formation of strand breaks in irradiated mammalian cells is similar to the oxygen dependence of radiation-produced cell killing, and (2) the oxygen dependence of the formation of DPCs in irradiated mammalian cells is the mirror image of the oxygen dependence of radiation-induced cell killing. However, the published studies that attempted to determine the relationship between the oxygen dependence of the formation of strand breaks and the radiation sensitivity of mammalian cells were not performed at 37 degrees C, the exact oxygen concentrations were not always known, and the results were conflicting. In addition, most of the data on the oxygen dependence of the formation of DPCs are unpublished. Consequently, we have undertaken a comprehensive investigation of one cell line, 9L/Ro rat brain tumor cells, to determine if the shape of the oxygen dependence curve and the K m value for radiation-induced strand breaks and DPCs were similar when 9L cells were irradiated under both ideal gas-liquid equilibrium conditions at 4 degrees C and nonideal gas-liquid equilibrium conditions at 37 degrees C. At 4 degrees C under ideal gas-liquid equilibrium conditions, the K m for the formation of strand breaks was approximately 0.0045 mM, and Km for radiation sensitivity was approximately 0.005mM. A similar comparison for the formation of DPCs at 4 degrees C could not be made, because the efficiency of the formation of DPC was much lower at 4 degrees C than at 37 degrees C. 30 refs., 3 figs

The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy

International Nuclear Information System (INIS)

Gray, L.H.; Conger, A.D.; Ebert, M.; Hornsey, S.; Scott, O.C.A.

1984-01-01

The sensitivity of tumour cells to X rays has been shown to be about three times as great when irradiated in a well-oxygenated medium as under anoxic conditions. The manner in which sensitivity depends on oxygen tension closely resembles that found by other workers for plant and insect tissues. The sensitivity of the tumour cells to fast neutron radiation is only slightly affected by oxygen tension. Consideration is given to the supply of oxygen to tissues as a factor in radiotherapy, and it is concluded on the basis of existing knowledge that in certain circumstances the effectiveness of X-ray treatment might be increased if the patient were breathing oxygen at the time of irradiation

Real-Time Monitoring of Singlet Oxygen and Oxygen Partial Pressure During the Deep Photodynamic Therapy In Vitro.

Science.gov (United States)

Li, Weitao; Huang, Dong; Zhang, Yan; Liu, Yangyang; Gu, Yueqing; Qian, Zhiyu

2016-09-01

Photodynamic therapy (PDT) is an effective noninvasive method for the tumor treatment. The major challenge in current PDT research is how to quantitatively evaluate therapy effects. To our best knowledge, this is the first time to combine multi-parameter detection methods in PDT. More specifically, we have developed a set of system, including the high-sensitivity measurement of singlet oxygen, oxygen partial pressure and fluorescence image. In this paper, the detection ability of the system was validated by the different concentrations of carbon quantum dots. Moreover, the correlation between singlet oxygen and oxygen partial pressure with laser irradiation was observed. Then, the system could detect the signal up to 0.5 cm tissue depth with 660 nm irradiation and 1 cm tissue depth with 980 nm irradiation by using up-conversion nanoparticles during PDT in vitro. Furthermore, we obtained the relationship among concentration of singlet oxygen, oxygen partial pressure and tumor cell viability under certain conditions. The results indicate that the multi-parameter detection system is a promising asset to evaluate the deep tumor therapy during PDT. Moreover, the system might be potentially used for the further study in biology and molecular imaging.

Coulomb string tension, asymptotic string tension, and the gluon chain

OpenAIRE

Greensite, Jeff; Szczepaniak, Adam P.

2014-01-01

We compute, via numerical simulations, the non-perturbative Coulomb potential of pure SU(3) gauge theory in Coulomb gauge. We find that that the Coulomb potential scales nicely in accordance with asymptotic freedom, that the Coulomb potential is linear in the infrared, and that the Coulomb string tension is about four times larger than the asymptotic string tension. We explain how it is possible that the asymptotic string tension can be lower than the Coulomb string tension by a factor of four.

Computed Tomography Demonstration of the Production and Distribution of Oxygen Gas Following Intratumoral Injection of a New Radiosensitizer (KORTUC) for Patients with Breast Cancer-Is Intratumoral Injection Not an Ideal Approach to Solve the Major Problem of Tumor Hypoxia in Radiotherapy?

Science.gov (United States)

Hayashi, Naoya; Ogawa, Yasuhiro; Kubota, Kei; Okino, Kazuhiro; Akima, Ryo; Morita-Tokuhiro, Shiho; Tsuzuki, Akira; Yaogawa, Shin; Nishioka, Akihito; Miyamura, Mitsuhiko

2016-04-01

We previously developed a new enzyme-targeting radiosensitization treatment named Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate for injection into various types of tumors. For breast cancer treatment, the radiosensitization agent was injected into the tumor tissue twice a week under ultrasonographic guidance, immediately prior to each administration of radiation therapy. At approximately three hours after the second or third injection, computed tomography (CT) was performed to confirm the production and distribution of oxygen gas generated from the KORTUC radiosensitization agent by catalysis of peroxidases contained mainly in tumor tissue. The purpose of this study was to demonstrate that tumor hypoxia could be overcome by such a procedure and to evaluate the method of intratumoral injection in terms of confirming oxygen distribution in the target tumor tissue and around the tumor to be visualized on dedicated CT imaging. Three-dimensional reconstructed maximum intensity projection imaging of contrast-enhanced breast magnetic resonance imaging was used to compare the position of the tumor and that of the generated oxygen. Distributed oxygen gas was confirmed in the tumor tissue and around it in all 10 patients examined in the study. A region of oxygen gas was measured as an average value of -457.2 Hounsfield units (HU) as a region of interest. A slightly increased HU value compared to the density of air or oxygen was considered due to the presence of tumor tissue in the low-density area on 5-mm-thick reconstructed CT imaging. The results of this study showed that intratumoral oxygen was successfully produced by intratumoral KORTUC injection under ultrasonographic guidance, and that tumor hypoxia, which is considered a main cause of radioresistance in currently used Linac (linear accelerator) radiation therapy for malignant neoplasms, could be resolved by this method.

Oxygen dynamics around buried lesser sandeels Ammodytes tobianus (Linnaeus 1785): mode of ventilation and oxygen requirements

DEFF Research Database (Denmark)

Behrens, Jane W; Stahl, Henrik J; Steffensen, John F

2007-01-01

The oxygen environment around buried sandeels (Ammodytes tobianus) was monitored by planar optodes. The oxygen penetration depth at the sediment interface was only a few mm. Thus fish, typically buried at 1-4 cm depth, were generally in anoxic sediment. However, they induced an advective transport...... down along the body, referred to as ;plume ventilation'. Yet, within approximately 30 min the oxic plume was replenished by oxygen-depleted water from the gills. The potential for cutaneous respiration by the buried fish was thus of no quantitative importance. Calculations derived by three independent...... methods (each with N=3) revealed that the oxygen uptake of sandeel buried for 6-7 h was 40-50% of previous estimates on resting respirometry of non-buried fish, indicating lower O(2) requirements during burial on a diurnal timescale. Buried fish exposed to decreasing oxygen tensions gradually approached...

Incorporating Oxygen-Enhanced MRI into Multi-Parametric Assessment of Human Prostate Cancer

Directory of Open Access Journals (Sweden)

Heling Zhou

2017-08-01

Full Text Available Hypoxia is associated with prostate tumor aggressiveness, local recurrence, and biochemical failure. Magnetic resonance imaging (MRI offers insight into tumor pathophysiology and recent reports have related transverse relaxation rate (R2* and longitudinal relaxation rate (R1 measurements to tumor hypoxia. We have investigated the inclusion of oxygen-enhanced MRI for multi-parametric evaluation of tumor malignancy. Multi-parametric MRI sequences at 3 Tesla were evaluated in 10 patients to investigate hypoxia in prostate cancer prior to radical prostatectomy. Blood oxygen level dependent (BOLD, tissue oxygen level dependent (TOLD, dynamic contrast enhanced (DCE, and diffusion weighted imaging MRI were intercorrelated and compared with the Gleason score. The apparent diffusion coefficient (ADC was significantly lower in tumor than normal prostate. Baseline R2* (BOLD-contrast was significantly higher in tumor than normal prostate. Upon the oxygen breathing challenge, R2* decreased significantly in the tumor tissue, suggesting improved vascular oxygenation, however changes in R1 were minimal. R2* of contralateral normal prostate decreased in most cases upon oxygen challenge, although the differences were not significant. Moderate correlation was found between ADC and Gleason score. ADC and R2* were correlated and trends were found between Gleason score and R2*, as well as maximum-intensity-projection and area-under-the-curve calculated from DCE. Tumor ADC and R2* have been associated with tumor hypoxia, and thus the correlations are of particular interest. A multi-parametric approach including oxygen-enhanced MRI is feasible and promises further insights into the pathophysiological information of tumor microenvironment.

Ion release from magnesium materials in physiological solutions under different oxygen tensions.

Science.gov (United States)

Feyerabend, Frank; Drücker, Heiko; Laipple, Daniel; Vogt, Carla; Stekker, Michael; Hort, Norbert; Willumeit, Regine

2012-01-01

Although magnesium as degradable biomaterial already showed clinical proof of concepts, the design of new alloys requires predictive in vitro methods, which are still lacking. Incubation under cell culture conditions to obtain "physiological" corrosion may be a solution. The aim of this study was to analyse the influence of different solutions, addition of proteins and of oxygen availability on the corrosion of different magnesium materials (pure Mg, WE43, and E11) with different surface finishing. Oxygen content in solution, pH, osmolality and ion release were determined. Corrosion led to a reduction of oxygen in solution. The influence of oxygen on pH was enhanced by proteins, while osmolality was not influenced. Magnesium ion release was solution-dependent and enhanced in the initial phase by proteins with delayed release of alloying elements. The main corrosion product formed was magnesium carbonate. Therefore, cell culture conditions are proposed as first step toward physiological corrosion.

Reduced muscle activation during exercise related to brain oxygenation and metabolism in humans

DEFF Research Database (Denmark)

Rasmussen, Peter; Nielsen, Jannie; Overgaard, M

2010-01-01

Maximal exercise may be limited by central fatigue defined as an inability of the central nervous system to fully recruit the involved muscles. This study evaluated whether a reduction in the cerebral oxygen-to-carbohydrate index (OCI) and in the cerebral mitochondrial oxygen tension relate to th...... indicating that reduced cerebral oxygenation may play a role in the development of central fatigue and may be an exercise capacity limiting factor.......Maximal exercise may be limited by central fatigue defined as an inability of the central nervous system to fully recruit the involved muscles. This study evaluated whether a reduction in the cerebral oxygen-to-carbohydrate index (OCI) and in the cerebral mitochondrial oxygen tension relate...... of perceived exertion (RPE), arm maximal voluntary force (MVC), and voluntary activation of elbow flexor muscles assessed with transcranial magnetic stimulation. Low intensity exercise did not produce any indication of central fatigue or marked cerebral metabolic deviations. Exercise in hypoxia (0.10) reduced...

Effects of hypoxia on expression of a panel of stem cell and chemosensitivity markers in glioblastoma cell line-derived spheroids

DEFF Research Database (Denmark)

Kolenda, Jesper; Jensen, Stine Skov; Aaberg-Jessen, Charlotte

Glioblastomas are the most frequent and malignant primary brain tumor. Tumor stem cells in these tumors have recently been suggested to possess innate resistance mechanisms against radiation and chemotherapy possibly explaining their high level of therapeutic resistance. Moreover tumor hypoxia...... for podoplanin, nestin and TIMP-1 as well as for Ki-67. Hif-2α, Sox-2, MGMT and MDR-1 were not detectable in normoxic and hypoxic U87 spheroids. In conclusion, the expression of tumor stem cell and chemosensitivity markers seems to depend on the oxygen tension suggesting that future development of therapeutic...... with oxygen tensions below 1-5% O2 has been attributed to play a crucial role in tumorigenesis and therapeutic resistance in glioblastoma. This is in contrast to most in vitro experiments in this field being performed in atmospheric air with 21% O2. In this study the influence of hypoxia on the expression...

Cryospectrophotometric determination of tumor intravascular oxyhemoglobin saturations: dependence on vascular geometry and tumor growth.

Science.gov (United States)

Fenton, B M; Rofstad, E K; Degner, F L; Sutherland, R M

1988-12-21

To delineate the complex relationships between overall tumor oxygenation and vascular configuration, intravascular oxyhemoglobin (HbO2) saturation distributions were measured with cryospectrophotometric techniques. Four factors related to vascular morphometry and tumor growth were evaluated: a) vessel diameter, b) distance of vessel from the tumor surface, c) tumor volume, and d) vascular density. To measure intertumor heterogeneity, two murine sarcomas (RIF-1 and KHT) and two human ovarian carcinoma xenografts (OWI and MLS) were utilized. In contrast to skeletal muscle, a preponderance of very low HbO2 saturations was observed for both large and small tumors of all lines. Saturations up to about 90% were also generally present, however, even in very large tumors. Variations in vascular configuration were predominantly tumor-line dependent rather than due to inherent characteristics of the host vasculature, and widely disparate HbO2 distributions were found for alternate lines implanted in identical host mice. Although peripheral saturations remained fairly constant with tumor growth, HbO2 values were markedly lower for vessels nearer the tumor center and further decreased with increasing tumor volume. HbO2 saturations did not change substantially with increasing vascular density (except for KHT tumors), although density did decrease with increasing distance from tumor surface. Combined effects of vessel diameter, tumor volume, and vessel location on HbO2 saturations were complex and varied markedly with both tumor line and vessel class. For specific classes, HbO2 distributions correlated closely with radiobiological hypoxic fractions, i.e., for tumor lines in which hypoxic fraction increased substantially with tumor volume, corresponding HbO2 values decreased, while for lines in which hypoxic fraction remained constant, HbO2 values also were unchanged. Although these trends may also be a function of differing oxygen consumption rates between tumor lines

Macrophages Under Low Oxygen Culture Conditions Respond to Ion Parametric Resonance Magnetic Fields

Science.gov (United States)

Macrophages, when entering inflamed tissue, encounter low oxygen tension due to the impairment of blood supply and/or the massive infiltration of cells that consume oxygen. Previously, we showed that such macrophages release more bacteriotoxic hydrogen peroxide (H202) when expose...

Effects of Changes in Arterial Carbon Dioxide and Oxygen Partial Pressures on Cerebral Oximeter Performance.

Science.gov (United States)

Schober, Andrew; Feiner, John R; Bickler, Philip E; Rollins, Mark D

2018-01-01

Cerebral oximetry (cerebral oxygen saturation; ScO2) is used to noninvasively monitor cerebral oxygenation. ScO2 readings are based on the fraction of reduced and oxidized hemoglobin as an indirect estimate of brain tissue oxygenation and assume a static ratio of arterial to venous intracranial blood. Conditions that alter cerebral blood flow, such as acute changes in PaCO2, may decrease accuracy. We assessed the performance of two commercial cerebral oximeters across a range of oxygen concentrations during normocapnia and hypocapnia. Casmed FORE-SIGHT Elite (CAS Medical Systems, Inc., USA) and Covidien INVOS 5100C (Covidien, USA) oximeter sensors were placed on 12 healthy volunteers. The fractional inspired oxygen tension was varied to achieve seven steady-state levels including hypoxic and hyperoxic PaO2 values. ScO2 and simultaneous arterial and jugular venous blood gas measurements were obtained with both normocapnia and hypocapnia. Oximeter bias was calculated as the difference between the ScO2 and reference saturation using manufacturer-specified weighting ratios from the arterial and venous samples. FORE-SIGHT Elite bias was greater during hypocapnia as compared with normocapnia (4 ± 9% vs. 0 ± 6%; P oxygen saturation and mixed venous oxygen tension, as well as increased oxygen extraction across fractional inspired oxygen tension levels (P oxygen extraction (P < 0.0001). Changes in PaCO2 affect cerebral oximeter accuracy, and increased bias occurs with hypocapnia. Decreased accuracy may represent an incorrect assumption of a static arterial-venous blood fraction. Understanding cerebral oximetry limitations is especially important in patients at risk for hypoxia-induced brain injury, where PaCO2 may be purposefully altered.

Necessary Tension in Marine Risers Tension des colonnes montantes en mer

Directory of Open Access Journals (Sweden)

Lubinski A.

2006-11-01

Full Text Available The tension governing transverse static and dynamic deflections in a riser is not the actual tension but the so-called « effective tension » The concept of effective tension and effective compression is thoroughly explained, and means for calculating effective forces are given. Numerical examples are worked out for risers whose length is between 152 m (520 ft and 920 m (3020 ft. The reciprocal of maximum bending moment of the vicinity of the hall joint is plotted versus the effective tension of the ball joint. Bending moments used were obtained through use of static and dynamic computer programs applied ta a variety of conditions of wave loading, use or non-use of buoyant moterial sleeves, etc. The most important parameters affecting riser performance are the effective La tension régissant les déflections transversales statiques et dynamiques d'une colonne montante n'est pas la tension réelle mais ce qu'on appelle « la tension effective ». Le concept de tension ou de compression effective est expliqué en détail et la façon de calculer les forces effectives est indiquée dans cet article. Des exemples numériques sont développés pour des colonnes montantes de longueur comprise entre 152 m (520 ft et 920 m (3 020 ft. On a tracé la courbe de l'inverse du moment fléchissant en fonction de la tension effective à l'articulation. Les moments fléchissants utilisés ont été calculés par ordinateur en utilisant des programmes dynamiques et statiques pour des conditions variées d'action des vagues, la colonne montante étant ou non munie de manchettes de flottabilité, etc. Les deux paramètres les plus importants qui affectent le bon comportement d'une colonne montante sont la tension effective et la charge latérale.

Non-Invasive Monitoring of Breast Tumor Oxygenation: A Key to Tumor Therapy Planning and Tumor Prognosis

National Research Council Canada - National Science Library

Liu, Hanli

2004-01-01

.... The aims have included (1) to evaluate a single-channel, dual wavelength, NIR, frequency-domain oximeter and the algorithms for obtaining tumor HbO2 against tumor PO2 measured by 19F magnetic resonance imaging (MRI), (2...

Effects of the differentiating agents sodium butyrate and N-methylformamide on the oxygen enhancement ratio of human colon tumor cells

International Nuclear Information System (INIS)

Hallows, K.R.; Bliven, S.F.; Leith, J.T.

1988-01-01

We have previously shown that chronic adaptation of human tumor cells to the differentiation-inducing agents N-methylformamide (NMF) and sodium butyrate (NAB) increases the sensitivity of oxic cells to graded single doses of X rays. These studies were carried out to define the sensitivity of hypoxic cells after adaptation. Clone A colon tumor cells were grown for three passages in medium containing 170 mM NMF or 2 mM NAB and irradiated in suspension culture, after gassing with either oxygen (60 min) or ultrapure nitrogen (90 min), and complete survival curves were generated. Using the linear-quadratic equation to describe the data, it was found that NMF and NAB produced increased X-ray killing of hypoxic cells. At the 10% level of survival, the dose-modifying factors were about 1.20 and 1.25 for NMF- and NAB-adapted hypoxic cells, respectively, as compared to hypoxic control cells. However, since both oxic and hypoxic cells exhibited increased sensitivity after NMF and NAB adaptation, there was no major change in the oxygen enhancement ratio

Correlation of regional disease and in vivo PO2 in rat mammary adenocarcinoma.

OpenAIRE

Cole, M. A.; Crawford, D. W.; Warner, N. E.; Puffer, H. W.

1983-01-01

A knowledge of the distribution of oxygen tension (PO2) and vascularization in neoplasia has been fundamental to understanding relationships between tumor growth, hypoxia, and therapy. We have combined recessed oxygen microcathode and freeze-substitution techniques to correlate in situ PO2 profiles and morphologic features in 7,12-dimethylbenz(a)anthracene (DMBA) tumors in rats. Overlying connective tissue of transplanted tumor was exposed by a 1-2 mm incision and a cross-stitch pattern demar...

Effects of Cyanate and 2,3-Diphosphoglycerate on Sickling RELATIONSHIP TO OXYGENATION

Science.gov (United States)

Jensen, Michael; Bunn, H. Franklin; Halikas, George; Kan, Yuet Wai; Nathan, David G.

1973-01-01

Cyanate and 2,3-diphosphoglycerate (2,3-DPG) both influence the oxygen affinity of hemoglobin. The studies presented here concern the effects of these compounds on the sickling phenomenon. The inhibitory effect of cyanate on sickling is largely due to the fact that it increases the percentage of oxyhemoglobin S at a given oxygen tension. In addition, cyanate inhibits sickling by a mechanism that is independent of oxygenation. In this paper, we have demonstrated that the viscosity of carbamylated sickle blood was lower than that of non-carbamylated controls at the same oxygen saturation. Furthermore, carbamylation resulted in an increase in the minimum concentration of deoxy-sickle hemoglobin required for gelation. Like cyanate, 2,3-DPG affected sickling of intact erythrocytes by two mechanisms. Since 2,3-DPG decreases the percentage of oxyhemoglobin S at a given oxygen tension, sickling is enhanced. In addition, 2,3-DPG had a direct effect. When the intracellular 2,3-DPG concentration was increased in vitro, a greater percentage of cells were sickled at a given oxygen saturation. Conversely, sickling was inhibited in cells in which 2,3-DPG was artificially lowered. These data indicate that the enhancement of sickling by 2,3-DPG is in part independent of its influence on oxygen affinity. PMID:4729047

Quantitative imaging of tumor vasculature using multispectral optoacoustic tomography (MSOT)

Science.gov (United States)

Tomaszewski, Michal R.; Quiros-Gonzalez, Isabel; Joseph, James; Bohndiek, Sarah E.

