Science.gov

Sample records for abnormal tumor vasculature

  1. Matrix stiffening promotes a tumor vasculature phenotype

    PubMed Central

    Bordeleau, Francois; Mason, Brooke N.; Lollis, Emmanuel Macklin; Mazzola, Michael; Zanotelli, Matthew R.; Somasegar, Sahana; Califano, Joseph P.; Montague, Christine; LaValley, Danielle J.; Huynh, John; Mencia-Trinchant, Nuria; Negrón Abril, Yashira L.; Hassane, Duane C.; Bonassar, Lawrence J.; Butcher, Jonathan T.; Weiss, Robert S.; Reinhart-King, Cynthia A.

    2017-01-01

    Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell–cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery. PMID:28034921

  2. Modulation of the Tumor Vasculature and Oxygenation to Improve Therapy

    PubMed Central

    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 nutritional support to tumor cells. As a consequence the expanding neoplastic cell population initiates its own vascular network which is both structurally and functionally abnormal. This aberrant vasculature impacts all aspects of the tumor microenvironment including the cells, extracellular matrix, and extracellular molecules which together are essential for the initiation, progression and spread of tumor cells. The physical conditions that arise are imposing and manifold, and include elevated interstitial pressure, localized extracellular acidity, and regions of oxygen and nutrient deprivation. No less 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 that create a significant hindrance to the control of cancers by conventional anticancer therapies. However, the aberrant nature of the tumor microenvironments also offers unique therapeutic opportunities. Particularly interventions that seek to improve tumor physiology and alleviate tumor hypoxia will selectively impair the neoplastic cell populations residing in these environments. Ultimately, by combining such therapeutic strategies with conventional anticancer treatments it may be possible to bring cancer growth, invasion, and metastasis to a halt. PMID:26073310

  3. Neocortical vasculature abnormalities in the Fragile X mental retardation syndrome.

    PubMed

    Galvan, Ashley M; Galvez, Roberto

    2012-08-30

    The Fragile X syndrome (FXS) is the leading form of inherited mental retardation. To date, the most prominent neuronal phenotype associated with the syndrome is an abundance of long thin spines exhibiting an immature morphology. However, in addition to synaptic abnormalities, recent case studies have demonstrated that Fragile X (FX) patients also exhibit abnormal cerebral blood flow (CBF). To examine the role of the Fragile X mental retardation protein (FMRP) in altering CBF, we examined blood vessel density (BVD) in the visual cortex of Adult and Middle-aged FX mice. Analysis of Middle-aged FX mice demonstrated elevated BVD compared to wildtype controls, suggesting that FX mice exhibit a lack of age-induced BVD plasticity. However, Adult FX and wildtype mice did not exhibit consistent differences in BVD. These data demonstrate that FMRP is required for age-induced neocortical vasculature plasticity. Furthermore, these data suggest a new role for FMRP in blood vessel regulation that would have profound implications towards appropriately timed delivery of neuronal nutrients, thus contributing to or exacerbating FX cognitive and neuronal abnormalities.

  4. The Pleiotropic Role of L1CAM in Tumor Vasculature

    PubMed Central

    Angiolini, Francesca; Cavallaro, Ugo

    2017-01-01

    Angiogenesis, the formation of new vessels, is a key step in the development, invasion, and dissemination of solid tumors and, therefore, represents a viable target in the context of antitumor therapy. Indeed, antiangiogenic approaches have given promising results in preclinical models and entered the clinical practice. However, in patients, the results obtained so far with antiangiogenic drugs have not completely fulfilled expectations, especially because their effect has been transient with tumors developing resistance and evasion mechanisms. A better understanding of the mechanisms that underlie tumor vascularization and the functional regulation of cancer vessels is a prerequisite for the development of novel and alternative antiangiogenic treatments. The L1 cell adhesion molecule (L1CAM), a cell surface glycoprotein previously implicated in the development and plasticity of the nervous system, is aberrantly expressed in the vasculature of various cancer types. L1CAM plays multiple pro-angiogenic roles in the endothelial cells of tumor-associated vessels, thus emerging as a potential therapeutic target. In addition, L1CAM prevents the maturation of cancer vasculature and its inhibition promotes vessel normalization, a process that is thought to improve the therapeutic response of tumors to cytotoxic drugs. We here provide an overview on tumor angiogenesis and antiangiogenic therapies and summarize the current knowledge on the biological role of L1CAM in cancer vasculature. Finally, we highlight the clinical implications of targeting L1CAM as a novel antiangiogenic and vessel-normalizing approach. PMID:28134764

  5. Physics of the tumor vasculature: Theory and experiment

    NASA Astrophysics Data System (ADS)

    Rieger, Heiko; Fredrich, Thierry; Welter, Michael

    2016-02-01

    Growing solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth and gain of metastatic potential. Consequently the tumor vasculature has been a major target of anti cancer therapies since four decades. The main underlying strategic concepts range from "starving a tumor to death" over "blood vessel normalization" to "blood vessel growth promotion" for improved drug delivery and oxygenation for increased success rates of radiation therapy. A mechanistic understanding of the these strategies is often elusive and call for a quantitative analysis of the underlying physics. Oxygen supply as well as drug delivery is determined by blood and interstitial fluid flow, for which reason such an analysis must focus on the relation between the intra- and extra-vascular transport characteristics and the tumor vasculature morphology. Here we review the current status of theoretical concepts and computational analysis of physical determinants of the tumor vasculature and the emerging predictions for blood flow, oxygen distribution, interstitial fluid pressure and efficiency of drug delivery.

  6. Image fusion for visualization of hepatic vasculature and tumors

    NASA Astrophysics Data System (ADS)

    Chou, Jin-Shin; Chen, Shiuh-Yung J.; Sudakoff, Gary S.; Hoffmann, Kenneth R.; Chen, Chin-Tu; Dachman, Abraham H.

    1995-05-01

    We have developed segmentation and simultaneous display techniques to facilitate the visualization of the three-dimensional spatial relationships between organ structures and organ vasculature. We concentrate on the visualization of the liver based on spiral computed tomography images. Surface-based 3-D rendering and maximal intensity projection algorithms are used for data visualization. To extract the liver in the serial of images accurately and efficiently, we have developed a user-friendly interactive program with a deformable-model segmentation. Surface rendering techniques are used to visualize the extracted structures, adjacent contours are aligned and fitted with a Bezier surface to yield a smooth surface. Visualization of the vascular structures, portal and hepatic veins, is achieved by applying a MIP technique to the extracted liver volume. To integrate the extracted structures they are surface-rendered and their MIP images are aligned and a color table is designed for simultaneous display of the combined liver/tumor and vasculature images. By combining the 3-D surface rendering and MIP techniques, portal veins, hepatic veins, and hepatic tumor can be inspected simultaneously and their spatial relationships can be more easily perceived. The proposed technique will be useful for visualization of both hepatic neoplasm and vasculature in surgical planning for tumor resection or living-donor liver transplantation.

  7. Targeting tumor vasculature through oncolytic virotherapy: recent advances.

    PubMed

    Toro Bejarano, Marcela; Merchan, Jaime R

    2015-01-01

    The oncolytic virotherapy field has made significant advances in the last decade, with a rapidly increasing number of early- and late-stage clinical trials, some of them showing safety and promising therapeutic efficacy. Targeting tumor vasculature by oncolytic viruses (OVs) is an attractive strategy that offers several advantages over nontargeted viruses, including improved tumor viral entry, direct antivascular effects, and enhanced antitumor efficacy. Current understanding of the biological mechanisms of tumor neovascularization, novel vascular targets, and mechanisms of resistance has allowed the development of oncolytic viral vectors designed to target tumor neovessels. While some OVs (such as vaccinia and vesicular stomatitis virus) can intrinsically target tumor vasculature and induce vascular disruption, the majority of reported vascular-targeted viruses are the result of genetic manipulation of their viral genomes. Such strategies include transcriptional or transductional endothelial targeting, "armed" viruses able to downregulate angiogenic factors, or to express antiangiogenic molecules. The above strategies have shown preclinical safety and improved antitumor efficacy, either alone, or in combination with standard or targeted agents. This review focuses on the recent efforts toward the development of vascular-targeted OVs for cancer treatment and provides a translational/clinical perspective into the future development of new generation biological agents for human cancers.

  8. Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy

    PubMed Central

    Adapala, Ravi K.; Thoppil, Roslin J.; Ghosh, Kaustabh; Cappelli, Holly; Dudley, Andrew C.; Paruchuri, Sailaja; Keshamouni, Venkateshwar; Klagsbrun, Michael; Meszaros, J. Gary; Chilian, William M.; Ingber, Donald E.; Thodeti, Charles K.

    2016-01-01

    Tumor vessels are characterized by abnormal morphology and hyper-permeability that together cause inefficient delivery of chemotherapeutic agents. Although VEGF has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here, we show that the mechanosensitive ion channel TRPV4 regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TEC exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards ECM stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 KO mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anti-cancer drug Cisplatin, significantly reduced tumor growth in WT mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies. PMID:25867067

  9. Biologic Effects of Dopamine on Tumor Vasculature in Ovarian Carcinoma12

    PubMed Central

    Moreno-Smith, Myrthala; Lee, Sun Joo; Lu, Chunhua; Nagaraja, Archana S; He, Guangan; Rupaimoole, Rajesha; Han, Hee Dong; Jennings, Nicholas B; Roh, Ju-Won; Nishimura, Masato; Kang, Yu; Allen, Julie K; Armaiz, Guillermo N; Matsuo, Koji; Shahzad, Mian M K; Bottsford-Miller, Justin; Langley, Robert R; Cole, Steve W; Lutgendorf, Susan K; Siddik, Zahid H; Sood, Anil K

    2013-01-01

    Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth. PMID:23633922

  10. Selective Alpha-Particle Mediated Depletion of Tumor Vasculature with Vascular Normalization

    PubMed Central

    Seshan, Surya V.; Kappel, Barry J.; Chattopadhyay, Debjit; May, Chad; McDevitt, Michael R.; Nolan, Daniel; Mittal, Vivek; Benezra, Robert; Scheinberg, David A.

    2007-01-01

    Background Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature. Methodology and Principal Findings Actinium-225 (225Ac)-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, 225Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in 225Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following 225Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following 225Ac-E4G10 therapy. Conclusions The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy. PMID:17342201

  11. Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes.

    PubMed

    Ruggiero, Alessandro; Villa, Carlos H; Holland, Jason P; Sprinkle, Shanna R; May, Chad; Lewis, Jason S; Scheinberg, David A; McDevitt, Michael R

    2010-10-05

    Single wall carbon nanotube (SWCNT) constructs were covalently appended with radiometal-ion chelates (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or desferrioxamine B [DFO]) and the tumor neovascular-targeting antibody E4G10. The E4G10 antibody specifically targeted the monomeric vascular endothelial-cadherin (VE-cad) epitope expressed in the tumor angiogenic vessels. The construct specific activity and blood compartment clearance kinetics were significantly improved relative to corresponding antibodyalone constructs. We performed targeted radioimmunotherapy with a SWCNT-([(225)Ac]DOTA) (E4G10) construct directed at the tumor vasculature in a murine xenograft model of human colon adenocarcinoma (LS174T). The specific construct reduced tumor volume and improved median survival relative to controls. We also performed positron emission tomographic (PET) radioimmunoimaging of the tumor vessels with a SWCNT-([(89)Zr]DFO)(E4G10) construct in the same murine LS174T xenograft model and compared the results to appropriate controls. Dynamic and longitudinal PET imaging of LS174T tumor-bearing mice demonstrated rapid blood clearance (<1 hour) and specific tumor accumulation of the specific construct. Incorporation of the SWCNT scaffold into the construct design permitted us to amplify the specific activity to improve the signal-to-noise ratio without detrimentally impacting the immunoreactivity of the targeting antibody moiety. Furthermore, we were able to exploit the SWCNT pharmacokinetic (PK) profile to favorably alter the blood clearance and provide an advantage for rapid imaging. Near-infrared three-dimensional fluorescent-mediated tomography was used to image the LS174T tumor model, collect antibody-alone PK data, and calculate the number of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that

  12. Multiscale imaging and computational modeling of blood flow in the tumor vasculature.

    PubMed

    Kim, Eugene; Stamatelos, Spyros; Cebulla, Jana; Bhujwalla, Zaver M; Popel, Aleksander S; Pathak, Arvind P

    2012-11-01

    The evolution in our understanding of tumor angiogenesis has been the result of pioneering imaging and computational modeling studies spanning the endothelial cell, microvasculature and tissue levels. Many of these primary data on the tumor vasculature are in the form of images from pre-clinical tumor models that provide a wealth of qualitative and quantitative information in many dimensions and across different spatial scales. However, until recently, the visualization of changes in the tumor vasculature across spatial scales remained a challenge due to a lack of techniques for integrating micro- and macroscopic imaging data. Furthermore, the paucity of three-dimensional (3-D) tumor vascular data in conjunction with the challenges in obtaining such data from patients presents a serious hurdle for the development and validation of predictive, multiscale computational models of tumor angiogenesis. In this review, we discuss the development of multiscale models of tumor angiogenesis, new imaging techniques capable of reproducing the 3-D tumor vascular architecture with high fidelity, and the emergence of "image-based models" of tumor blood flow and molecular transport. Collectively, these developments are helping us gain a fundamental understanding of the cellular and molecular regulation of tumor angiogenesis that will benefit the development of new cancer therapies. Eventually, we expect this exciting integration of multiscale imaging and mathematical modeling to have widespread application beyond the tumor vasculature to other diseases involving a pathological vasculature, such as stroke and spinal cord injury.

  13. Multiscale Imaging and Computational Modeling of Blood Flow in the Tumor Vasculature

    PubMed Central

    Kim, Eugene; Stamatelos, Spyros; Cebulla, Jana; Bhujwalla, Zaver M.; Popel, Aleksander S.; Pathak, Arvind P.

    2013-01-01

    The evolution in our understanding of tumor angiogenesis has been the result of pioneering imaging and computational modeling studies spanning the endothelial cell, microvasculature and tissue levels. Many of these primary data on the tumor vasculature are in the form of images from pre-clinical tumor models that provide a wealth of qualitative and quantitative information in many dimensions and across different spatial scales. However, until recently, the visualization of changes in the tumor vasculature across spatial scales remained a challenge due to a lack of techniques for integrating micro- and macroscopic imaging data. Furthermore, the paucity of three-dimensional (3-D) tumor vascular data in conjunction with the challenges in obtaining such data from patients presents a serious hurdle for the development and validation of predictive, multiscale computational models of tumor angiogenesis. In this review, we discuss the development of multiscale models of tumor angiogenesis, new imaging techniques capable of reproducing the 3-D tumor vascular architecture with high fidelity, and the emergence of “image-based models”of tumor blood flow and molecular transport. Collectively, these developments are helping us gain a fundamental understanding of the cellular and molecular regulation of tumor angiogenesis that will benefit the development of new cancer therapies. Eventually, we expect this exciting integration of multiscale imaging and mathematical modeling to have widespread application beyond the tumor vasculature to other diseases involving a pathological vasculature, such as stroke and spinal cord injury. PMID:22565817

  14. Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery

    PubMed Central

    2012-01-01

    Tumor vasculature expresses a distinct set of molecule signatures on the endothelial cell surface different from the resting blood vessels of other organs and tissues in the body. This makes them an attractive target for cancer therapy and molecular imaging. The current technology using the in vivo phage display biopanning allows us to quickly isolate and identify peptides potentially homing to various tumor blood vessels. Tumor-homing peptides in conjugation with chemotherapeutic drugs or imaging contrast have been extensively tested in various preclinical and clinical studies. These tumor-homing peptides have valuable potential as targeting probes for tumor molecular imaging and drug delivery. In this review, we summarize the recent advances about the applications of tumor-homing peptides selected by in vivo phage display library screening against tumor vasculature. We also introduce the characteristics of the latest discovered tumor-penetrating peptides in their potential clinical applications. PMID:23046982

  15. Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery.

    PubMed

    Li, Zhi Jie; Cho, Chi Hin

    2012-09-19

    Tumor vasculature expresses a distinct set of molecule signatures on the endothelial cell surface different from the resting blood vessels of other organs and tissues in the body. This makes them an attractive target for cancer therapy and molecular imaging. The current technology using the in vivo phage display biopanning allows us to quickly isolate and identify peptides potentially homing to various tumor blood vessels. Tumor-homing peptides in conjugation with chemotherapeutic drugs or imaging contrast have been extensively tested in various preclinical and clinical studies. These tumor-homing peptides have valuable potential as targeting probes for tumor molecular imaging and drug delivery. In this review, we summarize the recent advances about the applications of tumor-homing peptides selected by in vivo phage display library screening against tumor vasculature. We also introduce the characteristics of the latest discovered tumor-penetrating peptides in their potential clinical applications.

  16. Detecting abnormal vasculature from photoacoustic signals using wavelet-packet features

    NASA Astrophysics Data System (ADS)

    Zalev, Jason; Kolios, Michael C.

    2011-03-01

    Photoacoustic systems can produce high-resolution, high-contrast images of vascular structures. To reconstruct images at very high-resolution, signals must be collected from many transducer locations, which can be time consuming due to limitations in transducer array technology. A method is presented to quickly discriminate between normal and abnormal tissue based on the structural morphology of vasculature. To demonstrate that the approach may be useful for cancer detection, a special simulator that produces photoacoustic signals from 3D models of vascular tissue is developed. Results show that it is possible to differentiate tissue classes even when it is not possible to resolve individual blood vessels. Performance of the algorithm remains strong as the number of transducer locations decreases and in the presence of noise.

  17. Revisiting tumor angiogenesis: vessel co-option, vessel remodeling, and cancer cell-derived vasculature formation.

    PubMed

    Qian, Chao-Nan; Tan, Min-Han; Yang, Jun-Ping; Cao, Yun

    2016-01-08

    Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen, nutrients, and other essential factors. The well-known vascular endothelial growth factor (VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature, which has become therapeutic targets in clinical practice. However, the survival benefits gained from targeting VEGF signaling have been very limited, with the inevitable development of treatment resistance. In this article, we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy, with a special focus on vessel co-option, vessel remodeling, and tumor cell-derived vasculature establishment. Vessel co-option may occur in tumors independently of sprouting angiogenesis, and sprouting angiogenesis is not always required for tumor growth. The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced. The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.

  18. Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles.

    PubMed

    Zhen, Zipeng; Tang, Wei; Chuang, Yen-Jun; Todd, Trever; Zhang, Weizhong; Lin, Xin; Niu, Gang; Liu, Gang; Wang, Lianchun; Pan, Zhengwei; Chen, Xiaoyuan; Xie, Jin

    2014-06-24

    Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors' origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as "smart" carriers that site-specifically deliver (1)O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine.

  19. Cone beam CT tumor vasculature dynamic study (Murine model)

    NASA Astrophysics Data System (ADS)

    Yang, Dong; Ning, Ruola; Conover, David; Ricardo, Betancourt; Liu, Shaohua

    2008-03-01

    Tumor angiogenesis is the process by which new blood vessels are formed from the existing vessels in a tumor to promote tumor growth. Tumor angiogenesis has important implications in the diagnosis and treatment of various solid tumors. Flat panel detector based cone beam CT opens up a new way for detection of tumors, and tumor angiogenesis associated with functional CBCT has the potential to provide more information than traditional functional CT due to more overall coverage during the same scanning period and the reconstruction being isotropic resulting in a more accurate 3D volume intensity measurement. A functional study was conducted by using CBCT to determine the degree of the enhancement within the tumor after injecting the contrast agent intravenously. For typical doses of contrast material, the amount of enhancement is proportional to the concentration of this material within the region of interest. A series of images obtained at one location over time allows generation of time-attenuation data from which a number of semi-quantitative parameters, such as enhancement rate, can be determined. An in vivo mice study with and without mammo tumor was conducted on our prototype CBCT system, and half scan scheme is used to determine the time-intensity curve within the VOI of the mouse. The CBCT has an x-ray tube, a gantry with slip ring technology, and a 40×30 cm Varian Paxscan 4030CB real time FPD.

  20. Structure of solid tumors and their vasculature: Implications for therapy with monoclonal antibodies

    SciTech Connect

    Dvorak, H.F.; Nagy, J.A.; Dvorak, A.M. )

    1991-03-01

    Delivery of monoclonal antibodies to solid tumors is a vexing problem that must be solved if these antibodies are to realize their promise in therapy. Such success as has been achieved with monoclonal antibodies is attributable to the local hyperpermeability of the tumor vasculature, a property that favors antibody extravasation at tumor sites and that is mediated by a tumor-secreted vascular permeability factor. However, leaky tumor blood vessels are generally some distance removed from target tumor cells, separated by stroma and by other tumor cells that together represent significant barriers to penetration by extravasated monoclonal antibodies. For this reason, alternative approaches may be attractive. These include the use of antibody-linked cytotoxins, which are able to kill tumor cells without immediate contact, and direction of antibodies against nontumor cell targets, for example, antigens unique to the tumor vascular endothelium or to tumor stroma. 50 refs.

  1. Peptides homing to tumor vasculature: imaging and therapeutics for cancer.

    PubMed

    Liu, Zhiguo; Wu, Kaichun

    2008-11-01

    A major obstacle to advances in anti-vascular therapy is the lack of molecule candidates that are effective in selectively targeting cancer tissues while sparing normal ones. Phage display peptide library greatly eases the discovery of peptides with specific homing capacity. Many novel peptides homing to angiogenic vessels were isolated recently. Notably, many such peptides showed relatively specific affinity with particular tumor types. These peptides appear to be able to accumulate in the target vascular site of tumor, making them particularly efficient to deliver drugs or other therapeutic and imaging agents. Some homing peptides could not only target to the desired location, but also be internalized into targeted cells, or even induce destruction in desired cells all by the same peptide sequence itself. Accumulating evidence has shown that by tumor specific targeting delivery, improved local effect can be achieved with well tolerated side effects. In the current review, recent literatures and patents in this field have been summarized.

  2. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

    NASA Astrophysics Data System (ADS)

    Pandey, Ambarish; Sarangi, Sasmit; Chien, Kelly; Sengupta, Poulomi; Papa, Anne-Laure; Basu, Sudipta; Sengupta, Shiladitya

    2014-11-01

    Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

  3. A CD276 Antibody Guided Missile with One Warhead and Two Targets: The Tumor and Its Vasculature.

    PubMed

    Khan, Kabir A; Kerbel, Robert S

    2017-04-10

    In this issue of Cancer Cell, Seaman et al. demonstrate that antibody drug conjugates (ADCs) against CD276 expressed by tumor cells and tumor vasculature have promising anti-tumor activity while showing little toxicity. Importantly, these agents have the potential to target both angiogenic vessels and non-angiogenic vessels co-opted by tumor cells.

  4. In-vivo imaging of nanoshell extravasation from solid tumor vasculature by photoacoustic microscopy

    NASA Astrophysics Data System (ADS)

    Li, Meng-Lin; Schwartz, Jon A.; Wang, James; Stoica, George; Wang, Lihong V.

    2007-02-01

    In this study, high resolution reflection-mode (backward-mode) photoacoustic microscopy (PAM) is used to noninvasively image progressive extravasation and accumulation of nanoshells within a solid tumor in vivo. This study takes advantage of the strong near-infrared absorption of nanoshells, a novel type of optically tunable gold nanoparticles that tend to extravasate from leaky tumor vasculatures (i.e., passive targeting) via the "enhanced permeability and retention" effect due to their nanoscale size. Tumors were grown in immunocompetent BALB/c mice by subcutaneous inoculation of CT26.wt murine colon carcinoma cells. PEGylated nanoshells with a peak optical absorption at ~800 nm were intravenously administered. Pre-scans prior to nanoshell injection were taken using a 584-nm laser source to highlight blood content and an 800-nm laser source to mark the background limit for nanoshell accumulation. After injection, the three-dimensional nanoshell distribution inside the tumor was monitored by PAM for 7 hours. Experimental results show that nanoshell accumulation is heterogeneous in tumors: more concentrated within the tumor cortex and largely absent from the tumor core. This correlates with others' observation that drug delivery within tumor cores is ineffective because of both high interstitial pressure and tendency to necrosis of tumor cores. Since nanoshells have been recently applied to thermal therapy for subcutaneous tumors, we anticipate that PAM will be important to this therapeutic technique.

  5. Differentiation between normal and tumor vasculature of animal and human glioma by FTIR imaging.

    PubMed

    Wehbe, Katia; Pineau, Raphael; Eimer, Sandrine; Vital, Anne; Loiseau, Hugues; Déléris, Gérard

    2010-12-01

    Malignant gliomas are very aggressive tumors, highly angiogenic and invading heterogeneously the surrounding brain parenchyma, making their resection very difficult. To overcome the limits of current diagnostic imaging techniques used for gliomas, we proposed using FTIR imaging, with a spatial resolution from 6 to 10 μm, to provide molecular information for their histological examination, based on discrimination between normal and tumor vasculature. Differentiation between normal and tumor blood vessel spectra by hierarchical cluster analysis was performed on tissue sections obtained from xenografted brain tumors of Rag-gamma mice 28 days after intracranial implantation of glioma cells, as well as for human brain tumors obtained in clinics. Classical pathological examination and immunohistochemistry were performed in parallel to the FTIR spectral imaging of brain tissues. First on the animal model, classification of FTIR spectra of blood vessels could be performed using spectral intervals based on fatty acyl (3050-2800 cm(-1)) and carbohydrate (1180-950 cm(-1)) absorptions, with the formation of two clusters corresponding to healthy and tumor parts of the tissue sections. Further data treatments on these two spectral intervals provided interpretable information about the molecular contents involved in the differentiation between normal and tumor blood vessels, the latter presenting a higher level of fatty acyl chain unsaturation and an unexpected loss of absorption from osidic residues. This classification method was further successfully tested on human glioma tissue sections. These findings demonstrate that FTIR imaging could highlight discriminant molecular markers to distinguish between normal and tumor vasculature, and help to delimitate areas of corresponding tissue.

  6. Biomimetic carriers mimicking leukocyte plasma membrane to increase tumor vasculature permeability

    NASA Astrophysics Data System (ADS)

    Palomba, R.; Parodi, A.; Evangelopoulos, M.; Acciardo, S.; Corbo, C.; De Rosa, E.; Yazdi, I. K.; Scaria, S.; Molinaro, R.; Furman, N. E. Toledano; You, J.; Ferrari, M.; Salvatore, F.; Tasciotti, E.

    2016-10-01

    Recent advances in the field of nanomedicine have demonstrated that biomimicry can further improve targeting properties of current nanotechnologies while simultaneously enable carriers with a biological identity to better interact with the biological environment. Immune cells for example employ membrane proteins to target inflamed vasculature, locally increase vascular permeability, and extravasate across inflamed endothelium. Inspired by the physiology of immune cells, we recently developed a procedure to transfer leukocyte membranes onto nanoporous silicon particles (NPS), yielding Leukolike Vectors (LLV). LLV are composed of a surface coating containing multiple receptors that are critical in the cross-talk with the endothelium, mediating cellular accumulation in the tumor microenvironment while decreasing vascular barrier function. We previously demonstrated that lymphocyte function-associated antigen (LFA-1) transferred onto LLV was able to trigger the clustering of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Herein, we provide a more comprehensive analysis of the working mechanism of LLV in vitro in activating this pathway and in vivo in enhancing vascular permeability. Our results suggest the biological activity of the leukocyte membrane can be retained upon transplant onto NPS and is critical in providing the particles with complex biological functions towards tumor vasculature.

  7. Biomimetic carriers mimicking leukocyte plasma membrane to increase tumor vasculature permeability

    PubMed Central

    Palomba, R.; Parodi, A.; Evangelopoulos, M.; Acciardo, S.; Corbo, C.; de Rosa, E.; Yazdi, I. K.; Scaria, S.; Molinaro, R.; Furman, N. E. Toledano; You, J.; Ferrari, M.; Salvatore, F.; Tasciotti, E.

    2016-01-01

    Recent advances in the field of nanomedicine have demonstrated that biomimicry can further improve targeting properties of current nanotechnologies while simultaneously enable carriers with a biological identity to better interact with the biological environment. Immune cells for example employ membrane proteins to target inflamed vasculature, locally increase vascular permeability, and extravasate across inflamed endothelium. Inspired by the physiology of immune cells, we recently developed a procedure to transfer leukocyte membranes onto nanoporous silicon particles (NPS), yielding Leukolike Vectors (LLV). LLV are composed of a surface coating containing multiple receptors that are critical in the cross-talk with the endothelium, mediating cellular accumulation in the tumor microenvironment while decreasing vascular barrier function. We previously demonstrated that lymphocyte function-associated antigen (LFA-1) transferred onto LLV was able to trigger the clustering of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Herein, we provide a more comprehensive analysis of the working mechanism of LLV in vitro in activating this pathway and in vivo in enhancing vascular permeability. Our results suggest the biological activity of the leukocyte membrane can be retained upon transplant onto NPS and is critical in providing the particles with complex biological functions towards tumor vasculature. PMID:27703233

  8. Biomimetic carriers mimicking leukocyte plasma membrane to increase tumor vasculature permeability.

    PubMed

    Palomba, R; Parodi, A; Evangelopoulos, M; Acciardo, S; Corbo, C; de Rosa, E; Yazdi, I K; Scaria, S; Molinaro, R; Furman, N E Toledano; You, J; Ferrari, M; Salvatore, F; Tasciotti, E

    2016-10-05

    Recent advances in the field of nanomedicine have demonstrated that biomimicry can further improve targeting properties of current nanotechnologies while simultaneously enable carriers with a biological identity to better interact with the biological environment. Immune cells for example employ membrane proteins to target inflamed vasculature, locally increase vascular permeability, and extravasate across inflamed endothelium. Inspired by the physiology of immune cells, we recently developed a procedure to transfer leukocyte membranes onto nanoporous silicon particles (NPS), yielding Leukolike Vectors (LLV). LLV are composed of a surface coating containing multiple receptors that are critical in the cross-talk with the endothelium, mediating cellular accumulation in the tumor microenvironment while decreasing vascular barrier function. We previously demonstrated that lymphocyte function-associated antigen (LFA-1) transferred onto LLV was able to trigger the clustering of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Herein, we provide a more comprehensive analysis of the working mechanism of LLV in vitro in activating this pathway and in vivo in enhancing vascular permeability. Our results suggest the biological activity of the leukocyte membrane can be retained upon transplant onto NPS and is critical in providing the particles with complex biological functions towards tumor vasculature.

  9. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment.

    PubMed

    Hendry, Shona A; Farnsworth, Rae H; Solomon, Benjamin; Achen, Marc G; Stacker, Steven A; Fox, Stephen B

    2016-01-01

    Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

  10. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

    PubMed Central

    Hendry, Shona A.; Farnsworth, Rae H.; Solomon, Benjamin; Achen, Marc G.; Stacker, Steven A.; Fox, Stephen B.

    2016-01-01

    Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host’s immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion. PMID:28066431

  11. Functionalized near-infrared quantum dots for in vivo tumor vasculature imaging

    NASA Astrophysics Data System (ADS)

    Hu, Rui; Yong, Ken-Tye; Roy, Indrajit; Ding, Hong; Law, Wing-Cheung; Cai, Hongxing; Zhang, Xihe; Vathy, Lisa A.; Bergey, Earl J.; Prasad, Paras N.

    2010-04-01

    In this paper, we report the use of near-infrared (NIR)-emitting alloyed quantum dots (QDs) as efficient optical probes for high contrast in vivo imaging of tumors. Alloyed CdTe1 - xSex/CdS QDs were prepared in the non-aqueous phase using the hot colloidal synthesis approach. Water dispersion of the QDs were accomplished by their encapsulation within polyethyleneglycol (PEG)-grafted phospholipid micelles. For tumor-specific delivery in vivo, the micelle-encapsulated QDs were conjugated with the cyclic arginine-glycine-aspartic acid (cRGD) peptide, which targets the αvβ3 integrins overexpressed in the angiogenic tumor vasculatures. Using in vivo NIR optical imaging of mice bearing pancreatic cancer xenografts, implanted both subcutaneously and orthotopically, we have demonstrated that systemically delivered cRGD-conjugated QDs, but not the unconjugated ones, can efficiently target and label the tumors with high signal-to-noise ratio. Histopathological analysis of major organs of the treated mice showed no evidence of systemic toxicity associated with these QDs. These experiments suggest that cRGD-conjugated NIR QDs can serve as safe and efficient probes for optical bioimaging of tumors in vivo. Furthermore, by co-encapsulating these QDs and anticancer drugs within these micelles, we have demonstrated a promising theranostic, nanosized platform for both cancer imaging and therapy.

  12. A mutagenesis-derived Lrp5 mouse mutant with abnormal retinal vasculature and low bone mineral density

    PubMed Central

    Charette, Jeremy R.; Earp, Sarah E.; Bell, Brent A.; Ackert-Bicknell, Cheryl L.; Godfrey, Dana A.; Rao, Sujata; Anand-Apte, Bela; Nishina, Patsy M.

    2017-01-01

    Purpose Familial exudative vitreoretinopathy (FEVR) is caused by mutations in the genes encoding low-density lipoprotein receptor-related protein (LRP5) or its interacting partners, namely frizzled class receptor 4 (FZD4) and norrin cystine knot growth factor (NDP). Mouse models for Lrp5, Fzd4, and Ndp have proven to be important for understanding the retinal pathophysiology underlying FEVR and systemic abnormalities related to defective Wnt signaling. Here, we report a new mouse mutant, tvrm111B, which was identified by electroretinogram (ERG) screening of mice generated in the Jackson Laboratory Translational Vision Research Models (TVRM) mutagenesis program. Methods ERGs were used to examine outer retinal physiology. The retinal vasculature was examined by in vivo retinal imaging, as well as by histology and immunohistochemistry. The tvrm111B locus was identified by genetic mapping of mice generated in a cross to DBA/2J, and subsequent sequencing analysis. Gene expression was examined by real-time PCR of retinal RNA. Bone mineral density (BMD) was examined by peripheral dual-energy X-ray absorptiometry. Results The tvrm111B allele is inherited as an autosomal recessive trait. Genetic mapping of the decreased ERG b-wave phenotype of tvrm111B mice localized the mutation to a region on chromosome 19 that included Lrp5. Sequencing of Lrp5 identified the insertion of a cytosine (c.4724_4725insC), which is predicted to cause a frameshift that disrupts the last three of five conserved PPPSPxS motifs in the cytoplasmic domain of LRP5, culminating in a premature termination. In addition to a reduced ERG b-wave, Lrp5tvrm111B homozygotes have low BMD and abnormal features of the retinal vasculature that have been reported previously in Lrp5 mutant mice, including persistent hyaloid vessels, leakage on fluorescein angiography, and an absence of the deep retinal capillary bed. Conclusions The phenotype of the Lrp5tvrm111B mutant includes abnormalities of the retinal

  13. Vasculature segmentation for radio frequency ablation of non-resectable hepatic tumors

    NASA Astrophysics Data System (ADS)

    Hemler, Paul F.; McCreedy, Evan S.; Cheng, Ruida; Wood, Brad; McAuliffe, Matthew J.

    2006-03-01

    In Radio Frequency Ablation (RFA) procedures, hepatic tumor tissue is heated to a temperature where necrosis is insured. Unfortunately, recent results suggest that heating tumor tissue to necrosis is complicated because nearby major blood vessels provide a cooling effect. Therefore, it is fundamentally important for physicians to perform a careful analysis of the spatial relationship of diseased tissue to larger liver blood vessels. The liver contains many of these large vessels, which affect the RFA ablation shape and size. There are many sophisticated vasculature detection and segmentation techniques reported in the literature that identify continuous vessels as the diameter changes size and it transgresses through many bifurcation levels. However, the larger blood vessels near the treatment area are the only vessels required for proper RFA treatment plan formulation and analysis. With physician guidance and interaction, our system can segment those vessels which are most likely to affect the RFA ablations. We have found that our system provides the physician with therapeutic, geometric and spatial information necessary to accurately plan treatment of tumors near large blood vessels. The segmented liver vessels near the treatment region are also necessary for computing isolevel heating profiles used to evaluate different proposed treatment configurations.

  14. Pigment epithelium-derived factor enhances tumor response to radiation through vasculature normalization in allografted lung cancer in mice.

    PubMed

    Xu, Z; Dong, Y; Peng, F; Yu, Z; Zuo, Y; Dai, Z; Chen, Y; Wang, J; Hu, X; Zhou, Q; Ma, H; Bao, Y; Gao, G; Chen, M

    2015-03-01

    This study aimed to explore the potential therapeutic effects of the combination of pigment epithelium-derived factor (PEDF) and radiation on lung cancer. The Lewis lung cancer (LLC) allografts in nude mice were treated with radiation, PEDF and PEDF combined with radiation. The morphologic changes of tumor vasculature and the hypoxic fraction of tumor tissues were evaluated. Significant inhibition of tumor growth was observed when radiation was applied between the 3rd and 7th day (the vasculature normalization window) after the initiation of PEDF treatment. During the vasculature normalization window, the tumor blood vessels in PEDF-treated mice were less tortuous and more uniform than those in the LLC allograft tumor treated with phosphate-buffered saline. Meanwhile, the thickness of the basement membrane was remarkably reduced and pericyte coverage was significantly increased with the PEDF treatment. We also found that tumor hypoxic fraction decreased during the 3rd to the 7th day after PEDF treatment, suggesting improved intratumoral oxygenation. Taken together, our results show that PEDF improved the effects of radiation therapy on LLC allografts by inducing a vascular normalization window from the 3rd to the 7th day after PEDF treatment. Our findings provide a basis for treating lung cancer with the combination of PEDF and radiation.

  15. Functional Response of Tumor Vasculature to PaCO2: Determination of Total and Microvascular Blood Volume by MRI

    PubMed Central

    Packard, Scott D; Mandeville, Joseph B; Ichikawa, Tomotsugu; Ikeda, Keiro; Terada, Kinya; Niloff, Stephanie; Chiocca, E Antonio; Rosen, Bruce R; Marota, John J A

    2003-01-01

    Abstract In order to identify differences in functional activity, we compared the reactivity of glioma vasculature and the native cerebral vasculature to both dilate and constrict in response to altered PaCO2. Gliomas were generated by unilateral implantation of U87MGdEGFR human glioma tumor cells into the striatum of adult female athymic rats. Relative changes in total and microvascular cerebral blood volume were determined by steady state contrast agent-enhanced magnetic resonance imaging for transitions from normocarbia to hypercarbia and hypocarbia. Although hypercarbia induced a significant increase in both total and microvascular blood volume in normal brain and glioma, reactivity of glioma vasculature was significantly blunted in comparison to normal striatum; glioma total CBV increased by 0.6±0.1% / mm Hg CO2 whereas normal striatum increased by 1.5±0.2%/ mm Hg CO2, (P < .0001, group t-test). Reactivity of microvascular blood volume was also significantly blunted. In contrast, hypocarbia decreased both total and microvascular blood volumes more in glioma than in normal striatum. These results indicate that cerebral blood vessels derived by tumor-directed angiogenesis do retain reactivity to CO2. Furthermore, reduced reactivity of tumor vessels to a single physiological perturbation, such as hypercarbia, should not be construed as a generalized reduction of functional activity of the tumor vascular bed. PMID:14511404

  16. Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases.

    PubMed

    Gil, Margaret; Seshadri, Mukund; Komorowski, Marcin P; Abrams, Scott I; Kozbor, Danuta

    2013-04-02

    Oncolytic viruses hold promise for the treatment of cancer, but their interaction with the tumor microenvironment needs to be elucidated for optimal tumor cell killing. Because the CXCR4 receptor for the stromal cell-derived factor-1 (SDF-1/CXCL12) chemokine is one of the key stimuli involved in signaling interactions between tumor cells and their stromal microenvironment, we used oncolytic virotherapy with a CXCR4 antagonist to target the CXCL12/CXCR4 signaling axis in a triple-negative 4T1 breast carcinoma in syngeneic mice. We show here that CXCR4 antagonist expression from an oncolytic vaccinia virus delivered intravenously to mice with orthotopic tumors attains higher intratumoral concentration than its soluble counterpart and exhibits increased efficacy over that mediated by oncolysis alone. A systemic delivery of the armed virus after resection of the primary tumor was efficacious in inhibiting the development of spontaneous metastasis and increased overall tumor-free survival. Inhibition of tumor growth with the armed virus was associated with destruction of tumor vasculature, reductions in expression of CXCL12 and VEGF, and decrease in intratumoral numbers of bone marrow-derived endothelial and myeloid cells. These changes led to induction of antitumor antibody responses and resistance to tumor rechallenge. Engineering an oncolytic virus armed with a CXCR4 antagonist represents an innovative strategy that targets multiple elements within the tumor microenvironment. As such, this approach could have a significant therapeutic impact against primary and metastatic breast cancer.

  17. Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activation

    PubMed Central

    Wang, Yurong; Wang, Bin; Guerram, Mounia; Sun, Li; Shi, Wei; Tian, Chongchong; Zhu, Xiong; Jiang, Zhenzhou; Zhang, Luyong

    2015-01-01

    Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer. PMID:26470595

  18. Using Fractal Geometry and Universal Growth Curves as Diagnostics for Comparing Tumor Vasculature and Metabolic Rate With Healthy Tissue and for Predicting Responses to Drug Therapies.

    PubMed

    Savage, Van M; Herman, Alexander B; West, Geoffrey B; Leu, Kevin

    2013-06-01

    Healthy vasculature exhibits a hierarchical branching structure in which, on average, vessel radius and length change systematically with branching order. In contrast, tumor vasculature exhibits less hierarchy and more variability in its branching patterns. Although differences in vasculature have been highlighted in the literature, there has been very little quantification of these differences. Fractal analysis is a natural tool for comparing tumor and healthy vasculature, especially because it has already been used extensively to model healthy tissue. In this paper, we provide a fractal analysis of existing vascular data, and we present a new mathematical framework for predicting tumor growth trajectories by coupling: (1) the fractal geometric properties of tumor vascular networks, (2) metabolic properties of tumor cells and host vascular systems, and (3) spatial gradients in resources and metabolic states within the tumor. First, we provide a new analysis for how the mean and variation of scaling exponents for ratios of vessel radii and lengths in tumors differ from healthy tissue. Next, we use these characteristic exponents to predict metabolic rates for tumors. Finally, by combining this analysis with general growth equations based on energetics, we derive universal growth curves that enable us to compare tumor and ontogenetic growth. We also extend these growth equations to include necrotic, quiescent, and proliferative cell states and to predict novel growth dynamics that arise when tumors are treated with drugs. Taken together, this mathematical framework will help to anticipate and understand growth trajectories across tumor types and drug treatments.

  19. Photodynamic Therapy Induced Enhancement of Tumor Vasculature Permeability Using an Upconversion Nanoconstruct for Improved Intratumoral Nanoparticle Delivery in Deep Tissues

    PubMed Central

    Gao, Weidong; Wang, Zhaohui; Lv, Liwei; Yin, Deyan; Chen, Dan; Han, Zhihao; Ma, Yi; Zhang, Min; Yang, Man; Gu, Yueqing

    2016-01-01

    Photodynamic therapy (PDT) has recently emerged as an approach to enhance intratumoral accumulation of nanoparticles. However, conventional PDT is greatly limited by the inability of the excitation light to sufficiently penetrate tissue, rendering PDT ineffective in the relatively deep tumors. To address this limitation, we developed a novel PDT platform and reported for the first time the effect of deep-tissue PDT on nanoparticle uptake in tumors. This platform employed c(RGDyK)-conjugated upconversion nanoparticles (UCNPs), which facilitate active targeting of the nanoconstruct to tumor vasculature and achieve the deep-tissue photosensitizer activation by NIR light irradiation. Results indicated that our PDT system efficiently enhanced intratumoral uptake of different nanoparticles in a deep-seated tumor model. The optimal light dose for deep-tissue PDT (34 mW/cm2) was determined and the most robust permeability enhancement was achieved by administering the nanoparticles within 15 minutes following PDT treatment. Further, a two-step treatment strategy was developed and validated featuring the capability of improving the therapeutic efficacy of Doxil while simultaneously reducing its cardiotoxicity. This two-step treatment resulted in a tumor inhibition rate of 79% compared with 56% after Doxil treatment alone. These findings provide evidence in support of the clinical application of deep-tissue PDT for enhanced nano-drug delivery. PMID:27279907

  20. Importance of the interaction between immune cells and tumor vasculature mediated by thalidomide in cancer treatment (Review).

    PubMed

    Wang, Xin; Shen, Yanwei; Li, Shuting; Lv, Meng; Zhang, Xiaoman; Yang, Jiao; Wang, Fan; Yang, Jin

    2016-10-01

    Over the past 60 years, thalidomide has metamorphosized from a drug prescribed to treat morning sickness in pregnant women, which was subsequently found to induce birth defects, into a highly effective therapy for treating leprosy and multiple myeloma. Several mechanisms have been proposed to explain the anticancer effects of thalidomide, including antiangiogenic and immunomodulatory activities. At present, evidence suggests that thalidomide may induce vessel maturation. Vascular normalization may be an effective strategy to enhance cancer immunotherapy. Numerous studies have shown that the tumor infiltrating immune cell subsets are important in regulating the process of tumor angiogenesis. The mechanisms associated with antiangiogenesis and the potent immunomodulatory effects of thalidomide obtained the most support. The studies of the antiangiogenic activity of thalidomide were guided in a novel direction by a hypothesis regarding the vascular normalization of tumors. Hence, thalidomide is effective in cancer treatment due to the interaction between immune cells and tumor vasculature. This mechanism provides new avenues to explore for the treatment of cancer.

  1. Effects of Irradiation on Brain Vasculature Using an In Situ Tumor Model

    SciTech Connect

    Zawaski, Janice A.; Gaber, M. Waleed; Sabek, Omaima M.; Wilson, Christy M.; Duntsch, Christopher D.; Merchant, Thomas E.

    2012-03-01

    Purpose: Damage to normal tissue is a limiting factor in clinical radiotherapy (RT). We tested the hypothesis that the presence of tumor alters the response of normal tissues to irradiation using a rat in situ brain tumor model. Methods and Materials: Intravital microscopy was used with a rat cranial window to assess the in situ effect of rat C6 glioma on peritumoral tissue with and without RT. The RT regimen included 40 Gy at 8 Gy/day starting Day 5 after tumor implant. Endpoints included blood-brain barrier permeability, clearance index, leukocyte-endothelial interactions and staining for vascular endothelial growth factor (VEGF) glial fibrillary acidic protein, and apoptosis. To characterize the system response to RT, animal survival and tumor surface area and volume were measured. Sham experiments were performed on similar animals implanted with basement membrane matrix absent of tumor cells. Results: The presence of tumor alone increases permeability but has little effect on leukocyte-endothelial interactions and astrogliosis. Radiation alone increases tissue permeability, leukocyte-endothelial interactions, and astrogliosis. The highest levels of permeability and cell adhesion were seen in the model that combined tumor and irradiation; however, the presence of tumor appeared to reduce the volume of rolling leukocytes. Unirradiated tumor and peritumoral tissue had poor clearance. Irradiated tumor and peritumoral tissue had a similar clearance index to irradiated and unirradiated sham-implanted animals. Radiation reduces the presence of VEGF in peritumoral normal tissues but did not affect the amount of apoptosis in the normal tissue. Apoptosis was identified in the tumor tissue with and without radiation. Conclusions: We developed a novel approach to demonstrate that the presence of the tumor in a rat intracranial model alters the response of normal tissues to irradiation.

  2. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors

    PubMed Central

    Bergers, Gabriele; Song, Steven; Meyer-Morse, Nicole; Bergsland, Emily; Hanahan, Douglas

    2003-01-01

    Functions of receptor tyrosine kinases implicated in angiogenesis were pharmacologically impaired in a mouse model of pancreatic islet cancer. An inhibitor targeting VEGFRs in endothelial cells (SU5416) is effective against early-stage angiogenic lesions, but not large, well-vascularized tumors. In contrast, a kinase inhibitor incorporating selectivity for PDGFRs (SU6668) is shown to block further growth of end-stage tumors, eliciting detachment of pericytes and disruption of tumor vascularity. Importantly, PDGFRs were expressed only in perivascular cells of this tumor type, suggesting that PDGFR+ pericytes in tumors present a complimentary target to endothelial cells for efficacious antiangiogenic therapy. Therapeutic regimes combining the two kinase inhibitors (SU5416 and SU6668) were more efficacious against all stages of islet carcinogenesis than either single agent. Combination of the VEGFR inhibitor with another distinctive kinase inhibitor targeting PDGFR activity (Gleevec) was also able to regress late-stage tumors. Thus, combinatorial targeting of receptor tyrosine kinases shows promise for treating multiple stages in tumorigenesis, most notably the often-intractable late-stage solid tumor. PMID:12727920

  3. Single-Walled Carbon Nanotubes Targeted to the Tumor Vasculature for Breast Cancer Treatment

    DTIC Science & Technology

    2008-09-01

    plastic-immobilized phosphatidylserine ( PS ). Annexin V was conjugated with a suspension of single-walled carbon nanotubes (SWNTs) and carboxymethyl...of this complex to human endothelial cells with PS exposed on the cell surface showed strong binding, indicating that the covalently bound annexin V...been shown to bind to phospohatidylserine ( PS ) exposed on the surface of endothelial cells in blood vessels in tumors; PS is not exposed on the

  4. Genetic abnormality predicts benefit for a rare brain tumor

    Cancer.gov

    A clinical trial has shown that addition of chemotherapy to radiation therapy leads to a near doubling of median survival time in patients with a form of brain tumor (oligodendroglioma) that carries a chromosomal abnormality called the 1p19q co-deletion.

  5. CA-1H, a novel oxazole bearing analogue of combretastatin A-4, disrupts the tumor vasculatures and inhibits the tumor growth via inhibiting tubulin polymerization.

    PubMed

    Han, Fuguo; Wang, Peng; Zhang, Wei; Li, Jing; Zhang, Qun; Qi, Xin; Liu, Ming

    2016-05-01

    Vascular disrupting agents destroy established tumor vasculatures selectively, and have achieved encouraging antitumor activity in both pre-clinical and clinical trials. In the present study, we reported the vascular disruption and antitumor effects of CA-1H and its prodrug CA-1HP, oxazole bearing analogues of combretastatin A-4 (CA4). CA-1H was a tighter binder of tubulin than CA4 with the same binding site to chochcine and CA4, and inhibited tubulin polymerization both in cell free system and in human umbilical vein endothelial cells (HUVECs). Furthermore, CA-1H significantly disrupted the microtubulin skeleton in proliferating HUVECs rather than the quiescent ones, damaged the HUVECs-preformed tubes markedly, and lead to necrosis in tumor tissues in NCI-H1975 xenograft mice. Continuous administration for 19 days, CA-1HP could inhibit the NCI-H1975 xenograft tumor growth significantly without obvious weight loss and normal tissue damage, in addition, CA-1HP also inhibited the tumor growth in H22 hepatocellular carcinoma bearing mice; and combination CA-1HP with cisplatin showed more potent antitumor activity than used alone. Taken together, our present investigation suggested that CA-1H was a potential vascular disrupting agent for further development of antitumor drugs.

  6. RGD-conjugated Two-photon Absorbing Near-IR Emitting Fluorescent Probes for Tumor Vasculature Imaging

    PubMed Central

    Yue, Xiling; Morales, Alma R.; Githaiga, Grace W.; Woodward, Adam W.; Tang, Simon; Sawada, Junko; Komatsu, Masanobu; Liu, Xuan; Belfield, Kevin D.

    2015-01-01

    Observation of the activation and inhibition of angiogenesis processes is important in the progression of cancer. Application of targeting peptides, such as a small peptide that contains adjacent L-arginine (R), glycine (G) and L-aspartic acid (D) residues can afford high selectivity and deep penetration in vessel imaging. To facilitate deep tissue vasculature imaging, probes that can be excited via two-photon absorption (2PA) in the near-infrared (NIR) and subsequently emit in the NIR are essential. In this study, the enhancement of tissue image quality with RGD conjugates was investigated with new NIR-emitting pyranyl fluorophore derivatives in two-photon fluorescence microscopy. Linear and nonlinear photophysical properties of the new probes were comprehensively characterized; significantly the probes exhibited good 2PA over a broad spectral range from 700–1100 nm. Cell and tissue images were then acquired and examined, revealing deep penetration and high contrast with the new pyranyl RGD-conjugates up to 350 μm in tumor tissue. PMID:26351137

  7. Optimization of the dorsal skinfold window chamber model and multi-parametric characterization of tumor-associated vasculature

    PubMed Central

    Maeda, Azusa; DaCosta, Ralph S

    2014-01-01

    The dorsal skinfold window chamber (DSWC) model is a unique tool that enables analysis of various aspects of tumor biology and therapeutic response. Although the protocol for the murine DSWC model is standardized, certain tumors fail to grow or require a particular environment to promote growth. Given such limitations, we optimized the DSWC model for a slow-growing tumor that regresses spontaneously in the standard protocol. We further characterized the vascular network in the tumor model compared with that of non-tumor-bearing mice and observed significant differences in multiple parameters related to vascular structure and function. PMID:28243506

  8. Inhibition of Vascular Endothelial Growth Factor A and Hypoxia-Inducible Factor 1α Maximizes the Effects of Radiation in Sarcoma Mouse Models Through Destruction of Tumor Vasculature

    SciTech Connect

    Lee, Hae-June; Yoon, Changhwan; Park, Do Joong; Kim, Yeo-Jung; Schmidt, Benjamin; Lee, Yoon-Jin; Tap, William D.; Eisinger-Mathason, T.S. Karin; Choy, Edwin; Kirsch, David G.; Simon, M. Celeste; and others

    2015-03-01

    Purpose: To examine the addition of genetic or pharmacologic inhibition of hypoxia-inducible factor 1α (HIF-1α) to radiation therapy (RT) and vascular endothelial growth factor A (VEGF-A) inhibition (ie trimodality therapy) for soft-tissue sarcoma. Methods and Materials: Hypoxia-inducible factor 1α was inhibited using short hairpin RNA or low metronomic doses of doxorubicin, which blocks HIF-1α binding to DNA. Trimodality therapy was examined in a mouse xenograft model and a genetically engineered mouse model of sarcoma, as well as in vitro in tumor endothelial cells (ECs) and 4 sarcoma cell lines. Results: In both mouse models, any monotherapy or bimodality therapy resulted in tumor growth beyond 250 mm{sup 3} within the 12-day treatment period, but trimodality therapy with RT, VEGF-A inhibition, and HIF-1α inhibition kept tumors at <250 mm{sup 3} for up to 30 days. Trimodality therapy on tumors reduced HIF-1α activity as measured by expression of nuclear HIF-1α by 87% to 95% compared with RT alone, and cytoplasmic carbonic anhydrase 9 by 79% to 82%. Trimodality therapy also increased EC-specific apoptosis 2- to 4-fold more than RT alone and reduced microvessel density by 75% to 82%. When tumor ECs were treated in vitro with trimodality therapy under hypoxia, there were significant decreases in proliferation and colony formation and increases in DNA damage (as measured by Comet assay and γH2AX expression) and apoptosis (as measured by cleaved caspase 3 expression). Trimodality therapy had much less pronounced effects when 4 sarcoma cell lines were examined in these same assays. Conclusions: Inhibition of HIF-1α is highly effective when combined with RT and VEGF-A inhibition in blocking sarcoma growth by maximizing DNA damage and apoptosis in tumor ECs, leading to loss of tumor vasculature.

  9. A novel model for evaluating therapies targeting human tumor vasculature and human cancer stem-like cells

    PubMed Central

    Burgos-Ojeda, Daniela; McLean, Karen; Bai, Shoumei; Pulaski, Heather; Gong, Yusong; Silva, Ines; Skorecki, Karl; Tzukerman, Maty; Buckanovich, Ronald J.

    2013-01-01

    Human tumor vessels express tumor vascular markers (TVMs), proteins that are not expressed in normal blood vessels. Antibodies targeting TVMs could act as potent therapeutics. Unfortunately, preclinical in vivo studies testing anti-human TVM therapies have been difficult to perform due to a lack of in vivo models with confirmed expression of human TVMs. We therefore evaluated TVM expression in a human embryonic stem cell derived teratoma (hESCT) tumor model previously shown to have human vessels. We now report that, in the presence of tumor cells, hESCT tumor vessels express human TVMs. The addition of mouse embryonic fibroblasts and human tumor endothelial cells significantly increases the number of human tumor vessels. TVM induction is mostly tumor type specific with ovarian cancer cells inducing primarily ovarian TVMs while breast cancer cells induce breast cancer specific TVMs. We demonstrate the utility of this model to test an anti-human specific TVM immunotherapeutics; anti-human Thy-1 TVM immunotherapy results in central tumor necrosis and a three-fold reduction in human tumor vascular density. Finally, we tested the ability of the hESCT model, with human tumor vascular niche, to enhance the engraftment rate of primary human ovarian cancer stem-like cells (CSC). ALDH+ CSC from patients (n=6) engrafted in hESCT within 4–12 weeks whereas none engrafted in the flank. ALDH- ovarian cancer cells showed no engraftment in the hESCT or flank (n=3). Thus this model represents a useful tool to test anti-human TVM therapy and evaluate in vivo human CSC tumor biology. PMID:23576551

  10. In vivo characterization of tumor vasculature using iodine and gold nanoparticles and dual energy micro-CT

    NASA Astrophysics Data System (ADS)

    Clark, Darin P.; Ghaghada, Ketan; Moding, Everett J.; Kirsch, David G.; Badea, Cristian T.

    2013-03-01

    Tumor blood volume and vascular permeability are well established indicators of tumor angiogenesis and important predictors in cancer diagnosis, planning and treatment. In this work, we establish a novel preclinical imaging protocol which allows quantitative measurement of both metrics simultaneously. First, gold nanoparticles are injected and allowed to extravasate into the tumor, and then liposomal iodine nanoparticles are injected. Combining a previously optimized dual energy micro-CT scan using high-flux polychromatic x-ray sources (energies: 40 kVp, 80 kVp) with a novel post-reconstruction spectral filtration scheme, we are able to decompose the results into 3D iodine and gold maps, allowing simultaneous measurement of extravasated gold and intravascular iodine concentrations. Using a digital resolution phantom, the mean limits of detectability (mean CNR = 5) for each element are determined to be 2.3 mg mL-1 (18 mM) for iodine and 1.0 mg mL-1 (5.1 mM) for gold, well within the observed in vivo concentrations of each element (I: 0-24 mg mL-1, Au: 0-9 mg mL-1) and a factor of 10 improvement over the limits without post-reconstruction spectral filtration. Using a calibration phantom, these limits are validated and an optimal sensitivity matrix for performing decomposition using our micro-CT system is derived. Finally, using a primary mouse model of soft-tissue sarcoma, we demonstrate the in vivo application of the protocol to measure fractional blood volume and vascular permeability over the course of five days of active tumor growth.

  11. Delivery of kinesin spindle protein targeting siRNA in solid lipid nanoparticles to cellular models of tumor vasculature

    SciTech Connect

    Ying, Bo; Campbell, Robert B.

    2014-04-04

    Highlights: • siRNA-lipid nanoparticles are solid particles not lipid bilayers with aqueous core. • High, but not low, PEG content can prevent nanoparticle encapsulation of siRNA. • PEG reduces cellular toxicity of cationic nanoparticles in vitro. • PEG reduces zeta potential while improving gene silencing of siRNA nanoparticles. • Kinesin spindle protein can be an effective target for tumor vascular targeting. - Abstract: The ideal siRNA delivery system should selectively deliver the construct to the target cell, avoid enzymatic degradation, and evade uptake by phagocytes. In the present study, we evaluated the importance of polyethylene glycol (PEG) on lipid-based carrier systems for encapsulating, and delivering, siRNA to tumor vessels using cellular models. Lipid nanoparticles containing different percentage of PEG were evaluated based on their physical chemical properties, density compared to water, siRNA encapsulation, toxicity, targeting efficiency and gene silencing in vitro. siRNA can be efficiently loaded into lipid nanoparticles (LNPs) when DOTAP is included in the formulation mixture. However, the total amount encapsulated decreased with increase in PEG content. In the presence of siRNA, the final formulations contained a mixed population of particles based on density. The major population which contains the majority of siRNA exhibited a density of 4% glucose, and the minor fraction associated with a decreased amount of siRNA had a density less than PBS. The inclusion of 10 mol% PEG resulted in a greater amount of siRNA associated with the minor fraction. Finally, when kinesin spindle protein (KSP) siRNA was encapsulated in lipid nanoparticles containing a modest amount of PEG, the proliferation of endothelial cells was inhibited due to the efficient knock down of KSP mRNA. The presence of siRNA resulted in the formation of solid lipid nanoparticles when prepared using the thin film and hydration method. LNPs with a relatively modest amount of

  12. Hypoxia-Induced Reactive Oxygen Species Cause Chromosomal Abnormalities in Endothelial Cells in the Tumor Microenvironment

    PubMed Central

    Hida, Yasuhiro; Maishi, Nako; Towfik, Alam Mohammad; Inoue, Nobuo; Shindoh, Masanobu; Hida, Kyoko

    2013-01-01

    There is much evidence that hypoxia in the tumor microenvironment enhances tumor progression. In an earlier study, we reported abnormal phenotypes of tumor-associated endothelial cells such as those resistant to chemotherapy and chromosomal instability. Here we investigated the role of hypoxia in the acquisition of chromosomal abnormalities in endothelial cells. Tumor-associated endothelial cells isolated from human tumor xenografts showed chromosomal abnormalities, >30% of which were aneuploidy. Aneuploidy of the tumor-associated endothelial cells was also shown by simultaneous in-situ hybridization for chromosome 17 and by immunohistochemistry with anti-CD31 antibody for endothelial staining. The aneuploid cells were surrounded by a pimonidazole-positive area, indicating hypoxia. Human microvascular endothelial cells expressed hypoxia-inducible factor 1 and vascular endothelial growth factor A in response to either hypoxia or hypoxia-reoxygenation, and in these conditions, they acquired aneuploidy in 7 days. Induction of aneuploidy was inhibited by either inhibition of vascular endothelial growth factor signaling with vascular endothelial growth factor receptor 2 inhibitor or by inhibition of reactive oxygen species by N-acetyl-L-cysteine. These results indicate that hypoxia induces chromosomal abnormalities in endothelial cells through the induction of reactive oxygen species and excess signaling of vascular endothelial growth factor in the tumor microenvironment. PMID:24260373

  13. Complexity analysis of angiogenesis vasculature

    NASA Astrophysics Data System (ADS)

    Mahadevan, Vijay; Tyrell, James A.; Tong, Ricky T.; Brown, Edward B.; Jain, Rakesh K.; Roysam, Badrinath

    2005-04-01

    Tumor vasculature has a high degree of irregularity as compared to normal vasculature. The quantification of the morphometric complexity in tumor images can be useful in diagnosis. Also, it is desirable in several other medical applications to have an automated complexity analysis to aid in diagnosis and prognosis under treatment. e.g. in diabetic retinopathy and in arteriosclerosis. In addition, prior efforts at segmentation of the tumor vasculature using matched filtering, template matching and splines have been hampered by the irregularity of these vessels. We try to solve both problems by introducing a novel technique for vessel detection, followed by a tracing-independent complexity analysis based on a combination of ideas. First, the vessel cross-sectional profile is modeled using a continuous and everywhere differentiable family of super-Gaussian curves. This family generates rectangular profiles that can accurately localize the vessel boundaries in microvasculature images. Second, a robust non-linear regression algorithm based on M-estimators is used to estimate the parameters that optimally characterize the vessel"s shape. A framework for the quantitative analysis of the complexity of the vasculature based on the vessel detection is presented. A set of measures that quantify the complexity are proposed viz. Squared Error, Entropy-based and Minimum Description Length-based Shape Complexities. They are completely automatic and can deal with complexities of the entire vessel unlike existing tortuousity measures which deal only with vessel centerlines. The results are validated using carefully constructed phantom and real image data with ground truth information from an expert observer.

  14. High expression of prostate-specific membrane antigen in the tumor-associated neo-vasculature is associated with worse prognosis in squamous cell carcinoma of the oral cavity.

    PubMed

    Haffner, Michael C; Laimer, Johannes; Chaux, Alcides; Schäfer, Georg; Obrist, Peter; Brunner, Andrea; Kronberger, Irmgard E; Laimer, Klaus; Gurel, Bora; Koller, Johann-Benedikt; Seifarth, Christof; Zelger, Bettina; Klocker, Helmut; Rasse, Michael; Doppler, Wolfgang; Bander, Neil H

    2012-08-01

    Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in prostate cancer as well as in the neo-vasculature of nonprostatic solid tumors. Here, we determined the expression pattern of PSMA in the vasculature of oral squamous cell carcinoma. Using a previously validated antibody, PSMA staining distribution and cyclooxygenase 2 (COX2) expression status was evaluated in a cohort of patients with squamous cell carcinoma of the oral cavity (n=96) using immunohistochemistry and was correlated with clinicopathological features as well as outcome. Twenty-four (25%) cases showed no detectable PSMA staining, 48 (50%) demonstrated positive immunoreactivity for PSMA in less than 50% of microvessels and 24 (25%) cases showed strong endothelial PSMA expression in more than 50% of tumor-associated microvessels. High endothelial PSMA expression was associated with greatly reduced survival (18.2 vs 77.3 months; P=0.0001) and maintained prognostic significance after adjusting for grade and stage in multivariate analysis (hazard ratio=2.19, P=0.007). Furthermore, we observed a strong association between endothelial PSMA and cancer cell-specific COX2 expression. In conclusion, we provide the first evidence for the prognostic significance of endothelial PSMA expression in oral squamous cell carcinoma and, suggest a potential interaction between arachidonic acid metabolites and endothelial PSMA expression in the tumor neo-vasculature.

  15. Gpr177 regulates pulmonary vasculature development.

    PubMed

    Jiang, Ming; Ku, Wei-yao; Fu, Jiang; Offermanns, Stefan; Hsu, Wei; Que, Jianwen

    2013-09-01

    Establishment of the functional pulmonary vasculature requires intimate interaction between the epithelium and mesenchyme. Previous genetic studies have led to inconsistent conclusions about the contribution of epithelial Wnts to pulmonary vasculature development. This discrepancy is possibly due to the functional redundancy among different Wnts. Here, we use Shh-Cre to conditionally delete Gpr177 (the mouse ortholog of Drosophila Wntless, Wls), a chaperon protein important for the sorting and secretion of Wnt proteins. Deletion of epithelial Gpr177 reduces Wnt signaling activity in both the epithelium and mesenchyme, resulting in severe hemorrhage and abnormal vasculature, accompanied by branching defects and abnormal epithelial differentiation. We then used multiple mouse models to demonstrate that Wnt/β-catenin signaling is not only required for the proliferation and differentiation of mesenchyme, but also is important for the maintenance of smooth muscle cells through the regulation of the transcription factor Kruppel-like factor 2 (Klf2). Together, our studies define a novel mechanism by which epithelial Wnts regulate the normal development and maintenance of pulmonary vasculature. These findings provide insight into the pathobiology of congenital lung diseases, such as alveolar capillary dysplasia (ACD), that have abnormal alveolar development and dysmorphic pulmonary vasculature.

