In vivo Measurement of Regional Brain and Tumor pH Using [14C]Dimethyloxazolidinedione and Quantitative Autoradiography. II: Characterization of the Extracellular Fluid Compartment Using pH-Sensitive Microelectrodes and [14C]Sucrose

We measured the extracellular (interstitial) pH (pHe) of RG-2 rat gliomas using H+-sensitive microelectrodes and estimated the volume of tumor extracellular space based on the tissue-plasma ratio of [14C]sucrose. The average RG-2 pHe was 7.63 ± 0.15 (mean ± SD, n = 6), whereas the average pHe of contralateral brain tissue was 7.34 ± 0.10 (n = 3) and arterial pH was 7.36 ± 0.02. RG-2 extracellular space water volume was estimated to be 0.3 ml water/g tissue. In separate experiments in normal, nontumored rats, intracellular pH (pHi) was calculated for nine gray and white matter regions based on measurements of tissue and plasma [14C]dimethyloxazolidinedione concentration. pHi values ranged from 6.80 to 6.94, and no consistent gray–white differences were observed. Our data suggest that tumor pHi is not more acidic than that of normal brain tissue and that the observed alkalinity of primary brain tumors is due to the presence of a large alkaline extracellular space.

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In vivo Measurement of Intra- and Extracellular Space of Brain Tissue by Electrical Impedance Method

Brain Edema VIII ◽

10.1007/978-3-7091-9115-6_8 ◽

1990 ◽

pp. 22-24

Author(s):

Sadao Suga ◽

S. Mitani ◽

Y. Shimamoto ◽

T. Kawase ◽

S. Toya ◽

...

Keyword(s):

Brain Tissue ◽

Extracellular Space ◽

Electrical Impedance ◽

Impedance Method ◽

In Vivo Measurement

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Protein Kinase A Distribution in Meningioma

Cancers ◽

10.3390/cancers11111686 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1686 ◽

Cited By ~ 1

Author(s):

Caretta ◽

Denaro ◽

D’Avella ◽

Mucignat-Caretta

Keyword(s):

Brain Tissue ◽

Catalytic Subunit ◽

Therapeutic Interventions ◽

Normal Brain ◽

Local Concentration ◽

Correlation Pattern ◽

Catalytic Subunits ◽

Tissue Specimens ◽

Pka Catalytic Subunit

Deregulation of intracellular signal transduction pathways is a hallmark of cancer cells, clearly differentiating them from healthy cells. Differential intracellular distribution of the cAMP-dependent protein kinases (PKA) was previously detected in cell cultures and in vivo in glioblastoma and medulloblastoma. Our goal is to extend this observation to meningioma, to explore possible differences among tumors of different origins and prospective outcomes. The distribution of regulatory and catalytic subunits of PKA has been examined in tissue specimens obtained during surgery from meningioma patients. PKA RI subunit appeared more evenly distributed throughout the cytoplasm, but it was clearly detectable only in some tumors. RII was present in discrete spots, presumably at high local concentration; these aggregates could also be visualized under equilibrium binding conditions with fluorescent 8-substituted cAMP analogues, at variance with normal brain tissue and other brain tumors. The PKA catalytic subunit showed exactly overlapping pattern to RII and in fixed sections could be visualized by fluorescent cAMP analogues. Gene expression analysis showed that the PKA catalytic subunit revealed a significant correlation pattern with genes involved in meningioma. Hence, meningioma patients show a distinctive distribution pattern of PKA regulatory and catalytic subunits, different from glioblastoma, medulloblastoma, and healthy brain tissue. These observations raise the possibility of exploiting the PKA intracellular pathway as a diagnostic tool and possible therapeutic interventions.

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In vivo Measurement of Regional Brain and Tumor pH Using [14C]Dimethyloxazolidinedione and Quantitative Autoradiography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1985.51 ◽

1985 ◽

Vol 5 (3) ◽

pp. 369-375 ◽

Cited By ~ 16

Author(s):

James B. Arnold ◽

Larry Junck ◽

David A. Rottenberg

Keyword(s):

Water Content ◽

Gray Matter ◽

Quantitative Autoradiography ◽

Water Volume ◽

Consistent Difference ◽

Extracellular Water ◽

Tissue Water ◽

Constant Weight ◽

Tumor Ph

Using [14C]dimethyloxazolidinedione ([14C]-DMO) and quantitative autoradiography, we estimated tissue pH (pHt) and intracellular pH (pHi) in nine regions of the normal rat brain and in intracerebrally implanted RG-2 gliomas. Calculations of regional pHt, based on equilibrium tissue and arterial plasma [14C]DMO concentration, ranged from 6.83 to 6.94; pHi, calculated assuming an extracellular water volume of 0.15 ml/g for gray matter and 0.11 ml/g for white matter, ranged from 6.61 to 6.78. No consistent difference was found in pH, or pHi between white and gray matter regions. Tumor tissue water content was determined by drying to constant weight, and extracellular space water volume ( Ve) was estimated with [14C]sucrose in nephrectomized rats using quantitative autoradiography. Tumor pHt ranged from 7.08 to 7.18. For Ve = 0.17 (measured), pHi was 6.94–7.06; for Ve = 0.30 (assumed), the corresponding range for pHi was 6.63–6.90. Thus, the RG-2 glioma is not more “acidic” than adjacent brain tissue and its “alkaline” pHt probably reflects a large extracellular water content and plasma-like extracellular pH.

