Study of Tumor Microenvironment to Vascular Normalization Based on 3-D Simulation of Tumor Haemodynamics

2009 ◽  
Author(s):  
Jie Wu ◽  
Shixiong Xu ◽  
Quan Long
Keyword(s):  
Experimental Data ◽  
Tumor Microenvironment ◽  
Transport Properties ◽  
Experimental Studies ◽  
Tumor Vasculature ◽  
Clinical Settings ◽  
Vascular Normalization ◽  
Angiogenic Therapy

In recent years, anti-angiogenic therapy has been extensively studied in both preclinical and clinical settings. Experimental studies have approved its effects on the normalization of tumor vasculature as well as the microenvironment in tumors [1]. However, little is known about how tumor microenvironment is affected by the changes in structure of vasculature or transport properties of vessels and interstitium that are associated with anti-angiogenic therapy, since the experimental data are difficult to obtain [2].

scholarly journals 730 Hypoxia reduction in tandem with anti-angiogenic therapy remodels the PDAC microenvironment and potentiates CD40 agonist therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A759-A759
Author(s):  
Arthur Liu ◽  
Michael Curran
Keyword(s):  
Prostate Cancer ◽  
Pancreatic Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Function ◽  
Tumor Vasculature ◽  
Cd8 T Cell ◽  
Agonist Therapy ◽  
Angiogenic Therapy ◽  
T Cell Infiltration

BackgroundThe majority of patients with pancreatic ductal adenocarcinoma (PDAC) fail to derive any durable responses from single agent immune checkpoint blockade therapy. This refractory state originates from PDAC's unique tumor microenvironment that is densely populated by immunosuppressive myeloid cells while excluding most antitumor CD8 T cells.1 In addition, PDAC is highly hypoxic and exhibits poor vascularity, both qualities which further limit antitumor immunity.2 3 We showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) potentiates immunotherapy responses.4 Mechanistically, TH-302 decreases intratumoral hypoxia and initiates normalization of the tumor vasculature. While TH-302 facilitates a cellular remodeling process that diminishes tumor hypoxia, the nature of the vascular remodeling involved remains unknown, as do the downstream consequences for the composition of the tumor microenvironment and responsiveness to immunotherapy. We hypothesized that anti-angiogenic therapy and Evofosfamide might cooperate to normalize tumor vasculature and diminish hypoxia.MethodsTH-302 and a vascular endothelial growth factor receptor-2 (VEGFR-2) blocking antibody were used to treat several syngeneic murine models, including orthotopic pancreatic cancer and a transplantable model of prostate cancer. Immunofluorescence and flow cytometry were used to assess intratumoral hypoxia, vessel normalization, and tumor immune infiltrate.ResultsWe find that anti-VEGFR-2 (DC101) in combination with TH-302 demonstrates a cooperative benefit to combat both orthotopically implanted pancreatic cancer and transplantable prostate cancer. Combination therapy reduces intratumoral hypoxia, leads to pruning of the tumor vasculature, and increases the infiltration of endothelial cells into hypoxic regions. Across models, the combination of DC101 and TH-302 significantly enhance CD8 T cell function and limits their exhausted state. At the same time, tumor associated macrophages exhibit decreased expression of M2-like features. Similar to other anti-angiogenic therapies, combination DC101 and TH-302 leads to an increased frequency of PD-L1 expressing cells. Concurrent anti-PD-1 failed to provide any additional therapeutic benefit, which in part may be due poor CD8 T cell infiltration. Instead, we find that CD40 agonist therapy is improved when combined with TH-302 and DC101.ConclusionsTH-302 and DC101 utilize unique yet complementary mechanisms to improve the survival of mice challenged with pancreatic or prostate tumors. This combination relieves hypoxia and simultaneously reinvigorates T cell function and reduces macrophage mediated immunosuppression. In this setting, CD40 agonist therapy provides an additive benefit in prolonging mouse survival. Put together, these data indicate that targeted hypoxia reduction with anti-angiogenic therapy remodels the tumor microenvironment and enhances immunotherapy responses in PDAC.ReferencesBear AS, Vonderheide RH, O'Hara MH. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell. 2020;38(6):788–802. doi: 10.1016/j.ccell.2020.08.004. Epub 2020 Sep 17. PMID: 32946773; PMCID: PMC7738380.Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000;48(4):919–22. doi: 10.1016/s0360-3016(00)00803-8. PMID: 11072146.Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324(5933):1457–61. doi: 10.1126/science.1171362. Epub 2009 May 21. PMID: 19460966; PMCID: PMC2998180.Jayaprakash P, Ai M, Liu A, Budhani P, Bartkowiak T, Sheng J, Ager C, Nicholas C, Jaiswal AR, Sun Y, Shah K, Balasubramanyam S, Li N, Wang G, Ning J, Zal A, Zal T, Curran MA. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest 2018;128(11):5137–5149. doi: 10.1172/JCI96268. Epub 2018 Oct 15. PMID: 30188869; PMCID: PMC6205399.