  16. Bilaterally Abnormal Head Impulse Tests Indicate a Large Cerebellopontine Angle Tumor

    PubMed Central

    Kim, Hyo-Jung; Park, Seong-Ho; Koo, Ja Won; Kim, Chae-Yong; Kim, Young-Hoon; Han, Jung Ho

    2016-01-01

    Background and Purpose Tumors involving the cerebellopontine angle (CPA) pose a diagnostic challenge due to their diverse manifestations. Head impulse tests (HITs) have been used to evaluate vestibular function, but few studies have explored the head impulse gain of the vestibulo-ocular reflex (VOR) in patients with a vestibular schwannoma. This study tested whether the head impulse gain of the VOR is an indicator of the size of a unilateral CPA tumor. Methods Twenty-eight patients (21 women; age=64±12 years, mean±SD) with a unilateral CPA tumor underwent a recording of the HITs using a magnetic search coil technique. Patients were classified into non-compressing (T1-T3) and compressing (T4) groups according to the Hannover classification. Results Most (23/28, 82%) of the patients showed abnormal HITs for the semicircular canals on the lesion side. The bilateral abnormality in HITs was more common in the compressing group than the non-compressing group (80% vs. 8%, Pearson's chi-square test: p<0.001). The tumor size was inversely correlated with the head impulse gain of the VOR in either direction. Conclusions Bilaterally abnormal HITs indicate that a patient has a large unilateral CPA tumor. The abnormal HITs in the contralesional direction may be explained either by adaptation or by compression and resultant dysfunction of the cerebellar and brainstem structures. The serial evaluation of HITs may provide information on tumor growth, and thereby reduce the number of costly brain scans required when following up patients with CPA tumors. PMID:26754780

  17. Carney triad, SDH-deficient tumors, and Sdhb+/- mice share abnormal mitochondria.

    PubMed

    Szarek, Eva; Ball, Evan R; Imperiale, Alessio; Tsokos, Maria; Faucz, Fabio R; Giubellino, Alessio; Moussallieh, François-Marie; Namer, Izzie-Jacques; Abu-Asab, Mones S; Pacak, Karel; Taïeb, David; Carney, J Aidan; Stratakis, Constantine A

    2015-06-01

    Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr. For the present study, we examined mitochondrial structure in human tumors and GI tissue (GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), those with isolated GIST (n=1), and those with CSS caused by SDHC (n=1) and SDHD (n=2) mutations were studied by electron microscopy (EM). Samples of GIT from mice with a heterozygous deletion in Sdhb (Sdhb(+) (/-), n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located, round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GISTs of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained an increased number of mitochondria with a 'hypoxic' phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities, and were of variable size. Occasionally, mitochondria were small and round; rarely, they were thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. A similar mitochondrial hypoxic phenotype was seen in Sdhb(+) (/-) mice. We concluded that tissues from SDH-deficient tumors, those from mouse GIT, and those from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still-elusive CTr defect(s) is(are) likely to affect mitochondrial function

  18. Genetic determinants of hyaloid and retinal vasculature in zebrafish

    PubMed Central

    Alvarez, Yolanda; Cederlund, Maria L; Cottell, David C; Bill, Brent R; Ekker, Stephen C; Torres-Vazquez, Jesus; Weinstein, Brant M; Hyde, David R; Vihtelic, Thomas S; Kennedy, Breandan N

    2007-01-01

    Background The retinal vasculature is a capillary network of blood vessels that nourishes the inner retina of most mammals. Developmental abnormalities or microvascular complications in the retinal vasculature result in severe human eye diseases that lead to blindness. To exploit the advantages of zebrafish for genetic, developmental and pharmacological studies of retinal vasculature, we characterised the intraocular vasculature in zebrafish. Results We show a detailed morphological and developmental analysis of the retinal blood supply in zebrafish. Similar to the transient hyaloid vasculature in mammalian embryos, vessels are first found attached to the zebrafish lens at 2.5 days post fertilisation. These vessels progressively lose contact with the lens and by 30 days post fertilisation adhere to the inner limiting membrane of the juvenile retina. Ultrastructure analysis shows these vessels to exhibit distinctive hallmarks of mammalian retinal vasculature. For example, smooth muscle actin-expressing pericytes are ensheathed by the basal lamina of the blood vessel, and vesicle vacuolar organelles (VVO), subcellular mediators of vessel-retinal nourishment, are present. Finally, we identify 9 genes with cell membrane, extracellular matrix and unknown identity that are necessary for zebrafish hyaloid and retinal vasculature development. Conclusion Zebrafish have a retinal blood supply with a characteristic developmental and adult morphology. Abnormalities of these intraocular vessels are easily observed, enabling application of genetic and chemical approaches in zebrafish to identify molecular regulators of hyaloid and retinal vasculature in development and disease. PMID:17937808

  19. NORMALIZATION OF THE VASCULATURE FOR TREATMENT OF CANCER AND OTHER DISEASES

    PubMed Central

    Goel, Shom; Duda, Dan G.; Xu, Lei; Munn, Lance L.; Boucher, Yves; Fukumura, Dai; Jain, Rakesh K.

    2012-01-01

    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

  20. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors

    SciTech Connect

    Hua Chiaho; Wu Shengjie; Chemaitilly, Wassim; Lukose, Renin C.; Merchant, Thomas E.

    2012-11-15

    Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

  1. Prognostic value of serum tumor abnormal protein in gastric cancer patients

    PubMed Central

    LAN, FENG; ZHU, MING; QI, QIUFENG; ZHANG, YAPING; LIU, YONGPING

    2016-01-01

    Aberrant glycosylation of protein occurs in nearly all types of cancers and has been confirmed to be associated with tumor progression, metastasis and the survival rate of patients. The present study aimed to explore the prognostic value of tumor abnormal protein (TAP) in gastric cancer patients. TAP was detected in the blood of 42 gastric cancer patients and 56 healthy volunteers by using the TAP testing kit. Univariate and multivariate Cox regression analysis were performed to evaluate the prognostic value of TAP. In total, 64.3% of gastric cancer patients were positive for TAP, and TAP was significantly correlated with poor prognosis [progression-free survival (PFS), 4.2 vs. 12.6 months; P=0.043]. TAP [hazard ratio (HR), 64.487; P<0.01), differentiation (HR, 17.279; P<0.01) and TNM stage (HR, 45.480; P<0.01) were found to be independent predictive factors for PFS. Furthermore, Kaplan-Meier curves indicated that TAP is associated with a reduced PFS in gastric cancer patients. The results of the present study therefore indicated that the TAP test has significant prognostic value for gastric cancer patients. PMID:27330802

  2. Gold nanoparticles as high-resolution X-ray imaging contrast agents for the analysis of tumor-related micro-vasculature

    SciTech Connect

    Chien C.; Yong C.; Hsiang-Hsin, C.; Sheng-Feng, L.; Kang-Chao W.; Xiaoqing C.; Yeukuang, H.; Petibois, C.; Margaritondo, G.

    2012-03-12

    Angiogenesis is widely investigated in conjunction with cancer development, in particular because of the possibility of early stage detection and of new therapeutic strategies. However, such studies are negatively affected by the limitations of imaging techniques in the detection of microscopic blood vessels (diameter 3-5 {micro}m) grown under angiogenic stress. We report that synchrotron-based X-ray imaging techniques with very high spatial resolution can overcome this obstacle, provided that suitable contrast agents are used. We tested different contrast agents based on gold nanoparticles (AuNPs) for the detection of cancer-related angiogenesis by synchrotron microradiology, microtomography and high resolution X-ray microscopy. Among them only bare-AuNPs in conjunction with heparin injection provided sufficient contrast to allow in vivo detection of small capillary species (the smallest measured lumen diameters were 3-5 {micro}m). The detected vessel density was 3-7 times higher than with other nanoparticles. We also found that bare-AuNPs with heparin allows detecting symptoms of local extravascular nanoparticle diffusion in tumor areas where capillary leakage appeared. Although high-Z AuNPs are natural candidates as radiology contrast agents, their success is not guaranteed, in particular when targeting very small blood vessels in tumor-related angiography. We found that AuNPs injected with heparin produced the contrast level needed to reveal--for the first time by X-ray imaging--tumor microvessels with 3-5 {micro}m diameter as well as extravascular diffusion due to basal membrane defenestration. These results open the interesting possibility of functional imaging of the tumor microvasculature, of its development and organization, as well as of the effects of anti-angiogenic drugs.

  3. Characteristics of intraoperative abnormal hemodynamics during resection of an intra-fourth ventricular tumor located on the dorsal medulla oblongata.

    PubMed

    Ideguchi, Makoto; Kajiwara, Koji; Yoshikawa, Koichi; Sadahiro, Hirokazu; Nomura, Sadahiro; Fujii, Masami; Suzuki, Michiyasu

    2013-01-01

    Abnormal hemodynamics during extirpation of a para-medulla oblongata (MO) tumor is common and may be associated with direct vagal stimulation of the medullary circuit. However, resection of tumors on the dorsal MO may also induce hemodynamic instability without direct vagal stimulus. The objective of this study was to examine the characteristics of hemodynamic instability unrelated to vagal stimulus during dissection of an intra-fourth ventricular tumor with attachment to the dorsal MO. A retrospective analysis was performed in 13 patients. Abnormal hemodynamics were defined as a > 20% change from the means of the intraoperative mean arterial pressure (MAP) and heart rate (HR). Relationships of intraoperative hemodynamics were evaluated with various parameters, including the volume of the MO. Six patients (46.2%) had intraoperative hypertension during separation of the tumor bulk from the dorsal MO. The maximum MAP and HR in these patients were significantly greater than those in patients with normal hemodynamics (116.0 ± 18.0 mmHg versus 85.6 ± 6.5 mmHg; 124.3 ± 22.8 bpm versus 90.5 ± 14.7 bpm). All six cases with abnormal hemodynamics showed hemodynamic fluctuation during separation of the tumor bulk from the dorsal MO. The preoperative volume of the MO in these patients was 1.11 cc less than that in patients with normal hemodynamics, but the volume after tumor resection was similar in the two groups (5.23 cc and 5.12 cc). This suggests that the MO was compressed by the conglutinate tumor bulk, with resultant fluctuation of hemodynamics. Recognition of and preparation for this phenomenon are important for surgery on a tumor located on the dorsal MO.

  4. Pulmonary vasculature in COPD: The silent component.

    PubMed

    Blanco, Isabel; Piccari, Lucilla; Barberà, Joan Albert

    2016-08-01

    Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that results from an inflammatory process affecting the airways and lung parenchyma. Despite major abnormalities taking place in bronchial and alveolar structures, changes in pulmonary vessels also represent an important component of the disease. Alterations in vessel structure are highly prevalent and abnormalities in their function impair gas exchange and may result in pulmonary hypertension (PH), an important complication of the disease associated with reduced survival and worse clinical course. The prevalence of PH is high in COPD, particularly in advanced stages, although it remains of mild to moderate severity in the majority of cases. Endothelial dysfunction, with imbalance between vasodilator/vasoconstrictive mediators, is a key determinant of changes taking place in pulmonary vasculature in COPD. Cigarette smoke products may perturb endothelial cells and play a critical role in initiating vascular changes. The concurrence of inflammation, hypoxia and emphysema further contributes to vascular damage and to the development of PH. The use of drugs that target endothelium-dependent signalling pathways, currently employed in pulmonary arterial hypertension, is discouraged in COPD due to the lack of efficacy observed in randomized clinical trials and because there is compelling evidence indicating that these drugs may worsen pulmonary gas exchange. The subgroup of patients with severe PH should be ideally managed in centres with expertise in both PH and chronic lung diseases because alterations of pulmonary vasculature might resemble those observed in pulmonary arterial hypertension. Because this condition entails poor prognosis, it warrants specialist treatment.

  5. [Biologic mechanisms of mitotic abnormalities and chromosome number changes in malignant tumors].

    PubMed

    Hegyi, Katalin

    2015-12-01

    The main goal of this work was to study the effect of Aurora kinase expression on cell ploidy and tumorigenesis. Fifty invasive breast cancer, 50 diffuse large B-cell lymphoma and 10 reactive lymph node samples were recruited in the study. Because of the significant correlation with the overall cell proliferation rate, the overexpression of Aurora B could not be stated on the basis of kinase expressing tumor cell fractions alone. The relative expression of Aurora B kinase is better reflected by the AMI index which represents the Aurora B expression in relation to the whole proliferative fraction of the tumor. A higher relative Aurora B expression was associated with higher mitotic activity in B-cell lymphoma. FISH analysis of the AURKB locus did not show any gains or amplifications in the samples analyzed. On the other hand, we have observed the loss of the gene in breast carcinoma and lymphoma samples as well. A strong correlation was shown between AURKB and TP53 copy numbers: AURKB loss was associated with TP53 deletion in all samples. According to our results on breast carcinoma, losses at 17p13.1 and chromosome 17 aneusomy determined by FISH showed a statistically significant correlation. Our study presents the frequent occurrence of chromosome 17 aneusomy in breast carcinoma and B-cell lymphoma samples. Chromosome 17 aneusomy evaluated by FISH correlated with aneuploidy determined by flow cytometry. Direct correlation between kinase expression and ploidy could not be shown. The highest AMI values were seen in B-ALCL samples, and it was associated with high chromosome 17 copy numbers and mitotic activity. The damaged Aurora B kinase function results in regulatory deficiencies in the CPC complex leading to mitotic errors, while p53 deficiency helps malignant cells to survive due to insufficient activation of the intrinsic apoptotic pathways. The upregulation of Aurora kinase B function may cause error in an important mitotic checkpoint, thus resulting in

  6. Targeting Breast Cancer Vasculature

    DTIC Science & Technology

    2006-03-01

    Scadden, D. T. & Weissleder, R. (2000) Nat. Biotechnol. 18, 410–414. 28. Bulte, J. W. M., Douglas, T., Witwer, B., Zhang, S., Strable, E., Lewis , B. K...Liu, J., Razani, B., Tang, S., Terman , B.I., Ware, J.A., Lisanti, M.P., 1999. Angiogenesis activators and inhibitors differentially regulate caveolin-1...peptide produced a fibrillar network in mouse Lewis lung carcinoma similar to that seen in the tumors after i.v. injection of the peptide (Fig. 2A

  7. Sarcomas related to the heart and vasculature.

    PubMed

    Raaf, H N; Raaf, J H

    1994-01-01

    Soft tissue sarcoma is the most common malignant neoplasm of the heart, pericardium, and great vessels. Its presentation is infrequent, nonspecific, and subtle. For example, emboli from these tumors to the lungs or peripheral arteries may mimic thrombotic embolic disease. New noninvasive techniques such as echocardiography and magnetic resonance imaging (MRI) aid in diagnosis and preoperative assessment. Angiosarcoma, the most common cardiac sarcoma, is aggressive and usually arises in the right atrium. Kaposi's sarcoma of the heart has been found in patients with AIDS and in immunosuppressed organ transplant recipients. Most primary sarcomas of the aorta and pulmonary artery (the elastic arteries) show minimal differentiation and are classified as "intimal, sarcomas," whereas leiomyosarcomas predominate in the muscular arteries and great veins. Surgical resection of any sarcoma of the vasculature, when feasible, is technically challenging but may result in cure or palliation. Adjuvant chemotherapy and radiation therapy can also relieve symptoms and prolong survival.

  8. Absence of RET proto-oncogene abnormalities in sporadic parathyroid tumors

    SciTech Connect

    Pausova, Z.; Janicic, N.; Konrad, E.

    1994-09-01

    Parathyroid tumors can occur either sporadically or as a part of inherited cancer syndromes such as multiple endocrine neoplasia (MEN) type 2A. Recently, development of this syndrome has been shown to be related to specific mutations in the RET proto-oncogene, a putative receptor tyrosine kinase. Activation of this proto-oncogene has been demonstrated not only in tumors of the MEN 2A syndrome, but also in other neoplasia of neuroectoderm origin, namely papillary thyroid carcinoma where a rearrangement of the RET proto-oncogene has been found. In the present study, a role of the RET proto-oncogene in the development of sporadic parathyroid tumors was investigated by analyzing DNA samples obtained from 13 parathyroid adenomas and 6 parathyroid hyperplasias. Southern blot, using BamHI restricted DNA, did not reveal any gross alteration of the gene. Polymerase chain reaction (PCR) was then employed to amplify DNA fragments corresponding to exons 10 and 11 in which all MEN 2A mutations have been identified. Amplified DNA fragments were all of expected size (exon 10, 182 bp; exon 11, 233 bp). Since a single point mutation at codon 634 has been found to be associated in close to 90% of cases with development of parathyroid tumors in patients with the MEN 2A syndrome, exon 11, containing this codon, was further examined by direct sequence analysis. Sequences obtained from all tumors tested, however, did not differ from the wild type sequence. Therefore, the mutation of the RET proto-oncogene commonly associated with parathyroid neoplasias in MEN 2A is uncommon in sporadic parathyroid tumors. This suggests that the pathogenesis of parathyroid tumors occurring sporadically may be different from those occurring in patients with the MEN 2A syndrome.

  9. Effects of Vascular-Endothelial Protein Tyrosine Phosphatase Inhibition on Breast Cancer Vasculature and Metastatic Progression

    PubMed Central

    2013-01-01

    Background The solid tumor microvasculature is characterized by structural and functional abnormality and mediates several deleterious aspects of tumor behavior. Here we determine the role of vascular endothelial protein tyrosine phosphatase (VE-PTP), which deactivates endothelial cell (EC) Tie-2 receptor tyrosine kinase, thereby impairing maturation of tumor vessels. Methods AKB-9778 is a first-in-class VE-PTP inhibitor. We examined its effects on ECs in vitro and on embryonic angiogenesis in vivo using zebrafish assays. We studied the impact of AKB-9778 therapy on the tumor vasculature, tumor growth, and metastatic progression using orthotopic models of murine mammary carcinoma as well as spontaneous and experimental metastasis models. Finally, we used endothelial nitric oxide synthase (eNOS)–deficient mice to establish the role of eNOS in mediating the effects of VE-PTP inhibition. All statistical tests were two-sided. Results AKB-9778 induced ligand-independent Tie-2 activation in ECs and impaired embryonic zebrafish angiogenesis. AKB-9778 delayed the early phase of mammary tumor growth by maintaining vascular maturity (P < .01, t test); slowed growth of micrometastases (P < .01, χ2 test) by preventing extravasation of tumor cells (P < 0.01, Fisher exact test), resulting in a trend toward prolonged survival (27.0 vs 36.5 days; hazard ratio of death = 0.33, 95% confidence interval = 0.11 to 1.03; P = .05, Mantel–Cox test); and stabilized established primary tumor blood vessels, enhancing tumor perfusion (P = .03 for 4T1 tumor model and 0.05 for E0771 tumor model, by two-sided t tests) and, hence, radiation response (P < .01, analysis of variance; n = 7 mice per group). The effects of AKB-9778 on tumor vessels were mediated in part by endothelial nitric oxide synthase activation. Conclusions Our results demonstrate that pharmacological VE-PTP inhibition can normalize the structure and function of tumor vessels through Tie-2 activation, which delays tumor

  10. The Vasculature in Chagas Disease

    PubMed Central

    Prado, Cibele M.; Jelicks, Linda A.; Weiss, Louis M.; Factor, Stephen M.; Tanowitz, Herbert B.; Rossi, Marcos A.

    2013-01-01

    The cardiovascular manifestations of Chagas disease are well known. However, the contribution of the vasculature and specifically the microvasculature has received little attention. This chapter reviews the evidence supporting the notion that alterations in the microvasculature especially in the heart contribute to the pathogenesis of chagasic cardiomyopathy. These data may also be important in understanding the contributions of the microvasculature in the aetiologies of other cardiomyopathies. The role of endothelin-1 and of thromboxane A2 vascular spasm and platelet aggregation is also discussed. Further, these observations may provide target(s) for intervention. PMID:21884888

  11. Abnormal expression of paxillin correlates with tumor progression and poor survival in patients with gastric cancer

    PubMed Central

    2013-01-01

    Background Paxillin (PXN) has been found to be aberrantly regulated in various malignancies and involved in tumor growth and invasion. The clinicopathological and prognostic significance of PXN in gastric cancer is still unclear. Methods The expression of PXN was determined in paired gastric cancer tissues and adjacent normal tissues by Western blotting and real-time PCR. Immunohistochemistry was performed to detect the expression of PXN in 239 gastric cancer patients. Statistical analysis was applied to investigate the correlation between PXN expression and clinicopathological characteristics and prognosis in patients. Additionally, the effects of PXN on gastric cancer cell proliferation and migration were also evaluated. Results PXN was up-regulated in gastric cancer tissues and cell lines as compared with adjacent normal tissues and normal gastric epithelial cell line GES-1. Overexpression of PXN was correlated with distant metastasis (P = 0.001) and advanced tumor stage (P = 0.021) in gastric cancer patients. Patients with high PXN expression tended to have poor prognosis compared with patients with low PXN expression (P < 0.001). Multivariate analysis demonstrated that PXN expression was an independent prognostic factor (P = 0.020). Moreover, ectopic expression of PXN promotes cell proliferation and migration in AGS cells whereas knockdown of PXN inhibits cell proliferation and migration in SGC7901 cells. Conclusions PXN plays an important role in tumor progression and may be used as a potential prognostic indicator in gastric cancer. PMID:24180516

  12. Microvascular architecture of experimental colon tumors in the rat.

    PubMed

    Skinner, S A; Tutton, P J; O'Brien, P E

    1990-04-15

    Tumor cell proliferation is dependent upon concurrent growth of a supporting vasculature. This study aims to characterize the structural features of the microvasculature within a primary tumor model. There were 22 colon tumors induced in 16 rats by repeated administration of dimethylhydrazine. A cast of the microvessels was prepared by intraarterial administration of acrylic resin (Mercox). After corrosion of the tissue, the cast was examined by scanning electron microscopy. Tumors 2.6 to 12.0 mm in diameter were examined. Within polypoid carcinomas up to 5.7 mm in diameter, there were two distinct vascular zones, a luminal vascular zone continuous with the vasculature of normal mucosa and a central zone continuous with the normal submucosa and muscularis propria vessels. Within both vascular zones, the organization of microvessels had the same general pattern as in normal mucosa. However, in tumors with diameters greater than 5.7 mm, the vasculature was seen to be disorganized and of a greater density than normal. In the smallest tumors, few morphological changes were seen in the individual microvessels when compared to normal. However, with tumor growth, there was elongation and increased diameters of the microvessels within the tumor. Microvessels within the luminal zone of the tumors which could definitely be traced to veins had diameters of 50 to 100 microns (compared to 12 to 30 microns for normal venules). Individual microvessels varied in diameter along their course forming saccular dilations in places. Networks of frequently anastomosing microvessels were formed. Extravasation of resin occurred from some microvessels. Elongated vessels of uniform diameter which travel distances up to 2 mm without branching were seen and were probably arterioles. These appearances indicate that there are two distinct stages of development of the vasculature within primary tumors, an early phase where the tumor is supplied by the preexisting host microvessels, followed by a

  13. Role of lymphatic vasculature in regional and distant metastases.

    PubMed

    Podgrabinska, Simona; Skobe, Mihaela

    2014-09-01

    In cancer, lymphatic vasculature has been traditionally viewed only as a transportation system for metastatic cells. It has now become clear that lymphatics perform many additional functions which could influence cancer progression. Lymphangiogenesis, induced at the primary tumor site and at distant sites, potently augments metastasis. Lymphatic endothelial cells (LECs) control tumor cell entry and exit from the lymphatic vessels. LECs also control immune cell traffic and directly modulate adaptive immune responses. This review highlights advances in our understanding of the mechanisms by which lymphatic vessels, and in particular lymphatic endothelium, impact metastasis.

  14. Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected].

    PubMed

    Cortis, Elisabetta; De Benedetti, Fabrizio; Insalaco, Antonella; Cioschi, Stefania; Muratori, Flaminia; D'Urbano, Leila E; Ugazio, Alberto G

    2004-12-01

    We report a family with pyogenic sterile arthritis, pyoderna and acne syndrome (PAPA). The proband presented several episodes of sterile pyogenic arthritis and became unresponsive to glucocorticoids. After treatment with the tumor necrosis factor inhibitor etanercept, the disease underwent rapid and sustained clinical remission. Production of tumor necrosis factor-alpha by mononuclear cells of the proband and of the affected relatives was abnormally elevated.

  15. In vivo imaging of pulmonary nodule and vasculature using endoscopic co-registered optical coherence tomography and autofluorescence imaging (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Pahlevaninezhad, Hamid; Lee, Anthony; Hohert, Geoffrey; Schwartz, Carely; Shaipanich, Tawimas; Ritchie, Alexander J.; Zhang, Wei; MacAulay, Calum E.; Lam, Stephen; Lane, Pierre M.

    2016-03-01

    Peripheral lung nodules found by CT-scans are difficult to localize and biopsy bronchoscopically particularly for those ≤ 2 cm in diameter. In this work, we present the results of endoscopic co-registered optical coherence tomography and autofluorescence imaging (OCT-AFI) of normal and abnormal peripheral airways from 40 patients using 0.9 mm diameter fiber optic rotary pullback catheter. Optical coherence tomography (OCT) can visualize detailed airway morphology endoscopically in the lung periphery. Autofluorescence imaging (AFI) can visualize fluorescing tissue components such as collagen and elastin, enabling the detection of airway lesions with high sensitivity. Results indicate that AFI of abnormal airways is different from that of normal airways, suggesting that AFI can provide a sensitive visual presentation for rapidly identifying possible sites of pulmonary nodules. AFI can also rapidly visualize in vivo vascular networks using fast scanning parameters resulting in vascular-sensitive imaging with less breathing/cardiac motion artifacts compared to Doppler OCT imaging. It is known that tumor vasculature is structurally and functionally different from normal vessels. Thus, AFI can be potentially used for differentiating normal and abnormal lung vasculature for studying vascular remodeling.

  16. Delivering nanomedicine to solid tumors

    PubMed Central

    Jain, Rakesh K.; Stylianopoulos, Triantafyllos

    2011-01-01

    Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors. PMID:20838415

  17. Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis.

    PubMed

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-03-09

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage.

  18. Vascular Normalization Induced by Sinomenine Hydrochloride Results in Suppressed Mammary Tumor Growth and Metastasis

    PubMed Central

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-01-01

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage. PMID:25749075

  19. Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.

    PubMed

    Zhang, Lei; Kundu, Soumi; Feenstra, Tjerk; Li, Xiujuan; Jin, Chuan; Laaniste, Liisi; El Hassan, Tamador Elsir Abu; Ohlin, K Elisabet; Yu, Di; Olofsson, Tommie; Olsson, Anna-Karin; Pontén, Fredrik; Magnusson, Peetra U; Nilsson, Karin Forsberg; Essand, Magnus; Smits, Anja; Dieterich, Lothar C; Dimberg, Anna

    2015-12-08

    Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.

  20. Tumor Microvasculature and Microenvironment: Novel Insights Through Intravital Imaging in Pre-Clinical Models

    PubMed Central

    Fukumura, Dai; Duda, Dan G.; Munn, Lance L.; Jain, Rakesh K.

    2010-01-01

    Intravital imaging techniques have provided unprecedented insight into tumor microcirculation and microenvironment. For example, these techniques allowed quantitative evaluations of tumor blood vasculature to uncover its abnormal organization, structure and function (e.g., hyper-permeability, heterogeneous and compromised blood flow). Similarly, imaging of functional lymphatics has documented their absence inside tumors. These abnormalities result in elevated interstitial fluid pressure and hinder the delivery of therapeutic agents to tumors. In addition, they induce a hostile microenvironment characterized by hypoxia and acidosis, as documented by intravital imaging. The abnormal microenvironment further lowers the effectiveness of anti-tumor treatments such as radiation therapy and chemotherapy. In addition to these mechanistic insights, intravital imaging may also offer new opportunities to improve therapy. For example, tumor angiogenesis results in immature, dysfunctional vessels—primarily caused by an imbalance in production of pro- and anti-angiogenic factors by the tumors. Restoring the balance of pro- and anti-angiogenic signaling in tumors can “normalize” tumor vasculature and thus, improve its function, as demonstrated by intravital imaging studies in preclinical models and in cancer patients. Administration of cytotoxic therapy during periods of vascular normalization has the potential to enhance treatment efficacy. PMID:20374484

  1. Response of the cerebral vasculature following traumatic brain injury.

    PubMed

    Salehi, Arjang; Zhang, John H; Obenaus, Andre

    2017-01-01

    The critical role of the vasculature and its repair in neurological disease states is beginning to emerge particularly for stroke, dementia, epilepsy, Parkinson's disease, tumors and others. However, little attention has been focused on how the cerebral vasculature responds following traumatic brain injury (TBI). TBI often results in significant injury to the vasculature in the brain with subsequent cerebral hypoperfusion, ischemia, hypoxia, hemorrhage, blood-brain barrier disruption and edema. The sequalae that follow TBI result in neurological dysfunction across a host of physiological and psychological domains. Given the importance of restoring vascular function after injury, emerging research has focused on understanding the vascular response after TBI and the key cellular and molecular components of vascular repair. A more complete understanding of vascular repair mechanisms are needed and could lead to development of new vasculogenic therapies, not only for TBI but potentially vascular-related brain injuries. In this review, we delineate the vascular effects of TBI, its temporal response to injury and putative biomarkers for arterial and venous repair in TBI. We highlight several molecular pathways that may play a significant role in vascular repair after brain injury.

  2. Exploring the Tumor Microenvironment with Nanoparticles

    PubMed Central

    Miao, Lei

    2016-01-01

    Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. While enhanced permeability and retention effect (EPR) promotes nanoparticle (NP) extravasation, the abnormal tumor vasculature, high interstitial pressure and dense stroma structure limit homogeneous intratumoral distribution of NP and compromise their imaging and therapeutic effect. Moreover, heterogeneous distribution of NP in nontumor-stroma cells damages the nontumor cells, and interferes with tumor-stroma crosstalk. This can lead to inhibition of tumor progression, but can also paradoxically induce acquired resistance and facilitate tumor cell proliferation and metastasis. Overall, the tumor microenvironment plays a crucial, yet controversial role in regulating NP distribution and their biological effects. In this review, we summarize recent studies on the stroma barriers for NP extravasation, and discuss the consequential effects of NP distribution in stroma cells. We also highlight design considerations to improve NP delivery and propose potential combinatory strategies to overcome acquired resistance induced by damaged stroma cells. PMID:25895870

  3. RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord.

    PubMed

    Brohawn, David G; O'Brien, Laura C; Bennett, James P

    2016-01-01

    ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned >50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG's). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network "hub" gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF's involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful

  4. Evaluation of uptake and distribution of gold nanoparticles in solid tumors*

    PubMed Central

    England, Christopher G.; Gobin, André M.; Frieboes, Hermann B.

    2015-01-01

    Although nanotherapeutics offer a targeted and potentially less toxic alternative to systemic chemotherapy in cancer treatment, nanotherapeutic transport is typically hindered by abnormal characteristics of tumor tissue. Once nanoparticles targeted to tumor cells arrive in the circulation of tumor vasculature, they must extravasate from irregular vessels and diffuse through the tissue to ideally reach all malignant cells in cytotoxic concentrations. The enhanced permeability and retention effect can be leveraged to promote extravasation of appropriately sized particles from tumor vasculature; however, therapeutic success remains elusive partly due to inadequate intra-tumoral transport promoting heterogeneous nanoparticle uptake and distribution. Irregular tumor vasculature not only hinders particle transport but also sustains hypoxic tissue kregions with quiescent cells, which may be unaffected by cycle-dependent chemotherapeutics released from nanoparticles and thus regrow tumor tissue following nanotherapy. Furthermore, a large proportion of systemically injected nanoparticles may become sequestered by the reticuloendothelial system, resulting in overall diminished efficacy. We review recent work evaluating the uptake and distribution of gold nanoparticles in pre-clinical tumor models, with the goal to help improve nanotherapy outcomes. We also examine the potential role of novel layered gold nanoparticles designed to address some of these critical issues, assessing their uptake and transport in cancerous tissue. PMID:27014559

  5. Evaluation of uptake and distribution of gold nanoparticles in solid tumors

    NASA Astrophysics Data System (ADS)

    England, Christopheri G.; Gobin, André M.; Frieboes, Hermann B.

    2015-11-01

    Although nanotherapeutics offer a targeted and potentially less toxic alternative to systemic chemotherapy in cancer treatment, nanotherapeutic transport is typically hindered by abnormal characteristics of tumor tissue. Once nanoparticles targeted to tumor cells arrive in the circulation of tumor vasculature, they must extravasate from irregular vessels and diffuse through the tissue to ideally reach all malignant cells in cytotoxic concentrations. The enhanced permeability and retention effect can be leveraged to promote extravasation of appropriately sized particles from tumor vasculature; however, therapeutic success remains elusive partly due to inadequate intra-tumoral transport promoting heterogeneous nanoparticle uptake and distribution. Irregular tumor vasculature not only hinders particle transport but also sustains hypoxic tissue kregions with quiescent cells, which may be unaffected by cycle-dependent chemotherapeutics released from nanoparticles and thus regrow tumor tissue following nanotherapy. Furthermore, a large proportion of systemically injected nanoparticles may become sequestered by the reticulo-endothelial system, resulting in overall diminished efficacy. We review recent work evaluating the uptake and distribution of gold nanoparticles in pre-clinical tumor models, with the goal to help improve nanotherapy outcomes. We also examine the potential role of novel layered gold nanoparticles designed to address some of these critical issues, assessing their uptake and transport in cancerous tissue.

  6. Tumor vasculature is regulated by FGF/FGFR signaling-mediated angiogenesis and bone marrow-derived cell recruitment: this mechanism is inhibited by SSR128129E, the first allosteric antagonist of FGFRs.

    PubMed

    Fons, Pierre; Gueguen-Dorbes, Geneviève; Herault, Jean-Pascal; Geronimi, Fabien; Tuyaret, Joël; Frédérique, Dol; Schaeffer, Paul; Volle-Challier, Cécile; Herbert, Jean-Marc; Bono, Françoise

    2015-01-01

    Tumor angiogenesis is accompanied by vasculogenesis, which is involved in the differentiation and mobilization of human bone marrow cells. In order to further characterize the role of vasculogenesis in the tumor growth process, the effects of FGF2 on the differentiation of human bone marrow AC133(+) cells (BM-AC133(+)) into vascular precursors were studied in vitro. FGF2, like VEGFA, induced progenitor cell differentiation into cell types with endothelial cell characteristics. SSR128129E, a newly discovered specific FGFR antagonist acting by allosteric interaction with FGFR, abrogated FGF2-induced endothelial cell differentiation, showing that FGFR signaling is essential during this process. To assess the involvement of the FGF/FRGR signaling in vivo, the pre-clinical model of Lewis lung carcinoma (LL2) in mice was used. Subcutaneous injection of LL2 cells into mice induced an increase of circulating EPCs from peripheral blood associated with tumor growth and an increase of intra-tumoral vascular index. Treatment with the FGFR antagonist SSR128129E strongly decreased LL2 tumor growth as well as the intra-tumoral vascular index (41% and 50% decrease vs. vehicle-treated mice respectively, P < 0.01). Interestingly, SSR128129E treatment significantly decreased the number of circulating EPCs from the peripheral blood (53% inhibition vs. vehicle-treated mice, P < 0.01). These results demonstrate for the first time that the blockade of the FGF/FGFR pathway by SSR128129E reduces EPC recruitment during angiogenesis-dependent tumor growth. In this context, circulating EPCs could be a reliable surrogate marker for tumor growth and angiogenic activity.

  7. Improvement of intratumor microdistribution of PEGylated liposome via tumor priming by metronomic S-1 dosing

    PubMed Central

    Doi, Yusuke; Abu Lila, Amr S; Matsumoto, Haruna; Okada, Tomoko; Shimizu, Taro; Ishida, Tatsuhiro

    2016-01-01

    The efficient delivery of nanocarrier-based cancer therapeutics into tumor tissue is problematic. Structural abnormalities, tumor vasculature heterogeneity, and elevated intratumor pressure impose barriers against the preferential accumulation of nanocarrier-based cancer therapeutics within tumor tissues and, consequently, compromise their therapeutic efficacy. Recently, we have reported that metronomic S-1, orally available tegafur formulation, dosing synergistically augmented the therapeutic efficacy of oxaliplatin (l-OHP)-containing PEGylated liposome without increasing the toxicity in animal model. However, the exact mechanism behind such synergistic effect was not fully elucidated. In this study, therefore, we tried to shed the light on the contributions of metronomic S-1 dosing to the enhanced accumulation and/or spatial distribution of PEGylated liposome within tumor tissue. Tumor priming with metronomic S-1 treatment induced a potent apoptotic response against both angiogenic endothelial cells and tumor cells adjacent to tumor blood vessels, resulting in enhanced tumor blood flow via transient normalization of tumor vasculature, along with alleviation of intratumor pressure. Such a change in the tumor microenvironment imparted by S-1 treatment allows efficient delivery of PEGylated liposome to tumor tissue and permits their deep penetration/distribution into the tumor mass. Such a priming effect of S-1 dosing can be exploited as a promising strategy to enhance the therapeutic efficacy of nanocarrier-based cancer therapeutics suffering from inadequate/heterogeneous delivery to tumor tissues. PMID:27822036

  8. Down-regulation of caveolin-1 in glioma vasculature: modulation by radiotherapy.

    PubMed

    Régina, Anthony; Jodoin, Julie; Khoueir, Paul; Rolland, Yannève; Berthelet, France; Moumdjian, Robert; Fenart, Laurence; Cecchelli, Romeo; Demeule, Michel; Béliveau, Richard

    2004-01-15

    Primary brain tumors, particularly glioblastomas (GB), remain a challenge for oncology. An element of the malignant brain tumors' aggressive behavior is the fact that GB are among the most densely vascularized tumors. To determine some of the molecular regulations occuring at the brain tumor endothelium level during tumoral progression would be an asset in understanding brain tumor biology. Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling, oncogenesis, and angiogenesis. In this work we investigated regulation of caveolin-1 expression in brain endothelial cells (ECs) under angiogenic conditions. In vitro, brain EC caveolin-1 is down-regulated by angiogenic factors treament and by hypoxia. Coculture of brain ECs with tumoral cells induced a similar down-regulation. In addition, activation of the p42/44 MAP kinase is demonstrated. By using an in vivo brain tumor model, we purified ECs from gliomas as well as from normal brain to investigate possible regulation of caveolin-1 expression in tumoral brain vasculature. We show that caveolin-1 expression is strikingly down-regulated in glioma ECs, whereas an increase of phosphorylated caveolin-1 is observed. Whole-brain radiation treatment, a classical way in which GB is currently being treated, resulted in increased caveolin-1 expression in tumor isolated ECs. The level of tumor cells spreading around newly formed blood vessels was also elevated. The regulation of caveolin-1 expression in tumoral ECs may reflect the tumoral vasculature state and correlates with angiogenesis kinetics.

  9. Emerging Roles of Lymphatic Vasculature in Immunity

    PubMed Central

    2017-01-01

    The lymphatic vasculature has been regarded as a passive conduit for interstitial fluid and responsible for the absorption of macromolecules such as proteins or lipids and transport of nutrients from food. However, emerging data show that the lymphatic vasculature system plays an important role in immune modulation. One of its major roles is to coordinate antigen transport and immune-cell trafficking from peripheral tissues to secondary lymphoid organs, lymph nodes. This perspective was recently updated with the notion that the interaction between lymphatic endothelial cells and leukocytes controls the immune-cell migration and immune responses by regulating lymphatic flow and various secreted molecules such as chemokines and cytokines. In this review, we introduce the lymphatic vasculature networks and genetic transgenic models for research on the lymphatic vasculature system. Next, we discuss the contribution of lymphatic endothelial cells to the control of immune-cell trafficking and to maintenance of peripheral tolerance. Finally, the physiological roles and features of the lymphatic vasculature system are further discussed regarding inflammation-induced lymphangiogenesis in a pathological condition, especially in mucosal tissues such as the gastrointestinal tract and respiratory tract. PMID:28261022

  10. Posterior tunica vasculosa lentis and "brittle star" of persistent fetal vasculature.

    PubMed

    Pellegrini, Marco; Shields, Carol L; Arepalli, Sruthi; Shields, Jerry A

    2014-11-19

    A 17-month-old girl referred for a suspected ciliary body medulloepithelioma was found to have persistent fetal vasculature. Fluorescein angiography showed perfused hyaloid artery posterior tunica vasculosa lentis with brittle star appearance and nonperfused anterior pupillary membrane. Ultrasound biomicroscopy confirmed absence of iris or ciliary body solid tumor.

  11. The Instructive Role of the Vasculature in Stem Cell Niches

    PubMed Central

    Putnam, Andrew J.

    2014-01-01

    An important hallmark of many adult stem cell niches is their proximity to the vasculature in vivo, a feature common to neural stem cells (NSCs), mesenchymal stem cells (MSCs) from bone marrow, adipose, and other tissues, hematopoietic stem cells (HSCs), and many tumor stem cells. This review summarizes key studies supporting the vasculature’s instructive role in adult stem cell niches, and the putative underlying molecular mechanisms by which blood vessels in these niches exert control over progenitor cell fates. The importance of the perivascular niche for pathology, notably tumor metastasis and dormancy, is also highlighted. Finally, the implications of the perivascular regulation of stem and progenitor cells on biomaterial design and the impact on future research directions are discussed. PMID:25530848

  12. Nonclassical Patrolling Monocyte Function in the Vasculature

    PubMed Central

    Thomas, Graham; Tacke, Robert; Hedrick, Catherine C.

    2015-01-01

    Nonclassical patrolling monocytes are characterized by their unique ability to actively patrol the vascular endothelium under homeostatic and inflammatory conditions. Patrolling monocyte subsets (CX3CR1highLy6C− in mouse, and CX3CR1highCD14dimCD16+ in humans) are distinct from the classical monocyte subsets (CCR2highLy6C+ in mouse, and CCR2highCD14+CD16− in humans) and exhibit unique functions in the vasculature and inflammatory disease. Patrolling monocytes function in a number of disease settings to remove damaged cells and debris from the vasculature, and have been associated with wound healing and the resolution of inflammation in damaged tissues. This review highlights the unique functions of these patrolling monocytes in the vasculature and during inflammation. PMID:25838429

  13. Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy

    PubMed Central

    Zhang, Yin; Yang, Yunlong; Hosaka, Kayoko; Huang, Guichun; Zang, Jingwu; Chen, Fang; Zhang, Yun; Samani, Nilesh J.; Cao, Yihai

    2016-01-01

    Anti-VEGF–based antiangiogenic drugs are designed to block tumor angiogenesis for treatment of cancer patients. However, anti-VEGF drugs produce off-tumor target effects on multiple tissues and organs and cause broad adverse effects. Here, we show that vasculatures in endocrine organs were more sensitive to anti-VEGF treatment than tumor vasculatures. In thyroid, adrenal glands, and pancreatic islets, systemic treatment with low doses of an anti-VEGF neutralizing antibody caused marked vascular regression, whereas tumor vessels remained unaffected. Additionally, a low dose of VEGF blockade significantly inhibited the formation of thyroid vascular fenestrae, leaving tumor vascular structures unchanged. Along with vascular structural changes, the low dose of VEGF blockade inhibited vascular perfusion and permeability in thyroid, but not in tumors. Prolonged treatment with the low-dose VEGF blockade caused hypertension and significantly decreased circulating levels of thyroid hormone free-T3 and -T4, leading to functional impairment of thyroid. These findings show that the fenestrated microvasculatures in endocrine organs are more sensitive than tumor vasculatures in response to systemic anti-VEGF drugs. Thus, our data support the notion that clinically nonbeneficial treatments with anti-VEGF drugs could potentially cause adverse effects. PMID:27035988

  14. Ultrasound imaging beyond the vasculature with new generation contrast agents.

    PubMed

    Perera, Reshani H; Hernandez, Christopher; Zhou, Haoyan; Kota, Pavan; Burke, Alan; Exner, Agata A

    2015-01-01

    Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 µm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer.

  15. The lymphatic vasculature in disease.

    PubMed

    Alitalo, Kari

    2011-11-07

    Blood vessels form a closed circulatory system, whereas lymphatic vessels form a one-way conduit for tissue fluid and leukocytes. In most vertebrates, the main function of lymphatic vessels is to collect excess protein-rich fluid that has extravasated from blood vessels and transport it back into the blood circulation. Lymphatic vessels have an important immune surveillance function, as they import various antigens and activated antigen-presenting cells into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation. Defects in lymphatic function can lead to lymph accumulation in tissues, dampened immune responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema. This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.

  16. NF1 frameshift mutation (c.6520_6523delGAGA) association with nervous system tumors and bone abnormalities in a Chinese patient with neurofibromatosis type 1.

    PubMed

    Su, S Y; Zhou, X; Pang, X M; Chen, C Y; Li, S H; Liu, J L

    2016-04-07

    Neurofibromatosis type 1, also known as NF1 or von Recklinghausen's disease, is a common neurocutaneous syndrome that presents with multiple café-au-lait patches, skinfold freckling, dermatofibromas, neurofibromas, and Lisch nodules. The mutations of the gene NF1, encoding the protein neurofibromin, have been identified as the cause of this disease. Here, we report a clinical and molecular study of a Chinese patient with multiple café-au-lait skin freckles, dermatofibroma, central and peripheral nervous system tumors, and bone abnormalities attributed to NF1. The patient showed >6 café-au-lait spots on the body and multiple dermatofibromas. A brain glioma and multiple nerve sheath tumors inside and outside the vertebral canal were identified by magnetic resonance imaging, which also showed multiple intercostal nerve schwannomas and hydrocephalies above the cerebellar tentorium. Talipes equinus was also apparent. A mutation analysis of the NF1 gene revealed a novel frameshift mutation in exon 43, consisting of a heterozygous deletion of four nucleotides (GAGA) between positions 6520 and 6523. No NF1 mutations were detected in the patient's parents or younger brother. These results extend the list of known mutations in this gene. The absence of the NF1 mutation in the healthy family members suggests that it is responsible for the NF1 phenotype. To our knowledge, this frameshift mutation represents a novel NF1 case, and may be associated with nervous system tumors and bone abnormalities.

  17. Molecular specialization of breast vasculature: A breast-homing phage-displayed peptide binds to aminopeptidase P in breast vasculature

    NASA Astrophysics Data System (ADS)

    Essler, Markus; Ruoslahti, Erkki

    2002-02-01

    In vivo phage display identifies peptides that selectively home to the vasculature of individual organs, tissues, and tumors. Here we report the identification of a cyclic nonapeptide, CPGPEGAGC, which homes to normal breast tissue with a 100-fold selectivity over nontargeted phage. The homing of the phage is inhibited by its cognate synthetic peptide. Phage localization in tissue sections showed that the breast-homing phage binds to the blood vessels in the breast, but not in other tissues. The phage also bound to the vasculature of hyperplastic and malignant lesions in transgenic breast cancer mice. Expression cloning with a phage-displayed cDNA library yielded a phage that specifically bound to the breast-homing peptide. The cDNA insert was homologous to a fragment of aminopeptidase P. The homing peptide bound aminopeptidase P from malignant breast tissue in affinity chromatography. Antibodies against aminopeptidase P inhibited the in vitro binding of the phage-displayed cDNA to the peptide and the in vivo homing of phage carrying the peptide. These results indicate that aminopeptidase P is the receptor for the breast-homing peptide. This peptide may be useful in designing drugs for the prevention and treatment of breast cancer.

  18. Description of the prevalence, histologic characteristics, concomitant abnormalities, and outcomes of mammary gland tumors in companion rats (Rattus norvegicus): 100 cases (1990-2015).

    PubMed

    Vergneau-Grosset, Claire; Keel, M Kevin; Goldsmith, Dayna; Kass, Philip H; Paul-Murphy, Joanne; Hawkins, Michelle G

    2016-11-15

    OBJECTIVE To describe the prevalence, histologic characteristics, concomitant abnormalities, and outcomes for various types of mammary gland tumors in companion rats (Rattus norvegicus). DESIGN Retrospective case series. ANIMALS 100 client-owned rats. PROCEDURES Medical records of companion rats that had an SC mass and were examined at a veterinary teaching hospital between 1990 and 2015 were reviewed. Information regarding the signalment, age at mass detection, reproductive sterilization status, histologic diagnosis of the SC mass, location of the initial and all subsequent SC masses, treatments administered, and clinical outcomes was extracted from each record and summarized. RESULTS 105 SC masses were initially detected in 100 rats. The most prevalent SC mass identified was mammary gland fibroadenoma (56/105 [53%]), followed by mammary gland carcinoma (13/105 [12%]). Overall, 26 of 105 (25%) masses were malignant. Sexually intact males were more likely to have nonmammary SC tumors than sexually intact females. In rats receiving no adjunctive treatment after excision of a mammary gland fibroadenoma (n = 16), a second fibroadenoma was detected 1 to 8 months after initial excision, at a median of 4.5 months after surgery. A concomitant pituitary gland tumor was identified in most rats with mammary gland fibroadenoma (21/28 [75%]) and other types of mammary gland tumors (10/17 [59%]). Fourteen of 35 (40%) rats with mammary gland fibroadenoma had concomitant reproductive tract abnormalities. CONCLUSION AND CLINICAL RELEVANCE Results suggested that, like other species, companion rats with SC masses should undergo a thorough diagnostic workup that includes histologic examination of the excised mass.

  19. Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

    PubMed Central

    Carouge, Delphine; Blanc, Valerie; Knoblaugh, Sue E.; Hunter, Robert J.; Davidson, Nicholas O.; Nadeau, Joseph H.

    2016-01-01

    Testicular tumors, the most common cancer in young men, arise from abnormalities in germ cells during fetal development. Unconventional inheritance for testicular germ cell tumor (TGCT) risk both in humans and mice implicates epigenetic mechanisms. Apolipoprotein B mRNA-editing enzyme complex 1 (APOBEC1) cytidine deaminase and Deadend-1, which are involved in C-to-U RNA editing and microRNA-dependent mRNA silencing, respectively, are potent epigenetic modifiers of TGCT susceptibility in the genetically predisposed 129/Sv inbred mouse strain. Here, we show that partial loss of either APOBEC1 complementation factor (A1CF), the RNA-binding cofactor of APOBEC1 in RNA editing, or Argonaute 2 (AGO2), a key factor in the biogenesis of certain noncoding RNAs, modulates risk for TGCTs and testicular abnormalities in both parent-of-origin and conventional genetic manners. In addition, non-Mendelian inheritance was found among progeny of A1cf and Ago2 mutant intercrosses but not in backcrosses and without fetal loss. Together these findings suggest nonrandom union of gametes rather than meiotic drive or preferential lethality. Finally, this survey also suggested that A1CF contributes to long-term reproductive performance. These results directly implicate the RNA-binding proteins A1CF and AGO2 in the epigenetic control of germ-cell fate, urogenital development, and gamete functions. PMID:27582469

  20. Congenital Abnormalities

    MedlinePlus

    ... Listen Español Text Size Email Print Share Congenital Abnormalities Page Content Article Body About 3% to 4% ... of congenital abnormalities earlier. 5 Categories of Congenital Abnormalities Chromosome Abnormalities Chromosomes are structures that carry genetic ...

  1. Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis

    PubMed Central

    Chen, Yu; Doughman, Yong-qiu; Gu, Shi; Jarrell, Andrew; Aota, Shin-ichi; Cvekl, Ales; Watanabe, Michiko; Dunwoodie, Sally L.; Johnson, Randall S.; van Heyningen, Veronica; Kleinjan, Dirk A.; Beebe, David C.; Yang, Yu-Chung

    2009-01-01

    Cited2 is a transcriptional modulator with pivotal roles in different biological processes. Cited2-deficient mouse embryos manifested two major defects in the developing eye. An abnormal corneal-lenticular stalk was characteristic of Cited2−/− developing eyes, a feature reminiscent of Peters’ anomaly, which can be rescued by increased Pax6 gene dosage in Cited2−/− embryonic eyes. In addition, the hyaloid vascular system showed hyaloid hypercellularity consisting of aberrant vasculature, which might be correlated with increased VEGF expression in the lens. Deletion of Hif1a (which encodes HIF-1α) in Cited2−/− lens specifically eliminated the excessive accumulation of cellular mass and aberrant vasculature in the developing vitreous without affecting the corneal-lenticular stalk phenotype. These in vivo data demonstrate for the first time dual functions for Cited2: one upstream of, or together with, Pax6 in lens morphogenesis; and another in the normal formation of the hyaloid vasculature through its negative modulation of HIF-1 signaling. Taken together, our study provides novel mechanistic revelation for lens morphogenesis and hyaloid vasculature formation and hence might offer new insights into the etiology of Peters’ anomaly and ocular hypervascularity. PMID:18653562

  2. Mesenteric Vasculature-guided Small Bowel Segmentation on 3D CT

    PubMed Central

    Zhang, Weidong; Liu, Jiamin; Yao, Jianhua; Louie, Adeline; Nguyen, Tan B.; Wank, Stephen; Nowinski, Wieslaw L.; Summers, Ronald M.

    2014-01-01

    Due to its importance and possible applications in visualization, tumor detection and pre-operative planning, automatic small bowel segmentation is essential for computer-aided diagnosis of small bowel pathology. However, segmenting the small bowel directly on CT scans is very difficult because of the low image contrast on CT scans and high tortuosity of the small bowel and its close proximity to other abdominal organs. Motivated by the intensity characteristics of abdominal CT images, the anatomic relationship between the mesenteric vasculature and the small bowel, and potential usefulness of the mesenteric vasculature for establishing the path of the small bowel, we propose a novel mesenteric vasculature map-guided method for small bowel segmentation on high-resolution CT angiography scans. The major mesenteric arteries are first segmented using a vessel tracing method based on multi-linear subspace vessel model and Bayesian inference. Second, multi-view, multi-scale vesselness enhancement filters are used to segment small vessels, and vessels directly or indirectly connecting to the superior mesenteric artery are classified as mesenteric vessels. Third, a mesenteric vasculature map is built by linking vessel bifurcation points, and the small bowel is segmented by employing the mesenteric vessel map and fuzzy connectness. The method was evaluated on 11 abdominal CT scans of patients suspected of having carcinoid tumors with manually labeled reference standard. The result, 82.5% volume overlap accuracy compared with the reference standard, shows it is feasible to segment the small bowel on CT scans using the mesenteric vasculature as a roadmap. PMID:23807437

  3. 3D numerical study of tumor microenvironmental flow in response to vascular-disrupting treatments.

    PubMed

    Wu, Jie; Cai, Yan; Xu, Shixiong; Longs, Quan; Ding, Zurong; Dong, Cheng

    2012-06-01

    The effects of vascular-disrupting treatments on normalization of tumor microvasculature and its microenvironmental flow were investigated, by mathematical modeling and numerical simulation of tumor vascular-disrupting and tumor haemodynamics. Four disrupting approaches were designed according to the abnormal characteristics of tumor microvasculature compared with the normal one. The results predict that the vascular-disrupting therapies could improve tumor microenvironment, eliminate drug barrier and inhibit metastasis of tumor cells to some extent. Disrupting certain types of vessels may get better effects. In this study, the flow condition on the networks with "vascular-disrupting according to flowrate" is the best comparing with the other three groups, and disrupting vessels of lower maturity could effectively enhance fluid transport across vasculature into interstitial space.

  4. A New Transgenic Approach to Target Tumor Vasculature

    DTIC Science & Technology

    2006-06-01

    H. E. (1993). A receptor for subgroup A Rous sarcoma virus is related to the low density lipoprotein receptor. Cell 74, 1043-51. Bautch, V. L...Montaner, S., Sodhi, A., Servitja, J. M., Ramsdell, A. K., Barac, A., Sawai, E. T. and Gutkind, J. S. (2004). The small GTPase Rac1 links the Kaposi ... sarcoma -associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood 104, 2903-11. Mukouyama, Y. S., Shin, D., Britsch, S

  5. Optical imaging of the chorioretinal vasculature in the living human eye.

    PubMed

    Kim, Dae Yu; Fingler, Jeff; Zawadzki, Robert J; Park, Susanna S; Morse, Lawrence S; Schwartz, Daniel M; Fraser, Scott E; Werner, John S

    2013-08-27

    Detailed visualization of microvascular changes in the human retina is clinically limited by the capabilities of angiography imaging, a 2D fundus photograph that requires an intravenous injection of fluorescent dye. Whereas current angiography methods enable visualization of some retinal capillary detail, they do not adequately reveal the choriocapillaris or other microvascular features beneath the retina. We have developed a noninvasive microvascular imaging technique called phase-variance optical coherence tomography (pvOCT), which identifies vasculature three dimensionally through analysis of data acquired with OCT systems. The pvOCT imaging method is not only capable of generating capillary perfusion maps for the retina, but it can also use the 3D capabilities to segment the data in depth to isolate vasculature in different layers of the retina and choroid. This paper demonstrates some of the capabilities of pvOCT imaging of the anterior layers of choroidal vasculature of a healthy normal eye as well as of eyes with geographic atrophy (GA) secondary to age-related macular degeneration. The pvOCT data presented permit digital segmentation to produce 2D depth-resolved images of the retinal vasculature, the choriocapillaris, and the vessels in Sattler's and Haller's layers. Comparisons are presented between en face projections of pvOCT data within the superficial choroid and clinical angiography images for regions of GA. Abnormalities and vascular dropout observed within the choriocapillaris for pvOCT are compared with regional GA progression. The capability of pvOCT imaging of the microvasculature of the choriocapillaris and the anterior choroidal vasculature has the potential to become a unique tool to evaluate therapies and understand the underlying mechanisms of age-related macular degeneration progression.

  6. Effects of cultured Cordyceps mycelia polysaccharide A on tumor neurosis factor-α induced hepatocyte injury with mitochondrial abnormality.

    PubMed

    Tang, Huiling; Wei, Weikun; Wang, Wang; Zha, Zhengqi; Li, Ting; Zhang, Zhijie; Luo, Chen; Yin, Hongping; Huang, Fengjie; Wang, Ying

    2017-05-01

    Cordyceps sinensis mycelia polysaccharide A (CPS-A), was isolated from cultured Cordyceps mycelia by 65% alcohol extraction and ion-exchange column chromatography. The molecular weight of CPS-A was 1.2×10(4)Da and the backbone was mainly composed of (1→2)-linked β-d-mannopyranose, (1→2,4)-linked β-d-mannopyranose and (1→4)-linked α-d-glucopyranose with terminal β-d-mannopyranose and α-d-glucopyranose residues. CPS-A played a protective role against TNF-α induced mitochondria injury in L02 cells via up-regulation of mitofusin 2, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and membrane potential. CPS-A also played a protective role against TNF-α induced L02 cells apoptosis via up-regulation of Bcl-2 and down-regulation of Bid, Bax, cleaved caspase-3, cleaved caspase-9 and ROS production. Moreover, CPS-A attenuated both the normal expression and overexpression of TNF-α receptor 1 (TNFR1) induced by TNF-α administration. In conclusion, CPS-A was involved in TNF-α induced mitochondria abnormality via TNFR1/ROS/Mfn2 pathway.

  7. Abnormal Localization and Tumor Suppressor Function of Epithelial Tissue-Specific Transcription Factor ESE3 in Esophageal Squamous Cell Carcinoma.

    PubMed

    Wang, Li; Xing, Jie; Cheng, Rui; Shao, Ying; Li, Peng; Zhu, Shengtao; Zhang, Shutian

    2015-01-01

    Esophageal cancer is one of the most common malignant cancers worldwide. The molecular mechanism of esophageal squamous cell carcinoma (ESCC) is still poorly understood. ESE3 is a member of the Ets transcription family, which is only expressed in epithelial tissues and acts as a tumor suppressor gene in prostate cancer. Our study aim was to confirm whether ESE3 is involved in the carcinogenesis of ESCC. Immunohistochemical analysis revealed that ESE3 was mainly located in cell nuclei of normal tissues and the cytoplasm in ESCC tissues. Immunofluorescence and western blot analyses of the normal esophageal cell line HEEpiC and ESCC cell lines EC9706 TE-1, KYSE150, and KYSE410 confirmed these results. pEGFP-ESE3 and pcDNA3.1-V5/HisA-ESE3 plasmids were constructed for overexpression of ESE3 in EC9706 and KYSE150 cells. The stably transfected cells showed restoration of the nuclear localization of ESE3. EC9706 cells with re-localization of ESE3 to the nucleus showed inhibition of proliferation, colony formation, migration, and invasion. To explore the possible mechanism of the differences in localization of ESE3 in normal esophageal cells and ESCC cells, ESCC cell lines were treated with the nuclear export inhibitor leptomycin B, transcription inhibitor actinomycin D, PKC inhibitor sphinganine, P38 MAPK inhibitor SB202190, and CK II inhibitor TBCA. These reagents were chosen according to the well-known mechanisms of protein translocation. However, the localization of ESE3 was unchanged after these treatments. The sequence of ESE3 cDNA in ESCC cells was identical to the standard sequence of ESE3 in the NCBI Genebank database, indicating that there was no mutation in the coding region of ESE3 in ESCC. Taken together, our study suggests that ESE3 plays an important role in the carcinogenesis of ESCC through changes in subcellular localization and may act as a tumor suppressor gene in ESCC, although the mechanisms require further study.

  8. Fractal analysis of the retinal vasculature and chronic kidney disease.

    PubMed

    Sng, Chelvin C A; Sabanayagam, Charumathi; Lamoureux, Ecosse L; Liu, Erica; Lim, Su Chi; Hamzah, Haslina; Lee, Jeannette; Tai, E Shyong; Wong, Tien Y

    2010-07-01

    BACKGROUND. Fractal analysis provides a global index of the geometric complexity and optimality of vascular networks. In this study, we investigated the relationship between fractal measurements of the retinal vasculature and chronic kidney disease (CKD). METHODS. This was a population-based case-control study which included participants from the Singapore Prospective Study Program. We identified 261 participants with CKD, defined as estimated glomerular filtration rate of <60 mL/min/1.73 m(2), and 651 controls. The retinal fractal dimension (D(f)) was quantified from digitized fundus photographs using a computer-based programme. RESULTS. The mean D(f) was 1.43 +/- 0.048 in the participants with CKD and 1.44 +/- 0.042 in controls (P = 0.013). Suboptimal D(f) in the lowest (first) and highest (fifth) quintiles were associated with an increased prevalence of CKD after adjusting for age, systolic blood pressure, diabetes and other risk factors [odds ratio (OR) 2.10, 95% confidence interval (CI) 1.15, 3.83 and OR 1.84, 95% CI 1.06, 3.17; compared to the fourth quintile, respectively). This association was present even in participants without diabetes or hypertension. CONCLUSIONS. Our study found that an abnormal retinal vascular network is associated with an increased risk of CKD, supporting the hypothesis that deviations from optimal microvascular architecture may be related to kidney damage.

  9. What optimization principle explains the zebrafish vasculature?

    NASA Astrophysics Data System (ADS)

    Chang, Shyr-Shea; Baek, Kyung In; Hsiai, Tzung; Roper, Marcus

    2016-11-01

    Many multicellular organisms depend on biological transport networks; from the veins of leaves to the animal circulatory system, to redistribute nutrients internally. Since natural selection rewards efficiency, those networks are thought to minimize the cost of maintaining the flow inside. But optimizing these costs creates tradeoffs with other functions, e.g. mixing or uniform distribution of nutrients. We develop an extended Lagrange multiplier approach that allows the optimization of general network functionals. We also follow the real zebrafish vasculature and blood flows during organism development. Taken together, our work shows that the challenge of uniform oxygen perfusion, and not transport efficiency, explain zebrafish vascular organization. Ruth L. Kirschstein National Research Service Award (T32-GM008185).

  10. Tendon Vasculature in Health and Disease

    PubMed Central

    Tempfer, Herbert; Traweger, Andreas

    2015-01-01

    Tendons represent a bradytrophic tissue which is poorly vascularized and, compared to bone or skin, heal poorly. Usually, a vascularized connective scar tissue with inferior functional properties forms at the injury site. Whether the increased vascularization is the root cause of tissue impairments such as loss of collagen fiber orientation, ectopic formation of bone, fat or cartilage, or is a consequence of these pathological changes remains unclear. This review provides an overview of the role of tendon vasculature in healthy and chronically diseased tendon tissue as well as its relevance for tendon repair. Further, the nature and the role of perivascular tendon stem/progenitor cells residing in the vascular niche will be discussed and compared to multipotent stromal cells in other tissues. PMID:26635616

  11. Understanding Brain Tumors

    MedlinePlus

    ... to Know About Brain Tumors . What is a Brain Tumor? A brain tumor is an abnormal growth
 ... Tumors” from Frankly Speaking Frankly Speaking About Cancer: Brain Tumors Download the full book Questions to ask ...

  12. Endothelial cell metabolism in normal and diseased vasculature

    PubMed Central

    Eelen, Guy; de Zeeuw, Pauline; Simons, Michael; Carmeliet, Peter

    2015-01-01

    Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying vital nutrients and oxygen to distant tissues. Not surprisingly, vascular pathologies rank among the most life-threatening diseases. At the crux of most of these vascular pathologies are (dysfunctional) endothelial cells (ECs), the cells lining the blood vessel lumen. ECs display the remarkable capability to switch rapidly from a quiescent state to a highly migratory and proliferative state during vessel sprouting. This angiogenic switch has long been considered to be dictated by angiogenic growth factors (eg vascular endothelial growth factor; VEGF) and other signals (eg Notch) alone, but recent findings show that it is also driven by a metabolic switch in ECs. Furthermore, these changes in metabolism may even override signals inducing vessel sprouting. Here, we review how EC metabolism differs between the normal and dysfunctional/diseased vasculature and how it relates to or impacts the metabolism of other cell types contributing to the pathology. We focus on the biology of ECs in tumor blood vessel and diabetic ECs in atherosclerosis as examples of the role of endothelial metabolism in key pathological processes. Finally, current as well as unexplored ‘EC metabolism’-centric therapeutic avenues are discussed. PMID:25814684

  13. The association between retinal vasculature changes and stroke: a literature review and Meta-analysis

    PubMed Central

    Wu, Hui-Qun; Wu, Huan; Shi, Li-Li; Yu, Li-Yuan; Wang, Li-Yuan; Chen, Ya-Lan; Geng, Jin-Song; Shi, Jian; Jiang, Kui; Dong, Jian-Cheng

    2017-01-01

    AIM To determine the association between retinal vasculature changes and stroke. METHODS MEDLINE and EMBASE were searched for relevant human studies to September 2015 that investigated the association between retinal vasculature changes and the prevalence or incidence of stroke; the studies were independently examined for their qualities. Data on clinical characteristics and calculated summary odds ratios (ORs) were extracted for associations between retinal microvascular abnormalities and stroke, including stroke subtypes where possible, and adjusted for key variables. RESULTS Nine cases were included in the study comprising 20 659 patients, 1178 of whom were stroke patients. The retinal microvascular morphological markers used were hemorrhage, microaneurysm, vessel caliber, arteriovenous nicking, and fractal dimension. OR of retinal arteriole narrowing and retinal arteriovenous nicking and stroke was 1.42 and 1.91, respectively, indicating that a small-caliber retinal arteriole and retinal arteriovenous nicking were associated with stroke. OR of retinal hemorrhage and retinal microaneurysm and stroke was 3.21 and 3.83, respectively, indicating that retinal microvascular lesions were highly associated with stroke. Results also showed that retinal fractal dimension reduction was associated with stroke (OR: 2.28 for arteriole network, OR: 1.80 for venular network). CONCLUSION Retinal vasculature changes have a specific relationship to stroke, which is promising evidence for the prediction of stroke using computerized retinal vessel analysis. PMID:28149786

  14. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by or linked with viruses are: Cervical cancer (human papillomavirus) Most anal cancers (human papillomavirus) Some throat ...

