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Sample records for assess mucosal angiogenesis

  1. Narrow-band imaging endoscopy to assess mucosal angiogenesis in inflammatory bowel disease: A pilot study

    Institute of Scientific and Technical Information of China (English)

    Silvio; Danese; Gionata; Fiorino; Erika; Angelucci; Stefania; Vetrano; Nico; Pagano; Giacomo; Rando; Antonino; Spinelli; Alberto; Malesci; Alessandro; Repici

    2010-01-01

    AIM: To investigate whether narrow band imaging (NBI) is a useful tool for the in vivo detection of angiogenesis in inflammatory bowel disease (IBD) patients. METHODS: Conventional and NBI colonoscopy was performed in 14 patients with colonic inflammation (8 ulcerative colitis and 6 Crohn’s disease). Biopsy samples were taken and CD31 expression was assayed immuno- histochemically; microvascular density was assessed by vessel count. RESULTS: In areas that were endoscopically normal but positive on NBI, ther...

  2. Assessing Tumor Angiogenesis with Dynamic Contrast Enhanced Magnetic Resonance Imaging

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    Esparza-Coss, Emilio; Jackson, Edward F.

    2006-09-01

    Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is a method able of assessing microvascular changes at high spatial resolution and without ionizing radiation. The microcirculation and structure of tumors are fundamentally chaotic in that tumor-derived factors stimulate the endothelial cells to form new small vessels (angiogenesis) and this vasculature deviates markedly from normal hierarchical branching patterns. The tumor-induced microvascular changes lead to blood flow that is both spatially and temporally more heterogeneous than the efficient and uniform perfusion of normal organs and tissues. DCE-MRI allows for the assessment of perfusion and permeability of the tumor microvasculature, including the network of vessels with diameters less than 100 μm, which are beyond the resolution of conventional angiograms. The microvessel permeability to small molecular weight contrast media as well as measures of tumor response can be assessed with different analysis techniques ranging from simple measures of enhancement to pharmacokinetic models. In this work, such DCE-MRI analysis techniques are discussed.

  3. Serological assessment of gastric mucosal atrophy in gastric cancer

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    Bornschein Jan

    2012-01-01

    Full Text Available Abstract Background Non-invasive tools for gastric cancer screening and diagnosis are lacking. Serological testing with the detection of pepsinogen 1 (PG1, pepsinogen 2 (PG2 and gastrin 17 (G17 offers the possibility to detect preneoplastic gastric mucosal conditions. Aim of this study was to assess the performance of these serological tests in the presence of gastric neoplasia. Methods Histological and serological samples of 118 patients with gastric cancer have been assessed for tumor specific characteristics (Laurén type, localisation, degree of mucosal abnormalities (intestinal metaplasia, atrophy and serological parameters (PG1, PG2, PG1/2-ratio, G17, H. pylori IgG, CagA status. Association of the general factors to the different serological values have been statistically analyzed. Results Patients with intestinal type gastric cancer had lower PG1 levels and a lower PG1/2-ratio compared to those with diffuse type cancer (p = 0.003. The serum levels of PG2 itself and G17 were not significantly altered. H. pylori infection in general had no influence on the levels of PG1, PG2 and G17 in the serum of gastric cancer patients. There was a trend towards lower PG1 levels in case of positive CagA-status (p = 0.058. The degree of both intestinal metaplasia and atrophy correlated inversely with serum levels for PG1 and the PG1/2-ratio (p Conclusions Glandular atrophy and a positive CagA status are determinant factors for decreased pepsinogen 1 levels in the serum of patients with gastric cancer. The serological assessment of gastric atrophy by analysis of serum pepsinogen is only adequate for patients with intestinal type cancer.

  4. Assessment methods for angiogenesis and current approaches for its quantification

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    Waleed Hassan AlMalki

    2014-01-01

    Full Text Available Angiogenesis is a physiological process which describes the development of new blood vessels from the existing vessels. It is a common and the most important process in the formation and development of blood vessels, so it is supportive in the healing of wounds and granulation of tissues. The different assays for the evaluation of angiogenesis have been described with distinct advantages and some limitations. In order to develop angiogenic and antiangiogenic techniques, continuous efforts have been resulted to give animal models for more quantitative analysis of angiogenesis. Most of the studies on angiogenic inducers and inhibitors rely on various models, both in vitro, in vivo and in ova, as indicators of efficacy. The angiogenesis assays are very much helpful to test efficacy of both pro- and anti- angiogenic agents. The development of non-invasive procedures for quantification of angiogenesis will facilitate this process significantly. The main objective of this review article is to focus on the novel and existing methods of angiogenesis and their quantification techniques. These findings will be helpful to establish the most convenient methods for the detection, quantification of angiogenesis and to develop a novel, well tolerated and cost effective anti-angiogenic treatment in the near future.

  5. Assessment of tumor angiogenesis using fluorescence contrast agents

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    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.

  6. Imaging techniques used for the real-time assessment of angiogenesis in digestive cancers

    DEFF Research Database (Denmark)

    Saftoiu, Adrian; Vilmann, Peter; Săftoiu, Adrian

    2011-01-01

    Angiogenesis has a critical role in primary tumor growth and the development of metastases. Several angiogenesis inhibitors were recently developed, being a very attractive target for digestive tumor therapy. However, individualized therapy should not only be based on the pre-treatment imaging...... of reviews was to analyze and enhance current knowledge and future perspectives about the real-time assessment of angiogenesis in digestive cancers, used for the longitudinal monitoring of the effects of chemo-radiotherapy (including anti-angiogenic therapies), as well as for the precise targeting of drugs...... through molecular-based drug-delivery systems....

  7. Limitations in assessment of mucosal healing in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Hugh; James; Freeman

    2010-01-01

    An emerging parameter to define the effectiveness of new therapeutic agents in clinical trials,and by extension,for use in day-to-day clinical practice has been labeled mucosal healing.It has been hypothesized that complete healing of the intestinal mucosa in inflammatory bowel diseases should result in reduced disease complications,reduced hospitalization and reduced surgical treatment.By implication,the natural history of inflammatory bowel disease might then be altered. Measurement of mucosal healing,how...

  8. Imaging techniques used for the real-time assessment of angiogenesis in digestive cancers

    Institute of Scientific and Technical Information of China (English)

    Adrian S(a)ftoiu; Peter Vilmann

    2011-01-01

    Angiogenesis has a critical role in primary tumor growth and the development of metastases.Several angiogenesis inhibitors were recently developed,being a very attractive target for digestive tumor therapy.However,individualized therapy should not only be based on the pre-treatment imaging evaluation,but also on sensitive monitoring of microvascular changes during treatment.State-of-theart imaging techniques have the potential to visualize and characterize angiogenesis,although the technology and methodologies employed are recent and need further validation.The aim of this series of reviews was to analyze and enhance current knowledge and future perspectives about the real-time assessment of angiogenesis in digestive cancers,used for the longitudinal monitoring of the effects of chemo-radiotherapy(including anti-angiogenic therapies),as well as for the precise targeting of drugs through molecular-based drug-delivery systems.

  9. Utility of Computed Tomographic Enteroclysis/Enterography for the Assessment of Mucosal Healing in Crohn's Disease

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    Shinichi Hashimoto

    2013-01-01

    Full Text Available Aim. When determining therapeutic strategy, it is important to diagnose small intestinal lesions in Crohn's disease (CD precisely and to evaluate mucosal healing as well as clinical remission in CD. The purpose of this study was to compare findings from computed tomographic enteroclysis/enterography (CTE with those from the mucosal surface and to determine whether the state of mucosal healing can be determined by CTE. Materials and Methods. Of the patients who underwent CTE for CD, 39 patients were examined whose mucosal findings could be confirmed by colonoscopy, capsule endoscopy, balloon endoscopy, or with the resected surgical specimens. Results. According to the CTE findings, patients were determined to be in the active CD group (n=31 or inactive CD group (n=8. The proportion of previous surgery, clinical remission, stenosis, and CDAI score all showed significant difference between groups. Mucosal findings showed an association with ulcer in 93.6% of active group patients but in only 12.5% of inactive group patients (P<0.0001, whereas mucosal healing was found in 62.5% of inactive group patients but in only 3.2% of active group patients (P<0.0001. Conclusion. CTE appeared to be a useful diagnostic method for assessment of mucosal healing in Crohn's disease.

  10. Assessment of oral mucositis in adult and pediatric oncology patients: an evidence-based approach.

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    Farrington, Michele; Cullen, Laura; Dawson, Cindy

    2010-01-01

    Oral mucositis is a frequent side effect of cancer treatment and can lead to delayed treatment, reduced treatment dosage, altered nutrition, dehydration, infections, xerostomia, pain, and higher healthcare costs. Mucositis is defined as "inflammatory lesions of the oral and/or gastrointestinal tract caused by high-dose cancer therapies. Alimentary tract mucositis refers to the expression of mucosal injury across the continuum of oral and gastrointestinal mucosa, from the mouth to the anus" (Peterson, Bensadoun, & Roila, 2008, p. ii122). Evidence demonstrates that oral mucositis is quite distressing for patients. In addition, the majority of oncology nurses are unaware of available guidelines related to the care of oral mucositis. A multidisciplinary Oral Mucositis Committee was formed by the University of Iowa Hospitals and Clinics to develop evidence-based prevention and treatment strategies for adult and pediatric oncology patients experiencing oral mucositis. The first step was implementing an evidence-based nursing oral assessment. The Iowa Model was used to guide this evidence-based practice initiative. The Oral Assessment Guide (OAG) is reliable and valid, feasible, and sensitive to changing conditions. The OAG was piloted on an Adult Leukemia and Bone Marrow Transplant Unit leading to modification and adaptation. The pilot evaluation found 87% of patients had an abnormal oral assessment involving all categories in the tool. Nursing questionnaires showed that staff (8/23; 35% response) felt they were able to identify at risk patients using the OAG (3.3; 1-4 scale), and the tool accurately identifies mucosal changes (2.9; 1-4 scale). A knowledge assessment found nurses correctly identified OAG components 63% of the time. Unlike results from a national survey, most University of Iowa Hospitals and Clinics nurses (63%) were aware of national guidelines for prevention and treatment of oral mucositis. Developing an evidence-based nursing policy and updating

  11. In Vivo Assays for Assessing the Role of the Wilms' Tumor Suppressor 1 (Wt1) in Angiogenesis.

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    McGregor, Richard J; Ogley, R; Hadoke, Pwf; Hastie, Nicholas

    2016-01-01

    The Wilms' tumor suppressor gene (WT1) is widely expressed during neovascularization, but it is almost entirely absent in quiescent adult vasculature. However, in vessels undergoing angiogenesis, WT1 is dramatically upregulated. Studies have shown Wt1 has a role in both tumor and ischemic angiogenesis, but the mechanism of Wt1 action in angiogenic tissue remains to be elucidated. Here, we describe two methods for induction of in vivo angiogenesis (subcutaneous sponge implantation, femoral artery ligation) that can be used to assess the influence of Wt1 on new blood vessel formation. Subcutaneously implanted sponges stimulate an inflammatory and fibrotic response including cell infiltration and angiogenesis. Femoral artery ligation creates ischemia in the distal hindlimb and produces an angiogenic response to reperfuse the limb which can be quantified in vivo by laser Doppler flowmetry. In both of these models, the role of Wt1 in the angiogenic process can be assessed using histological/immunohistochemical staining, molecular analysis (qPCR) and flow cytometry. Furthermore, combined with suitable genetic modifications, these models can be used to explore the causal relationship between Wt1 expression and angiogenesis and to trace the lineage of cells expressing Wt1. This approach will help to clarify the importance of Wt1 in regulating neovascularization in the adult, and its potential as a therapeutic target.

  12. Assessment of oral mucosal lesions among eunuchs residing in Bhopal city, Madhya Pradesh, India: A cross-sectional study

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    Nilesh Arjun Torwane

    2015-01-01

    Full Text Available Aim: The present cross-sectional study following the STROBE guidelines was conducted to assess the prevalence of oral mucosal lesions among males, females, and eunuchs residing in Bhopal city, Madhya Pradesh India. Materials and Methods: Based on convenient non-probability snowball sampling technique, all the self-identified eunuchs residing in the city of Bhopal who were present at the time of examination and who fulfilled the selection criteria were examined. A cross section of the general population (males and females residing in the same locality where these eunuchs live was also examined. The World Health Organization (WHO oral health assessment proforma (1997 was used to collect the information on oral mucosal lesions. All the obtained data were analyzed by using a Statistical Package for Social Sciences version 20. Results: Overall prevalence of oral mucosal lesions was 127 (19.9% among the study subjects. Fifty-nine (28.5% eunuchs, 56 (25.7% males, and 12 (5.6% females were observed to have some oral mucosal lesions. Oral submucous fibrosis (6.4%, leukoplakia (5.5%, and traumatic ulceration (4.2% were the major oral mucosal conditions observed. Conclusion: The information presented in this study adds to our understanding of the common oral mucosal lesions occurring in the eunuch population. Efforts to increase patient awareness of the oral effects of tobacco use and to eliminate the habit are needed to improve the oral and general health of eunuchs.

  13. Assessment of oral mucosal lesions among eunuchs residing in Bhopal city, Madhya Pradesh, India: a cross-sectional study.

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    Torwane, Nilesh Arjun; Hongal, Sudhir; Goel, Pankaj; Chandrashekar, Byarakele; Saxena, Vrinda

    2015-01-01

    The present cross-sectional study following the STROBE guidelines was conducted to assess the prevalence of oral mucosal lesions among males, females, and eunuchs residing in Bhopal city, Madhya Pradesh India. Based on convenient non-probability snowball sampling technique, all the self-identified eunuchs residing in the city of Bhopal who were present at the time of examination and who fulfilled the selection criteria were examined. A cross section of the general population (males and females) residing in the same locality where these eunuchs live was also examined. The World Health Organization (WHO) oral health assessment proforma (1997) was used to collect the information on oral mucosal lesions. All the obtained data were analyzed by using a Statistical Package for Social Sciences version 20. Overall prevalence of oral mucosal lesions was 127 (19.9%) among the study subjects. Fifty-nine (28.5%) eunuchs, 56 (25.7%) males, and 12 (5.6%) females were observed to have some oral mucosal lesions. Oral submucous fibrosis (6.4%), leukoplakia (5.5%), and traumatic ulceration (4.2%) were the major oral mucosal conditions observed. The information presented in this study adds to our understanding of the common oral mucosal lesions occurring in the eunuch population. Efforts to increase patient awareness of the oral effects of tobacco use and to eliminate the habit are needed to improve the oral and general health of eunuchs.

  14. Zebrafish Caudal Fin Angiogenesis Assay-Advanced Quantitative Assessment Including 3-Way Correlative Microscopy.

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    Ruslan Hlushchuk

    Full Text Available Researchers evaluating angiomodulating compounds as a part of scientific projects or pre-clinical studies are often confronted with limitations of applied animal models. The rough and insufficient early-stage compound assessment without reliable quantification of the vascular response counts, at least partially, to the low transition rate to clinics.To establish an advanced, rapid and cost-effective angiogenesis assay for the precise and sensitive assessment of angiomodulating compounds using zebrafish caudal fin regeneration. It should provide information regarding the angiogenic mechanisms involved and should include qualitative and quantitative data of drug effects in a non-biased and time-efficient way.Basic vascular parameters (total regenerated area, vascular projection area, contour length, vessel area density were extracted from in vivo fluorescence microscopy images using a stereological approach. Skeletonization of the vasculature by our custom-made software Skelios provided additional parameters including "graph energy" and "distance to farthest node". The latter gave important insights into the complexity, connectivity and maturation status of the regenerating vascular network. The employment of a reference point (vascular parameters prior amputation is unique for the model and crucial for a proper assessment. Additionally, the assay provides exceptional possibilities for correlative microscopy by combining in vivo-imaging and morphological investigation of the area of interest. The 3-way correlative microscopy links the dynamic changes in vivo with their structural substrate at the subcellular level.The improved zebrafish fin regeneration model with advanced quantitative analysis and optional 3-way correlative morphology is a promising in vivo angiogenesis assay, well-suitable for basic research and preclinical investigations.

  15. Nerve growth factor injected into the gastric ulcer base incorporates into endothelial, neuronal, glial and epithelial cells: implications for angiogenesis, mucosal regeneration and ulcer healing.

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    Tanigawa, T; Ahluwalia, A; Watanabe, T; Arakawa, T; Tarnawski, A S

    2015-08-01

    A previous study has demonstrated that locally administered growth factors such as epidermal growth factor, basic fibroblast growth factor and hepatocyte growth factor can accelerate healing of experimental gastric ulcers in rats. That study indicates that locally administered growth factors can exert potent biological effects resulting in enhanced gastric ulcers healing. However, the fate of injected growth factors, their retention and localization to specific cellular compartments have not been examined. In our preliminary study, we demonstrated that local injection of nerve growth factor to the base of experimental gastric ulcers dramatically accelerates ulcer healing, increases angiogenesis - new blood vessel formation, and improves the quality of vascular and epithelial regeneration. Before embarking on larger, definitive and time sequence studies, we wished to determine whether locally injected nerve growth factor is retained in gastric ulcer's tissues and taken up by specific cells during gastric ulcer healing. Gastric ulcers were induced in anesthetized rats by local application of acetic acid using standard methods; and, 60 min later fluorescein isothiocyanate-labeled nerve growth factor was injected locally to the ulcer base. Rats were euthanized 2, 5 and 10 days later. Gastric specimens were obtained and processed for histology. Unstained paraffin sections were examined under a fluorescence microscope, and the incorporation of fluorescein isothiocyanate-labeled nerve growth factor into various gastric tissue cells was determined and quantified. In addition, we performed immunostaining for S100β protein that is expressed in neural components. Five and ten days after ulcer induction labeled nerve growth factor (injected to the gastric ulcer base) was incorporated into endothelial cells of blood vessels, neuronal, glial and epithelial cells, myofibroblasts and muscle cells. This study demonstrates for the first time that during gastric ulcer healing

  16. Noninvasive and Quantitative Assessment of In Vivo Fetomaternal Interface Angiogenesis Using RGD-Based Fluorescence

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    M. Keramidas

    2014-01-01

    Full Text Available Angiogenesis is a key process for proper placental development and for the success of pregnancy. Although numerous in vitro methods have been developed for the assessment of this process, relatively few reliable in vivo methods are available to evaluate this activity throughout gestation. Here we report an in vivo technique that specifically measures placental neovascularization. The technique is based on the measurement of a fluorescent alpha v beta 3 (αvβ3 integrin-targeting molecule called Angiolone-Alexa-Fluor 700. The αvβ3 integrin is highly expressed by endothelial cells during the neovascularization and by trophoblast cells during their invasion of the maternal decidua. Angiolone was injected to gravid mice at 6.5 and 11.5 days post coitus (dpc. The fluorescence was analyzed one day later at 7.5 and 12.5 dpc, respectively. We demonstrated that (i Angiolone targets αvβ3 protein in the placenta with a strong specificity, (ii this technique is quantitative as the measurement was correlated to the increase of the placental size observed with increasing gestational age, and (iii information on the outcome is possible, as abnormal placentation could be detected early on during gestation. In conclusion, we report the validation of a new noninvasive and quantitative method to assess the placental angiogenic activity, in vivo.