scholarly journals Transport Properties of Thermoplastic R-BAPB Polyimide: Molecular Dynamics Simulations and Experiment

Polymers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1775 ◽  
Author(s):  
Igor V. Volgin ◽  
Maria V. Andreeva ◽  
Sergey V. Larin ◽  
Andrey L. Didenko ◽  
Gleb V. Vaganov ◽  
...  
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Transport Properties ◽  
Diffusion Coefficients ◽  
Experimental Studies ◽  
Simulation Models ◽  
Quantitative Agreement ◽  
Critical Temperatures ◽  
Dynamics Simulations

The present work evaluates the transport properties of thermoplastic R-BAPB polyimide based on 1,3-bis(3,3′,4,4′-dicarboxyphenoxy)benzene (dianhydride R) and 4,4′-bis(4-aminophenoxy)biphenyl (diamine BAPB). Both experimental studies and molecular dynamics simulations were applied to estimate the diffusion coefficients and solubilities of various gases, such as helium (He), oxygen (O2), nitrogen (N2), and methane (CH4). The validity of the results obtained was confirmed by studying the correlation of the experimental solubilities and diffusion coefficients of He, O2, and N2 in R-BAPB, with their critical temperatures and the effective sizes of the gas molecules, respectively. The solubilities obtained in the molecular dynamics simulations are in good quantitative agreement with the experimental data. A good qualitative relationship between the simulation results and the experimental data is also observed when comparing the diffusion coefficients of the gases. Analysis of the Robeson plots shows that R-BAPB has high selectivity for He, N2, and CO2 separation from CH4, which makes it a promising polymer for developing gas-separation membranes. From this point of view, the simulation models developed and validated in the present work may be put to effective use for further investigations into the transport properties of R-BAPB polyimide and nanocomposites based on it.

scholarly journals Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Saket Jain ◽  
Eric J. Chalif ◽  
Manish K. Aghi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Randomized Clinical Trials ◽  
Neutralizing Antibody ◽  
Tumor Vasculature ◽  
Tumor Evolution ◽  
Therapeutic Modalities ◽  
Angiogenic Therapy ◽  
T Cell Infiltration ◽  
Immunosuppressive Microenvironment

Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.

Diagnostics of metal samples using the results of experimental and theoretical study of positively charged microparticles formed upon sample destruction

2018 ◽  
Vol 84 (10) ◽  
pp. 23-28
Author(s):  
D. A. Golentsov ◽  
A. G. Gulin ◽  
Vladimir A. Likhter ◽  
K. E. Ulybyshev
Keyword(s):  
Experimental Data ◽  
Early Stage ◽  
Experimental Studies ◽  
Material Model ◽  
Total Charge ◽  
Cross Sectional ◽  
Practical Applications ◽  
Mechanical And Electrical Properties ◽  
Order Of Magnitude ◽  
Using Data

Destruction of bodies is accompanied by formation of both large and microscopic fragments. Numerous experiments on the rupture of different samples show that those fragments carry a positive electric charge. his phenomenon is of interest from the viewpoint of its potential application to contactless diagnostics of the early stage of destruction of the elements in various technical devices. However, the lack of understanding the nature of this phenomenon restricts the possibility of its practical applications. Experimental studies were carried out using an apparatus that allowed direct measurements of the total charge of the microparticles formed upon sample rupture and determination of their size and quantity. The results of rupture tests of duralumin and electrical steel showed that the size of microparticles is several tens of microns, the particle charge per particle is on the order of 10–14 C, and their amount can be estimated as the ratio of the cross-sectional area of the sample at the point of discontinuity to the square of the microparticle size. A model of charge formation on the microparticles is developed proceeding from the experimental data and current concept of the electron gas in metals. The model makes it possible to determine the charge of the microparticle using data on the particle size and mechanical and electrical properties of the material. Model estimates of the total charge of particles show order-of-magnitude agreement with the experimental data.