  15. Functional photoacoustic microscopy of diabetic vasculature.

    PubMed

    Krumholz, Arie; Wang, Lidai; Yao, Junjie; Wang, Lihong V

    2012-06-01

    We used functional photoacoustic microscopy to image diabetes-induced damage to the microvasculature. To produce an animal model for Type 1 diabetes, we used streptozotocin (STZ), which is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. A set number of ND4 Swiss Webster mice received intraperitoneal injections of STZ for five consecutive days at 50 mg/kg. Most mice developed a significant rise in blood glucose level (≈ 400 mg/dL) within three weeks of the first injection. Changes in vasculature and hemodynamics were monitored for six weeks. The mouse ear was imaged with an optical-resolution photoacoustic microscope at a main blood vessel branch from the root of the ear. There are noticeable and measurable changes associated with the disease, including decreased vessel diameter and possible occlusion due to vessel damage and polyurea. We also observed an increase in the blood flow speed in the vein and a decrease in the artery, which could be due to compensation for the dehydration and vessel diameter changes. Functional and metabolic parameters such as hemoglobin oxygen saturation, oxygen extraction fraction, and oxygen consumption rate were also measured, but showed no significant change.

  16. Vascular metallomics: copper in the vasculature

    PubMed Central

    Easter, Renee N.; Chan, Qilin; Lai, Barry; Ritman, Erik L.; Caruso, Joseph A.; Qin, Zhenyu

    2009-01-01

    Due to recent progress in analytical techniques, metallomics are evolving from detecting distinct trace metals in a defined state to monitoring the dynamic changes in the abundance and location of trace metals in vitro and in vivo. Vascular metallomics is an emerging field that studies the role of trace metals in vasculature. This review will introduce common metallomics techniques including atomic absorption spectrometry, inductively coupled plasma-atomic emission spectrometry, inductively coupled plasma-mass spectrometry and X-ray fluorescence spectrometry with a summary table to compare these techniques. Moreover, we will summarize recent research findings that have applied these techniques to human population studies in cardiovascular diseases, with a particular emphasis on the role of copper in these diseases. In order to address the issue of interdisciplinary studies between metallomics and vascular biology, we will review the progress of efforts to understand the role of copper in neovascularization. This recent progress in the metallomics field may be a powerful tool to elucidating the signaling pathways and specific biological functions of these trace metals. Finally, we summarize the evidence to support the notion that copper is a dynamic signaling molecule. As a future direction, vascular metallomics studies may lead to the identification of targets for diagnosis and therapy in cardiovascular disease. PMID:19808712

  17. Functional photoacoustic microscopy of diabetic vasculature

    NASA Astrophysics Data System (ADS)

    Krumholz, Arie; Wang, Lidai; Yao, Junjie; Wang, Lihong V.

    2012-06-01

    We used functional photoacoustic microscopy to image diabetes-induced damage to the microvasculature. To produce an animal model for Type 1 diabetes, we used streptozotocin (STZ), which is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. A set number of ND4 Swiss Webster mice received intraperitoneal injections of STZ for five consecutive days at 50 mg/kg. Most mice developed a significant rise in blood glucose level (~400 mg/dL) within three weeks of the first injection. Changes in vasculature and hemodynamics were monitored for six weeks. The mouse ear was imaged with an optical-resolution photoacoustic microscope at a main blood vessel branch from the root of the ear. There are noticeable and measurable changes associated with the disease, including decreased vessel diameter and possible occlusion due to vessel damage and polyurea. We also observed an increase in the blood flow speed in the vein and a decrease in the artery, which could be due to compensation for the dehydration and vessel diameter changes. Functional and metabolic parameters such as hemoglobin oxygen saturation, oxygen extraction fraction, and oxygen consumption rate were also measured, but showed no significant change.

  18. Retinal vasculature classification using novel multifractal features

    NASA Astrophysics Data System (ADS)

    Ding, Y.; Ward, W. O. C.; Duan, Jinming; Auer, D. P.; Gowland, Penny; Bai, L.

    2015-11-01

    Retinal blood vessels have been implicated in a large number of diseases including diabetic retinopathy and cardiovascular diseases, which cause damages to retinal blood vessels. The availability of retinal vessel imaging provides an excellent opportunity for monitoring and diagnosis of retinal diseases, and automatic analysis of retinal vessels will help with the processes. However, state of the art vascular analysis methods such as counting the number of branches or measuring the curvature and diameter of individual vessels are unsuitable for the microvasculature. There has been published research using fractal analysis to calculate fractal dimensions of retinal blood vessels, but so far there has been no systematic research extracting discriminant features from retinal vessels for classifications. This paper introduces new methods for feature extraction from multifractal spectra of retinal vessels for classification. Two publicly available retinal vascular image databases are used for the experiments, and the proposed methods have produced accuracies of 85.5% and 77% for classification of healthy and diabetic retinal vasculatures. Experiments show that classification with multiple fractal features produces better rates compared with methods using a single fractal dimension value. In addition to this, experiments also show that classification accuracy can be affected by the accuracy of vessel segmentation algorithms.

  19. Alveolar abnormalities

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001093.htm Alveolar abnormalities To use the sharing features on this page, please enable JavaScript. Alveolar abnormalities are changes in the tiny air sacs in ...

  20. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... 2012:chap 71. Zaiac MN, Walker A. Nail abnormalities associated with systemic pathologies. Clin Dermatol . 2013;31: ...

  1. GPU accelerating technique for rendering implicitly represented vasculatures.

    PubMed

    Hong, Qingqi; Wang, Beizhan; Li, Qingde; Li, Yan; Wu, Qingqiang

    2014-01-01

    With the flooding datasets of medical Computed Tomography (CT) and Magnetic Resonance Imaging (MRI), implicit modeling techniques are increasingly applied to reconstruct the human organs, especially the vasculature. However, displaying implicitly represented geometric objects arises heavy computational burden. In this study, a Graphics Processing Unit (GPU) accelerating technique was developed for high performance rendering of implicitly represented objects, especially the vasculatures. The experimental results suggested that the rendering performance was greatly enhanced via exploiting the advantages of modern GPUs.

  2. Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment.

    PubMed

    Kirkpatrick, Nathaniel D; Chung, Euiheon; Cook, Daniel C; Han, Xiaoxing; Gruionu, Gabriel; Liao, Shan; Munn, Lance L; Padera, Timothy P; Fukumura, Dai; Jain, Rakesh K

    2012-01-01

    The abnormal tumor microenvironment fuels tumor progression, metastasis, immune suppression, and treatment resistance. Over last several decades, developments in and applications of intravital microscopy have provided unprecedented insights into the dynamics of the tumor microenvironment. In particular, intravital multiphoton microscopy has revealed the abnormal structure and function of tumor-associated blood and lymphatic vessels, the role of aberrant tumor matrix in drug delivery, invasion and metastasis of tumor cells, the dynamics of immune cell trafficking to and within tumors, and gene expression in tumors. However, traditional multiphoton microscopy suffers from inherently slow imaging rates-only a few frames per second, thus unable to capture more rapid events such as blood flow, lymphatic flow, and cell movement within vessels. Here, we report the development and implementation of a video-rate multiphoton microscope (VR-MPLSM) based on resonant galvanometer mirror scanning that is capable of recording at 30 frames per second and acquiring intravital multispectral images. We show that the design of the system can be readily implemented and is adaptable to various experimental models. As examples, we demonstrate the utility of the system to directly measure flow within tumors, capture metastatic cancer cells moving within the brain vasculature and cells in lymphatic vessels, and image acute responses to changes in a vascular network. VR-MPLSM thus has the potential to further advance intravital imaging and provide new insight into the biology of the tumor microenvironment.

  3. Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy.

    PubMed

    Johansson, Anna; Hamzah, Juliana; Payne, Christine J; Ganss, Ruth

    2012-05-15

    Solid tumors are intrinsically resistant to immune rejection. Abnormal tumor vasculature can act as a barrier for immune cell migration into tumors. We tested whether targeting IFNγ and/or TNFα into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFNγ causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low-dose TNFα enhances T-cell infiltration and overall survival, an effect that is exclusively mediated by CD8(+) effector cells. Intriguingly, lymphocyte influx does not correlate with increased vessel leakiness. Instead, low-dose TNFα stabilizes the vascular network and improves vessel perfusion. Inflammatory vessel remodeling is, at least in part, mediated by tumor-resident macrophages that are reprogrammed to secrete immune and angiogenic modulators. Moreover, inflammatory vessel remodeling with low-dose TNFα substantially improves antitumor vaccination or adoptive T-cell therapy. Thus, low-dose TNFα promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy.

  4. Brain Tumors

    MedlinePlus

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  5. Overview of Methods for Overcoming Hindrance to Drug Delivery to Tumors, with Special Attention to Tumor Interstitial Fluid

    PubMed Central

    Baronzio, Gianfranco; Parmar, Gurdev; Baronzio, Miriam

    2015-01-01

    Every drug used to treat cancer (chemotherapeutics, immunological, monoclonal antibodies, nanoparticles, radionuclides) must reach the targeted cells through the tumor environment at adequate concentrations, in order to exert their cell-killing effects. For any of these agents to reach the goal cells, they must overcome a number of impediments created by the tumor microenvironment (TME), beginning with tumor interstitial fluid pressure (TIFP), and a multifactorial increase in composition of the extracellular matrix (ECM). A primary modifier of TME is hypoxia, which increases the production of growth factors, such as vascular endothelial growth factor and platelet-derived growth factor. These growth factors released by both tumor cells and bone marrow recruited myeloid cells form abnormal vasculature characterized by vessels that are tortuous and more permeable. Increased leakiness combined with increased inflammatory byproducts accumulates fluid within the tumor mass (tumor interstitial fluid), ultimately creating an increased pressure (TIFP). Fibroblasts are also up-regulated by the TME, and deposit fibers that further augment the density of the ECM, thus, further worsening the TIFP. Increased TIFP with the ECM are the major obstacles to adequate drug delivery. By decreasing TIFP and ECM density, we can expect an associated rise in drug concentration within the tumor itself. In this overview, we will describe all the methods (drugs, nutraceuticals, and physical methods of treatment) able to lower TIFP and to modify ECM used for increasing drug concentration within the tumor tissue. PMID:26258072

  6. Arterial Abnormalities Leading to Tinnitus.

    PubMed

    Miller, Timothy R; Serulle, Yafell; Gandhi, Dheeraj

    2016-05-01

    Tinnitus is a common symptom that usually originates in the middle ear. Vascular causes of pulsatile tinnitus are categorized by the location of the source of the noise within the cerebral-cervical vasculature: arterial, arteriovenous, and venous. Arterial stenosis secondary to atherosclerotic disease or dissection, arterial anatomic variants at the skull base, and vascular skull base tumors are some of the more common causes of arterial and arteriovenous pulsatile tinnitus. Noninvasive imaging is indicated to evaluate for possible causes of pulsatile tinnitus, and should be followed by catheter angiography if there is a strong clinical suspicion for a dural arteriovenous fistula.

  7. Tumor angiogenesis in mice and men.

    PubMed

    Alani, Rhoda M; Silverthorn, Courtney F; Orosz, Kate

    2004-06-01

    Over the past decade much research has focused on understanding the molecular pathways that regulate the development of a tumor-associated vasculature. In 1999, Lyden and colleagues showed that mice deficient in one to three Id1 or Id3 alleles could not support the growth of tumor xenografts due to defects in tumor-associated angiogenesis. Three recently published manuscripts have now re-examined the role of Id genes in the development of a tumor-associated vasculature using more clinically relevant tumor model systems. Remarkably, all three studies have found strikingly different results compared to the original xenograft data published in 1999. Below we review the current understanding of the role of Id genes in the development of a tumor-associated vasculature given the most recent data and suggest ways in which animal tumor model systems might be put to better use to provide more clinically relevant information.

  8. VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors.

    PubMed

    Röhrig, F; Vorlová, S; Hoffmann, H; Wartenberg, M; Escorcia, F E; Keller, S; Tenspolde, M; Weigand, I; Gätzner, S; Manova, K; Penack, O; Scheinberg, D A; Rosenwald, A; Ergün, S; Granot, Z; Henke, E

    2017-01-05

    The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor's vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors. We demonstrate that, in anti-VEGF-refractory murine tumors, vascular changes after VEGF ablation result in reduced delivery leading to therapeutic failure. In these tumors, the impaired response after anti-VEGF treatment is directly linked to strong deposition of fibrillar extracellular matrix (ECM) components and high expression of lysyl oxidases. The resulting condensed, highly crosslinked ECM impeded drug permeation, protecting tumor cells from exposure to small-molecule drugs. The reduced vascular density after anti-VEGF treatment further decreased delivery in these tumors, an effect not compensated by the improved vessel quality. Pharmacological inhibition of lysyl oxidases improved drug delivery in various tumor models and reversed the negative effect of VEGF ablation on drug delivery and therapeutic response in anti-VEGF-resistant tumors. In conclusion, the vascular changes after anti-VEGF therapy can have a context-dependent negative impact on overall therapeutic efficacy. A determining factor is the tumor ECM, which strongly influences the effect of anti-VEGF therapy. Our results reveal the prospect to revert a possible negative effect and to potentiate responsiveness to antiangiogenic therapy by concomitantly targeting ECM-modifying enzymes.

  9. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  10. Childhood Brain Tumors

    MedlinePlus

    Brain tumors are abnormal growths inside the skull. They are among the most common types of childhood ... still be serious. Malignant tumors are cancerous. Childhood brain and spinal cord tumors can cause headaches and ...

  11. Vascular endothelial growth factor receptor-2 promotes the development of the lymphatic vasculature.

    PubMed

    Dellinger, Michael T; Meadows, Stryder M; Wynne, Katherine; Cleaver, Ondine; Brekken, Rolf A

    2013-01-01

    Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed by lymphatic endothelial cells and has been shown to stimulate lymphangiogenesis in adult mice. However, the role VEGFR2 serves in the development of the lymphatic vascular system has not been defined. Here we use the Cre-lox system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that Lyve-1(wt/Cre);Vegfr2(flox/flox) mice possess significantly fewer dermal lymphatic vessels than Vegfr2(flox/flox) mice. Although Lyve-1(wt/Cre);Vegfr2(flox/flox) mice exhibit lymphatic hypoplasia, the lymphatic network is functional and contains all of the key features of a normal lymphatic network (initial lymphatic vessels and valved collecting vessels surrounded by smooth muscle cells (SMCs)). We also show that Lyve-1(Cre) mice display robust Cre activity in macrophages and in blood vessels in the yolk sac, liver and lung. This activity dramatically impairs the development of blood vessels in these tissues in Lyve-1(wt/Cre);Vegfr2(flox/flox) embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of Vegfr2 in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of Lyve-1(wt/Cre);Vegfr2(flox/flox) mice is due to the deletion of Vegfr2 in the lymphatic vasculature not macrophages. Together, this work demonstrates that VEGFR2 directly promotes the expansion of the lymphatic network and further defines the molecular mechanisms controlling the development of the lymphatic vascular system.

  12. Abnormal fetal-maternal interactions: an evolutionary value?

    PubMed

    Espinoza, Jimmy

    2012-08-01

    There is clinical and ultrasonographic evidence that "abnormal fetal-maternal interactions" or "fetal-maternal conflicts" may be central to the mechanisms of injury in pregnancy complications such as fetal growth restriction, preeclampsia, fetal death, gestational diabetes, and a subset of patients with preterm parturition. This conceptual framework integrates abnormalities in the placental bed, placental vasculature, and other areas of fetal-maternal interactions with pregnancy complications in light of their possible evolutionary value.

  13. The Multifaceted Role of the Vasculature in Endochondral Fracture Repair

    PubMed Central

    Bahney, Chelsea S.; Hu, Diane P.; Miclau, Theodore; Marcucio, Ralph S.

    2015-01-01

    Fracture healing is critically dependent upon an adequate vascular supply. The normal rate for fracture delayed or non-union is estimated to be between 10 and 15%, and annual fracture numbers are approximately 15 million cases per year. However, when there is decreased vascular perfusion to the fracture, incidence of impaired healing rises dramatically to 46%. Reduction in the blood supply to the fracture can be the result of traumatic injuries that physically disrupt the vasculature and damage supportive soft tissue, the result of anatomical location (i.e., distal tibia), or attributed to physiological conditions such as age, diabetes, or smoking. The role of the vasculature during repair is multifaceted and changes during the course of healing. In this article, we review recent insights into the role of the vasculature during fracture repair. Taken together these data highlight the need for an updated model for endochondral repair to facilitate improved therapeutic approaches to promote bone healing. PMID:25699016

  14. Modeling Nanoparticle Transport and Distribution in Lung Vasculature

    NASA Astrophysics Data System (ADS)

    Liu, Yaling; Zheng, Junda

    2013-11-01

    The nanoparticle targeted delivery in vascular system involves interplay of transport, hydrodynamic force, and multivalent interactions with targeted biosurfaces. To estimate the percentage of NPs delivered to the targeted region, properties of the vascular environment must be considered, i.e., the vascular geometry and flow conditions. This paper describes a computational model for NP transport and distribution in a complex lung vasculature through combined NP Brownian dynamics and computational fluid dynamics approaches. MRI sliced lung vasculature images are transferred into vascular geometry, discretized into tetrahedral meshes, and used in blood velocity calculation and particle deposition simulation. A non-uniform NP distribution is observed on the vascular surface, with a high NP concentration in the bifurcation region. The simulation results show that NPs with different size have different distribution pattern in lung vasculature. This study provides a tool to predict NP distribution in a complex vascular network.

  15. Swept-source OCT Angiography of the Retinal Vasculature using Intensity Differentiation Based OMAG Algorithms

    PubMed Central

    Huang, Yanping; Zhang, Qinqin; Thorell, Mariana Rossi; An, Lin; Durbin, Mary; Laron, Michal; Sharma, Utkarsh; Gregori, Giovanni; Rosenfeld, Philip J.; Wang, Ruikang K

    2014-01-01

    Background and Objective To demonstrate the feasibility of using a 1050 nm swept-source OCT (SS-OCT) system to achieve noninvasive retinal vasculature imaging in human eyes. Materials and Methods Volumetric datasets were acquired using a ZEISS 1 µm SS-OCT prototype that operated at an A-line rate of 100 kHz. A scanning protocol designed to allow for motion contrast processing, referred to as OCT angiography or optical microangiography (OMAG), was used to scan ~3 mm × 3 mm area in the central macular region of the retina within ~4.5 seconds. Intensity differentiation based OMAG algorithm was used to extract 3-D retinal functional microvasculature information. Results Intensity signal differentiation generated capillary-level resolution en face OMAG images of the retina. The parafoveal capillaries were clearly visible, thereby allowing visualization of the foveal avascular zone (FAZ) in normal subjects. Conclusion The capability of OMAG to produce retinal vascular images was demonstrated using the ZEISS 1 µm SS-OCT prototype. This technique can potentially have clinical value for studying retinal vasculature abnormalities. PMID:25230403

  16. On the way to subcellular imaging of mechanotransduction in the developing vasculature

    NASA Astrophysics Data System (ADS)

    Larina, Irina V.; Wang, Yingxiao; Chien, Shu; Lane, Mary E.; Dickinson, Mary E.

    2007-05-01

    Endothelial cells that comprise vessels and line the heart are known to respond to mechanical forces imparted by fluid flow. It is also known that blood flow is required for vascular remodeling and that abnormal heart contractions lead to the failure of the vasculature to remodel properly. Although there is considerable evidence to indicate that flow is necessary, little is known about how mechanical signals are transduced in endothelial cells in the embryo. This project is focused on understanding the role mechanical forces play in the development of the cardiovascular system using recently generated FRET (Fluorescence Resonance Energy Transfer) reporter that can detect real-time Src-kinase activity in cells using fluorescence microscopy. Src kinase regulates integrin-cytoskeleton interactions that are essential for mechanotransduction, and its activity is upregulated in cultured endothelial cells exposed to flow. Experiments reported here were focused on testing potential feasibility of the proposed technique to sense Src changes in vivo. Successful implementation of this project will reveal previously unknown signaling events involved in the mechanism of vascular remodeling and their relation to the blood flow, thus providing a unique tool for in vivo sub-cellular imaging of mechanotransduction in the vasculature and other organs.

  17. A novel NF1 mutation in a Chinese patient with giant café-au-lait macule in neurofibromatosis type 1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

    PubMed

    Tong, H-X; Li, M; Zhang, Y; Zhu, J; Lu, W-Q

    2012-08-29

    Neurofibromatosis type 1 (NF1; OMIM#162200) is a common neurocutaneous disorder that is characterized by multiple café-au-lait, skinfold freckling, Lisch nodules, and neurofibromas. Mutations in the NF1 gene, which encodes the neurofibromin protein, have been identified as the pathogenic gene of NF1. In this study, we present a clinical and molecular study of a Chinese patient with giant café-au-lait in NF1. The patient showed >6 café-au-lait spots on the body, axillary freckling, and multiple subcutaneous neurofibromas. He also had a malignant peripheral nerve sheath tumor and bone abnormalities. The germline mutational analysis of the NF1 gene revealed a novel missense mutation in exon 13. It is a novel heterozygous nucleotide G>A transition at position 2241 of the NF1 gene. We found no mutation in malignant peripheral nerve sheath tumor DNA from this patient. This expands the database for NF1 gene mutations in NF1. Its absence in the normal chromosomes suggests that it is responsible for the NF1 phenotype. To our knowledge, this is the first case of giant café-au-lait macule in NF1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

  18. Gold nanoparticle induced vasculature damage in radiotherapy: Comparing protons, megavoltage photons, and kilovoltage photons

    PubMed Central

    Lin, Yuting; Paganetti, Harald; McMahon, Stephen J.; Schuemann, Jan

    2015-01-01

    to the inner vascular wall, the damage to the inner vascular wall can be up to 207% of the prescribed dose for the 250 kVp photon source, 4% for the 6 MV photon source, and 2% for the proton beam. Even though the average dose increase from the proton beam and MV photon beam was not large, there were high dose spikes that elevate the local dose of the parts of the blood vessel to be higher than 15 Gy even for 2 Gy prescribed dose, especially when the GNPs can be actively targeted to the endothelial cells. Conclusions: GNPs can potentially be used to enhance radiation therapy by causing vasculature damage through high dose spikes caused by the addition of GNPs especially for hypofractionated treatment. If GNPs are designed to actively accumulate at the tumor vasculature walls, vasculature damage can be increased significantly. The largest enhancement is seen using kilovoltage photons due to the photoelectric effect. Although no significant average dose enhancement was observed for the whole vasculature structure for both MV photons and protons, they can cause high local dose escalation (>15 Gy) to areas of the blood vessel that can potentially contribute to the disruption of the functionality of the blood vessels in the tumor. PMID:26429263

  19. Gold nanoparticle induced vasculature damage in radiotherapy: Comparing protons, megavoltage photons, and kilovoltage photons

    SciTech Connect

    Lin, Yuting Paganetti, Harald; Schuemann, Jan; McMahon, Stephen J.

    2015-10-15

    to the inner vascular wall, the damage to the inner vascular wall can be up to 207% of the prescribed dose for the 250 kVp photon source, 4% for the 6 MV photon source, and 2% for the proton beam. Even though the average dose increase from the proton beam and MV photon beam was not large, there were high dose spikes that elevate the local dose of the parts of the blood vessel to be higher than 15 Gy even for 2 Gy prescribed dose, especially when the GNPs can be actively targeted to the endothelial cells. Conclusions: GNPs can potentially be used to enhance radiation therapy by causing vasculature damage through high dose spikes caused by the addition of GNPs especially for hypofractionated treatment. If GNPs are designed to actively accumulate at the tumor vasculature walls, vasculature damage can be increased significantly. The largest enhancement is seen using kilovoltage photons due to the photoelectric effect. Although no significant average dose enhancement was observed for the whole vasculature structure for both MV photons and protons, they can cause high local dose escalation (>15 Gy) to areas of the blood vessel that can potentially contribute to the disruption of the functionality of the blood vessels in the tumor.

  20. Abnormal vasculature interferes with optic fissure closure in lmo2 mutant zebrafish embryos.

    PubMed

    Weiss, Omri; Kaufman, Rivka; Michaeli, Natali; Inbal, Adi

    2012-09-15

    Ocular coloboma is a potentially blinding congenital eye malformation caused by failure of optic fissure closure during early embryogenesis. The optic fissure is a ventral groove that forms during optic cup morphogenesis, and through which hyaloid artery and vein enter and leave the developing eye, respectively. After hyaloid artery and vein formation, the optic fissure closes around them. The mechanisms underlying optic fissure closure are poorly understood, and whether and how this process is influenced by hyaloid vessel development is unknown. Here we show that a loss-of-function mutation in lmo2, a gene specifically required for hematopoiesis and vascular development, results in failure of optic fissure closure in zebrafish. Analysis of ocular blood vessels in lmo2 mutants reveals that some vessels are severely dilated, including the hyaloid vein. Remarkably, reducing vessel size leads to rescue of optic fissure phenotype. Our results reveal a new mechanism leading to coloboma, whereby malformed blood vessels interfere with eye morphogenesis.

  1. Speckle variance OCT imaging of the vasculature in live mammalian embryos

    NASA Astrophysics Data System (ADS)

    Sudheendran, N.; Syed, S. H.; Dickinson, M. E.; Larina, I. V.; Larin, K. V.

    2011-03-01

    Live imaging of normal and abnormal vascular development in mammalian embryos is important tool in embryonic research, which can potentially contribute to understanding, prevention and treatment of cardiovascular birth defects. Here, we used speckle variance analysis of swept source optical coherence tomography (OCT) data sets acquired from live mouse embryos to reconstruct the 3-D structure of the embryonic vasculature. Both Doppler OCT and speckle variance algorithms were used to reconstruct the vascular structure. The results demonstrates that speckle variance imaging provides more accurate representation of the vascular structure, as it is not sensitive to the blood flow direction, while the Doppler OCT imaging misses blood flow component perpendicular to the beam direction. These studies suggest that speckle variance imaging is a promising tool to study vascular development in cultured mouse embryos.

  2. Identification of functional progenitor cells in the pulmonary vasculature

    PubMed Central

    Firth, Amy L.; Yuan, Jason X. -J.

    2012-01-01

    The pulmonary vasculature comprises a complex network of branching arteries and veins all functioning to reoxygenate the blood for circulation around the body. The cell types of the pulmonary artery are able to respond to changes in oxygen tension in order to match ventilation to perfusion. Stem and progenitor cells in the pulmonary vasculature are also involved, be it in angiogenesis, endothelial dysfunction or formation of vascular lesions. Stem and progenitor cells may be circulating around the body, residing in the pulmonary artery wall or stimulated for release from a central niche like the bone marrow and home to the pulmonary vasculature along a chemotactic gradient. There may currently be some controversy over the pathogenic versus therapeutic roles of stem and progenitor cells and, indeed, it is likely both chains of evidence are correct due to the specific influence of the immediate environmental niche a progenitor cell may be in. Due to their great plasticity and a lack of specific markers for stem and progenitor cells, they can be difficult to precisely identify. This review discusses the methodological approaches used to validate the presence of and subtype of progenitors cells in the pulmonary vasculature while putting it in context of the current knowledge of the therapeutic and pathogenic roles for such progenitor cells. PMID:22558524

  3. Thermal modelling using discrete vasculature for thermal therapy: a review

    PubMed Central

    Kok, H.P.; Gellermann, J.; van den Berg, C.A.T.; Stauffer, P.R.; Hand, J.W.; Crezee, J.

    2013-01-01

    Reliable temperature information during clinical hyperthermia and thermal ablation is essential for adequate treatment control, but conventional temperature measurements do not provide 3D temperature information. Treatment planning is a very useful tool to improve treatment quality and substantial progress has been made over the last decade. Thermal modelling is a very important and challenging aspect of hyperthermia treatment planning. Various thermal models have been developed for this purpose, with varying complexity. Since blood perfusion is such an important factor in thermal redistribution of energy in in vivo tissue, thermal simulations are most accurately performed by modelling discrete vasculature. This review describes the progress in thermal modelling with discrete vasculature for the purpose of hyperthermia treatment planning and thermal ablation. There has been significant progress in thermal modelling with discrete vasculature. Recent developments have made real-time simulations possible, which can provide feedback during treatment for improved therapy. Future clinical application of thermal modelling with discrete vasculature in hyperthermia treatment planning is expected to further improve treatment quality. PMID:23738700

  4. The lymphatic vasculature: development and role in shaping immunity.

    PubMed

    Betterman, Kelly L; Harvey, Natasha L

    2016-05-01

    The lymphatic vasculature is an integral component of the immune system. Lymphatic vessels are a key highway via which immune cells are trafficked, serving not simply as a passive route of transport, but to actively shape and coordinate immune responses. Reciprocally, immune cells provide signals that impact the growth, development, and activity of the lymphatic vasculature. In addition to immune cell trafficking, lymphatic vessels are crucial for fluid homeostasis and lipid absorption. The field of lymphatic vascular research is rapidly expanding, fuelled by rapidly advancing technology that has enabled the manipulation and imaging of lymphatic vessels, together with an increasing recognition of the involvement of lymphatic vessels in a myriad of human pathologies. In this review we provide an overview of the genetic pathways and cellular processes important for development and maturation of the lymphatic vasculature, discuss recent work revealing important roles for the lymphatic vasculature in directing immune cell traffic and coordinating immune responses and highlight the involvement of lymphatic vessels in a range of pathological settings.

  5. Effect of Ergot Alkaloids on Bovine Foregut Vasculature

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ergot alkaloids induce vasoconstriction of bovine foregut vasculature. Ergovaline induced the greatest response in ruminal artery while ergovaline and ergotamine induced the greatest response in ruminal vein. Lysergic acid did not stimulate a contractile response in either the ruminal artery or vein...

  6. Automatic quantification of neo-vasculature from micro-CT

    NASA Astrophysics Data System (ADS)

    Mallya, Yogish; Narayanan, A. K.; Zagorchev, Lyubomir

    2009-02-01

    Angiogenesis is the process of formation of new blood vessels as outgrowths of pre-existing ones. It occurs naturally during development, tissue repair, and abnormally in pathologic diseases such as cancer. It is associated with proliferation of blood vessels/tubular sprouts that penetrate deep into tissues to supply nutrients and remove waste products. The process starts with migration of endothelial cells. As the cells move towards the target area they form small tubular sprouts recruited from the parent vessel. The sprouts grow in length due to migration, proliferation, and recruitment of new endothelial cells and the process continues until the target area becomes fully vascular. Accurate quantification of sprout formation is very important for evaluation of treatments for ischemia as well as angiogenesis inhibitors and plays a key role in the battle against cancer. This paper presents a technique for automatic quantification of newly formed blood vessels from Micro-CT volumes of tumor samples. A semiautomatic technique based on interpolation of Bezier curves was used to segment out the cancerous growths. Small vessels as determined by their diameter within the segmented tumors were enhanced and quantified with a multi-scale 3-D line detection filter. The same technique can be easily extended for quantification of tubular structures in other 3-D medical imaging modalities. Experimental results are presented and discussed.

  7. Modeling Tumor-Associated Edema in Gliomas during Anti-Angiogenic Therapy and Its Impact on Imageable Tumor

    PubMed Central

    Hawkins-Daarud, Andrea; Rockne, Russell C.; Anderson, Alexander R. A.; Swanson, Kristin R.

    2013-01-01

    Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors

  8. Modeling Tumor-Associated Edema in Gliomas during Anti-Angiogenic Therapy and Its Impact on Imageable Tumor.

    PubMed

    Hawkins-Daarud, Andrea; Rockne, Russell C; Anderson, Alexander R A; Swanson, Kristin R

    2013-01-01

    Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors

  9. Mapping the Extracellular and Membrane Proteome Associated with the Vasculature and the Stroma in the Embryo*

    PubMed Central

    Soulet, Fabienne; Kilarski, Witold W.; Roux-Dalvai, Florence; Herbert, John M. J.; Sacewicz, Izabela; Mouton-Barbosa, Emmanuelle; Bicknell, Roy; Lalor, Patricia; Monsarrat, Bernard; Bikfalvi, Andreas

    2013-01-01

    In order to map the extracellular or membrane proteome associated with the vasculature and the stroma in an embryonic organism in vivo, we developed a biotinylation technique for chicken embryo and combined it with mass spectrometry and bioinformatic analysis. We also applied this procedure to implanted tumors growing on the chorioallantoic membrane or after the induction of granulation tissue. Membrane and extracellular matrix proteins were the most abundant components identified. Relative quantitative analysis revealed differential protein expression patterns in several tissues. Through a bioinformatic approach, we determined endothelial cell protein expression signatures, which allowed us to identify several proteins not yet reported to be associated with endothelial cells or the vasculature. This is the first study reported so far that applies in vivo biotinylation, in combination with robust label-free quantitative proteomics approaches and bioinformatic analysis, to an embryonic organism. It also provides the first description of the vascular and matrix proteome of the embryo that might constitute the starting point for further developments. PMID:23674615

  10. Walking abnormalities

    MedlinePlus

    ... or head trauma Brain tumor Cerebrovascular accident (stroke) Cerebral palsy Cervical spondylosis with myelopathy (a problem with the ... 22. Read More Arthritis Bunions Central nervous system Cerebral palsy Dizziness Ingrown toenail Multiple sclerosis Muscular dystrophy Myositis ...

  11. Leukocyte abnormalities.

    PubMed

    Gabig, T G

    1980-07-01

    Certain qualitative abnormalities in neutrophils and blood monocytes are associated with frequent, severe, and recurrent bacterial infections leading to fatal sepsis, while other qualitative defects demonstrated in vitro may have few or no clinical sequelae. These qualitative defects are discussed in terms of the specific functions of locomotion, phagocytosis, degranulation, and bacterial killing.

  12. From the Cover: Adipose tissue mass can be regulated through the vasculature

    NASA Astrophysics Data System (ADS)

    Rupnick, Maria A.; Panigrahy, Dipak; Zhang, Chen-Yu; Dallabrida, Susan M.; Lowell, Bradford B.; Langer, Robert; Judah Folkman, M.

    2002-08-01

    Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.

  13. Imaging of retinal vasculature using adaptive optics SLO/OCT

    PubMed Central

    Felberer, Franz; Rechenmacher, Matthias; Haindl, Richard; Baumann, Bernhard; Hitzenberger, Christoph K.; Pircher, Michael

    2015-01-01

    We use our previously developed adaptive optics (AO) scanning laser ophthalmoscope (SLO)/ optical coherence tomography (OCT) instrument to investigate its capability for imaging retinal vasculature. The system records SLO and OCT images simultaneously with a pixel to pixel correspondence which allows a direct comparison between those imaging modalities. Different field of views ranging from 0.8°x0.8° up to 4°x4° are supported by the instrument. In addition a dynamic focus scheme was developed for the AO-SLO/OCT system in order to maintain the high transverse resolution throughout imaging depth. The active axial eye tracking that is implemented in the OCT channel allows time resolved measurements of the retinal vasculature in the en-face imaging plane. Vessel walls and structures that we believe correspond to individual erythrocytes could be visualized with the system. PMID:25909024

  14. Unilateral persistent fetal vasculature coexisting with anterior segment dysgenesis.

    PubMed

    Khokhar, Sudarshan; Gupta, Shikha; Arora, Tarun; Gogia, Varun; Dada, Tanuj

    2013-08-01

    Persistent fetal vasculature (PFV) is a common congenital developmental anomaly of the eye which results from failure of the embryological primary vitreous and hyaloid vasculature to regress by the time of birth (Int Ophthalmol Clin 48: 53-62, 2008). Typically, it is divided into anterior, posterior or combined types and is characterized by the presence of a vascular stalk located between the optic disc and the posterior lens capsule (Int Ophthalmol Clin 48: 53-62, 2008). Although it has been reported to manifest itself differently, in our case it presented in a microphthalmic eye as anterior segment dysgenesis with broad-based mid-peripheral synechiae, posterior embryotoxon, iridoschisis, ectropion uveae, hypotony and subluxated cataractous lens with a taut anterior hyaloid face which are rare associations with PFV.

  15. Imaging of retinal vasculature using adaptive optics SLO/OCT.

    PubMed

    Felberer, Franz; Rechenmacher, Matthias; Haindl, Richard; Baumann, Bernhard; Hitzenberger, Christoph K; Pircher, Michael

    2015-04-01

    We use our previously developed adaptive optics (AO) scanning laser ophthalmoscope (SLO)/ optical coherence tomography (OCT) instrument to investigate its capability for imaging retinal vasculature. The system records SLO and OCT images simultaneously with a pixel to pixel correspondence which allows a direct comparison between those imaging modalities. Different field of views ranging from 0.8°x0.8° up to 4°x4° are supported by the instrument. In addition a dynamic focus scheme was developed for the AO-SLO/OCT system in order to maintain the high transverse resolution throughout imaging depth. The active axial eye tracking that is implemented in the OCT channel allows time resolved measurements of the retinal vasculature in the en-face imaging plane. Vessel walls and structures that we believe correspond to individual erythrocytes could be visualized with the system.

  16. System for definition of the central-chest vasculature

    NASA Astrophysics Data System (ADS)

    Taeprasartsit, Pinyo; Higgins, William E.

    2009-02-01

    Accurate definition of the central-chest vasculature from three-dimensional (3D) multi-detector CT (MDCT) images is important for pulmonary applications. For instance, the aorta and pulmonary artery help in automatic definition of the Mountain lymph-node stations for lung-cancer staging. This work presents a system for defining major vascular structures in the central chest. The system provides automatic methods for extracting the aorta and pulmonary artery and semi-automatic methods for extracting the other major central chest arteries/veins, such as the superior vena cava and azygos vein. Automatic aorta and pulmonary artery extraction are performed by model fitting and selection. The system also extracts certain vascular structure information to validate outputs. A semi-automatic method extracts vasculature by finding the medial axes between provided important sites. Results of the system are applied to lymph-node station definition and guidance of bronchoscopic biopsy.

  17. 3D morphological measurement of whole slide histological vasculature reconstructions

    NASA Astrophysics Data System (ADS)

    Xu, Yiwen; Pickering, J. G.; Nong, Zengxuan; Ward, Aaron D.

    2016-03-01

    Properties of the microvasculature that contribute to tissue perfusion can be assessed using immunohistochemistry on 2D histology sections. However, the vasculature is inherently 3D and the ability to measure and visualize the vessel wall components in 3D will aid in detecting focal pathologies. Our objectives were (1) to develop a method for 3D measurement and visualization of microvasculature in 3D, (2) to compare the normal and regenerated post-ischemia mouse hind limb microvasculature, and (3) to compare the 2D and 3D vessel morphology measures. Vessels were stained for smooth muscle using 3,3'-Diaminobenzidine (DAB) immunostain for both normal (n = 6 mice) and regenerated vasculature (n = 5 mice). 2D vessel segmentations were reconstructed into 3D using landmark based registration. No substantial bias was found in the 2D measurements relative to 3D, but larger differences were observed for individual vessels oriented non-orthogonally to the plane of sectioning. A larger value of area, perimeter, and vessel wall thickness was found in the normal vasculature as compared to the regenerated vasculature, for both the 2D and 3D measurements (p < 0.01). Aggregated 2D measurements are sufficient for identifying morphological differences between groups of mice; however, one must interpret individual 2D measurements with caution if the vessel centerline direction is unknown. Visualization of 3D measurements permits the detection of localized vessel morphology aberrations that are not revealed by 2D measurements. With vascular measure visualization methodologies in 3D, we are now capable of locating focal pathologies on a whole slide level.

  18. Segmentation and separation of venous vasculatures in liver CT images

    NASA Astrophysics Data System (ADS)

    Wang, Lei; Hansen, Christian; Zidowitz, Stephan; Hahn, Horst K.

    2014-03-01

    Computer-aided analysis of venous vasculatures including hepatic veins and portal veins is important in liver surgery planning. The analysis normally consists of two important pre-processing tasks: segmenting both vasculatures and separating them from each other by assigning different labels. During the acquisition of multi-phase CT images, both of the venous vessels are enhanced by injected contrast agent and acquired either in a common phase or in two individual phases. The enhanced signals established by contrast agent are often not stably acquired due to non-optimal acquisition time. Inadequate contrast and the presence of large lesions in oncological patients, make the segmentation task quite challenging. To overcome these diffculties, we propose a framework with minimal user interactions to analyze venous vasculatures in multi-phase CT images. Firstly, presented vasculatures are automatically segmented adopting an efficient multi-scale Hessian-based vesselness filter. The initially segmented vessel trees are then converted to a graph representation, on which a series of graph filters are applied in post-processing steps to rule out irrelevant structures. Eventually, we develop a semi-automatic workow to refine the segmentation in the areas of inferior vena cava and entrance of portal veins, and to simultaneously separate hepatic veins from portal veins. Segmentation quality was evaluated with intensive tests enclosing 60 CT images from both healthy liver donors and oncological patients. To quantitatively measure the similarities between segmented and reference vessel trees, we propose three additional metrics: skeleton distance, branch coverage, and boundary surface distance, which are dedicated to quantifying the misalignment induced by both branching patterns and radii of two vessel trees.

  19. Effects of dietary amines on the gut and its vasculature.

    PubMed

    Broadley, Kenneth J; Akhtar Anwar, M; Herbert, Amy A; Fehler, Martina; Jones, Elen M; Davies, Wyn E; Kidd, Emma J; Ford, William R

    2009-06-01

    Trace amines, including tyramine and beta-phenylethylamine (beta-PEA), are constituents of many foods including chocolate, cheeses and wines and are generated by so-called 'friendly' bacteria such as Lactobacillus, Lactococcus and Enterococcus species, which are found in probiotics. We therefore examined whether these dietary amines could exert pharmacological effects on the gut and its vasculature. In the present study we examined the effects of tyramine and beta-PEA on the contractile activity of guinea-pig and rat ileum and upon the isolated mesenteric vasculature and other blood vessels. Traditionally, these amines are regarded as sympathomimetic amines, exerting effects through the release of noradrenaline from sympathetic nerve endings, which should relax the gut. A secondary aim was therefore to confirm this mechanism of action. However, contractile effects were observed in the gut and these were independent of noradrenaline, acetylcholine, histamine and serotonin receptors. They were therefore probably due to the recently described trace amine-associated receptors. These amines relaxed the mesenteric vasculature. In contrast, the aorta and coronary arteries were constricted, a response that was also independent of a sympathomimetic action. From these results, we propose that after ingestion, trace amines could stimulate the gut and improve intestinal blood flow. Restriction of blood flow elsewhere diverts blood to the gut to aid digestion. Thus, trace amines in the diet may promote the digestive process through stimulation of the gut and improved gastrointestinal circulation.

  20. Anthropometry of fetal vasculature in the chorionic plate.

    PubMed

    Gordon, Z; Elad, D; Almog, R; Hazan, Y; Jaffa, A J; Eytan, O

    2007-12-01

    Normal fetal development is dependent on adequate placental blood perfusion. The functional role of the placenta takes place mainly in the capillary system; however, ultrasound imaging of fetal blood flow is commonly performed on the umbilical artery, or on its first branches over the chorionic plate. The objective of this study was to evaluate the structural organization of the feto-placental vasculature of the chorionic plate. Casting of the placental vasculature was performed on 15 full-term placentas using a dental polymer mixed with colored ink. Observations of the cast models revealed that the branching architecture of the chorionic vessel is a combination of dichotomous and monopodial patterns, where the first two to three generations are always of a dichotomous nature. Analysis of the daughter-to-mother diameter ratios in the chorionic vessels provided a maximum in the range of 0.6-0.8 for the dichotomous branches, whereas in monopodial branches it was in the range of 0.1-0.3. Similar to previous studies, this study reveals that the vasculature architecture is mostly monopodial for the marginal cord insertion and mostly dichotomous for the central insertion. The more marginal the umbilical cord insertion is on the chorionic plate, the more monopodial branching patterns are created to compensate the dichotomous pattern deficiency to perfuse peripheral placental territories.

  1. Lung vasculature imaging using speckle variance optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Cua, Michelle; Lee, Anthony M. D.; Lane, Pierre M.; McWilliams, Annette; Shaipanich, Tawimas; MacAulay, Calum E.; Yang, Victor X. D.; Lam, Stephen

    2012-02-01

    Architectural changes in and remodeling of the bronchial and pulmonary vasculature are important pathways in diseases such as asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. However, there is a lack of methods that can find and examine small bronchial vasculature in vivo. Structural lung airway imaging using optical coherence tomography (OCT) has previously been shown to be of great utility in examining bronchial lesions during lung cancer screening under the guidance of autofluorescence bronchoscopy. Using a fiber optic endoscopic OCT probe, we acquire OCT images from in vivo human subjects. The side-looking, circumferentially-scanning probe is inserted down the instrument channel of a standard bronchoscope and manually guided to the imaging location. Multiple images are collected with the probe spinning proximally at 100Hz. Due to friction, the distal end of the probe does not spin perfectly synchronous with the proximal end, resulting in non-uniform rotational distortion (NURD) of the images. First, we apply a correction algorithm to remove NURD. We then use a speckle variance algorithm to identify vasculature. The initial data show a vascaulture density in small human airways similar to what would be expected.

  2. Pancreatic islet cell tumor

    MedlinePlus

    ... functions. These include blood sugar level and the production of stomach acid. Tumors that arise from islet ... try and shrink the tumors. If the abnormal production of hormones is causing symptoms, you may receive ...

  3. Radiologic atlas of pulmonary abnormalities in children

    SciTech Connect

    Singleton, E.B.; Wagner, M.L.; Dutton, R.V.

    1988-01-01

    This book is an atlas about thoracic abnormalities in infants and children. The authors include computed tomographic, digital subtraction angiographic, ultrasonographic, and a few magnetic resonance (MR) images. They recognize and discuss how changes in the medical treatment of premature infants and the management of infection and pediatric tumors have altered some of the appearances and considerations in these diseases. Oriented toward all aspects of pulmonary abnormalities, the book starts with radiographic techniques and then discusses the normal chest, the newborn, infections, tumors, and pulmonary vascular diseases. There is comprehensive treatment of mediastinal abnormalities and a discussion of airway abnormalities.

  4. Tumor Endothelial Cells

    PubMed Central

    Dudley, Andrew C.

    2012-01-01

    The vascular endothelium is a dynamic cellular “organ” that controls passage of nutrients into tissues, maintains the flow of blood, and regulates the trafficking of leukocytes. In tumors, factors such as hypoxia and chronic growth factor stimulation result in endothelial dysfunction. For example, tumor blood vessels have irregular diameters; they are fragile, leaky, and blood flow is abnormal. There is now good evidence that these abnormalities in the tumor endothelium contribute to tumor growth and metastasis. Thus, determining the biological basis underlying these abnormalities is critical for understanding the pathophysiology of tumor progression and facilitating the design and delivery of effective antiangiogenic therapies. PMID:22393533

  5. Characterization of tumor microvascular structure and permeability: comparison between magnetic resonance imaging and intravital confocal imaging

    NASA Astrophysics Data System (ADS)

    Reitan, Nina Kristine; Thuen, Marte; Goa, Pa˚L. Erik; de Lange Davies, Catharina

    2010-05-01

    Solid tumors are characterized by abnormal blood vessel organization, structure, and function. These abnormalities give rise to enhanced vascular permeability and may predict therapeutic responses. The permeability and architecture of the microvasculature in human osteosarcoma tumors growing in dorsal window chambers in athymic mice were measured by confocal laser scanning microscopy (CLSM) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Dextran (40 kDa) and Gadomer were used as molecular tracers for CLSM and DCE-MRI, respectively. A significant correlation was found between permeability indicators. The extravasation rate Ki as measured by CLSM correlated positively with DCE-MRI parameters, such as the volume transfer constant Ktrans and the initial slope of the contrast agent concentration-time curve. This demonstrates that these two techniques give complementary information. Extravasation was further related to microvascular structure and was found to correlate with the fractal dimension and vascular density. The structural parameter values that were obtained from CLSM images were higher for abnormal tumor vasculature than for normal vessels.

  6. [Molecular abnormalities in lymphomas].

    PubMed

    Delsol, G

    2010-11-01

    Numerous molecular abnormalities have been described in lymphomas. They are of diagnostic and prognostic value and are taken into account for the WHO classification of these tumors. They also shed some light on the underlying molecular mechanisms involved in lymphomas. Overall, four types of molecular abnormalities are involved: mutations, translocations, amplifications and deletions of tumor suppressor genes. Several techniques are available to detect these molecular anomalies: conventional cytogenetic analysis, multicolor FISH, CGH array or gene expression profiling using DNA microarrays. In some lymphomas, genetic abnormalities are responsible for the expression of an abnormal protein (e.g. tyrosine-kinase, transcription factor) detectable by immunohistochemistry. In the present review, molecular abnormalities observed in the most frequent B, T or NK cell lymphomas are discussed. In the broad spectrum of diffuse large B-cell lymphomas microarray analysis shows mostly two subgroups of tumors, one with gene expression signature corresponding to germinal center B-cell-like (GCB: CD10+, BCL6 [B-Cell Lymphoma 6]+, centerine+, MUM1-) and a subgroup expressing an activated B-cell-like signature (ABC: CD10-, BCL6-, centerine-, MUM1+). Among other B-cell lymphomas with well characterized molecular abnormalies are follicular lymphoma (BCL2 deregulation), MALT lymphoma (Mucosa Associated Lymphoid Tissue) [API2-MALT1 (mucosa-associated-lymphoid-tissue-lymphoma-translocation-gene1) fusion protein or deregulation BCL10, MALT1, FOXP1. MALT1 transcription factors], mantle cell lymphoma (cycline D1 [CCND1] overexpression) and Burkitt lymphoma (c-Myc expression). Except for ALK (anaplastic lymphoma kinase)-positive anaplastic large cell lymphoma, well characterized molecular anomalies are rare in lymphomas developed from T or NK cells. Peripheral T cell lymphomas not otherwise specified are a heterogeneous group of tumors with frequent but not recurrent molecular abnormalities

  7. Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation

    PubMed Central

    Fatima, Anees; Wang, Ying; Uchida, Yutaka; Norden, Pieter; Liu, Ting; Culver, Austin; Dietz, William H.; Culver, Ford; Millay, Meredith; Mukouyama, Yoh-suke

    2016-01-01

    The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in FOXC2 are dominantly associated with late-onset lymphedema; however, the precise role of FOXC2 and a closely related factor, FOXC1, in the lymphatic system remains largely unknown. Here we identified a molecular cascade by which FOXC1 and FOXC2 regulate ERK signaling in lymphatic vessel growth. In mice, lymphatic endothelial cell–specific (LEC-specific) deletion of Foxc1, Foxc2, or both resulted in increased LEC proliferation, enlarged lymphatic vessels, and abnormal lymphatic vessel morphogenesis. Compared with LECs from control animals, LECs from mice lacking both Foxc1 and Foxc2 exhibited aberrant expression of Ras regulators, and embryos with LEC-specific deletion of Foxc1 and Foxc2, alone or in combination, exhibited ERK hyperactivation. Pharmacological ERK inhibition in utero abolished the abnormally enlarged lymphatic vessels in FOXC-deficient embryos. Together, these results identify FOXC1 and FOXC2 as essential regulators of lymphangiogenesis and indicate a new potential mechanistic basis for lymphatic-associated diseases. PMID:27214551

  8. [Abnormal expression of insulin-like growth factor-I receptor and inhibitory effect of its transcription intervention on nude mice xenograft tumor].

    PubMed

    Yao, M; Yan, X D; Cai, Y; Gu, J J; Yang, X L; Pan, L H; Wang, L; Yao, D F

    2016-11-20

    Objective: To investigate the expression of insulin-like growth factor-I receptor (IGF-IR) in liver cancer and the inhibitory effect of its transcription intervention on nude mice xenograft tumor. Methods: A total of 40 patients with primary liver cancer were enrolled, and 40 samples of cancer lesions, peri-cancerous tissues (with a distance of 2 cm to the margin of cancer lesion), or distal liver tissues (with a distance of 5 cm to the margin of cancer lesion), with a weight of 200 mg, were collected after surgery. Some of these samples were used for pathological examination, and the rest were stored at -85°C. A total of 18 BALB/c nude mice aged 4-6 weeks with a body weight of 18-20 g (9 male and 9 female mice) were randomly divided into control group, negative control group, and co-intervention group, with 6 mice in each group, and fed under specific pathogen-free conditions. The cell line was cultured in the dimethyl sulfoxide complete medium containing 10% fetal bovine serum in a CO2incubator at 37°C. When the cell confluence reached 90% after cell inoculation, shRNA was divided into co-intervention group, negative control group, and untreated control group and were transfected to hepatoma cells using PolyJetTM transfection reagent. Stable cell clones obtained by G418 screening and used for the in vivo study. Immunohistochemistry, Western blotting, and quantitative real-time PCR were used to analyze the expression of IGF-IR in the human hepatoma tissue and cell line. The IGF-IR shRNA eukaryotic expression plasmids were established and screened for the most effective sequence; they were transfected to PLC/PRF/5 hepatoma cells, and the CCK-8 assay was used to analyze the changes in cell proliferation. The stable cell line screened out by G418 was inoculated to establish the subcutaneous xenograft tumor in nude mice. The tumor growth curve was plotted and histological examination was performed. Graphpad Prism 5.0 and SPSS 18.0 were used for plotting and data

  9. Low-Dose Metronomic Cyclophosphamide Combined with Vascular Disrupting Therapy Induces Potent Anti-Tumor Activity in Preclinical Human Tumor Xenograft Models

    PubMed Central

    Daenen, Laura G.; Shaked, Yuval; Man, Shan; Xu, Ping; Voest, Emile E.; Hoffman, Robert M.; Chaplin, David; Kerbel, Robert S.

    2009-01-01

    Purpose Vascular disrupting agents (VDAs) preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part via mobilization and tumor colonization of circulating endothelial progenitor cells (CEPs). Co-treatment with an agent that blocks CEPs, such as VEGF-pathway targeting biologic antiangiogenic drugs, results in enhanced anti-tumor efficacy. We asked whether an alternative therapeutic modality – low-dose metronomic (LDM) chemotherapy could achieve the same result, given its CEP targeting effects. Experimental Design We studied the combination of the VDA OXi-4503 with daily administration of CEP-inhibiting, low-dose metronomic (LDM) cyclophosphamide to treat primary orthotopic tumors using the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. Results We found that daily oral LDM cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi-4503; this was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as SCID mice. Similar results were found in MeWo bearing nude mice. The delay in tumor growth was accompanied by significant decreases in micro-vessel density, perfusion and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. Conclusions The combination of OXi-4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy. PMID:19825805

  10. Nonlinear analysis using Lyapunov exponents in breast thermograms to identify abnormal lesions

    NASA Astrophysics Data System (ADS)

    EtehadTavakol, M.; Ng, E. Y. K.; Lucas, C.; Sadri, S.; Ataei, M.

    2012-07-01

    Breast diseases are one of the major issues in women's health today. Early detection of breast cancer plays a significant role in reducing the mortality rate. Breast thermography is a potential early detection method which is non-invasive, non-radiating, passive, fast, painless, low cost, risk free with no contact with the body. By identifying and removing malignant tumors in early stages before they metastasize and spread to neighboring regions, cancer threats can be minimized. Cancer is often characterized as a chaotic, poorly regulated growth. Cancerous cells, tumors, and vasculature defy have irregular shapes which have potential to be described by a nonlinear dynamical system. Chaotic time series can provide the tools necessary to generate the procedures to evaluate the nonlinear system. Computing Lyapunov exponents is thus a powerful means of quantifying the degree of the chaos. In this paper, we present a novel approach using nonlinear chaotic dynamical system theory for estimating Lyapunov exponents in establishing possible difference between malignant and benign patterns. In order to develop the algorithm, the first hottest regions of breast thermal images are identified first, and then one dimensional scalar time series is obtained in terms of the distance between each subsequent boundary contour points and the center of the mass of the first hottest region. In the next step, the embedding dimension is estimated, and by time delay embedding method, the phase space is reconstructed. In the last step, the Lyapunov exponents are computed to analyze normality or abnormality of the lesions. Positive Lyapunov exponents indicates abnormality while negative Lyapunov exponents represent normality. The normalized errors show the algorithm is satisfactorily, and provide a measure of chaos. It is shown that nonlinear analysis of breast thermograms using Lyapunov exponents may potentially capable of improving reliability of thermography in breast tumor detection as

  11. Vatuximab (Trademark): Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

    DTIC Science & Technology

    2006-12-01

    novel antibody 3G4, which targets phosphatidylserine ( PS ) expressed on tumor vasculature was developed by Thorpe et al. and is being developed by...Peregrine Pharmaceuticals for clinical trials. Normally, PS exclusively resides on the cytosolic leaflet of the plasma membrane. However, in tumors PS ...they generated a novel antibody 3G4, which targets phosphatidylserine ( PS ) expressed on tumor vasculature. 3G4 is a naked antibody, which recruits

  12. Pulmonary vascular development goes awry in congenital lung abnormalities.

    PubMed

    Kool, Heleen; Mous, Daphne; Tibboel, Dick; de Klein, Annelies; Rottier, Robbert J

    2014-12-01

    Pulmonary vascular diseases of the newborn comprise a wide range of pathological conditions with developmental abnormalities in the pulmonary vasculature. Clinically, pulmonary arterial hypertension (PH) is characterized by persistent increased resistance of the vasculature and abnormal vascular response. The classification of PH is primarily based on clinical parameters instead of morphology and distinguishes five groups of PH. Congenital lung anomalies, such as alveolar capillary dysplasia (ACD) and PH associated with congenital diaphragmatic hernia (CDH), but also bronchopulmonary dysplasia (BPD), are classified in group three. Clearly, tight and correct regulation of pulmonary vascular development is crucial for normal lung development. Human and animal model systems have increased our knowledge and make it possible to identify and characterize affected pathways and study pivotal genes. Understanding of the normal development of the pulmonary vasculature will give new insights in the origin of the spectrum of rare diseases, such as CDH, ACD, and BPD, which render a significant clinical problem in neonatal intensive care units around the world. In this review, we describe normal pulmonary vascular development, and focus on four diseases of the newborn in which abnormal pulmonary vascular development play a critical role in morbidity and mortality. In the future perspective, we indicate the lines of research that seem to be very promising for elucidating the molecular pathways involved in the origin of congenital pulmonary vascular disease.

  13. Brief Communication: Tissue-engineered Microenvironment Systems for Modeling Human Vasculature

    PubMed Central

    Tourovskaia, Anna; Fauver, Mark; Kramer, Gregory; Simonson, Sara; Neumann, Thomas

    2015-01-01

    The high attrition rate of drug candidates late in the development process has led to an increasing demand for test assays that predict clinical outcome better than conventional 2D cell culture systems and animal models. Government agencies, the military, and the pharmaceutical industry have started initiatives for the development of novel in-vitro systems that recapitulate functional units of human tissues and organs. There is growing evidence that 3D cell arrangement, co-culture of different cell types, and physico-chemical cues lead to improved predictive power. A key element of all tissue microenvironments is the vasculature. Beyond transporting blood the microvasculature assumes important organ-specific functions. It is also involved in pathologic conditions, such as inflammation, tumor growth, metastasis, and degenerative diseases. To provide a tool for modeling this important feature of human tissue microenvironments, we developed a microfluidic chip for creating tissue-engineered microenvironment systems (TEMS) composed of tubular cell structures. Our chip design encompasses a small chamber that is filled with an extracellular matrix (ECM) surrounding one or more tubular channels. Endothelial cells seeded into the channels adhere to the ECM walls and grow into perfusable tubular tissue structures that are fluidically connected to upstream and downstream fluid channels in the chip. Using these chips we created models of angiogenesis, the blood-brain-barrier (BBB), and tumor-cell extravasation. Our angiogenesis model recapitulates true angiogenesis, in which sprouting occurs from a “parent” vessel in response to a gradient of growth factors. Our BBB model is composed of a microvessel generated from brain-specific endothelial cells (ECs) within an ECM populated with astrocytes and pericytes. Our tumor-cell extravasation model can be utilized to visualize and measure tumor-cell migration through vessel walls into the surrounding matrix. The described

  14. In Vitro Study of Directly Bioprinted Perfusable Vasculature Conduits

    PubMed Central

    Zhang, Yahui; Yu, Yin; Akkouch, Adil; Dababneh, Amer; Dolati, Farzaneh

    2014-01-01

    The ability to create three dimensional (3D) thick tissues is still a major tissue engineering challenge. It requires the development of a suitable vascular supply for an efficient media exchange. An integrated vasculature network is particularly needed when building thick functional tissues and/or organs with high metabolic activities, such as the heart, liver and pancreas. In this work, human umbilical vein smooth muscle cells (HUVSMCs) were encapsulated in sodium alginate and printed in the form of vasculature conduits using a coaxial deposition system. Detailed investigations were performed to understand the dehydration, swelling and degradation characteristics of printed conduits. In addition, because perfusional, permeable and mechanical properties are unique characteristics of natural blood vessels, for printed conduits these properties were also explored in this work. The results show that cells encapsulated in conduits had good proliferation activities and that their viability increased during prolonged in vitro culture. Deposition of smooth muscle matrix and collagen was observed around the peripheral and luminal surface in long-term cultured cellular vascular conduit through histology studies. PMID:25574378

  15. Role of VDR in anti-proliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo

    PubMed Central

    Chung, Ivy; Han, Guangzhou; Seshadri, Mukund; Gillard, Bryan M.; Yu, Wei-dong; Foster, Barbara A.; Trump, Donald L.; Johnson, Candace S.

    2008-01-01

    Calcitriol (1, 25-dihydroxycholecalciferol), the major active form of vitamin D, is anti-proliferative in tumor cells and tumor-derived endothelial cells (TDEC). These actions of calcitriol are mediated at least in part by vitamin D receptor (VDR), which is expressed in many tissues including endothelial cells. To investigate the role of VDR in calcitriol effects on tumor vasculature, we established TRAMP-2 tumors subcutaneously into either VDR wild type (WT) or knockout (KO) mice. Within 30 days post inoculation, tumors in KO mice were larger than those in WT (P<0.001). TDEC from WT expressed VDR and were able to transactivate a reporter gene whereas TDEC from KO mice were not. Treatment with calcitriol resulted in growth inhibition in TDEC expressing VDR. However, TDEC from KO mice were relatively resistant, suggesting that calcitriol-mediated growth inhibition on TDEC is VDR-dependent. Further analysis of the TRAMP-C2 tumor sections revealed that the vessels in KO mice were enlarged and had less pericyte coverage compared to WT (P<0.001). Contrast-enhanced MRI demonstrated an increase in vascular volume of TRAMP tumors grown in VDR KO mice compared to WT mice (P<0.001) and FITC-dextran permeability assay suggested a higher extent of vascular leakage in tumors from KO mice. Using ELISA and Western blot analysis, there was an increase of HIF-1 alpha, VEGF, Ang1 and PDGF-BB levels observed in tumors from KO mice. These results indicate that calcitriol-mediated anti-proliferative effects on TDEC are VDR dependent and loss of VDR can lead to abnormal tumor angiogenesis. PMID:19141646

  16. Three-dimensional stereotactic atlas of the extracranial vasculature correlated with the intracranial vasculature, cranial nerves, skull and muscles

    PubMed Central

    Shoon Let Thaung, Thant; Choon Chua, Beng; Hnin Wut Yi, Su; Yang, Yili; Urbanik, Andrzej

    2015-01-01

    Our objective was to construct a 3D, interactive, and reference atlas of the extracranial vasculature spatially correlated with the intracranial blood vessels, cranial nerves, skull, glands, and head muscles. The atlas has been constructed from multiple 3T and 7T magnetic resonance angiogram (MRA) brain scans, and 3T phase contrast and inflow MRA neck scans of the same specimen in the following steps: vessel extraction from the scans, building 3D tubular models of the vessels, spatial registration of the extra- and intracranial vessels, vessel editing, vessel naming and color-coding, vessel simplification, and atlas validation. This new atlas contains 48 names of the extracranial vessels (25 arterial and 23 venous) and it has been integrated with the existing brain atlas. The atlas is valuable for medical students and residents to easily get familiarized with the extracranial vasculature with a few clicks; is useful for educators to prepare teaching materials; and potentially can serve as a reference in the diagnosis of vascular disease and treatment, including craniomaxillofacial surgeries and radiologic interventions of the face and neck. PMID:25923683

  17. Three-dimensional stereotactic atlas of the extracranial vasculature correlated with the intracranial vasculature, cranial nerves, skull and muscles.

    PubMed

    Nowinski, Wieslaw L; Shoon Let Thaung, Thant; Choon Chua, Beng; Hnin Wut Yi, Su; Yang, Yili; Urbanik, Andrzej

    2015-04-01

    Our objective was to construct a 3D, interactive, and reference atlas of the extracranial vasculature spatially correlated with the intracranial blood vessels, cranial nerves, skull, glands, and head muscles.The atlas has been constructed from multiple 3T and 7T magnetic resonance angiogram (MRA) brain scans, and 3T phase contrast and inflow MRA neck scans of the same specimen in the following steps: vessel extraction from the scans, building 3D tubular models of the vessels, spatial registration of the extra- and intracranial vessels, vessel editing, vessel naming and color-coding, vessel simplification, and atlas validation.This new atlas contains 48 names of the extracranial vessels (25 arterial and 23 venous) and it has been integrated with the existing brain atlas.The atlas is valuable for medical students and residents to easily get familiarized with the extracranial vasculature with a few clicks; is useful for educators to prepare teaching materials; and potentially can serve as a reference in the diagnosis of vascular disease and treatment, including craniomaxillofacial surgeries and radiologic interventions of the face and neck.

  18. Hepatic perfusion abnormalities during CT angiography: Detection and interpretation

    SciTech Connect

    Freeny, P.C.; Marks, W.M.