  17. Guidelines for the assessment of oral mucositis in adult chemotherapy, radiotherapy and haematopoietic stem cell transplant patients.

    NARCIS (Netherlands)

    Quinn, B.; Potting, C.M.J.; Stone, R.; Blijlevens, N.M.A.; Fliedner, M.; Margulies, A.; Sharp, L.

    2008-01-01

    Oral mucositis (OM) is a serious consequence of some chemotherapy and radiotherapy regimens. A number of reliable instruments are available to assess OM, but none are universally accepted. A unique collaboration of multi-disciplinary experts from Europe was formed to make recommendations on OM asses

  18. Biomarkers in the assessment of oral mucositis in head and neck cancer patients: a systematic review and meta-analysis.

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    Normando, Ana Gabriela Costa; Rocha, Camila Lopes; de Toledo, Isabela Porto; de Souza Figueiredo, Paulo Tadeu; Dos Reis, Paula Elaine Diniz; De Luca Canto, Graziela; Guerra, Eliete Neves Silva

    2017-09-01

    The aim of this study was to evaluate the capability of biomarkers to predict the risk of oral mucositis in head and neck cancer patients, as well as to assess the correlation between these biomarkers and the severity of mucositis. The search was performed at LILACS, PubMed, Science Direct, Scopus, and Web of Science. A search of the gray literature was performed on Google Scholar, OpenGrey, and ProQuest. The methodological quality of the included studies was assessed using the Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) tool, and the evidence quality was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system. After a two-step selection process, 26 studies met the eligibility criteria. In total, 27 biomarkers were evaluated, and the most frequent were the epidermal growth factor (EGF), C-reactive protein (CRP), genetic polymorphisms, tumor necrosis factor alpha (TNF-α), and erythrocyte sedimentation rate (ESR). The meta-analysis showed an expression of polymorphisms in XRCC1 (32.66%), XRCC3 (31.00%), and RAD51 (39.16%) genes, as well as an expression of protein biomarkers (39.57%), in patients with an increased risk of developing oral mucositis. Dosing biomarkers before starting radiation therapy may be a promising method to predict the risk of developing mucositis and allow radiosensitive patients to have a customized treatment. Although there is currently limited evidence to confirm the putative implementation of serum and salivary biomarkers to assess the correlation between them and the severity of mucositis, this current review provides new research directions.

  19. Clinical assessment of oral mucositis and candidiasis compare to chemotherapic nadir in transplanted patients.

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    Patussi, Cleverson; Sassi, Laurindo Moacir; Munhoz, Eduardo Ciliao; Zanicotti, Roberta Targa Stramandinoli; Schussel, Juliana Lucena

    2014-01-01

    Oral mucositis is a chief complication in patients undergoing hematopoietic stem cell transplantation (HSCT). It is considered a toxic inflammatory reaction that interferes with the patient's recuperation and quality of life. Oral candidiasis is a common fungal infection observed in dental practice, particularly in immunocompromised patients. The aim of this study was to evaluate the presence of oral mucositis and oral candidiasis in patients who underwent HSCT and their correlation with the chemotherapeutic nadir (lowest possible outcome). We evaluated patients with different diagnoses who underwent HSCT at the Hospital Erasto Gaertner. No chemotherapeutic nadir curves could be associated with mucositis, and patients had different presentations of mucositis. No patient developed oral candidiasis during hospitalization. Together with cell counts, we collected demographic data including age, oral hygiene, habits harmful to health, and the use of oral prostheses. It was observed that patients who smoked cigarettes before hospitalization showed less mucositis, resulting in no feeding problems or other comorbid conditions due to the effect of mucositis. However, the nadir of the chemotherapy curve, in isolation, is not a predictive tool for the appearance (or no appearance) of oral mucositis.

  20. Role of angiogenesis in the pathogenesis of oral lichen planus

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    Nitasha Mittal

    2012-01-01

    Full Text Available Background: The etiology of oral lichen planus (OLP is not fully understood. It is generally considered to be a T-cell mediated chronic inflammatory oral mucosal disease. There is increasing evidence that chronic inflammation is linked to the diseases associated with endothelial dysfunction and is involved in the induction of aberrant angiogenesis. Aim: Our aim was to evaluate the role of angiogenesis in the pathogenesis of OLP by immunohistochemistry, using the CD34 antibody. Materials and Methods: Forty tissue sections (7 of erosive lichen planus, 18 of reticular oral lichen planus, and 15 of normal oral mucosa, were assessed for microvessel density (MVD in five selected areas of high inflammatory infiltrate by immunohistochemistry for the expression of CD34 antibody. Results and Conclusion: The mean MVD was 44.47 in the control group (normal oral mucosa and 97.24 in the OLP group, showing that there is increased angiogenesis in the latter. Reticular OLP had mean MVD of 84.61 and erosive OLP had mean MVD of 129.71, showing relatively greater angiogenesis in erosive OLP as compared to reticular OLP. Thus, angiogenesis can be considered to play a role in both the etiopathogenesis and the progression of OLP.

  1. Base-metal dental casting alloy biocompatibility assessment using a human-derived three-dimensional oral mucosal model.

    LENUS (Irish Health Repository)

    McGinley, E L

    2012-01-01

    Nickel-chromium (Ni-Cr) alloys used in fixed prosthodontics have been associated with type IV Ni-induced hypersensitivity. We hypothesised that the full-thickness human-derived oral mucosa model employed for biocompatibility testing of base-metal dental alloys would provide insights into the mechanisms of Ni-induced toxicity. Primary oral keratinocytes and gingival fibroblasts were seeded onto Alloderm™ and maintained until full thickness was achieved prior to Ni-Cr and cobalt-chromium (Co-Cr) alloy disc exposure (2-72 h). Biocompatibility assessment involved histological analyses with cell viability measurements, oxidative stress responses, inflammatory cytokine expression and cellular toxicity analyses. Inductively coupled plasma mass spectrometry analysis determined elemental ion release levels. We detected adverse morphology with significant reductions in cell viability, significant increases in oxidative stress, inflammatory cytokine expression and cellular toxicity for the Ni-Cr alloy-treated oral mucosal models compared with untreated oral mucosal models, and adverse effects were increased for the Ni-Cr alloy that leached the most Ni. Co-Cr demonstrated significantly enhanced biocompatibility compared with Ni-Cr alloy-treated oral mucosal models. The human-derived full-thickness oral mucosal model discriminated between dental alloys and provided insights into the mechanisms of Ni-induced toxicity, highlighting potential clinical relevance.

  2. Clinical implications of the sugar absorption test : Intestinal permeability test to assess mucosal barrier function

    NARCIS (Netherlands)

    Uil, JJ; VanElburg, RM; VanOverbeek, FM; Mulder, CJJ; VanbergeHenegouwen, GP; Heymans, HSA

    1997-01-01

    Background: Functional integrity as an aspect of the mucosal barrier function of the small bowel can be estimated by the intestinal permeability for macromolecules. In the first part of this paper, an overview of intestinal permeability and its measurement is given. Methods: In the second part of th

  3. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis.

    Science.gov (United States)

    Hu, Zhiwei; Brooks, Samira A; Dormoy, Valérian; Hsu, Chia-Wen; Hsu, Hsue-Yin; Lin, Liang-Tzung; Massfelder, Thierry; Rathmell, W Kimryn; Xia, Menghang; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G; Prudhomme, Kalan R; Colacci, Annamaria; Hamid, Roslida A; Mondello, Chiara; Raju, Jayadev; Ryan, Elizabeth P; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Salem, Hosni K; Lowe, Leroy; Jensen, Lasse; Bisson, William H; Kleinstreuer, Nicole

    2015-06-01

    One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.

  4. Quantitative comparison of angiogenesis and lymphangiogenesis in cutaneous lichen planus and psoriasis: immunohistochemical assessment.

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    Výbohová, Desanka; Mellová, Yvetta; Adamicová, Katarína; Adamkov, Marián; Hešková, Gabriela

    2015-01-01

    Recent experimental studies revealed that angiogenesis and lymphangiogenesis are closely related to chronic inflammation. The present study aims to evaluate quantitative changes of blood and lymphatic microcirculatory beds in cutaneous lichen planus (CLP) and psoriatic lesions using immunohistochemical analysis with antibodies to CD34, D2-40 and VEGF. Morphometric software was used to determine the area of blood and lymphatic vessels (BVA and LVA) and also the VEGF positive area. Statistical analysis of these parameters confirmed a significant enlargement of both the blood and lymphatic microcirculatory beds in psoriatic and CLP lesions. BVA in CLP lesions was increased by 56% however this augmentation was not as great as in psoriatic lesions where BVA was increased by 123%. Interestingly, LVA in psoriatic and CLP lesions was increased equally by 85%. The strongest VEGF expression was detected in psoriatic lesions, with lower, but still significant, overexpression in CLP lesions. VEGF-C was significantly increased in both psoriatic and CLP lesions in comparable level. Noticeably higher VEGF and VEGF-C expression was observed in the epidermis than in the dermis. Finally, our results indicate that the level of angiogenesis is considerably greater in psoriatic lesions than in CLP lesions, but the level of lymphangiogenesis is equal in both psoriatic and CLP lesions.

  5. Assessment of indomethacin oral spray for the treatment of oropharyngeal mucositis-induced pain during anticancer therapy.

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    Momo, Kenji; Nagaoka, Hiroka; Kizawa, Yoshiyuki; Bukawa, Hiroki; Chiba, Shigeru; Kohda, Yukinao; Homma, Masato

    2017-07-15

    The efficacy and safety of indomethacin (IM) oral spray (OS) as a pain control therapy for oropharyngeal mucositis due to anticancer chemo- and radiotherapy were assessed in patients with head and neck carcinomas and haematological tumours. We observed 35 patients (male/female, 20/15; 53 ± 17 years) with oropharyngeal mucositis who were treated with IM-OS preparation for pain relief at University of Tsukuba Hospital, Japan. Analgesic effects were assessed using the six-grade face scale for pain in 28 patients at the start of IM oral spray treatment. Systemic exposure was assessed by determining urinary excretions of IM in seven patients. Pain relief was achieved in 26 (93%) patients at 25 (5-60) min after applying the IM-OS preparation (15.6 ± 3.4 μg/kg) and analgesic effects were maintained for 120 (10-360) min. The pain was significantly decreased after using the spray (3.6 ± 0.7 vs. 2.4 ± 0.9, p < 0.01). Moreover, urinary IM excretion rates after applying the IM spray preparation were 1.8 ± 0.8% of the IM oral spray dose (130.5 ± 77.7 μg/kg/day), which was markedly lower than that following oral administration of IM (60%). No adverse events were observed following application of the spray. The present IM spray is an effective and safe preparation for pain relief and can be used as an alternative therapeutic option for oropharyngeal mucositis in cancer patients.

  6. Closed-form solution of the convolution integral in the magnetic resonance dispersion model for quantitative assessment of angiogenesis.

    Science.gov (United States)

    Turco, S; Janssen, A J E M; Lavini, C; de la Rosette, J J; Wijkstra, H; Mischi, M

    2014-01-01

    Prostate cancer (PCa) diagnosis and treatment is still limited due to the lack of reliable imaging methods for cancer localization. Based on the fundamental role played by angiogenesis in cancer growth and development, several dynamic contrast enhanced (DCE) imaging methods have been developed to probe tumor angiogenic vasculature. In DCE magnetic resonance imaging (MRI), pharmacokinetic modeling allows estimating quantitative parameters related to the physiology underlying tumor angiogenesis. In particular, novel magnetic resonance dispersion imaging (MRDI) enables quantitative assessment of the microvascular architecture and leakage, by describing the intravascular dispersion kinetics of an extravascular contrast agent with a dispersion model. According to this model, the tissue contrast concentration at each voxel is given by the convolution between the intravascular concentration, described as a Brownian motion process according to the convective-dispersion equation, with the interstitium impulse response, represented by a mono-exponential decay, and describing the contrast leakage in the extravascular space. In this work, an improved formulation of the MRDI method is obtained by providing an analytical solution for the convolution integral present in the dispersion model. The performance of the proposed method was evaluated by means of dedicated simulations in terms of estimation accuracy, precision, and computation time. Moreover, a preliminary clinical validation was carried out in five patients with proven PCa. The proposed method allows for a reduction by about 40% of computation time without any significant change in estimation accuracy and precision, and in the clinical performance.

  7. 3D discrete angiogenesis dynamic model and stochastic simulation for the assessment of blood perfusion coefficient and impact on heat transfer between nanoparticles and malignant tumors.

    Science.gov (United States)

    Yifat, Jonathan; Gannot, Israel

    2015-03-01

    Early detection of malignant tumors plays a crucial role in the survivability chances of the patient. Therefore, new and innovative tumor detection methods are constantly searched for. Tumor-specific magnetic-core nano-particles can be used with an alternating magnetic field to detect and treat tumors by hyperthermia. For the analysis of the method effectiveness, the bio-heat transfer between the nanoparticles and the tissue must be carefully studied. Heat diffusion in biological tissue is usually analyzed using the Pennes Bio-Heat Equation, where blood perfusion plays an important role. Malignant tumors are known to initiate an angiogenesis process, where endothelial cell migration from neighboring vasculature eventually leads to the formation of a thick blood capillary network around them. This process allows the tumor to receive its extensive nutrition demands and evolve into a more progressive and potentially fatal tumor. In order to assess the effect of angiogenesis on the bio-heat transfer problem, we have developed a discrete stochastic 3D model & simulation of tumor-induced angiogenesis. The model elaborates other angiogenesis models by providing high resolution 3D stochastic simulation, capturing of fine angiogenesis morphological features, effects of dynamic sprout thickness functions, and stochastic parent vessel generator. We show that the angiogenesis realizations produced are well suited for numerical bio-heat transfer analysis. Statistical study on the angiogenesis characteristics was derived using Monte Carlo simulations. According to the statistical analysis, we provide analytical expression for the blood perfusion coefficient in the Pennes equation, as a function of several parameters. This updated form of the Pennes equation could be used for numerical and analytical analyses of the proposed detection and treatment method.

  8. Nanotherapeutics in angiogenesis: synthesis and in vivo assessment of drug efficacy and biocompatibility in zebrafish embryos

    Directory of Open Access Journals (Sweden)

    Cheng J

    2011-09-01

    Full Text Available Jinping Cheng1*, Yan-Juan Gu2*, Yajun Wang3, Shuk Han Cheng1, Wing-Tak Wong21Department of Biology and Chemistry, The City University of Hong Kong, Kowloon, 2Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, 3Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, People's Republic of China *These authors contributed equally to this work Background: Carbon nanotubes have shown broad potential in biomedical applications, given their unique mechanical, optical, and chemical properties. In this pilot study, carbon nanotubes have been explored as multimodal drug delivery vectors that facilitate antiangiogenic therapy in zebrafish embryos. Methods: Three different agents, ie, an antiangiogenic binding site (cyclic arginine-glycine-aspartic acid, an antiangiogenic drug (thalidomide, and a tracking dye (rhodamine, were conjugated onto single-walled carbon nanotubes (SWCNT. The biodistribution, efficacy, and biocompatibility of these triple functionalized SWCNT were tested in mammalian cells and validated in transparent zebrafish embryos. Results: Accumulation of SWCNT-associated nanoconjugates in blastoderm cells facilitated drug delivery applications. Mammalian cell xenograft assays demonstrated that these antiangiogenic SWCNT nanoconjugates specifically inhibited ectopic angiogenesis in the engrafted zebrafish embryos. Conclusion: This study highlights the potential of using SWCNT for generating efficient nanotherapeutics. Keywords: carbon nanotubes, drug delivery, antiangiogenic therapy

  9. Treatment for Cancer Patients with Oral Mucositis: Assessment Based on the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer in International Society of Oral Oncology (MASCC/ISOO) in 2013 and Proposal of Possible Novel Treatment with a Japanese Herbal Medicine.

    Science.gov (United States)

    Miyano, Kanako; Ueno, Takao; Yatsuoka, Wakako; Uezono, Yasuhito

    2016-01-01

    The cancer patients who received chemotherapy, radiotherapy, hematopoietic stem cell transplant and terminal care often have a wide range of stomatitis, which induces severe pain and limits fundamental life behaviors such as "eating, drinking and talking". In addition, oral mucositis frequently leads to systemic infection through opportunistic microorganisms, which causes extension of hospitalization. Severe oral mucositis often causes cancer patients to partially or completely discontinue/modify cancer therapy regimen, which adversely affects the curative effects of cancer. Therefore, the control of oral mucositis is important and indispensable for improvement of quality of life and prognosis. In this review, we introduce recent trends of the oral mucositis management in cancer patients, according to the following sentences; 1) pathophysiological mechanisms of oral mucositis, 2) assessment, 3) risk factors, 4) prevention and treatment, and 5) development of novel therapy for oral mucositis.

  10. Angiogenesis Assays.

    Science.gov (United States)

    Nambiar, Dhanya K; Kujur, Praveen K; Singh, Rana P

    2016-01-01

    Neoangiogenesis constitutes one of the first steps of tumor progression beyond a critical size of tumor growth, which supplies a dormant mass of cancerous cells with the required nutrient supply and gaseous exchange through blood vessels essentially needed for their sustained and aggressive growth. In order to understand any biological process, it becomes imperative that we use models, which could mimic the actual biological system as closely as possible. Hence, finding the most appropriate model is always a vital part of any experimental design. Angiogenesis research has also been much affected due to lack of simple, reliable, and relevant models which could be easily quantitated. The angiogenesis models have been used extensively for studying the action of various molecules for agonist or antagonistic behaviour and associated mechanisms. Here, we have described two protocols or models which have been popularly utilized for studying angiogenic parameters. Rat aortic ring assay tends to bridge the gap between in vitro and in vivo models. The chorioallantoic membrane (CAM) assay is one of the most utilized in vivo model system for angiogenesis-related studies. The CAM is highly vascularized tissue of the avian embryo and serves as a good model to study the effects of various test compounds on neoangiogenesis.