2017-03-01

The ability to evaluate tumor oxygenation in the clinic could indicate prognosis and enable treatment monitoring, since oxygen deficient cancer cells are often more resistant to chemotherapy and radiotherapy. MultiSpectral Optoacoustic Tomography (MSOT) is a hybrid technique combining the high contrast of optical imaging with spatial resolution and penetration depth similar to ultrasound. We hypothesized that MSOT could reveal both tumor vascular density and function based on modulation of blood oxygenation. We performed MSOT on nude mice (n=8) bearing subcutaneous xenograft PC3 tumors using an inVision 256 (iThera Medical). The mice were maintained under inhalation anesthesia during imaging and respired oxygen content was modified from 21% to 100% and back. After imaging, Hoechst 33348 was injected to indicate vascular perfusion and permeability. Tumors were then extracted for histopathological analysis and fluorescence microscopy. The acquired data was analyzed to extract a bulk measurement of blood oxygenation (SO2MSOT) from the whole tumor using different approaches. The tumors were also automatically segmented into 5 regions to investigate the effect of depth on SO2MSOT. Baseline SO2MSOT values at 21% and 100% oxygen breathing showed no relationship with ex vivo measures of vascular density or function, while the change in SO2MSOT showed a strong negative correlation to Hoechst intensity (r=- 0.92, p=0.0016). Tumor voxels responding to oxygen challenge were spatially heterogeneous. We observed a significant drop in SO2 MSOT value with tumor depth following a switch of respiratory gas from air to oxygen (0.323+/-0.017 vs. 0.11+/-0.05, p=0.009 between 0 and 1.5mm depth), but no such effect for air breathing (0.265+/-0.013 vs. 0.19+/-0.04, p=0.14 between 0 and 1.5mm depth). Our results indicate that in subcutaneous prostate tumors, baseline SO2MSOT levels do not correlate to tumor vascular density or function while the magnitude of the response to oxygen

Optimal oxygen saturation in premature infants

Directory of Open Access Journals (Sweden)

Meayoung Chang

2011-09-01

Full Text Available There is a delicate balance between too little and too much supplemental oxygen exposure in premature infants. Since underuse and overuse of supplemental oxygen can harm premature infants, oxygen saturation levels must be monitored and kept at less than 95% to prevent reactive oxygen species-related diseases, such as retinopathy of prematurity and bronchopulmonary dysplasia. At the same time, desaturation below 80 to 85% must be avoided to prevent adverse consequences, such as cerebral palsy. It is still unclear what range of oxygen saturation is appropriate for premature infants; however, until the results of further studies are available, a reasonable target for pulse oxygen saturation (SpO2 is 90 to 93% with an intermittent review of the correlation between SpO2 and the partial pressure of arterial oxygen tension (PaO2. Because optimal oxygenation depends on individuals at the bedside making ongoing adjustments, each unit must define an optimal target range and set alarm limits according to their own equipment or conditions. All staff must be aware of these values and adjust the concentration of supplemental oxygen frequently.

Development of an oxygen-sensitive degradable peptide probe for the imaging of hypoxia-inducible factor-1-active regions in tumors.

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Ueda, Masashi; Ogawa, Kei; Miyano, Azusa; Ono, Masahiro; Kizaka-Kondoh, Shinae; Saji, Hideo

2013-12-01

We aimed to develop a radiolabeled peptide probe for the imaging of hypoxia-inducible factor-1 (HIF-1)-active tumors. We synthesized the peptide probes that contain or lack an essential sequence of the oxygen-dependent degradation of HIF-1α in proteasomes ((123/125)I-DKOP30 or (125)I-mDKOP, respectively). The degradation of probes was evaluated in vitro using cell lysates containing proteasomes. In vivo biodistribution study, planar imaging, autoradiography, and comparison between probe accumulation and HIF-1 transcriptional activity were also performed. The (125)I-DKOP30 underwent degradation in a proteasome-dependent manner, while (125)I-mDKOP was not degraded. Biodistribution analysis showed (125)I-DKOP30 accumulation in tumors. The tumors were clearly visualized by in vivo imaging, and intratumoral distribution of (125)I-DKOP30 coincided with the HIF-1α-positive hypoxic regions. Tumoral accumulation of (125)I-DKOP30 was significantly correlated with HIF-1-dependent luciferase bioluminescence, while that of (125)I-mDKOP was not. (123)I-DKOP30 is a useful peptide probe for the imaging of HIF-1-active tumors.

Tension pneumothorax accompanied by type A aortic dissection.

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Hifumi, Toru; Kiriu, Nobuaki; Inoue, Junichi; Koido, Yuichi

2012-11-09

A 51-year-old man was brought to the emergency room because of a sudden onset of severe dysponea. On presentation, his blood pressure was 94/55 mm Hg. Oxygen saturation was 86% while he was receiving 10 l/min oxygen through a non-rebreather mask. On physical examination, no jugular venous distention was noted, but breath sounds over the left lung were diminished. A bedside chest radiograph showed left tension pneumothorax, for which urgent needle decompression followed by chest thoracostomy was performed. Ventricular tachycardia developed, but a biphasic shock at 120 J immediately restored normal sinus rhythm. His vital signs, however, did not improve. A CT scan of the chest showed type A aortic dissection with bullae in the upper lobe of the left lung. He had an emergency operation for distal aortic arch displacement and was discharged on the 37th day of hospitalisation.

Simultaneous sampling of tissue oxygenation and oxygen consumption in skeletal muscle.

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Nugent, William H; Song, Bjorn K; Pittman, Roland N; Golub, Aleksander S

2016-05-01

Under physiologic conditions, microvascular oxygen delivery appears to be well matched to oxygen consumption in respiring tissues. We present a technique to measure interstitial oxygen tension (PISFO2) and oxygen consumption (VO2) under steady-state conditions, as well as during the transitions from rest to activity and back. Phosphorescence Quenching Microscopy (PQM) was employed with pneumatic compression cycling to achieve 1 to 10 Hz sampling rates of interstitial PO2 and simultaneous recurrent sampling of VO2 (3/min) in the exteriorized rat spinotrapezius muscle. The compression pressure was optimized to 120-130 mmHg without adverse effect on the tissue preparation. A cycle of 5s compression followed by 15s recovery yielded a resting VO2 of 0.98 ± 0.03 ml O2/100 cm(3)min while preserving microvascular oxygen delivery. The measurement system was then used to assess VO2 dependence on PISFO2 at rest and further tested under conditions of isometric muscle contraction to demonstrate a robust ability to monitor the on-kinetics of tissue respiration and the compensatory changes in PISFO2 during contraction and recovery. The temporal and spatial resolution of this approach is well suited to studies seeking to characterize microvascular oxygen supply and demand in thin tissues. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibitory effects of various oxygenated sterols on the differentiation and function of tumor-specific cytotoxic T lymphocytes

International Nuclear Information System (INIS)

Spangrude, G.J.; Sherris, D.; Daynes, R.A.

1982-01-01

Irradiation of skin with ultraviolet light (UVL) is capable of causing many biological and biochemical changes in this complex organ. One early consequence is the oxidation of epidermal plasma membrane cholesterol, causing the induction of a wide variety of photoproducts. It is well recognized that some oxygenated sterols possess potent biological activity on mammalian cells by their ability to inhibit endogeneous mevalonate and cholesterol biosynthesis. In the few immunological systems that have been studied, there is general agreement that lymphocyte function is lacking, as both afferent and efferent blockades have been suggested. These studies were undertaken to determine the effect of various oxygenated sterols (representing a number of known cholesterol-derived photoproducts) on the generation (afferent) and function (efferent) of cytotoxic T lymphocytes (CTLs). Cell-mediated immune responses which result in the generation of both alloantigen-specific and syngeneic tumor-specific CTLs were evaluated

Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma

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Salvesen Gerd S

2009-12-01

Full Text Available Abstract Background Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix. Methods One group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO treatment (2 bar, pO2 = 2 bar, 4 exposures à 90 min, whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO2 = 0.2 bar served as controls. Three doses of 5FU were tested for dose response. Uptake of [3H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (Pif, collagen content, oxygen stress (measured as malondialdehyd levels, lymphatics and transcapillary transport in the tumors. Results The uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%, but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor Pif and collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake. Conclusion We showed that hyperoxia increases the uptake of [3H]-5FU in DMBA-induced mammary tumors per se, independently of changes in Pif, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO2.

Optimizing the calculation of DM,CO and VC via the single breath single oxygen tension DLCO/NO method.

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Coffman, Kirsten E; Taylor, Bryan J; Carlson, Alex R; Wentz, Robert J; Johnson, Bruce D

2016-01-15

Alveolar-capillary membrane conductance (D(M,CO)) and pulmonary-capillary blood volume (V(C)) are calculated via lung diffusing capacity for carbon monoxide (DL(CO)) and nitric oxide (DL(NO)) using the single breath, single oxygen tension (single-FiO2) method. However, two calculation parameters, the reaction rate of carbon monoxide with blood (θ(CO)) and the D(M,NO)/D(M,CO) ratio (α-ratio), are controversial. This study systematically determined optimal θ(CO) and α-ratio values to be used in the single-FiO2 method that yielded the most similar D(M,CO) and V(C) values compared to the 'gold-standard' multiple-FiO2 method. Eleven healthy subjects performed single breath DL(CO)/DL(NO) maneuvers at rest and during exercise. D(M,CO) and V(C) were calculated via the single-FiO2 and multiple-FiO2 methods by implementing seven θ(CO) equations and a range of previously reported α-ratios. The RP θ(CO) equation (Reeves, R.B., Park, H.K., 1992. Respiration Physiology 88 1-21) and an α-ratio of 4.0-4.4 yielded DM,CO and VC values that were most similar between methods. The RP θ(CO) equation and an experimental α-ratio should be used in future studies. Copyright © 2015 Elsevier B.V. All rights reserved.

Dissolved oxygen concentration in the medium during cell culture: Defects and improvements.

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Zhang, Kuan; Zhao, Tong; Huang, Xin; He, Yunlin; Zhou, Yanzhao; Wu, Liying; Wu, Kuiwu; Fan, Ming; Zhu, Lingling

2016-03-01

In vitro cell culture has provided a useful model to study the effects of oxygen on cellular behavior. However, it remains unknown whether the in vitro operations themselves affect the medium oxygen levels and the living states of cells. In addition, a prevailing controversy is whether reactive oxygen species (ROS) production is induced by continuous hypoxia or reoxygenation. In this study, we have measured the effects of different types of cell culture containers and the oxygen environment where medium replacement takes place on the actual oxygen tension in the medium. We found that the deviations of oxygen concentrations in the medium are much greater in 25-cm(2) flasks than in 24-well plates and 35-mm dishes. The dissolved oxygen concentrations in the medium were increased after medium replacement in normoxia, but remained unchanged in glove boxes in which the oxygen tension remained at a low level (11.4, 5.7, and 0.5% O2 ). We also found that medium replacement in normoxia increased the number of ROS-positive cells and reduced the cell viability; meanwhile, medium replacement in a glove box did not produce the above effects. Therefore, we conclude that the use of 25-cm(2) flasks should be avoided and demonstrate that continuous hypoxia does not produce ROS, whereas the reoxygenation that occurs during the harvesting of cells leads to ROS and induces cell death. © 2015 International Federation for Cell Biology.

Prompt meningeal reconstruction mediated by oxygen-sensitive AKAP12 scaffolding protein after central nervous system injury

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Cha, Jong-Ho; Wee, Hee-Jun; Seo, Ji Hae; Ahn, Bum Ju; Park, Ji-Hyeon; Yang, Jun-Mo; Lee, Sae-Won; Lee, Ok-Hee; Lee, Hyo-Jong; Gelman, Irwin H.; Arai, Ken; Lo, Eng H.; Kim, Kyu-Won

2015-01-01

The meninges forms a critical epithelial barrier, which protects the central nervous system (CNS), and therefore its prompt reconstruction after CNS injury is essential for reducing neuronal damage. Meningeal cells migrate into the lesion site after undergoing an epithelial-mesenchymal transition (EMT) and repair the impaired meninges. However, the molecular mechanisms of meningeal EMT remain largely undefined. Here we show that TGF-β1 and retinoic acid (RA) released from the meninges, together with oxygen tension, could constitute the mechanism for rapid meningeal reconstruction. AKAP12 is an effector of this mechanism, and its expression in meningeal cells is regulated by integrated upstream signals composed of TGF-β1, RA and oxygen tension. Functionally, AKAP12 modulates meningeal EMT by regulating the TGF-β1-non-Smad-SNAI1 signalling pathway. Collectively, TGF-β1, RA and oxygen tension can modulate the dynamic change in AKAP12 expression, causing prompt meningeal reconstruction after CNS injury by regulating the transition between the epithelial and mesenchymal states of meningeal cells. PMID:25229625

A noninvasive multimodal technique to monitor brain tumor vascularization

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Saxena, Vishal; Gonzalez-Gomez, Ignacio; Laug, Walter E.

2007-09-01

Determination of tumor oxygenation at the microvascular level will provide important insight into tumor growth, angiogenesis, necrosis and therapeutic response and will facilitate to develop protocols for studying tumor behavior. The non-ionizing near infrared spectroscopy (NIRS) technique has the potential to differentiate lesion and hemoglobin dynamics; however, it has a limited spatial resolution. On the other hand, magnetic resonance imaging (MRI) has achieved high spatial resolution with excellent tissue discrimination but is more susceptible to limited ability to monitor the hemoglobin dynamics. In the present work, the vascular status and the pathophysiological changes that occur during tumor vascularization are studied in an orthotopic brain tumor model. A noninvasive multimodal approach based on the NIRS technique, namely steady state diffuse optical spectroscopy (SSDOS) along with MRI, is applied for monitoring the concentrations of oxyhemoglobin, deoxyhemoglobin and water within tumor region. The concentrations of oxyhemoglobin, deoxyhemoglobin and water within tumor vasculature are extracted at 15 discrete wavelengths in a spectral window of 675-780 nm. We found a direct correlation between tumor size, intratumoral microvessel density and tumor oxygenation. The relative decrease in tumor oxygenation with growth indicates that though blood vessels infiltrate and proliferate the tumor region, a hypoxic trend is clearly present.

A noninvasive multimodal technique to monitor brain tumor vascularization

International Nuclear Information System (INIS)

Saxena, Vishal; Gonzalez-Gomez, Ignacio; Laug, Walter E

2007-01-01

Determination of tumor oxygenation at the microvascular level will provide important insight into tumor growth, angiogenesis, necrosis and therapeutic response and will facilitate to develop protocols for studying tumor behavior. The non-ionizing near infrared spectroscopy (NIRS) technique has the potential to differentiate lesion and hemoglobin dynamics; however, it has a limited spatial resolution. On the other hand, magnetic resonance imaging (MRI) has achieved high spatial resolution with excellent tissue discrimination but is more susceptible to limited ability to monitor the hemoglobin dynamics. In the present work, the vascular status and the pathophysiological changes that occur during tumor vascularization are studied in an orthotopic brain tumor model. A noninvasive multimodal approach based on the NIRS technique, namely steady state diffuse optical spectroscopy (SSDOS) along with MRI, is applied for monitoring the concentrations of oxyhemoglobin, deoxyhemoglobin and water within tumor region. The concentrations of oxyhemoglobin, deoxyhemoglobin and water within tumor vasculature are extracted at 15 discrete wavelengths in a spectral window of 675-780 nm. We found a direct correlation between tumor size, intratumoral microvessel density and tumor oxygenation. The relative decrease in tumor oxygenation with growth indicates that though blood vessels infiltrate and proliferate the tumor region, a hypoxic trend is clearly present

Cerebral oxygenation decreases during exercise in humans with beta-adrenergic blockade

DEFF Research Database (Denmark)

Seifert, T.; Rasmussen, P.; Secher, Niels H.

2009-01-01

AIM: Beta-blockers reduce exercise capacity by attenuated increase in cardiac output, but it remains unknown whether performance also relates to attenuated cerebral oxygenation. METHODS: Acting as their own controls, eight healthy subjects performed a continuous incremental cycle test to exhaustion...... attenuated the increase in cardiac output of consequence for cerebral perfusion and oxygenation. We suggest that a decrease in cerebral oxygenation limits exercise capacity Udgivelsesdato: 2009/7...... with or without administration of the non-selective beta-blocker propranolol. Changes in cerebral blood flow velocity were measured with transcranial Doppler ultrasound and those in cerebral oxygenation were evaluated using near-infrared spectroscopy and the calculated cerebral mitochondrial oxygen tension...

Tensile Forces Originating from Cancer Spheroids Facilitate Tumor Invasion.

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Katarzyna S Kopanska

Full Text Available The mechanical properties of tumors and the tumor environment provide important information for the progression and characterization of cancer. Tumors are surrounded by an extracellular matrix (ECM dominated by collagen I. The geometrical and mechanical properties of the ECM play an important role for the initial step in the formation of metastasis, presented by the migration of malignant cells towards new settlements as well as the vascular and lymphatic system. The extent of this cell invasion into the ECM is a key medical marker for cancer prognosis. In vivo studies reveal an increased stiffness and different architecture of tumor tissue when compared to its healthy counterparts. The observed parallel collagen organization on the tumor border and radial arrangement at the invasion zone has raised the question about the mechanisms organizing these structures. Here we study the effect of contractile forces originated from model tumor spheroids embedded in a biomimetic collagen I matrix. We show that contractile forces act immediately after seeding and deform the ECM, thus leading to tensile radial forces within the matrix. Relaxation of this tension via cutting the collagen does reduce invasion, showing a mechanical relation between the tensile state of the ECM and invasion. In turn, these results suggest that tensile forces in the ECM facilitate invasion. Furthermore, simultaneous contraction of the ECM and tumor growth leads to the condensation and reorientation of the collagen at the spheroid's surface. We propose a tension-based model to explain the collagen organization and the onset of invasion by forces originating from the tumor.

Reduced-Gravity Measurements of the Effect of Oxygen on Properties of Zirconium

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Zhao, J.; Lee, J.; Wunderlich, R.; Fecht, H.-J.; Schneider, S.; SanSoucie, M.; Rogers, J.; Hyers, R.

2016-01-01

The influence of oxygen on the thermophysical properties of zirconium is being investigated using MSL-EML (Material Science Laboratory - Electromagnetic Levitator) on ISS (International Space Station) in collaboration with NASA, ESA (European Space Agency), and DLR (German Aerospace Center). Zirconium samples with different oxygen concentrations will be put into multiple melt cycles, during which the density, viscosity, surface tension, heat capacity, and electric conductivity will be measured at various undercooled temperatures. The facility check-up of MSL-EML and the first set of melting experiments have been successfully performed in 2015. The first zirconium sample will be tested near the end of 2015. As part of ground support activities, the thermophysical properties of zirconium and ZrO were measured using a ground-based electrostatic levitator located at the NASA Marshall Space Flight Center. The influence of oxygen on the measured surface tension was evaluated. The results of this research will serve as reference data for those measured in ISS.

Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship.

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Netea-Maier, Romana T; Smit, Johannes W A; Netea, Mihai G

2018-01-28

In order to adapt to the reduced availability of nutrients and oxygen in the tumor microenvironment and the increased requirements of energy and building blocks necessary for maintaining their high proliferation rate, malignant cells undergo metabolic changes that result in an increased production of lactate, nitric oxide, reactive oxygen species, prostaglandins and other byproducts of arachidonic acid metabolism that influence both the composition of the inflammatory microenvironment and the function of the tumor-associated macrophages (TAMs). In response to cues present in the TME, among which products of altered tumor cell metabolism, TAMs are also required to reprogram their metabolism, with activation of glycolysis, fatty acid synthesis and altered nitrogen cycle metabolism. These changes result in functional reprogramming of TAMs which includes changes in the production of cytokines and angiogenetic factors, and contribute to the tumor progression and metastasis. Understanding the metabolic changes governing the intricate relationship between the tumor cells and the TAMs represents an essential step towards developing novel therapeutic approaches targeting the metabolic reprogramming of the immune cells to potentiate their tumoricidal potential and to circumvent therapy resistance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Tumor-Derived Microvesicles Modulate Antigen Cross-Processing via Reactive Oxygen Species-Mediated Alkalinization of Phagosomal Compartment in Dendritic Cells

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Federico Battisti

2017-09-01

Full Text Available Dendritic cells (DCs are the only antigen-presenting cells able to prime naïve T cells and cross-prime antigen-specific CD8+ T cells. Their functionality is a requirement for the induction and maintenance of long-lasting cancer immunity. Albeit intensively investigated, the in vivo mechanisms underlying efficient antigen cross-processing and presentation are not fully understood. Several pieces of evidence indicate that antigen transfer to DCs mediated by microvesicles (MVs enhances antigen immunogenicity. This mechanism is also relevant for cross-presentation of those tumor-associated glycoproteins such as MUC1 that are blocked in HLA class II compartment when internalized by DCs as soluble molecules. Here, we present pieces of evidence that the internalization of tumor-derived MVs modulates antigen-processing machinery of DCs. Employing MVs derived from ovarian cancer ascites fluid and established tumor cell lines, we show that MV uptake modifies DC phagosomal microenvironment, triggering reactive oxygen species (ROS accumulation and early alkalinization. Indeed, tumor MVs carry radical species and the MV uptake by DCs counteracts the chemically mediated acidification of the phagosomal compartment. Further pieces of evidence suggest that efficacious antigen cross-priming of the MUC1 antigen carried by the tumor MVs results from the early signaling induced by MV internalization and the function of the antigen-processing machinery of DCs. These results strongly support the hypothesis that tumor-derived MVs impact antigen immunogenicity by tuning the antigen-processing machinery of DCs, besides being carrier of tumor antigens. Furthermore, these findings have important implications for the exploitation of MVs as antigenic cell-free immunogen for DC-based therapeutic strategies.