scholarly journals Hypoxic tumor microenvironment: Implications for cancer therapy

2020 ◽  
Vol 245 (13) ◽  
pp. 1073-1086
Author(s):  
Sukanya Roy ◽  
Subhashree Kumaravel ◽  
Ankith Sharma ◽  
Camille L Duran ◽  
Kayla J Bayless ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Tumor Vasculature ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Low Oxygen ◽  
Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

An investigation of effects of level density models and gamma ray strength functions on cross-section calculations for the production of 90Y, 153Sm, 169Er, 177Lu and 186Re therapeutic radioisotopes via (n,γ) reactions

2019 ◽  
Vol 108 (1) ◽  
pp. 11-17
Author(s):  
Mert Şekerci ◽  
Hasan Özdoğan ◽  
Abdullah Kaplan
Keyword(s):  
Experimental Data ◽  
Cross Section ◽  
Production Cross Section ◽  
Gamma Ray ◽  
Production Cross ◽  
Level Density ◽  
Experimental Studies ◽  
Level Density Models ◽  
Strength Functions ◽  
Cancer Diseases

Abstract One of the methods used to treat different cancer diseases is the employment of therapeutic radioisotopes. Therefore, many clinical, theoretical and experimental studies are being carried out on those radioisotopes. In this study, the effects of level density models and gamma ray strength functions on the theoretical production cross-section calculations for the therapeutic radioisotopes 90Y, 153Sm, 169Er, 177Lu and 186Re in the (n,γ) route have been investigated. TALYS 1.9 code has been used by employing different level density models and gamma ray strength functions. The theoretically obtained data were compared with the experimental data taken from the literature. The results are presented graphically for better interpretation.

Microemulsion Phase Behavior Observations, Thermodynamic Essentials, Mathematical Simulation

1981 ◽  
Vol 21 (06) ◽  
pp. 747-762 ◽  
Author(s):  
Karl E. Bennett ◽  
Craig H.K. Phelps ◽  
H. Ted Davis ◽  
L.E. Scriven
Keyword(s):  
Experimental Data ◽  
Phase Behavior ◽  
Experimental Studies ◽  
Mathematical Framework ◽  
Alkyl Aryl Sulfonate ◽  
Phase Volume ◽  
Displacement Efficiency ◽  
Alkyl Aryl ◽  
Theoretical Understanding ◽  
Tie Lines

Abstract The phase behavior of microemulsions of brine, hydrocarbon, alcohol, and a pure alkyl aryl sulfonate-sodium 4-(1-heptylnonyl) benzenesulfonate (SHBS or Texas 1) was investigated as a function of the concentration of salt (NaCl, MgCl2, or CaCl2), the hydrocarbon (n-alkanes, octane to hexadecane), the alcohol (butyl and amyl isomers), the concentration of surfactant, and temperature. The phase behavior mimics that of similar systems with the commercial surfactant Witco TRS 10–80. The phase volumes follow published trends, though with exceptions.A mathematical framework is presented for modeling phase behavior in a manner consistent with the thermodynamically required critical tie lines and plait point progressions from the critical endpoints. Hand's scheme for modeling binodals and Pope and Nelson's approach to modeling the evolution of the surfactant-rich third phase are extended to satisfy these requirements.An examination of model-generated progressions of ternary phase diagrams enhances understanding of the experimental data and reveals correlations of relative phase volumes (volume uptakes) with location of the mixing point (overall composition) relative to the height of the three-phase region and the locations of the critical tie lines (critical endpoints and conjugate phases). The correlations account, on thermodynamic grounds, for cases in which the surfactant is present in more than one phase or the phase volumes change discontinuously, both cases being observed in the experimental study. Introduction The phase behavior of a surfactant-based micellar formulation is one of the major factors governing the displacement efficiency of any chemical flooding process employing that formulation. Knowledge of phase behavior is, thus, important for the interpretation of laboratory core floods, the design of flooding processes, and the evaluation of field tests. Phase behavior is connected intimately with other determinants of the flooding process, such as interfacial tension and viscosity. Since the number of equilibrium phases and their volumes and appearances are easier to measure and observe than phase compositions, viscosities, and interfacial tensions, there is great interest in understanding the phase-volume/phase-property relationships. Commercial surfactants, such as Witco TRS 10-80, are sulfonates of crude or partially refined oil. While they seem to be the most economically practicable surfactants for micellar flooding, their behavior, particularly with crude oils and reservoir brines, can be difficult to interpret, the phases varying with time and from batch to batch. Phase behavior studies with a small number of components, in conjunction with a theoretical understanding of phase behavior progressions, can aid in understanding more complex behavior. In particular, one can begin to appreciate which seemingly abnormal experimental observations (e.g., surfactant present in more than one phase or a discontinuity in phase volume trends) are merely features of certain regions of any phase diagram and which are peculiar to the specific crude oil or commercial surfactant used in the study.We report here experimental studies of the phase behavior of microemulsions of a pure sulfonate surfactant (Texas 1), a single normal alkane hydrocarbon, a simple brine, and a small amount of a suitable alcohol as cosurfactant or cosolvent. The controlled variables are hydrocarbon chain length, alcohol, salinity, salt type (NaCl, MgCl2, or CaCl2), surfactant purity, surfactant concentration, and temperature. Many of these experimental data were presented earlier. SPEJ P. 747^