  11. Comprehensive Assessment of Host Responses to 5-Fluorouracil-Induced Oral Mucositis through Transcriptomic Analysis.

    Directory of Open Access Journals (Sweden)

    Chung-Ta Chang

    Full Text Available Chemotherapy plays an important role in current cancer therapy; however, several problems remain unsolved on the issue of host-therapeutics interaction. The purpose of this study was to investigate the host responses after 5-flurouracil (5-FU administration and to find the target genes and their relationship with other cytokines in the 5-FU-induced oral mucositis (OM mouse model through transcriptomic analysis.Thirty-six 6 to 8 week-old male BALB/c mice were randomly divided into the control group and 5-FU-treated group. In the 5-FU group, mice received 5-FU (100 mg/kg, intraperitoneally on day 1, day 8, day 15, day 22, and day 29, respectively. We evaluated the oral mucosal change under macroanalysis and histological examination at indicated periods, and then applied transcriptomic analysis of gene expression profile and Immunohistochemical stain to identify the target molecules related to 5-FU-induced OM.The most prominent histological change in this model was observed in the fifth week. The gene expression of Bone gamma-carboxyglutamate protein, related sequence 1 (Bglap-rs1 (-12.69-fold and Chitinase 3-like 4 (Chi3l4 (-6.35-fold were significantly down-regulated in this phase. The quantitative real-time PCR results also revealed the expression levels were 0.62-fold in Bglap-rs1 and 0.13-fold in Chi3l4 compared with the control group. Immunohistochemical stain showed significant expression of cluster of differentiation 11b (p<0.01, interleukin-1β (p<0.001 and tumor necrosis factor-α (p<0.05, and down-regulation of Bglap-rs1 (p<0.01 compared with the control group. By Kyoto Encyclopedia of Genes and Genomes pathway analysis, there were twenty-three pathways significantly participated in this study (p<0.05.Through comprehensively transcriptomic analysis and IHC stain, we discovered several valuable pathways, verified the main pro-inflammatory cytokines, and revealed two significantly down-regulated genes in the 5-FU-induced OM model. These

  12. Semiautomatic quantification of angiogenesis.

    Science.gov (United States)

    Boettcher, Markus; Gloe, Torsten; de Wit, Cor

    2010-07-01

    Angiogenesis is of major interest in developmental biology and cancer research. Different experimental approaches are available to study angiogenesis that have in common the need for microscopy, image acquisition, and analysis. Problems that are encountered hereby are the size of the structures, which requires generation of composite images and difficulties in quantifying angiogenic activity reliably and rapidly. Most graphic software packages lack some of the required functions for easy, semiautomatic quantification of angiogenesis and, consequently, multiple software packages or expensive programs have to be used to cover all necessary functions. A software package (AQuaL) to analyze angiogenic activity was developed using Java, which can be used platform-independently. It includes image acquisition relying on the Java Media Framework and an easy to use image alignment tool. Multiple overlapping images can be aligned and saved without limitations and loss of resolution into a composite image, which requires only the selection of a single point representing a characteristic structure in adjacent images. Angiogenic activity can be quantified in composite images semiautomatically by the assessment of the area overgrown by cells after filtering and image binarization. In addition, tagging of capillary-like structures allows quantification of their length and branching pattern. Both developed methods deliver reliable and correlating data as exemplified in the aortic ring angiogenesis assay. The developed software provides modular functions specifically targeted to quantify angiogenesis. Whereas the area measurement is time saving, length measurement provides additional information about the branching patterns, which is required for a qualitative differentiation of capillary growth. (c) 2010 Elsevier Inc. All rights reserved.

  13. Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice

    DEFF Research Database (Denmark)

    Willmann, Jürgen K; Cheng, Zhen; Davis, Corrine;

    2008-01-01

    To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice....

  14. Research progress in assessment of mucosal immunity to HIV%抗HIV黏膜免疫评价方法研究进展

    Institute of Scientific and Technical Information of China (English)

    杨二霞

    2011-01-01

    Mucosa is one of the most main transmission routes of HIV,and it is quite important to assess mucosal immune response for HIV vaccine effect evaluation. The assays for measuring immune response at mucosal sites in various animal models and human,including sampling methods,sample storage,types of mucosal biomarkers and measurements,are different. Thus,to estabilish a consensus set of evaluation system of mucosal response to HIV has important significance%黏膜是人类免疫缺陷病毒(human immunodeficiency virus,HIV)侵人机体最主要的途径之一,评价黏膜免疫应答对评价HIV疫苗效果至关重要.用于检测不同动物模型和人体黏膜免疫应答的方法不尽相同,包括黏膜取样方法、样品保存、黏膜标记物种类和检测等方面,因此,建立统一的抗HIV黏膜免疫应答评价系统具有重要的意义.

  15. Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation.

    Directory of Open Access Journals (Sweden)

    Xinhua Chen

    Full Text Available BACKGROUND AND AIMS: Saccharomyces boulardii (Sb can protect against intestinal injury and tumor formation, but how this probiotic yeast controls protective mucosal host responses is unclear. Angiogenesis is an integral process of inflammatory responses in inflammatory bowel diseases (IBD and required for mucosal remodeling during restitution. The aim of this study was to determine whether Sb alters VEGFR (vascular endothelial growth factor receptor signaling, a central regulator of angiogenesis. METHODS: HUVEC were used to examine the effects of Sb on signaling and on capillary tube formation (using the ECMatrix™ system. The effects of Sb on VEGF-mediated angiogenesis were examined in vivo using an adenovirus expressing VEGF-A(164 in the ears of adult nude mice (NuNu. The effects of Sb on blood vessel volume branching and density in DSS-induced colitis was quantified using VESsel GENeration (VESGEN software. RESULTS: 1 Sb treatment attenuated weight-loss (p<0.01 and histological damage (p<0.01 in DSS colitis. VESGEN analysis of angiogenesis showed significantly increased blood vessel density and volume in DSS-treated mice compared to control. Sb treatment significantly reduced the neo-vascularization associated with acute DSS colitis and accelerated mucosal recovery restoration of the lamina propria capillary network to a normal morphology. 2 Sb inhibited VEGF-induced angiogenesis in vivo in the mouse ear model. 3 Sb also significantly inhibited angiogenesis in vitro in the capillary tube assay in a dose-dependent manner (p<0.01. 4 In HUVEC, Sb reduced basal VEGFR-2 phosphorylation, VEGFR-2 phosphorylation in response to VEGF as well as activation of the downstream kinases PLCγ and Erk1/2. CONCLUSIONS: Our findings indicate that the probiotic yeast S boulardii can modulate angiogenesis to limit intestinal inflammation and promote mucosal tissue repair by regulating VEGFR signaling.

  16. Dietary proteins and angiogenesis.

    Science.gov (United States)

    Medina, Miguel Ángel; Quesada, Ana R

    2014-01-17

    Both defective and persistent angiogenesis are linked to pathological situations in the adult. Compounds able to modulate angiogenesis have a potential value for the treatment of such pathologies. Several small molecules present in the diet have been shown to have modulatory effects on angiogenesis. This review presents the current state of knowledge on the potential modulatory roles of dietary proteins on angiogenesis. There is currently limited available information on the topic. Milk contains at least three proteins for which modulatory effects on angiogenesis have been previously demonstrated. On the other hand, there is some scarce information on the potential of dietary lectins, edible plant proteins and high protein diets to modulate angiogenesis.

  17. [Markers of angiogenesis in tumor growth].

    Science.gov (United States)

    Nefedova, N A; Kharlova, O A; Danilova, N V; Malkov, P G; Gaifullin, N M

    2016-01-01

    Angiogenesis is a process of new blood vessels formation. The role of angiogenesis in growth, invasion and metastasis of malignant tumours is nowdays universally recognized. Though, investigation of mechanisms of blood vessels formation and elaboration methods for assessment of tumour angiogenesis are still up-dated. Another important concern are different aspects of usage of immunohistochemical markers of blood vessels endothelium (CD31 and CD34) for assessment of tumour aggressiveness and prognosis. The problems of malignant lymphangiogenesis are also up-to-date. The focus is on methods of immunohistochemical visualization of forming lymphatic vessels, role of podoplanin, the most reliable marker of lymphatic vessels, in their identification, and formulization of the main criteria for lymphangiogenesis estimation, its correlation with metastatic activity and prognostic potential. Studying of angiogenesis and lymph angiogenesis in malignant tumors is important and challenging direction for researching tumour progression and invention of antiangiogenic therapy.

  18. Quantitative assessment of tumor angiogenesis using real-time motion-compensated contrast-enhanced ultrasound imaging

    Science.gov (United States)

    Pysz, Marybeth A.; Guracar, Ismayil; Foygel, Kira; Tian, Lu; Willmann, Jürgen K.

    2015-01-01

    Purpose To develop and test a real-time motion compensation algorithm for contrast-enhanced ultrasound imaging of tumor angiogenesis on a clinical ultrasound system. Materials and methods The Administrative Institutional Panel on Laboratory Animal Care approved all experiments. A new motion correction algorithm measuring the sum of absolute differences in pixel displacements within a designated tracking box was implemented in a clinical ultrasound machine. In vivo angiogenesis measurements (expressed as percent contrast area) with and without motion compensated maximum intensity persistence (MIP) ultrasound imaging were analyzed in human colon cancer xenografts (n = 64) in mice. Differences in MIP ultrasound imaging signal with and without motion compensation were compared and correlated with displacements in x- and y-directions. The algorithm was tested in an additional twelve colon cancer xenograft-bearing mice with (n = 6) and without (n = 6) anti-vascular therapy (ASA-404). In vivo MIP percent contrast area measurements were quantitatively correlated with ex vivo microvessel density (MVD) analysis. Results MIP percent contrast area was significantly different (P < 0.001) with and without motion compensation. Differences in percent contrast area correlated significantly (P < 0.001) with x- and y-displacements. MIP percent contrast area measurements were more reproducible with motion compensation (ICC = 0.69) than without (ICC = 0.51) on two consecutive ultrasound scans. Following anti-vascular therapy, motion-compensated MIP percent contrast area significantly (P = 0.03) decreased by 39.4 ± 14.6 % compared to non-treated mice and correlated well with ex vivo MVD analysis (Rho = 0.70; P = 0.05). Conclusion Real-time motion-compensated MIP ultrasound imaging allows reliable and accurate quantification and monitoring of angiogenesis in tumors exposed to breathing-induced motion artifacts. PMID:22535383

  19. Oral mucositis - self-care

    Science.gov (United States)

    Cancer treatment - mucositis; Cancer treatment - mouth pain; Cancer treatment - mouth sores; Chemotherapy - mucositis; Chemotherapy - mouth pain; Chemotherapy - mouth sores; Radiation therapy - mucositis; Radiation therapy - mouth pain; Radiation ...

  20. Mediators of ocular angiogenesis

    Indian Academy of Sciences (India)

    Yureeda Qazi; Surekha Maddula; Balamurali K. Ambati

    2009-12-01

    Angiogenesis is the formation of new blood vessels from pre-existing vasculature. Pathologic angiogenesis in the eye can lead to severe visual impairment. In our review, we discuss the roles of both pro-angiogenic and anti-angiogenic molecular players in corneal angiogenesis, proliferative diabetic retinopathy, exudative macular degeneration and retinopathy of prematurity, highlighting novel targets that have emerged over the past decade.

  1. Prospective small bowel mucosal assessment immediately after chemoradiotherapy of unresectable locally advanced pancreatic cancer using capsule endoscopy: a case series.

    Science.gov (United States)

    Yamashina, Takeshi; Takada, Ryoji; Uedo, Noriya; Akasaka, Tomofumi; Hanaoka, Noboru; Takeuchi, Yoji; Higashino, Koji; Ioka, Tatsuya; Ishihara, Ryu; Teshima, Teruki; Nishiyama, Kinji; Iishi, Hiroyasu

    2016-01-01

    In this case series, three consecutive patients with unresectable locally advanced pancreatic cancer (ULAPC) underwent capsule endoscopy (CE) before and after chemoradiotherapy (CRT) to evaluate duodenal and jejunal mucosa, and to examine the relationship between CE findings and dose distribution. CE after CRT showed duodenitis and proximal jejunitis in all three patients. The most inflamed region was the third part of the duodenum, and in dose distribution, this was the closest region to the center of irradiation. This case series shows that CE can safely diagnose acute duodenitis and proximal jejunitis caused by CRT for ULAPC, and that dose distribution is possible to predict the degree of duodenal and jejunal mucosal injuries.

  2. Biomarkers and non-invasive tests for gastrointestinal mucositis

    NARCIS (Netherlands)

    N.S.S. Kuiken (Nicoline S. S.); E.H.H.M. Rings (Edmond); N.M. Blijlevens (Nicole ); W.J.E. Tissing (Wim)

    2017-01-01

    textabstractGastrointestinal mucositis is a complex inflammatory reaction of the mucous membranes, a side effect of both chemotherapy and radiotherapy. Currently, assessment scales are used to diagnose mucositis. However, a biomarker which would determine whether there is mucositis and thereby

  3. Biomarkers and non-invasive tests for gastrointestinal mucositis

    NARCIS (Netherlands)

    Kuiken, N. S. S.; Rings, E. H. H. M.; Blijlevens, N. M. A.; Tissing, Wim J. E.

    Gastrointestinal mucositis is a complex inflammatory reaction of the mucous membranes, a side effect of both chemotherapy and radiotherapy. Currently, assessment scales are used to diagnose mucositis. However, a biomarker which would determine whether there is mucositis and thereby establish the

  4. Angiogenesis in tissue-engineered small intestine.

    Science.gov (United States)

    Gardner-Thorpe, James; Grikscheit, Tracy C; Ito, Hiromichi; Perez, Alexander; Ashley, Stanley W; Vacanti, Joseph P; Whang, Edward E

    2003-12-01

    Tissue-engineered intestine offers promise as a potential novel therapy for short bowel syndrome. In this study we characterized the microvasculature and angiogenic growth factor profile of the engineered intestine. Twenty-three tissue-engineered small intestinal grafts were harvested from Lewis rat recipients 1 to 8 weeks after implantation. Architectural similarity to native bowel obtained from juvenile rats was assessed with hematoxylin and eosin-stained sections. Capillary density, measured after immunohistochemical staining for CD34, was expressed as number of capillaries per 1000 nuclei. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) tissue levels were measured by ELISA and normalized to total protein. Over the 8-week period cysts increased in volume (0.5 cm(3) at week 1 versus 12.6 cm(3) at week 8) and mass (1.30 +/- 0.29 versus 9.74 +/- 0.3 g; mean +/- SEM). Muscular and mucosal layers increased in thickness, but capillary density remained constant (82.95 +/- 4.81 capillaries per 1000 nuclei). The VEGF level was significantly higher in juvenile rat bowel than in engineered cyst (147.6 +/- 23.9 versus 42.3 +/- 3.4 pg/mg; p < 0.001). Tissue bFGF levels were also higher (315 +/- 65.48 versus 162.3 +/- 15.09 pg/mg; p < 0.05). The mechanism driving angiogenesis differs in engineered intestine and in normal bowel. VEGF and bFGF delivery may prove useful for bioengineering of intestine.

  5. Soliton driven angiogenesis

    Science.gov (United States)

    Bonilla, L. L.; Carretero, M.; Terragni, F.; Birnir, B.

    2016-08-01

    Angiogenesis is a multiscale process by which blood vessels grow from existing ones and carry oxygen to distant organs. Angiogenesis is essential for normal organ growth and wounded tissue repair but it may also be induced by tumours to amplify their own growth. Mathematical and computational models contribute to understanding angiogenesis and developing anti-angiogenic drugs, but most work only involves numerical simulations and analysis has lagged. A recent stochastic model of tumour-induced angiogenesis including blood vessel branching, elongation, and anastomosis captures some of its intrinsic multiscale structures, yet allows one to extract a deterministic integropartial differential description of the vessel tip density. Here we find that the latter advances chemotactically towards the tumour driven by a soliton (similar to the famous Korteweg-de Vries soliton) whose shape and velocity change slowly. Analysing these collective coordinates paves the way for controlling angiogenesis through the soliton, the engine that drives this process.

  6. Angiogenesis and liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Gülsüm ?zlem Elpek

    2015-01-01

    Recent data indicate that hepatic angiogenesis,regardless of the etiology, takes place in chronic liverdiseases (CLDs) that are characterized by inflammationand progressive fibrosis. Because antiangiogenictherapy has been found to be efficient inthe prevention of fibrosis in experimental models ofCLDs, it is suggested that blocking angiogenesis couldbe a promising therapeutic option in patients withadvanced fibrosis. Consequently, efforts are beingdirected to revealing the mechanisms involved inangiogenesis during the progression of liver fibrosis.Literature evidences indicate that hepatic angiogenesisand fibrosis are closely related in both clinical andexperimental conditions. Hypoxia is a major inducer ofangiogenesis together with inflammation and hepaticstellate cells. These profibrogenic cells stand at theintersection between inflammation, angiogenesis andfibrosis and play also a pivotal role in angiogenesis.This review mainly focuses to give a clear view on therelevant features that communicate angiogenesis withprogression of fibrosis in CLDs towards the-end point ofcirrhosis that may be translated into future therapies.The pathogenesis of hepatic angiogenesis associatedwith portal hypertension, viral hepatitis, non-alcoholicfatty liver disease and alcoholic liver disease are alsodiscussed to emphasize the various mechanisms involvedin angiogenesis during liver fibrogenesis.

  7. Monocyte Subpopulations in Angiogenesis

    Science.gov (United States)

    Dalton, Heather J.; Armaiz-Pena, Guillermo; Gonzalez-Villasana, Vianey; Lopez-Berestein, Gabriel; Bar-Eli, Menashe; Sood, Anil K.

    2014-01-01

    Growing understanding of the role of the tumor microenvironment in angiogenesis has brought monocyte-derived cells into focus. Monocyte subpopulations are an increasingly attractive therapeutic target in many pathologic states, including cancer. Before monocyte-directed therapies can be fully harnessed for clinical use, understanding of monocyte-driven angiogenesis in tissue development and homeostasis, as well as malignancy, is required. Here, we provide an overview of the mechanisms by which monocytic subpopulations contribute to angiogenesis in tissue and tumor development, highlight gaps in our existing knowledge, and discuss opportunities to exploit these cells for clinical benefit. PMID:24556724

  8. Angiogenesis and tumor

    Directory of Open Access Journals (Sweden)

    Kamran Mansouri

    2010-12-01

    Full Text Available Angiogenesis, the process of new blood vessel formation from existing ones, plays an important role in the physiologic circumstances such as embryonic development, placenta formation, and wound healing. It is also crucial to progress of pathogenic processes of a variety of disorders, including tumor growth and metastasis. In general, angiogenesis process is a multi-factorial and highly structured sequence of cellular events comprising migration, proliferation and differentiation of endothelial cells and finally vascular formation, maturation and remodeling.Thereby, angiogenesis inhibition as a helping agent to conventional therapies such as chemotherapy and radiation has attracted the scientists’ attentions studying in this field.