    1986-06-01

    Twenty-seven perfusion abnormalities were detected in 17 of 50 patients who underwent computed tomographic angiography (CTA) of the liver. All but one of the perfusion abnormalities occurred in patients with primary or metastatic liver tumors. Perfusion abnormalities were lobar in nine cases, segmental in 11, and subsegmental in seven; 14 were hypoperfusion and 13 were hyperperfusion abnormalities. The causes for the abnormalities included nonperfusion of a replaced hepatic artery (n = 11), cirrhosis and nodular regeneration (n = 3), altered hepatic hemodynamics (e.g., siphoning, laminar flow) caused by tumor (n = 7), contrast media washout from a nonperfused vessel (n = 1), compression of adjacent hepatic parenchyma (n = 1), and unknown (n = 4). Differentiation of perfusion abnormalities from tumor usually can be made by comparing the morphology of the known tumor with the suspected perfusion abnormality, changes of each on delayed CTA scans, and review of initial angiograms and other imaging studies.

  19. Impact of a Combined High Cholesterol Diet and High Glucose Environment on Vasculature

    PubMed Central

    Cui, Taixing; Tang, Dongqi; Wang, Xing Li

    2013-01-01

    Aims Vascular complications are the leading cause of mortality and morbidity in patients with diabetes. However, proper animal models of diabetic vasculopathy that recapitulate the accelerated progression of vascular lesions in human are unavailable. In the present study, we developed a zebrafish model of diabetic vascular complications and the methodology for quantifying vascular lesion formation real-time in the living diabetic zebrafish. Methods and Results Wild type zebrafish (AB) and transgenic zebrafish lines of fli1:EGFP, lyz:EGFP, gata1:dsRed, double transgenic zebrafish of gata1:dsRed/fli1:EGFP were exposed to high cholesterol diet and 3% glucose (HCD-HG) for 10 days. The zebrafish model with HCD-HG treatment was characterized by significantly increased tissue levels of insulin, glucagon, glucose, total triglyceride and cholesterol. Confocal microscopic analysis further revealed that the diabetic larvae developed clearly thickened endothelial layers, distinct perivascular lipid depositions, substantial accumulations of inflammatory cells in the injured vasculature, and a decreased velocity of blood flow. Moreover, the vascular abnormalities were improved by the treatment of pioglitazone and metformin. Conclusion A combination of high cholesterol diet and high glucose exposure induces a rapid onset of vascular complications in zebrafish similar to the early atherosclerotic vascular injuries in mammalian diabetic models, suggesting that zebrafish may be used as a novel animal model for diabetic vasculopathy. PMID:24349075

  20. Imaging Nanotherapeutics in Inflamed Vasculature by Intravital Microscopy

    PubMed Central

    Wang, Zhenjia

    2016-01-01

    Intravital microscopy (IVM) is the application of light microscopy to real time study biology of live animal tissues in intact and physiological conditions with the high spatial and temporal resolution. Advances in imaging systems, genetic animal models and imaging probes, IVM has offered quantitative and dynamic insight into cell biology, immunology, neurobiology and cancer. In this review, we will focus on the targeting of nanotherapeutics to inflamed vasculature. We will introduce the basic concept and principle of IVM and demonstrate that IVM is a powerful tool used to quantitatively determine the molecular mechanisms of interactions between nanotherapeutics and neutrophils or endothelium in living mice. In the future, it is needed to develop new imaging systems and novel imaging contrast agents to better understand molecular mechanisms of tissue processing of nanotherapeutics in vivo. PMID:27877245

  1. 3D visualization of the human cerebral vasculature

    NASA Astrophysics Data System (ADS)

    Zrimec, Tatjana; Mander, Tom; Lambert, Timothy; Parker, Geoffrey

    1995-04-01

    Computer assisted 3D visualization of the human cerebro-vascular system can help to locate blood vessels during diagnosis and to approach them during treatment. Our aim is to reconstruct the human cerebro-vascular system from the partial information collected from a variety of medical imaging instruments and to generate a 3D graphical representation. This paper describes a tool developed for 3D visualization of cerebro-vascular structures. It also describes a symbolic approach to modeling vascular anatomy. The tool, called Ispline, is used to display the graphical information stored in a symbolic model of the vasculature. The vascular model was developed to assist image processing and image fusion. The model consists of a structural symbolic representation using frames and a geometrical representation of vessel shapes and vessel topology. Ispline has proved to be useful for visualizing both the synthetically constructed vessels of the symbolic model and the vessels extracted from a patient's MR angiograms.

  2. Emerging concepts regarding pannexin 1 in the vasculature

    PubMed Central

    Good, Miranda E.; Begandt, Daniela; DeLalio, Leon J.; Keller, Alexander S.; Billaud, Marie; Isakson, Brant E.

    2016-01-01

    Pannexin channels are newly discovered ATP release channels expressed throughout the body. Pannexin 1 (Panx1) channels have become of great interest as they appear to participate in a multitude of signalling cascades, including regulation of vascular function. Although numerous Panx1 pharmacological inhibitors have been discovered, these inhibitors are not specific for Panx1 and have additional effects on other proteins. Therefore, molecular tools, such as RNA interference and knockout animals, are needed to demonstrate the role of pannexins in various cellular functions. This review focuses on the known roles of Panx1 related to purinergic signalling in the vasculature focusing on post-translational modifications and channel gating mechanisms that may participate in the regulated release of ATP. PMID:26009197

  3. Oligodendrocyte precursors migrate along vasculature in the developing nervous system.

    PubMed

    Tsai, Hui-Hsin; Niu, Jianqin; Munji, Roeben; Davalos, Dimitrios; Chang, Junlei; Zhang, Haijing; Tien, An-Chi; Kuo, Calvin J; Chan, Jonah R; Daneman, Richard; Fancy, Stephen P J

    2016-01-22

    Oligodendrocytes myelinate axons in the central nervous system and develop from oligodendrocyte precursor cells (OPCs) that must first migrate extensively during brain and spinal cord development. We show that OPCs require the vasculature as a physical substrate for migration. We observed that OPCs of the embryonic mouse brain and spinal cord, as well as the human cortex, emerge from progenitor domains and associate with the abluminal endothelial surface of nearby blood vessels. Migrating OPCs crawl along and jump between vessels. OPC migration in vivo was disrupted in mice with defective vascular architecture but was normal in mice lacking pericytes. Thus, physical interactions with the vascular endothelium are required for OPC migration. We identify Wnt-Cxcr4 (chemokine receptor 4) signaling in regulation of OPC-endothelial interactions and propose that this signaling coordinates OPC migration with differentiation.

  4. Contrast-enhanced imaging of cerebral vasculature with laser speckle

    NASA Astrophysics Data System (ADS)

    Murari, K.; Li, N.; Rege, A.; Jia, X.; All, A.; Thakor, N.

    2007-08-01

    High-resolution cerebral vasculature imaging has applications ranging from intraoperative procedures to basic neuroscience research. Laser speckle, with spatial contrast processing, has recently been used to map cerebral blood flow. We present an application of the technique using temporal contrast processing to image cerebral vascular structures with a field of view a few millimeters across and approximately 20 μm resolution through a thinned skull. We validate the images using fluorescent imaging and demonstrate a factor of 2-4 enhancement in contrast-to-noise ratios over reflectance imaging using white or spectrally filtered green light. The contrast enhancement enables the perception of approximately 10%-30% more vascular structures without the introduction of any contrast agent.

  5. Studying Cerebral Vasculature Using Structure Proximity and Graph Kernels

    PubMed Central

    Kwitt, Roland; Pace, Danielle; Niethammer, Marc; Aylward, Stephen

    2014-01-01

    An approach to study population differences in cerebral vasculature is proposed. This is done by 1) extending the concept of encoding cerebral blood vessel networks as spatial graphs and 2) quantifying graph similarity in a kernel-based discriminant classifier setup. We argue that augmenting graph vertices with information about their proximity to selected brain structures adds discriminative information and consequently leads to a more expressive encoding. Using graph-kernels then allows us to quantify graph similarity in a principled way. To demonstrate our approach, we assess the hypothesis that gender differences manifest as variations in the architecture of cerebral blood vessels, an observation that previously had only been tested and confirmed for the Circle of Willis. Our results strongly support this hypothesis, i.e, we can demonstrate non-trivial, statistically significant deviations from random gender classification in a cross-validation setup on 40 healthy patients. PMID:24579182

  6. Dilated iris vasculature in the setting of the neonatal hypoxic encephelopathy.

    PubMed

    Gorovoy, Ian R; Vaccari, Jordan C

    2015-07-01

    The differential diagnosis of dilated iris vasculature in a neonate includes retinopathy of prematurity with anterior segment plus disease, persistent fetal vasculature, intrauterine cocaine exposure, maternal diabetes, and other pathologies associated with iris neovascularization and ischemia seen in adult populations, such as central retinal vein occlusions, ocular ischemic syndrome, and chronic retinal detachment. We present neonatal hypoxic ischemic encephalopathy as a new etiology of dilated iris vasculature in a male baby who suffered a large in-utero brain vasculature insult three weeks prior to delivery but with normal fundi, no risk factors for retinopathy of prematurity (normal birth weight, and gestational age), and no other explanatory etiologies. The mechanism of the dilated iris vasculature is likely also ischemic and therefore its presence likely portends a poor prognosis. We recommend that the neonatologist evaluate for this sign for this reason and consult ophthalmology to ensure its correct etiology.

  7. Chromosome abnormalities in primary ovarian cancer

    SciTech Connect

    Yonescu, R.; Currie, J.; Griffin, C.A.

    1994-09-01

    Chromosome abnormalities that are specific and recurrent may occur in regions of the genome that are involved in the conversion of normal cells to those with tumorigenic potential. Ovarian cancer is the primary cause of death among patients with gynecological malignancies. We have performed cytogenetic analysis of 16 ovarian tumors from women age 28-82. Three tumors of low malignant potential and three granulosa cell tumors had normal karyotypes. To look for the presence of trisomy 12, which has been suggested to be a common aberration in this group of tumors, interphase fluorescence in situ hybridization was performed on direct preparations from three of these tumors using a probe for alpha satellite sequences of chromosome 12. In the 3 preparations, 92-98 percent of the cells contained two copies of chromosome 12, indicating that trisomy 12 is not a universal finding in low grade ovarian tumors. Endometrioid carcinoma of the ovary is histologically indistinguishable from endometial carcinoma of the uterus. We studied 10 endometrioid tumors to determine the degree of genetic similarity between these two carcinomas. Six out of ten endometrioid tumors showed a near-triploid modal number, and one presented with a tetraploid modal number. Eight of the ten contained structural chromosome abnormalities, of which the most frequent were 1p- (5 tumors), 19q+ (3 tumors), 6q- or ins(6) (4 tumors), 3q- or 3q+ (4 tumors). These cytogenetic results resemble those reported for papillary ovarian tumors and differ from those of endometrial carcinoma of the uterus. We conclude that despite the histologic similarities between the endometrioid and endometrial carcinomas, the genetic abnormalities in the genesis of these tumors differ significantly.

  8. Improving delivery and efficacy of nanomedicines in solid tumors: Role of tumor priming

    PubMed Central

    Wang, Jie; Lu, Ze; Gao, Yue; Wientjes, M. Guillaume; Au, Jessie L.-S.

    2013-01-01

    Effectiveness of nanomedicines in cancer therapy is limited in part by inadequate delivery and transport in tumor interstitium. This report reviews the experimental approaches to improve nanomedicines delivery and transport in solid tumors. These approaches include tumor vasculature normalization, interstitial fluid pressure modulation, enzymatic extracellular matrix degradation, and apoptosis-inducing tumor priming technology. We advocate the latter approach due to its ease and practicality (accomplished with standard-of-care chemotherapy such as paclitaxel) and tumor selectivity. Examples of applying tumor priming to deliver nanomedicines and to design drug/RNAi-loaded carriers are discussed. PMID:22077464

  9. The lymphatic vasculature revisited-new developments in the zebrafish.

    PubMed

    Padberg, Y; Schulte-Merker, S; van Impel, A

    2017-01-01

    The lymphatic system is lined by endothelial cells and part of the vasculature. It is essential for tissue fluid homeostasis, absorption of dietary fats, and immune surveillance in vertebrates. Misregulation of lymphatic vessel formation and dysfunction of the lymphatic system have been indicated in a number of pathological conditions including lymphedema formation, obesity or chronic inflammatory diseases such as rheumatoid arthritis. In zebrafish, lymphatics were discovered about 10years ago, and the underlying molecular pathways involved in its development have since been studied in detail. Due to its superior live cell imaging possibilities and the broad tool kit for forward and reverse genetics, the zebrafish has become an important model organism to study the development of the lymphatic system during early embryonic development. In the current review, we will focus on the key players during zebrafish lymphangiogenesis and compare the roles of these genes to their mammalian counterparts. In particular, we will focus on novel findings that shed new light on the molecular mechanisms of lymphatic cell fate specification, as well as sprouting and migration of lymphatic precursor cells.

  10. Importance Rat Liver Morphology and Vasculature in Surgical Research

    PubMed Central

    Vdoviaková, Katarína; Petrovová, Eva; Krešáková, Lenka; Maloveská, Marcela; Teleky, Jana; Jenčová, Janka; Živčák, Jozef; Jenča, Andrej

    2016-01-01

    Background The laboratory rat is one of the most popular experimental models for the experimental surgery of the liver. The objective of this study was to investigate the morphometric parameters, physiological data, differences in configuration of liver lobes, biliary system, and vasculature (arteries, veins, and lymphatic vessels) of the liver in laboratory rats. In addition, this study supports the anatomic literature and identified similarities and differences with human and other mammals. Material/Methods Forty laboratory rats were dissected to prepare corrosion casts of vascular system specimens (n=20), determine the lymph vessels and lymph nodes (n=10), and for macroscopic anatomical dissection (n=10) of the rat liver. The results are listed in percentages. The anatomical nomenclature of the liver morphology, its arteries, veins, lymph nodes, and lymphatic vessels are in accordance with Nomina Anatomica Veterinaria. Results We found many variations in origin, direction, and division of the arterial, venous, and lymphatic systems in rat livers, and found differences in morphometric parameters compared to results reported by other authors. The portal vein was formed by 4 tributaries in 23%, by 3 branches in 64%, and by 2 tributaries in 13%. The liver lymph was drained to the 2 different lymph nodes. The nomenclature and morphological characteristics of the rat liver vary among authors. Conclusions Our results may be useful for the planing of experimental surgery and for cooperation with other investigation methods to help fight liver diseases in human populations. PMID:27911356

  11. Hematopoietic progenitors are required for proper development of coronary vasculature

    PubMed Central

    Lluri, Gentian; Huang, Vincent; Touma, Marlin; Liu, Xiaoqian; Harmon, Andrew W.; Nakano, Atsushi

    2015-01-01

    Rationale During embryogenesis, hematopoietic cells appear in the myocardium prior to the initiation of coronary formation. However, their role is unknown. Objective Here we investigate whether pre-existing hematopoietic cells are required for the formation of coronary vasculature. Methods and Results As a model of for hematopoietic cell deficient animals, we used Runx1 knockout embryos and Vav1-cre; R26-DTA embryos, latter of which genetically ablates 2/3 of CD45+ hematopoietic cells. Both Runx1 knockout embryos and Vav1-cre; R26-DTA embryos revealed disorganized, hypoplastic microvasculature of coronary vessels on section and whole-mount stainings. Furthermore, coronary explant experiments showed that the mouse heart explants from Runx1 and Vav1-cre; R26-DTA embryos exhibited impaired coronary formation ex vivo. Interestingly, in both models it appears that epicardial to mesenchymal transition is adversely affected in the absence of hematopoietic progenitors. Conclusion Hematopoietic cells are not merely passively transported via coronary vessel, but substantially involved in the induction of the coronary growth. Our findings suggest a novel mechanism of coronary growth. PMID:26241844

  12. Three-dimensional ultrasound imaging of the vasculature.

    PubMed

    Fenster, A; Lee, D; Sherebrin, S; Rankin, R; Downey, D

    1998-02-01

    With conventional ultrasonography, the diagnostician must view a series of two-dimensional images in order to form a mental impression of the three-dimensional anatomy, an efficient and time consuming practice prone to operator variability, which may cause variable or even incorrect diagnoses. Also, a conventional two-dimensional ultrasound image represents a thin slice of the patients anatomy at a single location and orientation, which is difficult to reproduce at a later time. These factors make conventional ultrasonography non-optimal for prospective or follow-up studies. Our efforts have focused on overcoming these deficiencies by developing three-dimensional ultrasound imaging techniques that are capable of acquiring B-mode, colour Doppler and power Doppler images of the vasculature, by using a conventional ultrasound system to acquire a series of two-dimensional images and then mathematically reconstructing them into a single three-dimensional image, which may then be viewed interactively on an inexpensive desktop computer. We report here on two approaches: (1) free-hand scanning, in which a magnetic positioning device is attached to the ultrasound transducer to record the position and orientation of each two-dimensional image needed for the three-dimensional image reconstruction; and (2) mechanical scanning, in which a motor-driven assembly is used to translate the transducer linearly across the neck, yielding a set of uniformly-spaced parallel two-dimensional images.

  13. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature.

    PubMed

    Ayata, Cenk; Lauritzen, Martin

    2015-07-01

    Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases.

  14. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

    PubMed Central

    Ayata, Cenk; Lauritzen, Martin

    2015-01-01

    Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases. PMID:26133935

  15. Three-dimensional volume analysis of vasculature in engineered tissues

    NASA Astrophysics Data System (ADS)

    YousefHussien, Mohammed; Garvin, Kelley; Dalecki, Diane; Saber, Eli; Helguera, María.

    2013-01-01

    Three-dimensional textural and volumetric image analysis holds great potential in understanding the image data produced by multi-photon microscopy. In this paper, an algorithm that quantitatively analyzes the texture and the morphology of vasculature in engineered tissues is proposed. The investigated 3D artificial tissues consist of Human Umbilical Vein Endothelial Cells (HUVEC) embedded in collagen exposed to two regimes of ultrasound standing wave fields under different pressure conditions. Textural features were evaluated using the normalized Gray-Scale Cooccurrence Matrix (GLCM) combined with Gray-Level Run Length Matrix (GLRLM) analysis. To minimize error resulting from any possible volume rotation and to provide a comprehensive textural analysis, an averaged version of nine GLCM and GLRLM orientations is used. To evaluate volumetric features, an automatic threshold using the gray level mean value is utilized. Results show that our analysis is able to differentiate among the exposed samples, due to morphological changes induced by the standing wave fields. Furthermore, we demonstrate that providing more textural parameters than what is currently being reported in the literature, enhances the quantitative understanding of the heterogeneity of artificial tissues.

  16. Importance Rat Liver Morphology and Vasculature in Surgical Research.

    PubMed

    Vdoviaková, Katarína; Vdoviaková, Katarína; Petrovová, Eva; Krešáková, Lenka; Maloveská, Marcela; Teleky, Jana; Jenčová, Janka; Živčák, Jozef; Jenča, Andrej

    2016-12-02

    BACKGROUND The laboratory rat is one of the most popular experimental models for the experimental surgery of the liver. The objective of this study was to investigate the morphometric parameters, physiological data, differences in configuration of liver lobes, biliary system, and vasculature (arteries, veins, and lymphatic vessels) of the liver in laboratory rats. In addition, this study supports the anatomic literature and identified similarities and differences with human and other mammals. MATERIAL AND METHODS Forty laboratory rats were dissected to prepare corrosion casts of vascular system specimens (n=20), determine the lymph vessels and lymph nodes (n=10), and for macroscopic anatomical dissection (n=10) of the rat liver. The results are listed in percentages. The anatomical nomenclature of the liver morphology, its arteries, veins, lymph nodes, and lymphatic vessels are in accordance with Nomina Anatomica Veterinaria. RESULTS We found many variations in origin, direction, and division of the arterial, venous, and lymphatic systems in rat livers, and found differences in morphometric parameters compared to results reported by other authors. The portal vein was formed by 4 tributaries in 23%, by 3 branches in 64%, and by 2 tributaries in 13%. The liver lymph was drained to the 2 different lymph nodes. The nomenclature and morphological characteristics of the rat liver vary among authors. CONCLUSIONS Our results may be useful for the planing of experimental surgery and for cooperation with other investigation methods to help fight liver diseases in human populations.

  17. Schistosomiasis and the pulmonary vasculature (2013 Grover Conference series)

    PubMed Central

    2014-01-01

    Abstract Inflammation is associated with multiple forms of pulmonary arterial hypertension (PAH), including autoimmune (scleroderma) and infectious (HIV, schistosomiasis) etiologies. More than 200 million people worldwide are infected with Schistosoma, predominantly in Brazil, Africa, the Middle East, and South Asia. Schistosomiasis causes PAH in about 6.1% of those chronically infected and is particularly associated with the species Schistosoma mansoni. Treatment for schistosomiasis-associated PAH includes antihelminthic treatment, if active infection is present (although associated with little immediate benefit to the pulmonary hypertension), and then pharmacologic treatment with targeted pulmonary vascular therapies, including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists. The pathophysiological mechanism by which this parasitic infection causes pulmonary hypertension is unknown but is unlikely to be simple mechanical obstruction of the pulmonary vasculature by parasite eggs. Preexisting hepatosplenic disease due to Schistosoma infection is likely important because of portopulmonary hypertension and/or because it allows egg embolization to the lung by portocaval shunts. Potential immune signaling originating in the periegg granulomas causing the pulmonary vascular disease includes the cytokines interleukin (IL)-4, IL-6, IL-13, and transforming growth factor β. Modulating these pathways may be possible targets for future therapy of schistosomiasis-associated PAH specifically, and study of this disease may provide novel insights into other inflammatory causes of PAH. PMID:25621148

  18. Local oestrogenic/androgenic balance in the cerebral vasculature.

    PubMed

    Krause, D N; Duckles, S P; Gonzales, R J

    2011-09-01

    Reproductive effects of sex steroids are well-known; however it is increasingly apparent that these hormones have important actions on non-reproductive tissues such as the vasculature. The latter effects can be relevant throughout the lifespan, not just limited to reproductive years, and are not necessarily restricted to one gender or the other. Our work has established that cerebral blood vessels are a non-reproductive target tissue for sex steroids. We have found that oestrogen and androgens alter vascular tone, endothelial function, oxidative stress and inflammatory responses in cerebral vessels. Often the actions of oestrogen and androgens oppose each other. Moreover, it is clear that cerebral vessels are directly targeted by sex steroids, as they express specific receptors for these hormones. Interestingly, cerebral blood vessels also express enzymes that metabolize sex steroids. These findings suggest that local synthesis of 17ß-estradiol and dihydrotestosterone can occur within the vessel wall. One of the enzymes present, aromatase, converts testosterone to 17ß-estradiol, which would alter the local balance of androgenic and oestrogenic influences. Thus cerebral vessels are affected by circulating sex hormones as well as locally synthesized sex steroids. The presence of vascular endocrine effector mechanisms has important implications for male-female differences in cerebrovascular function and disease. Moreover, the cerebral circulation is a target for gonadal hormones as well as anabolic steroids and therapeutic drugs used to manipulate sex steroid actions. The long-term consequences of these influences are yet to be determined.

  19. Chemokine guided angiogenesis directs coronary vasculature formation in zebrafish

    PubMed Central

    Harrison, Michael R.M.; Bussmann, Jeroen; Huang, Ying; Zhao, Long; Osorio, Arthela; Burns, C. Geoffrey; Burns, Caroline E.; Sucov, Henry M.; Siekmann, Arndt F.; Lien, Ching-Ling

    2015-01-01

    SUMMARY Interruption of coronary blood supply severely impairs heart function with often-fatal consequences for heart disease patients. However the formation and maturation of these coronary vessels is not fully understood. Here we provide a detailed analysis of coronary vessel development in zebrafish. We observe that coronary vessels form in zebrafish by angiogenic sprouting of arterial cells derived from the endocardium at the atrioventricular canal. Endothelial cells express the CXC-motif chemokine receptor Cxcr4a and migrate to vascularize the ventricle under the guidance of the myocardium-expressed ligand Cxcl12b. cxcr4a mutant zebrafish fail to form a vascular network, whereas ectopic expression of Cxcl12b ligand induces coronary vessel formation. Importantly, cxcr4a mutant zebrafish fail to undergo heart regeneration following injury. Our results suggest that chemokine-signaling has an essential role in coronary vessel formation by directing migration of endocardium-derived endothelial cells. Poorly developed vasculature in cxcr4a mutants likely underlies decreased regenerative potential in adults. PMID:26017769

  20. Computational approach for designing tumor homing peptides

    PubMed Central

    Sharma, Arun; Kapoor, Pallavi; Gautam, Ankur; Chaudhary, Kumardeep; Kumar, Rahul; Chauhan, Jagat Singh; Tyagi, Atul; Raghava, Gajendra P. S.

    2013-01-01

    Tumor homing peptides are small peptides that home specifically to tumor and tumor associated microenvironment i.e. tumor vasculature, after systemic delivery. Keeping in mind the huge therapeutic importance of these peptides, we have made an attempt to analyze and predict tumor homing peptides. It was observed that certain types of residues are preferred in tumor homing peptides. Therefore, we developed support vector machine based models for predicting tumor homing peptides using amino acid composition and binary profiles of peptides. Amino acid composition, dipeptide composition and binary profile-based models achieved a maximum accuracy of 86.56%, 82.03%, and 84.19% respectively. These methods have been implemented in a user-friendly web server, TumorHPD. We anticipate that this method will be helpful to design novel tumor homing peptides. TumorHPD web server is freely accessible at http://crdd.osdd.net/raghava/tumorhpd/. PMID:23558316

  1. Stromal Barriers and Strategies for the Delivery of Nanomedicine to Desmoplastic Tumors

    PubMed Central

    Miao, Lei; Lin, C. Michael; Huang, Leaf

    2015-01-01

    Nanoparticle based delivery formulations have become a leading delivery strategy for cancer imaging and therapy. The success of nanoparticle-based therapy relies heavily on their ability to utilize the enhanced permeability and retention (EPR) effect and active targeting moieties to their advantage. However, these methods often fail to enable a uniform NP distribution across the tumor, and lead to insufficient local concentrations of drug. Oftentimes, this heterogeneous drug distribution is one of the primary reasons for suboptimal treatment efficacy in NP delivery platforms. Herein, we seek to examine the biophysical causes of heterogeneous NP distribution in stroma-rich desmoplastic tumors; namely the abnormal tumor vasculature, deregulated extracellular matrix and high interstitial hypertension associated with these tumors. It is suggested that these factors help explain the discrepancy between promising outlooks for many NP formulations in preclinical studies, but suboptimal clinical outcomes for most FDA approved nanoformulations. Furthermore, examination into the role of the physicochemical properties of NPs on successful drug delivery was conducted in this review. In light of the many formidable barriers against successful NP drug delivery, we provided possible approaches to mitigate delivery issues from the perspective of stromal remodeling and NP design. In all, this review seeks to provide guidelines for optimizing nanoparticle-based cancer drug delivery through both modified nanoparticle design and alleviation of biological barriers to successful therapy. PMID:26277065

  2. Normal Doppler velocimetry of renal vasculature in Persian cats.

    PubMed

    Carvalho, Cibele F; Chammas, Maria C

    2011-06-01

    Renal diseases are common in older cats. Decreased renal blood flow may be the first sign of dysfunction and can be evaluated by Doppler ultrasound. But previous studies suggest that the resistive index (RI) has a low sensitivity for detecting renal disease. Doppler waveforms of renal and intrarenal arteries demonstrate decreased blood flow before there are any changes in the RI. The purpose of this study was to evaluate the normal Doppler flowmetrics parameters of renal arteries (RAs), interlobar arteries (IAs) and abdominal aorta (AO) in adult healthy, Persian cats. Twenty-five Persian cats (13 females and 12 males with mean age of 30 months and an age range 12-60 months) with normal clinical examinations and biochemical tests and normal systemic blood pressure were given B-mode ultrasonographies in order to exclude all nephropathies, including polycystic kidney disease. All measurements were performed on both kidneys. Both kidneys (n=50) were examined by color mapping of the renal vasculature. Pulsed Doppler was used to examine both RAs, the IAs at cranial, middle and caudal sites, and the AO. The RI was calculated for all of the vessels. Early systolic acceleration (ESA) of RA and IA was obtained with Doppler spectral analysis. Furthermore, the ratio indices between RA/AO, and IA/RA velocities were calculated. The mean values of peak systolic velocity (PSV) and the diameter for AO were 53.17±13.46 cm/s and 0.38±0.08 cm, respectively. The mean RA diameter for all 50 kidneys was 0.15±0.02 cm. Considering the velocimetric values in both RAs, the mean PSV and RI that were obtained were 41.17±9.40 cm/s and 0.54±0.07. The RA had a mean ESA of 1.12±1.14 m/s(2) and the calculated upper limit of the reference value was 3.40 m/s(2). The mean renal-aortic ratio was 0.828±0.296. The IA showed PSV and RI values of 32.16±9.33 cm/s and 0.52±0.06, respectively. The mean ESA of all IAs was 0.73±0.61 m/s(2). The calculated upper limit of the reference value was 2.0m

  3. Homology of lungs and gas bladders: insights from arterial vasculature.

    PubMed

    Longo, Sarah; Riccio, Mark; McCune, Amy R

    2013-06-01

    Gas bladders of ray-finned fishes serve a variety of vital functions and are thus an important novelty of most living vertebrates. The gas bladder has long been regarded as an evolutionary modification of lungs. Critical evidence for this hypothesized homology is whether pulmonary arteries supply the gas bladder as well as the lungs. Pulmonary arteries, paired branches of the fourth efferent branchial arteries, deliver blood to the lungs in osteichthyans with functional lungs (lungfishes, tetrapods, and the ray-finned polypterid fishes). The fact that pulmonary arteries also supply the respiratory gas bladder of Amia calva (bowfin) has been used to support the homology of lungs and gas bladders, collectively termed air-filled organs (AO). However, the homology of pulmonary arteries in bowfin and lunged osteichthyans has been uncertain, given the apparent lack of pulmonary arteries in critical taxa. To re-evaluate the homology of pulmonary arteries in bowfin and lunged osteichthyans, we studied, using micro-CT technology, the arterial vasculature of Protopterus, Polypterus, Acipenser, Polyodon, Amia, and Lepisosteus, and analyzed these data using a phylogenetic approach. Our data reveal that Acipenser and Polyodon have paired posterior branches of the fourth efferent branchial arteries, which are thus similar in origin to pulmonary arteries. We hypothesize that these arteries are vestigial pulmonary arteries that have been coopted for new functions due to the dorsal shift of the AO and/or the loss of respiration in these taxa. Ancestral state reconstructions support pulmonary arteries as a synapomorphy of the Osteichthyes, provide the first concrete evidence for the retention of pulmonary arteries in Amia, and support thehomology of lungs and gas bladders due to a shared vascular supply. Finally, we use ancestral state reconstructions to show that arterial AO supplies from the celiacomesenteric artery or dorsal aorta appear to be convergent between teleosts and

  4. Single-Walled Carbon Nanotubes Targeted to the Tumor Vasculature for Breast Cancer Treatment

    DTIC Science & Technology

    2009-09-01

    Adsorption of a linker containing fluorene followed by reaction with the protein – This is a new method we developed that uses a linker that contains a... fluorene aromatic group for strong π-π binding to the graphite nanotube sidewall, polyethylene glycol (PEG) to increase the aqueous solubility of...Schematic of protein attachment to an SWNT using the Fmoc-amine-PEG- succinimidyl carboxy methyl ester linker. We have used fluorene in the linker

  5. [Chromosome abnormalities in human cancer].

    PubMed

    Salamanca-Gómez, F

    1995-01-01

    Recent investigation on the presence of chromosome abnormalities in neoplasias has allowed outstanding advances in the knowledge of malignant transformation mechanisms and important applications in the clinical diagnosis and prognosis of leukaemias, lymphomas and solid tumors. The purpose of the present paper is to discuss the most relevant cytogenetic aberrations, some of them described at the Unidad de Investigación Médica en Genética Humana, Instituto Mexicano del Seguro Social, and to correlate these abnormalities with recent achievements in the knowledge of oncogenes, suppressor genes or antioncogenes, their chromosome localization, and their mutations in human neoplasia; as well as their perspectives in prevention and treatment of cancer that such findings permit to anticipate.

  6. Urine - abnormal color

    MedlinePlus

    ... medlineplus.gov/ency/article/003139.htm Urine - abnormal color To use the sharing features on this page, please enable JavaScript. The usual color of urine is straw-yellow. Abnormally colored urine ...

  7. Tooth - abnormal colors

    MedlinePlus

    ... medlineplus.gov/ency/article/003065.htm Tooth - abnormal colors To use the sharing features on this page, please enable JavaScript. Abnormal tooth color is any color other than white to yellowish- ...

  8. Abnormal Head Position

    MedlinePlus

    ... cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal head posture could cause permanent ... occipitocervical synostosis and unilateral hearing loss. Are there any ... postures? Yes. Abnormal head postures can usually be improved depending ...

  9. Skeletal limb abnormalities

    MedlinePlus

    ... medlineplus.gov/ency/article/003170.htm Skeletal limb abnormalities To use the sharing features on this page, please enable JavaScript. Skeletal limb abnormalities refers to a variety of bone structure problems ...

  10. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... PROBLEMS Abnormal Uterine Bleeding • What is a normal menstrual cycle? • When is bleeding abnormal? • At what ages is ... treat abnormal bleeding? •Glossary What is a normal menstrual cycle? The normal length of the menstrual cycle is ...

  11. Tumor Endothelium FasL Establishes a Selective Immune Barrier Promoting Tolerance in Tumors

    PubMed Central

    Motz, Gregory T.; Santoro, Stephen P.; Wang, Li-Ping; Garrabrant, Tom; Lastra, Ricardo R.; Hagemann, Ian S.; Lal, Priti; Feldman, Michael D.; Benencia, Fabian; Coukos, George

    2014-01-01

    We describe a novel mechanism regulating the tumor endothelial barrier and T cell homing to tumors. Selective expression of the death mediator Fas ligand (FasL/CD95L) was detected in the vasculature of many human and mouse solid tumors but not in normal vasculature, and in these tumors it was associated with scarce CD8+ infiltration and predominance of FoxP3+ T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression on endothelial cells, which acquired the ability to kill effector CD8+ T cells, but not Treg cells, due to higher levels of cFLIP expression in Tregs. In the mouse, genetic or pharmacologic suppression of FasL produced a significant increase in the influx of tumor-rejecting CD8+ over FoxP3+ T cells. Pharmacologic inhibition of VEGF and PGE2 attenuated tumor endothelial FasL expression, produced a significant increase in the influx of tumor-rejecting CD8+ over FoxP3+ T cells, which was FasL-dependent, and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which plays a critical role in establishing immune tolerance and determining the fate of tumors. PMID:24793239

  12. ET-04MEBENDAZOLE IS EFFICACIOUS IN DIVERSE MEDULLOBLASTOMA TUMOR MODELS AND INHIBITS TUMOR ANGIOGENESIS

    PubMed Central

    Bai, Renyuan; Staedtke, Verena; Rudin, Charles; Bunz, Fred; Riggins, Gregory

    2014-01-01

    Medulloblastoma is the leading cause of cancer death in children. Surgery, radiotherapy and chemotherapy regimens are the current standard for treatment. While effective in most patients, those have long-term neurological sequelae in survivors, and a significant fraction of patients still succumb to the disease. In this study, we found that mebendazole (MBZ), an FDA-approved antiparasitic, demonstrated significant anti-tumor efficacy in etiologically distinct medulloblastoma mouse models. MBZ significantly improved the survival of mice with orthotopic xenograft tumors derived from the SHH group and group 3 medulloblastomas and was also highly efficacious against a PTCH1-mutant medulloblastoma with acquired resistance to the SMO inhibitor vismodgib. Analysis of the vasculature in rodent tumors revealed that MBZ selectively inhibited tumor angiogenesis but not the normal brain vasculature, and inhibited the kinase activity of VEGFR2 in vitro and in vivo. This study demonstrates that MBZ could be a highly promising therapeutic for medulloblastoma with anti- angiogenesis activity.

  13. Visualization of tumor-related blood vessels in human breast by photoacoustic imaging system with a hemispherical detector array

    PubMed Central

    Toi, M.; Asao, Y.; Matsumoto, Y.; Sekiguchi, H.; Yoshikawa, A.; Takada, M.; Kataoka, M.; Endo, T.; Kawaguchi-Sakita, N.; Kawashima, M.; Fakhrejahani, E.; Kanao, S.; Yamaga, I.; Nakayama, Y.; Tokiwa, M.; Torii, M.; Yagi, T.; Sakurai, T.; Togashi, K.; Shiina, T.

    2017-01-01

    Noninvasive measurement of the distribution and oxygenation state of hemoglobin (Hb) inside the tissue is strongly required to analyze the tumor-associated vasculatures. We developed a photoacoustic imaging (PAI) system with a hemispherical-shaped detector array (HDA). Here, we show that PAI system with HDA revealed finer vasculature, more detailed blood-vessel branching structures, and more detailed morphological vessel characteristics compared with MRI by the use of breast shape deformation of MRI to PAI and their fused image. Morphologically abnormal peritumoral blood vessel features, including centripetal photoacoustic signals and disruption or narrowing of vessel signals, were observed and intratumoral signals were detected by PAI in breast cancer tissues as a result of the clinical study of 22 malignant cases. Interestingly, it was also possible to analyze anticancer treatment-driven changes in vascular morphological features and function, such as improvement of intratumoral blood perfusion and relevant changes in intravascular hemoglobin saturation of oxygen. This clinical study indicated that PAI appears to be a promising tool for noninvasive analysis of human blood vessels and may contribute to improve cancer diagnosis. PMID:28169313

  14. Tumor Blood Vessel Dynamics

    NASA Astrophysics Data System (ADS)

    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

  15. Human liver tumors in relation to steroidal usage.

    PubMed Central

    Barrows, G H; Christopherson, W M

    1983-01-01

    Since 1973 a number of investigators have reported an association between liver neoplasia and steroid usage. Through referral material we have examined the histology of over 250 cases of hepatic neoplasia, most in patients receiving steroid medications. The majority have been benign, predominantly focal nodular hyperplasia (55%) and hepatocellular adenoma (39%). The average age was 31.4 years; 83% had significant steroid exposure with an average duration of 71 months for focal nodular hyperplasia and 79.6 months for hepatocellular adenoma. The type of estrogenic agent was predominantly mestranol; however, during the period mestranol was the most frequently used synthetic steroid. A distinct clinical entity of life threatening hemorrhage from the lesion occurred in 31% of patients with hepatocellular adenoma and 9% of patients with focal nodular hyperplasia. Recurrence of benign tumors has occurred in some patients who continued using steroids and regression has been observed in patients who had incomplete tumor removal but discontinued steroid medication. Medial and intimal vascular changes have been present in a large number of the benign tumors. The relationship of these vascular changes to oncogenesis is unclear, but similar lesions have been described in the peripheral vasculature associated with steroid administration. A number of hepatocellular carcinomas have also been seen. Of significance is the young age of these patients and lack of abnormal histology in adjacent nonneoplastic liver. A striking number of the malignant hepatocellular tumors have been of the uncommon type described as "eosinophilic hepatocellular carcinoma with lamellar fibrosis." The epidemiology of liver lesions within this series is difficult to assess, since the material has been referred from very diverse locations. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. PMID:6307679

  16. FOXF1 Transcription Factor Is Required for Formation of Embryonic Vasculature by Regulating VEGF Signaling in Endothelial Cells

    PubMed Central

    Ren, Xiaomeng; Ustiyan, Vladimir; Pradhan, Arun; Cai, Yuqi; Havrilak, Jamie A.; Bolte, Craig S.; Shannon, John M.; Kalin, Tanya V.; Kalinichenko, Vladimir V.

    2016-01-01

    Rationale Inactivating mutations in the FOXF1 gene locus are frequently found in patients with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV), a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardio-vascular and gastro-intestinal systems. In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal and gall bladder morphogenesis. Objective While FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and ACD/MPV patients remain uncharacterized due to lack of mouse models with cell-restricted inactivation of the Foxf1 gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach. Methods and Results A novel mouse line harboring Foxf1-floxed alleles was generated by homologous recombination. Tie2-Cre and Pdgfb-CreER transgenes were used to delete Foxf1 from endothelial cells. FOXF1-deficient embryos exhibited embryonic lethality, growth retardation, polyhydramnios, cardiac ventricular hypoplasia and vascular abnormalities in the lung, placenta, yolk sac and retina. Deletion of FOXF1 from endothelial cells reduced endothelial proliferation, increased apoptosis, inhibited VEGF signaling and decreased expression of endothelial genes critical for vascular development, including VEGF receptors Flt1 and Flk1, Pdgfb, Pecam1, CD34, integrin β3, ephrin B2, Tie2 and the non-coding RNA Fendrr. ChIP assay demonstrated that Flt1, Flk1, Pdgfb, Pecam1 and Tie2 genes are direct transcriptional targets of FOXF1. Conclusions FOXF1 is required for formation of embryonic vasculature by regulating endothelial genes critical for vascular development and VEGF signaling. PMID:25091710

  17. Targeting Breast Cancer with T Cells Redirected to the Vasculature

    DTIC Science & Technology

    2012-10-01

    against PSMA using scFv (PZ1) and T cells bearing PZ1 and CD28 ζ produce a robust polyfunctional repertoire of cytokines. A tumor vascular mouse... PSMA , scFv 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a...carrying CD3ζ (stimulatory) from a CIR recognizing prostate specific membrane antigen ( PSMA ), which will carry CD28 and/or 4-1BB (costimulatory). 3

  18. Hyperglycemia-Induced Vasculopathy in the Murine Vitelline Vasculature

    PubMed Central

    Pinter, Emese; Mahooti, Sepi; Wang, Yi; Imhof, Beat A.; Madri, Joseph A.

    1999-01-01

    Maternal diabetes mellitus is associated with an increased incidence of congenital abnormalities as well as embryonic and perinatal lethality. In particular, a wide range of cardiovascular abnormalities have been noted in children of diabetic mothers and in the offspring of diabetic animals. The vascular system is the first organ system to develop in the embryo and is critical for normal organogenesis. The organization of mesodermal cells into endothelial and hematopoietic cells and into a complex vascular system is, in part, mediated by a series of specific cell-cell, cell-extracellular matrix, and cell-factor interactions. PECAM-1 expression has been observed during the earliest stages of vasculogenesis, and changes in PECAM-1 tyrosine phosphorylation have been associated with endothelial cell migration, vasculogenesis, and angiogenesis both in vitro and in vivo. In this report we demonstrate that exposure to hyperglycemia during gastrulation causes yolk sac and embryonic vasculopathy in cultured murine conceptuses and in the conceptuses of streptozotocin-induced diabetic pregnant mice. In addition, we correlate the presence of yolk sac and embryonic vasculopathy with the failure of PECAM-1 tyrosine dephosphorylation during the formation of blood islands/vessels from clusters of extra-embryonic and embryonic angioblasts in the murine conceptus using both in vitro and in vivo models. The importance of these findings in the development of vasculopathy in the offspring of diabetic mothers and the potential effects and benefits of glucose regulation during the periods of vasculogenesis/angiogenesis in embryonic development are discussed. PMID:10329590

  19. CLARITY reveals dynamics of ovarian follicular architecture and vasculature in three-dimensions

    PubMed Central

    Feng, Yi; Cui, Peng; Lu, Xiaowei; Hsueh, Brian; Möller Billig, Fredrik; Zarnescu Yanez, Livia; Tomer, Raju; Boerboom, Derek; Carmeliet, Peter; Deisseroth, Karl; Hsueh, Aaron J. W.

    2017-01-01

    Optimal distribution of heterogeneous organelles and cell types within an organ is essential for physiological processes. Unique for the ovary, hormonally regulated folliculogenesis, ovulation, luteal formation/regression and associated vasculature changes lead to tissue remodeling during each reproductive cycle. Using the CLARITY approach and marker immunostaining, we identified individual follicles and corpora lutea in intact ovaries. Monitoring lifetime changes in follicle populations showed age-dependent decreases in total follicles and percentages of advanced follicles. Follicle development from primordial to preovulatory stage was characterized by 3 × 105-fold increases in volume, decreases in roundness, and decreased clustering of same stage follicles. Construction of follicle-vasculature relationship maps indicated age- and gonadotropin-dependent increases in vasculature and branching surrounding follicles. Heterozygous mutant mice with deletion of hypoxia-response element in the vascular endothelial growth factor A (VEGFA) promoter showed defective ovarian vasculature and decreased ovulatory responses. Unilateral intrabursal injection of axitinib, an inhibitor of VEGF receptors, retarded neo-angiogenesis that was associated with defective ovulation in treated ovaries. Our approach uncovers unique features of ovarian architecture and essential roles of vasculature in organizing follicles to allow future studies on normal and diseased human ovaries. Similar approaches could also reveal roles of neo-angiogenesis during embryonic development and tumorigenesis. PMID:28333125

  20. Renal primitive neuroectodermal tumors.

    PubMed

    Bartholow, Tanner; Parwani, Anil

    2012-06-01

    Primitive neuroectodermal tumors exist as a part of the Ewing sarcoma/primitive neuroectodermal tumor family. These tumors most commonly arise in the chest wall and paraspinal regions; cases with a renal origin are rare entities, but have become increasingly reported in recent years. Although such cases occur across a wide age distribution, the average age for a patient with a renal primitive neuroectodermal tumor is the mid- to late 20s, with both males and females susceptible. Histologically, these tumors are characterized by pseudorosettes. Immunohistochemically, CD99 is an important diagnostic marker. Clinically, these are aggressive tumors, with an average 5-year disease-free survival rate of only 45% to 55%. Given that renal primitive neuroectodermal tumor bears many similarities to other renal tumors, it is important to review the histologic features, immunostaining profile, and genetic abnormalities that can be used for its correct diagnosis.

  1. Vascular endothelial growth factor co-ordinates proper development of lung epithelium and vasculature.

    PubMed

    Zhao, Liqing; Wang, Ke; Ferrara, Napoleone; Vu, Thiennu H

    2005-07-01

    The vasculature forms an intrinsic functional component of the lung and its development must be tightly regulated and coordinated with lung epithelial morphogenesis. Vascular endothelial growth factor (VEGF) and its receptors are highly expressed in a complementary pattern in the lungs during embryonic development. VEGF is expressed by epithelium and the receptors in the surrounding mesenchyme. To determine the function of VEGF in lung formation, we inhibited its activity using a soluble receptor in lung renal capsule grafts. Inhibition of VEGF results in inhibition of vascular development and significant alteration in epithelial development. Epithelial proliferation is inhibited, sacculation is impaired, and the epithelium undergoes apoptosis. Interestingly, when VEGF is attenuated, epithelial differentiation still proceeds, as shown by acquisition of both proximal and distal markers. These data show that VEGF co-ordinates epithelial and vascular development. It is required for the development of the lung vasculature and the vasculature is necessary for epithelial proliferation and morphogenesis, but not for cell differentiation.

  2. Anatomy and development of the cardiac lymphatic vasculature: Its role in injury and disease.

    PubMed

    Norman, Sophie; Riley, Paul R

    2016-04-01

    Lymphatic vessels are present throughout the entire body in all mammals and function to regulate tissue fluid balance, lipid transport and survey the immune system. Despite the presence of an extensive lymphatic plexus within the heart, until recently the importance of the cardiac lymphatic vasculature and its origins were unknown. Several studies have described the basic anatomy of the developing cardiac lymphatic vasculature and more recently the detailed development of the murine cardiac lymphatics has been documented, with important insight into their cellular sources during embryogenesis. In this review we initially describe the development of systemic lymphatic vasculature, to provide the background for a comparative description of the spatiotemporal development of the cardiac lymphatic vessels, including detail of both canonical, typically venous, and noncanonical (hemogenic endothelium) cellular sources. Subsequently, we address the response of the cardiac lymphatic network to myocardial infarction (heart attack) and the therapeutic potential of targeting cardiac lymphangiogenesis.

  3. Label-free imaging of developing vasculature in zebrafish with phase variance optical coherence microscopy

    NASA Astrophysics Data System (ADS)

    Chen, Yu; Fingler, Jeff; Trinh, Le A.; Fraser, Scott E.

    2016-03-01

    A phase variance optical coherence microscope (pvOCM) has been created to visualize blood flow in the vasculature of zebrafish embryos, without using exogenous labels. The pvOCM imaging system has axial and lateral resolutions of 2 μm in tissue, and imaging depth of more than 100 μm. Imaging of 2-5 days post-fertilization zebrafish embryos identified the detailed structures of somites, spinal cord, gut and notochord based on intensity contrast. Visualization of the blood flow in the aorta, veins and intersegmental vessels was achieved with phase variance contrast. The pvOCM vasculature images were confirmed with corresponding fluorescence microscopy of a zebrafish transgene that labels the vasculature with green fluorescent protein. The pvOCM images also revealed functional information of the blood flow activities that is crucial for the study of vascular development.

  4. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  5. Morphological abnormalities among lampreys

    USGS Publications Warehouse

    Manion, Patrick J.

    1967-01-01

    The experimental control of the sea lamprey (Petromyzon marinus) in the Great Lakes has required the collection of thousands of lampreys. Representatives of each life stage of the four species of the Lake Superior basin were examined for structural abnormalities. The most common aberration was the presence of additional tails. The accessory tails were always postanal and smaller than the normal tail. The point of origin varied; the extra tails occurred on dorsal, ventral, or lateral surfaces. Some of the extra tails were misshaped and curled, but others were normal in shape and pigment pattern. Other abnormalities in larval sea lampreys were malformed or twisted tails and bodies. The cause of the structural abnormalities is unknown. The presence of extra caudal fins could be genetically controlled, or be due to partial amputation or injury followed by abnormal regeneration. Few if any lampreys with structural abnormalities live to sexual maturity.

  6. Use of labeled tomato lectin for imaging vasculature structures.

    PubMed

    Robertson, Richard T; Levine, Samantha T; Haynes, Sherry M; Gutierrez, Paula; Baratta, Janie L; Tan, Zhiqun; Longmuir, Kenneth J

    2015-02-01

    Intravascular injections of fluorescent or biotinylated tomato lectin were tested to study labeling of vascular elements in laboratory mice. Injections of Lycopersicon esculentum agglutinin (tomato lectin) (50-100 µg/100 µl) were made intravascularly, through the tail vein, through a cannula implanted in the jugular vein, or directly into the left ventricle of the heart. Tissues cut for thin 10- to 12-µm cryostat sections, or thick 50- to 100-µm vibratome sections, were examined using fluorescence microscopy. Tissue labeled by biotinylated lectin was examined by bright field microscopy or electron microscopy after tissue processing for biotin. Intravascular injections of tomato lectin led to labeling of vascular structures in a variety of tissues, including brain, kidney, liver, intestine, spleen, skin, skeletal and cardiac muscle, and experimental tumors. Analyses of fluorescence in serum indicated the lectin was cleared from circulating blood within 2 min. Capillary labeling was apparent in tissues collected from animals within 1 min of intravascular injections, remained robust for about 1 h, and then declined markedly until difficult to detect 12 h after injection. Light microscopic images suggest the lectin bound to the endothelial cells that form capillaries and endothelial cells that line some larger vessels. Electron microscopic studies confirmed the labeling of luminal surfaces of endothelial cells. Vascular labeling by tomato lectin is compatible with a variety of other morphological labeling techniques, including histochemistry and immunocytochemistry, and thus appears to be a sensitive and useful method to reveal vascular patterns in relationship to other aspects of parenchymal development, structure, and function.

  7. Constriction of bovine vasculature caused by endophyte-infected tall fescue seed extract is similar to pure ergovaline

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A mixture of ergot alkaloids does not increase the contractile response of peripheral bovine vasculature, but may increase the contractile response of foregut vasculature. Preliminary data indicated that an extract of tall fescue seed induced a greater contractile response in ruminal artery and vein...

  8. Interaction of isoflavones and endophyte-infected tall fescue seed extract on vasoactivity of bovine mesenteric vasculature

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It was hypothesized that isoflavones may attenuate ergot alkaloid-induced vasoconstriction and possibly alleviate diminished contractility of vasculature after exposure to ergot alkaloids. The objective of this study was to determine if prior incubation of bovine mesenteric vasculature with the isof...

  9. In vivo volumetric depth-resolved vasculature imaging of human limbus and sclera with 1 μm swept source phase-variance optical coherence angiography

    NASA Astrophysics Data System (ADS)

    Poddar, Raju; Zawadzki, Robert J.; Cortés, Dennis E.; Mannis, Mark J.; Werner, John S.

    2015-06-01

    We present in vivo volumetric depth-resolved vasculature images of the anterior segment of the human eye acquired with phase-variance based motion contrast using a high-speed (100 kHz, 105 A-scans/s) swept source optical coherence tomography system (SSOCT). High phase stability SSOCT imaging was achieved by using a computationally efficient phase stabilization approach. The human corneo-scleral junction and sclera were imaged with swept source phase-variance optical coherence angiography and compared with slit lamp images from the same eyes of normal subjects. Different features of the rich vascular system in the conjunctiva and episclera were visualized and described. This system can be used as a potential tool for ophthalmological research to determine changes in the outflow system, which may be helpful for identification of abnormalities that lead to glaucoma.

  10. In vivo volumetric depth-resolved vasculature imaging of human limbus and sclera with 1μm swept source phase-variance optical coherence angiography

    PubMed Central

    Poddar, Raju; Zawadzki, Robert J; Cortés, Dennis E; Mannis, Mark J; Werner, John S

    2015-01-01

    We present nnnnnin vivo volumetric depth-resolved vasculature images of the anterior segment of the human eye acquired with phase-variance based motion contrast using a high-speed (100 kHz, 105 A-scans/s) swept source optical coherence tomography system (SSOCT). High phase stability SSOCT imaging was achieved by using a computationally efficient phase stabilization approach. The human corneo–scleral junction and sclera were imaged with swept source phase-variance optical coherence angiography and compared with slit lamp images from the same eyes of normal subjects. Different features of the rich vascular system in the conjunctiva and episclera were visualized and described. This system can be used as a potential tool for ophthalmological research to determine changes in the outflow system, which may be helpful for identification of abnormalities that lead to glaucoma. PMID:25984290

  11. A New Presentation and Exploration of Human Cerebral Vasculature Correlated with Surface and Sectional Neuroanatomy

    ERIC Educational Resources Information Center

    Nowinski, Wieslaw L.; Thirunavuukarasuu, Arumugam; Volkau, Ihar; Marchenko, Yevgen; Aminah, Bivi; Gelas, Arnaud; Huang, Su; Lee, Looi Chow; Liu, Jimin; Ng, Ting Ting; Nowinska, Natalia G.; Qian, Guoyu Yu; Puspitasari, Fiftarina; Runge, Val M.

    2009-01-01

    The increasing complexity of human body models enabled by advances in diagnostic imaging, computing, and growing knowledge calls for the development of a new generation of systems for intelligent exploration of these models. Here, we introduce a novel paradigm for the exploration of digital body models illustrating cerebral vasculature. It enables…

  12. TISSUE-SPECIFIC VENOUS EXPRESSION OF THE EPH FAMILY RECEPTOR EPHB1 IN THE SKIN VASCULATURE

    PubMed Central

    Li, Wenling; Mukouyama, Yoh-suke

    2013-01-01

    Background The major arteries and veins are formed early during development. The molecular tools to identify arterial and venous endothelial cells improve our understanding of arterial-venous differentiation and branching morphogenesis. Compared to arterial differentiation, relatively little is known about what controls venous development, due to a lack of definitive molecular markers for venous endothelial cells. Results Here we report that the antibody against EphB1, an EphB class receptor, makes it possible to establish a reliable whole-mount immunohistochemical analysis of venous identity with greater resolution than previously possible in embryonic and adult skin vasculature models. EphB1 expression is restricted to the entire venous vasculature throughout embryonic development to adulthood, whereas the previously established venous marker EphB4 is also detectable in lymphatic vasculature. This venous-restricted expression of EphB1 is established after the vascular remodeling of the primary capillary plexus has occurred. Compared to its venous-specific expression in the skin, however, EphB1 is not restricted to the venous vasculature in yolk sac, trunk and lung. Conclusions These studies introduce EphB1 as a new venous-restricted marker in a tissue-specific and time-dependent manner. PMID:23649798

  13. Pregnane X receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress

    PubMed Central

    Swales, Karen E.; Moore, Rick; Truss, Nicola J.; Tucker, Arthur; Warner, Timothy D.; Negishi, Masahiko; Bishop-Bailey, David

    2012-01-01

    Aims Circulating endogenous, dietary, and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene programme in the vasculature. Methods and results PXR was detected in primary human and rat aortic endothelial and smooth muscle cells (SMC) and blood vessels including the human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C, and glutathione S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR-null mice stimulated in vivo or in rat aortic SMC expressing dominant-negative PXR. Activation of aortic PXR by classical agonists had several protective effects: increased xenobiotic metabolism demonstrated by bioactivation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death. Conclusion PXR co-ordinately up-regulates drug metabolism, transport, and antioxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence. PMID:22166712

  14. Targeting prion-like protein doppel selectively suppresses tumor angiogenesis

    PubMed Central

    Al-Hilal, Taslim A.; Chung, Seung Woo; Choi, Jeong Uk; Kim, Seong Who; Kim, Sang Yoon; Ahsan, Fakhrul; Kim, In-San

    2016-01-01

    Controlled and site-specific regulation of growth factor signaling remains a major challenge for current antiangiogenic therapies, as these antiangiogenic agents target normal vasculature as well tumor vasculature. In this article, we identified the prion-like protein doppel as a potential therapeutic target for tumor angiogenesis. We investigated the interactions between doppel and VEGFR2 and evaluated whether blocking the doppel/VEGFR2 axis suppresses the process of angiogenesis. We discovered that tumor endothelial cells (TECs), but not normal ECs, express doppel; tumors from patients and mouse xenografts expressed doppel in their vasculatures. Induced doppel overexpression in ECs enhanced vascularization, whereas doppel constitutively colocalized and complexed with VEGFR2 in TECs. Doppel inhibition depleted VEGFR2 from the cell membrane, subsequently inducing the internalization and degradation of VEGFR2 and thereby attenuating VEGFR2 signaling. We also synthesized an orally active glycosaminoglycan (LHbisD4) that specifically binds with doppel. We determined that LHbisD4 concentrates over the tumor site and that genetic loss of doppel in TECs decreases LHbisD4 binding and targeting both in vitro and in vivo. Moreover, LHbisD4 eliminated VEGFR2 from the cell membrane, prevented VEGF binding in TECs, and suppressed tumor growth. Together, our results demonstrate that blocking doppel can control VEGF signaling in TECs and selectively inhibit tumor angiogenesis. PMID:26950422

  15. Pleiotrophin is a driver of vascular abnormalization in glioblastoma.

    PubMed

    Zhang, Lei; Dimberg, Anna

    2016-01-01

    In a recent report by Zhang et al., pleiotrophin (PTN) was demonstrated to enhance glioma growth by promoting vascular abnormalization. PTN stimulates glioma vessels through anaplastic lymphoma kinase (Alk)-mediated perivascular deposition of vascular endothelial growth factor (VEGF). Targeting of Alk or VEGF signaling normalizes tumor vessels in PTN-expressing tumors.

  16. Floral vasculature and its variation for carpellary supply in Anthurium (Araceae, Alismatales)

    PubMed Central

    Temponi, Lívia G.; Coan, Alessandra I.

    2017-01-01

    Introduction and Aims Anthurium is the largest genus of Araceae, with 950 species distributed in the neotropics. Despite the great diversity of the genus, the knowledge of its floral vasculature is based on observations in only two species, viz. A. denudatum and A. lhotzkyanum, with remarkable variation in vascular carpellary supply: carpels are either vascularized by ventral bundles alone or by reduced dorsal bundles in addition to the ventral ones. Our main objective is to test this peculiar variation through a detailed anatomical study of the floral vasculature in taxa belonging to some sections of Anthurium designated as monophyletic groups in recent phylogenies. Methods We compare the floral vasculature of 20 neotropical species belonging to distinct sections of Anthurium, using both light and confocal laser scanning microscopies. Results The number and position of vascular bundles are constant within the tepals and stamens, regardless of the species and sections studied. However, the gynoecium vasculature exhibits variation between species belonging to the same or different sections. Our results reveal two patterns of vasculature: carpels vascularized by synlateral bundles alone (Pattern A) and carpels vascularized by both dorsal and synlateral bundles (Pattern B). Pattern A is shared by the majority of species studied here and corroborates the previous data in the literature. Pattern B occurs in three species: A. affine (Anthurium sect. Pachyneurium series Pachyneurium), A. obtusum and A. scandens (Anthurium sect. Tetraspermium), described here for the first time for the genus. Conclusions The variation in the supply to the carpels in Anthurium is corroborated here. However, our results in addition to those from the available literature suggest the existence of three patterns (A, B and C) of carpellary vasculature. Based on the recent phylogeny of Anthurium it is possible to notice that the three patterns of carpellary vasculature occur in representatives of

  17. CAVAREV—an open platform for evaluating 3D and 4D cardiac vasculature reconstruction

    NASA Astrophysics Data System (ADS)

    Rohkohl, Christopher; Lauritsch, Günter; Keil, Andreas; Hornegger, Joachim

    2010-05-01

    The 3D reconstruction of cardiac vasculature, e.g. the coronary arteries, using C-arm CT (rotational angiography) is an active and challenging field of research. There are numerous publications on different reconstruction techniques. However, there is still a lack of comparability of achieved results for several reasons: foremost, datasets used in publications are not open to public and thus experiments are not reproducible by other researchers. Further, the results highly depend on the vasculature motion, i.e. cardiac and breathing motion patterns which are also not comparable across publications. We aim to close this gap by providing an open platform, called Cavarev (CArdiac VAsculature Reconstruction EValuation). It features two simulated dynamic projection datasets based on the 4D XCAT phantom with contrasted coronary arteries which was derived from patient data. In the first dataset, the vasculature undergoes a continuous periodic motion. The second dataset contains aperiodic heart motion by including additional breathing motion. The geometry calibration and acquisition protocol were obtained from a real-world C-arm system. For qualitative evaluation of the reconstruction results, the correlation of the morphology is used. Two segmentation-based quality measures are introduced which allow us to assess the 3D and 4D reconstruction quality. They are based on the spatial overlap of the vasculature reconstruction with the ground truth. The measures enable a comprehensive analysis and comparison of reconstruction results independent from the utilized reconstruction algorithm. An online platform (www.cavarev.com) is provided where the datasets can be downloaded, researchers can manage and publish algorithm results and download a reference C++ and Matlab implementation.

  18. Cytogenetics of human brain tumors

    SciTech Connect

    Finkernagel, S.W.; Kletz, T.; Day-Salvatore, D.L.

    1994-09-01

    Chromosome studies of 55 brain tumors, including meningiomas, gliomas, astrocyomas and pituatary adenomas, were performed. Primary and first passage cultures were successfully obtained in 75% of these samples with an average of 18 G-banded metaphases analyzed per tumor. 44% of all the brain tumors showed numerical and or structural abnormalities. 46% of the primary and 38% of the first passage cultures showed similar numerical gains/losses and complex karyotypic changes. The most frequent numerical abnormalities (n {ge} 5) included loss of chromosomes 10, 22, and Y. The structural abnormalities most often seen involved 1p, 2, 5, 7, 17q and 19. This is an ongoing study which will attempt to correlate tumor type with specific karyotypic changes and to see if any of the observed chromosomal abnormalities provide prognostic indicators.

  19. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  20. Crawling phagocytes recruited in the brain vasculature after pertussis toxin exposure through IL6, ICAM1 and ITGαM.

    PubMed

    Richard, Jean-François; Roy, Monica; Audoy-Rémus, Julie; Tremblay, Pierrot; Vallières, Luc

    2011-11-01

    The cerebral vasculature is constantly patrolled by rod-shaped leukocytes crawling on the luminal endothelial surface. These cells are recruited in greater numbers after exposure to bacterial lipopolysaccharide (LPS) by a mechanism involving tumor necrosis factor (TNF), interleukin-1β (IL1β) and angiopoietin-2 (Angpt2). Here, we report that the population of crawling leukocytes, consisting mainly of granulocytes, is also increased in the brains of mice suffering from experimental autoimmune encephalomyelitis (EAE) or injected with pertussis toxin (PTX), which is commonly used to induce EAE. However, this recruitment occurs through an alternative mechanism, independent of Angpt2. In a series of experiments using DNA microarrays, knockout mice and neutralizing antibodies, we found that PTX acts indirectly on the endothelium in part through IL6, which is essential for the post-transcriptional upregulation of intercellular adhesion molecule 1 (ICAM1) in response to PTX but not to LPS. We also found that phagocytes adhere to brain capillaries through the interaction of integrin αM (ITGαM) with ICAM1 and an unidentified ligand. In conclusion, this study supports the concept that PTX promotes EAE, at least in part, by inducing vascular changes necessary for the recruitment of patrolling leukocytes.

  1. Photoacoustic endoscopic imaging study of melanoma tumor growth in a rat colorectum in vivo

    NASA Astrophysics Data System (ADS)

    Li, Chiye; Yang, Joon-Mo; Chen, Ruimin; Zhang, Yu; Xia, Younan; Zhou, Qifa; Shung, K. Kirk; Wang, Lihong V.

    2013-03-01

    We performed a photoacoustic endoscopic imaging study of melanoma tumor growth in a nude rat in vivo. After inducing the tumor at the colorectal wall of the animal, we monitored the tumor development in situ by using a photoacoustic endoscopic system. This paper introduces our experimental method for tumor inoculation and presents imaging results showing the morphological changes of the blood vasculature near the tumor region according to the tumor progress. Our study could provide insights for future studies on tumor development in small animals.

  2. Morphology of the adrenal medulla indicating multiple neuroectodermal abnormalities in pheochromocytoma patients.

    PubMed

    Jansson, S; Tisell, L E; Hansson, G

    1988-01-01

    25 of 85 (29.4%) consecutive patients operated on for pheochromocytoma had other neuroectodermal abnormalities. Medullary thyroid carcinoma was the most common associated neuroectodermal abnormality followed by von Recklinghausen's neurofibromatosis. Other abnormalities were intracranial tumors, parathyroid hyperplasia and midgut carcinoid. The adrenal medulla was studied to find out morphological characteristics in patients with associated neuroectodermal abnormalities. All patients with multiple pheochromocytomas (n = 7) and all patients with hyperplasia of the extratumoral adrenal medulla (n = 13) had other neuroectodermal abnormalities. It is important to detect the associated neuroectodermal abnormalities because they can be lethal. Patients with associated neuroectodermal abnormalities often have hereditary syndromes.

  3. Visual perceptual abnormalities: hallucinations and illusions.

    PubMed

    Norton, J W; Corbett, J J

    2000-01-01

    Visual perceptual abnormalities may be caused by diverse etiologies which span the fields of psychiatry and neurology. This article reviews the differential diagnosis of visual perceptual abnormalities from both a neurological and a psychiatric perspective. Psychiatric etiologies include mania, depression, substance dependence, and schizophrenia. Common neurological causes include migraine, epilepsy, delirium, dementia, tumor, and stroke. The phenomena of palinopsia, oscillopsia, dysmetropsia, and polyopia among others are also reviewed. A systematic approach to the many causes of illusions and hallucinations may help to achieve an accurate diagnosis, and a more focused evaluation and treatment plan for patients who develop visual perceptual abnormalities. This article provides the practicing neurologist with a practical understanding and approach to patients with these clinical symptoms.