Developing a Customized Perfusion Bioreactor Prototype with Controlled Positional Variability in Oxygen Partial Pressure for Bone and Cartilage Tissue Engineering.

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Lee, Poh Soo; Eckert, Hagen; Hess, Ricarda; Gelinsky, Michael; Rancourt, Derrick; Krawetz, Roman; Cuniberti, Gianaurelio; Scharnweber, Dieter

2017-05-01

Skeletal development is a multistep process that involves the complex interplay of multiple cell types at different stages of development. Besides biochemical and physical cues, oxygen tension also plays a pivotal role in influencing cell fate during skeletal development. At physiological conditions, bone cells generally reside in a relatively oxygenated environment whereas chondrocytes reside in a hypoxic environment. However, it is technically challenging to achieve such defined, yet diverse oxygen distribution on traditional in vitro cultivation platforms. Instead, engineered osteochondral constructs are commonly cultivated in a homogeneous, stable environment. In this study, we describe a customized perfusion bioreactor having stable positional variability in oxygen tension at defined regions. Further, engineered collagen constructs were coaxed into adopting the shape and dimensions of defined cultivation platforms that were precasted in 1.5% agarose bedding. After cultivating murine embryonic stem cells that were embedded in collagen constructs for 50 days, mineralized constructs of specific dimensions and a stable structural integrity were achieved. The end-products, specifically constructs cultivated without chondroitin sulfate A (CSA), showed a significant increase in mechanical stiffness compared with their initial gel-like constructs. More importantly, the localization of osteochondral cell types was specific and corresponded to the oxygen tension gradient generated in the bioreactor. In addition, CSA in complementary with low oxygen tension was also found to be a potent inducer of chondrogenesis in this system. In summary, we have demonstrated a customized perfusion bioreactor prototype that is capable of generating a more dynamic, yet specific cultivation environment that could support propagation of multiple osteochondral lineages within a single engineered construct in vitro. Our system opens up new possibilities for in vitro research on human

Serum Tumor Necrosis Factor-alpha associates with Myocardial Oxygen Demand and Exercise Tolerance in Postmenopausal Women.

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Carter, Stephen J; Bryan, David R; Neumeier, William H; Glasser, Stephen P; Hunter, Gary R

2018-01-01

The functional implications of serum tumor necrosis factor-alpha (TNF-α), a marker of oxidative stress, on hemodynamic parameters at rest and during physical exertion are unclear. The aims of this investigation were to examine the independent associations of TNF-α on myocardial oxygen demand at rest and during submaximal exercise, while also evaluating the association of TNF-α on exercise tolerance. Forty, postmenopausal women, provided blood samples and completed a modified-Balke protocol to measure maximal oxygen uptake (VO 2max ). Large artery compliance was measured by pulse contour analyses while rate-pressure product (RPP), an index of myocardial oxygen demand, was measured at rest and during two submaximal workloads (i.e., ≈55% and ≈75% VO 2max ). RPP was calculated by dividing the product of heart rate and systolic blood pressure (via auscultation) by 100. Exercise tolerance corresponded with the cessation of the graded exercise test. During higher-intensity exertion, ≈75% VO 2max , multiple linear regression revealed a positive association ( r = 0.43; p = 0.015) between TNF-α and RPP while adjusting for maximal heart rate, VO 2max , large artery compliance, and percent body fat. Path analyses revealed a significant indirect effect of large artery compliance on exercise tolerance through TNF-α, β = 0.13, CI [0.03, 0.35], indicating greater levels of TNF-α associated with poorer exercise tolerance. These data suggest TNF-α independently associates with myocardial oxygen demand during physical exertion, thus highlighting the utility of higher-intensity efforts to expose important phenomena not apparent at rest. TNF-α also appears to be indirectly associated with the link between large artery compliance and exercise tolerance.

Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species

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Alcayaga-Miranda, Francisca; González, Paz L.; Lopez-Verrilli, Alejandra; Varas-Godoy, Manuel; Aguila-Díaz, Carolina; Contreras, Luis; Khoury, Maroun

2016-01-01

Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancer-cell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-κB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-κB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1α expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies. PMID:27286448

Non-invasive pre-clinical MR imaging of prostate tumor hypoxia for radiation therapy prognosis

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Derek White

2014-03-01

Full Text Available Purpose: To investigate the usefulness of Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI changes in signal intensity related to oxygen challenge for predicting tumor response to radiation therapy.Methods: Dynamic MR signal changes were acquired using Varian 4.7T small animal MR scanner prior to image-guided radiation therapy (IGRT of small (n = 6 and large subcutaneous (n = 5 prostate tumors in adult male rats. An interleaved blood-oxygen level dependent (BOLD and tissue-oxygen level dependent (TOLD data acquisition or (IBT was performed using a baseline of medical air as positive control and using medical oxygen as a breathing challenge. BOLD used a 2-D multi-slice spoiled gradient-echo with multi-echo sequence. TOLD used a 2-D multi-slice spoiled gradient-echo sequence. Voxel changes in signal intensity were determined by a correlation coefficient mapping technique. Irradiation technique planned consisted of 1F × 15 Gy AP/PA or 2F × 7.5 Gy AP/PA to the gross tumor volume (GTV. Tumor growth measurements were recorded over time to assess the response to IGRT.Results: BOLD and TOLD signals variously illustrated positive or negative impulse responses in the tumor ROI due to inhaling medical oxygen. Correlation coefficient mapping demonstrated heterogeneity in tumors after inhaling medical oxygen. BOLD and TOLD signals exhibited increased changes in signal intensities after the first fraction of dose. Multi-fractionation had minimum effect until the second fraction of dose was applied. Tumor growth delays were observed when inhaling medical oxygen during IGRT.Conclusion: OE-MRI is a non-invasive imaging modality that can provide insight to the oxygen status of tumors. Observed increase percent changes in BOLD and TOLD signal intensities after the first fraction of dose suggest tumors experienced reoxygenation. OE-MRI could be used for predicting tumor response to IGRT when using medical oxygen for increasing GTV radiosensitivity, suggesting

A voxel-based multiscale model to simulate the radiation response of hypoxic tumors.

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Espinoza, I; Peschke, P; Karger, C P

2015-01-01

In radiotherapy, it is important to predict the response of tumors to irradiation prior to the treatment. This is especially important for hypoxic tumors, which are known to be highly radioresistant. Mathematical modeling based on the dose distribution, biological parameters, and medical images may help to improve this prediction and to optimize the treatment plan. A voxel-based multiscale tumor response model for simulating the radiation response of hypoxic tumors was developed. It considers viable and dead tumor cells, capillary and normal cells, as well as the most relevant biological processes such as (i) proliferation of tumor cells, (ii) hypoxia-induced angiogenesis, (iii) spatial exchange of cells leading to tumor growth, (iv) oxygen-dependent cell survival after irradiation, (v) resorption of dead cells, and (vi) spatial exchange of cells leading to tumor shrinkage. Oxygenation is described on a microscopic scale using a previously published tumor oxygenation model, which calculates the oxygen distribution for each voxel using the vascular fraction as the most important input parameter. To demonstrate the capabilities of the model, the dependence of the oxygen distribution on tumor growth and radiation-induced shrinkage is investigated. In addition, the impact of three different reoxygenation processes is compared and tumor control probability (TCP) curves for a squamous cells carcinoma of the head and neck (HNSSC) are simulated under normoxic and hypoxic conditions. The model describes the spatiotemporal behavior of the tumor on three different scales: (i) on the macroscopic scale, it describes tumor growth and shrinkage during radiation treatment, (ii) on a mesoscopic scale, it provides the cell density and vascular fraction for each voxel, and (iii) on the microscopic scale, the oxygen distribution may be obtained in terms of oxygen histograms. With increasing tumor size, the simulated tumors develop a hypoxic core. Within the model, tumor shrinkage was

A voxel-based multiscale model to simulate the radiation response of hypoxic tumors

International Nuclear Information System (INIS)

Espinoza, I.; Peschke, P.; Karger, C. P.

2015-01-01

Purpose: In radiotherapy, it is important to predict the response of tumors to irradiation prior to the treatment. This is especially important for hypoxic tumors, which are known to be highly radioresistant. Mathematical modeling based on the dose distribution, biological parameters, and medical images may help to improve this prediction and to optimize the treatment plan. Methods: A voxel-based multiscale tumor response model for simulating the radiation response of hypoxic tumors was developed. It considers viable and dead tumor cells, capillary and normal cells, as well as the most relevant biological processes such as (i) proliferation of tumor cells, (ii) hypoxia-induced angiogenesis, (iii) spatial exchange of cells leading to tumor growth, (iv) oxygen-dependent cell survival after irradiation, (v) resorption of dead cells, and (vi) spatial exchange of cells leading to tumor shrinkage. Oxygenation is described on a microscopic scale using a previously published tumor oxygenation model, which calculates the oxygen distribution for each voxel using the vascular fraction as the most important input parameter. To demonstrate the capabilities of the model, the dependence of the oxygen distribution on tumor growth and radiation-induced shrinkage is investigated. In addition, the impact of three different reoxygenation processes is compared and tumor control probability (TCP) curves for a squamous cells carcinoma of the head and neck (HNSSC) are simulated under normoxic and hypoxic conditions. Results: The model describes the spatiotemporal behavior of the tumor on three different scales: (i) on the macroscopic scale, it describes tumor growth and shrinkage during radiation treatment, (ii) on a mesoscopic scale, it provides the cell density and vascular fraction for each voxel, and (iii) on the microscopic scale, the oxygen distribution may be obtained in terms of oxygen histograms. With increasing tumor size, the simulated tumors develop a hypoxic core. Within the

Reactor vessel stud tensioner

International Nuclear Information System (INIS)

Malandra, L.J.; Beer, R.W.; Salton, R.B.; Spiegelman, S.R.; Cognevich, M.L.

1982-01-01

A quick-acting stud tensioner, for facilitating the loosening or tightening of a stud nut on a reactor vessel stud, has gripper jaws which when the tensioner is lowered into engagement with the upper end of the stud are moved inwards to grip the upper end and which when the tensioner is lifted move outward to release the upper end. (author)

Transcriptional response to hypoxia in human tumors.

NARCIS (Netherlands)

Lal, A.; Peters, H.; Croix, B. St.; Haroon, Z.A.; Dewhirst, M.W.; Strausberg, R.L.; Kaanders, J.H.A.M.; Kogel, A.J. van der; Riggins, G.J.

2001-01-01

BACKGROUND: The presence of hypoxic regions within solid tumors is associated with a more malignant tumor phenotype and worse prognosis. To obtain a blood supply and protect against cellular damage and death, oxygen-deprived cells in tumors alter gene expression, resulting in resistance to therapy.

Reactive oxygen species responsive drug releasing nanoparticle based on chondroitin sulfate-anthocyanin nanocomplex for efficient tumor therapy.

Science.gov (United States)

Jeong, Dooyong; Bae, Byoung-Chan; Park, Sin-Jung; Na, Kun

2016-01-28

To develop a reactive oxygen species (ROS) sensitive drug carrier, a chondroitin sulfate (CS)-anthocyanin (ATC) based nanocomplex was developed. Doxorubicin hydrochloride (DOX) was loaded in the CS-ATC nanocomplex (CS-ATC-DOX) via intermolecular stacking interaction. The nanocomplex was fabricated by a simple mixing method in the aqueous phase. The morphology and size of CS-ATC-DOX were determined by ATC content. In the group with 1.5mg/ml of ATC loaded CS-ATC-DOX (CS-ATC2-DOX), the drug content and loading efficiency were 8.5% and 99.1%, respectively. The ROS sensitive drug release of CS-ATC2-DOX was confirmed under in vitro physiological conditions. The results demonstrated that 1.67 times higher DOX release occurred in CS-ATC2-DOX for 48h compared to CS-DOX (ATC absent sample). Drug release and nanocomplex destruction were induced by ROS mediated ATC degradation. We determined that 66.7% of ROS was scavenged by CS-ATC2-DOX. Additionally, an HCT-116 tumor bearing animal model was used to confirm ROS sensitive therapeutic effects of CS-ATC2-DOX. The results indicate that DOX was released from the intravenously injected CS-ATC2-DOX in the tumor tissue. Thus, nuclei shrinkage and dead cells were observed in H&E staining and TUNEL assay, respectively. These data suggest that the tumor growth was effectively inhibited. This study means that CS-ATC2-DOX has potential in improving tumor therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

Pericellular oxygen monitoring with integrated sensor chips for reproducible cell culture experiments.

Science.gov (United States)

Kieninger, J; Aravindalochanan, K; Sandvik, J A; Pettersen, E O; Urban, G A

2014-04-01

Here we present an application, in two tumour cell lines, based on the Sensing Cell Culture Flask system as a cell culture monitoring tool for pericellular oxygen sensing. T-47D (human breast cancer) and T98G (human brain cancer) cells were cultured either in atmospheric air or in a glove-box set at 4% oxygen, in both cases with 5% CO2 in the gas phase. Pericellular oxygen tension was measured with the help of an integrated sensor chip comprising oxygen sensor arrays. Obtained results illustrate variation of pericellular oxygen tension in attached cells covered by stagnant medium. Independent of incubation conditions, low pericellular oxygen concentration levels, usually associated with hypoxia, were found in dense cell cultures. Respiration alone brought pericellular oxygen concentration down to levels which could activate hypoxia-sensing regulatory processes in cultures believed to be aerobic. Cells in culture believed to experience conditions of mild hypoxia may, in reality, experience severe hypoxia. This would lead to incorrect assumptions and suggests that pericellular oxygen concentration readings are of great importance to obtain reproducible results when dealing with hypoxic and normoxic (aerobic) incubation conditions. The Sensing Cell Culture Flask system allows continuous monitoring of pericellular oxygen concentration with outstanding long-term stability and no need for recalibration during cell culture experiments. The sensor is integrated into the flask bottom, thus in direct contact with attached cells. No additional equipment needs to be inserted into the flask during culturing. Transparency of the electrochemical sensor chip allows optical inspection of cells attached on top of the sensor. © 2014 John Wiley & Sons Ltd.

Aerobic Glycolysis as a Marker of Tumor Aggressiveness: Preliminary Data in High Grade Human Brain Tumors

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Andrei G. Vlassenko

2015-01-01

Full Text Available Objectives. Glucose metabolism outside of oxidative phosphorylation, or aerobic glycolysis (AG, is a hallmark of active cancer cells that is not directly measured with standard 18F-fluorodeoxyglucose (FDG positron emission tomography (PET. In this study, we characterized tumor regions with elevated AG defined based on PET measurements of glucose and oxygen metabolism. Methods. Fourteen individuals with high-grade brain tumors underwent structural MR scans and PET measurements of cerebral blood flow (CBF, oxygen (CMRO2 and glucose (CMRGlu metabolism, and AG, using 15O-labeled CO, O2 and H2O, and FDG, and were compared to a normative cohort of 20 age-matched individuals. Results. Elevated AG was observed in most high-grade brain tumors and it was associated with decreased CMRO2 and CBF, but not with significant changes in CMRGlu. Elevated AG was a dramatic and early sign of tumor growth associated with decreased survival. AG changes associated with tumor growth were differentiated from the effects of nonneoplastic processes such as epileptic seizures. Conclusions. Our findings demonstrate that high-grade brain tumors exhibit elevated AG as a marker of tumor growth and aggressiveness. AG may detect areas of active tumor growth that are not evident on conventional FDG PET.

Oxygen and Perfusion Kinetics in Response to Fractionated Radiation Therapy in FaDu Head and Neck Cancer Xenografts Are Related to Treatment Outcome

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Hu, Fangyao [Department of Biomedical Engineering, Duke University, Durham, North Carolina (United States); Vishwanath, Karthik [Department of Physics, Miami University, Oxford, Ohio (United States); Salama, Joseph K. [Department of Radiation Oncology, Duke University, Durham, North Carolina (United States); Division of Radiation Oncology, Veterans Administration Medical Center, Durham, North Carolina (United States); Erkanli, Alaattin; Peterson, Bercedis [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina (United States); Oleson, James R. [Department of Radiation Oncology, Duke University, Durham, North Carolina (United States); Division of Radiation Oncology, Veterans Administration Medical Center, Durham, North Carolina (United States); Lee, Walter T. [Department of Radiation Oncology, Duke University, Durham, North Carolina (United States); Division of Head and Neck Surgery and Communicative Sciences, Duke University Medical Center, Durham, North Carolina (United States); Section of Otolaryngology Head and Neck Surgery, Veterans Administration Medical Center, Durham, North Carolina (United States); Brizel, David M. [Department of Radiation Oncology, Duke University, Durham, North Carolina (United States); Division of Head and Neck Surgery and Communicative Sciences, Duke University Medical Center, Durham, North Carolina (United States); Ramanujam, Nimmi [Department of Biomedical Engineering, Duke University, Durham, North Carolina (United States); Dewhirst, Mark W., E-mail: mark.dewhirst@duke.edu [Department of Radiation Oncology, Duke University, Durham, North Carolina (United States)

2016-10-01

Purpose: To test whether oxygenation kinetics correlate with the likelihood for local tumor control after fractionated radiation therapy. Methods and Materials: We used diffuse reflectance spectroscopy to noninvasively measure tumor vascular oxygenation and total hemoglobin concentration associated with radiation therapy of 5 daily fractions (7.5, 9, or 13.5 Gy/d) in FaDu xenografts. Spectroscopy measurements were obtained immediately before each daily radiation fraction and during the week after radiation therapy. Oxygen saturation and total hemoglobin concentration were computed using an inverse Monte Carlo model. Results: First, oxygenation kinetics during and after radiation therapy, but before tumor volumes changed, were associated with local tumor control. Locally controlled tumors exhibited significantly faster increases in oxygenation after radiation therapy (days 12-15) compared with tumors that recurred locally. Second, within the group of tumors that recurred, faster increases in oxygenation during radiation therapy (day 3-5 interval) were correlated with earlier recurrence times. An area of 0.74 under the receiver operating characteristic curve was achieved when classifying the local control tumors from all irradiated tumors using the oxygen kinetics with a logistic regression model. Third, the rate of increase in oxygenation was radiation dose dependent. Radiation doses ≤9.5 Gy/d did not initiate an increase in oxygenation, whereas 13.5 Gy/d triggered significant increases in oxygenation during and after radiation therapy. Conclusions: Additional confirmation is required in other tumor models, but these results suggest that monitoring tumor oxygenation kinetics could aid in the prediction of local tumor control after radiation therapy.

Oxygen and Perfusion Kinetics in Response to Fractionated Radiation Therapy in FaDu Head and Neck Cancer Xenografts Are Related to Treatment Outcome

International Nuclear Information System (INIS)

Hu, Fangyao; Vishwanath, Karthik; Salama, Joseph K.; Erkanli, Alaattin; Peterson, Bercedis; Oleson, James R.; Lee, Walter T.; Brizel, David M.; Ramanujam, Nimmi; Dewhirst, Mark W.

2016-01-01

Purpose: To test whether oxygenation kinetics correlate with the likelihood for local tumor control after fractionated radiation therapy. Methods and Materials: We used diffuse reflectance spectroscopy to noninvasively measure tumor vascular oxygenation and total hemoglobin concentration associated with radiation therapy of 5 daily fractions (7.5, 9, or 13.5 Gy/d) in FaDu xenografts. Spectroscopy measurements were obtained immediately before each daily radiation fraction and during the week after radiation therapy. Oxygen saturation and total hemoglobin concentration were computed using an inverse Monte Carlo model. Results: First, oxygenation kinetics during and after radiation therapy, but before tumor volumes changed, were associated with local tumor control. Locally controlled tumors exhibited significantly faster increases in oxygenation after radiation therapy (days 12-15) compared with tumors that recurred locally. Second, within the group of tumors that recurred, faster increases in oxygenation during radiation therapy (day 3-5 interval) were correlated with earlier recurrence times. An area of 0.74 under the receiver operating characteristic curve was achieved when classifying the local control tumors from all irradiated tumors using the oxygen kinetics with a logistic regression model. Third, the rate of increase in oxygenation was radiation dose dependent. Radiation doses ≤9.5 Gy/d did not initiate an increase in oxygenation, whereas 13.5 Gy/d triggered significant increases in oxygenation during and after radiation therapy. Conclusions: Additional confirmation is required in other tumor models, but these results suggest that monitoring tumor oxygenation kinetics could aid in the prediction of local tumor control after radiation therapy.