  9. Radiation induced oral mucositis

    Directory of Open Access Journals (Sweden)

    P S Satheesh Kumar

    2009-01-01

    Full Text Available Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii who also received concomitant chemotherapy; (iii who received a total dose over 5,000 cGy; and (iv who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene

  10. May the assessment of baseline mucosal molecular pattern predict the development of gluten related disorders among microscopic enteritis?

    Science.gov (United States)

    Losurdo, Giuseppe; Giorgio, Floriana; Piscitelli, Domenico; Montenegro, Lucia; Covelli, Claudia; Fiore, Maria Grazia; Giangaspero, Antonio; Iannone, Andrea; Principi, Mariabeatrice; Amoruso, Annacinzia; Barone, Michele; Di Leo, Alfredo; Ierardi, Enzo

    2016-01-01

    AIM To evaluate mucosal baseline mRNA expression of tissue transglutaminase 2 (tTG2), interferon gamma (IFNγ), toll-like receptor 2 (TLR2) and Myeloid Differentiation factor 88 (MyD88) in patients with microscopic enteritis (ME). METHODS We retrospectively enrolled 89 patients with ME of different etiology, which was defined within a 2-year mean period of follow-up. Baseline histological examination was performed on Hematoxylin-Eosin stained sections and CD3 lymphocyte immunohistochemistry was used for intraepithelial lymphocyte count (IELs). ME was defined according to the criteria of Bucharest Consensus Conference. For each patient, formalin embedded biopsy samples of the duodenum referred to the period of ME diagnosis were retrieved. Real-time polymerase chain reaction (RT-PCR) was used to detect the amount of mRNA coding for tTG2, IFNγ, TLR2 and MyD88, and the quantity was expressed as fold change compared to controls. Control group was represented by duodenal normal specimens from 15 healthy subjects undergoing endoscopy for functional symptoms. Comparisons among continuous variables were performed by One way analysis of variance (ANOVA) and Bonferroni’s test. The χ2 test was used for categorical variables. Pearson’s test was used to evaluate correlations. Receiver operating curves were drawn for all four markers to estimate sensitivity and specificity in discriminating the development of CD and GS. RESULTS After a period of follow up of 21.7 ± 11.7 mo, the following diagnoses were achieved: gluten related disorders in 48 subjects (31 CD; 17 GS) and non-gluten related ones in 41 (29 Irritable Bowel Syndrome - IBS; 12 Others). CD patients had the highest tTG2 levels (8.3 ± 4.5). The ANOVA plus Bonferroni analysis showed that CD > Other ME > GS = IBS > negative controls. A cut off value of 2.258 was able to discriminate between CD and GS with a sensitivity of 52.94% and a specificity of 87.1%. Additionally, CD patients had the highest IFNγ levels (8

  11. Role of serum levels of angiogenic cytokines in assessment of angiogenesis after stem cell therapy of diabetic patients with critical limb ischemia.

    Science.gov (United States)

    Dubsky, Michal; Jirkovska, Alexandra; Bem, Robert; Fejfarova, Vladimira; Varga, Martin; Kolesar, Libor; Pagacova, Libuse; Sykova, Eva; Jude, Edward B

    2014-01-01

    The release of proangiogenic cytokines into the circulation after stem cell (SC) therapy and compensatory increase of angiogenesis inhibitors may reflect local vasculogenesis but also can increase the risk of side effects. The aim of our study was to evaluate serum levels of angiogenic cytokines with regard to the assessment of local and systemic vasculogenesis in diabetic patients with no-option critical limb ischemia (NO-CLI). Twenty-five diabetic patients with NO-CLI treated with SCs isolated from bone marrow or stimulated peripheral blood were included in the study. Serum levels of proangiogenic cytokines (VEGF, bFGF, Ang-1, PDGF-AA, and PDGF-BB) and an antiangiogenic cytokine (endostatin) were assessed 6 months after cell treatment, compared to baseline values, and correlated with the number of injected CD34(+) cells. The clinical effect of SC therapy (assessed by changes in TcPO2) and potential systemic vasculogenesis (assessed by eye fundus examination) were evaluated after 6 months. Serum levels of angiogenic inhibitor endostatin increased significantly after 1 and 3 months (p = 0.0003), but no significant increase in serum levels of proangiogenic cytokines was observed. A significant correlation between number of injected CD34(+) cells and serum levels of endostatin was observed (r = 0.41, p cytokines did not correlate with CD34(+) cells. No correlation between increase in TcPO2 after treatment and serum levels of any of the angiogenic cytokines were seen, and no signs of systemic vasculogenesis in the retina were observed after 6 months. Despite the significant increase in the levels of the angiogenic inhibitor endostatin following SC treatment, there was no risk of systemic vasculogenesis after SC therapy as documented by serum levels of proangiogenic cytokines or changes in the retina.

  12. Using Light to Treat Mucositis and Help Wounds Heal

    Science.gov (United States)

    Ignatius, Robert W.; Martin, Todd S.; Kirk, Charles

    2008-01-01

    A continuing program of research and development is focusing on the use of controlled illumination by light-emitting diodes (LEDs) to treat mucositis and to accelerate healing of wounds. The basic idea is to illuminate the affected area of a patient with light of an intensity, duration, and wavelength (or combination of wavelengths) chosen to produce a therapeutic effect while generating only a minimal amount of heat. This method of treatment was originally intended for treating the mucositis that is a common complication of chemotherapy and radiation therapy for cancer. It is now also under consideration as a means to accelerate the healing of wounds and possibly also to treat exposure to chemical and radioactive warfare agents. Radiation therapy and many chemotherapeutic drugs often damage the mucosal linings of the mouth and gastrointestinal tract, leading to mouth ulcers (oral mucositis), nausea, and diarrhea. Hyperbaric-oxygen therapy is currently the standard of care for ischemic, hypoxic, infected, and otherwise slowlyhealing problem wounds, including those of oral mucositis. Hyperbaric-oxygen therapy increases such cellular activities as collagen production and angiogenesis, leading to an increased rate of healing. Biostimulation by use of laser light has also been found to be effective in treating mucositis. For hyperbaricoxygen treatment, a patient must remain inside a hyperbaric chamber for an extended time. Laser treatment is limited by laser-wavelength capabilities and by narrowness of laser beams, and usually entails the generation of significant amounts of heat.

  13. Development, optimization and characterization of a full-thickness tissue engineered human oral mucosal model for biological assessment of dental biomaterials.

    Science.gov (United States)

    Moharamzadeh, K; Brook, I M; Van Noort, R; Scutt, A M; Smith, K G; Thornhill, M H

    2008-04-01

    Restorative dental materials and oral health care products come into direct contact with oral mucosa and can cause adverse reactions. In order to obtain an accurate risk assessment, the in vitro test model must reflect the clinical situation as closely as possible. The aim of this study was to develop and optimize a three-dimensional full-thickness engineered human oral mucosal model, which can be used for biological assessment of dental materials. In this study human oral fibroblasts and keratinocytes were isolated from patients and seeded onto a number of collagen-based and synthetic scaffolds using a variety of cell seeding techniques and grown at the air/liquid interface to construct human oral mucosa equivalents. Suitability of 10 different scaffolds for engineering human oral mucosa was evaluated in terms of biocompatibility, biostability, porosity, and the ability to mimic normal human oral mucosa morphology. Finally an optimized full-thickness engineered human oral mucosa was developed and characterized using transmission electron microscopy and immunostaining. The oral mucosa reconstruct resembled native human oral mucosa and it has the potential to be used as an accurate and reproducible test model in mucotoxicity and biocompatibility evaluation of dental materials.

  14. May the assessment of baseline mucosal molecular pattern predict the development of gluten related disorders among microscopic enteritis?

    Science.gov (United States)

    Losurdo, Giuseppe; Giorgio, Floriana; Piscitelli, Domenico; Montenegro, Lucia; Covelli, Claudia; Fiore, Maria Grazia; Giangaspero, Antonio; Iannone, Andrea; Principi, Mariabeatrice; Amoruso, Annacinzia; Barone, Michele; Di Leo, Alfredo; Ierardi, Enzo

    2016-09-21

    To evaluate mucosal baseline mRNA expression of tissue transglutaminase 2 (tTG2), interferon gamma (IFNγ), toll-like receptor 2 (TLR2) and Myeloid Differentiation factor 88 (MyD88) in patients with microscopic enteritis (ME). We retrospectively enrolled 89 patients with ME of different etiology, which was defined within a 2-year mean period of follow-up. Baseline histological examination was performed on Hematoxylin-Eosin stained sections and CD3 lymphocyte immunohistochemistry was used for intraepithelial lymphocyte count (IELs). ME was defined according to the criteria of Bucharest Consensus Conference. For each patient, formalin embedded biopsy samples of the duodenum referred to the period of ME diagnosis were retrieved. Real-time polymerase chain reaction (RT-PCR) was used to detect the amount of mRNA coding for tTG2, IFNγ, TLR2 and MyD88, and the quantity was expressed as fold change compared to controls. Control group was represented by duodenal normal specimens from 15 healthy subjects undergoing endoscopy for functional symptoms. Comparisons among continuous variables were performed by One way analysis of variance (ANOVA) and Bonferroni's test. The χ(2) test was used for categorical variables. Pearson's test was used to evaluate correlations. Receiver operating curves were drawn for all four markers to estimate sensitivity and specificity in discriminating the development of CD and GS. After a period of follow up of 21.7 ± 11.7 mo, the following diagnoses were achieved: gluten related disorders in 48 subjects (31 CD; 17 GS) and non-gluten related ones in 41 (29 Irritable Bowel Syndrome - IBS; 12 Others). CD patients had the highest tTG2 levels (8.3 ± 4.5). The ANOVA plus Bonferroni analysis showed that CD > Other ME > GS = IBS > negative controls. A cut off value of 2.258 was able to discriminate between CD and GS with a sensitivity of 52.94% and a specificity of 87.1%. Additionally, CD patients had the highest IFNγ levels (8.5 ± 4.1). ANOVA plus

  15. Nasal mucosal biopsy

    Science.gov (United States)

    Biopsy - nasal mucosa; Nose biopsy ... to fast for a few hours before the biopsy. ... Nasal mucosal biopsy is usually done when abnormal tissue is seen during examination of the nose. It may also be done ...

  16. ER Stress and Angiogenesis.

    Science.gov (United States)

    Binet, François; Sapieha, Przemyslaw

    2015-10-01

    Proper tissue vascularization is vital for cellular function as it delivers oxygen, nutrients, hormones, and immune cells and helps to clear cellular debris and metabolic waste products. Tissue angiogenesis occurs to satisfy energy requirements and cellular sensors of metabolic imbalance coordinate vessel growth. In this regard, the classical pathways of the unfolded protein response activated under conditions of ER stress have recently been described to generate angiomodulatory or angiostatic signals. This review elaborates on the link between angiogenesis and ER stress and discusses the implications for diseases characterized by altered vascular homeostasis, such as cancer, retinopathies, and atherosclerosis.

  17. Alteration in buccal mucosal cells due to the effect of tobacco and alcohol by assessing the silver-stained nucleolar organiser regions and micronuclei

    Directory of Open Access Journals (Sweden)

    Sachin Jindal

    2013-01-01

    Conclusions: Tobacco and alcohol consumption produce alteration in apparently normal buccal mucosal cells, which may cumulatively lead to carcinomatous changes. Result of these changes may be used as educational tool in cessation of habits.

  18. Cancer Immunotherapy of Targeting Angiogenesis

    Institute of Scientific and Technical Information of China (English)

    JianmeiHou; LingTian; YuquanWei

    2004-01-01

    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy may be a useful approach to cancer therapy. This review discussed tumor angiogenesis and immunotherapy of targeting tumor angiogenesis from two main aspects: (1) active vaccination to induce effective anti-angiogenesis immunity; (2) passive immunotherapy with anti-pro-angiogenic molecules relevant antibody. Evidence from the recent years suggested that anti-angiogenic therapy should be one of the most promising approaches to cancer therapy.

  19. Study on Angiogenesis Factor of Human Osteosarcoma

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Angiogenesis factor of human osteosarcoma was partially purified and its biological features were studied. The active peptide with 8000 to 10 000 u molecular weight in the conditioned medium obtained from the cultivation of human osteosarcoma cells were partially purified by ultrafiltration, chromatography and dialysis. The angiogenic effects of the fractions were assessed by proliferation assay of human umbilical vein and pig aorta thoracic endothelial cells. The results showed that the chromatography fractions of 4 to 6 could significantly promote the proliferation of the endothelial cells. It was suggested that the human osteosarcoma cells could synthesize and secrete angiogenesis factor with a molecular weight of 8000 to 10 000 u.

  20. In Vivo Models of Muscle Angiogenesis.

    Science.gov (United States)

    Egginton, Stuart

    2016-01-01

    Angiogenesis is an important determinant of tissue function, from delivery of oxygen and other substrates to removal of waste products, in health and disease (e.g., adaptive or pathological remodelling). The phenotype and functional responses of endothelial cells are conditioned by systemic humoral signals and local environmental factors, including the haemodynamic forces that act upon them. Here we describe some interventions that have been helpful in unraveling the integrative nature of the complex in vivo response, and quantitative assessment of angiogenesis in muscle.

  1. The Harvard angiogenesis story.

    Science.gov (United States)

    Miller, Joan W

    2014-01-01

    I shall discuss the work of researchers at Harvard Medical School who came together in the early 1990s. Scattered across various Harvard-affiliated hospitals and research centers, these individuals were unified by their interest in ocular neovascularization. Together and separately, they investigated models of ocular neovascularization, exploring tumor angiogenesis in eye development and disease.

  2. How phototherapy affects angiogenesis

    Science.gov (United States)

    Dyson, Mary

    2007-02-01

    Angiogenesis is essential for normal growth, tissue repair and regeneration. Its stimulation accelerates repair and regeneration including wound healing where these processes are delayed. Its inhibition can reduce the rate of growth of solid tumors. Phototherapy can accelerate the resolution of acute inflammation with the result that the proliferative phase of tissue repair, when angiogenesis occurs, begins earlier than in sham-irradiated controls. Evidence that angiogenesis is enhanced in dermal repair, tendon repair and bone regeneration in rodents is presented. The cellular mechanisms that control angiogenesis involve the interaction of endothelial cells, macrophages, pericytes and other cells in response, for example, to changes in the availability of oxygen in the local environment. Pericytes and macrophages modulate endothelial cell proliferation; pericytes guide endothelial cell migration. The stimulation of endothelial cell proliferation in vitro following exposure to red (660 nm) and infrared (820 nm) radiation, 15 mW, at 2-8 J/cm2 is presented. 1J/cm2 was ineffective. 820 nm irradiation, 15 mW, at 8 J/cm2 was observed to inhibit pericyte proliferation in vitro. Indirect effects on endothelial cell and pericyte proliferation followed stimulation of soluble mediator production by macrophages following exposure to red and infrared radiation. The potential clinical significance of the results obtained is discussed and the necessity of clinical trials emphasized.

  3. [Non-invasive assessment used to evaluate the nasal and oral mucosal cytological status in sociohygienic monitoring].

    Science.gov (United States)

    Beliaeva, N N; Ponomareva, O Iu; Aleksandrova, V P; Olesinov, A A; Budarina, O V; Gasimova, Z M

    2009-01-01

    By analyzing their own studies and the results of other studies by other investigators, the authors provide evidence that the noninvasive evaluation of the nasal and oral cytological status is one of techniques for assessing the health status and reflects the organism's state varying with environmental pollution, which enables it to be recommended for sociohygienic monitoring.

  4. Ischemia-driven angiogenesis.

    Science.gov (United States)

    Dor, Y; Keshet, E

    1997-11-01

    New blood vessels usually develop in places where they are most needed. A prime example of neovascularization representing a positive feedback response to insufficient perfusion is the development of collateral blood vessels in the ischemic myocardium and leg. The recent discoveries of hypoxia-inducible transcription and angiogenic factors have provided important mechanistic links between the metabolic consequences of ischemia and compensatory angiogenesis. Vascular endothelial growth factor (VEGF) has emerged as the key mediator of ischemia-driven angiogenesis. Environmental stresses, including hypoxia, hypoglycemia, and hypoferremia, upregulate VEGF expression at both the transcriptional and posttranscriptional levels. VEGF acts in turn on adjacent vascular beds expressing cognate receptors and induces sprouting and capillary growth toward the ischemic tissue. In addition to expanding the vasculature at sites where existing vessels have been occluded or obliterated, VEGF also functions to match the vascular density according to development and physiologic increases in oxygen consumption. Fine adjustment of the vasculature includes a step of oxygen-regulated vascular pruning mediated by VEGF in its capacity as a survival factor for newly formed vessels. Pathologic settings of ischemia-driven angiogenesis include a major component of stress-induced angiogenesis during tumor neovascularization and abnormal vessel growth associated with retinopathies. The latter represents an excessive angiogenic response to conditions of severe retinal ischemia. Further insights into the mechanism of stress-induced angiogenesis are likely to suggest new ways to augment growth of collateral vessels and to restrain unwarranted neovascularization in tumors and retinopathies. (Trends Cardiovasc Med 1997;7:289-294). © 1997, Elsevier Science Inc.

  5. A phase I study assessing the safety and pharmacokinetics of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin in patients with solid tumors

    NARCIS (Netherlands)

    Gietema, J. A.; Hoekstra, R.; de Vos, F. Y. F. L.; Uges, D. R. A.; van der Gaast, A.; Groen, H. J. M.; Loos, W. J.; Knight, R. A.; Carr, R. A.; Humerickhouse, R. A.; Eskens, F. A. L. M.

    2006-01-01

    Background: The aim of the study was to determine the safety profile, pharmacokinetics and potential drug interactions of the angiogenesis inhibitor ABT-510 combined with gemcitabine-cisplatin chemotherapy in patients with solid tumors. Patients and methods: Patients with advanced solid tumors recei

  6. Comparative assessment of the therapeutic effects of the topical and systemic forms of Hypericum perforatum extract on induced oral mucositis in golden hamsters.