Hybrid Analysis of Gas Annular Seals With Energy Equation

2013 ◽  
Author(s):  
Patrick J. Migliorini ◽  
Alexandrina Untaroiu ◽  
William C. Witt ◽  
Neal R. Morgan ◽  
Houston G. Wood
Keyword(s):  
Experimental Data ◽  
Hybrid Method ◽  
Energy Equation ◽  
Flow Analysis ◽  
Experimental Studies ◽  
Rotor System ◽  
Bulk Flow ◽  
Outlet Temperature ◽  
Cfd Analysis ◽  
Annular Seals

Annular seals are used in turbomachinery to reduce secondary flow between regions of high and low pressure. In a vibrating rotor system, the non-axisymmetric pressure field developed in the small clearance between the rotor and the seal generate reactionary forces that can affect the stability of the entire rotor system. Traditionally, two analyses have been used to study the fluid flow in seals, bulk-flow analysis and computational fluid dynamics (CFD). Bulk-flow methods are computational inexpensive, but solve simplified equations that rely on empirically derived coefficients and are moderately accurate. CFD analyses generally provide more accurate results than bulk-flow codes, but solution time can vary between days and weeks. For gas damper seals, these analyses have been developed with the assumption that the flow can be treated as isothermal. Some experimental studies show that the difference between the inlet and outlet temperature temperatures is less than 5% but initial CFD studies show that there can be a significant temperature change which can have an effect on the density field. Thus, a comprehensive analysis requires the solution of an energy equation. Recently, a new hybrid method that employs a CFD analysis for the base state, unperturbed flow and a bulk-flow analysis for the first order, perturbed flow has been developed. This method has shown to compare well with full CFD analysis and experimental data while being computationally efficient. In this study, the previously developed hybrid method is extended to include the effects of non-isothermal flow. The hybrid method with energy equation is then compared with the isothermal hybrid method and experimental data for several test cases of hole-pattern seals and the importance of the use of energy equation is studied.

Effect of Boundary Layer Suction on Aerodynamic Performance of High-Turning Compressor Cascade

2013 ◽  
Author(s):  
Longxin Zhang ◽  
Shaowen Chen ◽  
Hao Xu ◽  
Jun Ding ◽  
Songtao Wang
Keyword(s):  
Experimental Data ◽  
Boundary Layer ◽  
Experimental Studies ◽  
Aerodynamic Performance ◽  
Parameter Distribution ◽  
Compressor Cascade ◽  
Boundary Layer Suction ◽  
End Wall ◽  
Low Speed Wind Tunnel ◽  
Good Agreement

Compared with suction slots, suction holes are (1) flexible in distribution; (2) alterable in size; (3) easy to fabricate and (4) high in strength. In this paper, the numerical and experimental studies for a high turning compressor cascade with suction air removed by using suction holes in the end-wall at a low Mach numbers are carried out. The main objective of the investigation is to study the influence of different suction distributions on the aerodynamic performance of the compressor cascade and to find a better compound suction scheme. A numerical model was first made and validated by comparing with the experimental results. The computed flow visualization and exit parameter distribution showed a good agreement with experimental data. Second, the model was then used to simulate the influence of different suction distributions on the aerodynamic performance of the compressor cascade. A better compound suction scheme was obtained by summarizing numerical results and tested in a low speed wind tunnel. As a result, the compound suction scheme can be used to significantly improve the performance of the compressor cascade because the corner separation gets further suppressed.

Sign in / Sign up

Export Citation Format

Share Document