Cycling Hypoxia Induces a Specific Amplified Inflammatory Phenotype in Endothelial Cells and Enhances Tumor-Promoting Inflammation In Vivo

Directory of Open Access Journals (Sweden)

Céline Tellier

2015-01-01

Full Text Available Abnormal architecture of the tumor blood network, as well as heterogeneous erythrocyte flow, leads to temporal fluctuations in tissue oxygen tension exposing tumor and stromal cells to cycling hypoxia. Inflammation is another feature of tumor microenvironment and is considered as a new enabling characteristic of tumor progression. As cycling hypoxia is known to participate in tumor aggressiveness, the purpose of this study was to evaluate its role in tumor-promoting inflammation. Firstly, we assessed the impact of cycling hypoxia in vitro on endothelial inflammatory response induced by tumor necrosis factor α. Results showed that endothelial cells exposed to cycling hypoxia displayed an amplified proinflammatory phenotype, characterized by an increased expression of inflammatory cytokines, namely, interleukin (IL-6 and IL-8; by an increased expression of adhesion molecules, in particular intercellular adhesion molecule–1 (ICAM-1; and consequently by an increase in THP-1 monocyte adhesion. This exacerbation of endothelial inflammatory phenotype occurs through nuclear factor–κB overactivation. Secondly, the role of cycling hypoxia was studied on overall tumor inflammation in vivo in tumor-bearing mice. Results showed that cycling hypoxia led to an enhanced inflammation in tumors as prostaglandin-endoperoxide synthase 2 (PTGS2, IL-6, CXCL1 (C-X-C motif ligand 1, and macrophage inflammatory protein 2 (murine IL-8 functional homologs mRNA expression was increased and as a higher leukocyte infiltration was evidenced. Furthermore, cycling hypoxia–specific inflammatory phenotype, characterized by a simultaneous (baculoviral inhibitor of apoptosis repeat-containing 5low/PTGS2high/ICAM-1high/IL-6high/IL-8high expression, is associated with a poor prognosis in human colon cancer. This new phenotype could thus be used in clinic to more precisely define prognosis for colon cancer patients. In conclusion, our findings evidenced for the first time the

Matching the reaction-diffusion simulation to dynamic [18F]FMISO PET measurements in tumors: extension to a flow-limited oxygen-dependent model.

Science.gov (United States)

Shi, Kuangyu; Bayer, Christine; Gaertner, Florian C; Astner, Sabrina T; Wilkens, Jan J; Nüsslin, Fridtjof; Vaupel, Peter; Ziegler, Sibylle I

2017-02-01

Positron-emission tomography (PET) with hypoxia specific tracers provides a noninvasive method to assess the tumor oxygenation status. Reaction-diffusion models have advantages in revealing the quantitative relation between in vivo imaging and the tumor microenvironment. However, there is no quantitative comparison of the simulation results with the real PET measurements yet. The lack of experimental support hampers further applications of computational simulation models. This study aims to compare the simulation results with a preclinical [ 18 F]FMISO PET study and to optimize the reaction-diffusion model accordingly. Nude mice with xenografted human squamous cell carcinomas (CAL33) were investigated with a 2 h dynamic [ 18 F]FMISO PET followed by immunofluorescence staining using the hypoxia marker pimonidazole and the endothelium marker CD 31. A large data pool of tumor time-activity curves (TAC) was simulated for each mouse by feeding the arterial input function (AIF) extracted from experiments into the model with different configurations of the tumor microenvironment. A measured TAC was considered to match a simulated TAC when the difference metric was below a certain, noise-dependent threshold. As an extension to the well-established Kelly model, a flow-limited oxygen-dependent (FLOD) model was developed to improve the matching between measurements and simulations. The matching rate between the simulated TACs of the Kelly model and the mouse PET data ranged from 0 to 28.1% (on average 9.8%). By modifying the Kelly model to an FLOD model, the matching rate between the simulation and the PET measurements could be improved to 41.2-84.8% (on average 64.4%). Using a simulation data pool and a matching strategy, we were able to compare the simulated temporal course of dynamic PET with in vivo measurements. By modifying the Kelly model to a FLOD model, the computational simulation was able to approach the dynamic [ 18 F]FMISO measurements in the investigated

Lipid nanocarriers based on natural oils with high activity against oxygen free radicals and tumor cell proliferation

International Nuclear Information System (INIS)

Lacatusu, I.; Badea, N.; Badea, G.; Oprea, O.; Mihaila, M.A.; Kaya, D.A.; Stan, R.; Meghea, A.

2015-01-01

The development of nano-dosage forms of phytochemicals represents a significant progress of the scientific approach in the biomedical research. The aim of this study was to assess the effectiveness of lipid nanocarriers based on natural oils (grape seed oil, fish oil and laurel leaf oil) in counteracting free radicals and combating certain tumor cells. No drug was encapsulated in the nanocarriers. The cytotoxic effect exerted by bioactive nanocarriers against two tumor cells, MDA-MB 231 and HeLa cell lines, and two normal cells, L929 and B16 cell lines, was measured using the MTT assay, while oxidative damage was assessed by measuring the total antioxidant activity using chemiluminescence analysis. The best performance was obtained for nanocarriers based on an association of grape seed and laurel leaf oils, with a capacity to scavenge about 98% oxygen free radicals. A dose of nanocarriers of 5 mg·mL −1 has led to a drastic decrease in tumor cell proliferation even in the absence of an antitumor drug (e.g. about 50% viability for MDA-MB 231 cell line and 60% viability for HeLa cell line). A comparative survival profile of normal and tumor cells, which were exposed to an effective dose of 2.5 mg·mL −1 lipid nanocarriers, has revealed a death rate of 20% for normal B16 cells and of 40% death rate for MDA-MB 231 and HeLa tumor cells. The results in this study imply that lipid nanocarriers based on grape seed oil in association with laurel leaf oil could be a candidate to reduce the delivery system toxicity and may significantly improve the therapeutic efficacy of antitumor drugs in clinical applications. - Highlights: • Functional lipid nanocarriers with unique features and broad spectrum effectiveness • Lipid nanocarriers based on laureal leaf oil (LLO) and grape seed oil (GSO) • Antioxidant activity has reached 98% for nanocarriers containing 25% GSO and 2% LLO. • LLO exerts a significant cytotoxic effect against HeLa and MDA-MB 231 tumor cells. • 50

Lipid nanocarriers based on natural oils with high activity against oxygen free radicals and tumor cell proliferation

Energy Technology Data Exchange (ETDEWEB)

Lacatusu, I.; Badea, N.; Badea, G.; Oprea, O. [University Politehnica of Bucharest, Faculty of Applied Chemistry and Materials Science, Polizu Street No 1, 011061 Bucharest (Romania); Mihaila, M.A. [Institute of Virusology “Stefan S. Nicolau”, Center of Immunology, Bravu Road, No. 285, 030304 Bucharest (Romania); Kaya, D.A. [Department of Field Crops, Faculty of Agriculture, Mustafa Kemal University, 31030 Antakya, Hatay (Turkey); Stan, R., E-mail: rl_stan2000@yahoo.com [University Politehnica of Bucharest, Faculty of Applied Chemistry and Materials Science, Polizu Street No 1, 011061 Bucharest (Romania); Meghea, A. [University Politehnica of Bucharest, Faculty of Applied Chemistry and Materials Science, Polizu Street No 1, 011061 Bucharest (Romania)

2015-11-01

The development of nano-dosage forms of phytochemicals represents a significant progress of the scientific approach in the biomedical research. The aim of this study was to assess the effectiveness of lipid nanocarriers based on natural oils (grape seed oil, fish oil and laurel leaf oil) in counteracting free radicals and combating certain tumor cells. No drug was encapsulated in the nanocarriers. The cytotoxic effect exerted by bioactive nanocarriers against two tumor cells, MDA-MB 231 and HeLa cell lines, and two normal cells, L929 and B16 cell lines, was measured using the MTT assay, while oxidative damage was assessed by measuring the total antioxidant activity using chemiluminescence analysis. The best performance was obtained for nanocarriers based on an association of grape seed and laurel leaf oils, with a capacity to scavenge about 98% oxygen free radicals. A dose of nanocarriers of 5 mg·mL{sup −1} has led to a drastic decrease in tumor cell proliferation even in the absence of an antitumor drug (e.g. about 50% viability for MDA-MB 231 cell line and 60% viability for HeLa cell line). A comparative survival profile of normal and tumor cells, which were exposed to an effective dose of 2.5 mg·mL{sup −1} lipid nanocarriers, has revealed a death rate of 20% for normal B16 cells and of 40% death rate for MDA-MB 231 and HeLa tumor cells. The results in this study imply that lipid nanocarriers based on grape seed oil in association with laurel leaf oil could be a candidate to reduce the delivery system toxicity and may significantly improve the therapeutic efficacy of antitumor drugs in clinical applications. - Highlights: • Functional lipid nanocarriers with unique features and broad spectrum effectiveness • Lipid nanocarriers based on laureal leaf oil (LLO) and grape seed oil (GSO) • Antioxidant activity has reached 98% for nanocarriers containing 25% GSO and 2% LLO. • LLO exerts a significant cytotoxic effect against HeLa and MDA-MB 231 tumor

Validation of the protoporphyrin IX-triplet state lifetime technique for mitochondrial oxygen measurements in the skin

NARCIS (Netherlands)

F.A. Harms (Floor A.); S.I.A. Bodmer (Sander I. A.); N.J.H. Raat (Nicolaas); R.J. Stolker (Robert); E.G. Mik (Egbert)

2012-01-01

textabstractMitochondrial oxygen tension can be measured in vivo by means of oxygen-dependent quenching of delayed fluorescence of protoporphyrin IX (PpIX). Here we demonstrate that mitochondrial PO2 (mitoPO2) can be measured in the skin of a rat after topical application of the PpIX precursor

Effects of the kinematic viscosity and surface tension on the bubble take-off period in a catalase-hydrogen peroxide system.

Science.gov (United States)

Sasaki, Satoshi; Iida, Yoshinori

2009-06-01

The effect of kinematic viscosity and surface tension of the solution was investigated by adding catalase, glucose oxidase, or glucose on the bubble movement in a catalase-hydrogen peroxide system. The kinematic viscosity was measured using a Cannon-Fenske kinematic viscometer. The surface tension of the solution was measured by the Wilhelmy method using a self-made apparatus. The effects of the hole diameter/cell wall thickness, catalase concentration, glucose concentration, and glucose oxidase concentration on the kinematic viscosity, surface tension, and bubble take-off period were investigated. With our system, the effects of the changes in the solution materiality on the bubble take-off period were proven to be very small in comparison to the change in the oxygen-producing rate.

[Spontaneous tension hemothorax due to rupture of a solitary fibrous tumor of the posterior mediastinum].

Science.gov (United States)

Morita, Yohei; Ichimura, Hideo; Kikuchi, Shinji; Ozawa, Yuichiro; Inoue, Kazunari; Uchida, Atsushi; Kikuchi, Kazunori; Shiigai, Masanari; Shiotani, Seiji

2013-10-01

A 37-year-old man was transported by ambulance to our hospital due to abrupt chest pain. The pain began when he was practicing a combative-type sport. He denied any impact or blunt trauma. A chest radiograph revealed massive left pleural effusion with a mediastinal shift. Thoracentesis revealed a hemothorax;therefore, we performed an emergency thoracotomy. The intraoperative findings revealed a rupture of a posterior mediastinal tumor itself located between the descending aorta and the thoracic vertebra. After we identified the artery of Adamkiewicz that originates away from the tumor and evaluated the degree of tumor extension into the inter-vertebral foramen, we safely performed an elective tumor resection 1 month after the initial emergency operation. In patients with a hemothorax caused by rupture of the tumor itself, an elective tumor resection after detailed investigation should be considered if hemostasis can be achieved in the emergency thoracotomy.

General definition of gravitational tension

International Nuclear Information System (INIS)

Harmark, T.; Obers, N.A.

2004-01-01

In this note we give a general definition of the gravitational tension in a given asymptotically translationally-invariant spatial direction of a space-time. The tension is defined via the extrinsic curvature in analogy with the Hawking-Horowitz definition of energy. We show the consistency with the ADM tension formulas for asymptotically-flat space-times, in particular for Kaluza-Klein black hole solutions. Moreover, we apply the general tension formula to near-extremal branes, constituting a check for non-asymptotically flat space-times. (author)

Structural design significance of tension-tension fatigue data on composites

Science.gov (United States)

Grimes, G. C.

1977-01-01

Constant cycle tension-tension fatigue and related static tension data have been generated on six single composite material/orientation combinations and twenty-one hybrid composite material/orientation combinations. Anomalies are related to the temperature rise and stopped interval creep, whereas endurance limit stresses (runouts) are associated with static proportional limit values, when they occur, and internal damage. The significance of these room temperature-dry data on the design allowables and weight of aerodynamic structueres is discussed. Such structures are helicopter rotor blades and wing and horizontal stabilizer lower surfaces. Typical criteria for turning these data into preliminary allowables are shown, as are examples of such allowables developed from the data. These values are then compared to those that might be used if the structures were made of metal.

Tension type headache

Directory of Open Access Journals (Sweden)

Debashish Chowdhury

2012-01-01

Full Text Available Tension type headaches are common in clinical practice. Earlier known by various names, the diagnosis has had psychological connotations. Recent evidence has helped clarify the neurobiological basis and the disorder is increasingly considered more in the preview of neurologists. The classification, clinical features, differential diagnosis and treatment of tension type headache are discussed in this paper.

Effects of hyperbaric oxygen and normobaric carbogen on the radiation response of the rat rhabdomyosarcoma R1H

International Nuclear Information System (INIS)

Hartmann, K. Axel; Kleij, Ad J. van der; Carl, Ulrich M.; Hulshof, Maarten C.C.M.; Willers, Reinhart; Sminia, Peter

2001-01-01

Purpose: Hypoxic tumor cells are an important factor of radioresistance. Hyperbaric oxygen (HBO) and normobaric carbogen (95% oxygen, 5% carbon dioxide) increase the oxygen delivery to tumors. This study was performed to explore changes of tumor oxygenation during a course of fractionated irradiation and to determine the effectiveness of normobaric carbogen and HBO during the final phase of the radiation treatment. Methods and Materials: Experiments were performed on the rhabdomyosarcoma R1H growing on WAG/Rij rats. After 20 X-ray fractions of 2 Gy within 4 weeks, oxygen partial pressure (pO 2 ) was measured using the Eppendorf oxygen electrode under ambient conditions, with normobaric carbogen or HBO at a pressure of 240 kPa. Following the 4-week radiation course, a top-up dose of 10-50 Gy was applied in 2-10 fractions of 5 Gy with or without hyperoxygenation. Results: HBO but not carbogen significantly increased the median pO 2 in irradiated tumors. The radiation doses to control 50% of tumors were 38.0 Gy, 29.5 Gy, and 25.0 Gy for air, carbogen, and HBO, respectively. Both high oxygen content gas inspirations led to significantly improved tumor responses with oxygen enhancement ratios (OERs) of 1.3 for normobaric carbogen and 1.5 for HBO (air vs. carbogen: p=0.044; air vs. HBO: p=0.02; carbogen vs. HBO: p=0.048). Conclusion: Both normobaric carbogen and HBO significantly improved the radiation response of R1H tumors. HBO appeared to be more effective than normobaric carbogen, both with regard to tumor oxygenation and response to irradiation

In vivo studies of radiation potentiaton by iodoacetamide and observations on tumor transplantation immunity

Energy Technology Data Exchange (ETDEWEB)

Richards, W. Robert [Univ. of California, Berkeley, CA (United States); Kelly, Lola S. [Univ. of California, Berkeley, CA (United States)

1970-10-01

Iodoacetamide has been shown by others to be a radiation sensitizer for bacteria and for certain mammalian cells tested in vitro. This work describes an examination of the effectiveness of iodoacetamide used in vivo. Survival of ascites tumor cells maintained in the peritoneal cavity of mice was used as an indicator of sensitization. Survival was assessed using TD₅₀ and total tumor cell population determination methods. A comparison of results obtained by these methods is made. The effects of oxygen tension and radiation dose rate upon results was examined. Iodoacetamide was found to be effective as a radiation sensitizer under all conditions although to a lesser degree than that reported by others for in vitro experiments with bacteria. Radioactive tracer studies indicate that iodoacetamide has rapid and total access to most if not all tissues of the body. This fact coupled with the observation of a sensitization in an in vivo system where the anoxia so prevalent in well developed tumors was present, suggests the possibility of clinical usefulness of iodoacetamide in cancer radiation therapy. Certain observations are reported on the effect of various cell and host treatment procedures upon cell population growth kinetics seen subsequent to inoculation of hosts with the cells. A hypothesis is presented which can account for the observations made by the author and also for those made by some others who report that large inocula, i.e., greater than 10 cells, are required to give rise to a lethal tumor in isologous hosts of the strain of tumor origin. The hypothesis may also account for what is known in the literature as the 'Hybrid Effect.'

Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species.

Science.gov (United States)

De Milito, Angelo; Iessi, Elisabetta; Logozzi, Mariantonia; Lozupone, Francesco; Spada, Massimo; Marino, Maria Lucia; Federici, Cristina; Perdicchio, Maurizio; Matarrese, Paola; Lugini, Luana; Nilsson, Anna; Fais, Stefano

2007-06-01

Proton pumps like the vacuolar-type H+ ATPase (V-ATPase) are involved in the control of cellular pH in normal and tumor cells. Treatment with proton pump inhibitors (PPI) induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients. It is also known that low pH is the most suitable condition for a full PPI activation. Here, we tested whether PPI treatment in unbuffered culture conditions could affect survival and proliferation of human B-cell tumors. First, we showed that PPI treatment increased the sensitivity to vinblastine of a pre-B acute lymphoblastic leukemia (ALL) cell line. PPI, per se, induced a dose-dependent inhibition of proliferation of tumor B cells, which was associated with a dose- and time-dependent apoptotic-like cytotoxicity in B-cell lines and leukemic cells from patients with pre-B ALL. The effect of PPI was mediated by a very early production of reactive oxygen species (ROS), that preceded alkalinization of lysosomal pH, lysosomal membrane permeabilization, and cytosol acidification, suggesting an early destabilization of the acidic vesicular compartment. Lysosomal alterations were followed by mitochondrial membrane depolarization, release of cytochrome c, chromatin condensation, and caspase activation. However, inhibition of caspase activity did not affect PPI-induced cell death, whereas specific inhibition of ROS by an antioxidant (N-acetylcysteine) significantly delayed cell death and protected both lysosomal and mitochondrial membranes. The proapoptotic activity of PPI was consistent with a clear inhibition of tumor growth following PPI treatment of B-cell lymphoma in severe combined immunodeficient mice. This study further supports the importance of acidity and pH gradients in tumor cell homeostasis and suggests new therapeutic approaches for human B-cell tumors based on PPI.

Tumour oxygen dynamics measured simultaneously by near-infrared spectroscopy and 19F magnetic resonance imaging in rats

International Nuclear Information System (INIS)

Xia Mengna; Kodibagkar, Vikram; Liu Hanli; Mason, Ralph P

2006-01-01

Simultaneous near-infrared spectroscopy (NIRS) and magnetic resonance imaging (MRI) were used to investigate the correlation between tumour vascular oxygenation and tissue oxygen tension dynamics in rat breast 13762NF tumours with respect to hyperoxic gas breathing. NIRS directly detected global variations in the oxygenated haemoglobin concentration (Δ[HbO 2 ]) within tumours and oxygen tension (pO 2 ) maps were achieved using 19 F MRI of the reporter molecule hexafluorobenzene. Multiple correlations were examined between rates and magnitudes of vascular (Δ[HbO 2 ]) and tissue (pO 2 ) responses. Significant correlations were found between response to oxygen and carbogen breathing using either modality. Comparison of results for the two methods showed a correlation between the vascular perfusion rate ratio and the mean pO 2 values (R 2 > 0.7). The initial rates of increase of Δ[HbO 2 ] and the slope of dynamic pO 2 response, d(pO 2 )/dt, of well-oxygenated voxels in response to hyperoxic challenge were also correlated. These results demonstrate the feasibility of simultaneous measurements using NIRS and MRI. As expected, the rate of pO 2 response to oxygen is primarily dependent upon the well perfused rather than poorly perfused vasculature

Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells

Directory of Open Access Journals (Sweden)

Shigeo Saito

2015-06-01

Full Text Available Eukaryotic organisms require oxygen homeostasis to maintain proper cellular function for survival. During conditions of low oxygen tension (hypoxia, cells activate the transcription of genes that induce an adaptive response, which supplies oxygen to tissues. Hypoxia and hypoxia-inducible factors (HIFs may contribute to the maintenance of putative cancer stem cells, which can continue self-renewal indefinitely and express stemness genes in hypoxic stress environments (stem cell niches. Reactive oxygen species (ROS have long been recognized as toxic by-products of aerobic metabolism that are harmful to living cells, leading to DNA damage, senescence, or cell death. HIFs may promote a cancer stem cell state, whereas the loss of HIFs induces the production of cellular ROS and activation of proteins p53 and p16Ink4a, which lead to tumor cell death and senescence. ROS seem to inhibit HIF regulation in cancer cells. By contrast, controversial data have suggested that hypoxia increases the generation of ROS, which prevents hydroxylation of HIF proteins by inducing their transcription as negative feedback. Moreover, hypoxic conditions enhance the generation of induced pluripotent stem cells (iPSCs. During reprogramming of somatic cells into a PSC state, cells attain a metabolic state typically observed in embryonic stem cells (ESCs. ESCs and iPSCs share similar bioenergetic metabolisms, including decreased mitochondrial number and activity, and induced anaerobic glycolysis. This review discusses the current knowledge regarding the emerging roles of ROS homeostasis in cellular reprogramming and the implications of hypoxic regulation in cancer development.

Transcriptional and metabolic response of recombinant Escherichia coli to spatial dissolved oxygen tension gradients simulated in a scale-down system.