    Science.gov (United States)

    Tanideh, N; Namazi, F; Andisheh Tadbir, A; Ebrahimi, H; Koohi-Hosseinabadi, O

    2014-10-01

    Oral mucositis is a common and irritating complication of chemotherapy and radiotherapy for malignancies. Current treatments have failed to achieve complete remission of this complication. The St. John's wort plant (Hypericum perforatum) has long been known for its anti-inflammatory and antibacterial effects. The current study was designed to investigate the therapeutic efficacy of the topical and systemic administration of H. perforatum extract on oral mucositis. Oral mucositis was induced in 72 male golden hamsters by administration of 5-fluorouracil (60mg/kg), on days 0, 5, and 10 of the study. The cheek pouch was scratched with a sterile needle on days 1 and 2. On days 12-17, H. perforatum extract topical gel 10%, oral H. perforatum extract (300mg/kg), and gel base groups were treated and then compared with a control group. Weights and blood samples were evaluated, biopsies from buccal lesions were examined histopathologically, and tissue malondialdehyde (MDA) was measured. Both of the H. perforatum extract treatment groups saw a significant relief in oral mucositis compared to the control and base gel groups; the systemic form was superior to the topical form. H. perforatum extract, administered orally or topically, expedited the healing of chemotherapy-induced oral mucositis in hamsters.

  7. Molecular Imaging System for Monitoring Tumor Angiogenesis

    Science.gov (United States)

    Aytac, Esra; Burcin Unlu, Mehmet

    2012-02-01

    In cancer, non-invasive imaging techniques that monitor molecular processes associated with the tumor angiogenesis could have a central role in the evaluation of novel antiangiogenic and proangiogenic therapies as well as early detection of the disease. Matrix metalloproteinases (MMP) can serve as specific biological targets for imaging of angiogenesis since expression of MMPs is required for angiogenesis and has been found to be upregulated in every type of human cancer and correlates with stage, invasive, metastatic properties and poor prognosis. However, for most cancers it is still unknown when, where and how MMPs are involved in the tumor angiogenesis [1]. Development of high-resolution, high sensitivity imaging techniques in parallel with the tumor models could prove invaluable for assessing the physical location and the time frame of MMP enzymatic acitivity. The goal of this study is to understand where, when and how MMPs are involved in the tumor angiogenesis. We will accomplish this goal by following two objectives: to develop a high sensitivity, high resolution molecular imaging system, to develop a virtual tumor simulator that can predict the physical location and the time frame of the MMP activity. In order to achieve our objectives, we will first develop a PAM system and develop a mathematical tumor model in which the quantitative data obtained from the PAM can be integrated. So, this work will develop a virtual tumor simulator and a molecular imaging system for monitoring tumor angiogenesis. 1.Kessenbrock, K., V. Plaks, and Z. Werb, MMP:regulators of the tumor microenvironment. Cell, 2010. 141(1)

  8. Angiogenesis in vestibular schwannomas

    DEFF Research Database (Denmark)

    Møller, Martin Nue; Werther, Kim; Nalla, Amarnadh;

    2010-01-01

    Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are potent mediators of tumor angiogenesis. It has been demonstrated that vestibular schwannoma VEGF expression correlates with tumor growth pattern, whereas knowledge on the expression of MMPs is lacking. This study t...... targets the angiogenic process by investigation of tumor expression of MMP-2, MMP-9, and tissue inhibitors of metalloproteinase (TIMP)-1. A possible correlation with gender, patient age, symptom duration, tumor size, and the absolute and relative growth rate is explored....

  9. Perlecan and tumor angiogenesis

    DEFF Research Database (Denmark)

    Jiang, Xinnong; Couchman, John R

    2003-01-01

    Perlecan is a major heparan sulfate proteoglycan (HSPG) of basement membranes (BMs) and connective tissues. The core protein of perlecan is divided into five domains based on sequence homology to other known proteins. Commonly, the N-terminal domain I of mammalian perlecan is substituted with thr...... have unwanted promoting effects on tumor cell proliferation and tumor angiogenesis. Understanding of these attributes at the molecular level may offer opportunities for therapeutic intervention....

  10. The assessment of general well-being using spontaneous burrowing behaviour in a short-term model of chemotherapy-induced mucositis in the rat.

    Science.gov (United States)

    Whittaker, A L; Lymn, K A; Nicholson, A; Howarth, G S

    2015-01-01

    Mucositis is a common and serious side-effect experienced by cancer patients during treatment with chemotherapeutic agents. Consequently, programmes of research focus on the elucidation of novel therapeutics for alleviation of mucositis symptoms, and these frequently use animal models. However, although these models are assumed to be painful and distressing to the animal, endpoints are difficult to determine. The aim of this study was to evaluate whether a change in burrowing behaviour could provide an indication of disease onset and potentially be applied as a humane endpoint. Baseline burrowing behaviour was measured in healthy animals on three occasions by determining the weight of gravel displaced from a hollow tube. Mucositis was then induced in the same animals by intraperitoneal injection of 5-fluorouracil (150 mg/kg) and burrowing behaviour recorded over three consecutive days. Standard measures of disease progression, including body weight loss and clinical score, were also made. The presence of mucositis was confirmed at necropsy by findings of decreased duodenal and colon lengths, and reduced liver, spleen and thymus weights in comparison with non-treated control animals. Histological score of the jejunum and ileum was also significantly increased. Mucositis onset coincided with a decrease in mean burrowing behaviour which was progressive, however this result did not achieve statistical significance (P = 0.66).We conclude that burrowing may be a useful indicator of inflammation in the mucositis model, although this requires further characterization. Pre-selection of animals into treatment groups based on their prior burrowing performance should be pursued in further studies.

  11. A method to assess target gene involvement in angiogenesis in vitro and in vivo using lentiviral vectors expressing shRNA.

    Directory of Open Access Journals (Sweden)

    Wayne Blosser

    Full Text Available Current methods to study angiogenesis in cancer growth and development can be difficult and costly, requiring extensive use of in vivo methodologies. Here, we utilized an in vitro adipocyte derived stem cell and endothelial colony forming cell (ADSC/ECFC co-culture system to investigate the effect of lentiviral-driven shRNA knockdown of target genes compared to a non-targeting shRNA control on cord formation using High Content Imaging. Cord formation was significantly reduced following knockdown of the VEGF receptor VEGFR2 in VEGF-driven cord formation and the FGF receptor FGFR1 in basic FGF (bFGF-driven cord formation. In addition, cord formation was significantly reduced following knockdown of the transcription factor forkhead box protein O1 (FOXO1, a protein with known positive effects on angiogenesis and blood vessel stabilization in VEGF- and bFGF-driven cord formation. Lentiviral shRNA also demonstrated utility for stable knockdown of VEGFR2 and FOXO1 in ECFCs, allowing for interrogation of protein knockdown effects on in vivo neoangiogenesis in a Matrigel plug assay. In addition to interrogating the effect of gene knockdown in endothelial cells, we utilized lentiviral shRNA to knockdown specificity protein 1 (SP1, a transcription factor involved in the expression of VEGF, in U-87 MG tumor cells to demonstrate the ability to analyze angiogenesis in vitro in a tumor-driven transwell cord formation system and in tumor angiogenesis in vivo. A significant reduction in tumor-driven cord formation, VEGF secretion, and in vivo tumor angiogenesis was observed upon SP1 knockdown. Therefore, evaluation of target gene knockdown effects in the in vitro co-culture cord formation assay in the ADSC/ECFC co-culture, ECFCs alone, and in tumor cells translated directly to in vivo results, indicating the in vitro method as a robust, cost-effective and efficient in vitro surrogate assay to investigate target gene involvement in endothelial or tumor cell

  12. Endostatin derivative angiogenesis inhibitors

    Institute of Scientific and Technical Information of China (English)

    ZHENG Meng-jie

    2009-01-01

    Objective To throw light on the superiority of the anti-angiogenesis activity of endostatin (ES) derivatives by reviewing the recent progress in the field of ES molecular structure modification.Data sources The data used in this article were mainly from PubMed with relevant English articles published from 1971 to May 2008.The search terms were "endostatin" and "angiothesis".Study selection Articles involved in the ES molecular structure modification and the original milestone articles were selected.Results A number of ES derivatives were designed and studied to improve its clinical relevance.The modified ES with polyethylene glycol (PEG),low molecular weight heparin (LMWH) and IgG Fc domain extended the circulation half-life.Meanwhile the recombinant ESs showed more potent anti-tumor activity than native ES in mouse xenografts.Mutated ES also changed its anti-angiogenesis activity.Conclusions The anti-angiogenesis treatment remains a promising tumor therapeutic strategy.New ES derivatives would be a good choice to meet the future challenge on clinical application of ES.

  13. Mucosal vaccination of fish

    NARCIS (Netherlands)

    Rombout, J.H.W.M.; Kiron, V.

    2014-01-01

    Among the novel vaccination methods, mucosal vaccination seems to possess all the desired criteria. The chapter reviews the state-of-the-art knowledge regarding this type of vaccination with a focus on their uptake, immune stimulation, and where possible, discusses their potential as future vaccines

  14. Voice disorders in mucosal leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Ana Cristina Nunes Ruas

    Full Text Available INTRODUCTION: Leishmaniasis is considered as one of the six most important infectious diseases because of its high detection coefficient and ability to produce deformities. In most cases, mucosal leishmaniasis (ML occurs as a consequence of cutaneous leishmaniasis. If left untreated, mucosal lesions can leave sequelae, interfering in the swallowing, breathing, voice and speech processes and requiring rehabilitation. OBJECTIVE: To describe the anatomical characteristics and voice quality of ML patients. MATERIALS AND METHODS: A descriptive transversal study was conducted in a cohort of ML patients treated at the Laboratory for Leishmaniasis Surveillance of the Evandro Chagas National Institute of Infectious Diseases-Fiocruz, between 2010 and 2013. The patients were submitted to otorhinolaryngologic clinical examination by endoscopy of the upper airways and digestive tract and to speech-language assessment through directed anamnesis, auditory perception, phonation times and vocal acoustic analysis. The variables of interest were epidemiologic (sex and age and clinic (lesion location, associated symptoms and voice quality. RESULTS: 26 patients under ML treatment and monitored by speech therapists were studied. 21 (81% were male and five (19% female, with ages ranging from 15 to 78 years (54.5+15.0 years. The lesions were distributed in the following structures 88.5% nasal, 38.5% oral, 34.6% pharyngeal and 19.2% laryngeal, with some patients presenting lesions in more than one anatomic site. The main complaint was nasal obstruction (73.1%, followed by dysphonia (38.5%, odynophagia (30.8% and dysphagia (26.9%. 23 patients (84.6% presented voice quality perturbations. Dysphonia was significantly associated to lesions in the larynx, pharynx and oral cavity. CONCLUSION: We observed that vocal quality perturbations are frequent in patients with mucosal leishmaniasis, even without laryngeal lesions; they are probably associated to disorders of some

  15. Undernutrition, Vitamin A and Iron Deficiency Are Associated with Impaired Intestinal Mucosal Permeability in Young Bangladeshi Children Assessed by Lactulose/Mannitol Test.

    Science.gov (United States)

    Hossain, Md Iqbal; Haque, Rashidul; Mondal, Dinesh; Mahfuz, Mustafa; Ahmed, Am Shamsir; Islam, M Munirul; Guerrant, Richard L; Petri, William A; Ahmed, Tahmeed

    2016-01-01

    Lactulose/mannitol (L:M) test has been used as a non-invasive marker of intestinal mucosal -integrity and -permeability (enteropathy). We investigated the association of enteropathy with anthropometrics, micronutrient- status, and morbidity in children. The urine and blood samples were collected from 925 children aged 6-24 months residing in Mirpur slum of Dhaka, Bangladesh during November 2009 to April 2013. L:M test and micronutrient status were assessed in the laboratory of International Centre for Diarrhoeal Diseases Research, Bangladesh (icddr,b) following standard procedure. Mean±SD age of the children was 13.2±5.2 months and 47.8% were female. Urinary- lactulose recovery was 0.264±0.236, mannitol recovery was 3.423±3.952, and L:M was 0.109±0.158. An overall negative correlation (Spearman's-rho) of L:M was found with age (rs = -0.087; p = 0.004), weight-for-age (rs = -0.077; p = 0.010), weight-for-length (rs = -0.060; p = 0.034), mid-upper-arm-circumference (rs = -0.098; p = 0.001) and plasma-retinol (rs = -0.105; p = 0.002); and a positive correlation with plasma α-1-acid glycoprotein (rs = 0.066; p = 0.027). However, most of the correlations were not very strong. Approximately 44% of children had enteropathy as reflected by L:M of ≥0.09. Logistic regression analysis revealed that younger age (infancy) (adjusted odds ratio (AOR) = 1.35; p = 0.027), diarrhea (AOR = 4.00; p = 0.039) or fever (AOR = 2.18; p = 0.003) within previous three days of L:M test were the risk factors of enteropathy (L:M of ≥0.09). Enteropathy (high L:M) is associated with younger age, undernutrition, low vitamin A and iron status, and infection particularly diarrhea and fever.

  16. MUCOSAL DRUG DELIVERY SYSTEM

    OpenAIRE

    Madan Jyotsana; Banode Sagar; Dangi Mahesh

    2010-01-01

    The process of mucoadhesion involving a polymeric drug delivery system is a complex one that includes processes such as wetting, adsorption and interpenetration of polymer chains. The success and degree of mucoadhesion bonding is influenced by various polymer-based properties such as the degree of cross-linking, chain length and the presence of various functional groupings. The attractiveness of mucosal-targeted controlled drug delivery of active pharmaceutical ingredients, has led formulatio...

  17. Mucosal adaptation to aspirin induced gastric damage in humans. Studies on blood flow, gastric mucosal growth, and neutrophil activation.

    Science.gov (United States)

    Konturek, J W; Dembinski, A; Stoll, R; Domschke, W; Konturek, S J

    1994-01-01

    The gastropathy associated with the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin is a common side effect of this class of drugs, but the precise mechanisms by which they cause mucosal damage have not been fully explained. During continued use of an injurious substance, such as aspirin, the extent of gastric mucosal damage decreases and this phenomenon is named gastric adaptation. To assess the extent of mucosal damage by aspirin and subsequent adaptation the effects of 14 days of continuous, oral administration of aspirin (2 g per day) to eight healthy male volunteers was studied. To estimate the rate of mucosal damage, gastroscopy was performed before (day 0) and at days 3, 7, 14 of aspirin treatment. Gastric microbleeding and gastric mucosal blood flow were measured using laser Doppler flowmeter and mucosal biopsy specimens were taken for the estimation of tissue DNA synthesis and RNA and DNA concentration. In addition, the activation of neutrophils in peripheral blood was assessed by measuring their ability to associate with platelets. Aspirin induced acute damage mainly in gastric corpus, reaching at day 3 about 3.5 on the endoscopic Lanza score but lessened to about 1.5 at day 14 pointing to the occurrence of gastric adaptation. Mucosal blood flow increased at day 3 by about 50% in the gastric corpus and by 88% in the antrum. The in vitro DNA synthesis and RNA concentration, an index of mucosal growth, were reduced at day 3 but then increased to reach about 150% of initial value at the end of aspirin treatment. It is concluded that the treatment with aspirin in humans induces gastric adaptation to this agent, which entails the increase in mucosal blood flow, the rise in neutrophil activation, and the enhancement in mucosal growth. PMID:7959223

  18. Diabetes and Wound Angiogenesis

    Science.gov (United States)

    Okonkwo, Uzoagu A.; DiPietro, Luisa A.

    2017-01-01

    Diabetes Mellitus Type II (DM2) is a growing international health concern with no end in sight. Complications of DM2 involve a myriad of comorbidities including the serious complications of poor wound healing, chronic ulceration, and resultant limb amputation. In skin wound healing, which has definite, orderly phases, diabetes leads to improper function at all stages. While the etiology of chronic, non-healing diabetic wounds is multi-faceted, the progression to a non-healing phenotype is closely linked to poor vascular networks. This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis. Additionally, this review considers therapeutics that may offer promise to better wound healing outcomes. PMID:28671607

  19. Diabetes and Wound Angiogenesis

    Directory of Open Access Journals (Sweden)

    Uzoagu A. Okonkwo

    2017-07-01

    Full Text Available Diabetes Mellitus Type II (DM2 is a growing international health concern with no end in sight. Complications of DM2 involve a myriad of comorbidities including the serious complications of poor wound healing, chronic ulceration, and resultant limb amputation. In skin wound healing, which has definite, orderly phases, diabetes leads to improper function at all stages. While the etiology of chronic, non-healing diabetic wounds is multi-faceted, the progression to a non-healing phenotype is closely linked to poor vascular networks. This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis. Additionally, this review considers therapeutics that may offer promise to better wound healing outcomes.

  20. Buccal Mucosal Graft Urethroplasty

    Directory of Open Access Journals (Sweden)

    Angela M. Arlen

    2010-01-01

    Full Text Available At our institution, the majority of buccal mucosal graft urethroplasties are performed using a two-team approach with an otolaryngologic surgeon. We report our two-surgeon experience with buccal mucosal grafting for reconstruction of all anterior urethral strictures. Twenty-four men underwent autologous buccal mucosal graft urethroplasty between October 2001 and September 2008 for recurrent urethral stricture disease. Twenty-two underwent a single-stage repair and two underwent a two-stage repair. Medical charts were retrospectively reviewed for demographics, comorbidities, etiology, location and length of stricture, and prior interventions in order to identify predictors of buccal urethroplasty success, defined as no evidence of stricture recurrence. All patients underwent retrograde urethrogram and cystoscopy. Operative and anesthesia times were evaluated. We determined an overall success rate of 83.3% (20 of 24 cases. Mean anesthesia time for single-stage urethroplasty was 155 min and mean operative time was 123 min. One of the two two-stage urethroplasties experienced stricture recurrence (50%. The single-stage buccal graft success rate was 86.4% (19 of 22 cases. Two of the four who developed recurrent stricture disease that required intervention had undergone a previous mesh urethroplasty. Complications developed in four of 24 patients (16.6%, including superficial wound infection (one, superficial wound dehiscence (two, and abscess/fistula formation requiring reoperation (one. The buccal mucosa is an ideal tissue for both single- and two-stage substitution urethroplasty for patients with recurrent stricture disease. Our two-surgeon technique minimizes anesthesia and operative times, and contributes to the overall high success rate and relatively low complication rate.

  1. Natural Products for Management of Oral Mucositis Induced by Radiotherapy and Chemotherapy.

    Science.gov (United States)

    Aghamohamamdi, Azar; Hosseinimehr, Seyed Jalal

    2016-03-01

    Oral mucositis is a common side effect of systemic chemotherapy and radiotherapy of head and neck in patients with cancer. Severe oral mucositis is painful and affects oral functions, including intake of food and medications and speech. Prevention of oral mucositis affects the life quality of patients. Recent studies have been focused on natural products to improve or reduce this complication. Many clinical trials have been performed to assess natural products for treatment of mucositis and their results are promising. The authors reviewed the evidence for natural products in the prevention and treatment of oral mucositis induced by radiation therapy and chemotherapy.