  4. New Enzyme Prodrug and Methionine-Depletion Combination Therapy of Breast Cancer Designed for Effective Delivery to the Tumor

    DTIC Science & Technology

    2011-10-01

    the prodrug. Annexin V is known to bind with high affinity to phosphatidylserine (PS) in phospholipids bilayers. PS has recently been shown to be...We have tested a procedure to quantify the exposure of phosphatidylserine on the surface of the tumor vasculature in nude mice with MDA-MB-231... Phosphatidylserine is a marker of t umor vasculature and a potential target for cancer imaging and ttherapy, Int. J. Radiat. Oncol. Bioi. Phys. 54

  5. CT of trauma to the abnormal kidney

    SciTech Connect

    Rhyner, P.; Federle, M.P.; Jeffrey, R.B.

    1984-04-01

    Traumatic injuries to already abnormal kidneys are difficult to assess by excretory urography and clinical evaluation. Bleeding and urinary extravasation may accompany minor trauma; conversely, underlying tumors, perirenal hemorrhage, and extravasation may be missed on urography. Computed tomography (CT) was performed in eight cases including three neoplasms, one adult polycystic disease, one simple renal cyst, two hydronephrotic kidneys, and one horseshoe kidney. CT provided specific and clinically useful information in each case that was not apparent on excretory urography.

  6. MR imaging of the spleen: spectrum of abnormalities.

    PubMed

    Elsayes, Khaled M; Narra, Vamsidhar R; Mukundan, Govind; Lewis, James S; Menias, Christine O; Heiken, Jay P

    2005-01-01

    The spleen has the same relationship to the circulatory system that the lymph nodes have to the lymphatic system. A wide range of diseases can affect the spleen. Pathologic conditions of the spleen can be classified into the following categories: congenital diseases (accessory spleen, polysplenia, and asplenia); trauma; inflammation (abscess, candidiasis, histoplasmosis, and sarcoidosis); vascular disorders (infarction, diseases affecting the splenic vasculature, and arteriovenous malformation); hematologic disorders (sickle cell disease and extramedullary hematopoiesis); benign tumors (cysts, hemangioma, diffuse hemangiomatosis of the spleen, and hamartoma); malignant tumors (sarcoma, lymphoma, and metastases); and other disease processes that affect the spleen diffusely (portal hypertension, Gaucher disease, and sickle cell disease) or focally (Gamna-Gandy nodules). New magnetic resonance (MR) imaging techniques have increased the role of MR imaging in detection and characterization of splenic diseases. MR imaging is an excellent tool for diagnosis and evaluation of focal lesions and pathologic conditions of the spleen.

  7. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis

    PubMed Central

    Riabov, Vladimir; Gudima, Alexandru; Wang, Nan; Mickley, Amanda; Orekhov, Alexander; Kzhyshkowska, Julia

    2014-01-01

    Tumor angiogenesis is an essential process for supplying rapidly growing malignant tissues with essential nutrients and oxygen. An angiogenic switch allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic disease. Monocyte-derived macrophages recruited and reprogrammed by tumor cells serve as a major source of angiogenic factors boosting the angiogenic switch. Tumor endothelium releases angiopoietin-2 and further facilitates recruitment of TIE2 receptor expressing monocytes (TEM) into tumor sites. Tumor-associated macrophages (TAM) sense hypoxia in avascular areas of tumors, and react by production of angiogenic factors such as VEGFA. VEGFA stimulates chemotaxis of endothelial cells (EC) and macrophages. In some tumors, TAM appeared to be a major source of MMP9. Elevated expression of MMP9 by TAM mediates extracellular matrix (ECM) degradation and the release of bioactive VEGFA. Other angiogenic factors released by TAM include basic fibroblast growth factor (bFGF), thymidine phosphorylase (TP), urokinase-type plasminogen activator (uPA), and adrenomedullin (ADM). The same factors used by macrophages for the induction of angiogenesis [like vascular endothelial growth factor A (VEGF-A) and MMP9] support lymphangiogenesis. TAM can express LYVE-1, one of the established markers of lymphatic endothelium. TAM support tumor lymphangiogenesis not only by secretion of pro-lymphangiogenic factors but also by trans-differentiation into lymphatic EC. New pro-angiogenic factor YKL-40 belongs to a family of mammalian chitinase-like proteins (CLP) that act as cytokines or growth factors. Human CLP family comprises YKL-40, YKL-39, and SI-CLP. Production of all three CLP in macrophages is antagonistically regulated by cytokines. It was recently established that YKL-40 induces angiogenesis in vitro and in animal tumor models. YKL-40-neutralizing monoclonal antibody blocks tumor angiogenesis and progression. The role of YKL-39 and SI

  8. Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development.

    PubMed

    Singh, Anamika; Ramesh, Sindhu; Cibi, Dasan Mary; Yun, Lim Sze; Li, Jun; Li, Li; Manderfield, Lauren J; Olson, Eric N; Epstein, Jonathan A; Singh, Manvendra K

    2016-05-17

    Formation of the coronary vasculature is a complex and precisely coordinated morphogenetic process that begins with the formation of epicardium. The epicardium gives rise to many components of the coronary vasculature, including fibroblasts, smooth muscle cells, and endothelium. Hippo signaling components have been implicated in cardiac development and regeneration. However, a role of Hippo signaling in the epicardium has not been explored. Employing a combination of genetic and pharmacological approaches, we demonstrate that inhibition of Hippo signaling mediators Yap and Taz leads to impaired epicardial epithelial-to-mesenchymal transition (EMT) and a reduction in epicardial cell proliferation and differentiation into coronary endothelial cells. We provide evidence that Yap and Taz control epicardial cell behavior, in part by regulating Tbx18 and Wt1 expression. Our findings show a role for Hippo signaling in epicardial cell proliferation, EMT, and cell fate specification during cardiac organogenesis.

  9. Hippo signaling mediators Yap and Taz are required in the epicardium for coronary vasculature development

    PubMed Central

    Singh, Anamika; Ramesh, Sindhu; Cibi, Dasan Mary; Yun, Lim Sze; Li, Jun; Li, Li; Manderfield, Lauren J.; Olson, Eric N.; Epstein, Jonathan A.; Singh, Manvendra K.

    2016-01-01

    Summary Formation of the coronary vasculature is a complex and precisely coordinated morphogenetic process that begins with the formation of epicardium. The epicardium gives rise to many components of the coronary vasculature, including fibroblasts, smooth muscle cells and endothelium. Hippo signaling components have been implicated in cardiac development and regeneration. However a role of Hippo signaling in the epicardium has not been explored. Employing a combination of genetic and pharmacological approaches, we demonstrate that inhibition of Hippo signaling mediators Yap and Taz leads to impaired epicardial epithelial-to-mesenchymal transition (EMT) and a reduction in epicardial cell proliferation and differentiation into coronary endothelial cells. We provide evidence that Yap and Taz control epicardial cell behavior, in part by regulating Tbx18 and Wt1 expression. Our findings show a role for Hippo signaling in epicardial cell proliferation, EMT and cell fate specification during cardiac organogenesis. PMID:27160901

  10. A model for gas and nutrient exchange in the chorionic vasculature system of the mouse placenta

    NASA Astrophysics Data System (ADS)

    Mirbod, Parisa; Sled, John

    2015-11-01

    The aim of this study is to develop an analytical model for the oxygen and nutrient transport from the umbilical cord to the small villous capillaries. The nutrient and carbon dioxide removal from the fetal cotyledons in the mouse placental system has also been considered. This model describes the mass transfer between the fetal and the maternal red blood cells in the chorionic arterial vasculature system. The model reveals the detail fetal vasculature system and its geometry and the precise mechanisms of mass transfer through the placenta. The dimensions of the villous capillaries, the total length of the villous trees, the total villi surface area, and the total resistance to mass transport in the fetal villous trees has also been defined. This is the first effort to explain the reason why there are at least 7 lobules in the mouse placenta from the fluid dynamics point of view.

  11. A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis.

    PubMed

    Yoshida, Shosei; Sukeno, Mamiko; Nabeshima, Yo-Ichi

    2007-09-21

    Mammalian spermatogenesis produces numerous sperm for a long period based on a highly potent stem cell system, which relies on a special microenvironment, or niche, that has not yet been identified. In this study, using time-lapse imaging of green fluorescent protein-labeled undifferentiated spermatogonia (A(undiff)) and three-dimensional reconstitution, we revealed a biased localization of A(undiff) to the vascular network and accompanying Leydig and other interstitial cells, in intact testes. Differentiating spermatogonia left these niche regions and dispersed throughout the basal compartment of the seminiferous epithelium. Moreover, rearrangement of A(undiff) accompanied the vasculature alteration. We propose that the mammalian germline niche is established as a consequence of vasculature pattern formation. This is different from what is observed in Drosophila or Caenorhabditis elegans, which display developmentally specified niche structures within polarized gonads.

  12. The biomechanical properties of an epithelial tissue determine the location of its vasculature

    PubMed Central

    Kragl, Martin; Schubert, Rajib; Karsjens, Haiko; Otter, Silke; Bartosinska, Barbara; Jeruschke, Kay; Weiss, Jürgen; Chen, Chunguang; Alsteens, David; Kuss, Oliver; Speier, Stephan; Eberhard, Daniel; Müller, Daniel J.; Lammert, Eckhard

    2016-01-01

    An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor ‘empty sleeves' of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue. PMID:27995929

  13. Bone tumor

    MedlinePlus

    Tumor - bone; Bone cancer; Primary bone tumor; Secondary bone tumor; Bone tumor - benign ... The cause of bone tumors is unknown. They often occur in areas of the bone that grow rapidly. Possible causes include: Genetic defects ...

  14. Targeting the Tumour Vasculature: Exploitation of Low Oxygenation and Sensitivity to NOS Inhibition by Treatment with a Hypoxic Cytotoxin

    PubMed Central

    Baker, Jennifer H. E.; Kyle, Alastair H.; Bartels, Kirsten L.; Methot, Stephen P.; Flanagan, Erin J.; Balbirnie, Andrew; Cran, Jordan D.; Minchinton, Andrew I.

    2013-01-01

    Many cancer research efforts focus on exploiting genetic-level features that may be targeted for therapy. Tissue-level features of the tumour microenvironment also represent useful therapeutic targets. Here we investigate the presence of low oxygen tension and sensitivity to NOS inhibition of tumour vasculature as potential tumour-specific features that may be targeted by hypoxic cytotoxins, a class of therapeutics currently under investigation. We have previously demonstrated that tirapazamine (TPZ) mediates central vascular dysfunction in tumours. TPZ is a hypoxic cytotoxin that is also a competitive inhibitor of NOS. Here we further investigated the vascular-targeting activity of TPZ by combining it with NOS inhibitor L-NNA, or with low oxygen content gas breathing. Tumours were analyzed via multiplex immunohistochemical staining that revealed irreversible loss of perfusion and enhanced tumour cell death when TPZ was combined with either low oxygen or a NOS inhibitor. Tumour growth rate was reduced by TPZ + NOS inhibition, and tumours previously resistant to TPZ-mediated vascular dysfunction were sensitized by low oxygen breathing. Additional mapping analysis suggests that tumours with reduced vascular-associated stroma may have greater sensitivity to these effects. These results indicate that poorly oxygenated tumour vessels, also being abnormally organized and with inadequate smooth muscle, may be successfully targeted for significant anti-cancer effects by inhibition of NOS and hypoxia-activated prodrug toxicity. This strategy illustrates a novel use of hypoxia-activated cytotoxic prodrugs as vascular targeting agents, and also represents a novel mechanism for targeting tumour vessels. PMID:24204680

  15. Assessment of variability in cerebral vasculature for neuro-anatomical surgery planning in rodent brain

    NASA Astrophysics Data System (ADS)

    Rangarajan, J. R.; Van Kuyck, K.; Himmelreich, U.; Nuttin, B.; Maes, F.; Suetens, P.

    2011-03-01

    Clinical and pre-clinical studies show that deep brain stimulation (DBS) of targeted brain regions by neurosurgical techniques ameliorate psychiatric disorder such as anorexia nervosa. Neurosurgical interventions in preclinical rodent brain are mostly accomplished manually with a 2D atlas. Considering both the large number of animals subjected to stereotactic surgical experiments and the associated imaging cost, feasibility of sophisticated pre-operative imaging based surgical path planning and/or robotic guidance is limited. Here, we spatially normalize vasculature information and assess the intra-strain variability in cerebral vasculature for a neurosurgery planning. By co-registering and subsequently building a probabilistic vasculature template in a standard space, we evaluate the risk of a user defined electrode trajectory damaging a blood vessel on its path. The use of such a method may not only be confined to DBS therapy in small animals, but also could be readily applicable to a wide range of stereotactic small animal surgeries like targeted injection of contrast agents and cell labeling applications.

  16. Adaptive Image Enhancement for Tracing 3D Morphologies of Neurons and Brain Vasculatures.

    PubMed

    Zhou, Zhi; Sorensen, Staci; Zeng, Hongkui; Hawrylycz, Michael; Peng, Hanchuan

    2015-04-01

    It is important to digitally reconstruct the 3D morphology of neurons and brain vasculatures. A number of previous methods have been proposed to automate the reconstruction process. However, in many cases, noise and low signal contrast with respect to the image background still hamper our ability to use automation methods directly. Here, we propose an adaptive image enhancement method specifically designed to improve the signal-to-noise ratio of several types of individual neurons and brain vasculature images. Our method is based on detecting the salient features of fibrous structures, e.g. the axon and dendrites combined with adaptive estimation of the optimal context windows where such saliency would be detected. We tested this method for a range of brain image datasets and imaging modalities, including bright-field, confocal and multiphoton fluorescent images of neurons, and magnetic resonance angiograms. Applying our adaptive enhancement to these datasets led to improved accuracy and speed in automated tracing of complicated morphology of neurons and vasculatures.

  17. Quantitative in vivo optical tomography of cancer progression & vasculature development in adult zebrafish

    PubMed Central

    Kumar, Sunil; Lockwood, Nicola; Ramel, Marie-Christine; Correia, Teresa; Ellis, Matthew; Alexandrov, Yuriy; Andrews, Natalie; Patel, Rachel; Bugeon, Laurence; Dallman, Margaret J.; Brandner, Sebastian; Arridge, Simon; Katan, Matilda; McGinty, James; Frankel, Paul; French, Paul M.W.

    2016-01-01

    We describe a novel approach to study tumour progression and vasculature development in vivo via global 3-D fluorescence imaging of live non-pigmented adult zebrafish utilising angularly multiplexed optical projection tomography with compressive sensing (CS-OPT). This “mesoscopic” imaging method bridges a gap between established ~μm resolution 3-D fluorescence microscopy techniques and ~mm-resolved whole body planar imaging and diffuse tomography. Implementing angular multiplexing with CS-OPT, we demonstrate the in vivo global imaging of an inducible fluorescently labelled genetic model of liver cancer in adult non-pigmented zebrafish that also present fluorescently labelled vasculature. In this disease model, addition of a chemical inducer (doxycycline) drives expression of eGFP tagged oncogenic K-RASV12 in the liver of immune competent animals. We show that our novel in vivo global imaging methodology enables non-invasive quantitative imaging of the development of tumour and vasculature throughout the progression of the disease, which we have validated against established methods of pathology including immunohistochemistry. We have also demonstrated its potential for longitudinal imaging through a study of vascular development in the same zebrafish from early embryo to adulthood. We believe that this instrument, together with its associated analysis and data management tools, constitute a new platform for in vivo cancer studies and drug discovery in zebrafish disease models. PMID:27259259

  18. Tissue Myeloid Progenitors Differentiate into Pericytes through TGF-β Signaling in Developing Skin Vasculature.

    PubMed

    Yamazaki, Tomoko; Nalbandian, Ani; Uchida, Yutaka; Li, Wenling; Arnold, Thomas D; Kubota, Yoshiaki; Yamamoto, Seiji; Ema, Masatsugu; Mukouyama, Yoh-Suke

    2017-03-21

    Mural cells (pericytes and vascular smooth muscle cells) are essential for the regulation of vascular networks and maintenance of vascular integrity, but their origins are diverse in different tissues and not known in the organs that arise from the ectoderm, such as skin. Here, we show that tissue-localized myeloid progenitors contribute to pericyte development in embryonic skin vasculature. A series of in vivo fate-mapping experiments indicates that tissue myeloid progenitors differentiate into pericytes. Furthermore, depletion of tissue myeloid cells and their progenitors in PU.1 (also known as Spi1) mutants results in defective pericyte development. Fluorescence-activated cell sorting (FACS)-isolated myeloid cells and their progenitors from embryonic skin differentiate into pericytes in culture. At the molecular level, transforming growth factor-β (TGF-β) induces pericyte differentiation in culture. Furthermore, type 2 TGF-β receptor (Tgfbr2) mutants exhibit deficient pericyte development in skin vasculature. Combined, these data suggest that pericytes differentiate from tissue myeloid progenitors in the skin vasculature through TGF-β signaling.

  19. Quantitative in vivo optical tomography of cancer progression & vasculature development in adult zebrafish.

    PubMed

    Kumar, Sunil; Lockwood, Nicola; Ramel, Marie-Christine; Correia, Teresa; Ellis, Matthew; Alexandrov, Yuriy; Andrews, Natalie; Patel, Rachel; Bugeon, Laurence; Dallman, Margaret J; Brandner, Sebastian; Arridge, Simon; Katan, Matilda; McGinty, James; Frankel, Paul; French, Paul M W

    2016-07-12

    We describe a novel approach to study tumour progression and vasculature development in vivo via global 3-D fluorescence imaging of live non-pigmented adult zebrafish utilising angularly multiplexed optical projection tomography with compressive sensing (CS-OPT). This "mesoscopic" imaging method bridges a gap between established ~μm resolution 3-D fluorescence microscopy techniques and ~mm-resolved whole body planar imaging and diffuse tomography. Implementing angular multiplexing with CS-OPT, we demonstrate the in vivo global imaging of an inducible fluorescently labelled genetic model of liver cancer in adult non-pigmented zebrafish that also present fluorescently labelled vasculature. In this disease model, addition of a chemical inducer (doxycycline) drives expression of eGFP tagged oncogenic K-RASV12 in the liver of immune competent animals. We show that our novel in vivo global imaging methodology enables non-invasive quantitative imaging of the development of tumour and vasculature throughout the progression of the disease, which we have validated against established methods of pathology including immunohistochemistry. We have also demonstrated its potential for longitudinal imaging through a study of vascular development in the same zebrafish from early embryo to adulthood. We believe that this instrument, together with its associated analysis and data management tools, constitute a new platform for in vivo cancer studies and drug discovery in zebrafish disease models.

  20. [The relativity of abnormity].

    PubMed

    Nilson, Annika

    2006-01-01

    In the late 19th century and in the beginning of the 20th century, mental diseases and abnormal behavior was considered to be a great danger to culture and society. "Degeneration" was the buzzword of the time, used and misused by artists and scientists alike. At the same time, some scientists saw abnormity as the key to unlock the mysteries of the ordinary mind. Naturalistic curiosity left Pandoras box open when religion declined in Darwins wake. Two swedish scientists, the physician Bror Gadelius (1862-1938) and his friend the philosopher Axel Herrlin (1870-1937), inspired by the French psychologist Theodule Ribots (1839-1916) "psychology without a soul", denied all fixed demarcation lines between abnormity and normality. All humans are natures creatures ruled by physiological laws, not ruled by God or convention. Even ordinary morality was considered to be an utterly backward explanation and guideline for complex human behavior. Different forms of therapy, not various kinds of penalties for wicked and disturbing behavior, are the now the solution for lots of people, "normal" as well as "abnormal". Psychiatry is expanding.

  1. Abnormalities of gonadal differentiation.

    PubMed

    Berkovitz, G D; Seeherunvong, T

    1998-04-01

    Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less well understood. Abnormalities of gonadal differentiation result in a range of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external genitalia and come to clinical attention because of delayed puberty. Individuals with 46,XY partial gonadal dysgenesis usually present in the newborn period for the valuation of ambiguous genitalia. Gonadal histology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual in subjects with a 46,XY karyotype and abnormal gonadal development. 46,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majority of subjects with 46,XX maleness have Y sequences including SRY in genomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism involving the Y chromosome can also be associated with abnormal gonadal development. However, the vast majority of subjects with 45,X/46,XY mosaicism have normal testes and normal male external genitalia.

  2. The irradiated tumor microenvironment: role of tumor-associated macrophages in vascular recovery

    PubMed Central

    Russell, Jeffery S.; Brown, J. Martin

    2013-01-01

    Radiotherapy is an important modality used in the treatment of more than 50% of cancer patients in the US. However, despite sophisticated techniques for radiation delivery as well as the combination of radiation with chemotherapy, tumors can recur. Thus, any method of improving the local control of the primary tumor by radiotherapy would produce a major improvement in the curability of cancer patients. One of the challenges in the field is to understand how the tumor vasculature can regrow after radiation in order to support tumor recurrence, as it is unlikely that any of the endothelial cells within the tumor could survive the doses given in a typical radiotherapy regimen. There is now considerable evidence from both preclinical and clinical studies that the tumor vasculature can be restored following radiotherapy from an influx of circulating cells consisting primarily of bone marrow derived monocytes and macrophages. The radiation-induced influx of bone marrow derived cells (BMDCs) into tumors can be prevented through the blockade of various cytokine pathways and such strategies can inhibit tumor recurrence. However, the post-radiation interactions between surviving tumor cells, recruited immune cells, and the remaining stroma remain poorly defined. While prior studies have described the monocyte/macrophage inflammatory response within normal tissues and in the tumor microenvironment, less is known about this response with respect to a tumor after radiation therapy. The goal of this review is to summarize existing research studies to provide an understanding of how the myelomonocytic lineage may influence vascular recovery within the irradiated tumor microenvironment. PMID:23882218

  3. Use of the hollow fibre assay for studies of tumor neovasculature.

    PubMed

    Shnyder, Steven D

    2009-01-01

    In vivo preclinical assays are required to screen potential agents that target the tumor vasculature. Here, a hollow fibre-based assay for the quantification of neovasculature in the presence or absence of an agent that potentially targets tumor neovasculature is described. The neovasculature is developed as a consequence of the presence of tumor cells encapsulated in hollow fibres, which are transplanted subcutaneously in the dorsal flanks of mice.

  4. The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems

    PubMed Central

    Wu, Min; Frieboes, Hermann B.; Chaplain, Mark A.J.; McDougall, Steven R.; Cristini, Vittorio; Lowengrub, John

    2014-01-01

    Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but leads to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the

  5. Volume estimation of brain abnormalities in MRI data

    NASA Astrophysics Data System (ADS)

    Suprijadi, Pratama, S. H.; Haryanto, F.

    2014-02-01

    The abnormality of brain tissue always becomes a crucial issue in medical field. This medical condition can be recognized through segmentation of certain region from medical images obtained from MRI dataset. Image processing is one of computational methods which very helpful to analyze the MRI data. In this study, combination of segmentation and rendering image were used to isolate tumor and stroke. Two methods of thresholding were employed to segment the abnormality occurrence, followed by filtering to reduce non-abnormality area. Each MRI image is labeled and then used for volume estimations of tumor and stroke-attacked area. The algorithms are shown to be successful in isolating tumor and stroke in MRI images, based on thresholding parameter and stated detection accuracy.

  6. [Abnormal absence of displacement of the cerebral median line].

    PubMed

    de Tribolet, N; Oberson, R

    1975-03-08

    The angiographic cerebral midline is described. It is pointed out that the midline may be abnormally undisplaced despite the presence of a unilateral or bilateral expansive lesion. The causes of such abnormal non-displacement of the midline are reviewed in the light of examples, and the importance is stressed of bilateral carotid angiograms, sometimes with oblique series, in the case of head injuries and certain tumors.

  7. Heritable bovine fetal abnormalities.

    PubMed

    Whitlock, B K; Kaiser, L; Maxwell, H S

    2008-08-01

    The etiologies for congenital bovine fetal anomalies can be divided into heritable, toxic, nutritional, and infectious categories. Although uncommon in most herds, inherited congenital anomalies are probably present in all breeds of cattle and propagated as a result of specific trait selection that inadvertently results in propagation of the defect. In some herds, the occurrence of inherited anomalies has become frequent, and economically important. Anomalous traits can affect animals in a range of ways, some being lethal or requiring euthanasia on humane grounds, others altering structure, function, or performance of affected animals. Veterinary practitioners should be aware of the potential for inherited defects, and be prepared to investigate and report animals exhibiting abnormal characteristics. This review will discuss the morphologic characteristics, mode of inheritance, breeding lines affected, and the availability of genetic testing for selected heritable bovine fetal abnormalities.

  8. Liver abnormalities in pregnancy.

    PubMed

    Than, Nwe Ni; Neuberger, James

    2013-08-01

    Abnormalities of liver function (notably rise in alkaline phosphatase and fall in serum albumin) are common in normal pregnancy, whereas rise in serum bilirubin and aminotransferase suggest either exacerbation of underlying pre-existing liver disease, liver disease related to pregnancy or liver disease unrelated to pregnancy. Pregnant women appear to have a worse outcome when infected with Hepatitis E virus. Liver diseases associated with pregnancy include abnormalities associated hyperemesis gravidarum, acute fatty liver disease, pre-eclampsia, cholestasis of pregnancy and HELLP syndrome. Prompt investigation and diagnosis is important in ensuring a successful maternal and foetal outcome. In general, prompt delivery is the treatment of choice for acute fatty liver, pre-eclampsia and HELLP syndrome and ursodeoxycholic acid is used for cholestasis of pregnancy although it is not licenced for this indication.

  9. Morphological abnormalities in elasmobranchs.

    PubMed

    Moore, A B M

    2015-08-01

    A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed.

  10. Anatomical Abnormalities in Autism?

    PubMed

    Haar, Shlomi; Berman, Sigal; Behrmann, Marlene; Dinstein, Ilan

    2016-04-01

    Substantial controversy exists regarding the presence and significance of anatomical abnormalities in autism spectrum disorders (ASD). The release of the Autism Brain Imaging Data Exchange (∼1000 participants, age 6-65 years) offers an unprecedented opportunity to conduct large-scale comparisons of anatomical MRI scans across groups and to resolve many of the outstanding questions. Comprehensive univariate analyses using volumetric, thickness, and surface area measures of over 180 anatomically defined brain areas, revealed significantly larger ventricular volumes, smaller corpus callosum volume (central segment only), and several cortical areas with increased thickness in the ASD group. Previously reported anatomical abnormalities in ASD including larger intracranial volumes, smaller cerebellar volumes, and larger amygdala volumes were not substantiated by the current study. In addition, multivariate classification analyses yielded modest decoding accuracies of individuals' group identity (<60%), suggesting that the examined anatomical measures are of limited diagnostic utility for ASD. While anatomical abnormalities may be present in distinct subgroups of ASD individuals, the current findings show that many previously reported anatomical measures are likely to be of low clinical and scientific significance for understanding ASD neuropathology as a whole in individuals 6-35 years old.

  11. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  12. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.

    PubMed

    Benjamin, L E; Golijanin, D; Itin, A; Pode, D; Keshet, E

    1999-01-01

    Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.

  13. Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models.

    PubMed

    Muldoon, Leslie L; Gahramanov, Seymur; Li, Xin; Marshall, Deborah J; Kraemer, Dale F; Neuwelt, Edward A

    2011-01-01

    We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting α(V)-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4-6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting α(V)-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.

  14. Mathematical Modeling of Branching Morphogenesis and Vascular Tumor Growth

    NASA Astrophysics Data System (ADS)

    Yan, Huaming

    Feedback regulation of cell lineages is known to play an important role in tissue size control, but the effect in tissue morphogenesis has yet to be explored. We first use a non-spatial model to show that a combination of positive and negative feedback on stem and/or progenitor cell self-renewal leads to bistable or bi-modal growth behaviors and ultrasensitivity to external growth cues. Next, a spatiotemporal model is used to demonstrate spatial patterns such as local budding and branching arise in this setting, and are not consequences of Turing-type instabilities. We next extend the model to a three-dimensional hybrid discrete-continuum model of tumor growth to study the effects of angiogenesis, tumor progression and cancer therapies. We account for the crosstalk between the vasculature and cancer stem cells (CSCs), and CSC transdifferentiation into vascular endothelial cells (gECs), as observed experimentally. The vasculature stabilizes tumor invasiveness but considerably enhances growth. A gEC network structure forms spontaneously within the hypoxic core, consistent with experimental findings. The model is then used to study cancer therapeutics. We demonstrate that traditional anti-angiogenic therapies decelerate tumor growth, but make the tumor highly invasive. Chemotherapies help to reduce tumor sizes, but cannot control the invasion. Anti-CSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness. However, gECs inherit mutations present in CSCs and are resistant to traditional therapies. We show that anti-gEC treatments block the support on CSCs by gECs, and reduce both tumor size and invasiveness. Our study suggests that therapies targeting the vasculature, CSCs and gECs, when combined, are highly synergistic and are capable of controlling both tumor size and shape.

  15. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  16. Patrolling Monocytes Control Tumor Metastasis to the Lung

    PubMed Central

    Hanna, Richard N.; Cekic, Caglar; Sag, Duygu; Tacke, Robert; Thomas, Graham D.; Nowyhed, Heba; Herrley, Erica; Rasquinha, Nicole; McArdle, Sara; Wu, Runpei; Peluso, Esther; Metzger, Daniel; Ichinose, Hiroshi; Shaked, Iftach; Chodaczek, Grzegorz; Biswas, Subhra K.; Hedrick, Catherine C.

    2016-01-01

    The immune system plays an important role in regulating tumor growth and metastasis. For example, classical monocytes promote tumorigenesis and cancer metastasis; however, how nonclassical “patrolling” monocytes interact with tumors is unknown. Here we show that patrolling monocytes are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack patrolling monocytes, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient patrolling monocytes into Nr4a1-deficient mice prevented tumor invasion in lung. Patrolling monocytes established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature and promoted natural killer cell recruitment and activation. Thus, patrolling monocytes contribute to cancer immunosurveillance and may be targets for cancer immunotherapy. PMID:26494174

  17. Maternal heme oxygenase 1 regulates placental vasculature development via angiogenic factors in mice.

    PubMed

    Zhao, Hui; Azuma, Junya; Kalish, Flora; Wong, Ronald J; Stevenson, David K

    2011-11-01

    The placental vasculature is critical for nutrient, gas, and waste exchange between the maternal and fetal systems. Its development depends on the proper expression and interaction of angiogenesis and associated growth factors. Heme oxygenase (HMOX), the enzyme for heme degradation, plays a role in angiogenesis and is highly expressed in the placenta. To evaluate the role of maternal HMOX1, the inducible HMOX isozyme, on placental vasculature formation, mice with a partial deficiency in Hmox1 (Hmox1(+/-)) were used. Three-dimensional images of placental vasculatures as well as spiral arteries from Hmox1(+/+) or Hmox1(+/-) placentas were created by vascular corrosion casting technique and imaged by micro-computerized tomography (microCT). The structures and morphologies of fetomaternal interfaces were observed by histological staining and the ultrastructure of uterine natural killer (uNK) cells, a major regulator in spiral artery remodeling, was analyzed by transmission electron microscopy. A group of growth factors and angiogenic factors from the decidua/mesometrial lymphoid aggregate of pregnancy (MLAp) as well as labyrinth regions were quantified using an angiogenesis PCR array kit and compared between Hmox1(+/+) or Hmox1(+/-) placentas. In conclusion, a partial deficiency of maternal Hmox1 resulted in the malformation of fetomaternal interface, insufficiency of spiral artery remodeling, and alteration of uNK cell differentiation and maturation. These changes were independent of the fetal genotype, but relied on the maternal HMOX1 level, which determined the balance of expression levels of pro- and antiangiogenic factors in the decidua/MLAp region. These results implied that Hmox1 polymorphisms among the human population might contribute to some unexplained cases of pregnancy disorders, such as fetal growth retardation and preeclampsia.

  18. WE-G-BRE-04: Gold Nanoparticle Induced Vasculature Damage for Proton Therapy: Monte Carlo Simulation

    SciTech Connect

    Lin, Y; Paganetti, H; Schuemann, J

    2014-06-15

    Purpose: The aim of this work is to investigate the gold nanoparticle (GNP) induced vasculature damage in a proton beam. We compared the results using a clinical proton beam, 6MV photon beam and two kilovoltage photon beams. Methods: Monte Carlo simulations were carried out using TOPAS (TOol for PArticle Simulation) to obtain the spatial dose distribution in close proximity to GNPs up to 20μm distance. The spatial dose distribution was used as an input to calculate the additional dose deposited to the blood vessels. For this study, GNP induced vasculature damage is evaluated for three particle sources (proton beam, MV photon beam and kV photon beam), various treatment depths for each particle source, various GNP uptakes and three different vessel diameters (8μm, 14μm and 20μm). Results: The result shows that for kV photon, GNPs induce more dose in the vessel wall for 150kVp photon source than 250kVp. For proton therapy, GNPs cause more dose in the vessel wall at shallower treatment depths. For 6MV photons, GNPs induce more dose in the vessel wall at deeper treatment depths. For the same GNP concentration and prescribed dose, the additional dose at the inner vessel wall is 30% more than the prescribed dose for the kVp photon source, 15% more for the proton source and only 2% more for the 6MV photon source. In addition, the dose from GNPs deceases sharper for proton therapy than kVp photon therapy as the distance from the vessel inner wall increases. Conclusion: We show in this study that GNPs can potentially be used to enhance radiation therapy by causing vasculature damage using clinical proton beams. The GNP induced damage for proton therapy is less than for the kVp photon source but significantly larger than for the clinical MV photon source.

  19. Integrative models of vascular remodeling during tumor growth

    PubMed Central

    Rieger, Heiko; Welter, Michael

    2015-01-01

    Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551

  20. Changes of the vasculature and innervation in the anterior segment of the RCS rat eye.

    PubMed

    May, Christian Albrecht

    2011-12-01

    Investigating the anterior eye segment vasculature and innervation of dystrophic RCS rats, two major unique findings were observed: in the iris, young adult animals with retinal dystrophy showed an increase in substance P nerve fibres and a dilation of arterioles and capillaries. This finding continued during ageing. In the pars plana region, the surface covered by venules decreased continuously with age. In older animals, this decrease was parallelled by a local decrease of sympathetic TH-positive nerve fibres supplying these venules. For both conditions, no comparable data exists so far in the literature. They might point to a unique situation in the anterior eye segment of the dystrophic RCS rat.

  1. In vivo label-free three-dimensional imaging of zebrafish vasculature with optical projection tomography

    NASA Astrophysics Data System (ADS)

    Bassi, Andrea; Fieramonti, Luca; D'Andrea, Cosimo; Mione, Marina; Valentini, Gianluca

    2011-10-01

    We introduce flow optical projection tomography, an imaging technique capable of visualizing the vasculature of living specimens in 3-D. The method detects the movement of cells in the bloodstream and creates flow maps using a motion-analysis procedure. Then, flow maps obtained from projection taken at several angles are used to reconstruct sections of the circulatory system of the specimen. We therefore demonstrate an in vivo, 3-D optical imaging technique that, without the use of any labeling, is able to reconstruct and visualize the vascular network of transparent and weakly scattering living specimens.

  2. Exercises to Improve Gait Abnormalities

    MedlinePlus

    ... Home About iChip Articles Directories Videos Resources Contact Exercises to Improve Gait Abnormalities Home » Article Categories » Exercise and Fitness Font Size: A A A A Exercises to Improve Gait Abnormalities Next Page The manner ...

  3. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  4. Combined Effects of Pericytes in the Tumor Microenvironment

    PubMed Central

    Ribeiro, Aline Lopes; Okamoto, Oswaldo Keith

    2015-01-01

    Pericytes are multipotent perivascular cells whose involvement in vasculature development is well established. Evidences in the literature also suggest that pericytes display immune properties and that these cells may serve as an in vivo reservoir of stem cells, contributing to the regeneration of diverse tissues. Pericytes are also capable of tumor homing and are important cellular components of the tumor microenvironment (TME). In this review, we highlight the contribution of pericytes to some classical hallmarks of cancer, namely, tumor angiogenesis, growth, metastasis, and evasion of immune destruction, and discuss how collectively these hallmarks could be tackled by therapies targeting pericytes, providing a rationale for cancer drugs aiming at the TME. PMID:26000022

  5. Combined effects of pericytes in the tumor microenvironment.

    PubMed

    Ribeiro, Aline Lopes; Okamoto, Oswaldo Keith

    2015-01-01

    Pericytes are multipotent perivascular cells whose involvement in vasculature development is well established. Evidences in the literature also suggest that pericytes display immune properties and that these cells may serve as an in vivo reservoir of stem cells, contributing to the regeneration of diverse tissues. Pericytes are also capable of tumor homing and are important cellular components of the tumor microenvironment (TME). In this review, we highlight the contribution of pericytes to some classical hallmarks of cancer, namely, tumor angiogenesis, growth, metastasis, and evasion of immune destruction, and discuss how collectively these hallmarks could be tackled by therapies targeting pericytes, providing a rationale for cancer drugs aiming at the TME.

  6. Epilepsy and chromosomal abnormalities

    PubMed Central

    2010-01-01

    Background Many chromosomal abnormalities are associated with Central Nervous System (CNS) malformations and other neurological alterations, among which seizures and epilepsy. Some of these show a peculiar epileptic and EEG pattern. We describe some epileptic syndromes frequently reported in chromosomal disorders. Methods Detailed clinical assessment, electrophysiological studies, survey of the literature. Results In some of these congenital syndromes the clinical presentation and EEG anomalies seems to be quite typical, in others the manifestations appear aspecific and no strictly linked with the chromosomal imbalance. The onset of seizures is often during the neonatal period of the infancy. Conclusions A better characterization of the electro clinical patterns associated with specific chromosomal aberrations could give us a valuable key in the identification of epilepsy susceptibility of some chromosomal loci, using the new advances in molecular cytogenetics techniques - such as fluorescent in situ hybridization (FISH), subtelomeric analysis and CGH (comparative genomic hybridization) microarray. However further studies are needed to understand the mechanism of epilepsy associated with chromosomal abnormalities. PMID:20438626

  7. Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis

    PubMed Central

    Agrawal, Vijayendra; Kim, Dong Young; Kwon, Young-Guen

    2017-01-01

    Tumor growth is governed by the coordinated action of various types of cells that are present in the tumor environment. Fibroblasts, which constitute a major fraction of the stroma, participate actively in various signaling events and regulate tumor development and metastasis. The Hedgehog (Hh) pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood. Here we implanted B16F10 tumors in hhip+/− mice to study the tumor growth characteristics and the vascular phenotype. Furthermore, the mechanism involved in the observed phenomena was explored to reveal the role of hhip in tumor growth. The tumors that were implanted in hhip+/− mice exhibited accelerated growth and increased tumor angiogenesis. Although we observed a decrease in hypoxia, blood vessels still had abnormal phenotype. We found that increased Hh signaling in tumor fibroblasts induced a high expression of vascular endothelial growth factor (VEGF), which subsequently resulted in an increased proliferation of endothelial cells. Thus, the heterozygous knockdown of hhip in mice could affect Hh signaling in tumor fibroblasts, which could cause the increased production of the growth factor VEGF. This signaling, via a paracrine effect on endothelial cells, increased tumor vascular density. PMID:28127049

  8. Technical Note: Contrast free angiography of the pulmonary vasculature in live mice using a laboratory x-ray source

    PubMed Central

    Samarage, Chaminda R.; Carnibella, Richard; Preissner, Melissa; Jones, Heather D.; Pearson, James T.; Fouras, Andreas; Dubsky, Stephen

    2016-01-01

    Purpose: In vivo imaging of the pulmonary vasculature in small animals is difficult yet highly desirable in order to allow study of the effects of a host of dynamic biological processes such as hypoxic pulmonary vasoconstriction. Here the authors present an approach for the quantification of changes in the vasculature. Methods: A contrast free angiography technique is validated in silico through the use of computer-generated images and in vivo through microcomputed tomography (μCT) of live mice conducted using a laboratory-based x-ray source. Subsequent image processing on μCT data allowed for the quantification of the caliber of pulmonary vasculature without the need for external contrast agents. These measures were validated by comparing with quantitative contrast microangiography in the same mice. Results: Quantification of arterial diameters from the method proposed in this study is validated against laboratory-based x-ray contrast microangiography. The authors find that there is a high degree of correlation (R = 0.91) between measures from microangiography and their contrast free method. Conclusions: A technique for quantification of murine pulmonary vasculature without the need for contrast is presented. As such, this technique could be applied for longitudinal studies of animals to study changes to vasculature without the risk of premature death in sensitive mouse models of disease. This approach may also be of value in the clinical setting. PMID:27806595

  9. Real time imaging of peripheral nerve vasculature using optical coherence angiography

    NASA Astrophysics Data System (ADS)

    Vasudevan, Srikanth; Kumsa, Doe; Takmakov, Pavel; Welle, Cristin G.; Hammer, Daniel X.

    2016-03-01

    The peripheral nervous system (PNS) carries bidirectional information between the central nervous system and distal organs. PNS stimulation has been widely used in medical devices for therapeutic indications, such as bladder control and seizure cessation. Investigational uses of PNS stimulation include providing sensory feedback for improved control of prosthetic limbs. While nerve safety has been well documented for stimulation parameters used in marketed devices, novel PNS stimulation devices may require alternative stimulation paradigms to achieve maximum therapeutic benefit. Improved testing paradigms to assess the safety of stimulation will expedite the development process for novel PNS stimulation devices. The objective of this research is to assess peripheral nerve vascular changes in real-time with optical coherence angiography (OCA). A 1300-nm OCA system was used to image vasculature changes in the rat sciatic nerve in the region around a surface contacting single electrode. Nerves and vasculature were imaged without stimulation for 180 minutes to quantify resting blood vessel diameter. Walking track analysis was used to assess motor function before and 6 days following experiments. There was no significant change in vessel diameter between baseline and other time points in all animals. Motor function tests indicated the experiments did not impair functionality. We also evaluated the capabilities to image the nerve during electrical stimulation in a pilot study. Combining OCA with established nerve assessment methods can be used to study the effects of electrical stimulation safety on neural and vascular tissue in the periphery.

  10. Expression and activation of the farnesoid X receptor in the vasculature

    NASA Astrophysics Data System (ADS)

    Bishop-Bailey, David; Walsh, Desmond T.; Warner, Timothy D.

    2004-03-01

    The farnesoid X receptor/bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.

  11. A new presentation and exploration of human cerebral vasculature correlated with surface and sectional neuroanatomy.

    PubMed

    Nowinski, Wieslaw L; Thirunavuukarasuu, Arumugam; Volkau, Ihar; Marchenko, Yevgen; Aminah, Bivi; Gelas, Arnaud; Huang, Su; Lee, Looi Chow; Liu, Jimin; Ng, Ting Ting; Nowinska, Natalia G; Qian, Guoyu Yu; Puspitasari, Fiftarina; Runge, Val M

    2009-01-01

    The increasing complexity of human body models enabled by advances in diagnostic imaging, computing, and growing knowledge calls for the development of a new generation of systems for intelligent exploration of these models. Here, we introduce a novel paradigm for the exploration of digital body models illustrating cerebral vasculature. It enables dynamic scene compositing, real-time interaction combined with animation, correlation of 3D models with sectional images, quantification as well as 3D manipulation-independent labeling and knowledge-related meta labeling (with name, diameter, description, variants, and references). This novel exploration is incorporated into a 3D atlas of cerebral vasculature with arteries and veins along with the surrounding surface and sectional neuroanatomy derived from 3.0 Tesla scans. This exploration paradigm is useful in medical education, training, research, and clinical applications. It enables development of new generation systems for rapid and intelligent exploration of complicated digital body models in real time with dynamic scene compositing from highly parcellated 3D models, continuous navigation, and manipulation-independent labeling with multiple features.

  12. Functional and structural evaluation of the vasculature of skin flaps after ischemia and reperfusion

    SciTech Connect

    Marzella, L.; Jesudass, R.R.; Manson, P.N.; Myers, R.A.; Bulkley, G.B.

    1988-05-01

    Free radicals and other toxic oxygen species play a role in the pathogenesis of ischemic organ damage. The abdominal skin flap has been used as a model to study the effects of superoxide dismutase on the survival of ischemic skin. We have evaluated the evolution of functional and structural injury to the vasculature after ischemic injury in superoxide dismutase-treated and control skin flaps. Ischemia was induced by creating abdominal skin flaps and occluding either the venous or both the venous and arterial blood supplies. Superoxide dismutase was administered immediately after the occlusion was released. At 1 hour of reflow, erythrocyte stasis, platelet deposition, neutrophil adherence, and injury to the endothelium of the large vessels and of the microvasculature were evident. The blood flow in the ischemic skin was only 3 percent of normal. Superoxide dismutase caused no change in the ultrastructure of the vasculature and a marginal decrease in vascular permeability in the ischemic skin at 1 hour of reflow. Increased fluorescent staining of the skin was evident after 24 hours of reflow in the superoxide dismutase-treated flaps. These findings indicate that injury to vascular endothelium by ischemia and reperfusion plays a role in the evolution of skin necrosis.

  13. The Effects of Zoledronic Acid in the Bone and Vasculature Support of Hematopoietic Stem Cell Niches

    PubMed Central

    Soki, Fabiana N.; Li, Xin; Berry, Janice; Koh, Amy; Sinder, Benjamin P.; Qian, Xu; Kozloff, Kenneth M.; Taichman, Russell S.; McCauley, Laurie K.

    2013-01-01

    Hematopoietic stem cells (HSC) are maintained in a tightly regulated bone microenvironment constituted by a rich milieu of cells. Bone cells such as osteoblasts are associated with niche maintenance as regulators of the endosteal microenvironment. Bone remodeling also plays a role in HSC mobilization although it is poorly defined. The effects of zoledronic acid (ZA), a potent bisphosphonate that inhibits bone resorption, were investigated on bone marrow cell populations focusing on HSCs, and the endosteal and vascular niches in bone. ZA treatment significantly increased bone volume and HSCs in both young and adult mice (4 week and 4 month old, respectively). ZA increased vessel numbers with no overall change in vascular volume in bones of young and had no effect on vasculature in adult mice. Since both young and adult mice had increased HSCs and bone mass with differing vasculature responses, this suggests that ZA indirectly supports HSCs via the osteoblastic niche and not the vascular niche. Additionally, gene expression in Lin- cells demonstrated increased expression of self-renewal-related genes Bmi1 and Ink4a suggesting a role of ZA in the modulation of cell commitment and differentiation toward a long-term self-renewing cell. Genes that support the osteoblastic niche, BMP2 and BMP6 were also augmented in ZA treated mice. In conclusion, ZA-induced HSC expansion occurs independent of the vascular niche via indirect modulation of the osteoblastic niche. PMID:22833499

  14. The Cadaveric Perfusion and Angiography as a Teaching Tool: Imaging the Intracranial Vasculature in Cadavers

    PubMed Central

    Turkoglu, Erhan; Seckin, Hakan; Gurer, Bora; Ahmed, Azam; Uluc, Kutluay; Pulfer, Kari; Arat, Anıl; Niemann, David; Baskaya, Mustafa K.

    2014-01-01

    Background and Study Aim To enhance the visualization of the intracranial vasculature of cadavers under gross examination with a combination of imaging modalities. Material and Methods A total of 20 cadaver heads were used to test two different perfusion techniques. First, fixed cadaver heads were perfused with water; second, fresh cadavers were perfused with saline and 10% formalin. Subsequently, brains were removed and fixed. The compounds used were silicone rubber, silicone rubber mixed with powdered barium sulfate, and silicone rubber mixed with tantalum dioxide prepared by the first perfusion technique and gelatin mixed with liquid barium prepared with the second technique. Conventional X-ray imaging, computed tomography (CT), dynamic computed tomography (dCT), and postprocessing three-dimensional (3D) images were used to evaluate all the heads. Results Gelatinized barium was better visualized when compared with tantalum dioxide in conventional X-ray images. The blood vessels injected with either tantalum dioxide or gelatinized barium demonstrated a higher enhancement than the surrounding soft tissues with CT or dCT. The quality of the 3D reconstruction of the intracranial vasculature was significantly better in the CT images obtained from the gelatinized barium group. Conclusions Radiologic examinations of the heads injected with gelatinized barium facilitates the 3D understanding of cerebrovascular anatomy as an important tool for neuroanatomy training. PMID:25452903

  15. Claudin-5 expression in the vasculature of the developing chick embryo.

    PubMed

    Collins, Michelle M; Baumholtz, Amanda I; Ryan, Aimee K

    2012-01-01

    The claudin family of proteins are integral components of tight junctions and are responsible for determining the ion specificity and permeability of paracellular transport within epithelial and endothelial cell layers. Studies in human, mouse, Xenopus, and zebrafish have shown that only a limited number of claudins are expressed in endothelial cells. Here, we report the expression pattern of Claudin-5 during chick development. Between HH stage 4 and 6 Claudin-5 expression was observed exclusively in extraembryonic tissue. Claudin-5 expression was not observed in the embryo until HH stage 8, coincident with the onset of embryonic vascularization. Claudin-5 expression was maintained in the developing vasculature in the embryonic and extraembryonic tissue throughout organogenesis (HH stage 19-35), including the vasculature of the ectoderm and of organs derived from the mesoderm and endoderm lineages. These data describe a conserved expression pattern for Claudin-5 in the endothelial tight junction barrier and is the first report of the onset of Claudin-5 expression in a vertebrate embryo.

  16. In vivo photoacoustic imaging of vasculature with a low-cost miniature light emitting diode excitation.

    PubMed

    Dai, Xianjin; Yang, Hao; Jiang, Huabei

    2017-04-01

    In this Letter, we present a photoacoustic imaging (PAI) system based on a low-cost high-power miniature light emitting diode (LED) that is capable of in vivo mapping vasculature networks in biological tissue. Overdriving with 200 ns pulses and operating at a repetition rate of 40 kHz, a 1.2 W 405 nm LED with a radiation area of 1000  μm×1000  μm and a size of 3.5  mm×3.5  mm was used to excite photoacoustic signals in tissue. Phantoms including black stripes, lead, and hair were used to validate the system in which a volumetric PAI image was obtained by scanning the transducer and the light beam in a two-dimensional x-y plane over the object. In vivo imaging of the vasculature of a mouse ear shows that LED-based PAI could have great potential for label-free biomedical imaging applications where the use of bulky and expensive pulsed lasers is impractical.

  17. Hierarchical bioimaging and quantification of vasculature in disease models using corrosion casts and microcomputed tomography

    NASA Astrophysics Data System (ADS)

    Heinzer, Stefan; Krucker, Thomas; Stampanoni, Marco; Abela, Rafael; Meyer, Eric P.; Schuler, Alexandra; Schneider, Philipp; Muller, Ralph

    2004-10-01

    A wide range of disorders are associated with alterations of the central and peripheral vascular system. Modified vascular corrosion casting using a newly developed polymer, allows for the first time hierarchical assessment of 3D vessel data in animals down to the level of capillaries. Imaging of large volumes of vasculature at intermediate resolution (16 um) was performed using a desktop micro-computed tomography system. Subsequently regions of interest were identified for additional high resolution imaging (1.4 um) at the X-ray Tomographic Microscopy (XTM) station of the Swiss Light Source (SLS). A framework for systematic hierarchical imaging and quantification was developed. Issues addressed included enhanced XTM data acquisition, introduction of local tomography, sample navigation, advanced post processing, and data combination. In addition to visual assessment of qualitative changes, morphometrical and architectural indices were determined using direct 3D morphometry software developed in house. Vessel specific parameters included thickness, surface, connectivity, and vessel length. Reconstructions of cerebral vasculature in mutant mice modeling Alzheimer's disease revealed significant changes in vessel architecture and morphology. In the future, a combination of these techniques may support drug discovery. Additionally, future ultra-high-resolution in vivo systems may even allow non-invasive tracking of temporal alterations in vascular morphology.

  18. Variation in the position, relation and vasculature of left suprarenal gland: a case report.

    PubMed

    Oztürk, N C; Uzmansel, D; Kara, A; Oztürk, H

    2010-12-01

    A malposition of the left suprarenal gland with varied relations and vasculature was observed in a 50-year-old male cadaver during the routine dissection of the abdominal region. The gland was partly situated over the hilum of the left kidney. Its posterior surface was related to the left crus of the diaphragm and to the hilum of the left kidney extending some distance above on the medial margin of the kidney. Its anterior surface was totally covered by the body of the pancreas and the splenic artery and vein. There were only two suprarenal arteries. A left lateral branch of the aorta divided into three branches of which the middle and inferior branches entered the gland as seperate suprarenal arteries. There were the two suprarenal veins of the gland which were draining into the left renal vein. Such a malposition with varied relations and vasculature is of utmost importance from the surgical point of view because it can affect the orientation of the surgeon in laparoscopic adrenalectomy.

  19. Residual motion compensation in ECG-gated interventional cardiac vasculature reconstruction

    NASA Astrophysics Data System (ADS)

    Schwemmer, C.; Rohkohl, C.; Lauritsch, G.; Müller, K.; Hornegger, J.

    2013-06-01

    Three-dimensional reconstruction of cardiac vasculature from angiographic C-arm CT (rotational angiography) data is a major challenge. Motion artefacts corrupt image quality, reducing usability for diagnosis and guidance. Many state-of-the-art approaches depend on retrospective ECG-gating of projection data for image reconstruction. A trade-off has to be made regarding the size of the ECG-gating window. A large temporal window is desirable to avoid undersampling. However, residual motion will occur in a large window, causing motion artefacts. We present an algorithm to correct for residual motion. Our approach is based on a deformable 2D-2D registration between the forward projection of an initial, ECG-gated reconstruction, and the original projection data. The approach is fully automatic and does not require any complex segmentation of vasculature, or landmarks. The estimated motion is compensated for during the backprojection step of a subsequent reconstruction. We evaluated the method using the publicly available CAVAREV platform and on six human clinical datasets. We found a better visibility of structure, reduced motion artefacts, and increased sharpness of the vessels in the compensated reconstructions compared to the initial reconstructions. At the time of writing, our algorithm outperforms the leading result of the CAVAREV ranking list. For the clinical datasets, we found an average reduction of motion artefacts by 13 ± 6%. Vessel sharpness was improved by 25 ± 12% on average.

  20. The role of vasculature in bone development, regeneration and proper systemic functioning.

    PubMed

    Filipowska, Joanna; Tomaszewski, Krzysztof A; Niedźwiedzki, Łukasz; Walocha, Jerzy A; Niedźwiedzki, Tadeusz

    2017-02-13

    Bone is a richly vascularized connective tissue. As the main source of oxygen, nutrients, hormones, neurotransmitters and growth factors delivered to the bone cells, vasculature is indispensable for appropriate bone development, regeneration and remodeling. Bone vasculature also orchestrates the process of hematopoiesis. Blood supply to the skeletal system is provided by the networks of arteries and arterioles, having distinct molecular characteristics and localizations within the bone structures. Blood vessels of the bone develop through the process of angiogenesis, taking place through different, bone-specific mechanisms. Impaired functioning of the bone blood vessels may be associated with the occurrence of some skeletal and systemic diseases, i.e., osteonecrosis, osteoporosis, atherosclerosis or diabetes mellitus. When a disease or trauma-related large bone defects appear, bone grafting or bone tissue engineering-based strategies are required. However, a successful bone regeneration in both approaches largely depends on a proper blood supply. In this paper, we review the most recent data on the functions, molecular characteristics and significance of the bone blood vessels, with a particular emphasis on the role of angiogenesis and blood vessel functioning in bone development and regeneration, as well as the consequences of its impairment in the course of different skeletal and systemic diseases.

  1. Cosmos 1887: morphology, histochemistry, and vasculature of the growing rat tibia

    NASA Technical Reports Server (NTRS)

    Doty, S. B.; Morey-Holton, E. R.; Durnova, G. N.; Kaplansky, A. S.

    1990-01-01

    Light microscopy, electron microscopy, and enzyme histochemistry were used to study the effects of spaceflight on metaphyseal and cortical bone of the rat tibia. Cortical cross-sectional area and perimeter were not altered by a 12.5-day spaceflight in 3-month-old male rats. The endosteal osteoblast population and the vasculature near the periosteal surface in flight rats compared with ground controls showed more pronounced changes in cortical bone than in metaphyseal bone. The osteoblasts demonstrated greater numbers of transitional Golgi vesicles, possibly caused by a decreased cellular metabolic energy source, but no difference in the large Golgi saccules or the cell membrane-associated alkaline phosphatase activity. The periosteal vasculature in the diaphysis of flight rats often showed lipid accumulations within the lumen of the vessels, occasional degeneration of the vascular wall, and degeneration of osteocytes adjacent to vessels containing intraluminal deposits. These changes were not found in the metaphyseal region of flight animals. The focal vascular changes may be due to ischemia of bone or a developing fragility of the vessel walls as a result of spaceflight.

  2. Segmentation of digitized histological sections for quantification of the muscularized vasculature in the mouse hind limb.

    PubMed

    Xu, Yiwen; Pickering, J Geoffrey; Nong, Zengxuan; Ward, Aaron D

    2017-04-01

    Immunohistochemical tissue staining enhances microvasculature characteristics, including the smooth muscle in the medial layer of the vessel walls that is responsible for regulation of blood flow. The vasculature can be imaged in a comprehensive fashion using whole-slide scanning. However, since each such image potentially contains hundreds of small vessels, manual vessel delineation and quantification is not practically feasible. In this work, we present a fully automatic segmentation and vasculature quantification algorithm for whole-slide images. We evaluated its performance on tissue samples drawn from the hind limbs of wild-type mice, stained for smooth muscle using 3,3'-Diaminobenzidine (DAB) immunostain. The algorithm was designed to be robust to vessel fragmentation due to staining irregularity, and artefactual staining of nonvessel objects. Colour deconvolution was used to isolate the DAB stain for detection of vessel wall fragments. Complete vessels were reconstructed from the fragments by joining endpoints of topological skeletons. Automatic measures of vessel density, perimeter, wall area and local wall thickness were taken. The segmentation algorithm was validated against manual measures, resulting in a Dice similarity coefficient of 89%. The relationships observed between these measures were as expected from a biological standpoint, providing further reinforcement of the accuracy of this system. This system provides a fully automated and accurate means of measuring the arteriolar and venular morphology of vascular smooth muscle.

  3. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells.

    PubMed

    Carretero, Rafael; Sektioglu, Ibrahim M; Garbi, Natalio; Salgado, Oscar C; Beckhove, Philipp; Hämmerling, Günter J

    2015-06-01

    Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for tumor rejection in the presence of tumor-specific CD8(+) T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the tumor, which resulted in tumor eradication and survival. Activated eosinophils initiated substantial changes in the tumor microenvironment, including macrophage polarization and normalization of the tumor vasculature, which are known to promote tumor rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies.

  4. Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas

    PubMed Central

    Zang, Xingxing; Sullivan, Peggy S; Soslow, Robert A; Waitz, Rebecca; Reuter, Victor E; Wilton, Andrew; Thaler, Howard T; Arul, Manonmani; Slovin, Susan F; Wei, Joyce; Spriggs, David R; Dupont, Jakob; Allison, James P

    2010-01-01

    B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and

  5. Skeletal abnormalities in homocystinuria.

    PubMed Central

    Brenton, D. P.

    1977-01-01

    The skeletal changes of thirty-four patients with the biochemical and clinical features of cystathionine synthase deficiency are described. It is emphasized that there is clinical evidence of excessive bone growth and the formation for bone which is structurally weaker than normal. The similarities and differences between this condition and Marfan's syndrome are stressed and the possible nature of the connective tissue defect leading to the skeletal changes discussed. The most characteristic skeletal changes in homocystinuria are the skeletal disproportion (pubis-heel length greater than crown-pubis length), the abnormal vertebrae, sternal deformities, genu valgum and large metaphyses and epiphyses. Images Fig. 2 Fig. 3 Fig. 4 Fig. 8 Fig. 9 Fig. 10 PMID:917963

  6. Eye movement abnormalities.

    PubMed

    Moncayo, Jorge; Bogousslavsky, Julien

    2012-01-01

    Generation and control of eye movements requires the participation of the cortex, basal ganglia, cerebellum and brainstem. The signals of this complex neural network finally converge on the ocular motoneurons of the brainstem. Infarct or hemorrhage at any level of the oculomotor system (though more frequent in the brain-stem) may give rise to a broad spectrum of eye movement abnormalities (EMAs). Consequently, neurologists and particularly stroke neurologists are routinely confronted with EMAs, some of which may be overlooked in the acute stroke setting and others that, when recognized, may have a high localizing value. The most complex EMAs are due to midbrain stroke. Horizontal gaze disorders, some of them manifesting unusual patterns, may occur in pontine stroke. Distinct varieties of nystagmus occur in cerebellar and medullary stroke. This review summarizes the most representative EMAs from the supratentorial level to the brainstem.

  7. Hypoplastic left heart syndrome is associated with structural and vascular placental abnormalities and leptin dysregulation

    PubMed Central

    Jones, Helen N.; Olbrych, Stephanie K.; Smith, Kathleen L.; Cnota, James F.; Habli, Mounira; Gonzales-Ramos, Osniel; Owens, Kathryn J; Hinton, Andrea C.; Polzin, William J.; Muglia, Louis J.; Hinton, Robert B.

    2015-01-01

    Introduction Hypoplastic left heart syndrome (HLHS) is a severe cardiovascular malformation (CVM) associated with fetal growth abnormalities. Genetic and environmental factors have been identified that contribute to pathogenesis, but the role of the placenta is unknown. The purpose of this study was to systematically examine the placenta in HLHS with and without growth abnormalities. Methods HLHS term singleton births were identified from a larger cohort when placenta tissue was available. Clinical data were collected from maternal and neonatal medical records, including anthropometrics and placental pathology reports. Placental tissues from cases and controls were analyzed to assess parenchymal morphology, vascular architecture and leptin signaling. Results HLHS cases (n = 16) and gestational age-matched controls (n = 18) were analyzed. Among cases, the average birth weight was 2993 grams, including 31% that were small for gestational age. When compared with controls, gross pathology of HLHS cases demonstrated significantly reduced placental weight and increased fibrin deposition, while micropathology showed increased syncytial nuclear aggregates, decreased terminal villi, reduced vasculature and increased leptin expression in syncytiotrophoblast and endothelial cells. Discussion Placentas from pregnancies complicated by fetal HLHS are characterized by abnormal parenchymal morphology, suggesting immature structure may be due to vascular abnormalities. Increased leptin expression may indicate an attempt to compensate for these vascular abnormalities. Further investigation into the regulation of angiogenesis in the fetus and placenta may elucidate the causes of HLHS and associated growth abnormalities in some cases. PMID:26278057

  8. Tumor-induced hypophosphatemia

    PubMed Central

    Mulani, M.; Somani, K.; Bichu, S.; Billa, V.

    2017-01-01

    Significant hypophosphatemia is commonly due to Vitamin D deficiency. Any sporadic onset of hypophosphatemia in adults warrants workup to identify alternate causes. Hypophosphatemia may also be the only manifestation of an occult malignancy. A high index of clinical suspicion can help diagnose such conditions in early stages. Prompt treatment of the cause can correct this biochemical abnormality. We describe a case report of a woman presenting with severe hypophosphatemia and osteomalacia, leading eventually to the diagnosis of a phosphaturic mesenchymal tumor of the temporo-occipital bone. Surgical resection of tumor led to normalization of the biochemical parameters as well as a complete clinical recovery. PMID:28182049

  9. Assessment of tumor angiogenesis using fluorescence contrast agents

    NASA Astrophysics Data System (ADS)

    Chen, Yu; Liu, Qian; Huang, Ping; Hyman, Shay; Intes, Xavier; Lee, William; Chance, Britton

    2003-12-01

    Angiogenesis is an important factor for further tumor growth and thus could be an attractive therapeutic target. Optical imaging can provide a non-invasive way to measure the permeability of tumor blood vessels and assess the tumor vasculature. We have developed a dual-channel near-infrared fluorescence system for simultaneous measurement of the pharmacokinetics of tumorous and normal tissues with exogenous contrast agents. This frequency-domain system consists of the light source (780 nm laser diode), fiber optics, interference filter (830 nm) and the detector (PMT). The fluorescent contrast agent used in this study is Indocyanine Green (ICG), and the normal dosage is 100 μl at a concentration of 5 μM. In vivo animal study is performed on the K1735 melanoma-bearing mouse. The fluorescence signals both tumorous and normal tissues after the bolus injection of ICG through the tail vein are continuously recorded as a function of time. The data is fitted by a double-exponential model to reveal the wash-in and wash-out parameters of different tissues. We observed an elongated wash-out from the tumor compared with normal tissue (leg). The effect of radiation therapy on the tumor vasculature is also discussed.

  10. Evaluation of a New Marker of the Ovarian Tumor Vasculature for Predicting Response to Treatment and as a Therapeutic Target

    DTIC Science & Technology

    2012-10-01

    The first cell type was promising because we found that the endothelial cells in human placentas express FSHR. We obtained placental endothelial...receptors in placenta microvascular endothelial cells from pre- eclampsia. Placenta . 2008; 29(9):816-25. 7. O’Connell K, Landman G, Farmer E, Edidin M

  11. Dose reduction in CT urography and vasculature phantom studies using model-based iterative reconstruction.

    PubMed

    Page, Leland; Wei, Wei; Kundra, Vikas; Rong, John

    2016-11-08

    To evaluate the feasibility of radiation dose reduction using model-based iterative reconstruction (MBIR) for evaluating the ureters and vasculature in a phantom, a tissue-equivalent CT dose phantom was scanned using a 64-channel CT scan-ner. Tubes of varying diameters filled with different dilutions of a contrast agent, simulating ureters or vessels, were inserted into the center of the phantom. Each combination was scanned using an existing renal protocol at 140 kVp or 120 kVp, yielding a display volumetric CT dose index (CTDIvol) of 24 mGy. The scans were repeated using reduced scan techniques to achieve lower radiation doses down to 0.8 mGy. The images were reconstructed using filtered back-projection (FBP) and model-based iterative reconstruction (MBIR). The noise and contrast-to-noise ratio (CNR) was measured for each contrast object. Comparisons between the two reconstruction methods at different dose levels were evaluated using a factorial design. At each CTDIvol the measured image noise was lower using MBIR compared to FBP (p < 0.0001). At low doses, the percent change in measured image noise between FBP and MBIR was larger. For the 12 mm object simulating a ureter or large vessel with an HU of 600, the measured CNR using MBIR at a CTDIvol of 1.7 mGy was greater than the CNR of FBP at a CTIDvol of 24 mGy (p < 0.0001). For the 5 mm object simulating a medium-sized vessel with a HU of 250, the mea-sured CNR using MBIR at a CTDIvol of 1.7 mGy was equivalent to that of FBP at a CTDIvol of 24 mGy. For the 2 mm, 100 HU object simulating a small vessel, the measured CNR using MBIR at a CTDIvol of 1.7 mGy was equivalent to that of FBP at a CTDIvol of 24 mGy. Low-dose (3.6 mGy) CT imaging of vasculature and ureter phantoms using MBIR results in similar noise and CNR compared to FBP at approximately one-sixth the dose. This suggests that, using MBIR, a one milliSievert exam of the ureters and vasculature may be clinically possible whilst still maintaining adequate

  12. In vivo imaging of tumor vascular endothelial cells

    NASA Astrophysics Data System (ADS)

    Zhao, Dawen; Stafford, Jason H.; Zhou, Heling; Thorpe, Philip E.

