scholarly journals Modeling the Spatial Distribution of Chronic Tumor Hypoxia: Implications for Experimental and Clinical Studies

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Gibin Powathil ◽  
Mohammad Kohandel ◽  
Michael Milosevic ◽  
Siv Sivaloganathan
Keyword(s):  
Spatial Distribution ◽  
Cross Sections ◽  
Tumor Hypoxia ◽  
Image Data ◽  
Tumor Vasculature ◽  
Tumor Oxygenation ◽  
Needle Electrode ◽  
Optimum Number ◽  
Oxygenation Status ◽  
Polarographic Needle Electrode

Tumor oxygenation status is considered one of the important prognostic markers in cancer since it strongly influences the response of cancer cells to various treatments; in particular, to radiation therapy. Thus, a proper and accurate assessment of tumor oxygen distribution before the treatment may highly affect the outcome of the treatment. The heterogeneous nature of tumor hypoxia, mainly influenced by the complex tumor microenvironment, often makes its quantification very difficult. The usual methods used to measure tumor hypoxia are biomarkers and the polarographic needle electrode. Although these techniques may provide an acceptable assessment of hypoxia, they are invasive and may not always give a spatial distribution of hypoxia, which is very useful for treatment planning. An alternative method to quantify the tumor hypoxia is to use theoretical simulations with the knowledge of tumor vasculature. The purpose of this paper is to model tumor hypoxia using a known spatial distribution of tumor vasculature obtained from image data, to analyze the accuracy of polarographic needle electrode measurements in quantifying hypoxia, to quantify the optimum number of measurements required to satisfactorily evaluate the tumor oxygenation status, and to study the effects of hypoxia on radiation response. Our results indicate that the model successfully generated an accurate oxygenation map for tumor cross-sections with known vascular distribution. The method developed here provides a way to estimate tumor hypoxia and provides guidance in planning accurate and effective therapeutic strategies and invasive estimation techniques. Our results agree with the previous findings that the needle electrode technique gives a good estimate of tumor hypoxia if the sampling is done in a uniform way with 5-6 tracks of 20–30 measurements each. Moreover, the analysis indicates that the accurate measurement of oxygen profile can be very useful in determining right radiation doses to the patients.

scholarly journals Oxygenation Status of Malignant Tumors vs. Normal Tissues: Critical Evaluation and Updated Data Source Based on Direct Measurements with pO2 Microsensors

2021 ◽  
Author(s):  
Peter Vaupel ◽  
Ann Barry Flood ◽  
Harold M. Swartz
Keyword(s):  
Clinical Setting ◽  
Malignant Tumors ◽  
Tumor Hypoxia ◽  
Critical Evaluation ◽  
Treatment Strategies ◽  
Tumor Oxygenation ◽  
Vascular Networks ◽  
Normal Tissues ◽  
Characteristic Features ◽  
Oxygenation Status

AbstractImmature and chaotic vascular networks with critically increased intervascular distances are characteristic features of malignant tumors. Spatial and temporal heterogeneities of blood flow and associated availabilities of O2, together with limited diffusive O2 transport, and -in some patients- anemia, obligatorily lead to tumor hypoxia (= critically reduced O2 levels) on macro- and microscopic scales. This detrimental condition, recently classified as a key hallmark of malignant growth, acts (a) as a barrier in most antitumor treatments, and (b) leads to malignant progression based on hypoxia-induced changes of the genome, transcriptome, and proteome, and finally to poor patient survival. This knowledge is, to a great extent, based on the systematic detection of tumor hypoxia in the clinical setting since the late 1980s. Precise assessment of the tumor oxygenation status was made possible using minimally invasive polarographic pO2 microsensors in a series of research projects. To assess tumor hypoxia in the clinical setting, it is highly desirable to use technologies with (a) high spatial and temporal resolutions, (b) the capability to judge the severity of tumor hypoxia, (c) to allow mapping of pO2 of the whole tumor mass, and (d) to enable serial investigations in order to verify treatment-related changes in tumor hypoxia. Selection and treatment of cancer patients according to their individual tumor oxygenation/hypoxia status for intensified and/or personalized hypoxia-targeted treatment strategies should be the ultimate goal.

scholarly journals Functional Morphology of the Cardiac Jelly in the Tubular Heart of Vertebrate Embryos