  2. Assessment of tumor angiogenesis: dynamic contrast-enhanced MRI with paramagnetic nanoparticles compared with Gd-DTPA in a rabbit Vx-2 tumor model.

    Science.gov (United States)

    Kassner, Andrea; Thornhill, Rebecca E; Liu, Fang; Winter, Patrick M; Caruthers, Shelton D; Wickline, Samuel A; Lanza, Gregory M

    2010-01-01

    The purpose of this study was to evaluate the suitability of a macromolecular MRI contrast agent (paramagnetic nanoparticles, PNs) for the characterization of tumor angiogenesis. Our aim was to estimate the permeability of PNs in developing tumor vasculature and compare it with that of a low molecular weight contrast agent (Gd-DTPA) using dynamic contrast-enhanced MRI (DCE). Male New Zealand white rabbits (n = 5) underwent DCE MRI 12-14 days after Vx-2 tumor fragments were implanted into the left hind limb. Each contrast agent (PNs followed by Gd-DTPA) was evaluated using a DCE protocol and transendothelial transfer coefficient (K(i)) maps were calculated using a two-compartment model. Two regions of interest (ROIs) were located within the tumor core and hindlimb muscle and five ROIs were placed within the tumor rim. Comparisons were performed using repeated measures analysis of variance (ANOVA). The K(i) values estimated using PNs were significantly lower than those obtained for Gd-DTPA (p = 0.018). When PNs and Gd-DTPA data were analyzed separately, significant differences were identified among tumor rim ROIs for PNs (p < 0.0001), but not for Gd-DTPA data (p = 0.34). The mean K(i) for the tumor rim was significantly greater than that of either the core or the hindlimb muscle for both contrast agents (p < 0.05 for each comparison). In summary, the extravasation of Gd-DTPA was far greater than that of PNs, suggesting that PNs can reveal regional differences in tumor vascular permeability that are not otherwise apparent with clinical contrast agents such as Gd-DTPA. These results suggest that PNs show potential for the noninvasive delineation of tumor angiogenesis.

  3. Angiogenesis and Its Therapeutic Opportunities

    Directory of Open Access Journals (Sweden)

    So Young Yoo

    2013-01-01

    Full Text Available Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by “on-off switch signals” between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies. Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.

  4. Enhanced mucosal immune responses against tetanus toxoid using novel delivery system comprised of chitosan-functionalized gold nanoparticles and botanical adjuvant: characterization, immunogenicity, and stability assessment.

    Science.gov (United States)

    Barhate, Ganesh; Gautam, Manish; Gairola, Sunil; Jadhav, Suresh; Pokharkar, Varsha

    2014-11-01

    Approaches based on combined use of delivery systems and adjuvants are being favored to maximize efficient mucosal delivery of antigens. Here, we describe a novel delivery system comprised of chitosan-functionalized gold nanoparticles (CsAuNPs) and saponin-containing botanical adjuvant; Asparagus racemosus extract (ARE) for oral delivery of tetanus toxoid (TT). A significant increase in TT-specific IgG (34.53-fold) and IgA (43.75-fold) was observed when TT-CsAuNPs were formulated with ARE (TT-ARE-CsAuNPs). The local IgA immune responses for TT also showed a significant increase (106.5-fold in intestine washes and 99.74-fold in feces) with ARE-based formulations as compared with plain TT group. No effect of ARE was observed on size, charge, and loading properties of CsAuNPs. Additionally, no effect of ARE and CsAuNPs was observed on antigenicity and secondary structure of TT as determined by fluorescence, circular dichroism, and Fourier transform infrared spectroscopy. The stability studies demonstrated excellent stability profile of formulation at recommended storage conditions. The study establishes the possible role of immunomodulatory adjuvants in particulate delivery systems for mucosal delivery of vaccines.

  5. Gastric angiogenesis and Helicobacter pylori infection

    Directory of Open Access Journals (Sweden)

    I. D. Pousa

    Full Text Available The formation of new blood vessels seen in conditions commonly associated with Helicobacter pylori (H. pylori infection, including gastritis, peptic ulcer, and gastric carcinoma, prompts consideration of a potential relationship between mucosal colonization by this organism and the angiogenic process. H. pylori directly or indirectly damages endothelial cells, which induces a number of changes in the microvasculature of the gastric mucosa. In H. pylori-associated conditions, that is, in gastritis, peptic ulcer and gastric carcinoma, there is an increased concentration of angiogenic factors, and subsequently a formation of new blood vessels. However, this early angiogenesis -which is activated to repair the gastric mucosa- is subsequently inhibited in patients with peptic ulcer, and ulcer healing is thus delayed. This may be due to the antiproliferative action of this organism on endothelial cells. While the angiogenic process becomes inhibited in infected patients with peptic ulcer, it remains seemingly active in those with gastritis or gastric cancer. This fact is in support of the notion suggested by various studies that peptic ulcer and gastric cancer are mutually excluding conditions. In the case of gastric cancer, neoangiogenesis would enhance nutrient and oxygen supply to cancer cells, and thus tumor growth and metastatic spread.

  6. Angiogenesis in female reproductive system

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Neovascularization, i.e. new blood vessels formation, can be divided into two different processes: vasculogenesis, whereby a primitive vascular network is established during embryogenesis from multipotential mesenchymal progenitors; and angiogenesis, which refers to the new blood vessels formation from pre-existing vessels[1,2]. Angiogenesis contributes to the most process throughout the whole life span from embryonic development to adult growth[2]. In this meaning, neovascularization is usually used to imply angiogenesis. Under physiological condi-tions, angiogenesis is a strictly regulated event and rarely happens in most adult tissues except for fracture or heal-ing of wounds[2,3]. However, a notable phenomenon is that the tissues of ovary and uterine endometrium are unique in the cycle-specific changes in vascularity that occur in each estrous/menstrual cycle. Active angiogenesis occurs in placenta to satisfy the needs of embryonic implantation and development. Defects in angiogenesis are associated with some gynecopathies including luteal phase defect, endometriosis, pregnancy loss and preeclampsia[4].

  7. Mucositis and non-invasive markers of small intestinal function.

    Science.gov (United States)

    Tooley, Katie L; Howarth, Gordon S; Butler, Ross N

    2009-05-01

    Mucositis is a common and debilitating side effect of chemotherapy that manifests due to the inability of chemotherapy agents to discriminate between normal and neoplastic cells. This results in ulcerating lesions lining the gastrointestinal tract. Moreover, the development of efficacious treatments for small intestinal mucositis has been hindered as the pathobiology of mucositis is still not fully understood. The small intestine is an extensive organ which is largely inaccessible by conventional means. Non-invasive biomarkers such as small intestinal permeability, H(2) breath tests, serum citrulline tests and the (13)C-sucrose breath test (SBT) have emerged as potential markers of small intestinal function. The SBT is emerging as the more appropriate biomarker to assess chemotherapy-induced mucositis in cancer patients and animal models, where it measures the decrease in sucrase activity associated with villus blunting and crypt disruption. The SBT has been successfully applied to detect mucositis induced by different classes of chemotherapy agents and has been used successfully to monitor small intestinal function with a range of candidate anti-mucositis treatments. We propose the SBT a superior biomarker of small intestinal function that could be successfully applied in clinical practice for monitoring the development of mucositis in cancer patients undergoing chemotherapy.

  8. Dental students' ability to detect and diagnose oral mucosal lesions.

    Science.gov (United States)

    Ali, Mohammad A; Joseph, Bobby K; Sundaram, Devipriya B

    2015-02-01

    The aim of this study was to assess the ability of dental students in the screening clinic of the Kuwait University Dental Center to detect and diagnose oral mucosal lesions. Clinical examinations performed by dental students between January 2009 and February 2011 were included. All their findings regarding the oral mucosal lesions and dental carious lesions detected were recorded, after which the patients were re-examined by faculty examiners. The students rated their own ability to detect mucosal and carious lesions before each examination. Among the 341 patients screened, 375 oral mucosal lesions were found by the faculty examiners. Of those, the students detected 178 (47.5%). Out of the 375 lesions, including the ones they failed to detect, the students diagnosed 272 (72.5%) correctly. The students were more likely (p≤0.01) to correctly diagnose a mucosal lesion when they themselves had detected it (n=169/178) than when they failed to detect it and had it subsequently pointed out by the faculty examiners (n=103/197). The students were more competent in detecting carious lesions (p≤0.001) than in detecting mucosal lesions. A significantly higher proportion of students who felt confident in detecting mucosal lesions were actually more competent in detecting the lesions than those who were not confident (p≤0.001). Further educational strategies are needed to motivate Kuwait University dental students to develop the knowledge, skills, and judgment necessary to integrate a complete intraoral examination into their routine practice.

  9. Oral mucosal status and major salivary gland function

    Energy Technology Data Exchange (ETDEWEB)

    Wolff, A.; Fox, P.C.; Ship, J.A.; Atkinson, J.C.; Macynski, A.A.; Baum, B.J. (National Institute of Dental Research, Bethesda, MD (USA))

    1990-07-01

    Normal salivary function is considered to be critical for the maintenance of healthy oral mucosa. However, few studies have examined mucosal changes in patients with objectively documented salivary gland performance. In the present report, the mucosal status of 298 subjects being evaluated in a dry mouth clinic was assessed. A complete oral examination was performed and unstimulated and stimulated salivary samples were collected separately from the parotid and submandibular/sublingual glands. Data were analyzed according to diagnosis and salivary output after the assignment of an oral mucosal rating to each subject. In general, the mucosal surfaces were well preserved and infections were not seen. Patients evaluated for Sjoegren's syndrome and radiation-induced xerostomia had the lowest salivary gland performance but displayed a mucosal status similar to denture-wearing healthy subjects or patients with normal salivary flow who had idiopathic xerostomia. However, those patients with a total lack of salivary flow rarely had normal-appearing oral mucosa. These results confirm a role for saliva in oral mucosal preservation and also suggest that other factors may act to maintain oral mucosal integrity.

  10. JAM-related proteins in mucosal homeostasis and inflammation.

    Science.gov (United States)

    Luissint, Anny-Claude; Nusrat, Asma; Parkos, Charles A

    2014-03-01

    Mucosal surfaces are lined by epithelial cells that form a physical barrier protecting the body against external noxious substances and pathogens. At a molecular level, the mucosal barrier is regulated by tight junctions (TJs) that seal the paracellular space between adjacent epithelial cells. Transmembrane proteins within TJs include junctional adhesion molecules (JAMs) that belong to the cortical thymocyte marker for Xenopus family of proteins. JAM family encompasses three classical members (JAM-A, JAM-B, and JAM-C) and related molecules including JAM4, JAM-like protein, Coxsackie and adenovirus receptor (CAR), CAR-like membrane protein and endothelial cell-selective adhesion molecule. JAMs have multiple functions that include regulation of endothelial and epithelial paracellular permeability, leukocyte recruitment during inflammation, angiogenesis, cell migration, and proliferation. In this review, we summarize the current knowledge regarding the roles of the JAM family members in the regulation of mucosal homeostasis and leukocyte trafficking with a particular emphasis on barrier function and its perturbation during pathological inflammation.

  11. Berberine Reduces Uremia-Associated Intestinal Mucosal Barrier Damage.

    Science.gov (United States)

    Yu, Chao; Tan, Shanjun; Zhou, Chunyu; Zhu, Cuilin; Kang, Xin; Liu, Shuai; Zhao, Shuang; Fan, Shulin; Yu, Zhen; Peng, Ai; Wang, Zhen

    2016-11-01

    Berberine is one of the main active constituents of Rhizoma coptidis, a traditional Chinese medicine, and has long been used for the treatment of gastrointestinal disorders. The present study was designed to investigate the effects of berberine on the intestinal mucosal barrier damage in a rat uremia model induced by the 5/6 kidney resection. Beginning at postoperative week 4, the uremia rats were treated with daily 150 mg/kg berberine by oral gavage for 6 weeks. To assess the intestinal mucosal barrier changes, blood samples were collected for measuring the serum D-lactate level, and terminal ileum tissue samples were used for analyses of intestinal permeability, myeloperoxidase activity, histopathology, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity. Berberine treatment resulted in significant decreases in the serum D-lactate level, intestinal permeability, intestinal myeloperoxidase activity, and intestinal mucosal and submucosal edema and inflammation, and the Chiu's scores assessed for intestinal mucosal injury. The intestinal MDA level was reduced and the intestinal SOD activity was increased following berberine treatment. In conclusion, berberine reduces intestinal mucosal barrier damage induced by uremia, which is most likely due to its anti-oxidative activity. It may be developed as a potential treatment for preserving intestinal mucosal barrier function in patients with uremia.

  12. Breast Tumor Angiogenesis and Tumor-Associated Macrophages: Histopathologist's Perspective

    Directory of Open Access Journals (Sweden)

    Ewe Seng Ch'ng

    2011-01-01

    Full Text Available Much progress has been made since the conceptualization of tumor angiogenesis—the induction of growth of new blood vessels by tumor—as a salient feature of clinically significant primary or metastatic cancers. From a practicing histopathologist's point of view, we appraise the application of this concept in breast cancer with particular reference to the evaluation of proangiogenic factors and the assessment of new microvessels in histopathological examination. Recently, much focus has also been centered on the active roles played by tumor-associated macrophages in relation to tumor angiogenesis. We review the literature; many data supporting this facet of tumor angiogenesis were derived from the breast cancer models. We scrutinize the large body of clinical evidence exploring the link between the tumor-associated macrophages and breast tumor angiogenesis and discuss particularly the methodology and limitations of incorporating such an assessment in histopathological examination.

  13. Evaluation of Tumor Angiogenesis by MRI Study Using Iron Nanoparticles

    Directory of Open Access Journals (Sweden)

    Mansour Ashoor

    2010-05-01

    Full Text Available Angiogenesis is the growth of new blood vessels from existing ones and it is a perquisite for the growth, invasion and metastasis of solid tumors. This complex process involves multiple steps and pathways dependent on the local balance between positive and negative regulatory factors, as well as interactions among the tumor, its vasculature and the surrounding extracellular tissue matrix. Tumors lay dormant yet viable, unable to grow beyond 2-3 mm3 in size without angiogenesis."nWith the development of novel therapies for treat-ment of several diseases, directed noninvasive imaging strategies will be critical for defining the pathophysiology of angiogenesis. Imaging modalities used to detect angiogenesis include PET, SPECT, MRI, CT, US and near-infrared optical imaging. For these modalities, methods have been developed to measure blood volume, blood flow and several other semi quantitative and quantitative kinetic hemodynamic parameters such as vascular permeability. Characteristic molecular makers of angiogenesis may be visualized with the aid of molecular imaging agents such as VEGFs or the α vß3 integrin. "nMRI is a practical modality for assessing angiogenesis over time because it is already widely used clinically to assess tumor growth and for response evaluation. Anatomical information can be co registered with functional and molecular information within a single imaging method. Moreover, MRI does not involve ionizing radiation and the commonly used contrast agent has low toxicity. "nSuper paramagnetic iron oxides (SPIO are FDA-approved contrast agents for use in magnetic reson-ance (MR imaging. Most of the administered SPIO end up in the reticuloendotelial system via endocytosis and the iron core released from the SPIO is utilized in normal iron metabolism pathways. We utilize the paramagnetic characteristics of SPIO to improve the contrast of the image in MRI."nFor the first time we will introduce a method for evaluating angiogenesis

  14. Preliminary study of CT in combination with MRI perfusion imaging to assess hemodynamic changes during angiogenesis in a rabbit model of lung cancer

    Directory of Open Access Journals (Sweden)

    Zhang Q

    2013-06-01

    Full Text Available Qiang Zhang,1 Baoqi Shi,1 Zhaoxin Liu,1 Mingmin Zhang,1 Weijing Zhang21Radiology Department, Baotou Cancer Hospital, Inner Mongolia Autonomous Region, 2Department of Mathematics, College of Science, Beijing Institute of Technology, Beijing, People's Republic of ChinaBackground: This study used CT (computed tomography and magnetic resonance imaging (MRI to identify correlations between perfusion parameters for squamous cell lung carcinoma and tumor angiogenesis in a rabbit model of VX2 lung cancer.Methods: VX2 tumors were implanted in the lungs of 35 New Zealand White rabbits. CT and MRI perfusion scanning were performed on days 14, 17, 21, 25, and 28 after tumor implantation. CT perfusion parameters were perfusion, peak enhanced increment, transit time peak, and blood volume, and MRI perfusion parameters were wash in rate, wash out rate, maximum enhancement rate, and transit time peak. CT and MRI perfusion parameters were obtained at the tumor rim, in the tumor tissue, and in the muscle tissue surrounding the tumor.Results: On CT perfusion imaging, t values for perfusion, peak enhanced increment, and blood volume (tumor rim versus muscle were 16.31, 11.79, and 5.21, respectively (P 0.05. On MRI perfusion imaging, t values for wash in rate, wash out rate, and maximum enhancement rate (tumor rim versus muscle were 18.14, 8.79, and 6.02, respectively (P 0.05.Conclusion: A combination of CT and MRI perfusion imaging demonstrated hemodynamic changes in a rabbit model of VX2 lung cancer, and provides a theoretical foundation for treatment of human squamous cell lung carcinoma.Keywords: perfusion imaging, rabbits, animal model, lung, squamous carcinoma cell

  15. Angiogenesis in the corpus luteum

    Directory of Open Access Journals (Sweden)

    Wulff Christine

    2003-11-01

    Full Text Available Abstract The corpus luteum (CL is a site of intense angiogenesis. Within a short period, this is followed either by controlled regression of the microvascular tree in the non-fertile cycle, or maintenance and stabilisation of the new vasculature a conceptual cycle. The molecular regulation of these diverse aspects is examined. The CL provides a unique model system in which to study the cellular and molecular regulation of angiogenesis. Vascular endothelial growth factor (VEGF has been found to have a major role in the CL. By targeting its action at specific stages of the luteal phase in vivo by antagonists, profound inhibitory effects on luteal angiogenesis and function are observed.