    2013-02-01

    Phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, becomes exposed on the outer surface of viable (non-apoptotic) endothelial cells in tumor blood vessels, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we optically imaged exposed PS on tumor vasculature in vivo using PGN635, a novel human monoclonal antibody that targets PS. PGN635 F(ab')2 was labeled with the near infrared (NIR) dye, IRDye 800CW. Human glioma U87 cells or breast cancer MDA-MB-231 cells were implanted subcutaneously or orthotopically into nude mice. When the tumors reached ~5 mm in diameter, 800CW- PGN635 was injected via a tail vein and in vivo dynamic NIR imaging was performed. For U87 gliomas, NIR imaging allowed clear detection of tumors as early as 4 h later, which improved over time to give a maximal tumor/normal ratio (TNR = 2.9 +/- 0.5) 24 h later. Similar results were observed for orthotopic MDA-MB-231 breast tumors. Localization of 800CW-PGN635 to tumors was antigen specific since 800CW-Aurexis, a control probe of irrelevant specificity, did not localize to the tumors, and pre-administration of unlabeled PGN635 blocked the uptake of 800CW-PGN635. Fluorescence microscopy confirmed that 800CW-PGN635 was binding to PS-positive tumor vascular endothelium. Our studies suggest that tumor vasculature can be successfully imaged in vivo to provide sensitive tumor detection.

  13. Therapeutic potential of bacteria against solid tumors.

    PubMed

    Hatzikirou, Haralampos; Lopez Alfonso, Juan Carlos; Leschner, Sara; Weiss, Siegfried; Meyer-Hermann, Michael

    2017-02-15

    Intentional bacterial infections can produce efficacious anti-tumor responses in mice, rats, dogs and humans. However, low overall success rates and intense side-effects prevent such approaches from being employed clinically. In this work, we titered bacteria and/or the pro-inflammatory cytokine TNF-α in a set of established murine models of cancer. To interpret the experiments conducted, we considered and calibrated a tumor-effector cell recruitment model under the influence of functional tumor-associated vasculature. In this model, bacterial infections and TNF-α enhanced immune activity and altered vascularization in the tumor bed. Information to predict bacterial therapy outcomes was provided by pre-treatment tumor size and the underlying immune recruitment dynamics. Notably, increasing bacterial loads did not necessarily produce better long-term tumor control, suggesting that tumor sizes affected optimal bacterial loads. Short-term treatment responses were favored by high concentrations of effector cells post-injection, such as induced by higher bacterial loads, but in the longer term did not correlate with an effective restoration of immune surveillance. Overall, our findings suggested that a combination of intermediate bacterial loads with low levels TNF-α administration could enable more favorable outcomes elicited by bacterial infections in tumor-bearing subjects.

  14. Ear Tumors

    MedlinePlus

    ... Outer Ear Ear Blockages Ear Tumors External Otitis (Swimmer's Ear) Malignant External Otitis Perichondritis Tumors of the ... Outer Ear Ear Blockages Ear Tumors External Otitis (Swimmer's Ear) Malignant External Otitis Perichondritis NOTE: This is ...

  15. Cerebral aneurysms: relations between geometry, hemodynamics and aneurysm location in the cerebral vasculature

    NASA Astrophysics Data System (ADS)

    Passerini, Tiziano; Veneziani, Alessandro; Sangalli, Laura; Secchi, Piercesare; Vantini, Simone

    2010-11-01

    In cerebral blood circulation, the interplay of arterial geometrical features and flow dynamics is thought to play a significant role in the development of aneurysms. In the framework of the Aneurisk project, patient-specific morphology reconstructions were conducted with the open-source software VMTK (www.vmtk.org) on a set of computational angiography images provided by Ospedale Niguarda (Milano, Italy). Computational fluid dynamics (CFD) simulations were performed with a software based on the library LifeV (www.lifev.org). The joint statistical analysis of geometries and simulations highlights the possible association of certain spatial patterns of radius, curvature and shear load along the Internal Carotid Artery (ICA) with the presence, position and previous event of rupture of an aneurysm in the entire cerebral vasculature. Moreover, some possible landmarks are identified to be monitored for the assessment of a Potential Rupture Risk Index.

  16. Automated Protein Localization of Blood Brain Barrier Vasculature in Brightfield IHC Images

    PubMed Central

    Keenan, Brendan T.; Pack, Allan I.; Shackleford, James A.

    2016-01-01

    In this paper, we present an objective method for localization of proteins in blood brain barrier (BBB) vasculature using standard immunohistochemistry (IHC) techniques and bright-field microscopy. Images from the hippocampal region at the BBB are acquired using bright-field microscopy and subjected to our segmentation pipeline which is designed to automatically identify and segment microvessels containing the protein glucose transporter 1 (GLUT1). Gabor filtering and k-means clustering are employed to isolate potential vascular structures within cryosectioned slabs of the hippocampus, which are subsequently subjected to feature extraction followed by classification via decision forest. The false positive rate (FPR) of microvessel classification is characterized using synthetic and non-synthetic IHC image data for image entropies ranging between 3 and 8 bits. The average FPR for synthetic and non-synthetic IHC image data was found to be 5.48% and 5.04%, respectively. PMID:26828723

  17. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature

    PubMed Central

    Kolaczkowska, Elzbieta; Jenne, Craig N.; Surewaard, Bas G. J.; Thanabalasuriar, Ajitha; Lee, Woo-Yong; Sanz, Maria-Jesus; Mowen, Kerri; Opdenakker, Ghislain; Kubes, Paul

    2015-01-01

    Neutrophil extracellular traps (NETs) composed of DNA decorated with histones and proteases trap and kill bacteria but also injure host tissue. Here we show that during a bloodstream infection with methicillin-resistant Staphylococcus aureus, the majority of bacteria are sequestered immediately by hepatic Kupffer cells, resulting in transient increases in liver enzymes, focal ischaemic areas and a robust neutrophil infiltration into the liver. The neutrophils release NETs into the liver vasculature, which remain anchored to the vascular wall via von Willebrand factor and reveal significant neutrophil elastase (NE) proteolytic activity. Importantly, DNase although very effective at DNA removal, and somewhat effective at inhibiting NE proteolytic activity, fails to remove the majority of histones from the vessel wall and only partly reduces injury. By contrast, inhibition of NET production as modelled by PAD4-deficiency, or prevention of NET formation and proteolytic activity as modelled in NE−/− mice prevent collateral host tissue damage. PMID:25809117

  18. Macroscopic two-pump two-vasculature cardiovascular model to support treatment of acute heart failure.

    PubMed

    Sugimachi, Masaru; Sunagawa, Kenji; Uemura, Kazunori; Kamiya, Atsunori; Shimizu, Shuji; Inagaki, Masashi; Shishido, Toshiaki

    2009-01-01

    Comprehensive understanding of hemodynamics remains a challenge even for expert cardiologists, partially due to a lack of an appropriate macroscopic model. We attempted to amend three major problems of Guyton's conceptual model (unknown left atrial pressure, unilateral heart damage, blood redistribution) and developed a comprehensive macroscopic model of hemodynamics that provides quantitative information. We incorporated a third axis of left atrial pressure, resulting in a 3D coordinate system. Pump functions of left and right heart are expressed by an integrated cardiac output curve, and the capacitive function of total vasculature by a venous return surface. The equations for both the cardiac output curve and venous return surface would facilitate precise diagnosis (especially evaluation of blood volume) and choice of appropriate treatments, including application to autopilot systems.

  19. 3D reconstruction of digitized histological sections for vasculature quantification in the mouse hind limb

    NASA Astrophysics Data System (ADS)

    Xu, Yiwen; Pickering, J. Geoffrey; Nong, Zengxuan; Gibson, Eli; Ward, Aaron D.

    2014-03-01

    In contrast to imaging modalities such as magnetic resonance imaging and micro computed tomography, digital histology reveals multiple stained tissue features at high resolution (0.25μm/pixel). However, the two-dimensional (2D) nature of histology challenges three-dimensional (3D) quantification and visualization of the different tissue components, cellular structures, and subcellular elements. This limitation is particularly relevant to the vasculature, which has a complex and variable structure within tissues. The objective of this study was to perform a fully automated 3D reconstruction of histology tissue in the mouse hind limb preserving the accurate systemic orientation of the tissues, stained with hematoxylin and immunostained for smooth muscle α actin. We performed a 3D reconstruction using pairwise rigid registrations of 5μm thick, paraffin-embedded serial sections, digitized at 0.25μm/pixel. Each registration was performed using the iterative closest points algorithm on blood vessel landmarks. Landmarks were vessel centroids, determined according to a signed distance map of each pixel to a decision boundary in hue-saturation-value color space; this decision boundary was determined based on manual annotation of a separate training set. Cell nuclei were then automatically extracted and corresponded to refine the vessel landmark registration. Homologous nucleus landmark pairs appearing on not more than two adjacent slides were chosen to avoid registrations which force curved or non-sectionorthogonal structures to be straight and section-orthogonal. The median accumulated target registration errors ± interquartile ranges for the vessel landmark registration, and the nucleus landmark refinement were 43.4+/-42.8μm and 2.9+/-1.7μm, respectively (p<0.0001). Fully automatic and accurate 3D rigid reconstruction of mouse hind limb histology imaging is feasible based on extracted vasculature and nuclei.

  20. Mechanisms of the biphasic effects of peroxides on the retinal vasculature of newborn and adult pigs.

    PubMed

    Abran, D; Hardy, P; Varma, D R; Chemtob, S

    1995-09-01

    We tested whether the ontogenic differences in the constrictor effects of peroxides on the retinal vasculature were modulated by dilator cyclo-oxygenase products. Retinal arteriole (100-200 microns) vasomotor response to H2O2, t-butyl hydroperoxide, and cumene hydroperoxide were studied in isolated eyecup preparations using video camera monitoring of vessel diameter. A time- and dose-dependent biphasic retinal vasomotor response to all peroxides was observed on tissues of newborn and adult pigs. A rapid vasoconstriction (first 2 min) was followed by a relaxation which was greater in the adult than in the newborn tissues. The constrictor as well as the dilator response to peroxides and the observed increase in prostanoids were blocked by the cyclo-oxygenase inhibitor indomethacin. The peroxide-induced relaxation was inhibited or markedly attenuated by the prostaglandin I2 synthase blockers, trans-2-phenyl cyclopropylamine and minoxidil on tissues of newborn and adult animals. These agents also prevented the increase of the prostaglandin I2 receptor-coupled second messenger, cyclic 3',5'-adenosine monophosphate. Our data indicate that prostaglandin I2 plays a major role in counteracting the initial constrictor effects of peroxides in the retinal vasculature, and that the reversal of this constriction is greater in the adult than the newborn. These findings suggest that reduced reversal of vasoconstriction by the dilator prostaglandin I2 during an oxidative stress in the newborn may facilitate vasoconstriction by the dilator prostaglandin I2 during an oxidative stress in the newborn may facilitate neovascularization in retinopathy of prematurity.

  1. Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

    PubMed Central

    2014-01-01

    Background Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology? Discussion Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology. Mechanism Infection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of ‘immunosterol’ 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease. Summary We postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology

  2. Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice

    PubMed Central

    Rana, Ujala; Liu, Zhong; Kumar, Suresh N.; Zhao, Baofeng; Hu, Wenquan; Bordas, Michelle; Cossette, Stephanie; Szabo, Sara; Foeckler, Jamie; Weiler, Hartmut; Chrzanowska-Wodnicka, Magdalena; Holtz, Mary L.; Misra, Ravindra P.; Salato, Valerie; North, Paula; Ramchandran, Ramani; Miao, Qing Robert

    2016-01-01

    Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively. Our results showed that NgBR homozygous knockout mice are embryonically lethal at E7.5 or earlier, and Tie2Cre-mediated endothelial cell-specific NgBR knockout (NgBR ecKO) mice die at E11.5 and have severe blood vessel assembly defects in embryo. In addition, mutant embryos exhibit dilation of cerebral blood vessel, resulting in thin-walled endothelial caverns. The similar vascular defects also were detected in Cdh5(PAC)-CreERT2 NgBR inducible ecKO mice. Murine NgBR gene-targeting embryonic stem cells (ESC) were generated by homologous recombination approaches. Homozygous knockout of NgBR in ESC results in cell apoptosis. Heterozygous knockout of NgBR does not affect ESC cell survival, but reduces the formation and branching of primitive blood vessels in embryoid body culture systems. Mechanistically, NgBR knockdown not only decreases both Nogo-B and VEGF-stimulated endothelial cell migration by abolishing Akt phosphorylation, but also decreases the expression of CCM1 and CCM2 proteins. Furthermore, we performed immunofluorescence (IF) staining of NgBR in human cerebral cavernous malformation patient tissue sections. The quantitative analysis results showed that NgBR expression levels in CD31 positive endothelial cells is significantly decreased in patient tissue sections. These results suggest that NgBR may be one of important genes coordinating the cerebral vasculature development. PMID:26746789

  3. Classification of breast abnormalities using artificial neural network

    NASA Astrophysics Data System (ADS)

    Zaman, Nur Atiqah Kamarul; Rahman, Wan Eny Zarina Wan Abdul; Jumaat, Abdul Kadir; Yasiran, Siti Salmah

    2015-05-01

    Classification is the process of recognition, differentiation and categorizing objects into groups. Breast abnormalities are calcifications which are tumor markers that indicate the presence of cancer in the breast. The aims of this research are to classify the types of breast abnormalities using artificial neural network (ANN) classifier and to evaluate the accuracy performance using receiver operating characteristics (ROC) curve. The methods used in this research are ANN for breast abnormalities classifications and Canny edge detector as a feature extraction method. Previously the ANN classifier provides only the number of benign and malignant cases without providing information for specific cases. However in this research, the type of abnormality for each image can be obtained. The existing MIAS MiniMammographic database classified the mammogram images into three features only namely characteristic of background tissues, class of abnormality and radius of abnormality. However, in this research three other features are added-in. These three features are number of spots, area and shape of abnormalities. Lastly the performance of the ANN classifier is evaluated using ROC curve. It is found that ANN has an accuracy of 97.9% which is considered acceptable.

  4. Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis

    PubMed Central

    Lim, Sharon; Hosaka, Kayoko; Nakamura, Masaki; Cao, Yihai

    2016-01-01

    Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth. PMID:27203675

  5. The Pea Seedling as a Model of Normal and Abnormal Morphogenesis

    ERIC Educational Resources Information Center

    Kurkdjian, Armen; And Others

    1974-01-01

    Describes several simple and inexpensive experiments designed to facilitate the study of normal and abnormal morphogenesis in the biology laboratory. Seedlings of the common garden pea are used in the experiments, and abnormal morphogenesis (tumors) are induced by a virulent strain of the crown-gall organism, Agrobacterium tumefaciens. (JR)

  6. Tumor Types: Understanding Brain Tumors

    MedlinePlus

    ... Resources Tools & Publications Tumor Types: Understanding Brain Tumors World Health Organization (WHO) Updates Official Classification of Tumors ... Central Nervous System On May 9, 2016, the World Health Organization (WHO) published an official reclassification of ...

  7. iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation

    PubMed Central

    Thanabalasuriar, A; Neupane, A.S; Wang, J; Krummel, M.F; Kubes, P

    2017-01-01

    iNKT cells are a subset of innate T cells that recognize glycolipids presented on CD1d molecules and protect against a variety of bacterial infections including S. pneumoniae. Using lung intravital imaging, we examined the behavior and mechanism of pulmonary iNKT cell activation in response to the potent iNKT cell ligand α-galactosylceramide or during S. pneumoniae infection. In untreated mice the major fraction of iNKT cells resided in the vasculature, but a small critical population resided in the extravascular space in proximity to monocyte-derived DCs. Administration of either α-GalCer or S. pneumoniae, induced CD1d dependent rapid recruitment of neutrophils out of the vasculature. This neutrophil exodus paved the way for extravasation of iNKT cells from the lung vasculature via CCL17. Depletion of monocyte-derived DCs abrogated both the neutrophil and subsequent iNKT cell extravasation. Moreover, impairing iNKT cell migration out of the lung vasculature by blocking CCL17 greatly increased susceptibility to S. pneumoniae infection, suggesting a critical role for the secondary wave of iNKT cells in host defense. PMID:27653688

  8. Abnormal pressure in hydrocarbon environments

    USGS Publications Warehouse

    Law, B.E.; Spencer, C.W.

    1998-01-01

    Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

  9. Systemic abnormalities in liver disease

    PubMed Central

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2009-01-01

    Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases. PMID:19554648

  10. Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

    NASA Astrophysics Data System (ADS)

    Roy Chaudhuri, Tista

    An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

  11. Optimized time-resolved imaging of contrast kinetics (TRICKS) in dynamic contrast-enhanced MRI after peptide receptor radionuclide therapy in small animal tumor models.

    PubMed

    Haeck, Joost; Bol, Karin; Bison, Sander; van Tiel, Sandra; Koelewijn, Stuart; de Jong, Marion; Veenland, Jifke; Bernsen, Monique

    2015-01-01

    Anti-tumor efficacy of targeted peptide-receptor radionuclide therapy (PRRT) relies on several factors, including functional tumor vasculature. Little is known about the effect of PRRT on tumor vasculature. With dynamic contrast-enhanced (DCE-) MRI, functional vasculature is imaged and quantified using contrast agents. In small animals DCE-MRI is a challenging application. We optimized a clinical sequence for fast hemodynamic acquisitions, time-resolved imaging of contrast kinetics (TRICKS), to obtain DCE-MRI images at both high spatial and high temporal resolution in mice and rats. Using TRICKS, functional vasculature was measured prior to PRRT and longitudinally to investigate the effect of treatment on tumor vascular characteristics. Nude mice bearing H69 tumor xenografts and rats bearing syngeneic CA20948 tumors were used to study perfusion following PRRT administration with (177) lutetium octreotate. Both semi-quantitative and quantitative parameters were calculated. Treatment efficacy was measured by tumor-size reduction. Optimized TRICKS enabled MRI at 0.032 mm(3) voxel size with a temporal resolution of less than 5 s and large volume coverage, a substantial improvement over routine pre-clinical DCE-MRI studies. Tumor response to therapy was reflected in changes in tumor perfusion/permeability parameters. The H69 tumor model showed pronounced changes in DCE-derived parameters following PRRT. The rat CA20948 tumor model showed more heterogeneity in both treatment outcome and perfusion parameters. TRICKS enabled the acquisition of DCE-MRI at both high temporal resolution (Tres ) and spatial resolutions relevant for small animal tumor models. With the high Tres enabled by TRICKS, accurate pharmacokinetic data modeling was feasible. DCE-MRI parameters revealed changes over time and showed a clear relationship between tumor size and Ktrans .

  12. Absence of abnormal vessels in the subarachnoid space on conventional magnetic resonance imaging in patients with spinal dural arteriovenous fistulas.

    PubMed

    Miller, Timothy R; Eskey, Clifford J; Mamourian, Alexander C

    2012-05-01

    Spinal dural arteriovenous fistula (DAVF) is an uncommon condition that can be difficult to diagnose. This often results in misdiagnosis and treatment delay. Although conventional MRI plays an important role in the initial screening for the disease, the typical MRI findings may be absent. In this article, the authors present a series of 4 cases involving patients with angiographically proven spinal DAVFs who demonstrated cord T2 prolongation on conventional MRI but without abnormal subarachnoid flow voids or enhancement. These cases suggest that spinal DAVF cannot be excluded in symptomatic patients with cord edema based on conventional MRI findings alone. Dynamic Gd-enhanced MR angiography (MRA) was successful in demonstrating abnormal spinal vasculature in all 4 cases. This limited experience provides support for the role of spinal MRA in patients with abnormal cord signal and symptoms suggestive of DAVF even when typical MRI findings of a DAVF are absent.

  13. Motif mimetic of epsin perturbs tumor growth and metastasis

    PubMed Central

    Dong, Yunzhou; Wu, Hao; Rahman, H.N. Ashiqur; Liu, Yanjun; Pasula, Satish; Tessneer, Kandice L.; Cai, Xiaofeng; Liu, Xiaolei; Chang, Baojun; McManus, John; Hahn, Scott; Dong, Jiali; Brophy, Megan L.; Yu, Lili; Song, Kai; Silasi-Mansat, Robert; Saunders, Debra; Njoku, Charity; Song, Hoogeun; Mehta-D’Souza, Padmaja; Towner, Rheal; Lupu, Florea; McEver, Rodger P.; Xia, Lijun; Boerboom, Derek; Srinivasan, R. Sathish; Chen, Hong

    2015-01-01

    Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium–targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin–interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium–specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy. PMID:26571402

  14. P-selectin is a nanotherapeutic delivery target in the tumor microenvironment.

    PubMed

    Shamay, Yosi; Elkabets, Moshe; Li, Hongyan; Shah, Janki; Brook, Samuel; Wang, Feng; Adler, Keren; Baut, Emily; Scaltriti, Maurizio; Jena, Prakrit V; Gardner, Eric E; Poirier, John T; Rudin, Charles M; Baselga, José; Haimovitz-Friedman, Adriana; Heller, Daniel A

    2016-06-29

    Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor.

  15. P-selectin is a nanotherapeutic delivery target in the tumor microenvironment

    PubMed Central

    Shamay, Yosi; Elkabets, Moshe; Li, Hongyan; Shah, Janki; Brook, Samuel; Wang, Feng; Adler, Keren; Baut, Emily; Scaltriti, Maurizio; Jena, Prakrit V.; Gardner, Eric E.; Poirier, John T.; Rudin, Charles M.; Baselga, José; Haimovitz-Friedman, Adriana; Heller, Daniel A.

    2016-01-01

    Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor. PMID:27358497

  16. Postictal Magnetic Resonance Imaging Changes Masquerading as Brain Tumor Progression: A Case Series

    PubMed Central

    Dunn-Pirio, Anastasie M.; Billakota, Santoshi; Peters, Katherine B.

    2016-01-01

    Seizures are common among patients with brain tumors. Transient, postictal magnetic resonance imaging abnormalities are a long recognized phenomenon. However, these radiographic changes are not as well studied in the brain tumor population. Moreover, reversible neuroimaging abnormalities following seizure activity may be misinterpreted for tumor progression and could consequently result in unnecessary tumor-directed treatment. Here, we describe two cases of patients with brain tumors who developed peri-ictal pseudoprogression and review the relevant literature. PMID:27462237

  17. Chromosomal abnormalities and mental illness.

    PubMed

    MacIntyre, D J; Blackwood, D H R; Porteous, D J; Pickard, B S; Muir, W J

    2003-03-01

    Linkage studies of mental illness have provided suggestive evidence of susceptibility loci over many broad chromosomal regions. Pinpointing causative gene mutations by conventional linkage strategies alone is problematic. The breakpoints of chromosomal abnormalities occurring in patients with mental illness may be more direct pointers to the relevant gene locus. Publications that describe patients where chromosomal abnormalities co-exist with mental illness are reviewed along with supporting evidence that this may amount to an association. Chromosomal abnormalities are considered to be of possible significance if (a) the abnormality is rare and there are independent reports of its coexistence with psychiatric illness, or (b) there is colocalisation of the abnormality with a region of suggestive linkage findings, or (c) there is an apparent cosegregation of the abnormality with psychiatric illness within the individual's family. Breakpoints have been described within many of the loci suggested by linkage studies and these findings support the hypothesis that shared susceptibility factors for schizophrenia and bipolar disorder may exist. If these abnormalities directly disrupt coding regions, then combining molecular genetic breakpoint cloning with bioinformatic sequence analysis may be a method of rapidly identifying candidate genes. Full karyotyping of individuals with psychotic illness especially where this coexists with mild learning disability, dysmorphism or a strong family history of mental disorder is encouraged.

  18. Chromosomal abnormalities in human sperm

    SciTech Connect

    Martin, R.H.

    1985-01-01

    The ability to analyze human sperm chromosome complements after penetration of zona pellucida-free hamster eggs provides the first opportunity to study the frequency and type of chromosomal abnormalities in human gametes. Two large-scale studies have provided information on normal men. We have studied 1,426 sperm complements from 45 normal men and found an abnormality rate of 8.9%. Brandriff et al. (5) found 8.1% abnormal complements in 909 sperm from 4 men. The distribution of numerical and structural abnormalities was markedly dissimilar in the 2 studies. The frequency of aneuploidy was 5% in our sample and only 1.6% in Brandriff's, perhaps reflecting individual variability among donors. The frequency of 24,YY sperm was low: 0/1,426 and 1/909. This suggests that the estimates of nondisjunction based on fluorescent Y body data (1% to 5%) are not accurate. We have also studied men at increased risk of sperm chromosomal abnormalities. The frequency of chromosomally unbalanced sperm in 6 men heterozygous for structural abnormalities varied dramatically: 77% for t11;22, 32% for t6;14, 19% for t5;18, 13% for t14;21, and 0% for inv 3 and 7. We have also studied 13 cancer patients before and after radiotherapy and demonstrated a significant dose-dependent increase of sperm chromosome abnormalities (numerical and structural) 36 months after radiation treatment.

  19. Haematological abnormalities in mitochondrial disorders

    PubMed Central

    Finsterer, Josef; Frank, Marlies

    2015-01-01

    INTRODUCTION This study aimed to assess the kind of haematological abnormalities that are present in patients with mitochondrial disorders (MIDs) and the frequency of their occurrence. METHODS The blood cell counts of a cohort of patients with syndromic and non-syndromic MIDs were retrospectively reviewed. MIDs were classified as ‘definite’, ‘probable’ or ‘possible’ according to clinical presentation, instrumental findings, immunohistological findings on muscle biopsy, biochemical abnormalities of the respiratory chain and/or the results of genetic studies. Patients who had medical conditions other than MID that account for the haematological abnormalities were excluded. RESULTS A total of 46 patients (‘definite’ = 5; ‘probable’ = 9; ‘possible’ = 32) had haematological abnormalities attributable to MIDs. The most frequent haematological abnormality in patients with MIDs was anaemia. 27 patients had anaemia as their sole haematological problem. Anaemia was associated with thrombopenia (n = 4), thrombocytosis (n = 2), leucopenia (n = 2), and eosinophilia (n = 1). Anaemia was hypochromic and normocytic in 27 patients, hypochromic and microcytic in six patients, hyperchromic and macrocytic in two patients, and normochromic and microcytic in one patient. Among the 46 patients with a mitochondrial haematological abnormality, 78.3% had anaemia, 13.0% had thrombopenia, 8.7% had leucopenia and 8.7% had eosinophilia, alone or in combination with other haematological abnormalities. CONCLUSION MID should be considered if a patient’s abnormal blood cell counts (particularly those associated with anaemia, thrombopenia, leucopenia or eosinophilia) cannot be explained by established causes. Abnormal blood cell counts may be the sole manifestation of MID or a collateral feature of a multisystem problem. PMID:26243978

  20. Integrated intravital microscopy and mathematical modeling to optimize nanotherapeutics delivery to tumors

    NASA Astrophysics Data System (ADS)

    van de Ven, Anne L.; Wu, Min; Lowengrub, John; McDougall, Steven R.; Chaplain, Mark A. J.; Cristini, Vittorio; Ferrari, Mauro; Frieboes, Hermann B.

    2012-03-01

    Inefficient vascularization hinders the optimal transport of cell nutrients, oxygen, and drugs to cancer cells in solid tumors. Gradients of these substances maintain a heterogeneous cell-scale microenvironment through which drugs and their carriers must travel, significantly limiting optimal drug exposure. In this study, we integrate intravital microscopy with a mathematical model of cancer to evaluate the behavior of nanoparticle-based drug delivery systems designed to circumvent biophysical barriers. We simulate the effect of doxorubicin delivered via porous 1000 x 400 nm plateloid silicon particles to a solid tumor characterized by a realistic vasculature, and vary the parameters to determine how much drug per particle and how many particles need to be released within the vasculature in order to achieve remission of the tumor. We envision that this work will contribute to the development of quantitative measures of nanoparticle design and drug loading in order to optimize cancer treatment via nanotherapeutics.

  1. Optimization of vascular-targeting drugs in a computational model of tumor growth

    NASA Astrophysics Data System (ADS)

    Gevertz, Jana

    2012-04-01

    A biophysical tool is introduced that seeks to provide a theoretical basis for helping drug design teams assess the most promising drug targets and design optimal treatment strategies. The tool is grounded in a previously validated computational model of the feedback that occurs between a growing tumor and the evolving vasculature. In this paper, the model is particularly used to explore the therapeutic effectiveness of two drugs that target the tumor vasculature: angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs). Using sensitivity analyses, the impact of VDA dosing parameters is explored, as is the effects of administering a VDA with an AI. Further, a stochastic optimization scheme is utilized to identify an optimal dosing schedule for treatment with an AI and a chemotherapeutic. The treatment regimen identified can successfully halt simulated tumor growth, even after the cessation of therapy.

  2. Hepatocellular carcinoma with intra-atrial tumor extension identified on 99mTc-labeled macroaggregated albumin single photon emission computed tomography/computed tomography

    PubMed Central

    Chandra, Piyush; Shah, Sneha; Purandare, Nilendu; Agrawal, Archi; Rangarajan, Venkatesh

    2016-01-01

    99mTc macroaggregated albumin (MAA) scintigraphy is always performed before administration of 90Y--microspheres for the treatment of liver tumors for hepatopulmonary shunt calculation. Tumor thrombus visualization in the hepatic vasculature is an infrequent finding on the 99m Tc--MAA single photon emission computed tomography. We present a rare case of a hepatocellular carcinoma extending as a tumor thrombus through hepatic vein, inferior vena cava into the right atrium. PMID:27833324

  3. Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide

    PubMed Central

    Morales, Rommel C.; Bahnson, Edward S.M.; Havelka, George E.; Cantu-Medellin, Nadiezhda; Kelley, Eric E.; Kibbe, Melina R.

    2015-01-01

    Background Nitric oxide (•NO) is more effective at inhibiting neointimal hyperplasia following arterial injury in male versus female rodents, though the etiology is unclear. Given that superoxide (O2•−) regulates cellular proliferation, and •NO regulates superoxide dismutase-1 (SOD-1) in the vasculature, we hypothesized that •NO differentially regulates SOD-1 based on sex. Materials and methods Male and female vascular smooth muscle cells (VSMC) were harvested from the aortae of Sprague-Dawley rats. O2•− levels were quantified by electron paramagnetic resonance (EPR) and HPLC. sod-1 gene expression was assayed by qPCR. SOD-1, SOD-2, and catalase protein levels were detected by Western blot. SOD-1 activity was measured via colorimetric assay. The rat carotid artery injury model was performed on Sprague-Dawley rats ±•NO treatment and SOD-1 protein levels were examined by Western blot. Results In vitro, male VSMC have higher O2•− levels and lower SOD − 1 activity at baseline compared to female VSMC (P < 0.05). •NO decreased O2•− levels and increased SOD − 1 activity in male (P<0.05) but not female VSMC. •NO also increased sod− 1 gene expression and SOD − 1 protein levels in male (P<0.05) but not female VSMC. In vivo, SOD-1 levels were 3.7-fold higher in female versus male carotid arteries at baseline. After injury, SOD-1 levels decreased in both sexes, but •NO increased SOD-1 levels 3-fold above controls in males, but returned to baseline in females. Conclusions Our results provide evidence that regulation of the redox environment at baseline and following exposure to •NO is sex-dependent in the vasculature. These data suggest that sex-based differential redox regulation may be one mechanism by which •NO is more effective at inhibiting neointimal hyperplasia in male versus female rodents. PMID:25617803

  4. Tumor endothelial markers define novel subsets of cancer-specific circulating endothelial cells associated with antitumor efficacy

    PubMed Central

    Mehran, Reza; Nilsson, Monique; Khajavi, Mehrdad; Du, Zhiqiang; Cascone, Tina; Wu, Hua Kang; Cortes, Andrea; Xu, Li; Zurita, Amado; Schier, Robert; Riedel, Bernhard; El-Zein, Randa; Heymach, John V.

    2014-01-01

    Circulating endothelial cells (CEC) are derived from multiple sources including bone marrow (circulating endothelial progenitors [CEP]) and established vasculature (mature CEC). Although CEC have shown promise as a biomarker for cancer patients, their utility has been limited in part by the lack of specificity for tumor vasculature and the different non-malignant causes that can impact CEC. Tumor endothelial markers (TEM) are antigens enriched in tumor vs non-malignant endothelia. We hypothesized that TEMs may be detectable on CEC and that these circulating TEM+ endothelial cells (CTEC) may be a more specific marker for cancer and tumor response than standard CEC. We found that tumor-bearing mice had a relative increase in numbers of circulating CTEC, specifically with increased levels of TEM7 and TEM8 expression. Following treatment with various vascular targeting agents, we observed a decrease in CTEC that correlated with the reductions in tumor growth. We extended these findings to human clinical samples and observed that CTEC were present in esophageal cancer and non-small cell lung cancer (NSCLC) patients (N=40) and their levels decreased after surgical resection. These results demonstrate that CTEC are detectable in preclinical cancer models and cancer patients. Further, they suggest that CTEC offer a novel cancer-associated marker that may be useful as a blood-based surrogate for assessing the presence of tumor vasculature and antiangiogenic drug activity. PMID:24626092

  5. Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue.

    PubMed

    Kuiper, Caroline; Vissers, Margreet C M; Hicks, Kevin O

    2014-12-01

    Ascorbate is delivered to cells via the vasculature, but its ability to penetrate into tissues remote from blood vessels is unknown. This is particularly relevant to solid tumors, which often contain regions with dysfunctional vasculature, with impaired oxygen and nutrient delivery, resulting in upregulation of the hypoxic response and also the likely depletion of essential plasma-derived biomolecules, such as ascorbate. In this study, we have utilized a well-established multicell-layered, three-dimensional pharmacokinetic model to measure ascorbate diffusion and transport parameters through dense tissue in vitro. Ascorbate was found to penetrate the tissue at a slightly lower rate than mannitol and to travel via the paracellular route. Uptake parameters into the cells were also determined. These data were fitted to the diffusion model, and simulations of ascorbate pharmacokinetics in normal tissue and in hypoxic tumor tissue were performed with varying input concentrations, ranging from normal dietary plasma levels (10-100 μM) to pharmacological levels (>1 mM) as seen with intravenous infusion. The data and simulations demonstrate heterogeneous distribution of ascorbate in tumor tissue at physiological blood levels and provide insight into the range of plasma ascorbate concentrations and exposure times needed to saturate all regions of a tumor. The predictions suggest that supraphysiological plasma ascorbate concentrations (>100 μM) are required to achieve effective delivery of ascorbate to poorly vascularized tumor tissue.

  6. Computed tomography of the abnormal thymus

    SciTech Connect

    Baron, R.L.; Lee, J.K.T.; Sagel, S.S.; Levitt, R.G.

    1982-01-01

    Computed tomography (CT) should be the imaging method of choice following plain chest radiographs when a suspected thymic abnormality requires further evaluation. Based upon a six-year experience, including the evaluation of 25 patients with thymic pathology, CT was found useful in suggesting or excluding a diagnosis of thymoma and in distinguishing thymic hyperplasis from thymoma in patients with myasthenia gravis. The thickness of the thymic lobes determined by CT was found to be a more accurate indicator of infiltrative disease (thymic hyperplasia and lymphoma) than the width. CT was helpful in differentiating benign thymic cysts from solid tumors, and in defining the extent of a thymic neoplasms. On occasion, CT may suggest the specific histologic nature of a thymic lesion.

  7. Cerebral abnormalities: use of calculated T1 and T2 magnetic resonance images for diagnosis

    SciTech Connect

    Mills, C.M.; Crooks, L.E.; Kaufman, L.; Brant-Zawadzki, M.

    1984-01-01

    The potential clinical importance of T1 and T2 relaxation times in distinguishing normal and pathologic tissue with magnetic resonance (MR) is discussed and clinical examples of cerebral abnormalities are given. Five patients with cerebral infarction, 15 with multiple sclerosis, two with Wilson disease, and four with tumors were imaged. Hemorrhagic and ischemic cerebrovascular accidents were distinguished using the spin echo technique. In the patients with multiple sclerosis, lesions had prolonged T1 and T2 times, but the definition of plaque was limited by spatial resolution. No abnormalities in signal intensity were seen in the patient with Wilson disease who was no longer severly disabled; abnormal increased signal intensity in the basal ganglia was found in the second patient with Wilson disease. Four tumors produced abnormal T1 and T2 relaxation times but these values alone were not sufficient for tumor characterization.

  8. Congenital abnormalities and selective abortion.

    PubMed

    Seller, M J

    1976-09-01

    The technique of amniocentesis, by which an abnormal fetus can be detected in utero, has brought a technological advance in medical science but attendant medical and moral problems. Dr Seller describes those congenital disabilities which can be detected in the fetus before birth, for which the "remedy" is selective abortion. She then discusses the arguments for and against selective abortion, for the issue is not simple, even in the strictly genetic sense of attempting to ensure a population free of congenital abnormality.

  9. Sex Steroids Modulate Uterine-Placental Vasculature: Implications for Obstetrics and Neonatal Outcomes

    PubMed Central

    Maliqueo, Manuel; Echiburú, Bárbara; Crisosto, Nicolás

    2016-01-01

    Adequate blood supply to the uterine-placental region is crucial to ensure the transport of oxygen and nutrients to the growing fetus. Multiple factors intervene to achieve appropriate uterine blood flow and the structuring of the placental vasculature during the early stages of pregnancy. Among these factors, oxygen concentrations, growth factors, cytokines, and steroid hormones are the most important. Sex steroids are present in extremely high concentrations in the maternal circulation and are important paracrine and autocrine regulators of a wide range of maternal and placental functions. In this regard, progesterone and estrogens act as modulators of uterine vessels and decrease the resistance of the spiral uterine arteries. On the other hand, androgens have the opposite effect, increasing the vascular resistance of the uterus. Moreover, progesterone and estrogens modulate the synthesis and release of angiogenic factors by placental cells, which regulates trophoblastic invasion and uterine artery remodeling. In this scenario, it is not surprising that women with pregnancy-related pathologies, such as early miscarriages, preterm delivery, preeclampsia, and fetal growth restriction, exhibit altered sex steroid concentrations. PMID:27199767

  10. Expression and function of potassium channels in the human placental vasculature.

    PubMed

    Wareing, Mark; Bai, Xilian; Seghier, Fella; Turner, Claire M; Greenwood, Susan L; Baker, Philip N; Taggart, Michael J; Fyfe, Gregor K

    2006-08-01

    In the placental vasculature, where oxygenation may be an important regulator of vascular reactivity, there is a paucity of data on the expression of potassium (K) channels, which are important mediators of vascular smooth muscle tone. We therefore addressed the expression and function of several K channel subtypes in human placentas. The expression of voltage-gated (Kv)2.1, KV9.3, large-conductance Ca2+-activated K channel (BKCa), inward-rectified K+ channel (KIR)6.1, and two-pore domain inwardly rectifying potassium channel-related acid-sensitive K channels (TASK)1 in chorionic plate arteries, veins, and placental homogenate was assessed by RT-PCR and Western blot analysis. Functional activity of K channels was assessed pharmacologically in small chorionic plate arteries and veins by wire myography using 4-aminopyridine, iberiotoxin, pinacidil, and anandamide. Experiments were performed at 20, 7, and 2% oxygen to assess the effect of oxygenation on the efficacy of K channel modulators. KV2.1, KV9.3, BKCa, KIR6.1, and TASK1 channels were all demonstrated to be expressed at the message level. KV2.1, BKCa, KIR6.1, and TASK1 were all demonstrated at the protein level. Pharmacological manipulation of voltage-gated and ATP-sensitive channels produced the most marked modifications in vascular tone, in both arteries and veins. We conclude that K channels play an important role in controlling placental vascular function.

  11. Photoacoustic imaging of living mouse brain vasculature using hollow gold nanospheres

    PubMed Central

    Lu, Wei; Huang, Qian; Ku, Geng; Wen, Xiaoxia; Zhou, Min; Guzatov, Dmitry; Brecht, Peter; Su, Richard; Oraevsky, Alexander; Wang, Lihong V.; Li, Chun

    2010-01-01

    Photoacoustic tomography (PAT) also referred to as optoacoustic tomography (OAT) is a hybrid imaging modality that employs nonionizing optical radiation and ultrasonic detection. Here, we describe the application of a new class of optical contrast agents based on mesoscopic hollow gold nanospheres (HAuNS) to PAT. HAuNS are ~40 nm in diameter with a hollow interior and consist of a thin gold wall. They display strong resonance absorption tuned to the near infrared (NIR) range, with an absorption peak at 800 nm, whose photoacoustic efficiency is significantly greater than that of blood. Following surface conjugation with thiolated poly(ethylene glycol), the pegylated HAuNS (PEG-HAuNS) had distribution and elimination half-lives of 1.38±0.38 and 71.82±30.46 h, respectively. Compared with PAT images based on the intrinsic optical contrast in nude mice, the PAT images acquired within 2 h after intravenous administration of PEG-HAuNS showed the brain vasculature with greater clarity and detail. The image depicted brain blood vessels as small as ~100 µm in diameter using PEG-HAuNS as contrast agents. Preliminary results showed no acute toxicity to the liver, spleen, or kidneys in mice following a single imaging dose of PEG-HAuNS. Our results indicate that PEG-HAuNS are promising contrast agents for PAT, with high spatial resolution and enhanced sensitivity. PMID:20036000

  12. Circulatory therapeutics: use of antihypertensive agents and their effects on the vasculature

    PubMed Central

    Schiffrin, Ernesto L

    2010-01-01

    Abstract This review addresses the use of the different antihypertensive agents currently available and some in development, and their effects on the vasculature. The different classes of agents used in the treatment of hypertension, and the results of recent large clinical trials, dosing protocols and adverse effects are first briefly summarized. The consequences on blood vessels of the use of antihypertensive drugs and the differential effects on the biology of large and small arteries resulting in modulation of vascular remodelling and dysfunction in hypertensive patients are then described. Large elastic conduit arteries exhibit outward hypertrophic remodelling and increased stiffness, which contributes to raise systolic blood pressure and afterload on the heart. Small resistance arteries undergo eutrophic or hypertrophic inward remodelling, and impair tissue perfusion. By these mechanisms both large and small arteries may contribute to trigger cardiovascular events. Some antihypertensive agents correct these changes, which could contribute to improved outcome. The mechanisms that at the level of the vascular wall lead to remodelling and can be beneficially affected by antihypertensive agents will also be addressed. These include vasoconstriction, growth and inflammation. The molecular pathways contributing to growth and inflammation will be summarily described. Further identification of these signalling pathways should allow identification of novel targets leading to development of new and improved medications for the treatment of hypertension and cardiovascular disease. PMID:20345850

  13. Congenital cataract associated with persistent fetal vasculature: findings from IoLunder2.

    PubMed

    Solebo, A L; Russell-Eggitt, I; Cumberland, P; Rahi, J S

    2016-09-01

    PurposeTo describe the frequency, characteristics, and treatment outcome of persistent fetal vasculature (PFV) in children undergoing surgery for congenital and infantile cataract in the first 2 years of life.Patients and methodsObservational population-based cohort study with case identification through active surveillance and standardised data collection via a national clinical network, the British Isles Congenital Cataract Interest Group (BCCIG).ResultsThe IoLunder2 cohort comprises 246 children undergoing surgery for bilateral and unilateral congenital and infantile cataract in the first 2 years of life. A total of 58/246 (24%) children had PFV (%): overall, 46/95 (46%) with unilateral cataract, and 12/141 (8%) with bilateral disease. Anterior segment vascular remnants were more common in bilateral than unilateral disease (75 vs 11%, P=0.01). At 1 year after surgery, 20% of children with bilateral PFV and 24% with unilateral had achieved normal vision for age within the operated eye. The prevalence of post-operative glaucoma was 9% (of children with bilateral disease) and 4% (unilateral).ConclusionPFV is significantly more common than previously reported, and outcomes are comparable to that for congenital and infantile cataract overall.

  14. Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos.

    PubMed

    Yokomizo, Tomomasa; Dzierzak, Elaine

    2010-11-01

    Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of whole mouse embryos. Here, we combine an approach to make whole mouse embryos transparent, with multicolor marking, to allow observation of hematopoietic clusters using high-resolution 3-dimensional confocal microscopy. Our method provides the first complete map and temporal quantitation of all hematopoietic clusters in the mouse embryonic vasculature. We show that clusters peak in number at embryonic day 10.5, localize to specific vascular subregions and are heterogeneous, indicating a basal endothelial to non-basal (outer cluster) hematopoietic cell transition. Clusters enriched with the c-Kit(+)CD31(+)SSEA1(-) cell population contain functional hematopoietic progenitors and stem cells. Thus, three-dimensional cartography of transparent mouse embryos provides novel insight into the vascular subregions instrumental in hematopoietic progenitor/stem cell development, and represents an important technological advancement for comprehensive in situ hematopoietic cluster analysis.

  15. Manufactured Aluminum Oxide Nanoparticles Decrease Expression of Tight Junction Proteins in Brain Vasculature

    PubMed Central

    Yokel, Robert A.; Hennig, Bernhard

    2009-01-01

    Manufactured nanoparticles of aluminum oxide (nano-alumina) have been widely used in the environment; however, their potential toxicity provides a growing concern for human health. The present study focuses on the hypothesis that nano-alumina can affect the blood-brain barrier and induce endothelial toxicity. In the first series of experiments, human brain microvascular endothelial cells (HBMEC) were exposed to alumina and control nanoparticles in dose- and time-responsive manners. Treatment with nano-alumina markedly reduced HBMEC viability, altered mitochondrial potential, increased cellular oxidation, and decreased tight junction protein expression as compared to control nanoparticles. Alterations of tight junction protein levels were prevented by cellular enrichment with glutathione. In the second series of experiments, rats were infused with nano-alumina at the dose of 29 mg/kg and the brains were stained for expression of tight junction proteins. Treatment with nano-alumina resulted in a marked fragmentation and disruption of integrity of claudin-5 and occludin. These results indicate that cerebral vasculature can be affected by nano-alumina. In addition, our data indicate that alterations of mitochondrial functions may be the underlying mechanism of nano-alumina toxicity. PMID:18830698

  16. Ambient temperature affects glabrous skin vasculature and sweating responses to mental task in humans.

    PubMed

    Hayashi, Naoyuki; Someya, Nami; Hirooka, Yoshitaka; Koga, Shunsaku

    2008-09-01

    We compared responses in heart rate (HR), mean blood pressure (MAP), sweating rate (SR), sweating expulsion (SwE), and skin vascular conductance (VC) to mental task among different ambient temperature (Ta) conditions, i.e., 12, 16, 20, and 24 degrees C. Seven subjects (27+/-5 yrs, 64+/-14 kg) underwent a 2-min color word conflict test (CWT) after 2 mins of baseline data acquisition following a 20-min resting period. All subjects wore long sleeve shirts and long pants. The skin blood flow was measured with a laser Doppler probe on the left index finger pulp to calculate skin VC, and the SR and sweating expulsion (SwE) were measured with a ventilated capsule on the left thenar. CWT significantly increased the HR and MAP, while there was no significant effect of Ta on the magnitudes of these responses. CWT significantly decreased the skin VC when the Ta was 24 degrees C, whereas it significantly increased the skin VC when the Ta was 12 or 16 degrees C. CWT significantly increased SR and SwE in all Ta conditions, and the SwE was greater in warmer conditions. These findings suggest that different ambient temperatures induce different responses in finger skin vasculature to mental task, implying the independent response of cutaneous vasomotor tone and sweat glands in glabrous skin to mental task.

  17. Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos

    PubMed Central

    Yokomizo, Tomomasa; Dzierzak, Elaine

    2010-01-01

    Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of whole mouse embryos. Here, we combine an approach to make whole mouse embryos transparent, with multicolor marking, to allow observation of hematopoietic clusters using high-resolution 3-dimensional confocal microscopy. Our method provides the first complete map and temporal quantitation of all hematopoietic clusters in the mouse embryonic vasculature. We show that clusters peak in number at embryonic day 10.5, localize to specific vascular subregions and are heterogeneous, indicating a basal endothelial to non-basal (outer cluster) hematopoietic cell transition. Clusters enriched with the c-Kit+CD31+SSEA1– cell population contain functional hematopoietic progenitors and stem cells. Thus, three-dimensional cartography of transparent mouse embryos provides novel insight into the vascular subregions instrumental in hematopoietic progenitor/stem cell development, and represents an important technological advancement for comprehensive in situ hematopoietic cluster analysis. PMID:20876651

  18. Physiological and genomic basis of mechanical-functional trade-off in plant vasculature

    PubMed Central

    Sengupta, Sonali; Majumder, Arun Lahiri

    2014-01-01

    Some areas in plant abiotic stress research are not frequently addressed by genomic and molecular tools. One such area is the cross reaction of gravitational force with upward capillary pull of water and the mechanical-functional trade-off in plant vasculature. Although frost, drought and flooding stress greatly impact these physiological processes and consequently plant performance, the genomic and molecular basis of such trade-off is only sporadically addressed and so is its adaptive value. Embolism resistance is an important multiple stress- opposition trait and do offer scopes for critical insight to unravel and modify the input of living cells in the process and their biotechnological intervention may be of great importance. Vascular plants employ different physiological strategies to cope with embolism and variation is observed across the kingdom. The genomic resources in this area have started to emerge and open up possibilities of synthesis, validation and utilization of the new knowledge-base. This review article assesses the research till date on this issue and discusses new possibilities for bridging physiology and genomics of a plant, and foresees its implementation in crop science. PMID:24904619

  19. Manufactured aluminum oxide nanoparticles decrease expression of tight junction proteins in brain vasculature.

    PubMed

    Chen, Lei; Yokel, Robert A; Hennig, Bernhard; Toborek, Michal

    2008-12-01

    Manufactured nanoparticles of aluminum oxide (nano-alumina) have been widely used in the environment; however, their potential toxicity provides a growing concern for human health. The present study focuses on the hypothesis that nano-alumina can affect the blood-brain barrier and induce endothelial toxicity. In the first series of experiments, human brain microvascular endothelial cells (HBMEC) were exposed to alumina and control nanoparticles in dose- and time-responsive manners. Treatment with nano-alumina markedly reduced HBMEC viability, altered mitochondrial potential, increased cellular oxidation, and decreased tight junction protein expression as compared to control nanoparticles. Alterations of tight junction protein levels were prevented by cellular enrichment with glutathione. In the second series of experiments, rats were infused with nano-alumina at the dose of 29 mg/kg and the brains were stained for expression of tight junction proteins. Treatment with nano-alumina resulted in a marked fragmentation and disruption of integrity of claudin-5 and occludin. These results indicate that cerebral vasculature can be affected by nano-alumina. In addition, our data indicate that alterations of mitochondrial functions may be the underlying mechanism of nano-alumina toxicity.

  20. Binaural blood flow control by astrocytes: listening to synapses and the vasculature.

    PubMed

    Mishra, Anusha

    2017-03-15

    Astrocytes are the most common glial cells in the brain with fine processes and endfeet that intimately contact both neuronal synapses and the cerebral vasculature. They play an important role in mediating neurovascular coupling (NVC) via several astrocytic Ca(2+) -dependent signalling pathways such as K(+) release through BK channels, and the production and release of arachidonic acid metabolites. They are also involved in maintaining the resting tone of the cerebral vessels by releasing ATP and COX-1 derivatives. Evidence also supports a role for astrocytes in maintaining blood pressure-dependent change in cerebrovascular tone, and perhaps also in blood vessel-to-neuron signalling as posited by the 'hemo-neural hypothesis'. Thus, astrocytes are emerging as new stars in preserving the intricate balance between the high energy demand of active neurons and the supply of oxygen and nutrients from the blood by maintaining both resting blood flow and activity-evoked changes therein. Following neuropathology, astrocytes become reactive and many of their key signalling mechanisms are altered, including those involved in NVC. Furthermore, as they can respond to changes in vascular pressure, cardiovascular diseases might exert previously unknown effects on the central nervous system by altering astrocyte function. This review discusses the role of astrocytes in neurovascular signalling in both physiology and pathology, and the impact of these findings on understanding BOLD-fMRI signals.

  1. Selenoprotein expression in endothelial cells from different human vasculature and species.

    PubMed

    Miller, S; Walker, S W; Arthur, J R; Lewin, M H; Pickard, K; Nicol, F; Howie, A F; Beckett, G J

    2002-10-09

    Selenium (Se) can protect endothelial cells (EC) from oxidative damage by altering the expression of selenoproteins with antioxidant function such as cytoplasmic glutathione peroxidase (cyGPX), phospholipid hydroperoxide glutathione peroxidase (PHGPX) and thioredoxin reductase (TR). If the role of Se on EC function is to be studied, it is essential that a model system be chosen which reflects selenoprotein expression in human EC derived from vessels prone to developing atheroma. We have used [75Se]-selenite labelling and selenoenzyme measurements to compare the selenoproteins expressed by cultures of EC isolated from different human vasculature with EC bovine and porcine aorta. Only small differences were observed in selenoprotein expression and activity in EC originating from human coronary artery, human umbilical vein (HUVEC), human umbilical artery and the human EC line EAhy926. The selenoprotein profile in HUVEC was consistent over eight passages and HUVEC isolated from four cords also showed little variability. In contrast, EC isolated from pig and bovine aorta showed marked differences in selenoprotein expression when compared to human cells. This study firmly establishes the suitability and consistency of using HUVEC (and possibly the human cell line EAhy926) as a model to study the effects of Se on EC function in relation to atheroma development in the coronary artery. Bovine or porcine EC appear to be an inappropriate model.

  2. Surgical Anatomy of the Gastrointestinal Tract and Its Vasculature in the Laboratory Rat.

    PubMed

    Vdoviaková, Katarína; Petrovová, Eva; Maloveská, Marcela; Krešáková, Lenka; Teleky, Jana; Elias, Mario Zefanias Joao; Petrášová, Darina

    2016-01-01

    The aim of this study was to describe and illustrate the morphology of the stomach, liver, intestine, and their vasculature to support the planning of surgical therapeutic methods in abdominal cavity. On adult Wistar rats corrosion casts were prepared from the arterial system and Duracryl Dental and PUR SP were used as a casting medium and was performed macroscopic anatomical dissection of the stomach, liver, and intestine was performed. The rat stomach was a large, semilunar shaped sac with composite lining. On the stomach was very marked fundus, which formed a blind sac (saccus cecus). The rat liver was divided into six lobes, but without gall bladder. Intestine of the rat was simple, but cecum had a shape as a stomach. The following variations were observed in the origin of the cranial mesenteric artery. On the corrosion cast specimens we noticed the presence of the anastomosis between middle colic artery (a. colica media) and left colic artery (a. colica sinistra). We investigated the second anastomosis between middle colic artery and left colic artery. The results of this study reveal that the functional anatomical relationship between the rat stomach, liver and intestine is important for the development of surgical research in human and veterinary medicine.

  3. Multiscale bi-Gaussian filter for adjacent curvilinear structures detection with application to vasculature images.

    PubMed

    Xiao, Changyan; Staring, Marius; Wang, Yaonan; Shamonin, Denis P; Stoel, Berend C

    2013-01-01

    The intensity or gray-level derivatives have been widely used in image segmentation and enhancement. Conventional derivative filters often suffer from an undesired merging of adjacent objects because of their intrinsic usage of an inappropriately broad Gaussian kernel; as a result, neighboring structures cannot be properly resolved. To avoid this problem, we propose to replace the low-level Gaussian kernel with a bi-Gaussian function, which allows independent selection of scales in the foreground and background. By selecting a narrow neighborhood for the background with regard to the foreground, the proposed method will reduce interference from adjacent objects simultaneously preserving the ability of intraregion smoothing. Our idea is inspired by a comparative analysis of existing line filters, in which several traditional methods, including the vesselness, gradient flux, and medialness models, are integrated into a uniform framework. The comparison subsequently aids in understanding the principles of different filtering kernels, which is also a contribution of this paper. Based on some axiomatic scale-space assumptions, the full representation of our bi-Gaussian kernel is deduced. The popular γ-normalization scheme for multiscale integration is extended to the bi-Gaussian operators. Finally, combined with a parameter-free shape estimation scheme, a derivative filter is developed for the typical applications of curvilinear structure detection and vasculature image enhancement. It is verified in experiments using synthetic and real data that the proposed method outperforms several conventional filters in separating closely located objects and being robust to noise.

  4. Smartphone-Based Accurate Analysis of Retinal Vasculature towards Point-of-Care Diagnostics

    PubMed Central

    Xu, Xiayu; Ding, Wenxiang; Wang, Xuemin; Cao, Ruofan; Zhang, Maiye; Lv, Peilin; Xu, Feng

    2016-01-01

    Retinal vasculature analysis is important for the early diagnostics of various eye and systemic diseases, making it a potentially useful biomarker, especially for resource-limited regions and countries. Here we developed a smartphone-based retinal image analysis system for point-of-care diagnostics that is able to load a fundus image, segment retinal vessels, analyze individual vessel width, and store or uplink results. The proposed system was not only evaluated on widely used public databases and compared with the state-of-the-art methods, but also validated on clinical images directly acquired with a smartphone. An Android app is also developed to facilitate on-site application of the proposed methods. Both visual assessment and quantitative assessment showed that the proposed methods achieved comparable results to the state-of-the-art methods that require high-standard workstations. The proposed system holds great potential for the early diagnostics of various diseases, such as diabetic retinopathy, for resource-limited regions and countries. PMID:27698369

  5. Vasculature of the ophthalmic rete in night herons (Nycticorax nycticorax): scanning electron microscopy of corrosion casts.

    PubMed

    Ninomiya, Hiroyoshi

    2002-09-01

    Vasculature of the ophthalmic rete (rete ophthalmicum) in the night heron (Nycticorax nycticorax) was studied using scanning electron microscopy of vascular corrosion casts and light microscopy on tissue sections. Most blood to the eyeball and a lesser volume of blood to the brain passed through the ophthalmic rete via the external ophthalmic artery. The collateral retial arterioles originated from the external ophthalmic artery forming a flat and fusiform-shaped arterial network at the ventrotemporal region of the eyeball. The arterial network was intermixed with a similar complex of the veins from the eye. The ophthalmotemporal artery, which supplied the eyeball posteriorly, and supraorbital and infraorbital arteries, which supplied the eyeball anteriorly, originated from the rete. Blood from the eye, which is a site of potential heat loss, drained into the ophthalmic rete via the ophthalmotemporal vein. On the casts of retial arterioles, slit-like cleavages at branching sites representing flap valves, which might play a role as sluice valves, were seen. In addition, marks of circularly running grooves, which might represent tufts of smooth muscle cells and might contribute to a sphincter activity, were observed. These anatomical specializations of the avian ophthalmic rete, involving parallel arrangement of arteries and veins, may function to facilitate counter-current heat exchange and to regulate blood pressure and volume to the eye and the brain.

  6. Mechanosignaling in the vasculature: emerging concepts in sensing, transduction and physiological responses

    PubMed Central

    Fujiwara, Keigi; Pérez, Néstor Gustavo; Ushio-Fukai, Masuko; Fisher, Aron B.

    2015-01-01

    Cells are constantly exposed to mechanical forces that play a role in modulating cellular structure and function. The cardiovascular system experiences physical forces in the form of shear stress and stretch associated with blood flow and contraction, respectively. These forces are sensed by endothelial cells and cardiomyocytes and lead to responses that control vascular and cardiac homeostasis. This was highlighted at the Pan American Physiological Society meeting at Iguassu Falls, Brazil, in a symposium titled “Mechanosignaling in the Vasculature.” This symposium presented recent research that showed the existence of a vital link between mechanosensing and downstream redox sensitive signaling cascades. This link helps to transduce and transmit the physical force into an observable physiological response. The speakers showcased how mechanosensors such as ion channels, membrane receptor kinases, adhesion molecules, and other cellular components transduce the force via redox signals (such as reactive oxygen species and nitric oxide) to receptors (transcription factors, growth factors, etc.). Receptor activated pathways then lead to cellular responses including cellular proliferation, contraction, and remodeling. These responses have major relevance to the physiology and pathophysiology of various cardiovascular diseases. Thus an understanding of the complex series of events, from the initial sensing through the final response, is essential for progress in this field. Overall, this symposium addressed some important emerging concepts in the field of mechanosignaling and the eventual pathophysiological responses. PMID:25862828

  7. Vasculature of the orbital rete in the Japanese deer (Cervus nippon).

    PubMed

    Ninomiya, H.; Masui, M.

    1999-01-01

    The vasculature of the orbital rete (rete mirabile ophthalmicum) in Japanese deer (Cervus nippon) was studied using corrosion casting, scanning electron microscopy, and histology. The orbital rete is a flat, triangular- or leaf-shaped arterial network, which consists of a complex of small arterioles, that intermixes with a similar complex of the supraorbital vein at the base of the orbital cavity. Blood to the retina passes through the orbital rete. The orbital retial arterioles leave the parent external ophthalmic artery at right angles forming T-shaped bifurcations, and follow a tortuous, undulating course. Each retial arteriole is connected by side branches and forms a rope-ladder-like network. Some of the side branches are surrounded by a groove representing the intra-arterial cushion that regulates blood flow at branching sites. The central retinal artery supplying the retina originates from the orbital rete. The ciliary arteries supplying the choroid arise from the external ophthalmic artery proximal to the orbital rete. The anatomical specializations of the orbital rete may involve buffering the blood pressure and flow to the retina and regulating ocular tissue temperature as in the carotid rete. In addition, the orbital rete may help dampen the tension that the vessel exerts on the retina, by stretching in response to eyeball movement.

  8. Inflammatory lipid mediator generation elicited by viable hemolysin- forming Escherichia coli in lung vasculature

    PubMed Central

    1990-01-01

    Escherichia coli hemolysin, a transmembrane pore-forming exotoxin, is considered an important virulence factor for E. coli-related extraintestinal infections and sepsis. The possible significance of hemolysin liberation for induction of inflammatory lipid mediators was investigated in isolated rabbit lungs infused with viable bacteria (concentration range, 10(4)-10(7)/ml). Hemolysin-secreting E. coli (E. coli-Hly+), but not an E. coli strain that releases an inactive form of the exotoxin, induced marked lung leukotriene (LT) generation with predominance of cysteinyl LTs. Eicosanoid synthesis was not inhibited in the presence of plasma with toxin-neutralizing capacity. Pre- application of 2 x 10(8) human granulocytes, which sequestered in the lung microvasculature, caused a severalfold increase in leukotriene generation in response to E. coli-Hly+ challenge both in the absence and presence of plasma. Data are presented indicating neutrophil- endothelial cell cooperation in arachidonic acid lipoxygenase metabolism as an underlying mechanism. We conclude that liberation of hemolysin from viable E. coli induces marked lipid mediator generation in lung vasculature, which is potentiated in the presence of neutrophil sequestration and may contribute to microcirculatory disturbances during the course of severe infections. PMID:2120384

  9. Using Non-Invasive Multi-Spectral Imaging to Quantitatively Assess Tissue Vasculature

    SciTech Connect

    Vogel, A; Chernomordik, V; Riley, J; Hassan, M; Amyot, F; Dasgeb, B; Demos, S G; Pursley, R; Little, R; Yarchoan, R; Tao, Y; Gandjbakhche, A H

    2007-10-04

    This research describes a non-invasive, non-contact method used to quantitatively analyze the functional characteristics of tissue. Multi-spectral images collected at several near-infrared wavelengths are input into a mathematical optical skin model that considers the contributions from different analytes in the epidermis and dermis skin layers. Through a reconstruction algorithm, we can quantify the percent of blood in a given area of tissue and the fraction of that blood that is oxygenated. Imaging normal tissue confirms previously reported values for the percent of blood in tissue and the percent of blood that is oxygenated in tissue and surrounding vasculature, for the normal state and when ischemia is induced. This methodology has been applied to assess vascular Kaposi's sarcoma lesions and the surrounding tissue before and during experimental therapies. The multi-spectral imaging technique has been combined with laser Doppler imaging to gain additional information. Results indicate that these techniques are able to provide quantitative and functional information about tissue changes during experimental drug therapy and investigate progression of disease before changes are visibly apparent, suggesting a potential for them to be used as complementary imaging techniques to clinical assessment.

  10. Impact of Immune Deficiency on Remodeling of Maternal Resistance Vasculature 4 Weeks Postpartum in Mice.

    PubMed

    Bonney, Elizabeth A; Howard, Ann; Krebs, Kendall; Begin, Kelly; Veilleux, Kelsey; Gokina, Natalia I

    2017-04-01

    Pregnancy manifests changes in the vascular and immune systems that persist postpartum (PP), have important implications for future pregnancies, and may modify responses to cardiovascular stress in late life. The association between immune and vascular function and the generation or progression of cardiovascular disease beg the question of whether altered immunity modifies pregnancy-induced changes in the vasculature. Our objective was to compare changes in the function and remodeling of systemic resistance vessels 4 weeks PP in normal C57BL/6 (B6), and immunodeficient mice recombinase 1-deficient/B6 ( Rag1(-/-)). Immune deficiency did not change the responsiveness to acetylcholine (ACh) and phenylephrine at baseline but decreased arterial distensibility and increased stiffness PP. Adoptive transfer of CD8 T cells into Rag1(-/-) mice decreased the response to ACh while increasing distensibility and wall thickness. When compared to PP Rag1(-/-), vessels from PP CD4-deficient mice, which have B cells and CD8 T cells, but no CD4 cells, show increased distensibility and decreased responsiveness to ACh in a pattern similar to that seen in Rag1(-/-) given CD8 T cells prior to mating. These studies suggest a key role for T cell, particularly CD8 T cell, associated factors in the PP remodeling of maternal resistance vessels.

  11. Segmentation methods for breast vasculature in dual-energy contrast-enhanced digital breast tomosynthesis

    NASA Astrophysics Data System (ADS)

    Lau, Kristen C.; Lee, Hyo Min; Singh, Tanushriya; Maidment, Andrew D. A.

    2015-03-01

    Dual-energy contrast-enhanced digital breast tomosynthesis (DE CE-DBT) uses an iodinated contrast agent to image the three-dimensional breast vasculature. The University of Pennsylvania has an ongoing DE CE-DBT clinical study in patients with known breast cancers. The breast is compressed continuously and imaged at four time points (1 pre-contrast; 3 post-contrast). DE images are obtained by a weighted logarithmic subtraction of the high-energy (HE) and low-energy (LE) image pairs. Temporal subtraction of the post-contrast DE images from the pre-contrast DE image is performed to analyze iodine uptake. Our previous work investigated image registration methods to correct for patient motion, enhancing the evaluation of vascular kinetics. In this project we investigate a segmentation algorithm which identifies blood vessels in the breast from our temporal DE subtraction images. Anisotropic diffusion filtering, Gabor filtering, and morphological filtering are used for the enhancement of vessel features. Vessel labeling methods are then used to distinguish vessel and background features successfully. Statistical and clinical evaluations of segmentation accuracy in DE-CBT images are ongoing.