2019 ◽  
Author(s):  
Jörg Männer ◽  
Talat Mesud Yelbuz
Keyword(s):  
Spatial Distribution ◽  
Cross Sections ◽  
Embryonic Heart ◽  
Endocardial Cushions ◽  
Valveless Pumping ◽  
Matrix Layer ◽  
Heart Looping ◽  
Biological Aspects ◽  
Vertebrate Embryos ◽  
Heart Wall

The early embryonic heart is a multi-layered tube consisting of (1) an outer myocardial tube; (2) an inner endocardial tube; and (3) an extracellular matrix layer interposed between myocardium and endocardium, called “cardiac jelly” (CJ). During the past decades, research on CJ has mainly focused on its molecular and cell biological aspects. This review focuses on the morphological and biomechanical aspects of CJ. Special attention is given to (1) the spatial distribution and fiber architecture of CJ; (2) the morphological dynamics of CJ during the cardiac cycle; and (3) the removal/remodeling of CJ during advanced heart looping stages, which leads to the formation of ventricular trabeculations and endocardial cushions. CJ acts as a hydraulic skeleton displaying striking structural and functional similarities with the mesoglea of jellyfish. CJ not only represents a filler substance, facilitating end-systolic occlusion of the embryonic heart lumen. Its elastic components antagonize the systolic deformations of the heart wall and thereby power the refilling phase of the ventricular tube. Non-uniform spatial distribution of CJ generates non-circular cross sections of the opened endocardial tube (initially elliptic, later deltoid), which seem to be advantageous for valveless pumping. Endocardial cushions arise from non-removed remnants of the original CJ.

scholarly journals Hypo-fractionation radiotherapy normalizes tumor vasculature in non-small cell lung cancer xenografts through the p-STAT3/HIF-1 alpha signaling pathway

2020 ◽  
Vol 12 ◽  
pp. 175883592096585
Author(s):  
Fan Tong ◽  
Chun-jin Xiong ◽  
Chun-hua Wei ◽  
Ye Wang ◽  
Zhi-wen Liang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Signaling Pathway ◽  
Cell Lung Cancer ◽  
Tumor Hypoxia ◽  
Tumor Vasculature ◽  
Small Cell ◽  
Small Cell Lung ◽  
Subcutaneous Xenograft ◽  
Xenograft Models

Background: Hypo-fractionation radiotherapy (HFRT) was considered to be an important treatment for non-small cell lung cancer (NSCLC), but the radiobiological effects of HFRT on NSCLC remain unclear. The aim of this study was to investigate specific biological effect of HFRT on tumor angiogenesis, compared with conventional radiotherapy (CRT). Methods: The subcutaneous xenograft models and the dorsal skinfold window chamber (DSWC) models of nude mice bearing H460 and HCC827 NSCLC cells were irradiated with doses of 0 Gy (sham group), 22 Gy delivered into 11 fractions (CRT group) or 12 Gy delivered into 1 fraction (HFRT group). At certain time-points after irradiation, the volumes, hypoxic area, coverage rate of pericyte and micro-vessel density (MVD) of the subcutaneous xenograft models were detected, and the tumor vasculature was visualized in the DSMC model. The expressions of phosphorylated signal transducer and activator of transcription (p-STAT3), hypoxia-inducible factor 1-α (HIF-1α), CXCL12 and VEGFA were detected. Results: Compared with the CRT groups, HFRT showed more-efficient tumor growth-suppression, accompanied by a HFRT-induced window-period, during which vasculature was normalized, tumor hypoxia was improved and MVD was decreased. Moreover, during the window-period, the signal levels of p-STAT3/HIF-1α pathway and the expressions of its downstream angiogenic factors (VEGFA and CXCL12) were inhibited by HFRT. Conclusion: Compared with CRT, HFRT induced tumor vasculature normalization by rendering the remaining vessels less tortuous and increasing pericyte coverage of tumor blood vessels, thereby ameliorating tumor hypoxia and enhancing the tumor-killing effect. Moreover, HFRT might exert the aforementioned effects through p-STAT3/HIF-1α signaling pathway.