Science.gov (United States)

Lara, Alvaro R; Leal, Lidia; Flores, Noemí; Gosset, Guillermo; Bolívar, Francisco; Ramírez, Octavio T

2006-02-05

Escherichia coli, expressing recombinant green fluorescent protein (GFP), was subjected to dissolved oxygen tension (DOT) oscillations in a two-compartment system for simulating gradients that can occur in large-scale bioreactors. Cells were continuously circulated between the anaerobic (0% DOT) and aerobic (10% DOT) vessels of the scale-down system to mimic an overall circulation time of 50 s, and a mean residence time in the anaerobic and aerobic compartments of 33 and 17 s, respectively. Transcription levels of mixed acid fermentation genes (ldhA, poxB, frdD, ackA, adhE, pflD, and fdhF), measured by quantitative RT-PCR, increased between 1.5- to over 6-fold under oscillatory DOT compared to aerobic cultures (constant 10% DOT). In addition, the transcription level of fumB increased whereas it decreased for sucA and sucB, suggesting that the tricarboxylic acid cycle was functioning as two open branches. Gene transcription levels revealed that cytrochrome bd, which has higher affinity to oxygen but lower energy efficiency, was preferred over cytochrome bO3 in oscillatory DOT cultures. Post-transcriptional processing limited heterologous protein production in the scale-down system, as inferred from similar gfp transcription but 19% lower GFP concentration compared to aerobic cultures. Simulated DOT gradients also affected the transcription of genes of the glyoxylate shunt (aceA), of global regulators of aerobic and anaerobic metabolism (fnr, arcA, and arcB), and other relevant genes (luxS, sodA, fumA, and sdhB). Transcriptional changes explained the observed alterations in overall stoichiometric and kinetic parameters, and production of ethanol and organic acids. Differences in transcription levels between aerobic and anaerobic compartments were also observed, indicating that E. coli can respond very fast to intermittent DOT conditions. The transcriptional responses of E. coli to DOT gradients reported here are useful for establishing rational scale-up criteria and

Tumor Blood Vessel Dynamics

Science.gov (United States)

Munn, Lance

2009-11-01

``Normalization'' of tumor blood vessels has shown promise to improve the efficacy of chemotherapeutics. In theory, anti-angiogenic drugs targeting endothelial VEGF signaling can improve vessel network structure and function, enhancing the transport of subsequent cytotoxic drugs to cancer cells. In practice, the effects are unpredictable, with varying levels of success. The predominant effects of anti-VEGF therapies are decreased vessel leakiness (hydraulic conductivity), decreased vessel diameters and pruning of the immature vessel network. It is thought that each of these can influence perfusion of the vessel network, inducing flow in regions that were previously sluggish or stagnant. Unfortunately, when anti-VEGF therapies affect vessel structure and function, the changes are dynamic and overlapping in time, and it has been difficult to identify a consistent and predictable normalization ``window'' during which perfusion and subsequent drug delivery is optimal. This is largely due to the non-linearity in the system, and the inability to distinguish the effects of decreased vessel leakiness from those due to network structural changes in clinical trials or animal studies. We have developed a mathematical model to calculate blood flow in complex tumor networks imaged by two-photon microscopy. The model incorporates the necessary and sufficient components for addressing the problem of normalization of tumor vasculature: i) lattice-Boltzmann calculations of the full flow field within the vasculature and within the tissue, ii) diffusion and convection of soluble species such as oxygen or drugs within vessels and the tissue domain, iii) distinct and spatially-resolved vessel hydraulic conductivities and permeabilities for each species, iv) erythrocyte particles advecting in the flow and delivering oxygen with real oxygen release kinetics, v) shear stress-mediated vascular remodeling. This model, guided by multi-parameter intravital imaging of tumor vessel structure

Reactive oxygen species explicit dosimetry (ROSED) of a type 1 photosensitizer

Science.gov (United States)

Ong, Yi Hong; Kim, Michele M.; Huang, Zheng; Zhu, Timothy C.

2018-02-01

Type I photodynamic therapy (PDT) is based on the use of photochemical reactions mediated through an interaction between a tumor-selective photosensitizer, photoexcitation with a specific wavelength of light, and production of reactive oxygen species (ROS). The goal of this study is to develop a model to calculate reactive oxygen species concentration ([ROS]rx) after Tookad®-mediated vascular PDT. Mice with radiation-induced fibrosarcoma (RIF) tumors were treated with different light fluence and fluence rate conditions. Explicit measurements of photosensitizer drug concentration were made via diffuse reflective absorption spectrum using a contact probe before and after PDT. Blood flow and tissue oxygen concentration over time were measured during PDT as a mean to validate the photochemical parameters for the ROSED calculation. Cure index was computed from the rate of tumor regrowth after treatment and was compared against three calculated dose metrics: total light fluence, PDT dose, reacted [ROS]rx. The tumor growth study demonstrates that [ROS]rx serves as a better dosimetric quantity for predicting treatment outcome, as a clinically relevant tumor growth endpoint.

Improved Intratumoral Oxygenation Through Vascular Normalization Increases Glioma Sensitivity to Ionizing Radiation

International Nuclear Information System (INIS)

McGee, Mackenzie C.; Hamner, J. Blair; Williams, Regan F.; Rosati, Shannon F.; Sims, Thomas L.; Ng, Catherine Y.; Gaber, M. Waleed; Calabrese, Christopher; Wu Jianrong; Nathwani, Amit C.; Duntsch, Christopher; Merchant, Thomas E.; Davidoff, Andrew M.

2010-01-01

Purpose: Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation. Methods and Materials: Orthotopic U87 xenografts were treated with either continuous interferon-β (IFN-β) or bevacizumab, alone, or combined with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; the tumor vasculature using immunohistochemical staining, and tumor oxygenation using hypoxyprobe staining. Results: Both IFN-β and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-β caused a doubling in the percentage of area of perivascular cell staining, and bevacizumab caused a rapid decrease in the percentage of area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab, the effect was transient, being lost by 5 days. Administration of IFN-β or bevacizumab before RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-β or bevacizumab or 5 days after bevacizumab. Conclusion: Bevacizumab and continuous delivery of IFN-β each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the antitumor activity of ionizing radiation. Additional investigation into the use and timing of these and other agents that modify the vascular phenotype, combined with RT, is warranted to optimize cytotoxic activity.

On relation between the quark-gluon bag surface tension and the colour tube string tension

International Nuclear Information System (INIS)

Bugaev, K.A.; Zinovjev, G.M.

2010-01-01

We revisit the bag phenomenology of deconfining phase transition aiming to replenish it by introducing systematically the bag surface tension. Comparing the free energies of such bags and the strings confining the static quark-antiquark pair, we express the string tension in terms of the bag surface tension and the bulk pressure in order to estimate the bag characteristics using the lattice QCD (LQCD) data. Our analysis of the bag entropy density demonstrates that the surface tension coefficient is amazingly negative at the cross-over (continuous transition). The approach developed allows us to naturally account for an origin of a pronounced maximum (observed in the LQCD studies) in the behaviour of heavy quark-antiquark pair entropy. The vicinity of the (tri-)critical endpoint is also analyzed to clarify the meaning of vanishing surface tension coefficient.

Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

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Sophie Portron

2015-01-01

Full Text Available Background/Aims: Multipotent stem/stromal cells (MSC are considered promising for cartilage tissue engineering. However, chondrogenic differentiation of MSC can ultimately lead to the formation of hypertrophic chondrocytes responsible for the calcification of cartilage. To prevent the production of this calcified matrix at the articular site, the late hypertrophic differentiation of MSCs must be carefully controlled. Given that articular cartilage is avascular, we hypothesized that in addition to its stimulatory role in the early differentiation of chondrogenic cells, hypoxia may prevent their late hypertrophic conversion. Methods: Early and late chondrogenic differentiation were evaluated using human adipose MSC and murine ATDC5 cells cultured under either normoxic (21%O2 or hypoxic (5%O2 conditions. To investigate the effect of hypoxia on late chondrogenic differentiation, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1α and HIF-2α were evaluated using the NoShift DNA-binding assay and through modulation of their activity (chemical inhibitor, RNA interference. Results: Our data demonstrate that low oxygen tension not only stimulates the early chondrogenic commitment of two complementary models of chondrogenic cells, but also inhibits their hypertrophic differentiation. Conclusion: These results suggest that hypoxia can be used as an instrumental tool to prevent the formation of a calcified matrix in MSC-based cartilage tissue engineering.

The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma

Energy Technology Data Exchange (ETDEWEB)

Zhou, Hua; Yang, Ying-Hua [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Binmadi, Nada O. [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Department of Oral Basic and Clinical Sciences, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Proia, Patrizia [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Department of Sports Science (DISMOT), University of Palermo, Via Eleonora Duse 2 90146, Palermo (Italy); Basile, John R., E-mail: jbasile@umaryland.edu [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Greenebaum Cancer Center, 22S. Greene Street, Baltimore, MD 21201 (United States)

2012-08-15

Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to such stresses as chemotherapy or radiotherapy-induced hypoxia, and it therefore has become a tempting target for neutralizing antibodies in the treatment of advanced neoplasms. Emerging evidence has shown that the semaphorins, proteins originally associated with control of axonal growth and immunity, are regulated by changes in oxygen tension as well and may play a role in tumor-induced angiogenesis. Through the use of RNA interference, in vitro and in vivo angiogenesis assays and tumor xenograft experiments, we demonstrate that expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors. -- Highlights: Black-Right-Pointing-Pointer Similar to VEGF, SEMA4D promotes angiogenesis in vitro and in vivo. Black-Right-Pointing-Pointer Both VEGF and SEMA4D are produced by OSCC cells in a HIF-dependent manner. Black-Right-Pointing-Pointer These factors combine to elicit a robust pro-angiogenic phenotype in OSCC. Black-Right-Pointing-Pointer Anti-SEMA4D

The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma

International Nuclear Information System (INIS)

Zhou, Hua; Yang, Ying-Hua; Binmadi, Nada O.; Proia, Patrizia; Basile, John R.

2012-01-01

Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to such stresses as chemotherapy or radiotherapy-induced hypoxia, and it therefore has become a tempting target for neutralizing antibodies in the treatment of advanced neoplasms. Emerging evidence has shown that the semaphorins, proteins originally associated with control of axonal growth and immunity, are regulated by changes in oxygen tension as well and may play a role in tumor-induced angiogenesis. Through the use of RNA interference, in vitro and in vivo angiogenesis assays and tumor xenograft experiments, we demonstrate that expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors. -- Highlights: ► Similar to VEGF, SEMA4D promotes angiogenesis in vitro and in vivo. ► Both VEGF and SEMA4D are produced by OSCC cells in a HIF-dependent manner. ► These factors combine to elicit a robust pro-angiogenic phenotype in OSCC. ► Anti-SEMA4D blocking antibody inhibits Plexin-B1 activation. ► SEMA4D is a valid anti-angiogenic target in the

Hypofractionation results in reduced tumor cell kill compared to conventional fractionation for tumors with regions of hypoxia.

Science.gov (United States)

Carlson, David J; Keall, Paul J; Loo, Billy W; Chen, Zhe J; Brown, J Martin

2011-03-15

Tumor hypoxia has been observed in many human cancers and is associated with treatment failure in radiation therapy. The purpose of this study is to quantify the effect of different radiation fractionation schemes on tumor cell killing, assuming a realistic distribution of tumor oxygenation. A probability density function for the partial pressure of oxygen in a tumor cell population is quantified as a function of radial distance from the capillary wall. Corresponding hypoxia reduction factors for cell killing are determined. The surviving fraction of a tumor consisting of maximally resistant cells, cells at intermediate levels of hypoxia, and normoxic cells is calculated as a function of dose per fraction for an equivalent tumor biological effective dose under normoxic conditions. Increasing hypoxia as a function of distance from blood vessels results in a decrease in tumor cell killing for a typical radiotherapy fractionation scheme by a factor of 10(5) over a distance of 130 μm. For head-and-neck cancer and prostate cancer, the fraction of tumor clonogens killed over a full treatment course decreases by up to a factor of ∼10(3) as the dose per fraction is increased from 2 to 24 Gy and from 2 to 18 Gy, respectively. Hypofractionation of a radiotherapy regimen can result in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. There is a potential for large errors when calculating alternate fractionations using formalisms that do not account for tumor hypoxia. Copyright © 2011 Elsevier Inc. All rights reserved.

Effects of reactive oxygen species on metabolism monitored by longitudinal 1H single voxel MRS follow-up in patients with mitochondrial disease or cerebral tumors

International Nuclear Information System (INIS)

Constans, J M; Collet, S; Hossu, G; Courtheoux, P; Guillamo, J S; Lechapt-Zalcman, E; Valable, S; Lacombe, S; Houee Levin, C; Gauduel, Y A; Dou, W; Ruan, S; Barre, L; Rioult, F; Derlon, J M; Chapon, F; Fong, V; Kauffmann, F

2011-01-01

Free radicals, or Reactive Oxygen Species (ROS), have an effect on energy and glycolytic metabolism, mitochondrial function, lipid metabolism, necrosis and apoptosis, cell proliferation, and infiltration. These changes could be monitored longitudinally (every 4 months over 6 years) in humans with glial brain tumors (low and high grade) after therapy, using conventional magnetic resonance imaging (MRI) and spectroscopy (MRS) and MR perfusion. Some examples of early clinical data from longitudinal follow-up monitoring in humans of energy and glycolytic metabolism, lipid metabolism, necrosis, proliferation, and infiltration measured by conventional MRI, MRS and perfusion, and positron emission tomography (PET) are shown in glial brain tumors after therapy. Despite the difficulty, the variability and unknown factors, these repeated measurements give us a better insight into the nature of the different processes, tumor progression and therapeutic response.

Characterization of hemodynamics and oxygenation in the renal cortex of rats

Science.gov (United States)

Grosenick, Dirk; Wabnitz, Heidrun; Macdonald, Rainer; Niendorf, Thoralf; Cantow, Kathleen; Flemming, Bert; Arakelyan, Karen; Seeliger, Erdmann

2015-03-01

We have performed a pre-clinical study on 13 rats to investigate the potential of near-infrared spectroscopy for quantification of hemoglobin concentration and oxygen saturation of hemoglobin in the renal cortex of small animals. These measurements were combined with laser-Doppler fluxmetry and a fluorescence quenching technique for quantification of tissue oxygen tension. Hemoglobin concentration and oxygen saturation were determined from experimental data by a Monte Carlo model. The methods were applied to investigate and compare temporal changes during several types of interventions such as arterial and venous occlusions, as well as hyperoxia, hypoxia and hypercapnia induced by different mixtures of the inspired gas.

Soft-tissue tension total knee arthroplasty.

Science.gov (United States)

Asano, Hiroshi; Hoshino, Akiho; Wilton, Tim J

2004-08-01

It is far from clear how best to define the proper strength of soft-tissue tensioning in total knee arthroplasty (TKA). We attached a torque driver to the Monogram balancer/tensor device and measured soft-tissue tension in full extension and 90 degrees flexion during TKA. In our surgical procedure, when we felt proper soft-tissue tension was being applied, the mean distraction force was noted to be 126N in extension and 121N in flexion. There was no significant correlation between soft-tissue tension and the postoperative flexion angle finally achieved. To the best of our knowledge, this is the first study to assess the actual distraction forces in relation to soft-tissue tension in TKA. Further study may reveal the most appropriate forces to achieve proper soft-tissue tension in the wide variety of circumstances presenting at knee arthroplasty.

Cutaneous respirometry by dynamic measurement of mitochondrial oxygen tension for monitoring mitochondrial function in vivo.

Science.gov (United States)

Harms, Floor A; Voorbeijtel, Wilhelmina J; Bodmer, Sander I A; Raat, Nicolaas J H; Mik, Egbert G

2013-09-01

Progress in diagnosis and treatment of mitochondrial dysfunction in chronic and acute disease could greatly benefit from techniques for monitoring of mitochondrial function in vivo. In this study we demonstrate the feasibility of in vivo respirometry in skin. Mitochondrial oxygen measurements by means of oxygen-dependent delayed fluorescence of protoporphyrin IX are shown to provide a robust basis for measurement of local oxygen disappearance rate (ODR). The fundamental principles behind the technology are described, together with an analysis method for retrievel of respirometry data. The feasibility and reproducibility of this clinically useful approach are demonstrated in a series of rats. Copyright © 2012 Elsevier B.V. All rights reserved.

Temperature and oxygenation during organ preservation: friends or foes?

Science.gov (United States)

Gilbo, Nicholas; Monbaliu, Diethard

2017-06-01

The liberalization of donor selection criteria in organ transplantation, with the increased use of suboptimal grafts, has stimulated interest in ischemia-reperfusion injury prevention and graft reconditioning. Organ preservation technologies are changing considerably, mostly through the reintroduction of dynamic machine preservation. Here, we review the current evidence on the role of temperature and oxygenation during dynamic machine preservation. A large but complex body of evidence exists and comparative studies are few. Oxygenation seems to support an advantageous effect in hypothermic machine preservation and is mandatory in normothermic machine preservation, although in the latter, supraphysiological oxygen tensions should be avoided. High-risk grafts, such as suboptimal organs, may optimally benefit from oxygenated perfusion conditions that support metabolism and activate mechanisms of repair such as subnormothermic machine preservation, controlled oxygenated rewarming, and normothermic machine preservation. For lower risk grafts, oxygenation during hypothermic machine preservation may sufficiently reduce injuries and recharge the cellular energy to secure functional recovery after transplantation. The relationship between temperature and oxygenation in organ preservation is more complex than physiological laws would suggest. Rather than one default perfusion temperature/oxygenation standard, perfusion protocols should be tailored for specific needs of grafts of different quality.

Effects of Dissolved Oxygen Concentration and Iron Addition on Immediate-early Gene Expression of Magnetospirillum gryphiswaldense MSR-1

DEFF Research Database (Denmark)

Zhuang, Shiwen; Anyaogu, Diana Chinyere; Kasama, Takeshi

2017-01-01

in cultures at 0.5% O2 compared to those at higher oxygen tensions. Moreover, expression of katG (catalase-peroxidase gene) and feoB2 (ferrous transport protein B2 gene) was reduced markedly by iron addition, regardless of oxygen conditions. The data provides a greater understanding of molecular response...

31P nuclear magnetic resonance spectroscopy studies of tumor energy metabolism and its relationship to intracapillary oxyhemoglobin saturation status and tumor hypoxia.

Science.gov (United States)

Rofstad, E K; DeMuth, P; Fenton, B M; Sutherland, R M

1988-10-01

Relationships between tumor bioenergetic status on the one hand and intracapillary oxyhemoglobin (HbO2) saturation status and fraction of radiobiologically hypoxic cells on the other were studied using two murine sarcoma lines (KHT, RIF-1) and two human ovarian carcinoma xenograft lines (MLS, OWI). Tumor energy metabolism was studied in vivo by 31P nuclear magnetic resonance (NMR) spectroscopy and the resonance area ratio (PCr + NTP beta)/Pi was used as parameter for bioenergetic status. Intracapillary HbO2 saturation status reflects the oxygen supply conditions in tumors and was measured in vitro using a cryospectrophotometric method. The KHT, RIF-1, and MLS lines showed decreasing bioenergetic status, i.e., decreasing PCr and NTP beta resonances and an increasing Pi resonance, with increasing tumor volume, whereas the OWI line showed no changes in these resonances during tumor growth. The volume-dependence of the HbO2 saturation status differed similarly among the tumor lines; HbO2 saturation status decreased with increasing tumor volume for the KHT, RIF-1, and MLS lines and was independent of tumor volume for the OWI line. Moreover, linear correlations were found between bioenergetic status and HbO2 saturation status for individual tumors of the KHT, RIF-1, and MLS lines. These observations together indicated a direct relationship between 31P-NMR spectral parameters and tumor oxygen supply conditions. However, this relationship was not identical for the different tumor lines, suggesting that it was influenced by intrinsic properties of the tumor cells such as rate of respiration and ability to survive under hypoxia. Similarly, there was no correlation between bioenergetic status and fraction of radiobiologically hypoxic cells across the four tumor lines. This indicates that 31P-NMR spectroscopy data have to be supplemented with other data, e.g., rate of oxygen consumption, cell survival time under hypoxic stress, and/or fraction of metabolically active

In Vivo pO2 Imaging of Tumors: Oxymetry with Very Low-Frequency Electron Paramagnetic Resonance.

Science.gov (United States)

Epel, Boris; Halpern, Howard J

2015-01-01

For over a century, it has been known that tumor hypoxia, regions of a tumor with low levels of oxygenation, are important contributors to tumor resistance to radiation therapy and failure of radiation treatment of cancer. Recently, using novel pulse electron paramagnetic resonance (EPR) oxygen imaging, near absolute images of the partial pressure of oxygen (pO2) in tumors of living animals have been obtained. We discuss here the means by which EPR signals can be obtained in living tissues and tumors. We review development of EPR methods to image the pO2 in tumors and the potential for the pO2 image acquisition in human subjects. © 2015 Elsevier Inc. All rights reserved.

In vivo pO2 imaging of tumors: Oxymetry with very low frequency Electron Paramagnetic Resonance

Science.gov (United States)

Epel, Boris; Halpern, Howard J.

2016-01-01

For over a century it has been known that tumor hypoxia, regions of a tumor with low levels of oxygenation, are important contributors to tumor resistance to radiation therapy and failure of radiation treatment of cancer. Recently, using novel pulse electron paramagnetic resonance (EPR) oxygen imaging, near absolute images of the partial pressure of oxygen (pO2) in tumors of living animals have been obtained. We discuss here the means by which EPR signals can be obtained in living tissues and tumors. We review development of EPR methods to image the pO2 in tumors and the potential for the pO2 image acquisition in human subjects. PMID:26477263

[Effect of hemodilution with 10% hydroxyethyl starch solution (MW 200,000/9.5) on the flow properties of blood, arterial blood gases and conjunctival oxygen partial pressure in patients with cerebral infarct].