  16. Quantification of oral mucositis due to radiotherapy by determining viability and maturation of epithelial cells

    NARCIS (Netherlands)

    Stokman, MA; Spijkervet, FKL; Wymenga, ANM; Burlage, FR; Timens, W; Roodenburg, JLN; de Vries, EGE

    2002-01-01

    Background: An in-vitro assay has been developed for quantitative assessment of chemotherapy induced oral mucositis. In the present study this method was evaluated for assessment of irradiation mucositis at a cellular level. Methods: Ten patients participated in this consecutive study. All patients

  17. Cutaneous and mucosal pain syndromes

    Directory of Open Access Journals (Sweden)

    Siddappa K

    2002-01-01

    Full Text Available The cutaneous and mucosal pain syndromes are characterized by pain, burning sensation, numbness or paraesthesia of a particular part of the skin or mucosal surface without any visible signs. They are usually sensory disorders, sometimes with a great deal of psychologic overlay. In this article various conditions have been listed and are described. The possible causative mechanisms are discussed when they are applicable and the outline of their management is described.

  18. Angiogenesis Inhibition in Prostate Cancer: Current Uses and Future Promises

    Directory of Open Access Journals (Sweden)

    Jeanny B. Aragon-Ching

    2010-01-01

    Full Text Available Angiogenesis has been well recognized as a fundamental part of a multistep process in the evolution of cancer progression, invasion, and metastasis. Strategies for inhibiting angiogenesis have been one of the most robust fields of cancer investigation, focusing on the vascular endothelial growth factor (VEGF family and its receptors. There are numerous regulatory drug approvals to date for the use of these agents in treating a variety of solid tumors. While therapeutic efficacy has been established, challenges remain with regards to overcoming resistance and assessing response to antiangiogenic therapies. Prostate cancer is the most common noncutaneous malignancy among American men and angiogenesis plays a role in disease progression. The use of antiangiogenesis agents in prostate cancer has been promising and is hereby explored.

  19. In vivo monitoring of angiogenesis within Matrigel chambers using MRI

    DEFF Research Database (Denmark)

    Holm, David; Ley, Carsten Dan; Søgaard, Lise Vejby

    2006-01-01

    Angiogenesis is a critical process in tumour development and presents an important target for the development of a range of anti-cancer agents . To assess the in vivo efficacy of these ‘angiotherapeutics', a simple and reproducible in vivo model would be of significant value. Here we show...

  20. Narrow band (light) imaging of oral mucosa in routine dental patients. Part I: Assessment of value in detection of mucosal changes.

    Science.gov (United States)

    Truelove, Edmond L; Dean, David; Maltby, Samuel; Griffith, Matthew; Huggins, Kimberly; Griffith, Mickealla; Taylor, Stuart

    2011-01-01

    The purpose of this investigation was to determine the value of adding narrow band (light) imaging (NBI) to the standard oral soft tissue examination process used to detect mucosal change. A total of 620 dental patients who came to the clinic for regular dental evaluation or for treatment of acute dental problems were given a standard oral soft tissue examination by dental students under faculty supervision. The results of the white light examination were recorded after the tissues were examined with NBI, at which point areas with a loss of fluorescence (LOF) were recorded. The nature of the tissue change was classified clinically as normal variation, inflammatory, traumatic, dysplastic, or other, and patients were categorized depending on their clinical findings: normal, need follow-up visit, or immediate biopsy. Risk factors related to oral dysplasia also were recorded. The addition of NBI added between one and two minutes to the examination process. Of the 620 examinations, an area with an LOF suggestive of pathology was detected in 69 subjects (11.1%). After a second immediate evaluation, 28 of the 69 subjects were scheduled for follow-up or biopsy. None of the lesions discovered in these 28 subjects had been detected using standard (white light) examination. Adding NBI to the routine clinical examination resulted in detection of changes not seen with white light examination in 11.1% of patients; of these, a small but important number were found to have otherwise undetected persistent changes representing inflammatory lesions or potentially dangerous oral dysplasia. Adding NBI as an adjunctive diagnostic procedure improved the quality and outcome of the examination process.

  1. Prevalence of oral mucosal lesions among chewing tobacco users: A cross-sectional study

    Directory of Open Access Journals (Sweden)

    Sujatha S Reddy

    2015-01-01

    Statistical Analysis Used: Chi-square and Fisher′s exact tests were used to assess the statistical significance. Results: Of the 901 subjects with CT habits, 55.8% revealed no clinically detectable oral mucosal changes and 44.1% showed mucosal changes of which 63.8% were males and 36.1% were females. The most common finding was chewers mucositis (59.5% followed by submucous fibrosis (22.8%, leukoplakia (8%, lichenoid reaction (6.5%, oral cancer (2.7%, and lichen planus (0.5%. Conclusion: This study provides information about different CT habits and associated mucosal lesions among this population.

  2. The role of vascular endothelial growth factors and fibroblast growth factors in angiogenesis during otitis media.

    Science.gov (United States)

    Husseman, Jacob; Palacios, Sean D; Rivkin, Alexander Z; Oehl, Heinz; Ryan, Allen F

    2012-01-01

    The middle ear response to otitis media includes transformation and hyperplasia of the mucosal epithelium and subepithelial connective tissue. Significant neovascularization is also noted, which occurs both to support the hypertrophied mucosa and to mediate the increased trafficking of leukocytes. We investigated the role of two known potent angiogenic growth factor families, the fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), in middle ear mucosal angiogenesis. DNA microarrays were used to evaluate the expression of FGFs and VEGFs, as well as their receptors and unique signaling proteins, in the middle ears of mice undergoing a complete course of acute bacterial otitis media. In addition, a member of each family was introduced to the middle ear submucosal compartment of the normal middle ears of guinea pigs, by a continuous-release osmotic minipump system over 1 week. During the course of bacterial otitis media, a significant regulation of a number of genes important for angiogenesis was identified. Histologic evaluation of middle ear mucosa following micropump infusion of both FGF1 and VEGF-A showed significant angiogenesis at the site of infusion in comparison to control saline infusion. These results support a role for FGFs and VEGFs in the neovascularization of the middle ear mucosa during otitis media, and offer a potential avenue for therapeutic intervention.

  3. A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel.

    Directory of Open Access Journals (Sweden)

    Marla J Keller

    Full Text Available BACKGROUND: Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition. METHODS: 30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood. RESULTS: A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001 and fit a sigmoid E(max pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators. CONCLUSIONS: Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and

  4. Immunology of Gut Mucosal Vaccines

    Science.gov (United States)

    Pasetti, Marcela F.; Simon, Jakub K.; Sztein, Marcelo B.; Levine, Myron M.

    2011-01-01

    Summary Understanding the mechanisms underlying the induction of immunity in the gastrointestinal mucosa following oral immunization and the cross-talk between mucosal and systemic immunity should expedite the development of vaccines to diminish the global burden caused by enteric pathogens. Identifying an immunological correlate of protection in the course of field trials of efficacy, animal models (when available), or human challenge studies is also invaluable. In industrialized country populations, live attenuated vaccines (e.g. polio, typhoid, and rotavirus) mimic natural infection and generate robust protective immune responses. In contrast, a major challenge is to understand and overcome the barriers responsible for the diminished immunogenicity and efficacy of the same enteric vaccines in underprivileged populations in developing countries. Success in developing vaccines against some enteric pathogens has heretofore been elusive (e.g. Shigella). Different types of oral vaccines can selectively or inclusively elicit mucosal secretory immunoglobulin A and serum immunoglobulin G antibodies and a variety of cell-mediated immune responses. Areas of research that require acceleration include interaction between the gut innate immune system and the stimulation of adaptive immunity, development of safe yet effective mucosal adjuvants, better understanding of homing to the mucosa of immunologically relevant cells, and elicitation of mucosal immunologic memory. This review dissects the immune responses elicited in humans by enteric vaccines. PMID:21198669

  5. Mucosal immunity and the microbiome.

    Science.gov (United States)

    Neish, Andrew S

    2014-01-01

    By definition, the mucosal immune system is responsible for interfacing with the outside world, specifically responding to external threats, of which pathogenic microbes represent a primary challenge. However, it has become apparent that the human host possesses a numerically vast and taxonomically diverse resident microbiota, predominantly in the gut, and also in the airway, genitourinary tract, and skin. The microbiota is generally considered symbiotic, and has been implicated in the regulation of cellular growth, restitution after injury, maintenance of barrier function, and importantly, in the induction, development, and modulation of immune responses. The mucosal immune system uses diverse mechanisms that protect the host from overt pathogens, but necessarily has coevolved to monitor, nurture, and exploit the normal microbiota. As a whole, mucosal immunity encompasses adaptive immune regulation that can involve systemic processes, local tissue-based innate and inflammatory events, intrinsic defenses, and highly conserved cell autonomous cytoprotective responses. Interestingly, specific taxa within the normal microbiota have been implicated in roles shaping specific adaptive, innate, and cell autonomous responses. Taken together, the normal microbiota exerts profound effects on the mucosal immune system, and likely plays key roles in human physiology and disease.

  6. Angiogenesis and Anti-Angiogenic Treatments

    Directory of Open Access Journals (Sweden)

    Ersin Demirer

    2013-10-01

    Full Text Available Blood vessels in our body is developed by vasculogenesis and angiogenesis. There have been new advances in molecular pathology and tumor biology areas in recent years. Angiogenesis is modulated by the balance between angiogenic and anti-angiogenic factors. Angiogenesis plays a key role in tumor growth. Drugs inhibiting angiogenesis have been in use in various malign or non-malign diseases. Inhibition of angiogenesis in malign diseases is a very attractive subject in medicine and studies are going on about long term affects and toxicities. Inhibition of angiogenesis is not an only treatment choice alone. It is a supplemental treatment option applied with conventional chemotherapy, radiotherapy, surgery, immunotherapy and hormonal therapy. It has been used in colorectal carcinoma, renal cell carcinoma, non-small cell lung cancer, glioblastoma, heoatocellular carcinoma, pancreatic neuroendocrine tumor, tyroid medullary cancer.

  7. Role of angiogenesis in chronic lymphocytic leukemia.

    Science.gov (United States)

    Letilovic, Tomislav; Vrhovac, Radovan; Verstovsek, Srdan; Jaksic, Branimir; Ferrajoli, Alessandra

    2006-09-01

    Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications.

  8. Chemokine Regulation of Angiogenesis During Wound Healing

    OpenAIRE

    Bodnar, Richard J.

    2015-01-01

    Significance: Angiogenesis plays a critical role in wound healing. A defect in the formation of a neovasculature induces ulcer formation. One of the challenges faced by the clinician when devising strategies to promote healing of chronic wounds is the initiation of angiogenesis and the formation of a stable vasculature to support tissue regeneration. Understanding the molecular factors regulating angiogenesis during wound healing will lead to better therapies for healing chronic wounds.

  9. Hypoxia independent drivers of melanoma angiogenesis

    Directory of Open Access Journals (Sweden)

    Svenja eMeierjohann

    2015-05-01

    Full Text Available Tumor angiogenesis is a process which is traditionally regarded as the tumor`s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a prerequisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia independent mechanisms of tumor angiogenesis in melanoma.

  10. Therapeutic angiogenesis in cardiology using protein formulations

    National Research Council Canada - National Science Library

    Post, M J; Laham, R; Sellke, F W; Simons, M

    2001-01-01

    Therapeutic angiogenesis in cardiovascular disease aims at improving myocardial function by increasing blood flow to ischemic myocardium that is not amenable to traditional forms of revascularization...

  11. Oral cryotherapy reduced oral mucositis in patients having cancer treatments.

    Science.gov (United States)

    Spivakovsky, Sylvia

    2016-09-01

    Data sourcesCochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CANCERLIT, CINAHL, the US National Institutes of Health Trials Registry and the WHO Clinical Trials Registry Platform.Study selectionRandomised controlled trials (RCTs) assessing the effects of oral cryotherapy in patients with cancer receiving treatment compared to usual care, no treatment or other interventions to prevent mucositis. The primary outcome was incidence of mucositis and its severity.Data extraction and synthesisTwo reviewers carried out study assessment and data extraction independently. Treatment effect for continuous data was calculated using mean values and standard deviations and expressed as mean difference (MD) and 95% confidence interval. Risk ratio (RR) was calculated for dichotomous data. Meta-analysis was performed.ResultsFourteen studies with 1280 participants were included. Subgroup analysis was undertaken according to the main cancer treatment type. Cryotherapy reduced the risk of developing mucositis by 39% (RR = 0.61; 95%CI, 0.52 to 0.72) on patients treated with fluorouracil (5FU). For melphalan-based treatment the risk of developing mucositis was reduced by 41% (RR =0.59; 95%CI, 0.35 to 1.01). Oral cryotherapy was shown to be safe, with very low rates of minor adverse effects, such as headaches, chills, numbness/taste disturbance and tooth pain. This appears to contribute to the high rates of compliance seen in the included studies.ConclusionsThere is confidence that oral cryotherapy leads to a large reduction in oral mucositis in adults treated with 5FU. Although there is less certainty on the size of the reduction on patients treated with melphalan, it is certain there is reduction of severe mucositis.

  12. Proinflammatory mediators stimulate neutrophil-directed angiogenesis.

    LENUS (Irish Health Repository)

    McCourt, M

    2012-02-03

    BACKGROUND: Vascular endothelial growth factor (VEGF; vascular permeability factor) is one of the most potent proangiogenic cytokines, and it plays a central role in mediating the process of angiogenesis or new blood vessel formation. Neutrophils (PMNs) recently have been shown to produce VEGF. HYPOTHESIS: The acute inflammatory response is a potent stimulus for PMN-directed angiogenesis. METHODS: Neutrophils were isolated from healthy volunteers and stimulated with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and anti-human Fas monoclonal antibody. Culture supernatants were assayed for VEGF using enzyme-linked immunosorbent assays. Culture supernatants from LPS- and TNF-alpha-stimulated PMNs were then added to human umbilical vein endothelial cells and human microvessel endothelial cells and assessed for endothelial cell proliferation using 5-bromodeoxyuridine labeling. Tubule formation was also assessed on MATRIGEL basement membrane matrix. Neutrophils were lysed to measure total VEGF release, and VEGF expression was detected using Western blot analysis. RESULTS: Lipopolysaccharide and TNF-alpha stimulation resulted in significantly increased release of PMN VEGF (532+\\/-49 and 484+\\/-80 pg\\/mL, respectively; for all, presented as mean +\\/- SEM) compared with control experiments (32+\\/-4 pg\\/mL). Interleukin 6 and Fas had no effect. Culture supernatants from LPS- and TNF-alpha-stimulated PMNs also resulted in significant increases (P<.005) in macrovascular and microvascular endothelial cell proliferation and tubule formation. Adding anti-human VEGF-neutralizing polyclonal antibody to stimulated PMN supernatant inhibited these effects. Total VEGF release following cell lysis and Western blot analysis suggests that the VEGF is released from an intracellular store. CONCLUSION: Activated human PMNs are directly angiogenic by releasing VEGF, and this has important implications for inflammation, capillary leak syndrome

  13. The Mucosal Immune System of Teleost Fish

    Directory of Open Access Journals (Sweden)

    Irene Salinas

    2015-08-01

    Full Text Available Teleost fish possess an adaptive immune system associated with each of their mucosal body surfaces. Evidence obtained from mucosal vaccination and mucosal infection studies reveal that adaptive immune responses take place at the different mucosal surfaces of teleost. The main mucosa-associated lymphoid tissues (MALT of teleosts are the gut-associated lymphoid tissue (GALT, skin-associated lymphoid tissue (SALT, the gill-associated lymphoid tissue (GIALT and the recently discovered nasopharynx-associated lymphoid tissue (NALT. Teleost MALT includes diffuse B cells and T cells with specific phenotypes different from their systemic counterparts that have co-evolved to defend the microbe-rich mucosal environment. Both B and T cells respond to mucosal infection or vaccination. Specific antibody responses can be measured in the gills, gut and skin mucosal secretions of teleost fish following mucosal infection or vaccination. Rainbow trout studies have shown that IgT antibodies and IgT+ B cells are the predominant B cell subset in all MALT and respond in a compartmentalized manner to mucosal infection. Our current knowledge on adaptive immunity in teleosts is limited compared to the mammalian literature. New research tools and in vivo models are currently being developed in order to help reveal the great intricacy of teleost mucosal adaptive immunity and help improve mucosal vaccination protocols for use in aquaculture.

  14. Intra-laboratory validation of a human cell based in vitro angiogenesis assay for testing angiogenesis modulators

    Directory of Open Access Journals (Sweden)

    Jertta-Riina Sarkanen

    2011-01-01

    Full Text Available The developed standardized human cell based in vitro angiogenesis assay was intra-laboratory validated to verify that the method is reliable and relevant for routine testing of modulators of angiogenesis e.g. pharmaceuticals and industrial chemicals. This assay is based on the earlier published method but it was improved and shown to be more sensitive and rapid than the previous assay. The performance of the assay was assessed by using 6 reference chemicals, which are widely used pharmaceuticals that inhibit angiogenesis: acetyl salicylic acid, erlotinib, 2-methoxyestradiol, levamisole, thalidomide, and anti-vascular endothelial growth factor. In the intra-laboratory validation, the sensitivity of the assay (upper and lower limits of detection and linearity of response in tubule formation, batch to batch variation in tubule formation between different Master cell bank batches, and precision as well as the reliability of the assay (reproducibility and repeatability were tested. The pre-set acceptance criteria for the intra-laboratory validation study were met. The relevance of the assay in man was investigated by comparing the effects of reference chemicals and their concentrations to the published human data. The comparison showed a good concordance, which indicates that this human cell based angiogenesis model predicts well the effects in man and has the potential to be used to supplement and/or replace of animal tests.

  15. New molecular connections in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Qiling Xu; David Wilkinson

    2010-01-01

    @@ In vertebrates, oxygen and nutrients are delivered to tissues by the circula-tion of blood through vessels, comprised of a branched network of endothelial tubes termed the vasculature. Crucial for the formation of blood vessels during development is the process of angiogenesis, in which new sprouts form from pre-existing vessels in a complex cascade of cellular events. This involves the activation of an endothelial cell in the vessel to become a highly exploratory 'tip' cell that migrates to invade the surrounding tissues, while remaining tightly connected to the fol-lowing cells that subsequently generate the tubular structures of a new vessel.