AUTOMATIC CONTOURING USING BICUBIC FUNCTIONS

Geophysics ◽  
1972 ◽  
Vol 37 (4) ◽  
pp. 669-674 ◽  
Author(s):  
R. C. Hessing ◽  
Henry K. Lee ◽  
Alan Pierce ◽  
Eldon N. Powers
Keyword(s):  
Spatial Distribution ◽  
Cross Sections ◽  
Digital Computer ◽  
Smooth Surface ◽  
Contour Line ◽  
Contour Maps ◽  
Volume Calculations ◽  
Contour Lines ◽  
Data Points ◽  
Automatic Contouring

A method is described for using a digital computer to construct contour maps automatically. Contour lines produced by this method have correct relations to given discrete data points regardless of the spatial distribution of these points. The computer‐generated maps are comparable to those drawn manually. The region to be contoured is divided into quadrilaterals whose vertices include the data points. After supplying values at each of the remaining vertices by using a surface‐fitting technique, bicubic functions are constructed on each quadrilateral to form a smooth surface through the data points. Points on a contour line are obtained from these surfaces by solving the resulting cubic equations. The bicubic functions may be used for other calculations consistent with the contour maps, such as interpolation of equally spaced values, calculation of cross‐sections, and volume calculations.

Predictive factors in advanced head and neck cancer treated by radio-chemotherapy and hypoxia modification

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6085-6085
Author(s):  
B. Clavo ◽  
F. Robaina ◽  
A. Ruiz ◽  
M. Lloret ◽  
D. Macias ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Tumor Hypoxia ◽  
Disease Free Survival ◽  
Tumor Oxygenation ◽  
Free Survival ◽  
Stage Ivb ◽  
Radio Chemotherapy ◽  
Disease Free

6085 Background: Anemia and tumor hypoxia are known factors for resistance to radio-chemotherapy (RT-CT). In a previous report we have suggested that spinal cord stimulation (SCS) can modify tumor oxygenation and regional blood flow in head and neck cancer (HNC). The aim of the present prospective study was to test the predictive value of pO2 measurement in HNC treated by RT-CT and hypoxia modification using SCS. Methods: Twelve male patients with advanced HNC were analyzed. Stage IVb-IVa: 8–4; mean age 58 + 7.6 years (46–70). Scheduled therapy was hyperfractionated RT (120 cGy/fraction, two fractions/day, total dose 81.6 Gy) from a Co- 60 source, and tegafur 800 mg/day. SCS devices were placed before RT-CT under local anesthesia. During treatment, SCS was connected from 20–30 min before to 20–30 min after each radiotherapy session. Before treatment, they were assessed: Hemoglobin levels and tumor oxygenation pre-SCS and pos-SCS (measured by a polarographic probe system ‘pO2 Histograph‘), expressed as median-pO2, and the fraction of pO2 values less than 5 mmHg (HF5) and less than 2.5 mmHg (HF2.5). Correlations were assessed using Pearson and Spearman tests, and actuarial survival using Kaplan-Meier estimates and Log-rank test. Results: Hemoglobin levels were correlated with oxygenation pre-SCS and pos-SCS: median-pO2 (p=0.005 and p=0.011), HF5 (p=0.048 and p=0.005) respectively. Anemia was associated with more advanced stage (IVb vs IVa, p=0.022), higher HF5 pos-SCS (p=0.028) and lower disease-free survival (p=0.019). The HF2.5 pos-SCS was adversely correlated with the 2 years actuarial: disease-free survival (p=0.027), cause-specific survival (p=0.008) and overall survival (p=0.008). HF2.5 was also correlated with hematocrit (p=0.044). Conclusions: Low hemoglobin levels and anemia are associated with more hypoxic and more advanced tumors. Pre-treatment tumor hypoxia (assessed by the fraction of pO2 values less than 2.5 mmHg during-SCS) is a strong predictive factor for survival in advanced HNC. Patients with highly hypoxic tumors should be selected for more aggressive treatments. Partially supported by: Grant ‘FUNCIS: PI 31–98‘. Scientific supervision was carried out by GICOR. No significant financial relationships to disclose.

scholarly journals Normalization of the Vasculature for Treatment of Cancer and Other Diseases

2011 ◽  
Vol 91 (3) ◽  
pp. 1071-1121 ◽  
Author(s):  
Shom Goel ◽  
Dan G. Duda ◽  
Lei Xu ◽  
Lance L. Munn ◽  
Yves Boucher ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Solid Tumors ◽  
Tumor Angiogenesis ◽  
Interstitial Fluid ◽  
Tumor Hypoxia ◽  
Fluid Pressure ◽  
Tumor Vasculature ◽  
Interstitial Fluid Pressure ◽  
Vascular Normalization ◽  
Anti Vegf

New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a “normalization” of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more “mature” or “normal” phenotype. This “vascular normalization” is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Here, we review the pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases.