Science.gov (United States)

Staedt, U; Hütt, M; Herrmann, B; Seufzer, U; Leweling, H

1989-06-01

Hemorheological parameters, arterial blood gases and conjunctival oxygen tension were measured in 15 patients with acute ischemic stroke and compared with values obtained in an age matched reference group. Since the conjunctival capillary bed is perfused by the ophthalmic artery, it reflects the oxygen delivery to the areas supplied by the internal carotid artery. Measurements of conjunctival oxygen tension are simple and safe. Patients with acute ischemic stroke showed a lowered conjunctival oxygen tension; this holds true especially to the ipsilateral side, i.e. the side where the attack occurred, and to a lesser extent to the other side. By contrast, the ratio of arterial/conjunctival pO2 was disturbed only on the ipsilateral side. Furthermore, these patients had pathologically elevated values for red cell aggregation, whole blood and plasma viscosity. After infusing 500 ml 10% middle-molecular-weight hydroxyethyl starch (10% HAES-steril) and phlebotomy (250 ml) blood fluidity was normalized, although the hematokrit was only slightly reduced. Arterial pO2 improved slightly while pCO2 remained unchanged. Conjunctival oxygen tension improved by 30% on the ipsilateral and by 10% on the contralateral side, the ipsilateral values always remaining significantly lower. The ratio conjunctival/arterial pO2 raised only on the ipsilateral side where it was below the reference range before hemodilution. In addition to the well known improvement of blood fluidity and augmentation of cerebral blood flow following hemodilution in patients with acute ischemic stroke, there seems to be an increase in oxygen supply in the territories of both internal carotid arteries, especially on the ipsilateral side as indicated by the values of conjunctival oxygen tension and the ratio of conjunctival to arterial pO2.

Spontaneous tension haemopneumothorax

OpenAIRE

Patterson, Benjamin Oliver; Itam, Sarah; Probst, Fey

2008-01-01

Abstract We present a patient with sudden onset progressive shortness of breath and no history of trauma, who rapidly became haemodynamically compromised with a pneumothorax and pleural effusion seen on chest radiograph. He was treated for spontaneous tension pneumothorax but this was soon revealed to be a tension haemopneumothorax. He underwent urgent thoracotomy after persistent bleeding to explore an apical vascular abnormality seen on CT scanning. To our knowledge this is the first such c...

A hybrid multibreath wash-in wash-out lung function quantification scheme in human subjects using hyperpolarized 3 He MRI for simultaneous assessment of specific ventilation, alveolar oxygen tension, oxygen uptake, and air trapping.

Science.gov (United States)

Hamedani, Hooman; Kadlecek, Stephen; Xin, Yi; Siddiqui, Sarmad; Gatens, Heather; Naji, Joseph; Ishii, Masaru; Cereda, Maurizio; Rossman, Milton; Rizi, Rahim

2017-08-01

To present a method for simultaneous acquisition of alveolar oxygen tension (P A O 2 ), specific ventilation (SV), and apparent diffusion coefficient (ADC) of hyperpolarized (HP) gas in the human lung, allowing reinterpretation of the P A O 2 and SV maps to produce a map of oxygen uptake (R). An imaging scheme was designed with a series of identical normoxic HP gas wash-in breaths to measure ADC, SV, P A O 2 , and R in less than 2 min. Signal dynamics were fit to an iterative recursive model that regionally solved for these parameters. This measurement was successfully performed in 12 subjects classified in three healthy, smoker, and chronic obstructive pulmonary disease (COPD) cohorts. The overall whole lung ADC, SV, P A O 2 , and R in healthy, smoker, and COPD subjects was 0.20 ± 0.03 cm 2 /s, 0.39 ± 0.06,113 ± 2 Torr, and 1.55 ± 0.35 Torr/s, respectively, in healthy subjects; 0.21 ± 0.03 cm 2 /s, 0.33 ± 0.06, 115.9 ± 4 Torr, and 0.97 ± 0.2 Torr/s, respectively, in smokers; and 0.25 ± 0.06 cm 2 /s, 0.23 ± 0.08, 114.8 ± 6.0Torr, and 0.94 ± 0.12 Torr/s, respectively, in subjects with COPD. Hetrogeneity of SV, P A O 2 , and R were indicators of both smoking-related changes and disease, and the severity of the disease correlated with the degree of this heterogeneity. Subjects with symptoms showed reduced oxygen uptake and specific ventilation. High-resolution, nearly coregistered and quantitative measures of lung function and structure were obtained with less than 1 L of HP gas. This hybrid multibreath technique produced measures of lung function that revealed clear differences among the cohorts and subjects and were confirmed by correlations with global lung measurements. Magn Reson Med 78:611-624, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition.

Directory of Open Access Journals (Sweden)

Stuart J Smith

Full Text Available INTRODUCTION: Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS. METHODS: CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat. RESULTS: Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches. CONCLUSIONS: Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system.

Tension headache.

Science.gov (United States)

Ziegler, D K

1978-05-01

Headache is an extremely common symptom, and many headaches undoubtedly have a relationship to stressful situations. The clear definition, however, of a "tension headache" complex and its differentiation from migraine in some patients is difficult. The problems are in the identification of a specific headache pattern induced by stress or "tension" and the relationship of the symptom to involuntary contraction of neck and scalp muscles. Treatment consists of analgesics and occasionally mild tranquilizers. Psychotherapy consists of reassurance and often other supportive measures, including modification of life styles. Various feedback techniques have been reported of value, but their superiority to suggestion and hypnosis is still problematic.

Adult and newborn rat inner retinal oxygenation during carbogen and 100% oxygen breathing. Comparison using magnetic resonance imaging delta Po2 mapping.

Science.gov (United States)

Berkowitz, B A

1996-09-01

To test the hypothesis that breathing carbogen (95% O2-5% CO2) oxygenates the inner retina better than breathing 100% oxygen using an magnetic resonance imaging (MRI) method that noninvasively measures inner retinal oxygenation in normal adult and newborn rats. Urethane-anesthetized adult and newborn (day 18) rats were studied. Sequential images were acquired in room air combined with either 100% oxygen or carbogen breathing. Normalized vitreous signal intensity changes were converted to oxygen tension changes (delta PO2) either on a pixel-by-pixel basis or in specific regions of interest. Systemic levels of hyperoxia during carbogen or 100% oxygen breathing were not significantly different (P > 0.05). In the adult rat, a significant difference (P = 0.017) was found in the preretinal vitreous delta PO2 during the breathing of either carbogen (130 +/- 9 mm Hg, mean +/- SEM; n = 5) or 100% oxygen (88 +/- 16 mm Hg; n = 5). Agreement was found between the MRI-determined delta PO2 values and literature oxygen microelectrodes data. In the newborn rat, significant differences (P delta PO2 were found during carbogen (164 +/- 23 mm Hg; n = 3) and oxygen breathing (91 +/- 8 mm Hg; n = 3). MRI delta PO2 mapping demonstrated for the first time that in the normal adult and newborn rat eye, carbogen breathing oxygenates the inner retina better than 100% oxygen breathing.

Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302.

Science.gov (United States)

Wojtkowiak, Jonathan W; Cornnell, Heather C; Matsumoto, Shingo; Saito, Keita; Takakusagi, Yoichi; Dutta, Prasanta; Kim, Munju; Zhang, Xiaomeng; Leos, Rafael; Bailey, Kate M; Martinez, Gary; Lloyd, Mark C; Weber, Craig; Mitchell, James B; Lynch, Ronald M; Baker, Amanda F; Gatenby, Robert A; Rejniak, Katarzyna A; Hart, Charles; Krishna, Murali C; Gillies, Robert J

2015-01-01

Hypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models. Three human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized (13)C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors. Using metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to

Tensions in Distributed Leadership

Science.gov (United States)

Ho, Jeanne; Ng, David

2017-01-01

Purpose: This article proposes the utility of using activity theory as an analytical lens to examine the theoretical construct of distributed leadership, specifically to illuminate tensions encountered by leaders and how they resolved these tensions. Research Method: The study adopted the naturalistic inquiry approach of a case study of an…

A reason for intermittent fasting to suppress the awakening of dormant breast tumors.

NARCIS (Netherlands)

Lankelma, J.; Kooi, B.W.; Krab, K.; Dorsman, J.C.; Joenje, H.; Westerhoff, H.V.

2015-01-01

For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors

A reason for intermittent fasting to suppress the awakening of dormant breast tumors

NARCIS (Netherlands)

Lankelma, J.; Kooi, B.; Krab, K.; Dorsman, J.C.; Joenje, H.; Westerhoff, H.V.

2015-01-01

For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors

Tension pneumocephalus: Mount Fuji sign

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Pulastya Sanyal

2015-01-01

Full Text Available A 13-year-old male was operated for a space occupying lesion in the brain. A noncontrast computed tomography scan done in the late postoperative period showed massive subdural air collection causing compression of bilateral frontal lobes with widening of interhemispheric fissure and the frontal lobes acquiring a peak like configuration - causing tension pneumocephalus-"Mount Fuji sign." Tension pneumocephalus occurs when air enters the extradural or intradural spaces in sufficient volume to exert a mass or pressure effect on the brain, leading to brain herniation. Tension pneumocephalus is a surgical emergency, which needs immediate intervention in the form of decompression of the cranial cavity by a burr hole or needle aspiration. The Mount Fuji sign differentiates tension pneumocephalus from pneumocephalus.

Effects of reactive oxygen species on metabolism monitored by longitudinal {sup 1}H single voxel MRS follow-up in patients with mitochondrial disease or cerebral tumors

Energy Technology Data Exchange (ETDEWEB)

Constans, J M; Collet, S; Hossu, G; Courtheoux, P [MRI Unit, Caen University Hospital, Caen, Normandy (France); Guillamo, J S; Lechapt-Zalcman, E; Valable, S [CERVOxy Group, CI-NAPS, UMR 6232 CI-NAPS, Cyceron, Caen, Normandy (France); Lacombe, S; Houee Levin, C [Paris-Sud 11 University-CNRS, Orsay (France); Gauduel, Y A [LOA, Ecole Polytechnique - ENSTA ParisTech, Palaiseau (France); Dou, W [Tsinghua University, Beijing (China); Ruan, S [CReSTIC EA 3804, IUT Troyes, Troyes (France); Barre, L [GDMTEP, Group CI-NAPS, UMR 6232 CI-NAPS, Cyceron, Caen (France); Rioult, F [CNRS UMR 6072, GREYC, Caen, Normandy (France); Derlon, J M [Neurosurgery and Neurology, Caen University Hospital, Caen, Normandy (France); Chapon, F [Pathology, Caen University Hospital, Caen, Normandy (France); Fong, V [Caen University (France); Kauffmann, F, E-mail: constans-jm@chu-caen.fr [Mathematics LMNO CNRS UMR 6139, Caen University, Caen, Normandy (France)

2011-01-01

Free radicals, or Reactive Oxygen Species (ROS), have an effect on energy and glycolytic metabolism, mitochondrial function, lipid metabolism, necrosis and apoptosis, cell proliferation, and infiltration. These changes could be monitored longitudinally (every 4 months over 6 years) in humans with glial brain tumors (low and high grade) after therapy, using conventional magnetic resonance imaging (MRI) and spectroscopy (MRS) and MR perfusion. Some examples of early clinical data from longitudinal follow-up monitoring in humans of energy and glycolytic metabolism, lipid metabolism, necrosis, proliferation, and infiltration measured by conventional MRI, MRS and perfusion, and positron emission tomography (PET) are shown in glial brain tumors after therapy. Despite the difficulty, the variability and unknown factors, these repeated measurements give us a better insight into the nature of the different processes, tumor progression and therapeutic response.

Magnetic resonance imaging of tumor oxygenation and metabolic profile

DEFF Research Database (Denmark)

Krishna, Murali C.; Matsumoto, Shingo; Saito, Keita

2013-01-01

The tumor microenvironment is distinct from normal tissue as a result of abnormal vascular network characterized by hypoxia, low pH, high interstitial fluid pressure and elevated glycolytic activity. This poses a barrier to treatments including radiation therapy and chemotherapy. Imaging methods...... spectroscopic imaging. Imaging pO2 in tumors is now a robust pre-clinical imaging modality with potential for implementation clinically. Pre-clinical studies and an initial clinical study with hyperpolarized metabolic MR have been successful and suggest that the method may be part of image-guided radiotherapy...

Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors

Science.gov (United States)

Bendinger, Alina L.; Glowa, Christin; Peter, Jörg; Karger, Christian P.

2018-03-01

A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity.

Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors.

Science.gov (United States)

Bendinger, Alina L; Glowa, Christin; Peter, Jörg; Karger, Christian P

2018-03-01

A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity. (2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

Magnetic Resonance Spectroscopic Imaging of Tumor Metabolic Markers for Cancer Diagnosis, Metabolic Phenotyping, and Characterization of Tumor Microenvironment

Directory of Open Access Journals (Sweden)

Qiuhong He

2004-01-01

Full Text Available Cancer cells display heterogeneous genetic characteristics, depending on the tumor dynamic microenvironment. Abnormal tumor vasculature and poor tissue oxygenation generate a fraction of hypoxic tumor cells that have selective advantages in metastasis and invasion and often resist chemo- and radiation therapies. The genetic alterations acquired by tumors modify their biochemical pathways, which results in abnormal tumor metabolism. An elevation in glycolysis known as the “Warburg effect” and changes in lipid synthesis and oxidation occur. Magnetic resonance spectroscopy (MRS has been used to study tumor metabolism in preclinical animal models and in clinical research on human breast, brain, and prostate cancers. This technique can identify specific genetic and metabolic changes that occur in malignant tumors. Therefore, the metabolic markers, detectable by MRS, not only provide information on biochemical changes but also define different metabolic tumor phenotypes. When combined with the contrast-enhanced Magnetic Resonance Imaging (MRI, which has a high sensitivity for cancer diagnosis, in vivo magnetic resonance spectroscopic imaging (MRSI improves the diagnostic specificity of malignant human cancers and is becoming an important clinical tool for cancer management and care. This article reviews the MRSI techniques as molecular imaging methods to detect and quantify metabolic changes in various tumor tissue types, especially in extracranial tumor tissues that contain high concentrations of fat. MRI/MRSI methods have been used to characterize tumor microenvironments in terms of blood volume and vessel permeability. Measurements of tissue oxygenation and glycolytic rates by MRS also are described to illustrate the capability of the MR technology in probing molecular information non-invasively in tumor tissues and its important potential for studying molecular mechanisms of human cancers in physiological conditions.

Experimental and theoretical studies of oxygen gradients in rat pial microvessels

OpenAIRE

Sharan, Maithili; Vovenko, Eugene P; Vadapalli, Arjun; Popel, Aleksander S; Pittman, Roland N

2008-01-01

Using modified oxygen needle microelectrodes and intravital videomicroscopy, measurements were made of tissue oxygen tension (PO2) profiles near cortical arterioles and transmural PO2 gradients in the pial arterioles of the rat. Under control conditions, the transmural PO2 gradient averaged 1.17 ± 0.06 mm Hg/μm (mean ± s.e., n = 40). Local arteriolar dilation resulted in a marked decrease in the transmural PO2 gradient to 0.68 ± 0.04 mm Hg/μm (P < 0.001, n = 38). The major finding of this stu...

Effects of in vitro low oxygen tension preconditioning of adipose stromal cells on their in vivo chondrogenic potential: application in cartilage tissue repair.

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Sophie Portron

Full Text Available PURPOSE: Multipotent stromal cell (MSC-based regenerative strategy has shown promise for the repair of cartilage, an avascular tissue in which cells experience hypoxia. Hypoxia is known to promote the early chondrogenic differentiation of MSC. The aim of our study was therefore to determine whether low oxygen tension could be used to enhance the regenerative potential of MSC for cartilage repair. METHODS: MSC from rabbit or human adipose stromal cells (ASC were preconditioned in vitro in control or chondrogenic (ITS and TGF-β medium and in 21 or 5% O2. Chondrogenic commitment was monitored by measuring COL2A1 and ACAN expression (real-time PCR. Preconditioned rabbit and human ASC were then incorporated into an Si-HPMC hydrogel and injected (i into rabbit articular cartilage defects for 18 weeks or (ii subcutaneously into nude mice for five weeks. The newly formed tissue was qualitatively and quantitatively evaluated by cartilage-specific immunohistological staining and scoring. The phenotype of ASC cultured in a monolayer or within Si-HPMC in control or chondrogenic medium and in 21 or 5% O2 was finally evaluated using real-time PCR. RESULTS/CONCLUSIONS: 5% O2 increased the in vitro expression of chondrogenic markers in ASC cultured in induction medium. Cells implanted within Si-HPMC hydrogel and preconditioned in chondrogenic medium formed a cartilaginous tissue, regardless of the level of oxygen. In addition, the 3D in vitro culture of ASC within Si-HPMC hydrogel was found to reinforce the pro-chondrogenic effects of the induction medium and 5% O2. These data together indicate that although 5% O2 enhances the in vitro chondrogenic differentiation of ASC, it does not enhance their in vivo chondrogenesis. These results also highlight the in vivo chondrogenic potential of ASC and their potential value in cartilage repair.

Electron paramagnetic resonance highlights that the oxygen effect contributes to the radiosensitizing effect of paclitaxel.

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Fabienne Danhier

Full Text Available BACKGROUND: Paclitaxel (PTX is a potent anti-cancer chemotherapeutic agent and is widely used in the treatments of solid tumors, particularly of the breast and ovaries. An effective and safe micellar formulation of PTX was used to administer higher doses of PTX than Taxol® (the current commercialized drug. We hypothesize that PTX-loaded micelles (M-PTX may enhance tumor radiosensitivity by increasing the tumor oxygenation (pO(2. Our goals were (i to evaluate the contribution of the "oxygen effect" to the radiosensitizing effect of PTX; (ii to demonstrate the therapeutic relevance of the combination of M-PTX and irradiation and (iii to investigate the underlying mechanisms of the observed oxygen effect. METHODOLOGY AND PRINCIPAL FINDINGS: We used (PEG-p-(CL-co-TMC polymeric micelles to solubilize PTX. pO(2 was measured on TLT tumor-bearing mice treated with M-PTX (80 mg/kg using electron paramagnetic resonance (EPR oximetry. The regrowth delay following 10 Gy irradiation 24 h after M-PTX treatment was measured. The tumor perfusion was assessed by the patent blue staining. The oxygen consumption rate and the apoptosis were evaluated by EPR oximetry and the TUNEL assay, respectively. EPR oximetry experiments showed that M-PTX dramatically increases the pO(2 24 h post treatment. Regrowth delay assays demonstrated a synergy between M-PTX and irradiation. M-PTX increased the tumor blood flow while cells treated with M-PTX consumed less oxygen and presented more apoptosis. CONCLUSIONS: M-PTX improved the tumor oxygenation which leads to synergy between this treatment and irradiation. This increased pO(2 can be explained both by an increased blood flow and an inhibition of O(2 consumption.

Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response.

Science.gov (United States)

Hallac, Rami R; Zhou, Heling; Pidikiti, Rajesh; Song, Kwang; Stojadinovic, Strahinja; Zhao, Dawen; Solberg, Timothy; Peschke, Peter; Mason, Ralph P

2014-05-01

To examine the potential use of blood oxygenation level dependent (BOLD) and tissue oxygenation level dependent (TOLD) contrast MRI to assess tumor oxygenation and predict radiation response. BOLD and TOLD MRI were performed on Dunning R3327-AT1 rat prostate tumors during hyperoxic gas breathing challenge at 4.7 T. Animals were divided into two groups. In Group 1 (n = 9), subsequent (19) F MRI based on spin lattice relaxation of hexafluorobenzene reporter molecule provided quantitative oximetry for comparison. For Group 2 rats (n = 13) growth delay following a single dose of 30 Gy was compared with preirradiation BOLD and TOLD assessments. Oxygen (100%O2 ) and carbogen (95%O2 /5%CO2 ) challenge elicited similar BOLD, TOLD and pO2 responses. Strong correlations were observed between BOLD or R2* response and quantitative (19) F pO2 measurements. TOLD response showed a general trend with weaker correlation. Irradiation caused a significant tumor growth delay and tumors with larger changes in TOLD and R1 values upon oxygen breathing exhibited significantly increased tumor growth delay. These results provide further insight into the relationships between oxygen sensitive (BOLD/TOLD) MRI and tumor pO2 . Moreover, a larger increase in R1 response to hyperoxic gas challenge coincided with greater tumor growth delay following irradiation. Copyright © 2013 Wiley Periodicals, Inc.

Shape accuracy optimization for cable-rib tension deployable antenna structure with tensioned cables

Science.gov (United States)

Liu, Ruiwei; Guo, Hongwei; Liu, Rongqiang; Wang, Hongxiang; Tang, Dewei; Song, Xiaoke

2017-11-01

Shape accuracy is of substantial importance in deployable structures as the demand for large-scale deployable structures in various fields, especially in aerospace engineering, increases. The main purpose of this paper is to present a shape accuracy optimization method to find the optimal pretensions for the desired shape of cable-rib tension deployable antenna structure with tensioned cables. First, an analysis model of the deployable structure is established by using finite element method. In this model, geometrical nonlinearity is considered for the cable element and beam element. Flexible deformations of the deployable structure under the action of cable network and tensioned cables are subsequently analyzed separately. Moreover, the influence of pretension of tensioned cables on natural frequencies is studied. Based on the results, a genetic algorithm is used to find a set of reasonable pretension and thus minimize structural deformation under the first natural frequency constraint. Finally, numerical simulations are presented to analyze the deployable structure under two kinds of constraints. Results show that the shape accuracy and natural frequencies of deployable structure can be effectively improved by pretension optimization.

Spontaneous tension haemopneumothorax.