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Differential retention of rhodamine 123 by avian sarcoma virus-induced glioma and normal brain tissue of the rat in vivo

Cancer ◽

10.1002/1097-0142(19870115)59:2<266::aid-cncr2820590215>3.0.co;2-6 ◽

1987 ◽

Vol 59 (2) ◽

pp. 266-270 ◽

Cited By ~ 30

Author(s):

William C. Beckman ◽

Stephen K. Powers ◽

J. Tony Brown ◽

G. Yancey Gillespie ◽

Darell D. Bigner ◽

...

Keyword(s):

Brain Tissue ◽

Rhodamine 123 ◽

Normal Brain ◽

Avian Sarcoma Virus ◽

Normal Brain Tissue ◽

Differential Retention ◽

Sarcoma Virus ◽

Avian Sarcoma

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In Vivo Measurement of Brain Extracellular Space Diffusion by Cortical Surface Photobleaching

Journal of Neuroscience ◽

10.1523/jneurosci.2294-04.2004 ◽

2004 ◽

Vol 24 (37) ◽

pp. 8049-8056 ◽

Cited By ~ 142

Author(s):

D. K. Binder

Keyword(s):

Extracellular Space ◽

Cortical Surface ◽

In Vivo Measurement ◽

Brain Extracellular Space

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Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker

Journal of Neurosurgery ◽

10.3171/2011.2.jns101451 ◽

2011 ◽

Vol 115 (1) ◽

pp. 11-17 ◽

Cited By ~ 192

Author(s):

Pablo A. Valdés ◽

Frederic Leblond ◽

Anthony Kim ◽

Brent T. Harris ◽

Brian C. Wilson ◽

...

Keyword(s):

Brain Tissue ◽

Fluorescence Imaging ◽

Low Grade ◽

Normal Brain ◽

Intracranial Tumors ◽

Neoplastic Tissue ◽

Fluorescence Measurements ◽

Significant Difference ◽

Quantitative Fluorescence

Object Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies. Methods The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board–approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo. Results A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeon's visual perception were classified correctly in an analysis of all tumors. Conclusions These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of intracranial tumors.

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Multiple Irradiation Affects Cellular and Extracellular Components of the Mouse Brain Tissue and Adhesion and Proliferation of Glioblastoma Cells in Experimental System In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms222413350 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13350

Author(s):

Maxim O. Politko ◽

Alexandra Y. Tsidulko ◽

Oxana A. Pashkovskaya ◽

Konstantin E. Kuper ◽

Anastasia V. Suhovskih ◽

...

Keyword(s):

Brain Tissue ◽

Mouse Brain ◽

Glial Cells ◽

Ex Vivo ◽

Experimental System ◽

Normal Brain ◽

Biosynthetic Activity ◽

Normal Brain Tissue

Intensive adjuvant radiotherapy (RT) is a standard treatment for glioblastoma multiforme (GBM) patients; however, its effect on the normal brain tissue remains unclear. Here, we investigated the short-term effects of multiple irradiation on the cellular and extracellular glycosylated components of normal brain tissue and their functional significance. Triple irradiation (7 Gy*3 days) of C57Bl/6 mouse brain inhibited the viability, proliferation and biosynthetic activity of normal glial cells, resulting in a fast brain-zone-dependent deregulation of the expression of proteoglycans (PGs) (decorin, biglycan, versican, brevican and CD44). Complex time-point-specific (24–72 h) changes in decorin and brevican protein and chondroitin sulfate (CS) and heparan sulfate (HS) content suggested deterioration of the PGs glycosylation in irradiated brain tissue, while the transcriptional activity of HS-biosynthetic system remained unchanged. The primary glial cultures and organotypic slices from triple-irradiated brain tissue were more susceptible to GBM U87 cells’ adhesion and proliferation in co-culture systems in vitro and ex vivo. In summary, multiple irradiation affects glycosylated components of normal brain extracellular matrix (ECM) through inhibition of the functional activity of normal glial cells. The changed content and pattern of PGs and GAGs in irradiated brain tissues are accompanied by the increased adhesion and proliferation of GBM cells, suggesting a novel molecular mechanism of negative side-effects of anti-GBM radiotherapy.

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