  12. Response of the forelimb vasculature to vasoactive agents: effects of ouabain.

    PubMed

    Dobbins, D E; Swindall, B T; Haddy, F J; Dabney, J M

    1985-01-01

    The effect of the local intra-arterial infusion of ouabain (11.8 micrograms/min.) on the response of the forelimb to vasoactive agents was examined. In seven dogs, bolus injections of CaCl2, MgSO4, KCl, norepinephrine, adenosine, acetylcholine, PGE1 and saline were made into the forelimb perfused at constant flow before and three times during ouabain infusion. Ouabain blocked potassium vasodilation and changed the response to CaCl2 from vasoconstriction to vasodilation. The response of the forelimb to the other vasoactive agents was initially unaffected by ouabain but with time the forelimb vasculature became less sensitive to all agents studied. These changes were not seen in a series of 5 saline infused control animals. In a third series of animals steady-state dose responses to CaCl2, Ca-gluconate and KCl were explored by infusing solutions intrabrachially at three dosages. Before ouabain, forelimb resistance increased as a function of Ca++ and decreased as a function of K+. Ouabain completely blocked potassium vasodilation and on the average blocked Ca++ vasoconstriction although a number of animals evidenced vasodilation to Ca++ during ouabain infusion. These data indicate that K+ vasodilation is Na+, K+-ATPase dependent and that Na+, K+-ATPase inhibition unmasks a vasodilatory action of locally applied Ca++.

  13. Angiogenic inhibitors delivered by the type III secretion system of tumor-targeting Salmonella typhimurium safely shrink tumors in mice.

    PubMed

    Shi, Lei; Yu, Bin; Cai, Chun-Hui; Huang, Jian-Dong

    2016-12-01

    Despite of a growing number of bacterial species that apparently exhibit intrinsic tumor-targeting properties, no bacterium is able to inhibit tumor growth completely in the immunocompetent hosts, due to its poor dissemination inside the tumors. Oxygen and inflammatory reaction form two barriers and restrain the spread of the bacteria inside the tumors. Here, we engineered a Salmonella typhimurium strain named ST8 which is safe and has limited ability to spread beyond the anaerobic regions of tumors. When injected systemically to tumor-bearing immunocompetent mice, ST8 accumulated in tumors at levels at least 100-fold greater than parental obligate anaerobic strain ST4. ST8/pSEndo harboring therapeutic plasmids encoding Endostatin fused with a secreted protein SopA could target vasculature at the tumor periphery, can stably maintain and safely deliver a therapeutic vector, release angiogenic inhibitors through a type III secretion system (T3SS) to interfere with the pro-angiogenic action of growth factors in tumors. Mice with murine CT26 colon cancer that had been injected with ST8/pSEndo showed efficient tumor suppression by inducing more severe necrosis and inhibiting blooding vessel density within tumors. Our findings provide a therapeutic platform for indirectly acting therapeutic strategies such as anti-angiogenesis and immune therapy.

  14. Mammary tumors

    SciTech Connect

    Weller, R.E.

    1988-10-01

    Mammary neoplasia is one of the more common malignancies affecting domestic species. Despite their importance, they are often over- diagnosed, undertreated and subject to several misconceptions propagated by veterinarians and pet owners alike. Mammary neoplasia is the most frequent tumor type encountered in the female accounting for almost half of all malignancies reported. The canine has the highest incidence of mammary tumors of all domestic species. In the dog, about 65 percent of mammary tumors are benign mixed tumors, and 25 percent are carcinomas. The rest are adenomas, myoepitheliomas, and malignant mixed tumors. The age distribution of mammary tumors closely follows the age distribution of most tumors in the dog. Mammary tumors are rare in dogs 2 years old, but incidence begins to increase sharply at approximately 6 years of age. Median age at diagnosis is about 10 years. No breed predilection has been consistently reported.

  15. Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic Brain Tumors

    DTIC Science & Technology

    2015-09-01

    the role of myeloid/endothelial lineage in glioma progression by following animal study. Based on the analysis on large cohort of patients, we...deduction of CD11b cells compared with control group. In this case, we didn’t see effect on tumor growth . However, as Figure 10 showed, knockout KDR... growth , tumor-associated myeloid cells, and vasculatures. Chimeric C57/bl6 mice transplanted with rosa26ERT2-cre/KDRfl/fl bone marrow cells (labeled

  16. hESC Differentiation toward an Autonomic Neuronal Cell Fate Depends on Distinct Cues from the Co-Patterning Vasculature

    PubMed Central

    Acevedo, Lisette M.; Lindquist, Jeffrey N.; Walsh, Breda M.; Sia, Peik; Cimadamore, Flavio; Chen, Connie; Denzel, Martin; Pernia, Cameron D.; Ranscht, Barbara; Terskikh, Alexey; Snyder, Evan Y.; Cheresh, David A.

    2015-01-01

    Summary To gain insight into the cellular and molecular cues that promote neurovascular co-patterning at the earliest stages of human embryogenesis, we developed a human embryonic stem cell model to mimic the developing epiblast. Contact of ectoderm-derived neural cells with mesoderm-derived vasculature is initiated via the neural crest (NC), not the neural tube (NT). Neurovascular co-patterning then ensues with specification of NC toward an autonomic fate requiring vascular endothelial cell (EC)-secreted nitric oxide (NO) and direct contact with vascular smooth muscle cells (VSMCs) via T-cadherin-mediated homotypic interactions. Once a neurovascular template has been established, NT-derived central neurons then align themselves with the vasculature. Our findings reveal that, in early human development, the autonomic nervous system forms in response to distinct molecular cues from VSMCs and ECs, providing a model for how other developing lineages might coordinate their co-patterning. PMID:26004631

  17. A method for longitudinal, transcranial imaging of blood flow and remodeling of the cerebral vasculature in postnatal mice

    PubMed Central

    Letourneur, Annelise; Chen, Victoria; Waterman, Gar; Drew, Patrick J.

    2014-01-01

    Abstract In the weeks following birth, both the brain and the vascular network that supplies it undergo dramatic alteration. While studies of the postnatal evolution of the pial vasculature and blood flow through its vessels have been previously done histologically or acutely, here we describe a neonatal reinforced thin‐skull preparation for longitudinally imaging the development of the pial vasculature in mice using two‐photon laser scanning microscopy. Starting with mice as young as postnatal day 2 (P2), we are able to chronically image cortical areas >1 mm2, repeatedly for several consecutive days, allowing us to observe the remodeling of the pial arterial and venous networks. We used this method to measure blood velocity in individual vessels over multiple days, and show that blood flow through individual pial venules was correlated with subsequent diameter changes. This preparation allows the longitudinal imaging of the developing mammalian cerebral vascular network and its physiology. PMID:25524276

  18. [Diagnosticum of abnormalities of plant meiotic division].

    PubMed

    Shamina, N V

    2006-01-01

    Abnormalities of plant meiotic division leading to abnormal meiotic products are summarized schematically in the paper. Causes of formation of monads, abnormal diads, triads, pentads, polyads, etc. have been observed in meiosis with both successive and simultaneous cytokinesis.

  19. Urogenital tumors

    SciTech Connect

    Weller, R.E.

    1994-03-01

    An overview is provided for veterinary care of urogenital tumors in companion animals, especially the dog. Neoplasms discussed include tumors of the kidney, urinary bladder, prostate, testis, ovary, vagina, vulva and the canine transmissible venereal tumor. Topics addressed include description, diagnosis and treatment.

  20. Wilms Tumor

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Wilms Tumor KidsHealth > For Parents > Wilms Tumor Print A A A What's in this article? ... their child has cancer. Fortunately, most kids with Wilms tumor, a rare kidney cancer, survive and go on ...

  1. Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum.

    PubMed

    Grade, Sofia; Weng, Yuan C; Snapyan, Marina; Kriz, Jasna; Malva, João O; Saghatelyan, Armen

    2013-01-01

    Stroke induces the recruitment of neuronal precursors from the subventricular zone (SVZ) into the ischemic striatum. In injured areas, de-routed neuroblasts use blood vessels as a physical scaffold to their migration, in a process that resembles the constitutive migration seen in the rostral migratory stream (RMS). The molecular mechanism underlying injury-induced vasculature-mediated migration of neuroblasts in the post-stroke striatum remains, however, elusive. Using adult mice we now demonstrate that endothelial cells in the ischemic striatum produce brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the vasculature-mediated migration of neuronal precursors in the RMS, and that recruited neuroblasts maintain expression of p75NTR, a low-affinity receptor for BDNF. Reactive astrocytes, which are widespread throughout the damaged area, ensheath blood vessels and express TrkB, a high-affinity receptor for BDNF. Despite the absence of BDNF mRNA, we observed strong BDNF immunolabeling in astrocytes, suggesting that these glial cells trap extracellular BDNF. Importantly, this pattern of expression is reminiscent of the adult RMS, where TrkB-expressing astrocytes bind and sequester vasculature-derived BDNF, leading to the entry of migrating cells into the stationary phase. Real-time imaging of cell migration in acute brain slices revealed a direct role for BDNF in promoting the migration of neuroblasts to ischemic areas. We also demonstrated that cells migrating in the ischemic striatum display higher exploratory behavior and longer stationary periods than cells migrating in the RMS. Our findings suggest that the mechanisms involved in the injury-induced vasculature-mediated migration of neuroblasts recapitulate, at least partially, those observed during constitutive migration in the RMS.

  2. Correlative Imaging of the Murine Hind Limb Vasculature and Muscle Tissue by MicroCT and Light Microscopy

    PubMed Central

    Schaad, Laura; Hlushchuk, Ruslan; Barré, Sébastien; Gianni-Barrera, Roberto; Haberthür, David; Banfi, Andrea; Djonov, Valentin

    2017-01-01

    A detailed vascular visualization and adequate quantification is essential for the proper assessment of novel angiomodulating strategies. Here, we introduce an ex vivo micro-computed tomography (microCT)-based imaging approach for the 3D visualization of the entire vasculature down to the capillary level and rapid estimation of the vascular volume and vessel size distribution. After perfusion with μAngiofil®, a novel polymerizing contrast agent, low- and high-resolution scans (voxel side length: 2.58–0.66 μm) of the entire vasculature were acquired. Based on the microCT data, sites of interest were defined and samples further processed for correlative morphology. The solidified, autofluorescent μAngiofil® remained in the vasculature and allowed co-registering of the histological sections with the corresponding microCT-stack. The perfusion efficiency of μAngiofil® was validated based on lectin-stained histological sections: 98 ± 0.5% of the blood vessels were μAngiofil®-positive, whereas 93 ± 2.6% were lectin-positive. By applying this approach we analyzed the angiogenesis induced by the cell-based delivery of a controlled VEGF dose. Vascular density increased by 426% mainly through the augmentation of medium-sized vessels (20–40 μm). The introduced correlative and quantitative imaging approach is highly reproducible and allows a detailed 3D characterization of the vasculature and muscle tissue. Combined with histology, a broad range of complementary structural information can be obtained. PMID:28169309

  3. Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors

    PubMed Central

    Zhang, Xiaonan; de Milito, Angelo; Olofsson, Maria Hägg; Gullbo, Joachim; D’Arcy, Padraig; Linder, Stig

    2015-01-01

    The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS) or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an “Achilles heel” for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations. PMID:26580606

  4. Vasculature-Specific Adenovirus Vectors for Gene Therapy of Prostate Cancer

    DTIC Science & Technology

    2008-02-01

    University of Zurich, Switzerland) on developing designed ankyrin repeat protein ligands (DARPins) specific for Ad fiber knob domain, which will be used as...facilitate the identification of the human tumor xenografts grown in mice and also to allow for non- invasive monitoring of tumor growth , we made a...ψ NeoR PCMV hRluc-EGFP Figure 6. Schematic representation of LhRLuc-EGFP genome. LTR – long terminal repeat , ψ - packaging signal, NeoR – G418

  5. “Do-it-yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial-blood cell interactions”

    PubMed Central

    Mannino, Robert G.; Myers, David R.; Ahn, Byungwook; Wang, Yichen; Margo Rollins; Gole, Hope; Lin, Angela S.; Guldberg, Robert E.; Giddens, Don P.; Timmins, Lucas H.; Lam, Wilbur A.

    2015-01-01

    Investigating biophysical cellular interactions in the circulation currently requires choosing between in vivo models, which are difficult to interpret due in part to the hemodynamic and geometric complexities of the vasculature; or in vitro systems, which suffer from non-physiologic assumptions and/or require specialized microfabrication facilities and expertise. To bridge that gap, we developed an in vitro “do-it-yourself” perfusable vasculature model that recapitulates in vivo geometries, such as aneurysms, stenoses, and bifurcations, and supports endothelial cell culture. These inexpensive, disposable devices can be created rapidly (<2 hours) with high precision and repeatability, using standard off-the-shelf laboratory supplies. Using these “endothelialized” systems, we demonstrate that spatial variation in vascular cell adhesion molecule (VCAM-1) expression correlates with the wall shear stress patterns of vascular geometries. We further observe that the presence of endothelial cells in stenoses reduces platelet adhesion but increases sickle cell disease (SCD) red blood cell (RBC) adhesion in bifurcations. Overall, our method enables researchers from all disciplines to study cellular interactions in physiologically relevant, yet simple-to-make, in vitro vasculature models. PMID:26202603

  6. “Do-it-yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial-blood cell interactions”

    NASA Astrophysics Data System (ADS)

    Mannino, Robert G.; Myers, David R.; Ahn, Byungwook; Wang, Yichen; Margo Rollins; Gole, Hope; Lin, Angela S.; Guldberg, Robert E.; Giddens, Don P.; Timmins, Lucas H.; Lam, Wilbur A.

    2015-07-01

    Investigating biophysical cellular interactions in the circulation currently requires choosing between in vivo models, which are difficult to interpret due in part to the hemodynamic and geometric complexities of the vasculature; or in vitro systems, which suffer from non-physiologic assumptions and/or require specialized microfabrication facilities and expertise. To bridge that gap, we developed an in vitro “do-it-yourself” perfusable vasculature model that recapitulates in vivo geometries, such as aneurysms, stenoses, and bifurcations, and supports endothelial cell culture. These inexpensive, disposable devices can be created rapidly (<2 hours) with high precision and repeatability, using standard off-the-shelf laboratory supplies. Using these “endothelialized” systems, we demonstrate that spatial variation in vascular cell adhesion molecule (VCAM-1) expression correlates with the wall shear stress patterns of vascular geometries. We further observe that the presence of endothelial cells in stenoses reduces platelet adhesion but increases sickle cell disease (SCD) red blood cell (RBC) adhesion in bifurcations. Overall, our method enables researchers from all disciplines to study cellular interactions in physiologically relevant, yet simple-to-make, in vitro vasculature models.

  7. Impact of tumor microenvironment on oncolytic viral therapy

    PubMed Central

    Wojton, Jeffrey; Kaur, Balveen

    2010-01-01

    Interactions between tumor cells and their microenvironment have been shown to play a very significant role in the initiation, progression, and invasiveness of cancer. These tumor-stromal interactions are capable of altering the delivery and effectiveness of therapeutics into the tumor and are also known to influence future resistance and re-growth after treatment. Here we review recent advances in the understanding of the tumor microenvironment and its response to oncolytic viral therapy. The multifaceted environmental response to viral therapy can influence viral infection, replication, and propagation within the tumor. Recent studies have unveiled the complicated temporal changes in the tumor vasculature post OV treatment, and their impact on tumor biology. Similarly, the secreted extracellular matrix in solid tumors can affect both infection and spread of the therapeutic virus. Together, these complex changes in the tumor microenvironment also modulate the activation of the innate antiviral host immune response, leading to quick and efficient viral clearance. In order to combat these detrimental responses, viruses have been combined with pharmacological adjuvants and “armed” with therapeutic genes in order to suppress the pernicious environmental conditions following therapy. In this review we will discuss the impact of the tumor environment on viral therapy and examine some of the recent literature investigating methods of modulating this environment to enhance oncolysis. PMID:20399700

  8. Neovascularization and tumor growth in the rabbit brain. A model for experimental studies of angiogenesis and the blood-brain barrier.

    PubMed Central

    Zagzag, D.; Brem, S.; Robert, F.

    1988-01-01

    A model for the study of tumor angiogenesis within the rabbit brain is presented. Implantation of the VX2 carcinoma provides a reproducible tumor accompanied by angiogenesis. The authors report the sequential growth, histology, tumor neovascularization, and vascular permeability of this tumor following its intracerebral implantation. Tumor angiogenesis correlates with the rapid and logarithmic intracerebral tumor growth. The proliferation of blood vessels in the tumor and the organization of tumor cells around tumor vessels are described. Breakdown of the blood-brain barrier (detected by Evans blue leakage) starts in the early stages of tumor development and becomes prominent as the tumor vasculature and size increase. This model is useful for experimental studies of angiogenesis. Images Figure 2 Figure 3 Figure 6 Figure 4 Figure 5 Figure 7 Figure 8 Figure 10 Figure 12 Figure 13 Figure 15 PMID:2451889

  9. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    PubMed Central

    Li, Xiaoyu; Wu, Meiying; Pan, Limin; Shi, Jianlin

    2016-01-01

    To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. PMID:26766908

  10. Tracheobronchial tumors

    PubMed Central

    Milenkovic, Branislava

    2016-01-01

    Tumors of trachea and bronchi are uncommon and can occur in the form of benign or low- and high-grade malignant tumors. Although tracheobronchial tumors (TBTs) represent only 0.6% of all pulmonary tumors, they are clinically significant. Delays in diagnosis of these tumors commonly occur because the signs and symptoms caused by these tumors are nonspecific and chest radiographs are often considered unremarkable. Therefore, novel radiological techniques and better access to flexible bronchoscopy enable detection of larger number of TBT. The purpose of this article is to provide a review of tracheal and bronchial tumors and discuss significant aspects of the different TBT with focus on clinical manifestations and diagnostic procedures. PMID:28066620

  11. Computational Model for Tumor Oxygenation Applied to Clinical Data on Breast Tumor Hemoglobin Concentrations Suggests Vascular Dilatation and Compression

    PubMed Central

    Welter, Michael; Fredrich, Thierry; Rinneberg, Herbert; Rieger, Heiko

    2016-01-01

    We present a computational model for trans-vascular oxygen transport in synthetic tumor and host tissue blood vessel networks, aiming at qualitatively explaining published data of optical mammography, which were obtained from 87 breast cancer patients. The data generally show average hemoglobin concentration to be higher in tumors versus host tissue whereas average oxy-to total hemoglobin concentration (vascular segment RBC-volume-weighted blood oxygenation) can be above or below normal. Starting from a synthetic arterio-venous initial network the tumor vasculature was generated by processes involving cooption, angiogenesis, and vessel regression. Calculations of spatially resolved blood flow, hematocrit, oxy- and total hemoglobin concentrations, blood and tissue oxygenation were carried out for ninety tumor and associated normal vessel networks starting from various assumed geometries of feeding arteries and draining veins. Spatial heterogeneity in the extra-vascular partial oxygen pressure distribution can be related to various tumor compartments characterized by varying capillary densities and blood flow characteristics. The reported higher average hemoglobin concentration of tumors is explained by growth and dilatation of tumor blood vessels. Even assuming sixfold metabolic rate of oxygen consumption in tumorous versus host tissue, the predicted oxygen hemoglobin concentrations are above normal. Such tumors are likely associated with high tumor blood flow caused by high-caliber blood vessels crossing the tumor volume and hence oxygen supply exceeding oxygen demand. Tumor oxy- to total hemoglobin concentration below normal could only be achieved by reducing tumor vessel radii during growth by a randomly selected factor, simulating compression caused by intra-tumoral solid stress due to proliferation of cells and extracellular matrix. Since compression of blood vessels will impede chemotherapy we conclude that tumors with oxy- to total hemoglobin concentration

  12. Focal adhesion kinase regulates smooth muscle cell recruitment to the developing vasculature

    PubMed Central

    Cheng, Zhaokang; Sundberg-Smith, Liisa J.; Mangiante, Lee E.; Sayers, Rebecca L.; Hakim, Zeenat S.; Musunuri, Srilaxmi; Maguire, Colin T.; Majesky, Mark W.; Zhou, Zhigang; Mack, Christopher P.; Taylor, Joan M.

    2011-01-01

    Objective The investment of newly formed endothelial cell tubes with differentiated smooth muscle cells (SMC) is critical for appropriate vessel formation, but the underlying mechanisms remain unknown. We previously showed that depletion of focal adhesion kinase (FAK) in the nkx2.5 expression domain led to aberrant outflow tract (OFT) morphogenesis and strove herein to determine the cell types and mechanisms involved. Methods and Results We crossed fakloxp targeted mice with available Cre drivers to deplete FAK in OFT SMC (FAKwnt and FAKnk) or coronary SMC (FAKcSMC). In each case, depletion of FAK led to defective vasculogenesis that was incompatible with post-natal life. Immunohistochemical analysis of the mutant vascular structures revealed that FAK was not required for progenitor cell proliferation, survival, or differentiation into SMC, but was necessary for subsequent SMC recruitment to developing vasculature. Using a novel FAK-null SMC culture model, we found that depletion of FAK did not influence SMC growth or survival, but blocked directional SMC motility and invasion toward the potent endothelial-derived chemokine, PDGFBB. FAK depletion resulted in un-stable lamellipodial protrusions due to defective spatial-temporal activation of the small GTPase, Rac-1 and lack of Rac1-dependent recruitment of cortactin (an actin stabilizing protein) to the leading edge. Moreover, FAK null SMC exhibited a significant reduction in PDGF-stimulated extracellular matrix degradation. Conclusions FAK drives PDGFBB-stimulated SMC chemotaxis/invasion and is essential for SMC to appropriately populate the aorticopulmonary septum and the coronary vascular plexus. PMID:21757658

  13. A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus.

    PubMed

    Dunham-Snary, Kimberly J; Hong, Zhigang G; Xiong, Ping Y; Del Paggio, Joseph C; Herr, Julia E; Johri, Amer M; Archer, Stephen L

    2016-01-01

    The mammalian homeostatic oxygen sensing system (HOSS) initiates changes in vascular tone, respiration, and neurosecretion that optimize oxygen uptake and tissue oxygen delivery within seconds of detecting altered environmental or arterial PO2. The HOSS includes carotid body type 1 cells, adrenomedullary cells, neuroepithelial bodies, and smooth muscle cells (SMCs) in pulmonary arteries (PAs), ductus arteriosus (DA), and fetoplacental arteries. Hypoxic pulmonary vasoconstriction (HPV) optimizes ventilation-perfusion matching. In utero, HPV diverts placentally oxygenated blood from the non-ventilated lung through the DA. At birth, increased alveolar and arterial oxygen tension dilates the pulmonary vasculature and constricts the DA, respectively, thereby transitioning the newborn to an air-breathing organism. Though modulated by endothelial-derived relaxing and constricting factors, O2 sensing is intrinsic to PASMCs and DASMCs. Within the SMC's dynamic mitochondrial network, changes in PO2 alter the reduction-oxidation state of redox couples (NAD(+)/NADH, NADP(+)/NADPH) and the production of reactive oxygen species, ROS (e.g., H2O2), by complexes I and III of the electron transport chain (ETC). ROS and redox couples regulate ion channels, transporters, and enzymes, changing intracellular calcium [Ca(2+)]i and calcium sensitivity and eliciting homeostatic responses to hypoxia. In PASMCs, hypoxia inhibits ROS production and reduces redox couples, thereby inhibiting O2-sensitive voltage-gated potassium (Kv) channels, depolarizing the plasma membrane, activating voltage-gated calcium channels (CaL), increasing [Ca(2+)]i, and causing vasoconstriction. In DASMCs, elevated PO2 causes mitochondrial fission, increasing ETC complex I activity and ROS production. The DASMC's downstream response to elevated PO2 (Kv channel inhibition, CaL activation, increased [Ca(2+)]i, and rho kinase activation) is similar to the PASMC's hypoxic response. Impaired O2 sensing contributes to

  14. Histomorphometry of the placental vasculature and microcotyledons in Thoroughbred mares with chronic laminitis.

    PubMed

    Pazinato, Fernanda M; Curcio, Bruna da Rosa; Fernandes, Cristina G; Santos, Carlos A; Feijó, Lorena S; Varela, Antonio Sérgio; Nogueira, Carlos E W

    2017-03-15

    The objective of this study was to assess the placental vasculature and microcotyledons in pregnant mares with chronic laminitis. Twenty-six pregnant mares were enrolled in the study, 13 had chronic laminitis (Laminitis Group) and 13 were healthy mares (Healthy Group). Arterial systolic pressure and heart rate were measured in the last 30 days of gestation. After foaling, the fetal membranes were grossly evaluated and samples were harvested for histopathologic examination. All mares had digitalized images taken from chorioallantois for histomorphometry analyses (software-NIH ImageJ). Images were assessed for: (i) arterioles from the allantoic region: total and lumen vascular diameter and vascular wall thickness; (ii) microcotiledonary and capillary area/field. Mares in the Laminitis Group showed hypertension, shorter gestational length, lower placental weight and lower birthweight (p < 0.05) foal in comparison with mares in the Healthy Group. Laminitis mares had a reduction of vascular lumen diameters in the uterine body and pregnant horn (p < 0.05), vascular wall thickening in the pregnant horn (p < 0.05) and smaller capillary area/field in the microcotyledons of uterine body and pregnant horn (p < 0.05). In conclusion, pregnant mares with chronic laminitis presented signs of hypertension syndrome, and vascular abnormalitities in placental vessels such as reduction in the vascular lumen and capillary area in the microcotyledones, and thickening of the vascular wall. Foals born from mares with chronic laminitis showed lower birth weight and shorter gestation lengths.

  15. Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development

    PubMed Central

    van der Flier, Arjan; Badu-Nkansah, Kwabena; Whittaker, Charles A.; Crowley, Denise; Bronson, Roderick T.; Lacy-Hulbert, Adam; Hynes, Richard O.

    2010-01-01

    Integrin cell adhesion receptors and fibronectin, one of their extracellular matrix ligands, have been demonstrated to be important for angiogenesis using functional perturbation studies and complete knockout mouse models. Here, we report on the roles of the α5 and αv integrins, which are the major endothelial fibronectin receptors, in developmental angiogenesis. We generated an integrin α5-floxed mouse line and ablated α5 integrin in endothelial cells. Unexpectedly, endothelial-specific knockout of integrin α5 has no obvious effect on developmental angiogenesis. We provide evidence for genetic interaction between mutations in integrin α5 and αv and for overlapping functions and compensation between these integrins and perhaps others. Nonetheless, in embryos lacking both α5 and αv integrins in their endothelial cells, initial vasculogenesis and angiogenesis proceed normally, at least up to E11.5, including the formation of apparently normal embryonic vasculature and development of the branchial arches. However, in the absence of endothelial α5 and αv integrins, but not of either alone, there are extensive defects in remodeling of the great vessels and heart resulting in death at ~E14.5. We also found that fibronectin assembly is somewhat affected in integrin α5 knockout endothelial cells and markedly reduced in integrin α5/αv double-knockout endothelial cell lines. Therefore, neither α5 nor αv integrins are required in endothelial cells for initial vasculogenesis and angiogenesis, although they are required for remodeling of the heart and great vessels. These integrins on other cells, and/or other integrins on endothelial cells, might contribute to fibronectin assembly and vascular development. PMID:20570943

  16. A full 3-D reconstruction of the entire porcine coronary vasculature

    PubMed Central

    Kaimovitz, Benjamin; Lanir, Yoram

    2010-01-01

    We have previously reconstructed the entire coronary arterial tree of the porcine heart down to the first segment of capillaries. Here, we extend the vascular model through the capillary bed and the entire coronary venous system. The reconstruction was based on comprehensive morphometric data previously measured in the porcine heart. The reconstruction was formulated as a large-scale optimization process, subject to both global constraints relating to the location of the larger veins and to local constraints of measured morphological features. The venous network was partitioned into epicardial, transmural, and perfusion functional subnetworks. The epicardial portion was generated by a simulated annealing search for the optimal coverage of the area perfused by the arterial epicardial vessels. The epicardial subnetwork and coronary arterial capillary network served as boundary conditions for the reconstruction of the in-between transmural and perfusion networks, which were generated to optimize vascular homogeneity. Five sets of full coronary trees, which spanned the entire network down to the capillary level, were reconstructed. The total number of reconstructed venous segments was 17,148,946 ± 1,049,498 (n = 5), which spanned the coronary sinus (order −12) to the first segment of the venous capillary (order 0v). Combined with the reconstructed arterial network, the number of vessel segments for the entire coronary network added up to 27,307,376 ± 1,155,359 (n = 5). The reconstructed full coronary vascular network agreed with the gross anatomy of coronary networks in terms of structure, location of major vessels, and measured morphometric statistics of native coronary networks. This is the first full model of the entire coronary vasculature, which can serve as a foundation for realistic large-scale coronary flow analysis. PMID:20622105

  17. Effect of blood pressure on the retinal vasculature in a multi-ethnic Asian population.

    PubMed

    Jeganathan, V Swetha E; Sabanayagam, Charumathi; Tai, E Shyong; Lee, Jeannette; Sun, Cong; Kawasaki, Ryo; Nagarajan, Sangeetha; Huey-Shi, Maisie Ho; Sandar, Mya; Wong, Tien Yin

    2009-11-01

    Blood pressure has a significant effect on retinal arterioles. There are few data on whether this effect varies by race/ethnicity. We examined the relationship of blood pressure and retinal vascular caliber in a multi-ethnic Asian population. The study is population-based and cross sectional in design. A total of 3749 Chinese, Malay and Indian participants aged > or =24 years residing in Singapore were included in the study. Retinal vascular caliber was measured using a computer program from digital retinal photographs. The associations of retinal vascular caliber with blood pressure and hypertension in each racial/ethnic group were analyzed. The main outcome measures are retinal arteriolar caliber and venular caliber. The results show that retinal arterioles were narrower in persons with uncontrolled/untreated hypertension (140.0 microm) as compared with persons with controlled hypertension (142.1 microm, P=0.0001) and those with no hypertension (146.0 microm, P<0.0001). On controlling for age, gender, body mass index, lipids and smoking, each 10 mm Hg increase in mean arterial blood pressure was associated with a 3.1 microm decrease in arteriolar caliber (P<0.0001), with a similar magnitude seen in all three racial/ethnic groups: 3.1 microm in Chinese, 2.8 microm in Malays and 3.2 microm in Indians (P<0.0001 for all). Each 10 mm Hg increase in mean arterial blood pressure was associated with a 1.8 microm increase in venular caliber (P<0.0001); furthermore, the magnitude of this effect was similar across the three racial/ethnic groups. The effect of blood pressure on the retinal vasculature was similar across three major racial/ethnic groups in Asia.

  18. Abnormal insulin levels and vertigo.

    PubMed

    Proctor, C A

    1981-10-01

    Fifty patients with unexplained vertigo (36) or lightheadedness (14) are evaluated, all of whom had abnormal ENGs and normal audiograms. Five hour insulin glucose tolerance tests were performance on all patients, with insulin levels being obtained fasting and at one-half, one, two, and three hours. The results of this investigation were remarkable. Borderline or abnormal insulin levels were discovered in 82% of patients; 90% were found to have either an abnormal glucose tolerance test or at least borderline insulin levels. The response to treatment in these dizzy patients was also startling, with appropriate low carbohydrate diets improving the patient's symptoms in 90% of cases. It is, therefore, apparent that the earliest identification of carbohydrate imbalance with an insulin glucose tolerance test is extremely important in the work-up of the dizzy patients.

  19. Complex patterns of abnormal heartbeats

    NASA Technical Reports Server (NTRS)

    Schulte-Frohlinde, Verena; Ashkenazy, Yosef; Goldberger, Ary L.; Ivanov, Plamen Ch; Costa, Madalena; Morley-Davies, Adrian; Stanley, H. Eugene; Glass, Leon

    2002-01-01

    Individuals having frequent abnormal heartbeats interspersed with normal heartbeats may be at an increased risk of sudden cardiac death. However, mechanistic understanding of such cardiac arrhythmias is limited. We present a visual and qualitative method to display statistical properties of abnormal heartbeats. We introduce dynamical "heartprints" which reveal characteristic patterns in long clinical records encompassing approximately 10(5) heartbeats and may provide information about underlying mechanisms. We test if these dynamics can be reproduced by model simulations in which abnormal heartbeats are generated (i) randomly, (ii) at a fixed time interval following a preceding normal heartbeat, or (iii) by an independent oscillator that may or may not interact with the normal heartbeat. We compare the results of these three models and test their limitations to comprehensively simulate the statistical features of selected clinical records. This work introduces methods that can be used to test mathematical models of arrhythmogenesis and to develop a new understanding of underlying electrophysiologic mechanisms of cardiac arrhythmia.

  20. A Perspective on Vascular Disrupting Agents that Interact with Tubulin: Preclinical Tumor Imaging and Biological Assessment#

    PubMed Central

    Mason, Ralph P.; Zhao, Dawen; Liu, Li; Trawick, Mary Lynn; Pinney, Kevin G.

    2011-01-01

    The tumor microenvironment provides a rich source of potential targets for selective therapeutic intervention with properly designed anticancer agents. Significant physiological differences exist between the microvessels that nourish tumors and those that supply healthy tissue. Selective drug-mediated damage of these tortuous and chaotic microvessels starves a tumor of necessary nutrients and oxygen and eventually leads to massive tumor necrosis. Vascular targeting strategies in oncology are divided into two separate groups: angiogenesis inhibiting agents (AIAs) and vascular disrupting agents (VDAs). The mechanisms of action between these two classes of compounds are profoundly distinct. The AIAs inhibit the actual formation of new vessels, while the VDAs damage and/or destroy existing tumor vasculature. One subset of small-molecule VDAs functions by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature, triggered by a cascade of cell signaling events. Ultimately this results in catastrophic damage to the vessels feeding the tumor. The rapid emergence and subsequent development of the VDA field over the past decade has led to the establishment of a synergistic combination of preclinical state-of-the-art tumor imaging and biological evaluation strategies that are often indicative of future clinical efficacy for a given VDA. This review focuses on an integration of the appropriate biochemical and biological tools necessary to assess (preclinically) new small-molecule, tubulin active VDAs for their potential to be clinically effective anticancer agents. PMID:21321746

  1. Purinoceptor-mediated contractility of the perfused uterine vasculature of the guinea-pig: influence of oestradiol and pregnancy.

    PubMed

    Haynes, John M; Pennefather, Jocelyn N; Sikorski, Bogdan

    2003-01-01

    1. The effects of ATP, the stable ATP analogues alpha,beta-methylene ATP (alpha,beta-mATP), 2-methylthioATP (2meSATP) and adenosine tetraphosphate (ATP4), the pyrimidine nucleotide uridine 5'-triphosphate (UTP) and the alpha1-adrenoceptor agonist phenylephrine were examined on the isolated perfused uterine vasculature of dioestrous, oestradiol-treated, dexamethasone-treated and late-pregnant guinea-pigs. 2. The alpha1-adrenoceptor agonist phenylephrine elicited concentration-dependent vasoconstriction from preparations of perfused uterine vasculature from dioestrous, estradiol-treated and late-pregnant guinea-pigs. The mean maximal response to phenylephrine was unaffected by treatment of dioestrus guinea-pigs with oestradiol or dexamethasone, but was reduced in preparations from late-pregnant animals. 3. In perfused uterine arteries from dioestrous animals, the pyrimidine UTP, but not ATP4 and ATP, elicited vasoconstrictor responses. In preparations from oestradiol-treated animals, all three agonists elicited vasoconstriction, with a rank order of potency of ATP4 = UTP > ATP, whereas in preparations from late-pregnant animals this order of potency was ATP4 > UTP = ATP. In preparations from dexamethasone-treated animals, the vasoconstriction was similar to that seen in dioestrous animals. Vasoconstrictor responses to ATP4 were significantly greater in preparations of uterine vasculature from oestradiol-treated and pregnant animals than in preparations from dioestrous animals or dexamethasone-treated animals. 4. In preparations from dioestrous, oestradiol-treated, pregnant and dexamethasone-treated animals, alpha,beta-mATP was approximately two to three orders of magnitude more potent than 2meSATP. Compared with preparations from dioestrous animals, the maximal responses to alpha,beta-mATP were significantly greater in tissues from oestradiol-treated and pregnant animals. In preparations from dioestrous animals, the P2 purinoceptor antagonist suramin (100 micro mol

  2. Ectodermal dysplasia and abnormal thumbs.

    PubMed

    Lucky, A W; Esterly, N B; Tunnessen, W W

    1980-05-01

    Two unrelated children, a girl and a boy, with alopecia, anomalous cutaneous pigmentation, abnormal thumbs, and endocrine disorders, including short stature and delayed bone age in one patient and juvenile onset diabetes mellitus in the other, are described. In one instance, the mother and the maternal grandmother had similar abnormalities, although of a less severe nature. Both children had normal nails and no unusual susceptibility to infections. We believe these two patients represent a previously undescribed syndrome of ectodermal dysplasia that may be inherited as an autosomal-dominant trait.

  3. Feminizing adrenocortical tumors: Literature review

    PubMed Central

    Chentli, Farida; Bekkaye, Ilyes; Azzoug, Said

    2015-01-01

    Feminizing adrenal tumors (FAT) are extremely rare tumors prevailing in males. Clinical manifestations are gynecomastia and/or other hypogonadism features in adults. They are rarer in pediatric population and their main manifestation is peripheral sexual precocity. In women genital bleeding, uterus hypertrophy, high blood pressure and/or abdomen mass may be the only manifestations. On the biological point, estrogen overproduction with or without increase in other adrenal hormones are the main abnormalities. Radiological examination usually shows the tumor, describes its limits and its eventual metastases. Adrenal and endocrine origins are confirmed by biochemical assessments and histology, but that one is unable to distinguish between benign and malignant tumors, except if metastases are already present. Immunostaining using anti-aromatase antibodies is the only tool that distinguishes FAT from other adrenocortical tumors. Abdominal surgery is the best and the first line treatment. For large tumors (≥10 cm), an open access is preferred to coeliosurgery, but for the small ones, or when the surgeon is experienced, endoscopic surgery seems to give excellent results. Surgery can be preceded by adrenolytic agents such as ortho paraprime dichloro diphenyl dichloroethane (Mitotane), ketoconazole or by aromatase inhibitors, but till now there is not any controlled study to compare the benefit of different drugs. New anti-estrogens can be used too, but their results need to be confirmed in malignant tumors resistant to classical chemotherapy and to conventional radiotherapy. Targeted therapy can be used too, as in other adrenocortical tumors, but the results need to be confirmed. PMID:25932386

  4. Vestibular abnormalities in congenital disorders.

    PubMed

    Sando, I; Orita, Y; Miura, M; Balaban, C D

    2001-10-01

    This paper reviews the histopathologic features of vestibular abnormalities in congenital disorders affecting the inner ear, based upon a comprehensive literature survey and a review of cases in our temporal bone collection. The review proceeds in three systematic steps. First, we surveyed associated diseases with the major phenotypic features of congenital abnormalities of the inner ear (including the internal auditory canal and otic capsule). Second, the vestibular anomalies are examined specifically. Finally, the anomalies are discussed from a developmental perspective. Among vestibular anomalies, a hypoplastic endolymphatic duct and sac are observed most frequently. Anomalies of the semicircular canals are also often observed. From embryological and clinical viewpoints, many of these resemble the structural features from fetal stages and appear to be associated with vestibular dysfunction. It is expected that progress in genetic analysis and accumulation of temporal bone specimens with vestibular abnormalities in congenital diseases will provide crucial information not only for pathology of those diseases, but also for genetic factors that are responsible for the specific vestibular abnormalities.

  5. Radiation-induced tumor neoantigens: imaging and therapeutic implications

    PubMed Central

    Corso, Christopher D; Ali, Arif N; Diaz, Roberto

    2011-01-01

    Exposure of tumor cells to ionizing radiation (IR) is widely known to induce a number of cellular changes. One way that IR can affect tumor cells is through the development of neoantigens which are new molecules that tumor cells express at the cell membrane following some insult or change to the cell. There have been numerous reports in the literature of changes in both tumor and tumor vasculature cell surface molecule expression following treatment with IR. The usefulness of neoantigens for imaging and therapeutic applications lies in the fact that they are differentially expressed on the surface of irradiated tumor cells to a greater extent than on normal tissues. This differential expression provides a mechanism by which tumor cells can be “marked” by radiation for further targeting. Drug delivery vehicles or imaging agents conjugated to ligands that recognize and interact with the neoantigens can help to improve tumor-specific targeting and reduce systemic toxicity with cancer drugs. This article provides a review of the molecules that have been reported to be expressed on the surface of tumor cells in response to IR either in vivo or in vitro. Additionally, we provide a discussion of some of the methods used in the identification of these antigens and applications for their use in drug delivery and imaging. PMID:21969260

  6. Effect of photodynamic therapy with verteporfin on tumor blood flow

    NASA Astrophysics Data System (ADS)

    Chen, Bin; Pogue, Brian W.; Goodwin, Isak A.; O'Hara, Julia A.; Wilmot, Carmen M.; Hutchins, John E.; Hoopes, P. J.; Hasan, Tayyaba

    2003-06-01

    The success of photodynamic therapy with verteporfin is partially determined by the pharmacokinetic distribution of the sensitizer at the time of treatment. In this study tumor blood flow changes in the RIF-1 murine tumor model and tumor resopnse using the regrowth assay were measured, comparing two different intervals between drug and light administration. Blood flow measurements were taken with a laser Doppler system monitoring continuously over 1 hour and periodically up to 6 hours after treatment. Treatment after the longer interval caused significantly less flow decrease, to only 50% of the initial flow in 6 h. Hoechst staining of functional tumor vasculature confirmed the primary vascular damage and the decrease in tumor perfusion. The regrowth rate of tumors after the longer time interval, the regrowth rate was not signifincalty different from that of the control, indicating that only the 15-min interval group caused serious damage to the vascular bed of the tumor. These studies support the hypothesis that temporal pharmacokinetic changes in the photosensitizer distribution between the tumor parenchyma and blood vessels can significantly alter the mechanism of tumor targeting during therapy.

  7. Angiopoietin-1 Promotes Tumor Angiogenesis in a Rat Glioma Model

    PubMed Central

    Machein, Marcia Regina; Knedla, Anette; Knoth, Rolf; Wagner, Shawn; Neuschl, Elvira; Plate, Karl H.

    2004-01-01

    Angiopoietins have been implicated in playing an important role in blood vessel formation, remodeling, maturation, and maintenance. However, the role of angiopoietins in tumor angiogenesis remains uncertain. In this study, expression of human angiopoietin-1 (hAng-1) and angiopoietin (hAng-2) was amplified in the rat glioma cell line GS9L by stable transfection using an inducible tet-off system. Transfected cells were implanted intracerebrally into syngenic Fischer 344 rats. We demonstrated by means of magnetic resonance imaging that increased hAng-1 expression promoted a significant in vivo growth of intracerebral gliomas in rats. Overexpression of hAng-1 resulted in more numerous, more highly branched vessels, which were covered by pericytes. On the other hand, tumors derived from hAng-2-overexpressing cells were smaller than empty-plasmid control tumors. The tumor vasculature in these tumors was composed of aberrant small vascular cords, which were associated with few mural cells. Our results indicate that in the presence of hAng-1, tumors induce a more functional vascular network, which led to better tumor perfusion and growth. On the other hand, overexpression of hAng-2 led to less intact tumor vessels, inhibited capillary sprouting, and impaired tumor growth. PMID:15509526

  8. Development, differentiation, and vascular components of subcutaneous and intrahepatic Hepa129 tumors in a mouse model of hepatocellular carcinoma.

    PubMed

    Robertson, Richard T; Gutierrez, Paula M; Baratta, Janie L; Thordarson, Kristoffer; Braslow, Joshua; Haynes, Sherry M; Longmuir, Kenneth J

    2016-04-01

    Tumor models in mice offer opportunities for understanding tumor formation and development of therapeutic treatments for hepatocellular carcinoma. In this study, subcutaneous or intra-hepatic Hepa129 tumors were established in C3H mice. Tumor growth was determined by daily measurements of subcutaneous tumors and post-mortem studies of subcutaneous and intrahepatic tumors. Administration of Edu was used to determine cell generation dates of tumor cells. Immunohistochemistry with antibodies directed at CD31 or CD34, and intravenous injection of labeled tomato lectin revealed tumor vasculature. Tissue sections also were processed for immunohistochemistry using a panel of antibodies to proteoglycans. Comparison of Edu labeled cells with immunoreactivity allowed determination of development and differentiation of tumor cells after cell generation. Subcutaneous and intrahepatic tumors displayed similar growth over 3 weeks. Immunohistochemistry showed strong labeling for glypican-3, 9BA12, and chondroitin sulfate of tumors in both loci, while normal liver was negative. Tumor regions containing Edu labeled cells did not show significant immunohistochemical labeling for the tumor markers until 2-3 days after Edu treatment; overlap of Edu labeled cells and immunohistochemically labeled tumor regions appeared to reach a maximum at 5 days after Edu treatment. Ectopic subcutaneous tumors displayed vascular ingrowth as the tumor cells expressed immunocytochemical markers; subcutaneous tumors displayed significantly more vascular elements than did intrahepatic tumors.

  9. Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan

    PubMed Central

    Kohli, Aditya G.; Kivimäe, Saul; Tiffany, Matthew R.; Szoka, Francis C.

    2014-01-01

    Liposomes improve the pharmacokinetics and safety of rapidly cleared drugs, but have not yet improved the clinical efficacy compared to the non-encapsulated drug. This inability to improve efficacy may be partially due to the non-uniform distribution of liposomes in solid tumors. The tumor extra-cellular matrix is a barrier to distribution and includes the high molecular weight glycosaminoglycan, hyaluronan (HA). Strategies to remove HA or block its synthesis may improve drug delivery into solid tumors. Orally administered methylumbelliferone (MU) is an inhibitor of HA synthesis, but it is limited by low potency and limited solubility. In this study, we encapsulate a water-soluble phosphorylated prodrug of MU (MU-P) in a liposome (L-MU-P). We demonstrate that L-MU-P is a more potent inhibitor of HA synthesis than oral MU in the 4T1 murine mammary carcinoma model using both a quantitative ELISA and histochemistry. We show that HA depletion improves the tumor distribution of liposomes computed using Mander’s colocalization analysis of liposomes with the tumor vasculature. Hyaluronan depletion also increases the fraction of the tumor area positive for liposomes. This improved distribution extends the overall survival of mice treated with Doxil®. PMID:24852095

  10. Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan.

    PubMed

    Kohli, Aditya G; Kivimäe, Saul; Tiffany, Matthew R; Szoka, Francis C

    2014-10-10

    Liposomes improve the pharmacokinetics and safety of rapidly cleared drugs, but have not yet improved the clinical efficacy compared to the non-encapsulated drug. This inability to improve efficacy may be partially due to the non-uniform distribution of liposomes in solid tumors. The tumor extra-cellular matrix is a barrier to distribution and includes the high molecular weight glycosaminoglycan, hyaluronan (HA). Strategies to remove HA or block its synthesis may improve drug delivery into solid tumors. Orally administered methylumbelliferone (MU) is an inhibitor of HA synthesis, but it is limited by low potency and limited solubility. In this study, we encapsulate a water-soluble phosphorylated prodrug of MU (MU-P) in a liposome (L-MU-P). We demonstrate that L-MU-P is a more potent inhibitor of HA synthesis than oral MU in the 4T1 murine mammary carcinoma model using both a quantitative ELISA and histochemistry. We show that HA depletion improves the tumor distribution of liposomes computed using Mander's colocalization analysis of liposomes with the tumor vasculature. Hyaluronan depletion also increases the fraction of the tumor area positive for liposomes. This improved distribution extends the overall survival of mice treated with Doxil®.

  11. Tumor Irradiation Increases the Recruitment of Circulating Mesenchymal Stem Cells into the Tumor Microenvironment

    PubMed Central

    Klopp, Ann H.; Spaeth, Erika L.; Dembinski, Jennifer L.; Woodward, Wendy A.; Munshi, Anupama; Meyn, Raymond E.; Cox, James D.; Andreeff, Michael; Marini, Frank C.

    2011-01-01

    Mesenchymal stem cells (MSC) migrate to and proliferate within sites of inflammation and tumors as part of the tissue remodeling process. Radiation increases the expression of inflammatory mediators that could enhance the recruitment of MSC into the tumor microenvironment. To investigate this, bilateral murine 4T1 breast carcinomas (expressing renilla luciferase) were irradiated unilaterally (1 or 2 Gy). Twenty-four hours later, 2 × 105 MSC-expressing firefly luciferase were injected i.v. Mice were then monitored with bioluminescent imaging for expression of both renilla (tumor) and firefly (MSC) luciferase. Forty-eight hours postirradiation, levels of MSC engraftment were 34% higher in tumors receiving 2 Gy (P = 0.004) than in the contralateral unirradiated limb. Immunohistochemical staining of tumor sections from mice treated unilaterally with 2 Gy revealed higher levels of MSC in the parenchyma of radiated tumors, whereas a higher proportion of MSC remained vasculature-associated in unirradiated tumors. To discern the potential mediators involved in MSC attraction, in vitro migration assays showed a 50% to 80% increase in MSC migration towards conditioned media from 1 to 5 Gy-irradiated 4T1 cells compared with unirradiated 4T1 cells. Irradiated 4T1 cells had increased expression of the cytokines, transforming growth factor-β1, vascular endothelial growth factor, and platelet-derived growth factor-BB, and this up-regulation was confirmed by immunohistochemistry in tumors irradiated in vivo. Interestingly, the chemokine receptor CCR2 was found to be up-regulated in MSC exposed to irradiated tumor cells and inhibition of CCR2 led to a marked decrease of MSC migration in vitro. In conclusion, clinically relevant low doses of irradiation increase the tropism for and engraftment of MSC in the tumor microenvironment. PMID:18089798

  12. Patterns of Chromosomal Aberrations in Solid Tumors

    PubMed Central

    Grade, Marian; Difilippantonio, Michael J.

    2016-01-01

    Chromosomal abnormalities are a defining feature of solid tumors. Such cytogenetic alterations are mainly classified into structural chromosomal aberrations and copy number alterations, giving rise to aneuploid karyotypes. The increasing detection of these genetic changes allowed the description of specific tumor entities and the associated patterns of gene expression. In fact, tumor-specific landscapes of gross genomic copy number changes, including aneuploidies of entire chromosome arms and chromosomes result in a global deregulation of the transcriptome of cancer cells. Furthermore, the molecular characterization of cytogenetic abnormalities has provided insights into the mechanisms of tumorigenesis and has, in a few instances, led to the clinical implementation of effective diagnostic and prognostic tools, as well as treatment strategies that target a specific genetic abnormality. PMID:26376875

  13. Modeling the spatial distribution of chronic tumor hypoxia: implications for experimental and clinical studies.

    PubMed

    Powathil, Gibin; Kohandel, Mohammad; Milosevic, Michael; Sivaloganathan, Siv

    2012-01-01

    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

  14. iRGD tumor-penetrating peptide-modified oncolytic adenovirus shows enhanced tumor transduction, intratumoral dissemination and antitumor efficacy.

    PubMed

    Puig-Saus, C; Rojas, L A; Laborda, E; Figueras, A; Alba, R; Fillat, C; Alemany, R

    2014-08-01

    Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or tumor cells, exposure by proteolysis of a C-terminal motif that binds to neuropilin-1 (NRP-1) and cell internalization. We have genetically inserted the iRGD peptide in the fiber C terminus of ICOVIR15K, an oncolytic tumor-retargeted adenovirus to increase its tumor penetration. In vitro, NRP-1 interaction improved binding and internalization of the virus in different cancer cells overexpressing integrins and NRP-1. However, such NRP-1-mediated internalization did not affect transduction or cytotoxicity. In vivo, iRGD did not change the normal organ transduction pattern, with liver and spleen as main targeted organs. In tumors, however, iRGD enhanced transduction and early adenovirus dissemination through the tumor mass leading to an improved antitumor efficacy.

  15. Role of Notch/VEGF-Receptor 3 in Breast Tumor Angiogenesis and Lymphangiogenesis

    DTIC Science & Technology

    2006-05-01

    in a murine mammary tumor model. In aim 1, to study the role for notch in murine mammary tumorigenesis , progress has been made in developing two new...ACCOMPLISHMENTS • Developed a EF-1-flox-NotchIC mouse line that expresses an activated form of Notch1 with within the murine vasculature when...interaction between Notch and VEGFR-3 in breast cancer. To study the role for notch in murine mammary tumorigenesis , progress has been made in developing

  16. Elucidating the Tumor-Suppressive Role of SLITs in Maintaining the Basal Cell Niche

    DTIC Science & Technology

    2011-10-01

    of both the glandular epithelium and vasculature and promotes metastasis formation. Int J Oncol. 2009;35(3):525–36. 10. Marlow R, Strickland P, Lee JS...organize tissue structure, including cells in the breast stem cell niche, and to generate the barrier between epithelium and stroma by secreting the...Macias H., Cardiff R.D., Sukumar S., Hinck. 2008. SLITs suppress tumor growth and microenvironment by silencing Sdf1/Cxcr4 within breast epithelium

  17. A Platform to Monitor Tumor Cellular and Vascular Response to Radiation Therapy by Optical Coherence Tomography and Fluorescence Microscopy in vivo

    NASA Astrophysics Data System (ADS)

    Leung, Michael Ka Kit

    Radiotherapy plays a significant role in cancer treatment, and is thought to be curative by mainly killing tumor cells through damage to their genetic material. However, recent findings indicate that the tumor's vascular blood supply is also a major determinant of radiation response. The goals of this thesis are to: (1) develop an experimental platform for small animals to deliver ionizing radiation and perform high-resolution optical imaging to treatment targets, and (2) use this toolkit to longitudinally monitor the response of tumors and the associated vasculature. The thesis has achieved: (1) customization of a novel micro-irradiator for mice, (2) technical development of an improved optical coherence tomography imaging system, (3) comprehensive experimental protocol and imaging optimization for optical microscopy in a specialized animal model, and (4) completion of a feasibility study to demonstrate the capabilities of the experimental platform in monitoring the response of tumor and vasculature to radiotherapy.

  18. Hypothalamic tumor

    MedlinePlus

    ... occur at any age. They are often more aggressive in adults than in children. In adults, tumors ... The treatment depends on how aggressive the tumor is, and whether it is a glioma or another type of cancer. Treatment may involve combinations of surgery, radiation , ...

  19. Carcinoid Tumors

    MedlinePlus

    Carcinoid tumors are rare, slow-growing cancers. They usually start in the lining of the digestive tract or in the lungs. They grow ... trouble breathing. Surgery is the main treatment for carcinoid tumors. If they haven't spread to other parts of the body, surgery can cure the cancer.

  20. Pituitary Tumors

    MedlinePlus

    ... pituitary is the "master control gland" - it makes hormones that affect growth and the functions of other glands in the body. Pituitary tumors are common, but often they don't cause health ... tumor produces hormones and disrupts the balance of hormones in your ...

  1. Pindborg tumor

    PubMed Central

    Caliaperoumal, Santhosh Kumar; Gowri, S.; Dinakar, J.

    2016-01-01

    Calcifying epithelial odontogenic tumor (CEOT), also known as Pindborg tumor, is a rare odontogenic epithelial neoplasm. So far, nearly 200 cases have been reported in the literature. We are reporting a case of CEOT in a 42-year-old male patient with painless bony swelling in the mandible. The clinical, radiographic, and histopathologic features are discussed with relevant references. PMID:27041911

  2. Methyl tert butyl ether targets developing vasculature in zebrafish (Danio rerio) embryos

    PubMed Central

    Bonventre, Josephine A.; White, Lori A.; Cooper, Keith R.

    2015-01-01

    Disruption of vascular endothelial growth factor (VEGF) signaling during early development results in abnormal angiogenesis and increased vascular lesions. Embryonic exposure to 0.625 to 10 mM methyl tert butyl ether (MTBE), a highly water soluble gasoline additive, resulted in a dose dependent increase in pooled blood in the common cardinal vein (CCV), cranial hemorrhages and abnormal intersegmental vessels (ISVs). The EC50s for the lesions ranked in terms of likelihood to occur with MTBE exposure were: pooled blood in the CCV, 3.2 mM [95 % CI: 2.2 – 4.7] > cranial hemorrhage, 11 mM [5.9 – 20.5] > abnormal ISV, 14.5 mM [6.5 – 32.4]. Organ systems other than the vascular system appear to develop normally, which suggests MTBE toxicity targets developing blood vessels. Equal molar concentrations (0.625 to 10 mM) of the primary metabolites, tertiary butyl alcohol (TBA) and formaldehyde, did not result in vascular lesions, which suggested that the parent compound is responsible for the toxicity. Stage specific exposures were carried out to determine the developmental period most sensitive to MTBE vascular disruption. Embryos treated until 6-somites or treated after Prim-5 stages did not exhibit a significant increase in lesions, while embryos treated between 6-somites and Prim-5 had a significant increase in vascular lesions (p ≤ 0.05). During the critical window for MTBE-induced vascular toxicity, expression of vegfa, vegfc, and flk1/kdr were significantly decreased 50, 70 and 40%, respectively. This is the first study to characterize disruption in vascular development following embryonic exposure to MTBE. The unique specificity of MTBE to disrupt angiogenesis may be mediated by the down regulation of critical genes in the VEGF pathway. PMID:21684239

  3. Endocrine abnormalities in anorexia nervosa.

    PubMed

    Lawson, Elizabeth A; Klibanski, Anne

    2008-07-01

    Anorexia nervosa (AN) is a psychiatric disease associated with notable medical complications and increased mortality. Endocrine abnormalities, including hypogonadotropic hypogonadism, hypercortisolemia, growth hormone resistance and sick euthyroid syndrome, mediate the clinical manifestations of this disease. Alterations in anorexigenic and orexigenic appetite-regulating pathways have also been described. Decreases in fat mass result in adipokine abnormalities. Although most of the endocrine changes that occur in AN represent physiologic adaptation to starvation, some persist after recovery and might contribute to susceptibility to AN recurrence. In this Review, we summarize key endocrine alterations in AN, with a particular focus on the profound bone loss that can occur in this disease. Although AN is increasingly prevalent among boys and men, the disorder predominantly affects girls and women who are, therefore, the focus of this Review.

  4. Eye abnormalities in Fryns syndrome.

    PubMed

    Pierson, Diane M; Taboada, Eugenio; Butler, Merlin G

    2004-03-15

    Fryns syndrome is a rare, generally lethal, autosomal recessive multiple congenital anomaly (MCA) syndrome first described in 1979. Patients with the syndrome present with the classical findings of cloudy cornea, brain malformations, diaphragmatic defects, and distal limb deformities. Over 70 patients have been reported revealing a wide variety of phenotypic features. Although initially considered a major feature of Fryns syndrome, cloudy cornea has been relegated as a minor diagnostic sign and not commonly reported in patients since the original description. However, eye findings per se are not uncommon. Abnormal eye findings occasionally reported in Fryns syndrome potentially result in amblyopia and blindness, profoundly affecting neurologic outcome of those who survive the neonatal period. We reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of the reported cases. In addition, we contribute three new patients with Fryns syndrome, one of which demonstrated unilateral microphthalmia and cloudy cornea.

  5. Neuroendocrine abnormalities in Parkinson's disease.

    PubMed

    De Pablo-Fernández, Eduardo; Breen, David P; Bouloux, Pierre M; Barker, Roger A; Foltynie, Thomas; Warner, Thomas T

    2017-02-01

    Neuroendocrine abnormalities are common in Parkinson's disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinson's disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson's disease and suggest future areas for research.

  6. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels.

    PubMed

    Falcón, Beverly L; Hashizume, Hiroya; Koumoutsakos, Petros; Chou, Jeyling; Bready, James V; Coxon, Angela; Oliner, Jonathan D; McDonald, Donald M

    2009-11-01

    Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) have complex actions in angiogenesis and vascular remodeling due to their effects on Tie2 receptor signaling. Ang2 blocks Ang1-mediated activation of Tie2 in endothelial cells under certain conditions but is a Tie2 receptor agonist in others. We examined the effects of selective inhibitors of Ang1 (mL4-3) or Ang2 (L1-7[N]), alone or in combination, on the vasculature of human Colo205 tumors in mice. The Ang2 inhibitor decreased the overall abundance of tumor blood vessels by reducing tumor growth and keeping vascular density constant. After inhibition of Ang2, tumor vessels had many features of normal blood vessels (normalization), as evidenced by junctional accumulation of vascular endothelial-cadherin, junctional adhesion molecule-A, and platelet/endothelial cell adhesion molecule-1 in endothelial cells, increased pericyte coverage, reduced endothelial sprouting, and remodeling into smaller, more uniform vessels. The Ang1 inhibitor by itself had little noticeable effect on the tumor vasculature. However, when administered with the Ang2 inhibitor, the Ang1 inhibitor prevented tumor vessel normalization, but not the reduction in tumor vascularity produced by the Ang2 inhibitor. These findings are consistent with a model whereby inhibition of Ang2 leads to normalization of tumor blood vessels by permitting the unopposed action of Ang1, but decreases tumor vascularity primarily by blocking Ang2 actions.

  7. Contrasting Actions of Selective Inhibitors of Angiopoietin-1 and Angiopoietin-2 on the Normalization of Tumor Blood Vessels

    PubMed Central

    Falcón, Beverly L.; Hashizume, Hiroya; Koumoutsakos, Petros; Chou, Jeyling; Bready, James V.; Coxon, Angela; Oliner, Jonathan D.; McDonald, Donald M.

    2009-01-01

    Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) have complex actions in angiogenesis and vascular remodeling due to their effects on Tie2 receptor signaling. Ang2 blocks Ang1-mediated activation of Tie2 in endothelial cells under certain conditions but is a Tie2 receptor agonist in others. We examined the effects of selective inhibitors of Ang1 (mL4-3) or Ang2 (L1-7[N]), alone or in combination, on the vasculature of human Colo205 tumors in mice. The Ang2 inhibitor decreased the overall abundance of tumor blood vessels by reducing tumor growth and keeping vascular density constant. After inhibition of Ang2, tumor vessels had many features of normal blood vessels (normalization), as evidenced by junctional accumulation of vascular endothelial-cadherin, junctional adhesion molecule-A, and platelet/endothelial cell adhesion molecule-1 in endothelial cells, increased pericyte coverage, reduced endothelial sprouting, and remodeling into smaller, more uniform vessels. The Ang1 inhibitor by itself had little noticeable effect on the tumor vasculature. However, when administered with the Ang2 inhibitor, the Ang1 inhibitor prevented tumor vessel normalization, but not the reduction in tumor vascularity produced by the Ang2 inhibitor. These findings are consistent with a model whereby inhibition of Ang2 leads to normalization of tumor blood vessels by permitting the unopposed action of Ang1, but decreases tumor vascularity primarily by blocking Ang2 actions. PMID:19815705

  8. Tumor Targeting via Integrin Ligands

    PubMed Central

    Marelli, Udaya Kiran; Rechenmacher, Florian; Sobahi, Tariq Rashad Ali; Mas-Moruno, Carlos; Kessler, Horst

    2013-01-01

    Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side-effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability, and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor-specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug-delivery systems, and discuss the prospects of such therapies to specifically target tumor cells. PMID:24010121

  9. Congenital abnormalities of the goat.

    PubMed

    Basrur, P K

    1993-03-01

    Congenital abnormalities of genetic and environmental causes constitute a striking proportion of the afflictions seen in goats. These include a variety of malformations and metabolic diseases that could occur in all breeds but tend to exhibit predisposition in some breeds of goats. Genetic abnormalities for which the carrier state is detectable with the aid of enzymes and surface protein markers can be eliminated from goat populations, whereas common polygenic disorders including udder problems in does and gynecomastia in bucks are more difficult to eradicate because the mutant genes responsible for these traits generally do not declare themselves until inbreeding brings together a critical concentration of liability genes to create a crisis. A substantial reduction of common abnormalities in this species, such as intersexuality in dairy breeds, abortion in Angora breed, and arthritis in the Pygmy breed, will require a change in breeders' preference and selection practice. In making these changes, however, the beneficial traits will have to be balanced against the undesirable effects of the selected mutant genes (pleiotropy), which hold the key to success or failure of a breed under domestication.

  10. Meiotic abnormalities in infertile males.

    PubMed

    Egozcue, J; Sarrate, Z; Codina-Pascual, M; Egozcue, S; Oliver-Bonet, M; Blanco, J; Navarro, J; Benet, J; Vidal, F

    2005-01-01

    Meiotic anomalies, as reviewed here, are synaptic chromosome abnormalities, limited to germ cells that cannot be detected through the study of the karyotype. Although the importance of synaptic errors has been underestimated for many years, their presence is related to many cases of human male infertility. Synaptic anomalies can be studied by immunostaining of synaptonemal complexes (SCs), but in this case their frequency is probably underestimated due to the phenomenon of synaptic adjustment. They can also be studied in classic meiotic preparations, which, from a clinical point of view, is still the best approach, especially if multiplex fluorescence in situ hybridization is at hand to solve difficult cases. Sperm chromosome FISH studies also provide indirect evidence of their presence. Synaptic anomalies can affect the rate of recombination of all bivalents, produce achiasmate small univalents, partially achiasmate medium-sized or large bivalents, or affect all bivalents in the cell. The frequency is variable, interindividually and intraindividually. The baseline incidence of synaptic anomalies is 6-8%, which may be increased to 17.6% in males with a severe oligozoospermia, and to 27% in normozoospermic males with one or more previous IVF failures. The clinical consequences are the production of abnormal spermatozoa that will produce a higher number of chromosomally abnormal embryos. The indications for a meiotic study in testicular biopsy are provided.

  11. Targeting the PDGF signaling pathway in tumor treatment.

    PubMed

    Heldin, Carl-Henrik

    2013-12-20

    Platelet-derived growth factor (PDGF) isoforms and PDGF receptors have important functions in the regulation of growth and survival of certain cell types during embryonal development and e.g. tissue repair in the adult. Overactivity of PDGF receptor signaling, by overexpression or mutational events, may drive tumor cell growth. In addition, pericytes of the vasculature and fibroblasts and myofibroblasts of the stroma of solid tumors express PDGF receptors, and PDGF stimulation of such cells promotes tumorigenesis. Inhibition of PDGF receptor signaling has proven to useful for the treatment of patients with certain rare tumors. Whether treatment with PDGF/PDGF receptor antagonists will be beneficial for more common malignancies is the subject for ongoing studies.