Science.gov (United States)

Patterson, Benjamin Oliver; Itam, Sarah; Probst, Fey

2008-10-31

We present a patient with sudden onset progressive shortness of breath and no history of trauma, who rapidly became haemodynamically compromised with a pneumothorax and pleural effusion seen on chest radiograph. He was treated for spontaneous tension pneumothorax but this was soon revealed to be a tension haemopneumothorax. He underwent urgent thoracotomy after persistent bleeding to explore an apical vascular abnormality seen on CT scanning. To our knowledge this is the first such case reported.Aetiology and current approach to spontaneous haemothorax are discussed briefly.

Is oxygen availability a limiting factor for in vitro folliculogenesis?

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Riccardo Talevi

Full Text Available Transplantation of ovarian tissue for the preservation of fertility in oncological patients is becoming an accepted clinical practice. However, the risk of re-introducing tumour cells at transplantation has stirred an increased interest for complete in vitro folliculogenesis. This has not yet been achieved in humans possibly for the lack of knowledge on the environmental milieu that orchestrates folliculogenesis in vivo. The main aim of this study was to investigate the effect of oxygen availability on follicle health and growth during in vitro culture of ovarian tissue strips. To this end, a model was developed to predict the dissolved oxygen concentration in tissue under varying culture conditions. Ovarian cortical strips of bovine, adopted as an animal model, and human tissue were cultured in conventional (CD and gas permeable (PD dishes under different media column heights and gaseous oxygen tensions for 3, 6 and 9 days. Follicle quality, activation of primordial follicles to the primary stage, and progression to the secondary stage were analysed through histology. Follicle viability was assessed through a live-dead assay at the confocal scanning laser microscope. Findings showed a higher follicle quality and viability after culture of bovine ovarian strips in PD in adequate medium height and oxygen tensions. The best culture conditions found in the bovine were adopted for human ovarian strip culture and promoted a higher follicle quality, viability and progression. Overall, data demonstrated that modulation of oxygen availability in tissue plays a key role in maintaining follicles' health and their ability to survive and progress to the secondary stage during ovarian tissue in vitro culture. Such culture conditions could increase the yield of healthy secondary follicles for subsequent dissection and individual culture to obtain competent oocytes.

Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship

NARCIS (Netherlands)

Netea-Maier, R.T.; Smit, J.W.A.; Netea, M.G.

2018-01-01

In order to adapt to the reduced availability of nutrients and oxygen in the tumor microenvironment and the increased requirements of energy and building blocks necessary for maintaining their high proliferation rate, malignant cells undergo metabolic changes that result in an increased production

Correlation of cutaneous tension distribution and tissue oxygenation with acute external tissue expansion

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Marquardt C

2009-11-01

Full Text Available Abstract Today, the biomechanical fundamentals of skin expansion are based on viscoelastic models of the skin. Although many studies have been conducted in vitro, analyses performed in vivo are rare. Here, we present in vivo measurements of the expansion at the skin surface as well as measurement of the corresponding intracutaneous oxygen partial pressure. In our study the average skin stretching was 24%, with a standard deviation of 11%, excluding age or gender dependency. The measurement of intracutaneous oxygen partial pressure produced strong inter-individual fluctuations, including initial values at the beginning of the measurement, as well as varying individual patient reactions to expansion of the skin. Taken together, we propose that even large defect wounds can be closed successfully using the mass displacement caused by expansion especially in areas where soft, voluminous tissue layers are present.

Membrane tension regulates clathrin-coated pit dynamics

Science.gov (United States)

Liu, Allen

2014-03-01

Intracellular organization depends on close communication between the extracellular environment and a network of cytoskeleton filaments. The interactions between cytoskeletal filaments and the plasma membrane lead to changes in membrane tension that in turns help regulate biological processes. Endocytosis is thought to be stimulated by low membrane tension and the removal of membrane increases membrane tension. While it is appreciated that the opposing effects of exocytosis and endocytosis have on keeping plasma membrane tension to a set point, it is not clear how membrane tension affects the dynamics of clathrin-coated pits (CCPs), the individual functional units of clathrin-mediated endocytosis. Furthermore, although it was recently shown that actin dynamics counteracts membrane tension during CCP formation, it is not clear what roles plasma membrane tension plays during CCP initiation. Based on the notion that plasma membrane tension is increased when the membrane area increases during cell spreading, we designed micro-patterned surfaces of different sizes to control the cell spreading sizes. Total internal reflection fluorescence microscopy of living cells and high content image analysis were used to quantify the dynamics of CCPs. We found that there is an increased proportion of CCPs with short (<20s) lifetime for cells on larger patterns. Interestingly, cells on larger patterns have higher CCP initiation density, an effect unexpected based on the conventional view of decreasing endocytosis with increasing membrane tension. Furthermore, by analyzing the intensity profiles of CCPs that were longer-lived, we found CCP intensity decreases with increasing cell size, indicating that the CCPs are smaller with increasing membrane tension. Finally, disruption of actin dynamics significantly increased the number of short-lived CCPs, but also decreased CCP initiation rate. Together, our study reveals new mechanistic insights into how plasma membrane tension regulates

Tumor Hypoxia is Independent of Hemoglobin and Prognostic for Loco-regional Tumor Control after Primary Radiotherapy in Advanced Head and Neck Cancer

International Nuclear Information System (INIS)

Nordsmark, Marianne; Overgaard, Jens

2004-01-01

There is evidence that tumor hypoxia adversely affects loco-regional tumor control and survival in head and neck cancer. The aim of the current study was to compare pretreatment tumor oxygenation measured by Eppendorf pO2 electrodes with known prognostic factors in advanced head and neck tumors after definitive radiotherapy, and to evaluate the prognostic significance of these parameters on loco-regional tumor control. Sixty-seven patients, median age 56 years (22-82), all with primary stage III-IV squamous cell carcinoma were available for survival analysis. Tumor oxygenation was described as the fraction of pO2 values=2.5 mmHg (HP2.5) and the median tumor pO2. By regression analysis HP2.5 was independent of known prognostic factors including stage, pretreatment hemoglobin (Hb) and the largest tumor diameter at the site of pO2 measurement. By Kaplan-Meier analysis loco-regional tumor control at 5 years was in favor of less hypoxic tumors using either HP2.5 or median tumor pO2 as descriptors and stratifying by the median values. Also, Hb was prognostic of loco-regional tumor control at 5 years using the median value as cut off. HP2.5 as continuous parameter was highly significant for loco-regional tumor control in a multivariate analysis. In conclusion both HP2.5 and total Hb were prognostic for loco-regional tumor control, but HP2.5 as continuous variable was independently the strongest prognostic indicator for loco-regional tumor control after definitive primary radiotherapy in advanced head and neck tumors

Logic Learning Machine creates explicit and stable rules stratifying neuroblastoma patients

NARCIS (Netherlands)

Cangelosi, Davide; Blengio, Fabiola; Versteeg, Rogier; Eggert, Angelika; Garaventa, Alberto; Gambini, Claudio; Conte, Massimo; Eva, Alessandra; Muselli, Marco; Varesio, Luigi

2013-01-01

Neuroblastoma is the most common pediatric solid tumor. About fifty percent of high risk patients die despite treatment making the exploration of new and more effective strategies for improving stratification mandatory. Hypoxia is a condition of low oxygen tension occurring in poorly vascularized

Spontaneous tension haemopneumothorax

Directory of Open Access Journals (Sweden)

Itam Sarah

2008-10-01

Full Text Available Abstract We present a patient with sudden onset progressive shortness of breath and no history of trauma, who rapidly became haemodynamically compromised with a pneumothorax and pleural effusion seen on chest radiograph. He was treated for spontaneous tension pneumothorax but this was soon revealed to be a tension haemopneumothorax. He underwent urgent thoracotomy after persistent bleeding to explore an apical vascular abnormality seen on CT scanning. To our knowledge this is the first such case reported. Aetiology and current approach to spontaneous haemothorax are discussed briefly.

Longitudinal imaging studies of tumor microenvironment in mice treated with the mTOR inhibitor rapamycin.

Directory of Open Access Journals (Sweden)

Keita Saito

Full Text Available Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII by electron paramagnetic resonance imaging (EPRI and magnetic resonance imaging (MRI to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3 and measurements of tumor pO(2 and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2 levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2<10 mm Hg in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy.

Initial tension loss in cerclage cables.

Science.gov (United States)

Ménard, Jérémie; Émard, Maxime; Canet, Fanny; Brailovski, Vladimir; Petit, Yvan; Laflamme, George Y

2013-10-01

Cerclage cables, frequently used in the management of fractures and osteotomies, are associated with a high failure rate and significant loosening during surgery. This study compared the capacity to maintain tension of different types of orthopaedic cable systems. Multifilament Cobalt-Chrome (CoCr) cables with four different crimp/clamp devices (DePuy, Stryker, Zimmer and Smith&Nephew) and one non-metallic Nylon (Ny) cable from Kinamed were instrumented with a load cell to measure tension during insertion. Significant tension loss was observed with crimping for all cables (Ptensioner led to an additional unexpected tension loss (CoCr-DePuy: 18%, CoCr-Stryker: 29%, CoCr-Smith&Nephew: 33%, Ny: 46%, and CoCr-Zimmer: 52%). The simple CoCr (DePuy) cable system outperformed the more sophisticated locking devices due to its significantly better ability to prevent tension loss. Copyright © 2013 Elsevier Inc. All rights reserved.

The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease

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W. H. Davin Townley-Tilson

2015-01-01

Full Text Available Ischemic heart disease is the leading cause of death worldwide. Oxygen-sensing proteins are critical components of the physiological response to hypoxia and reperfusion injury, but the role of oxygen and oxygen-mediated effects is complex in that they can be cardioprotective or deleterious to the cardiac tissue. Over 200 oxygen-sensing proteins mediate the effects of oxygen tension and use oxygen as a substrate for posttranslational modification of other proteins. Hydroxylases are an essential component of these oxygen-sensing proteins. While a major role of hydroxylases is regulating the transcription factor HIF, we investigate the increasing scope of hydroxylase substrates. This review discusses the importance of oxygen-mediated effects in the heart as well as how the field of oxygen-sensing proteins is expanding, providing a more complete picture into how these enzymes play a multifaceted role in cardiac function and disease. We also review how oxygen-sensing proteins and hydroxylase function could prove to be invaluable in drug design and therapeutic targets for heart disease.

Toward a general psychological model of tension and suspense.

Science.gov (United States)

Lehne, Moritz; Koelsch, Stefan

2015-01-01

Tension and suspense are powerful emotional experiences that occur in a wide variety of contexts (e.g., in music, film, literature, and everyday life). The omnipresence of tension and suspense suggests that they build on very basic cognitive and affective mechanisms. However, the psychological underpinnings of tension experiences remain largely unexplained, and tension and suspense are rarely discussed from a general, domain-independent perspective. In this paper, we argue that tension experiences in different contexts (e.g., musical tension or suspense in a movie) build on the same underlying psychological processes. We discuss key components of tension experiences and propose a domain-independent model of tension and suspense. According to this model, tension experiences originate from states of conflict, instability, dissonance, or uncertainty that trigger predictive processes directed at future events of emotional significance. We also discuss possible neural mechanisms underlying tension and suspense. The model provides a theoretical framework that can inform future empirical research on tension phenomena.

Correlation of FMISO simulations with pimonidazole-stained tumor xenografts: A question of O{sub 2} consumption?

Energy Technology Data Exchange (ETDEWEB)

Wack, L. J., E-mail: linda-jacqueline.wack@med.uni-tuebingen.de; Thorwarth, D. [Section for Biomedical Physics, Department of Radiation Oncology, University Hospital Tübingen, Tübingen 72076 (Germany); Mönnich, D. [Section for Biomedical Physics, Department of Radiation Oncology, University Hospital Tübingen, Tübingen 72076 (Germany); German Cancer Consortium (DKTK), Tübingen 72076 (Germany); German Cancer Research Center (DKFZ), Heidelberg 69121 (Germany); Yaromina, A. [OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01309, Germany and Department of Radiation Oncology (MAASTRO), GROW—School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht 6229 ET (Netherlands); Zips, D. [German Cancer Consortium (DKTK), Tübingen 72076 (Germany); German Cancer Research Center (DKFZ), Heidelberg 69121 (Germany); Department of Radiation Oncology, University Hospital Tübingen, Tübingen 72076 (Germany); and others

2016-07-15

Purpose: To compare a dedicated simulation model for hypoxia PET against tumor microsections stained for different parameters of the tumor microenvironment. The model can readily be adapted to a variety of conditions, such as different human head and neck squamous cell carcinoma (HNSCC) xenograft tumors. Methods: Nine different HNSCC tumor models were transplanted subcutaneously into nude mice. Tumors were excised and immunoflourescently labeled with pimonidazole, Hoechst 33342, and CD31, providing information on hypoxia, perfusion, and vessel distribution, respectively. Hoechst and CD31 images were used to generate maps of perfused blood vessels on which tissue oxygenation and the accumulation of the hypoxia tracer FMISO were mathematically simulated. The model includes a Michaelis–Menten relation to describe the oxygen consumption inside tissue. The maximum oxygen consumption rate M{sub 0} was chosen as the parameter for a tumor-specific optimization as it strongly influences tracer distribution. M{sub 0} was optimized on each tumor slice to reach optimum correlations between FMISO concentration 4 h postinjection and pimonidazole staining intensity. Results: After optimization, high pixel-based correlations up to R{sup 2} = 0.85 were found for individual tissue sections. Experimental pimonidazole images and FMISO simulations showed good visual agreement, confirming the validity of the approach. Median correlations per tumor model varied significantly (p < 0.05), with R{sup 2} ranging from 0.20 to 0.54. The optimum maximum oxygen consumption rate M{sub 0} differed significantly (p < 0.05) between tumor models, ranging from 2.4 to 5.2 mm Hg/s. Conclusions: It is feasible to simulate FMISO distributions that match the pimonidazole retention patterns observed in vivo. Good agreement was obtained for multiple tumor models by optimizing the oxygen consumption rate, M{sub 0}, whose optimum value differed significantly between tumor models.

Tension type headaches: a review

African Journals Online (AJOL)

Location of the pain:There is often a typical location for tension- type headaches, as ... Cranial nerve abnormalities, including papilloedema. • Signs of ... peripheral and central mechanisms underlie tension-type ... Physiotherapy has been shown to be an effective management option for .... Acupuncture in primary headache.

Post-tensioning system surveillance program

International Nuclear Information System (INIS)

Drew, G.E.

1979-01-01

Nuclear power plant containment structure post-tensioning system tendon surveillance program is described in detail. Data collected over three yearly post-tensioning system Surveillance Programs is presented and evaluated to correlate anticipated stress losses with actual losses. In addition corrosion protected system performance is analyzed

The study and design of tension controller

Science.gov (United States)

Jun, G.; Lamei, X.

2018-02-01

Tension control is a wide used technology in areas such as textiles, paper and plastic films. In this article, the tension control system release and winding process is analyzed and the mathematical model of tension control system is established, and a high performance tension controller is designed. In hardware design, STM32F130 single chip microcomputer is used as the control core, which has the characteristics of fast running speed and rich peripheral features. In software design, μC/OS-II operating system is introduced to improve the efficiency of single chip microcomputer, and enhance the independence of each module, and make development and maintenance more convenient. The taper tension control is adopted in the winding part, which can effectively solve the problem of rolling shrinkage. The results show that the tension controller has the characteristics of simple structure, easy operation and stable performance.

Pulmonary Scintigraphy for Tumour Diagnosis; La Gammagrafia Pulmonar en Diagnostico Tumoral

Energy Technology Data Exchange (ETDEWEB)

Esteban, J.; Lasa, D.; Herranz, R.; Galvez, F.; Negueruela, J.; Perez-Modrego, S. [Hospital Oncologico Provincial, Madrid (Spain)

1969-05-15

Scanning of the lungs with albumin aggregates is one of the most useful methods for studying variations in pulmonary circulation and diagnosing embolisms and infarcts. However, its utilization for the diagnosis of tumours is barely in the trial stage. Using scintillation scanning, the authors have centered their attention on the study of patients with primary pulmonary tumours and secondary tumours at-other sites, and have observed that the tracer distribution pattern differs fundamentally according to the type of tumour. With metastatic tumours, the repercussion of the lesions in scintillation scanning is slight and is entirely dependent on the volume of the zone of condensation. The tumorous nodules behave entirely like inactive zones within a mass of active functional parenchyma and their effect on the scanning image depends solely on the size of the tumorous region and the amount of healthy parenchyma intervening between it and the detector. With primary pulmonary tumours and more especially those located in the hilar region, relatively small lesions give rise to defects in uptake in extensive areas of the lung, and these may affect various segments, a lobe or even the entire lung. This decrease in uptake cannot be entirely explained by the image of the tumour or by the associated zones of atelectasia, but must be due to serious alteration in the haemodynamics of the lung affected. Various kinds of phenomena associated with tumorous development may cause vascular changes affecting even the periphery of the lung: changes in breathing conditions accompanied by a reduction of oxygen tension, leading to change in haemodynamic conditions; pulmonary hypertension through compression of the veins in the lungs which are less resistant than the arteries; and direct nervous stimulation due to irritation of the bronchial plexi as a result of the growth of the tumour and, associated reactive. phenomena. (author) [Spanish] La gammagraffa de pulmon con agregados de albumina

End-Tidal CO2 Tension Is Predictive of Effective Nocturnal Oxygen Therapy in Patients with Chronic Heart Failure and Central Sleep Apnea.

Science.gov (United States)

Sugimura, Koichiro; Shinozaki, Tsuyoshi; Fukui, Shigefumi; Ogawa, Hiromasa; Shimokawa, Hiroaki

2016-05-01

Central sleep apnea (CSA) is characterized by recurring cycles of crescendo-decrescendo ventilation during sleep, and enhances sympathetic nerve activity. Thus CSA has a prognostic impact in patients with chronic heart failure (CHF). Although nocturnal oxygen (O2) therapy decreases frequency of CSA and improves functional exercise capacity, it is also known that some non-responders to the therapy exist. We thus aimed to identify predictors of responders to nocturnal O2 therapy in CHF patients with CSA. In 12 CHF patients with CSA hospitalized at our department, sleep study was performed at 2 consecutive nights. Patients nasally inhaled O2 at either the first or second night in a randomized manner. To predict the percentage reduction in apnea-hypopnea index (%ΔAHI) in response to the nocturnal O2 therapy, we performed multiple regression analysis with a stepwise method with variables including age, brain-natriuretic peptide, circulation time, baseline AHI, hypercapnic ventilatory response and end-tidal carbon dioxide tension (PETCO2). Nocturnal O2 therapy significantly decreased AHI (from 32 ± 13 /h to 12 ± 10 /h, P 50% reduction of AHI), with 88.9% of sensitivity and 66.7% of specificity. In conclusion, PETCO2 is useful to predict the efficacy of O2 therapy in CHF patients with CSA, providing important information to the current nocturnal O2 therapy.

Tension and robustness in multitasking cellular networks.

Directory of Open Access Journals (Sweden)

Jeffrey V Wong

Full Text Available Cellular networks multitask by exhibiting distinct, context-dependent dynamics. However, network states (parameters that generate a particular dynamic are often sub-optimal for others, defining a source of "tension" between them. Though multitasking is pervasive, it is not clear where tension arises, what consequences it has, and how it is resolved. We developed a generic computational framework to examine the source and consequences of tension between pairs of dynamics exhibited by the well-studied RB-E2F switch regulating cell cycle entry. We found that tension arose from task-dependent shifts in parameters associated with network modules. Although parameter sets common to distinct dynamics did exist, tension reduced both their accessibility and resilience to perturbation, indicating a trade-off between "one-size-fits-all" solutions and robustness. With high tension, robustness can be preserved by dynamic shifting of modules, enabling the network to toggle between tasks, and by increasing network complexity, in this case by gene duplication. We propose that tension is a general constraint on the architecture and operation of multitasking biological networks. To this end, our work provides a framework to quantify the extent of tension between any network dynamics and how it affects network robustness. Such analysis would suggest new ways to interfere with network elements to elucidate the design principles of cellular networks.

A theoretical evaluation of the oxygen concentration in a corrosion-fatigue crack

International Nuclear Information System (INIS)

Turnbull, A.