Nanoparticles in Lustre Reconstructions

2004 ◽  
Vol 852 ◽  
Author(s):  
P. Fredrickx ◽  
J. Verbeeck ◽  
D. Schryvers ◽  
D. Hélary ◽  
E. Darque-Ceretti
Keyword(s):  
Spatial Distribution ◽  
Cross Sections ◽  
Ag Nanoparticles ◽  
Cu Nanoparticles ◽  
The Difference

ABSTRACTIt is increasingly apparent that the spatial distribution of Ag and Cu nanoparticles in lustre glazes is an important factor in determining the colour displayed by the decoration. Using STEM-EDX of cross sections, this distribution can easily be imaged, as is demonstrated in two modern reconstructions of lustre decorations from Granada, Spain. On the nanoscale, the difference in colour can be related to a different spatial distribution of the Ag and Cu particles, with the brownish gold variant consisting of a top layer of Ag nanoparticles with an underlying layer of Cu nanoparticles while in the yellowish golden lustre Cu specks are unevenly dispersed.

scholarly journals Spatial distribution of Brevicoryne brassicae (L.) in Cabbage in mid-hills of Himachal Pradesh, India

2017 ◽  
Vol 9 (3) ◽  
pp. 1587-1591 ◽  
Author(s):  
S. C. Verma ◽  
P. L. Sharma ◽  
R. K. Bhardwaj
Keyword(s):  
Spatial Distribution ◽  
Negative Binomial ◽  
Himachal Pradesh ◽  
Brevicoryne Brassicae ◽  
Optimum Number ◽  
Sampling Protocol ◽  
Cabbage Aphid ◽  
Efficient Sampling ◽  
Mean Crowding ◽  
Precision Level

Investigations were carried out during two consecutive Rabi seasons of 2014 and2015 at the Experi-mental Farm of the Department of Seed Science and Technology, Dr Y S Parmar University of Horticulture and For-estry, Nauni, Solan, Himachal Pradesh, India to study the spatial distribution of Brevicoryne brassicae in cabbage. One month old cabbage seedlings were planted in the field in the month of November during both the years. Distri-bution pattern of any insect population is an important aspect as it represents the interaction between individuals of the species and their habitat. Spatial distribution is useful for designing efficient sampling programmes for population estimation and development of population models. Spatial distribution is also important to understand the bioecology of the pest and to determine the sampling protocol for that species. In the present study variance to mean ratio (s2/X),mean crowding (X*), ratio of mean crowding to mean (X*/X), ‘k’ of negative binomial, Taylor’s power equation(s2 = 0.9099X1.55 during 2014 and s2 = 2.9861X1.1949 during 2015), Iwao’s patchiness regression and optimum number of samples (Nopt) required to achieve the desired precision were calculated for different densities. Cabbage aphid, B. brassicae appeared in the fourth standard week i.e last week of January( 26.2 aphids/ plant during 2014 and 0.30 aphids/ plant during 2015) and persisted upto thirteenth standard week i.e last week of April ( 18.4 aphids/ plant during 2014 and 18.2 aphids/ plant during 2015) and followed a negative binomial distribution during both years. Optimum number of samples (Nopt) required varied with mean density as well as precision level. The present study will serve as basic information to develop a sampling plan of B. Brassicae in cabbage for its monitoring and management.

scholarly journals Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy

2021 ◽  
Vol 13 (604) ◽  
pp. eabc8922
Author(s):  
Yi Sun ◽  
Wei Chen ◽  
Robert J. Torphy ◽  
Sheng Yao ◽  
Gefeng Zhu ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Vascular Dysfunction ◽  
Tumor Hypoxia ◽  
Tumor Vasculature ◽  
Poor Response ◽  
Response To Therapy ◽  
Mouse Tumor ◽  
Programmed Death

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti–programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.

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