  12. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy

    PubMed Central

    Schadler, Keri L.; Thomas, Nicholas J.; Galie, Peter A.; Bhang, Dong Ha; Roby, Kerry C.; Addai, Prince; Till, Jacob E.; Sturgeon, Kathleen; Zaslavsky, Alexander; Chen, Christopher S.; Ryeom, Sandra

    2016-01-01

    Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical stimuli exerted on endothelial cells by blood flow, modulates vascular integrity. Increasing vascular shear stress through aerobic exercise can alter and remodel blood vessels in normal tissues. Our data in mouse models indicate that activation of calcineurin-NFAT-TSP1 signaling in endothelial cells plays a critical role in exercise-induced shear stress mediated tumor vessel remodeling. We show that moderate aerobic exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone through improved chemotherapy delivery after tumor vascular normalization. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant. PMID:27589843

  13. Pericyte–fibroblast transition promotes tumor growth and metastasis

    PubMed Central

    Hosaka, Kayoko; Yang, Yunlong; Seki, Takahiro; Fischer, Carina; Dubey, Olivier; Fredlund, Erik; Hartman, Johan; Religa, Piotr; Ishii, Yoko; Sasahara, Masakiyo; Larsson, Ola; Cossu, Giulio; Cao, Renhai; Lim, Sharon; Cao, Yihai

    2016-01-01

    Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte–fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that PDGF-BB-PDGFRβ signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB–activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRβ ablate the PDGF-BB–induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2:R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB–promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis. PMID:27608497

  14. Myxoid stroma and delicate vasculature of a superficial angiomyxoma give rise to the red planet sign.

    PubMed

    Green, Margaret; Logemann, Nichola; Sulit, Daryl J

    2014-09-16

    Superficial angiomyxomas are uncommon benign mesenchymal tumors. They often recur locally if partially removed. This case report demonstrates not only the characteristic pathological findings of a superficial angiomyxoma in a 33- year-old man, but also shows a unique dermatoscopic image, which in our estimation resembles a celestial red planet such as the blood moon seen during a lunar eclipse. We propose to call this the "red planet" sign for a superficial angiomyxoma on dermoscopic examination.

  15. Targeting Breast Cancer with T Cells Redirected to the Vasculature. Addendum

    DTIC Science & Technology

    2012-10-01

    validated a panel of multivalent antibodies for binding to recombinant proteins by ELISA assays.. We have generated CIRs against PSMA using scFv (PZ1) and T...tracer for PET imaging. 15. SUBJECT TERMS Chimeric Immune Receptor(CIR), tumor vascular targeting, PET, TEM1, PSMA , scFv 16. SECURITY...recognizing prostate specific membrane antigen ( PSMA ), which will carry CD28 and/or 4-1BB (costimulatory). 3) Test T-bodies against breast cancer

  16. Visual pathway abnormalities in tuberculous meningitis.

    PubMed

    Maurya, Pradeep Kumar; Singh, Ajai Kumar; Sharma, Lalit; Kulshreshtha, Dinkar; Thacker, Anup Kumar

    2016-11-01

    Ophthalmological complications are common and disabling in patients with tuberculous meningitis. We aimed to study the visual pathway abnormalities in patients with tuberculous meningitis. Forty-three patients with tuberculous meningitis were subjected to visual evoked responses (VER) and neuroophthalmologic assessment. Neuroophthalmologic assessment revealed abnormalities in 22 (51.3%) patients. VER were found to be abnormal in 27 (62.8%) patients. The VER abnormalities included prolonged P100 latencies with relatively normal amplitude and significant interocular latency differences. Visual pathways abnormalities are common in patients with tuberculous meningitis and are often subclinical. Pathophysiologic explanations for electrophysiological abnormalities on VER in these patients are incompletely understood and needs further exploration.

  17. Drug-induced abnormalities of potassium metabolism.

    PubMed

    Kokot, Franciszek; Hyla-Klekot, Lidia

    2008-01-01

    Pharmacotherapy has progressed rapidly over the last 20 years with the result that general practioners more and more often use drugs which may influence potassium metabolism at the kidney or gastrointestinal level, or the transmembrane transport of potassium at the cellular level. Potassium abnormalities may result in life-theatening clinical conditions. Hypokalemia is most frequently caused by renal loss of this electrolyte (thiazide, thiazide-like and loop diuretics, glucocorticoids) and the gastrointestinal tract (laxatives, diarrhea, vomiting, external fistula), and may be the result of an increased intracellular potassium influx induced by sympathicomimetics used mostly by patients with asthma, or by insulin overdosage in diabetic subjects. The leading symptoms of hypokalemia are skeletal and smooth muscle weakness and cardiac arrhythmias. Hyperkalemia may be caused by acute or end-stage renal failure, impaired tubular excretion of potassium (blockers of the renin-angiotensin-aldosterone system, nonsteroidal anti-inflammatory drugs, cyclosporine, antifungal drugs, potassium sparing diuretics), acidemia, and severe cellular injury (tumor lysis syndrome). Hyperkalemia may be the cause of severe injury of both skeletal and smooth muscle cells. The specific treatment counteracting hyperkalemia is a bolus injection of calcium salts and, when necessary, hemodialysis.

  18. Logarithmic intensity and speckle-based motion contrast methods for human retinal vasculature visualization using swept source optical coherence tomography

    PubMed Central

    Motaghiannezam, Reza; Fraser, Scott

    2012-01-01

    We formulate a theory to show that the statistics of OCT signal amplitude and intensity are highly dependent on the sample reflectivity strength, motion, and noise power. Our theoretical and experimental results depict the lack of speckle amplitude and intensity contrasts to differentiate regions of motion from static areas. Two logarithmic intensity-based contrasts, logarithmic intensity variance (LOGIV) and differential logarithmic intensity variance (DLOGIV), are proposed for serving as surrogate markers for motion with enhanced sensitivity. Our findings demonstrate a good agreement between the theoretical and experimental results for logarithmic intensity-based contrasts. Logarithmic intensity-based motion and speckle-based contrast methods are validated and compared for in vivo human retinal vasculature visualization using high-speed swept-source optical coherence tomography (SS-OCT) at 1060 nm. The vasculature was identified as regions of motion by creating LOGIV and DLOGIV tomograms: multiple B-scans were collected of individual slices through the retina and the variance of logarithmic intensities and differences of logarithmic intensities were calculated. Both methods captured the small vessels and the meshwork of capillaries associated with the inner retina in en face images over 4 mm2 in a normal subject. PMID:22435098

  19. The ultrasound brain helmet: early human feasibility study of multiple simultaneous 3D scans of cerebral vasculature

    NASA Astrophysics Data System (ADS)

    Lindsey, Brooks D.; Ivancevich, Nikolas M.; Whitman, John; Light, Edward; Fronheiser, Matthew; Nicoletto, Heather A.; Laskowitz, Daniel T.; Smith, Stephen W.

    2009-02-01

    We describe early stage experiments to test the feasibility of an ultrasound brain helmet to produce multiple simultaneous real-time 3D scans of the cerebral vasculature from temporal and suboccipital acoustic windows of the skull. The transducer hardware and software of the Volumetrics Medical Imaging real-time 3D scanner were modified to support dual 2.5 MHz matrix arrays of 256 transmit elements and 128 receive elements which produce two simultaneous 64° pyramidal scans. The real-time display format consists of two coronal B-mode images merged into a 128° sector, two simultaneous parasagittal images merged into a 128° × 64° C-mode plane, and a simultaneous 64° axial image. Real-time 3D color Doppler images acquired in initial clinical studies after contrast injection demonstrate flow in several representative blood vessels. An offline Doppler rendering of data from two transducers simultaneously scanning via the temporal windows provides an early visualization of the flow in vessels on both sides of the brain. The long-term goal is to produce real-time 3D ultrasound images of the cerebral vasculature from a portable unit capable of internet transmission, thus enabling interactive 3D imaging, remote diagnosis and earlier therapeutic intervention. We are motivated by the urgency for rapid diagnosis of stroke due to the short time window of effective therapeutic intervention.

  20. Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium

    PubMed Central

    Kerr, Bethany A.; West, Xiaoxia Z.; Kim, Young-Woong; Zhao, Yongzhong; Tischenko, Miroslava; Cull, Rebecca M.; Phares, Timothy W.; Peng, Xiao-Ding; Bernier-Latmani, Jeremiah; Petrova, Tatiana V.; Adams, Ralf H.; Hay, Nissim; Naga Prasad, Sathyamangla V.; Byzova, Tatiana V.

    2016-01-01

    The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis. In hearts, this causes a loss of arteries and arterioles and, despite a high capillary density, diminished vascular patency and severe cardiac dysfunction. Similarly, endothelial Akt deletion induces retinal VSMC loss and basement membrane deterioration resulting in vascular regression and retinal atrophy. Mechanistically, the Akt/mTOR axis controls endothelial Jagged1 expression and, thereby, Notch signalling regulating VSMC maintenance. Jagged1 peptide treatment of Akt1ΔEC;Akt2KO mice and Jagged1 re-expression in Akt-deficient endothelium restores VSMC coverage. Thus, sustained endothelial Akt1/2 signalling is critical in maintaining vascular stability and homeostasis, thereby preserving tissue and organ function. PMID:26971877

  1. Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1β in Retinal Endothelial Cells and Mouse Retinal Vasculature

    PubMed Central

    Jiang, Youde; Liu, Li; Curtiss, Elizabeth

    2017-01-01

    Inflammation is an important component of diabetic retinal damage. We previously reported that a novel β-adrenergic receptor agonist, Compound 49b, reduced Toll-like receptor 4 (TLR4) signaling in retinal endothelial cells (REC) grown in high glucose. Others reported that TLR4 activates high-mobility group box 1 (HMGB1), which has been associated with the NOD-like receptor 3 (NLRP3) inflammasome. Thus, we hypothesized that Epac1, a downstream mediator of β-adrenergic receptors, would block TLR4/HMGB1-mediated stimulation of the NLRP3 inflammasome, leading to reduced cleavage of caspase-1 and interleukin-1 beta (IL-1β). We generated vascular specific conditional knockout mice for Epac1 and used REC grown in normal and high glucose treated with an Epac1 agonist and/or NLRP3 siRNA. Protein analyses were done for Epac1, TLR4, HMGB1, NLRP3, cleaved caspase-1, and IL-1β. Loss of Epac1 in the mouse retinal vasculature significantly increased all of the inflammatory proteins. Epac1 effectively reduced high glucose-induced increases in TLR4, HMGB1, cleaved caspase-1, and IL-1β in REC. Taken together, the data suggest that Epac1 reduces formation of the NLRP3 inflammasome to reduce inflammatory responses in the retinal vasculature. PMID:28348460

  2. An immunocytochemical study of the germinal layer vasculature in the developing fetal brain using Ulex europaeus 1 lectin.

    PubMed

    Gould, S J; Howard, S

    1988-10-01

    The characteristics of the germinal matrix vasculature were studied in the developing fetal brain using immunocytochemical methods. A preliminary comparative immunocytochemical study was made on six fetal brains to compare endothelial staining by Ulex europaeus I lectin with that of antibody to Factor VIII related antigen. Ulex was found to stain germinal layer vessels better than Factor VIII related antigen. Subsequently, the germinal layers of a further 15 fetal and preterm infant brains ranging from 13 to 35 weeks' gestation were stained with Ulex europaeus I to demonstrate the vasculature. With increasing gestation, there was a gradual increase in vessel density, particularly of capillaries. This was not a uniform process. A plexus of capillaries was prominent immediately beneath the ependyma while the more central parts of the germinal matrix contained fewer, but often larger diameter, vessels. The variation in vessel density which was a feature of the later gestation brains may have implications for local blood flow and may be a factor in haemorrhage at this site.

  3. Tbx18 is essential for normal development of vasculature network and glomerular mesangium in the mammalian kidney.

    PubMed

    Xu, Jinshu; Nie, Xuguang; Cai, Xiaoqiang; Cai, Chen-Leng; Xu, Pin-Xian

    2014-07-01

    Tbx18 has been shown to be essential for ureteral development. However, it remains unclear whether it plays a direct role in kidney development. Here we addressed this by focusing on examining the pattern and contribution of Tbx18+ cells in the kidney and its role in kidney vascular development. Expression studies and genetic lineage tracing revealed that Tbx18 is expressed in renal capsule, vascular smooth muscle cells and pericytes and glomerular mesangial cells in the kidney and that Tbx18-expressing progenitors contribute to these cell types. Examination of Tbx18(-/-) kidneys revealed large reduction in vasculature density and dilation of glomerular capillary loops. While SMA+ cells were reduced in the mutant, PDGFRβ+ cells were seen in early capillary loop renal corpuscles in the mutant, but fewer than in the controls, and further development of the mesangium failed. Analysis of kidney explants cultured from E12.5 excluded the possibility that the defects observed in the mutant were caused by ureter obstruction. Reduced proliferation in glomerular tuft and increased apoptosis in perivascular mesenchyme were observed in Tbx18(-/-) kidneys. Thus, our analyses have identified a novel role of Tbx18 in kidney vasculature development.

  4. Photodynamic treatment of the RIF-1 tumor with verteporfin with online monitoring of tissue oxygen using electron paramagnetic resonance oximetry

    NASA Astrophysics Data System (ADS)

    Pogue, Brian W.; O'Hara, Julia A.; Liu, Ke J.; Hasan, Tayyaba; Swartz, Harold

    1999-06-01

    In this study, treatment of the RIF-1 tumor was examined with photodynamic therapy using Verteprofin (formerly benzoporphyrin derivative, BPD). The effects of two different optical dose rates were examined, with no detectable difference in the tumor regrowth time. Oxygen consumption during PDT could reliably be monitored with electron paramagnetic resonance (EPR) oximetry using an implanted paramagnetic material within the tumor. A reduction of the tumor pO2 was detected in the animals that were followed after treatment, suggesting that there was a compromise to the tumor vasculature that persisted throughout the measurements. At high total doses some of the tumors did not regrow. Altogether these results are indicative of the tumor destruction being caused by destruction of the blood vessels from the treatment.

  5. The Role of RhoJ in Endothelial Cell Biology and Tumor Pathology

    PubMed Central

    Shi, Ting-Ting; Li, Gang

    2016-01-01

    Background. RhoJ, an endothelially expressed member of Cdc42 (cell division cycle 42) subfamily of Rho GTPase, plays an important role in endocytic pathway, adipocyte differentiation, endothelial motility, tube formation, and focal adhesion. RhoJ is a selective and effective therapeutic target in tumor tissues or retinopathy. Methods. A systematic review was related to “small Rho GTPase” or “RhoJ” with “endothelial motility, tube formation and focal adhesion” and “tumor therapy”. This led to many cross-references involving RhoJ and these data have been incorporated into the following study. Results. We have grouped the role of RhoJ according to three main effects: RhoJ regulates endocytic pathway and adipocyte differentiation in early studies, and RhoJ shows an important role in endothelial cell biology; furthermore, RhoJ blockade serves as a target in tumor vasculature and enhances the effects of anticancer drug. Conclusions. More research is necessary to understand the role of RhoJ in many aspects, on the basis of current knowledge of the role of RhoJ blockade in tumor vessels, there are opportunities for the therapy of tumor, and RhoJ is expressed outside tumour vasculature and is involved in wound healing. Taking advantage of the opportunities could result in a development in tumor therapy. PMID:27556037

  6. Low-set ears and pinna abnormalities

    MedlinePlus

    Low-set ears; Microtia; "Lop" ear; Pinna abnormalities; Genetic defect-pinna; Congenital defect-pinna ... most cases, a health care provider finds pinna abnormalities during the first well-baby exam. This exam ...

  7. Tumor Markers

    MedlinePlus

    ... types: Germ cell tumors, lymphoma, leukemia, melanoma, and neuroblastoma Tissue analyzed: Blood How used: To assess stage, ... NSE) Cancer types: Small cell lung cancer and neuroblastoma Tissue analyzed: Blood How used: To help in ...

  8. Wilms' Tumor

    MedlinePlus

    ... team and have training in child development, recreation, psychology or social work. If your child must remain ... conditions/wilms-tumor/basics/definition/CON-20043492 . Mayo Clinic Footer Legal Conditions and Terms Any use of ...

  9. Tumor Grade

    MedlinePlus

    ... Other Funding Find NCI funding for small business innovation, technology transfer, and contracts Training Cancer Training at ... much of the tumor tissue has normal breast (milk) duct structures Nuclear grade : an evaluation of the ...

  10. Spinal tumor

    MedlinePlus

    ... Livingstone; 2014:chap 49. Read More Brain tumor - children Hodgkin lymphoma Metastasis Spinal cord trauma Review Date 8/15/2016 Updated by: Todd Gersten, MD, Hematology/Oncology, Florida Cancer Specialists & Research Institute, Wellington, FL. Review ...

  11. Wilms tumor

    MedlinePlus

    ... a type of kidney cancer that occurs in children. Causes WT is the most common form of childhood kidney cancer. The exact cause of this tumor in most children is unknown. A missing iris of the eye ( ...

  12. Pituitary tumor

    MedlinePlus

    ... enough of its hormones. This condition is called hypopituitarism . The causes of pituitary tumors are unknown. Some ... Cyst Endocrine glands Gigantism Growth hormone test Hyperthyroidism Hypopituitarism Multiple endocrine neoplasia (MEN) I Prolactin blood test ...

  13. Abnormalities of the erythrocyte membrane.

    PubMed

    Gallagher, Patrick G

    2013-12-01

    Primary abnormalities of the erythrocyte membrane are characterized by clinical, laboratory, and genetic heterogeneity. Among this group, hereditary spherocytosis patients are more likely to experience symptomatic anemia. Treatment of hereditary spherocytosis with splenectomy is curative in most patients. Growing recognition of the long-term risks of splenectomy has led to re-evaluation of the role of splenectomy. Management guidelines acknowledge these considerations and recommend discussion between health care providers, patient, and family. The hereditary elliptocytosis syndromes are the most common primary disorders of erythrocyte membrane proteins. However, most elliptocytosis patients are asymptomatic and do not require therapy.

  14. Foot abnormalities of wild birds

    USGS Publications Warehouse

    Herman, C.M.; Locke, L.N.; Clark, G.M.

    1962-01-01

    The various foot abnormalities that occur in birds, including pox, scaly-leg, bumble-foot, ergotism and freezing are reviewed. In addition, our findings at the Patuxent Wildlife Research Center include pox from dove, mockingbird, cowbird, grackle and several species of sparrows. Scaly-leg has been particularly prevalent on icterids. Bumble foot has been observed in a whistling swan and in a group of captive woodcock. Ergotism is reported from a series of captive Canada geese from North Dakota. Several drug treatments recommended by others are presented.

  15. Electrotransfer of plasmid DNA radiosensitizes B16F10 tumors through activation of immune response

    PubMed Central

    Savarin, Monika; Kamensek, Urska; Cemazar, Maja; Heller, Richard

    2017-01-01

    Abstract Background Tumor irradiation combined with adjuvant treatments, either vascular targeted or immunomodulatory, is under intense investigation. Gene electrotransfer of therapeutic genes is one of these approaches. The aim of this study was to determine, whether gene electrotransfer of plasmid encoding shRNA for silencing endoglin, with vascular targeted effectiveness, can radiosensitize melanoma B16F10 tumors. Materials and methods The murine melanoma B16F10 tumors, growing on the back of C57Bl/6 mice, were treated by triple gene electrotransfer and irradiation. The antitumor effect was evaluated by determination of tumor growth delay and proportion of tumor free mice. Furthermore, histological analysis of tumors (necrosis, apoptosis, proliferation, vascularization, presence of hypoxia and infiltration of immune cells,) was used to evaluate the therapeutic mechanisms. Results Gene electrotransfer of plasmid silencing endoglin predominantly indicated vascular targeted effects of the therapy, since significant tumor growth delay and 44% of tumor free mice were obtained. In addition, irradiation had minor effects on radioresistant melanoma, with 11% of mice tumor free. The combined treatment resulted in excellent effectiveness with 88% of mice tumor free, with more than half resistant to secondary tumor challenge, which was observed also with the plasmid devoid of the therapeutic gene. Histological analysis of tumors in the combined treatment group, demonstrated similar mode of action of the gene electrotransfer of plasmid encoding shRNA for silencing endoglin and devoid of it, both through the induction of an immune response. Conclusions The results of this study indicate that irradiation can in radioresistant melanoma tumors, by release of tumor associated antigens, serve as activator of the immune response, besides directly affecting tumor cells and vasculature. The primed antitumor immune response can be further boosted by gene electrotransfer of plasmid

  16. Volume-based features for detection of bladder wall abnormal regions via MR cystography.

    PubMed

    Duan, Chaijie; Yuan, Kehong; Liu, Fanghua; Xiao, Ping; Lv, Guoqing; Liang, Zhengrong

    2011-09-01

    This paper proposes a framework for detecting the suspected abnormal region of the bladder wall via magnetic resonance (MR) cystography. Volume-based features are used. First, the bladder wall is divided into several layers, based on which a path from each voxel on the inner border to the outer border is found. By using the path length to measure the wall thickness and a bent rate (BR) term to measure the geometry property of the voxels on the inner border, the seed voxels representing the abnormalities on the inner border are determined. Then, by tracing the path from each seed, a weighted BR term is constructed to determine the suspected voxels, which are on the path and inside the bladder wall. All the suspected voxels are grouped together for the abnormal region. This work is significantly different from most of the previous computer-aided bladder tumor detection reports on two aspects. First of all, the T (1)-weighted MR images are used which give better image contrast and texture information for the bladder wall, comparing with the computed tomography images. Second, while most previous reports detected the abnormalities and indicated them on the reconstructed 3-D bladder model by surface rendering, we further determine the possible region of the abnormality inside the bladder wall. This study aims at a noninvasive procedure for bladder tumor detection and abnormal region delineation, which has the potential for further clinical analysis such as the invasion depth of the tumor and virtual cystoscopy diagnosis. Five datasets including two patients and three volunteers were used to test the presented method, all the tumors were detected by the method, and the overlap rates of the regions delineated by the computer against the experts were measured. The results demonstrated the potential of the method for detecting bladder wall abnormal regions via MR cystography.

  17. Combinatorial effects of doxorubicin and retargeted tissue factor by intratumoral entrapment of doxorubicin and proapoptotic increase of tumor vascular infarction

    PubMed Central

    Brand, Caroline; Höltke, Carsten; Schliemann, Christoph; Kessler, Torsten; Schmidt, Lars Henning; Harrach, Saliha; Mantke, Verena; Hintelmann, Heike; Hartmann, Wolfgang; Wardelmann, Eva; Lenz, Georg; Wünsch, Bernhard; Müller-Tidow, Carsten; Mesters, Rolf M.; Schwöppe, Christian; Berdel, Wolfgang E.

    2016-01-01

    Truncated tissue factor (tTF), retargeted to tumor vasculature by GNGRAHA peptide (tTF-NGR), and doxorubicin have therapeutic activity against a variety of tumors. We report on combination experiments of both drugs using different schedules. We have tested fluorescence- and HPLC-based intratumoral pharmacokinetics of doxorubicin, flow cytometry for cellular phosphatidylserine (PS) expression, and tumor xenograft studies for showing in vivo apoptosis, proliferation decrease, and tumor shrinkage upon combination therapy with doxorubicin and induced tumor vascular infarction. tTF-NGR given before doxorubicin inhibits the uptake of the drug into human fibrosarcoma xenografts in vivo. Reverse sequence does not influence the uptake of doxorubicin into tumor, but significantly inhibits the late wash-out phase, thus entrapping doxorubicin in tumor tissue by vascular occlusion. Incubation of endothelial and tumor cells with doxorubicin in vitro increases PS concentrations in the outer layer of the cell membrane as a sign of early apoptosis. Cells expressing increased PS concentrations show comparatively higher procoagulatory efficacy on the basis of equimolar tTF-NGR present in the Factor X assay. Experiments using human M21 melanoma and HT1080 fibrosarcoma xenografts in athymic nude mice indeed show a combinatorial tumor growth inhibition applying doxorubicin and tTF-NGR in sequence over single drug treatment. Combination of cytotoxic drugs such as doxorubicin with tTF-NGR-induced tumor vessel infarction can improve pharmacodynamics of the drugs by new mechanisms, entrapping a cytotoxic molecule inside tumor tissue and reciprocally improving procoagulatory activity of tTF-NGR in the tumor vasculature via apoptosis induction in tumor endothelial and tumor cells. PMID:27738341

  18. Tumor formations in scleractinian corals

    NASA Astrophysics Data System (ADS)

    Loya, Y.; Bull, G.; Pichon, M.

    1984-03-01

    A highly localized incidence of skeletal malformations (tumors) in the scleractinian corals Platygyra pini and P. sinensis on an inshore fringing reef at Cockle Bay, Magnetic Island within the Great Barrier Reef province is reported. These tumors are typified by a localized area of increased growth rate resulting in roughly circular protuberances extending up to 4.5 cm above the colony's surface. In both species, similar proportions of their populations carried tumors (24.1 % in P. pini and 18.7 % in P. sinensis). Larger colonies (>80 cm in diameter) are at least 7 times more likely to possess tumors than smaller colonies (<40 cm in diameter). X-radiographs of the skeletal malformations indicate a point of origin, presumably from a single budded polyp with subsequent, localized, accelerated growth. The mean radial growth rate of the tumorous area was 29 % greater than that of the surrounding normal regions. In contrast to the normal tissue, the tumorous tissue exhibited proliferation of cells, atrophied gastrodermal cells and mesenterial filaments which were larger and disordered in structure. The environmental conditions at Cockle Bay are relatively extreme with high turbidity, periodic exposure of the reef flat, abrupt changes in salinity during the wet season and mechanical damage to corals caused by unpredictable cyclonic storms. It is suggested that a combination of environmental stresses coupled with an injury inflicted on the corals are possible stimuli that initiate the development of these abnormal growth through either bacterial attack or the development of an aberrant polyp during tissue repair.

  19. Lower extremity abnormalities in children.

    PubMed

    Sass, Pamela; Hassan, Ghinwa

    2003-08-01

    Rotational and angular problems are two types of lower extremity abnormalities common in children. Rotational problems include intoeing and out-toeing. Intoeing is caused by one of three types of deformity: metatarsus adductus, internal tibial torsion, and increased femoral anteversion. Out-toeing is less common than intoeing, and its causes are similar but opposite to those of intoeing. These include femoral retroversion and external tibial torsion. Angular problems include bowlegs and knock-knees. An accurate diagnosis can be made with careful history and physical examination, which includes torsional profile (a four-component composite of measurements of the lower extremities). Charts of normal values and values with two standard deviations for each component of the torsional profile are available. In most cases, the abnormality improves with time. A careful physical examination, explanation of the natural history, and serial measurements are usually reassuring to the parents. Treatment is usually conservative. Special shoes, cast, or braces are rarely beneficial and have no proven efficacy. Surgery is reserved for older children with deformity from three to four standard deviations from the normal.

  20. Normal and abnormal lid function.

    PubMed

    Rucker, Janet C

    2011-01-01

    This chapter on lid function is comprised of two primary sections, the first on normal eyelid anatomy, neurological innervation, and physiology, and the second on abnormal eyelid function in disease states. The eyelids serve several important ocular functions, the primary objectives of which are protection of the anterior globe from injury and maintenance of the ocular tear film. Typical eyelid behaviors to perform these functions include blinking (voluntary, spontaneous, or reflexive), voluntary eye closure (gentle or forced), partial lid lowering during squinting, normal lid retraction during emotional states such as surprise or fear (startle reflex), and coordination of lid movements with vertical eye movements for maximal eye protection. Detailed description of the neurological innervation patterns and neurophysiology of each of these lid behaviors is provided. Abnormal lid function is divided by conditions resulting in excessive lid closure (cerebral ptosis, apraxia of lid opening, blepharospasm, oculomotor palsy, Horner's syndrome, myasthenia gravis, and mechanical) and those resulting in excessive lid opening (midbrain lid retraction, facial nerve palsy, and lid retraction due to orbital disease).

  1. Metabolic origins of spatial organization in the tumor microenvironment

    PubMed Central

    Carmona-Fontaine, Carlos; Akkari, Leila; Thompson, Craig B.; Joyce, Johanna A.; Xavier, Joao B.

    2017-01-01

    The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity. PMID:28246332

  2. Slowed diffusion in tumors revealed by microfiberoptic epifluorescence photobleaching.

    PubMed

    Thiagarajah, Jay R; Kim, Jung Kyung; Magzoub, Mazin; Verkman, A S

    2006-04-01

    It has not been possible to measure diffusion deep in solid tissues such as tumors because of the limited light penetration of conventional optical techniques. Here we report a microfiberoptic epifluorescence photobleaching (MFEP) method in which photobleaching is done by laser epi-illumination through a multimode fiberoptic whose micron-sized tip can be introduced deep into tissues. We applied MFEP to measure the diffusion of fluorescent macromolecules in tumors in living mice, at depths well beyond those accessible by surface optical measurements. Macromolecule diffusion was slowed about twofold within 200 microm of the surface of a solid tumor, but was slowed greater than tenfold beyond 500 microm. Our results reveal a remarkable and previously unrecognized slowing of diffusion deep in tumors, which correlated with the differing tissue architectures of tumor periphery versus core, and with altered tumor vasculature produced by aquaporin-1 deletion. MFEP should have wide applications for measuring diffusion in organs, solid tumors and other light-inaccessible tissue masses.

  3. ATP-binding cassette transporters in tumor endothelial cells and resistance to metronomic chemotherapy.

    PubMed

    Hida, Kyoko; Kikuchi, Hiroshi; Maishi, Nako; Hida, Yasuhiro

    2017-02-16

    Drug resistance is a major problem in anticancer therapy. ATP-binding cassette (ABC) transporters have a role in the multidrug resistance. A new regimen of chemotherapy has been proposed, called "metronomic chemotherapy". Metronomic chemotherapy is the frequent, regular administration of drug doses designed to maintain low, but active, concentrations of chemotherapeutic drugs over prolonged periods of time, without causing serious toxicities. Metronomic chemotherapy regimens were developed to optimize the antitumor efficacy of agents that target the tumor vasculature instead of tumor cells, and to reduce toxicity of antineoplastic drugs [1]. Nevertheless, recent studies revealed that ABC transporters are expressed at a higher level in the endothelium in the tumor. To avoid resistance to metronomic anti-angiogenic chemotherapy, ABC transporter inhibition of tumor endothelial cells may be a promising strategy. In this mini-review, we discuss the possible mechanism of resistance to metronomic chemotherapy from the viewpoint of tumor endothelial cell biology, focusing on ABC transporters.

  4. Quantum dots and multifunctional nanoparticles: new contrast agents for tumor imaging.

    PubMed

    Rhyner, Matthew N; Smith, Andrew M; Gao, Xiaohu; Mao, Hui; Yang, Lily; Nie, Shuming

    2006-08-01

    Nanometer-sized particles, such as semiconductor quantum dots and iron oxide nanocrystals, have novel optical, electronic, magnetic or structural properties that are not available from either molecules or bulk solids. When linked with tumor-targeting ligands, such as monoclonal antibodies, peptide fragments of tumor-specific proteins or small molecules, these nanoparticles can be used to target tumor antigens (biomarkers) and tumor vasculatures with high affinity and specificity. In the mesoscopic size range of 5-100 nm diameter, quantum dots and related nanoparticles have large surface areas and functional groups that can be linked to multiple diagnostic (e.g., optical, radioisotopic or magnetic) and therapeutic (e.g., anticancer) agents. In this review, recent advances in the development and applications of bioconjugated quantum dots and multifunctional nanoparticles for in vivo tumor imaging and targeting are discussed.

  5. Microfabrication of polydimethylsiloxane phantoms to simulate tumor hypoxia and vascular anomaly.

    PubMed

    Wu, Qiang; Ren, Wenqi; Yu, Zelin; Dong, Erbao; Zhang, Shiwu; Xu, Ronald X

    2015-01-01

    We introduce a microfluidic approach to simulate tumor hypoxia and vascular anomaly. Polydimethylsiloxane (PDMS) phantoms with embedded microchannel networks were fabricated by a soft lithography process. A dialysis membrane was sandwiched between two PDMS slabs to simulate the controlled mass transport and oxygen metabolism. A tortuous microchannel network was fabricated to simulate tumor microvasculature. A dual-modal multispectral and laser speckle imaging system was used for oxygen and blood flow imaging in the tumor-simulating phantom. The imaging results were compared with those of the normal vasculature. Our experiments demonstrated the technical feasibility of simulating tumor hypoxia and vascular anomalies using the proposed PDMS phantom. Such a phantom fabrication technique may be potentially used to calibrate optical imaging devices, to study the mechanisms for tumor hypoxia and angiogenesis, and to optimize the drug delivery strategies.

  6. Microfabrication of polydimethylsiloxane phantoms to simulate tumor hypoxia and vascular anomaly

    NASA Astrophysics Data System (ADS)

    Wu, Qiang; Ren, Wenqi; Yu, Zelin; Dong, Erbao; Zhang, Shiwu; Xu, Ronald X.

    2015-12-01

    We introduce a microfluidic approach to simulate tumor hypoxia and vascular anomaly. Polydimethylsiloxane (PDMS) phantoms with embedded microchannel networks were fabricated by a soft lithography process. A dialysis membrane was sandwiched between two PDMS slabs to simulate the controlled mass transport and oxygen metabolism. A tortuous microchannel network was fabricated to simulate tumor microvasculature. A dual-modal multispectral and laser speckle imaging system was used for oxygen and blood flow imaging in the tumor-simulating phantom. The imaging results were compared with those of the normal vasculature. Our experiments demonstrated the technical feasibility of simulating tumor hypoxia and vascular anomalies using the proposed PDMS phantom. Such a phantom fabrication technique may be potentially used to calibrate optical imaging devices, to study the mechanisms for tumor hypoxia and angiogenesis, and to optimize the drug delivery strategies.

  7. Ultrastructural characterization of macrophage-like mononuclear leukocytes in human astrocytic tumors.

    PubMed

    Arismendi-Morillo, Gabriel; Castellano-Ramírez, Alan; Medina, Zulamita

    2010-12-01

    The aim of this study was to describe the ultrastructural features of macrophage-like mononuclear leukocytes associated with human astrocytic tumors. Tumoral biopsies of 10 patients with a pathological diagnosis of astrocytic tumor by means of transmission electron microscopy were examined. The macrophage-like mononuclear leukocyte shows ultrastructural characteristics related with the physiologic phenotype of the alternatively activated macrophage (M2), localized principally around of tumoral vasculature and tumor milieu; classically activated macrophages (M1) in surrounding necrosis areas were observed. The presence of these two ultrastructural kinds of macrophage-like mononuclear leukocytes into different areas of the tumor denotes that cellular response of TAMs is dependent of microenvironment stimuli in different parts of a tumor. The process of transvascular emigration of monocyte/macrophage-like mononuclear leukocytes into tumor is presented. The preponderance of alternatively activated macrophage-like mononuclear leukocytes suggests disequilibrium between pro-tumoral leukocytes and anti-tumoral leukocytes. Therefore, macrophage polarization toward anti-tumoral macrophage-like mononuclear leukocytes would be a potential target for therapeutic manipulation in human astrocytic tumors.

  8. Three-dimensional in vitro co-culture model of breast tumor using magnetic levitation.

    PubMed

    Jaganathan, Hamsa; Gage, Jacob; Leonard, Fransisca; Srinivasan, Srimeenakshi; Souza, Glauco R; Dave, Bhuvanesh; Godin, Biana

    2014-10-01

    In this study, we investigate a novel in vitro model to mimic heterogeneous breast tumors without the use of a scaffold while allowing for cell-cell and tumor-fibroblast interactions. Previous studies have shown that magnetic levitation system under conventional culturing conditions results in the formation of three-dimensional (3D) structures, closely resembling in vivo tissues (fat tissue, vasculature, etc.). Three-dimensional heterogeneous tumor models for breast cancer were designed to effectively model the influences of the tumor microenvironment on drug efficiency. Various breast cancer cells were co-cultured with fibroblasts and then magnetically levitated. Size and cell density of the resulting tumors were measured. The model was phenotypically compared to in vivo tumors and examined for the presence of ECM proteins. Lastly, the effects of tumor stroma in the 3D in vitro model on drug transport and efficiency were assessed. Our data suggest that the proposed 3D in vitro breast tumor is advantageous due to the ability to: (1) form large-sized (millimeter in diameter) breast tumor models within 24 h; (2) control tumor cell composition and density; (3) accurately mimic the in vivo tumor microenvironment; and (4) test drug efficiency in an in vitro model that is comparable to in vivo tumors.

  9. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development.

    PubMed

    Stachura, Joanna; Wachowska, Malgorzata; Kilarski, Witold W; Güç, Esra; Golab, Jakub; Muchowicz, Angelika

    2016-07-01

    Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT).

  10. Intestinal and peri-tumoral lymphatic endothelial cells are resistant to radiation-induced apoptosis

    SciTech Connect

    Sung, Hoon Ki; Morisada, Tohru; Cho, Chung-Hyun; Oike, Yuichi; Lee, Jayhun; Sung, Eon Ki; Chung, Jae Hoon; Suda, Toshio; Koh, Gou Young . E-mail: gykoh@kaist.ac.kr

    2006-06-30

    Radiation therapy is a widely used cancer treatment, but it is unable to completely block cancer metastasis. The lymphatic vasculature serves as the primary route for metastatic spread, but little is known about how lymphatic endothelial cells respond to radiation. Here, we show that lymphatic endothelial cells in the small intestine and peri-tumor areas are highly resistant to radiation injury, while blood vessel endothelial cells in the small intestine are relatively sensitive. Our results suggest the need for alternative therapeutic modalities that can block lymphatic endothelial cell survival, and thus disrupt the integrity of lymphatic vessels in peri-tumor areas.

  11. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

    PubMed Central

    Stachura, Joanna; Wachowska, Malgorzata; Kilarski, Witold W.; Güç, Esra; Golab, Jakub; Muchowicz, Angelika

    2016-01-01

    ABSTRACT Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT). PMID:27622039

  12. Spinal Cord Tumor

    MedlinePlus

    Spinal cord tumor Overview By Mayo Clinic Staff A spinal tumor is a growth that develops within your ... as vertebral tumors. Tumors that begin within the spinal cord itself are called spinal cord tumors. There are ...

  13. What Is Wilms Tumor?

    MedlinePlus

    ... Treatment? Wilms Tumor About Wilms Tumor What Is Wilms Tumor? Cancer starts when cells in the body begin ... live normal, healthy lives with just one kidney. Wilms tumors Wilms tumors are the most common cancers in ...

  14. Pallister-Killian syndrome: case report with pineal tumor.

    PubMed

    Mauceri, L; Sorge, G; Incorpora, G; Pavone, L

    2000-11-06

    Pallister-Killian syndrome, an aneuploidy syndrome, comprises a characteristic facial appearance, mental retardation, and multiple other anomalies. It is caused by mosaicism with a supernumerary isochromosome 12p. This chromosomal abnormality has been reported also in human germ cell tumors. We report on a 15-year-old girl with Pallister-Killian syndrome and pineal tumor.

  15. In vivo transcriptional targeting into the retinal vasculature using recombinant baculovirus carrying the human flt-1 promoter

    PubMed Central

    Luz-Madrigal, Agustín; Clapp, Carmen; Aranda, Jorge; Vaca, Luis

    2007-01-01

    Background Endothelial cells are a target for gene therapy because they are implicated in a number of vascular diseases. Recombinant baculovirus have emerged as novel gene delivery vectors. However, there is no information available concerning the use of endothelial-specific promoters in the context of the baculovirus genome. In the present study, we have generated a recombinant baculovirus containing the human flt-1 promoter (BacFLT-GFP) driving the expression of the green fluorescent protein. Transcriptional gene targeting was analyzed in vitro in different mammalian cell lines and in vivo in adult rat retinal vasculature. Results BacFLT-GFP evoked the highest levels of expression in the endothelial cell line BUVEC-E6E7-1, similar to those reached by recombinant baculovirus carrying the CMV promoter (112% relative to BacCMV-GFP, n = 4). Interestingly, BacFLT-GFP directed high levels of expression in rat glioma C6 and in human glioblastoma CH235 cells (34.78% and 47.86% relative to BacCMV-GFP, respectively). Histone deacetylase inhibitors such as butyrate or trichostatin A enhanced the transcriptional activity of both BacCMV-GFP and BacFLT-GFP. Thus, in this study histone deacetylation appears to be a central mechanism for the silencing of baculovirus, independently of the promoter utilized. In vivo transcriptional targeting was demonstrated in adult rat retinal vasculature by intravitreal delivery of BacFLT-GFP and immunohistochemical staining with von Willebrand factor (vWF). Analysis by fluorescence microscopy and deconvolved three-dimensional confocal microscopy of retinal whole mounts obtained after 3 days of baculovirus injection showed that most GFP-expressing cells localized to the inner limiting membrane (ILM) and ganglion cell layer (GCL) and colocalize with vWF (70%, n = 10) in blood vessels, confirming the endothelial phenotype of the transduced cells. Conclusion Taken together, our results indicate that the restricted expression in endothelial cells

  16. Consistent chromosome abnormalities including double minutes (dms) in adenocarcinoma of the pancreas

    SciTech Connect

    Griffin, C.A.; Morsberger, L.; Ellingham, T.

    1994-09-01

    Little is known about the somatic genetic changes which characterize pancreatic adenocarcinoma (PA), and identification of acquired genomic alterations would further our understanding of the biology of this neoplasm. We have studied 62 primary specimens of PA using classical and FISH methods. Clonally abnormal karyotypes were observed in 44 neoplasms. Karyotypes were generally complex (greater than 3 abnormalities) including both numerical and structural chromosome changes. Many tumors contained at least one marker chromosome. The most frequent whole chromosomal gains were chromosomes 20 (7 tumors) and 7 (5 tumors). Losses were much more frequent: chromosome 18 was lost in 22 tumors, followed by chromosomes 13 (15 tumors), 12 (13 tumors), and 6 (12 tumors). Structural abnormalities were common. 200 chromosome breakpoints were identified. Excluding Robertsonian translocations, chromosomal arms most frequently involved were 6q (12 chromosomes), 1p and 3p (10 each), 11p and 17p (9 each), 1q (8), 8p and 19q (7 each). Of particular interest, we found dms in 6 cases. These represent the first PAs with cytogenetic evidence of gene amplification, and are under investigation using chromosome microdissection. To begin to define the smallest region of 6q which is deleted, 5 tumors with 6q deletions were hybridized with a biotin-labeled probe, made by microdissection of 6q24-qter. Loss of one copy of this region was verified in 4/5 tumors; additional probes are being made. Our results are similar to those of 34 other reported PAs, and the combined data suggest that gains of chromosomes 7 and 20 and deletions and rearrangements of 1p and 6q may be particularly important in the biology of adenocarcinoma of the pancreas.

  17. Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region.

    PubMed

    Amin, Mohamadreza; Mansourian, Mercedeh; Koning, Gerben A; Badiee, Ali; Jaafari, Mahmoud Reza; ten Hagen, Timo L M

    2015-12-28

    Liposomes containing cytotoxic agents and targeted with Arg-Gly-Asp based peptides have frequently been used against αvβ3 integrin on tumor neovasculature. However, like many other ligand modified liposomes these preparations suffered from enhanced uptake by the reticulo endothelial system (RES) and off-targeted interaction with integrin receptors vastly expressed in normal organs causing poor biodistribution and toxic effects. Here we mainly focus on development of a RGD-modified liposomal delivery system to enhance both targeting selectivity and tumor uptake. First, sterically stabilized liposomal doxorubicin (SSLD) prepared and decorated with cRGDfK and RGDyC peptides differ in their physical properties. Stability assessments as well as in vitro and in vivo studies revealed that increasing the peptide hydrophobicity promotes the therapeutic efficacy of RGD-SSLD in a C-26 tumor model due to decreased recognition by RES and opsonization and limited off-targeted interactions. Then a novel N-methylated RGD peptide was designed and its capability in targeting integrin presenting cells was comprehensively assessed both in vitro and in vivo. RGDf[N-methyl]C promotes the liposome internalization by HUVEC via integrin mediated endocytosis. Intravital microscopy in window chamber bearing mice illustrated the capability of RGDf[N-methyl]C-liposomes in targeting both tumor vasculature and tumor cells in murine B16F0 and human BLM tumor models. Quantitative biodistribution in mice bearing B16F0 tumor revealed its high affinity to tumor with no considerable affinity to normal organs. Treatment by high dose of RGDf[N-methyl]C-SSLD was found more effective than non-targeted SSLD and no toxic side effect was observed. In conclusion, the RGDf[N-methyl]C-liposome was found promising in targeting tumor vasculature as well as other cells inside the tumor.

  18. Human cervical carcinoma detection and glucose monitoring in blood micro vasculatures with swept source OCT

    NASA Astrophysics Data System (ADS)

    Ullah, H.; Ahmed, E.; Ikram, M.

    2013-08-01

    We report a pilot method, i.e., speckle variance (SV) and structured optical coherence tomography to visualize normal and malignant blood microvasculature in three and two dimensions and to monitor the glucose levels in blood by analyzing the Brownian motion of the red blood cells. The technique was applied on nude live mouse's skin and the obtained images depict the enhanced intravasculature network forum up to the depth of ˜2 mm with axial resolution of ˜8 μm. Microscopic images have also been obtained for both types of blood vessels to observe the tumor spatially. Our SV-OCT methodologies and results give satisfactory techniques in real time imaging and can potentially be applied during therapeutic techniques such as photodynamic therapy as well as to quantify the higher glucose levels injected intravenously to animal by determining the translation diffusion coefficient.

  19. S1P₁ localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity.

    PubMed

    Montrose, David C; Scherl, Ellen J; Bosworth, Brian P; Zhou, Xi Kathy; Jung, Bongnam; Dannenberg, Andrew J; Hla, Timothy

    2013-03-01

    Signaling through sphingosine-1-phosphate receptor₁ (S1P₁) promotes blood vessel barrier function. Degradation of S1P₁ results in increased vascular permeability in the lung and may explain side effects associated with administration of FTY720, a functional antagonist of the S1P₁ receptor that is currently used to treat multiple sclerosis. Ulcerative colitis (UC) is characterized by an increased density of abnormal vessels. The expression or role of S1P₁ in blood vessels in the colon has not been investigated. In the present study, we show that S1P₁ is overexpressed in the colonic mucosa of UC patients. This increase in S1P₁ levels reflects increased vascular density in the inflamed mucosa. Genetic deletion of S1pr1 in mice increases colonic vascular permeability under basal conditions and increases bleeding in experimental colitis. In contrast, neither FTY720 nor AUY954, two S1P receptor-targeting agents, increases bleeding in experimental colitis. Taken together, our findings demonstrate that S1P₁ is critical to maintaining colonic vascular integrity and may play a role in UC pathogenesis.

  20. Quantitative Measurement of Blood Flow Dynamics in Embryonic Vasculature Using Spectral Doppler Velocimetry

    PubMed Central

    Davis, Anjul; Izatt, Joseph; Rothenberg, Florence

    2010-01-01

    The biophysical effects of blood flow are known to influence the structure and function of adult cardiovascular systems. Similar effects on the maturation of the cardiovascular system have been difficult to directly and non-invasively measure due to the small size of the embryo. Optical coherence tomography (OCT) has been shown to provide high spatial and temporal structural imaging of the early embryonic chicken heart. We have developed an extension of Doppler OCT, called spectral Doppler velocimetry (SDV), that will enable direct, non-invasive quantification of blood flow and shear rate from the early embryonic cardiovascular system. Using this technique, we calculated volumetric flow rate and shear rate from chicken embryo vitelline vessels. We present blood flow dynamics and spatial velocity profiles from three different vessels in the embryo as well as measurements from the outflow tract of the embryonic heart tube. This technology can potentially provide spatial mapping of blood flow and shear rate in embryonic cardiovascular structures, producing quantitative measurements that can be correlated with gene expression and normal and abnormal morphology. PMID:19248163

  1. Sleeping Parathyroid Tumor: Rapid Hyperfunction after Removal of the Dominant Tumor

    PubMed Central

    Simonds, William F.; Weinstein, Lee S.; Collins, Michael T.; Kebebew, Electron; Nilubol, Naris; Phan, Giao Q.; Libutti, Steven K.; Remaley, Alan T.; Van Deventer, Manuel; Marx, Stephen J.

    2012-01-01

    Context: Due to frequent multiplicity of tumors in multiple endocrine neoplasia type 1, it may be difficult to decide when to stop a parathyroid exploration. A fall of intraoperative serum PTH by a certain percentage during parathyroid surgery is often used as one criterion for ending the operation. Results: We report two patients with primary hyperparathyroidism due to multiple endocrine neoplasia type 1 who had their first parathyroidectomy at the National Institutes of Health. In both cases, two and a half glands were removed, an extensive search was done for an occult parathyroid tumor, and intraoperative PTH decreased markedly to the lower limits of normal, suggesting a successful operation. Despite this, both patients became hypercalcemic within 3 d after the operation and showed persistent primary hyperparathyroidism. Detailed findings suggest the following course: chronic hypercalcemia had caused near total suppression of PTH secretion by an undiscovered parathyroid tumor (sleeping parathyroid tumor). When the hypercalcemia decreased after surgery due to the removal of the dominant parathyroid tumor(s), the abnormal yet previously suppressed tumor rapidly began to oversecrete PTH and thus caused postoperative hypercalcemia. Conclusions: Even a fall of the intraoperative PTH to the lower limits of the normal range cannot guarantee that removal of all parathyroid tumors has been complete in cases with multiple tumors. These findings likely reflect strikingly differing PTH secretory functions among distinct tumors in the same patient, with hypercalcemia at least from a dominant tumor suppressing PTH secretion by one or more other parathyroid tumors. PMID:22508712

  2. The action of a dopamine (DA1) receptor agonist, fenoldopam in human vasculature in vivo and in vitro.

    PubMed Central

    Hughes, A; Thom, S; Martin, G; Redman, D; Hasan, S; Sever, P

    1986-01-01

    This study was designed to investigate dopaminergic mechanisms in human vasculature using the selective vascular dopamine receptor agonist fenoldopam in vivo and in vitro. In vivo, forearm blood flow was measured plethysmographically and in vitro isolated rings of human blood vessels from a variety of sites were used for tissue bath studies. Intra-arterial fenoldopam markedly increased forearm blood flow, this effect was antagonised by (R) sulpiride, a vascular dopamine (DA1) antagonist, but not by metoclopramide, a neuronal (DA2) antagonist, or by guanethidine, an adrenergic neurone blocking agent. In vitro, fenoldopam relaxed preconstricted human renal, mesenteric and lumbar arteries, but not saphenous vein in a concentration dependent manner. (RS) sulpiride and SCH 23390 competitively antagonised this effect. These studies demonstrate the presence of a vasodilatory vascular dopamine receptor in man both in vivo and in vitro. PMID:2878679

  3. Unilateral anterior persistent fetal vasculature in a child with blepharophimosis-ptosis-epicanthus inversus syndrome: A surgical challenge.

    PubMed

    Kemmanu, Vasudha; Rathod, Pragnya; Anaspure, Hemant; Yadav, Naresh K

    2016-06-01

    Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disease. It is clinically characterized by four major features; blepharophimosis, ptosis, epicanthus inversus, and telecanthus. We report a case of a 1-year-old female with BPES with unilateral anterior persistent fetal vasculature (PFV). On examination, she was found to have all the clinical features of BPES, along with calcified and partially absorbed cataract with elongated ciliary processes in her left eye. B-scan of left eye showed attached retina with no evidence of posterior PFV. Systemic examination was normal. She underwent cataract surgery with primary posterior capsulotomy with intraocular lens implantation under general anesthesia. Literature search did not reveal any previous reports of unilateral anterior PFV and BPES. The clinical features, other associations, and the difficulties in the surgical management of this condition are discussed.

  4. Unilateral anterior persistent fetal vasculature in a child with blepharophimosis-ptosis-epicanthus inversus syndrome: A surgical challenge

    PubMed Central

    Kemmanu, Vasudha; Rathod, Pragnya; Anaspure, Hemant; Yadav, Naresh K

    2016-01-01

    Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disease. It is clinically characterized by four major features; blepharophimosis, ptosis, epicanthus inversus, and telecanthus. We report a case of a 1-year-old female with BPES with unilateral anterior persistent fetal vasculature (PFV). On examination, she was found to have all the clinical features of BPES, along with calcified and partially absorbed cataract with elongated ciliary processes in her left eye. B-scan of left eye showed attached retina with no evidence of posterior PFV. Systemic examination was normal. She underwent cataract surgery with primary posterior capsulotomy with intraocular lens implantation under general anesthesia. Literature search did not reveal any previous reports of unilateral anterior PFV and BPES. The clinical features, other associations, and the difficulties in the surgical management of this condition are discussed. PMID:27488160

  5. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis

    NASA Astrophysics Data System (ADS)

    Zhang, Boyang; Montgomery, Miles; Chamberlain, M. Dean; Ogawa, Shinichiro; Korolj, Anastasia; Pahnke, Aric; Wells, Laura A.; Massé, Stéphane; Kim, Jihye; Reis, Lewis; Momen, Abdul; Nunes, Sara S.; Wheeler, Aaron R.; Nanthakumar, Kumaraswamy; Keller, Gordon; Sefton, Michael V.; Radisic, Milica

    2016-06-01

    We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimetre-thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted with direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion.

  6. Phase variance optical coherence microscopy for label-free imaging of the developing vasculature in zebrafish embryos

    NASA Astrophysics Data System (ADS)

    Chen, Yu; Trinh, Le A.; Fingler, Jeff; Fraser, Scott E.

    2016-12-01

    A phase variance optical coherence microscope (pvOCM) has been created to image blood flow in the microvasculature of zebrafish embryos, without the use of exogenous labels. The pvOCM imaging system has axial and lateral resolutions of 2.8 μm in tissue and imaging depth of more than 100 μm. Images of 2 to 5 days postfertilization zebrafish embryos identified the detailed anatomical structure based on OCM intensity contrast. Phase variance contrast offered visualization of blood flow in the arteries, veins, and capillaries. The pvOCM images of the vasculature were confirmed by direct comparisons with fluorescence microscopy images of transgenic embryos in which the vascular endothelium is labeled with green fluorescent protein. The ability of pvOCM to capture activities of regional blood flow permits it to reveal functional information that is of great utility for the study of vascular development.

  7. Abnormal Magnetic Resonance Imaging Findings in Patients With Sudden Sensorineural Hearing Loss: Vestibular Schwannoma as the Most Common Cause of MRI Abnormality.

    PubMed

    Jeong, Kyung-Hwa; Choi, Jin Woo; Shin, Jung Eun; Kim, Chang-Hee

    2016-04-01

    The etiology of sudden sensorineural hearing loss (SSNHL) remains unclear in most cases. This study aimed to assess abnormal magnetic resonance imaging (MRI) findings in patients with SSNHL and evaluate the value of MRI in identifying the cause of SSNHL.A retrospective analysis of the charts and MRI findings of 291 patients with SSNHL was performed.In 291 patients, MRI abnormality, which was considered a cause of SSNHL, was detected in 13 patients. Vestibular schwannoma involving the internal auditory canal (IAC) and/or cerebellopontine angle was observed in 9 patients. All 9 patients had intrameatal tumors, and 6 of the 9 patients displayed extrameatal extension of their tumors. The tumor was small (<1 cm) or medium-sized (1.1-2.9 cm) in these 6 patients. Intralabyrinthine schwannoma, labyrinthine hemorrhage, IAC metastasis, and a ruptured dermoid cyst were each observed in 1 patient.The most commonly observed MRI abnormality in patients with SSNHL was vestibular schwannoma, and all of the lesions were small or medium-sized tumors involving the IAC.

  8. Targeting tumor microenvironment: crossing tumor interstitial fluid by multifunctional nanomedicines

    PubMed Central

    Omidi, Yadollah; Barar, Jaleh

    2014-01-01

    Introduction: The genesis of cancer appears to be a complex matter, which is not simply based upon few genetic abnormalities/alteration. In fact, irregular microvasculature and aberrant interstitium of solid tumors impose significant pathophysiologic barrier functions against cancer treatment modalities, hence novel strategies should holistically target bioelements of tumor microenvironment (TME). In this study, we provide some overview and insights on TME and important strategies used to control the impacts of such pathophysiologic barriers. Methods: We reviewed all relevant literature for the impacts of tumor interstitium and microvasculature within the TME as well as the significance of the implemented strategies. Results: While tumorigenesis initiation seems to be in close relation with an emergence of hypoxia and alterations in epigenetic/genetic materials, large panoplies of molecular events emerge as intricate networks during oncogenesis to form unique lenient TME in favor of tumor progression. Within such irregular interstitium, immune system displays defective surveillance functionalities against malignant cells. Solid tumors show multifacial traits with coadaptation and self-regulation potentials, which bestow profound resistance against the currently used conventional chemotherapy and immunotherapy agents that target solely one face of the disease. Conclusion: The cancerous cells attain unique abilities to form its permissive microenvironment, wherein (a) extracellular pH is dysregulated towards acidification, (b) extracellular matrix (ECM) is deformed, (c) stromal cells are cooperative with cancer cells, (d) immune system mechanisms are defective, (e) non-integrated irregular microvasculature with pores (120-1200 nm) are formed, and (h) interstitial fluid pressure is high. All these phenomena are against cancer treatment modalities. As a result, to control such abnormal pathophysiologic traits, novel cancer therapy strategies need to be devised using

  9. Visualization of tumor vascular reactivity in response to respiratory challenges by optical coherence tomography (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Kim, Hoon Sup; Lee, Songhyun; Lee, Kiri; Eom, Tae Joong; Kim, Jae G.

    2016-02-01

    We previously reported the potential of using vascular reactivity during respiratory challenges as a marker to predict the response of breast tumor to chemotherapy in a rat model by using a continuous wave near-infrared spectroscopy. However, it cannot visualize how the vascular reactivity from tumor vessel can predict the tumor response to its treatment. In this study, we utilized a spectral domain optical coherence tomography (SD-OCT) system to visualize vascular reactivity of both tumor and normal vasculature during respiratory challenges in a mouse model. We adapted intensity based Doppler variance algorithm to draw angiogram from the ear of mouse (8-week-old Balb/c nu/nu). Animals were anesthetized using 1.5% isoflurane, and the body temperature was maintained by a heating pad. Inhalational gas was switched from air (10min) to 100% oxygen (10min), and a pulse oximeter was used to monitor arterial oxygen saturation and heart rate. OCT angiograms were acquired 5 min after the onset of each gas. The vasoconstriction effect of hyperoxic gas on vasculature was shown by subtracting an en-face image acquired during 100% oxygen from the image acquired during air inhalation. The quantitative change in the vessel diameter was measured from the en-face OCT images of the individual blood vessels. The percentage of blood vessel diameter reduction varied from 1% to 12% depending on arterial, capillary, or venous blood vessel. The vascular reactivity change during breast tumor progression and post chemotherapy will be monitored by OCT angiography.

  10. Abnormal vascular development in zebrafish models for fukutin and FKRP deficiency.

    PubMed

    Wood, Alasdair J; Müller, Juliane S; Jepson, Catherine D; Laval, Steve H; Lochmüller, Hanns; Bushby, Kate; Barresi, Rita; Straub, Volker

    2011-12-15

    Fukutin and fukutin-related protein (FKRP) are involved in the glycosylation of α-dystroglycan, a key receptor for basement membrane proteins. Aberrant α-dystroglycan glycosylation leads to a broad spectrum of disorders, ranging from limb girdle muscular dystrophy to Walker-Warburg syndrome. This is the first study investigating a role of fukutin and FKRP-mediated glycosylation in angiogenesis. Transgenic zebrafish expressing enhanced green fluorescent protein in blood vessels were treated with morpholino antisense oligonucleotides that blocked the expression of fukutin, FKRP and dystroglycan. All morphant fish showed muscle damage and vascular abnormalities at day 1 post-fertilization. Intersegmental vessels of somites failed to reach the dorsal longitudinal anastomosis and in more severe phenotypes retracted further or were in some cases even completely missing. In contrast, the eye vasculature was distorted in both fukutin and FKRP morphants, but not in dystroglycan morphants or control fish. The eye size was also smaller in the fukutin and FKRP morphants when compared with dystroglycan knockdown fish and controls. In general, the fukutin morphant fish had the most severe skeletal muscle and eye phenotype. Our findings suggest that fukutin and FKRP have functions that affect ocular development in zebrafish independently of dystroglycan. Despite anecdotal reports about vascular abnormalities in patients affected by dystroglycanopathies, the clinical relevance of such lesions remains unclear and should be subject to further review and investigations.

  11. Superior sulcus tumors (Pancoast tumors)

    PubMed Central

    Battistella, Lucia; Mammana, Marco; Calabrese, Francesca; Rea, Federico

    2016-01-01

    Superior Sulcus Tumors, frequently termed as Pancoast tumors, are a wide range of tumors invading the apical chest wall. Due to its localization in the apex of the lung, with the potential invasion of the lower part of the brachial plexus, first ribs, vertebrae, subclavian vessels or stellate ganglion, the superior sulcus tumors cause characteristic symptoms, like arm or shoulder pain or Horner’s syndrome. The management of superior sulcus tumors has dramatically evolved over the past 50 years. Originally deemed universally fatal, in 1956, Shaw and Paulson introduced a new treatment paradigm with combined radiotherapy and surgery ensuring 5-year survival of approximately 30%. During the 1990s, following the need to improve systemic as well as local control, a trimodality approach including induction concurrent chemoradiotherapy followed by surgical resection was introduced, reaching 5-year survival rates up to 44% and becoming the standard of care. Many efforts have been persecuted, also, to obtain higher complete resection rates using appropriate surgical approaches and involving multidisciplinary team including spine surgeon or vascular surgeon. Other potential treatment options are under consideration like prophylactic cranial irradiation or the addition of other chemotherapy agents or biologic agents to the trimodality approach. PMID:27429965

  12. Gene-expression profiling of different arms of lymphatic vasculature identifies candidates for manipulation of cell traffic

    PubMed Central

    Iftakhar-E-Khuda, Imtiaz; Fair-Mäkelä, Ruth; Kukkonen-Macchi, Anu; Elima, Kati; Karikoski, Marika; Rantakari, Pia; Miyasaka, Masayuki; Salmi, Marko; Jalkanen, Sirpa

    2016-01-01

    Afferent lymphatic vessels bring antigens and diverse populations of leukocytes to draining lymph nodes, whereas efferent lymphatics allow only lymphocytes and antigens to leave the nodes. Despite the fundamental importance of afferent vs. efferent lymphatics in immune response and cancer spread, the molecular characteristics of these different arms of the lymphatic vasculature are largely unknown. The objective of this work was to explore molecular differences behind the distinct functions of afferent and efferent lymphatic vessels, and find possible molecules mediating lymphocyte traffic. We used laser-capture microdissection and cell sorting to isolate lymphatic endothelial cells (LECs) from the subcapsular sinus (SS, afferent) and lymphatic sinus (LS, efferent) for transcriptional analyses. The results reveal marked differences between afferent and efferent LECs and identify molecules on lymphatic vessels. Further characterizations of Siglec-1 (CD169) and macrophage scavenger receptor 1 (MSR1/CD204), show that they are discriminatively expressed on lymphatic endothelium of the SS but not on lymphatic vasculature of the LS. In contrast, endomucin (EMCN) is present on the LS endothelium and not on lymphatic endothelium of the SS. Moreover, both murine and human MSR1 on lymphatic endothelium of the SS bind lymphocytes and in in vivo studies MSR1 regulates entrance of lymphocytes from the SS to the lymph node parenchyma. In conclusion, this paper reports surprisingly distinct molecular profiles for afferent and efferent lymphatics and a function for MSR1. These results may open avenues to explore some of the now-identified molecules as targets to manipulate the function of lymphatic vessels. PMID:27601677

  13. Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature.

    PubMed

    Cushing, Leah; Costinean, Stefan; Xu, Wei; Jiang, Zhihua; Madden, Lindsey; Kuang, Pingping; Huang, Jingshu; Weisman, Alexandra; Hata, Akiko; Croce, Carlo M; Lü, Jining

    2015-05-01

    Differentiation of lung vascular smooth muscle cells (vSMCs) is tightly regulated during development or in response to challenges in a vessel specific manner. Aberrant vSMCs specifically associated with distal pulmonary arteries have been implicated in the pathogenesis of respiratory diseases, such as pulmonary arterial hypertension (PAH), a progressive and fatal disease, with no effective treatment. Therefore, it is highly relevant to understand the underlying mechanisms of lung vSMC differentiation. miRNAs are known to play critical roles in vSMC maturation and function of systemic vessels; however, little is known regarding the role of miRNAs in lung vSMCs. Here, we report that miR-29 family members are the most abundant miRNAs in adult mouse lungs. Moreover, high levels of miR-29 expression are selectively associated with vSMCs of distal vessels in both mouse and human lungs. Furthermore, we have shown that disruption of miR-29 in vivo leads to immature/synthetic vSMC phenotype specifically associated with distal lung vasculature, at least partially due to the derepression of KLF4, components of the PDGF pathway and ECM-related genes associated with synthetic phenotype. Moreover, we found that expression of FBXO32 in vSMCs is significantly upregulated in the distal vasculature of miR-29 null lungs. This indicates a potential important role of miR-29 in smooth muscle cell function by regulating FBXO32 and SMC protein degradation. These results are strongly supported by findings of a cell autonomous role of endogenous miR-29 in promoting SMC differentiation in vitro. Together, our findings suggested a vessel specific role of miR-29 in vSMC differentiation and function by targeting several key negative regulators.

  14. In Vivo Quantitative Microcomputed Tomographic Analysis of Vasculature and Organs in a Normal and Diseased Mouse Model

    PubMed Central

    Das, Nanditha Mohan; Hatsell, Sarah; Nannuru, Kalyan; Huang, Lily; Wen, Xialing; Wang, Lili; Wang, Li-Hsien; Idone, Vincent; Meganck, Jeffrey A.; Murphy, Andrew; Economides, Aris; Xie, LiQin

    2016-01-01

    Non-bone in vivo micro-CT imaging has many potential applications for preclinical evaluation. Specifically, the in vivo quantification of changes in the vascular network and organ morphology in small animals, associated with the emergence and progression of diseases like bone fracture, inflammation and cancer, would be critical to the development and evaluation of new therapies for the same. However, there are few published papers describing the in vivo vascular imaging in small animals, due to technical challenges, such as low image quality and low vessel contrast in surrounding tissues. These studies have primarily focused on lung, cardiovascular and brain imaging. In vivo vascular imaging of mouse hind limbs has not been reported. We have developed an in vivo CT imaging technique to visualize and quantify vasculature and organ structure in disease models, with the goal of improved quality images. With 1–2 minutes scanning by a high speed in vivo micro-CT scanner (Quantum CT), and injection of a highly efficient contrast agent (Exitron nano 12000), vasculature and organ structure were semi-automatically segmented and quantified via image analysis software (Analyze). Vessels of the head and hind limbs, and organs like the heart, liver, kidneys and spleen were visualized and segmented from density maps. In a mouse model of bone metastasis, neoangiogenesis was observed, and associated changes to vessel morphology were computed, along with associated enlargement of the spleen. The