1981-01-01

The oxygen concentration in a corrosion-fatigue crack has been evaluated theoretically by assuming that oxygen was consumed by cathodic reduction on the walls of the crack and mass transport occurred by diffusion and advection (forced convection), with the latter resulting from the sinusoidal variation of the displacement of the crack walls. By using parameters relevant to a compact tension specimen, the time-dependent distribution of the oxygen concentration in the crack was calculated as a function of ΔK (the range of the stress intensity factor), R-value (minimum load/maximum load), frequency, crack length, and electrode potential. The influence of advection was to significantly enhance the mass transport of oxygen in the crack compared with ''diffusion-only'' even at low frequencies and low ΔK. Regions in the crack were identified in which advection dominance or diffusion dominance of the mass transport of oxygen occurred

Mentoring Preservice Teachers: Identifying Tensions and Possible Resolutions

Science.gov (United States)

Hudson, Peter; Hudson, Sue

2018-01-01

Tensions can occur in the mentor-mentee relationship during school-based professional experiences that require problem solving. What are the tensions for mentor teachers in preservice teacher education and how might these tensions be resolved? This qualitative study collected data from 31 high school mentor teachers about tensions experienced with…

Oxygen status of cervical cancers prior and during definitive radiotherapy: possible impact of pretreatment with INF-α-2a/retinol acid on oxygenation

International Nuclear Information System (INIS)

Haensgen, Gabriele; Haensgen, Klaus; Dunst, Juergen

1996-01-01

Objective: Modern techniques have raised the possibility to measure intratumoral pO 2 with needle electrodes. We have investigated the oxygenation status of cervical cancers in patients undergoing definitive radiotherapy. Materials and Methods: From July 1995 through February 1996, 28 patients with squamous cell carcinoma of the cervix uteri FIGO II/III underwent polarographic measurement of tumor oxygenation prior to and during definitive radiotherapy. All received combined external irradiation and HDR-brachytherapy. 14 patients were enrolled in a phase II-protocol and received additional treatment with interferon-alpha-2a (INF-α-2a, daily dose 6x10 6 IU s.c. over 12 days) and cis-retinol acid (cRA, daily dose 1 mg/kg orally) starting 12 days before radiotherapy. During radiotherapy, INF-α-2a was given three times weekly in a dosage of 3x10 6 IU s.c. and cRA in daily doses of 0.5 mg/kg. Tumor oxygenation was measured with an Eppendorf-pO 2 -histograph prior to radiotherapy, after 20Gy and after completion of radiotherapy. Results: We found a broad range of pO 2 -values in the 28 patients. Significant hypoxic areas were detectable in about one third of the patients. The mean and median pO 2 -values did not correlate with tumor stage or tumor volume. At the beginning of radiotherapy, the patients with INF-α-2a/cRA-pretreatment had significant higher mean pO 2 -values as compared to patients without INF-α-2a/cRA-pretreatment: mean pO 2 34.7 ± 25.9 mmHg versus 18.0 ± 9.9 mmHg, p=0.03, median pO 2 28.6 versus 17.3 mmHg). Only two patients had pO 2 -measurements before and after INF-α-2a/cRA-pretreatment; in both the mean pO 2 increased threefold during INF-α-2a/cRA. During radiotherapy, the median pO 2 -value increased in both groups of patients. In patients with primary hypoxia, different patterns of oxygenation were detectable after 20Gy showing persistent hypoxia or an increase in the mean pO 2 . Persistent hypoxia without 'reoxygenation' was associated with

Radiotherapy plus cis-retinoic acid/interferon-α in cervical cancers: response and impact of cRA/IFN on tumor tissue oxygenation

International Nuclear Information System (INIS)

Haensgen, Gabriele; Koehler, Uwe; Dunst, Juergen

1997-01-01

Background: We have evaluated the impact of 13-cis-retinoic acid plus interferon in combination with radiotherapy on response and on tumor oxygenation in a phase II-study. Materials and methods: From June 1995 through April 1996, thirty-four patients with squamous cell carcinoma FIGO IIB (N=8) and IIIB (N=26) of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-α-2a (IFN-α-2a) as part of a phase-II-protocol at the Universities of Halle-Wittenberg (N=25), Leipzig (N=7) and Dresden (N=2). cRA/IFN-α-2a started 14 days prior to radiotherapy (1 mg per kilogramm body weight cRA orally daily plus 6x10 6 I.U. IFN-α-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 45Gy in 25 fractions of 1.8Gy plus HDR-brachytherapy with 5x7Gy). During radiotherapy, cRA/IFN-α-2a-treatment was continued with 50% of the daily doses. In 14 patients treated at the University of Halle-Wittenberg, tumor tissue pO 2 -measurements were performed prior to radiotherapy, at 20Gy, and at the end of radiotherapy with an Eppendorf-pO 2 -histograph. The oxygenation data of these patients were compared to 14 patients who had also pO 2 -measurements but had refused to participate in the cRA/IFN-α-2a-protocol and received radiotherapy alone during the same period. Results: All 8 patients with FIGO IIB tumors had a complete clinical remission 3 months after radiotherapy. In FIGO IIIB cancers, (19(26)) (73%) achieved a cCR, 5 (19%) had a PR and 2 died within six months after treatment due to intercurrent disease. The toxicity of cRA/IFN-α-2a was only mild to moderate (fever 43%, skin toxicity 36%, diarrhea 20%, elevation of liver enzymes 20%) with no grade (3(4)) toxicity. The 14 patients with cRA/IFN-α-2a-pretreatment prior to radiotherapy had significant higher median pO 2 -values in their tumors at the

Delayed Tension Pneumothorax - Identification and Treatment in Traumatic Bronchial Injury: An Interesting Presentation.

Science.gov (United States)

Gupta, Amit; Rattan, Amulya; Kumar, Sunil; Rathi, Vinita

2017-09-01

A 13-year-old girl, who did not receive any treatment for few hours following Road Traffic Injury (RTI), reported to the Casualty Department and found to have patent airway with clinically normal C spine, air-hunger (RR 42/minute), trachea deviated to left, distended neck veins and absent breath sounds on the right side. The chest X-ray she carried, done immediately after the injury, showed right sided tension pneumothorax. She was put on oxygen at 11 L/minute and an Intercostal chest tube drainage (ICD) was inserted on right side. Her oxygen saturation (40%) failed to improve. ICD bag showed continuous bubbling and air entry remained absent on the right side. An urgent right thoracotomy was done which revealed right main bronchus tear; the tear was repaired using interrupted Prolene ® sutures. Patient recovered well and was discharged 10 days later in a stable condition.

Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

Energy Technology Data Exchange (ETDEWEB)

Pagan, Jonathan, E-mail: jdpagan@uams.edu; Przybyla, Beata; Jamshidi-Parsian, Azemat [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States); Gupta, Kalpna [Vascular Biology Center and Division of Hematology-Oncology Transplantation, Department of Medicine, University of Minnesota Medical School, MN 72223 (United States); Griffin, Robert J. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States)

2013-02-18

Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm{sup 3}) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

International Nuclear Information System (INIS)

Pagan, Jonathan; Przybyla, Beata; Jamshidi-Parsian, Azemat; Gupta, Kalpna; Griffin, Robert J.

2013-01-01

Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm 3 ) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

Comparison Between Cerebral Tissue Oxygen Tension and Energy Metabolism in Experimental Subdural Hematoma

DEFF Research Database (Denmark)

Nielsen, Troels Halfeld; Engell, Susanne I; Johnsen, Rikke Aagaard

2011-01-01

BACKGROUND: An experimental swine model (n = 7) simulating an acute subdural hematoma (ASDH) was employed (1) to explore the relation between the brain tissue oxygenation (PbtO(2)) and the regional cerebral energy metabolism as obtained by microdialysis, and (2) to define the lowest level of PbtO(2...

Potential role of the glycolytic oscillator in acute hypoxia in tumors

International Nuclear Information System (INIS)

Fru, Leonard Che; Adamson, Erin B; Campos, David D; Fain, Sean B; Song, Chihwa; Kissick, Michael W; Jacques, Steven L; Van der Kogel, Albert J; Nickel, Kwang P; Kimple, Randall J

2015-01-01

Tumor acute hypoxia has a dynamic component that is also, at least partially, coherent. Using blood oxygen level dependent magnetic resonance imaging, we observed coherent oscillations in hemoglobin saturation dynamics in cell line xenograft models of head and neck squamous cell carcinoma. We posit a well-established biochemical nonlinear oscillatory mechanism called the glycolytic oscillator as a potential cause of the coherent oscillations in tumors. These data suggest that metabolic changes within individual tumor cells may affect the local tumor microenvironment including oxygen availability and therefore radiosensitivity. These individual cells can synchronize the oscillations in patches of similar intermediate glucose levels. These alterations have potentially important implications for radiation therapy and are a potential target for optimizing the cancer response to radiation. (paper)

Acidosis-Induced Changes in Proteome Patterns of the Prostate Cancer-Derived Tumor Cell Line AT-1.

Science.gov (United States)

Ihling, Angelika; Ihling, Christian H; Sinz, Andrea; Gekle, Michael

2015-09-04

Under various pathological conditions, such as inflammation, ischemia and in solid tumors, physiological parameters (local oxygen tension or extracellular pH) show distinct tissue abnormalities (hypoxia and acidosis). For tumors, the prevailing microenvironment exerts a strong influence on the phenotype with respect to proliferation, invasion, and metastasis formation and therefore influences prognosis. In this study, we investigate the impact of extracellular metabolic acidosis (pH 7.4 versus 6.6) on the proteome patterns of a prostate cancer-derived tumor cell type (AT-1) using isobaric labeling and LC-MS/MS analysis. In total, 2710 proteins were identified and quantified across four biological replicates, of which seven were significantly affected with changes >50% and used for validation. Glucose transporter 1 and farnesyl pyrophosphatase were found to be down-regulated after 48 h of acidic treatment, and metallothionein 2A was reduced after 24 h and returned to control values after 48 h. After 24 and 48 h at pH 6.6, glutathione S transferase A3 and NAD(P)H dehydrogenase 1, cellular retinoic acid-binding protein 2, and Na-bicarbonate transporter 3 levels were found to be increased. The changes in protein levels were confirmed by transcriptome and functional analyses. In addition to the experimental in-depth investigation of proteins with changes >50%, functional profiling (statistical enrichment analysis) including proteins with changes >20% revealed that acidosis upregulates GSH metabolic processes, citric acid cycle, and respiratory electron transport. Metabolism of lipids and cholesterol biosynthesis were downregulated. Our data comprise the first comprehensive report on acidosis-induced changes in proteome patterns of a tumor cell line.

Detection of cerebral arterial gas embolism using regional cerebral oxygen saturation, quantitative electroencephalography, and brain oxygen tension in the swine

NARCIS (Netherlands)

Weenink, R. P.; Hollmann, M. W.; Stevens, M. F.; Kager, J.; van Gulik, T. M.; van Hulst, R. A.

2014-01-01

Cerebral air emboli occur as a complication of invasive medical procedures. The sensitivity of cerebral monitoring methods for the detection of air emboli is not known. This study investigates the utility of electroencephalography and non-invasively measured cerebral oxygen saturation in the

Perceiving the affordance of string tension for power strokes in badminton: expertise allows effective use of all string tensions.

Science.gov (United States)

Zhu, Qin

2013-01-01

Affordances mean opportunities for action. These affordances are important for sports performance and relevant to the abilities developed by skilled athletes. In racquet sports such as badminton, different players prefer widely different string tension because it is believed to provide opportunities for effective strokes. The current study examined whether badminton players can perceive the affordance of string tension for power strokes and whether the perception of affordance itself changed as a function of skill level. The results showed that string tension constrained the striking performance of both novice and recreational players, but not of expert players. When perceptual capability was assessed, perceptual mode did not affect perception of the optimal string tension. Skilled players successfully perceived the affordance of string tension, but only experts were concerned about saving energy. Our findings demonstrated that perception of the affordance of string tension in badminton was determined by action abilities. Furthermore, experts could adjust the action to maintain a superior level of performance based on the perception of affordance.

The partial pressure of oxygen affects biomarkers of oxidative stress in cultured rainbow trout (Oncorhynchus mykiss) hepatocytes.

Science.gov (United States)

Finne, E F; Olsvik, P A; Berntssen, M H G; Hylland, K; Tollefsen, K E

2008-09-01

Oxidative stress, the imbalance between production of reactive oxygen species and the cellular detoxification of these reactive compounds, is believed to be involved in the pathology of various diseases. Several biomarkers for oxidative stress have been proposed to serve as tools in toxicological and ecotoxicological research. Not only may exposure to various pro-oxidants create conditions of cellular oxidative stress, but hyperoxic conditions may also increase the production of reactive oxygen species. The objective of the current study was to determine the extent to which differences in oxygen partial pressure would affect biomarkers of oxidative stress in a primary culture of hepatocytes from rainbow trout (Oncorhynchus mykiss). Membrane integrity, metabolic activity, levels of total and oxidized glutathione (tGSH/GSSG) was determined, as well as mRNA expression levels of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), gamma-glutamyl-cystein synthetase (GCS) and thioredoxin (TRX). The results show that different biomarkers of oxidative stress are affected when the cell culture is exposed to atmospheric oxygen, and that changes such as increased GSSG content and induction of GSSG-R and GSH-Px can be reduced by culturing the cells under lower oxygen tension. Oxygen tension may thus influence results of in vitro based cell research and is particularly important when assessing parameters in the antioxidant defence system. Further research is needed to establish the magnitude of this effect in different cellular systems.

Tension waves in tethered satellite cables

Science.gov (United States)

Lallman, F. J.

1984-01-01

A one-degree-of-freedom simulation of the Tethered Satellite System (TSS) was programmed using a distributed system model of the tether based on the one-dimensional wave equation. This model represents the time varying tension profile along the tether as the sum of two traveling waves of tension moving in opposite directions. A control loop was devised which combines a deployment rate command with the measured tension at the deployer to produce a smooth, stable rate of deployment of the subsatellite. Simulation results show a buildup of periodic bursts of high frequency oscillation in tension. This report covers the mathematical modelling and simulation results and explains the reason for the observed oscillations. The design of a possible vibration damping device is discussed.

Modeling and experimental methods to predict oxygen distribution in bone defects following cell transplantation.

Science.gov (United States)

Heylman, Christopher M; Santoso, Sharon; Krebs, Melissa D; Saidel, Gerald M; Alsberg, Eben; Muschler, George F

2014-04-01

We have developed a mathematical model that allows simulation of oxygen distribution in a bone defect as a tool to explore the likely effects of local changes in cell concentration, defect size or geometry, local oxygen delivery with oxygen-generating biomaterials (OGBs), and changes in the rate of oxygen consumption by cells within a defect. Experimental data for the oxygen release rate from an OGB and the oxygen consumption rate of a transplanted cell population are incorporated into the model. With these data, model simulations allow prediction of spatiotemporal oxygen concentration within a given defect and the sensitivity of oxygen tension to changes in critical variables. This information may help to minimize the number of experiments in animal models that determine the optimal combinations of cells, scaffolds, and OGBs in the design of current and future bone regeneration strategies. Bone marrow-derived nucleated cell data suggest that oxygen consumption is dependent on oxygen concentration. OGB oxygen release is shown to be a time-dependent function that must be measured for accurate simulation. Simulations quantify the dependency of oxygen gradients in an avascular defect on cell concentration, cell oxygen consumption rate, OGB oxygen generation rate, and OGB geometry.

Vented versus unvented chest seals for treatment of pneumothorax and prevention of tension pneumothorax in a swine model.

Science.gov (United States)

Kheirabadi, Bijan S; Terrazas, Irasema B; Koller, Alexandra; Allen, Paul B; Klemcke, Harold G; Convertino, Victor A; Dubick, Michael A; Gerhardt, Robert T; Blackbourne, Lorne H

2013-07-01

Unvented chest seals (CSs) are currently recommended for the management of penetrating thoracic injuries in the battlefield. Since no supporting data exist, we compared the efficacy of a preferred unvented with that of a vented CS in a novel swine model of pneumothorax (PTx). An open chest wound was created in the left thorax of spontaneously air-breathing anesthetized pigs (n = 8). A CS was applied over the injury, then tension PTx was induced by incremental air injections (0.2 L) into the pleural cavity via a cannula that was also used to measure intrapleural pressure (IP). Both CS were tested on each pig in series. Tidal volume (V(T)), respiratory rate, IP, heart rate, mean arterial pressure, cardiac output, central venous pressure, pulmonary arterial pressure, venous and peripheral oxygen saturations (SvO2, SpO2) were recorded. Tension PTx was defined as a mean IP equal to or greater than +1 mm Hg plus significant (20-30%) deviation in baseline levels of the previously mentioned parameters and confirmed by chest x-ray study. PaO2 and PaCo2 were also measured. PTx produced immediate breathing difficulty and significant rises in IP and pulmonary arterial pressure and falls in V(T), SpO2, and SvO2. Both CSs returned these parameters to near baseline within 5 minutes of application. After vented CS was applied, serial air injections up to 2 L resulted in no significant change in the previously mentioned parameters. After unvented CS application, progressive deterioration of all respiratory parameters and onset of tension PTx were observed in all subjects after approximately 1.4-L air injection. Both vented and unvented CSs provided immediate improvements in breathing and blood oxygenation in our model of penetrating thoracic trauma. However, in the presence of ongoing intrapleural air accumulation, the unvented CS led to tension PTx, hypoxemia, and possible respiratory arrest, while the vented CS prevented these outcomes.

Effects of acetazolamide on cerebral blood flow and brain tissue oxygenation

DEFF Research Database (Denmark)

Lassen, N A; Friberg, L; Kastrup, J

1987-01-01

Oral administration of 1 g of acetazolamide to 8 normal subjects studied at sea level and in normoxia caused an acute increase in cerebral blood flow (CBF). During the subsequent prolonged oral treatment with 1 g of acetazolamide daily, CBF returned to normal within 2 days. The alveolar CO2 tension...... decreased gradually to 70% of the control value, indicating hyperventilation. At sea level hyperventilation will not increase brain oxygenation significantly in normal man, as the arterial oxygen content only increases minimally, while CBF is unchanged. At high altitude the beneficial effects...... of acetazolamide on the symptoms of acute mountain sickness may well be due to an improved oxygen supply to the brain, as hyperventilation will, at the low ambient PO2, cause a significant increase of the arterial oxygen content, while CBF presumably is unaffected by the drug. During hypoxia at high altitude...

Effects of whole body UV-irradiation on oxygen delivery from the erythrocyte

International Nuclear Information System (INIS)

Humpeler, E.; Mairbaeurl, H.; Hoenigsmann, H.

1982-01-01

In 16 healthy caucasian volunteers (mean age: 22.2 years) the influence of whole body UV-irradiation on the oxygen transport properties of erythrocytes was investigated. Four hours after irradiation with UV (using the minimal erythema dose, MED) no variation of haemoglobin concentration, hematocrit, mean corpuscular haemoglobin concentration, pH or standard bicarbonate could be found, whereas inorganic plasma phosphate (Psub(i)), calcium, the intraerythrocytic 2,3-diphosphoglycerate (2,3-DPG), the activity of erythrocytic phosphofructokinase (PFK) and pyruvatekinase (PK) increased significantly. The half saturation tension of oxygen (P 50 -value) tended to increase. The increase of Psub(i) causes - via a stimulation of the glycolytic pathway - an increase in 2,3-DPG concentration and thus results in a shift of the oxygen dissociation curve. It is therefore possible to enhance tissue oxygenation by whole body UV-irradiation. (orig.)

Photodynamic therapy of solid tumors

Science.gov (United States)

Jori, Giulio

Some porphyrin compounds, which are characterized by a relatively large degree of hydrophobicity (n-octanol/water partition coefficient above 8), are accumulated in greater amounts and retained for longer periods of time by neoplastic as compared with normal tissues. The affinity of these dyes for tumors is partially a consequence of their in vivo transport by low-density lipoproteins, which are preferentially endocytosized by hyperproliferating tissues in a receptor-mediated process. In general, at 24-48 h after the systematic administration of porphyrin doses in the range of 2.5 mg/kg body weight, the ratio of drug concentration between the neoplastic and the surrounding tissues is sufficiently large to guarantee a selective photoexcitation of the porphyrin. Toward this aim, the porphyrin-containing tumor tissues are irradiated with light wavelengths longer than 600 nm, since the transmittance of biological tissues is maximal in this spectral region. The electronically excited porphyrin transfers its excitation energy to oxygen, thus generating activated oxygen species (mainly, singlet oxygen): as a consequence, the photooxidative modification of subcellular targets (e.g. the plasma membrane and mitochondria) is readily obtained leading to an irreversible necrosis of the cell. With the most frequently used porphyrins for clinical phototherapy (including hematoporphyrin and its derivatives HpD and Photofrin II), one observes the preferential photosensitized destruction of endothelial cells, hence the vascular damage is a major process involved in the necrosis of tumors. The optimization of the phototherapy of tumors is presently pursued by the definition of clinical protocols tailored to the optical properties of specific neoplastic tissues as well as by the use of porphyrin analogs, such as chlorins and phthalocyanines, having an extinction coefficient in the red spectral region larger than that typical of hematoporphyrin and HpD.

Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells

Science.gov (United States)

Rios, Carmen; D'Ippolito, Gianluca; Curtis, Kevin M.; Delcroix, Gaëtan J.-R.; Gomez, Lourdes A.; El Hokayem, Jimmy; Rieger, Megan; Parrondo, Ricardo; de las Pozas, Alicia; Perez-Stable, Carlos; Howard, Guy A.

2016-01-01

Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and β-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells. PMID:27059084

Influence of oxygen levels on chondrogenesis of porcine mesenchymal stem cells cultured in polycaprolactone scaffolds.

Science.gov (United States)

Rodenas-Rochina, Joaquin; Kelly, Daniel J; Gómez Ribelles, Jose Luis; Lebourg, Myriam

2017-06-01

Chondrogenesis of mesenchymal stem cells (MSCs) is known to be regulated by a number of environmental factors, including local oxygen levels. The hypothesis of this study is that the response of MSCs to hypoxia is dependent on the physical and chemical characteristics of the substrate used. The objective of this study was to explore how different modifications to polycaprolactone (PCL) scaffolds influenced the response of MSCs to hypoxia. PCL, PCL-hyaluronic acid (HA), and PCL-Bioglass ® (BG) scaffolds were seeded with MSCs derived from bone marrow and cultured for 35 days under normoxic or low oxygen conditions, and the resulting biochemical properties of the MSC laden construct were assessed. Low oxygen tension has a positive effect over cell proliferation and macromolecules biosynthesis. Furthermore, hypoxia enhanced the distribution of collagen and glycosaminoglycans (GAGs) deposition through the scaffold. On the other hand, MSCs displayed certain material dependent responses to hypoxia. Low oxygen tension had a positive effect on cell proliferation in BG and HA scaffolds, but only a positive effect on GAGs synthesis in PCL and HA scaffolds. In conclusion, hypoxia increased cell viability and expression of chondrogenic markers but the cell response was modulated by the type of scaffold used. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1684-1691, 2017. © 2017 Wiley Periodicals, Inc.