  16. Dexmedetomidine decreases the oral mucosal blood flow.

    Science.gov (United States)

    Kawaai, Hiroyoshi; Yoshida, Kenji; Tanaka, Eri; Togami, Kohei; Tada, Hitoshi; Ganzberg, Steven; Yamazaki, Shinya

    2013-12-01

    There is an abundance of blood vessels in the oral cavity, and intraoperative bleeding can disrupt operations. There have been some interesting reports about constriction of vessels in the oral cavity, one of which reported that gingival blood flow in cats is controlled by sympathetic α-adrenergic fibres that are involved with vasoconstriction. Dexmedetomidine is a sedative and analgesic agent that acts through the α-2 adrenoceptor, and is expected to have a vasoconstrictive action in the oral cavity. We have focused on the relation between the effects of α-adrenoceptors by dexmedetomidine and vasoconstriction in oral tissues, and assessed the oral mucosal blood flow during sedation with dexmedetomidine. The subjects comprised 13 healthy male volunteers, sedated with dexmedetomidine in a loading dose of 6 μg/kg/h for 10 min and a continuous infusion of 0.7 μg/kg/h for 32 min. The mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and palatal mucosal blood flow (PMBF) were measured at 0, 5, 10, 12, 22, and 32 min after the start of the infusion. The HR, CO, and PBMF decreased significantly during the infusion even though there were no differences in the SV. The SVR increased significantly but the PMBF decreased significantly. In conclusion, PMBF was reduced by the mediating effect of dexmedetomidine on α-2 adrenoceptors.

  17. Vestibuloplasty: allograft versus mucosal graft.

    Science.gov (United States)

    Hashemi, H M; Parhiz, A; Ghafari, S

    2012-04-01

    The aim of the present study was to compare the application of alloderm and mucosal graft for vestibuloplasty. This randomized controlled trial with split mouth design was carried out on 20 edentulous patients. Patients underwent vestibuloplasty surgery with the Clark technique. Half of the prepared bed in each patient was covered with alloderm and the other half with mucosal graft. Vestibule depth (width of fixed tissue) and relapse in the two sides immediately after surgery, and 1, 3 and 6 months after surgery were measured and compared. Statistical analysis was carried out using the Kolmogorov-Smirnov, Student's paired t and Friedman tests. The width of the fixed tissue in the alloderm graft at 1, 3 and 6 month intervals was significantly lower than that in the autograft (Pvestibuloplasty. Copyright © 2011 International Association of Oral and Maxillofacial Surgeons. All rights reserved.

  18. Role of angiogenesis in endodontics: contributions of stem cells and proangiogenic and antiangiogenic factors to dental pulp regeneration.

    Science.gov (United States)

    Saghiri, Mohammad Ali; Asatourian, Armen; Sorenson, Christine M; Sheibani, Nader

    2015-06-01

    Dental pulp regeneration is a part of regenerative endodontics, which includes isolation, propagation, and re-transplantation of stem cells inside the prepared root canal space. The formation of new blood vessels through angiogenesis is mandatory to increase the survival rate of re-transplanted tissues. Angiogenesis is defined as the formation of new blood vessels from preexisting capillaries, which has great importance in pulp regeneration and homeostasis. Here the contribution of human dental pulp stem cells and proangiogenic and antiangiogenic factors to angiogenesis process and regeneration of dental pulp is reviewed. A search was performed on the role of angiogenesis in dental pulp regeneration from January 2005 through April 2014. The recent aspects of the relationship between angiogenesis, human dental pulp stem cells, and proangiogenic and antiangiogenic factors in regeneration of dental pulp were assessed. Many studies have indicated an intimate relationship between angiogenesis and dental pulp regeneration. The contribution of stem cells and mechanical and chemical factors to dental pulp regeneration has been previously discussed. Angiogenesis is an indispensable process during dental pulp regeneration. The survival of inflamed vital pulp and engineered transplanted pulp tissue are closely linked to the process of angiogenesis at sites of application. However, the detailed regulatory mechanisms involved in initiation and progression of angiogenesis in pulp tissue require investigation. Published by Elsevier Inc.

  19. Mucosal biofilm communities in the human intestinal tract.

    Science.gov (United States)

    Macfarlane, Sandra; Bahrami, Bahram; Macfarlane, George T

    2011-01-01

    Complex and highly variable site-dependent bacterial ecosystems exist throughout the length of the human gastrointestinal tract. Until relatively recently, the majority of our information on intestinal microbiotas has come from studies on feces, or from aspirates taken from the upper gut. However, there is evidence showing that mucosal bacteria growing in biofilms on surfaces lining the gut differ from luminal populations, and that due to their proximity to the epithelial surface, these organisms may be important in modulating the host's immune system and contributing to some chronic inflammatory diseases. Over the past decade, increasing interest in mucosal bacteria, coupled with advances in molecular approaches for assessing microbial diversity, has begun to provide some insight into the complexity of these mucosa-associated communities. In gastrointestinal conditions such as inflammatory bowel diseases (ulcerative colitis, Crohn's disease), it has been shown that a dysbiosis exists in microbial community structure, and that there is a reduction in putatively protective mucosal organisms such as bifidobacteria. Therefore, manipulation of mucosal communities may be beneficial in restoring normal functionality in the gut, thereby improving the immune status and general health of the host. Biofilm structure and function has been studied intensively in the oral cavity, and as a consequence, mucosal communities in the mouth will not be covered in this chapter. This review addresses our current knowledge of mucosal populations in the gastrointestinal tract, changes that can occur in community structure in disease, and therapeutic modulation of biofilm composition by antibiotics, prebiotics, and probiotics. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. The relationship between angiogenesis and cyclooxygenase-2 expression in prostate cancer

    OpenAIRE

    Mukherjee, R.; Edwards, J; Underwood, M.A.; Bartlett, J M S

    2005-01-01

    OBJECTIVE: To test the hypothesis that angiogenesis in prostate cancer is associated with tumour invasion and metastasis, and that this is mediated through increased cyclooxygenase-2 (COX-2) expression.\\ud \\ud PATIENTS AND METHODS: Angiogenesis was assessed in 105 patients with either prostate cancer (79) or benign prostatic hyperplasia (BPH, 26) and these data correlated with levels of COX-2 expression in the same dataset. The mean microvessel density (MVD) was analysed as a marker of angiog...

  1. Hydrogels for therapeutic cardiovascular angiogenesis.

    Science.gov (United States)

    Rufaihah, Abdul Jalil; Seliktar, Dror

    2016-01-15

    Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor or cell therapy is promising, the retention of bioactive agents in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Various types of biomaterials with different physical and chemical properties have been developed to improve the localized delivery of growth factor and/or cells for therapeutic angiogenesis in ischemic tissues. Hydrogels are particularly advantageous as carrier systems because they are structurally similar to the tissue extracellular matrix (ECM), they can be processed under relatively mild conditions and can be delivered in a minimally invasive manner. Moreover, hydrogels can be designed to degrade in a timely fashion that coincides with the angiogenic process. For these reasons, hydrogels have shown great potential as pro-angiogenic matrices. This paper reviews a few of the hydrogel systems currently being applied together with growth factor delivery and/or cell therapy to promote therapeutic angiogenesis in ischemic tissues, with emphasis on myocardial applications.

  2. Complex role of matrix metalloproteinases in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    SANGQINGXIANGAMY

    1998-01-01

    Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a significant role in regulating angiogenesis,the process of new blood vessel formation.Interstitial collagenase (MMP-1),72kDa gelatinase A/type IV collagenase (MMP-2),and 92 kDA gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and promote angiogenesis.TIMP-1,TIMP-2,TIMP-3,and possibly,TIMP-4 inhibit neovascularization.A new paradign is emerging that matrilysin (MMP-7),MMP-9,and metalloelastase (MMP-12) may block angiogenesis by converting plasminogen to angiostatin,which is one of the most potent angiogenesis antagonists.MMPs and TIMPs play a complex role in regulating angiogenesis.An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide important information to allow the control of angiogenesis,e.g.the stimulation of angiogenesis for coronary collateral circulation formation;while the inhibition for treating arthritis and cancer.

  3. Magnetic resonance imaging of brain angiogenesis after stroke

    OpenAIRE

    Seevinck, Peter R.; Deddens, Lisette H; Dijkhuizen, Rick M.

    2010-01-01

    Stroke is a major cause of mortality and long-term disability worldwide. The initial changes in local perfusion and tissue status underlying loss of brain function are increasingly investigated with noninvasive imaging methods. In addition, there is a growing interest in imaging of processes that contribute to post-stroke recovery. In this review, we discuss the application of magnetic resonance imaging (MRI) to assess the formation of new vessels by angiogenesis, which is hypothesized to par...

  4. Immunotherapy of tumor by targeting angiogenesis

    Institute of Scientific and Technical Information of China (English)

    HOU; Jianmei; TIAN; Ling; WEI; Yuquan

    2004-01-01

    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy represents a new strategy for the development of anti-cancer therapies. In recent years, there has been made great progress in anti-angiogenic therapy. As far as the passive immunotherapy is concerned, a recombinant humanized antibody to vascular endothelial growth factor (VEGF)-Avastin has been approved by FDA as the first angiogenesis inhibitor to treat colorectal cancer. For active specific immunotherapy, various strategies for cancer vaccines, including whole endothelial cell vaccines, dendritic cell vaccines, DNA vaccines, and peptides or protein vaccines, have been developed to break immune tolerance against important molecules associated with tumor angiogenesis and induce angiogenesis-specific immune responses. This article reviews the angiogenesis-targeted immunotherapy of tumor from the above two aspects.

  5. Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models

    Directory of Open Access Journals (Sweden)

    Iskra Tuero

    2014-08-01

    Full Text Available An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV is transmitted primarily across mucosal surfaces, development of immunity at these sites is critical, but few clinical vaccine trials have targeted these sites or assessed vaccine-elicited mucosal immune responses. Pre-clinical studies in non-human primate models have facilitated progress in mucosal vaccine development by evaluating candidate vaccine approaches, developing methodologies for collecting and assessing mucosal samples, and providing clues to immune correlates of protective immunity for further investigation. In this review we have focused on non-human primate studies which have provided important information for future design of vaccine strategies, targeting of mucosal inductive sites, and assessment of mucosal immunity. Knowledge gained in these studies will inform mucosal vaccine design and evaluation in human clinical trials.

  6. Cardiac functions assessment in children with celiac disease and its correlation with the degree of mucosal injury: Doppler tissue imaging study

    Directory of Open Access Journals (Sweden)

    Abeer Fathy

    2016-01-01

    Full Text Available Background/Aims: Celiac disease (CD-associated cardiologic disorders is a growing concern. However, data regarding cardiac affection in children with CD are few. This study aimed at assessing the subclinical impact of CD on the global myocardial performance in Saudi children with CD using Doppler tissue imaging (DTI. Patients and Methods: Conventional two-dimensional echocardiography was performed among 20 Saudi children with CDas well as 20 age and sex-matched healthy controls. DTI were used to determine right ventricular (RV and left ventricular (LV Tei indexes. These findings were correlated with the Modified Marsh Classification of the histologic findings in CD. Results: LV and RV Tei indexes were significantly higher in children with CD than the control group (mean ± standard deviation: 0.47 ± 0.05 vs. 0.31 ± 0.18; P< 0.0005 and 0.51 ± 0.04 vs. 0.32 ± 0.05; P< 0.0001, respectively. RV Tei index was found to be positively correlated with the Modified Marsh Classification of CD (r = 0.7753, P< 0.0001. LV Tei index tended to be more affected in patients with more severe histologic findings, however, such relation did not reach statistical significance (r = 0.2479, P = 0.292. Fractional shortening did not correlate with the Modified Marsh Classification of histologic findings in CD patients (r= −0.11, P = 0.641. Conclusions: Subclinical myocardial dysfunction of both ventricles occurs in children with CD. The DTI method appears to be more sensitive than conventional two-dimensional echocardiography in the early detection of myocardial dysfunction in children with CD.

  7. Paradoxical effects of polyphenolic compounds from Clusiaceae on angiogenesis.

    Science.gov (United States)

    Lavaud, Alexis; Soleti, Raffaella; Hay, Anne-Emmanuelle; Richomme, Pascal; Guilet, David; Andriantsitohaina, Ramaroson

    2012-02-15

    Clusiaceae plants display high contents of xanthones and coumarins, the effects of which on endothelium, more particularly on angiogenesis, have not been assessed yet. We screened the capacity of six molecules from Clusiaceae--belonging to xanthones, coumarins and acid chromanes classes--to induce endothelium-dependent relaxation on mice aortic rings. Endothelial nitric oxide (NO) production was assessed in endothelial cell line using electron paramagnetic resonance technique. Then, the capacity of these molecules to induce capillary-like structures of endothelial cells was assessed. Cellular processes implicated in angiogenesis (adhesion, migration and proliferation) and Western blot analyses were then investigated. Among the tested molecules, isocalolongic acid (IA) and 2-deprenylrheediaxanthone (DRX) induced an endothelium-dependent relaxation of the aorta associated with an increase of NO production in endothelial cells. Using in vitro and ex vivo angiogenesis assays, it was shown that IA treatment promoted the formation of capillary-like network. In contrast, DRX prevented the ability of vascular endothelial growth factor (VEGF) to increase the formation of capillary-like network. IA increased endothelial cell proliferation while DRX decreased all cellular processes of angiogenesis. Western blot analysis showed that IA increased VEGF expression whereas DRX decreased ICAM-1 expression. Altogether, these data allowed identifying isolated molecules from Clusiaceae that exhibit a potential activity towards the modulation of endothelium-dependent relaxation involving NO release. Interestingly, they also highlighted paradoxical effects of the two compounds on cellular angiogenic processes, IA being pro-angiogenic and DRX anti-angiogenic. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Angiogenesis gene expression in murine endothelial cells during post-pneumonectomy lung growth

    Directory of Open Access Journals (Sweden)

    Konerding Moritz A

    2011-07-01

    Full Text Available Abstract Although blood vessel growth occurs readily in the systemic bronchial circulation, angiogenesis in the pulmonary circulation is rare. Compensatory lung growth after pneumonectomy is an experimental model with presumed alveolar capillary angiogenesis. To investigate the genes participating in murine neoalveolarization, we studied the expression of angiogenesis genes in lung endothelial cells. After left pneumonectomy, the remaining right lung was examined on days 3, 6, 14 and 21days after surgery and compared to both no surgery and sham thoracotomy controls. The lungs were enzymatically digested and CD31+ endothelial cells were isolated using flow cytometry cell sorting. The transcriptional profile of the CD31+ endothelial cells was assessed using quantitative real-time polymerase chain reaction (PCR arrays. Focusing on 84 angiogenesis-associated genes, we identified 22 genes with greater than 4-fold regulation and significantly enhanced transcription (p

  9. Imaging of angiogenesis in cardiology

    Energy Technology Data Exchange (ETDEWEB)

    Higuchi, Takahiro; Wester, Hans Juergen; Schwaiger, Markus [Nuklearmedizinische Klinik und Poliklinik der Technischen Universitaet Muenchen, Klinikum rechts der Isar, Munich (Germany)

    2007-06-15

    In the past decade, there have been major improvements in our understanding of angiogenesis at the genetic, molecular and cellular levels. Concentrated efforts in this area have led to new therapeutic approaches to ischaemic heart disease using angiogenic factors, gene therapy and progenitor cells. Despite very promising experimental results in animal studies, large clinical trials have failed to confirm the results in patients with coronary artery disease. Important questions such as selection of growth factors and donor cells, as well as the timing, dose and route of administration, have been raised and need to be answered. Molecular imaging approaches which may provide specific markers of the angiogenic process (e.g. integrin expression in endothelial cells) have been introduced and are expected to address some of these questions. Although few clinical imaging results are currently available, animal studies suggest the potential role of molecular imaging for characterisation of the angiogenetic process in vivo and for the monitoring of therapeutic effects. (orig.)

  10. The Development of an AIDS Mucosal Vaccine

    Directory of Open Access Journals (Sweden)

    Xian Tang

    2010-01-01

    Full Text Available It is well known that mucosal tissues contain the largest surface area of the human body and are the front line of natural host defense against various pathogens. In fact, more than 80% of infectious disease pathogens probably gain entry into the susceptible human hosts through open mucosal surfaces. Human immunodeficiency virus type one (HIV-1, a mainly sexually transmitted virus, also primarily targets the vaginal and gastrointestinal mucosa as entry sites for viral transmission, seeding, replication and amplification. Since HIV-1 establishes its early replication in vaginal or rectal mucosal tissues, the induction of sufficient mucosal immunity at the initial site of HIV-1 transmission becomes essential for a protective vaccine. However, despite the fact that current conventional vaccine strategies have remained unsuccessful in preventing HIV-1 infection, sufficient financial support and resources have yet to be given to develop a vaccine able to elicit protective mucosal immunity against sexual transmissions. Interestingly, Chinese ancestors invented variolation through intranasal administration about one thousand years ago, which led to the discovery of a successful smallpox vaccine and the final eradication of the disease. It is the hope for all mankind that the development of a mucosal AIDS vaccine will ultimately help control the AIDS pandemic. In order to discover an effective mucosal AIDS vaccine, it is necessary to have a deep understanding of mucosal immunology and to test various mucosal vaccination strategies.

  11. The Partial Purification of Angiogenesis Factor of Human Osteosarcoma

    Institute of Scientific and Technical Information of China (English)

    WUHua; DENGZhongduan; 等

    2002-01-01

    Objective To partially purify the angiogenesis factor of human osteosarcoma(HuOs) and study its biological features. Methods The active peptide with a molecular weight of 8000-10000 Da in the conditioned medium obtained from the cultivation of Hu-Os cells(osteoblastic osteosarcoma) was partially purified by ultrafiltration, chromatography and dialysis.The angiogenic effects of the fractions were assessed by proliferation assay of human umbilical vein and pig thoracic aorta endothelial cells. Results The chromatography fractions 4-6 could significantly promote the proliferation of the endothelial cells.Conclusion The HuOs cells could synthesize and secrete angiogenesis factor with a molecular weight of 8000-10000 Da.

  12. Mechanical and Chemical Signaling in Angiogenesis

    CERN Document Server

    2013-01-01

    This volume of Studies in Mechanobiology, Tissue Engineering and Biomaterials describes the most recent advances in angiogenesis research at all biological length scales: molecular, cellular and tissue, in both in vivo and in vitro settings.  Angiogenesis experts from diverse fields including engineering, cell and developmental biology, and chemistry have contributed chapters which focus on the mechanical and chemical signals which affect and promote blood vessel growth. Specific emphasis is given to novel methodologies and biomaterials that have been developed and applied to angiogenesis research. 

  13. Mucosal immunity and probiotics in fish.

    Science.gov (United States)

    Lazado, Carlo C; Caipang, Christopher Marlowe A

    2014-07-01

    Teleost mucosal immunity has become the subject of unprecedented research studies in recent years because of its diversity and defining characteristics. Its immune repertoire is governed by the mucosa-associated lymphoid tissues (MALT) which are divided into gut-associated lymphoid tissues (GALT), skin-associated lymphoid tissues (SALT), and gill-associated lymphoid tissues (GIALT). The direct contact with its immediate environment makes the mucosal surfaces of fish susceptible to a wide variety of pathogens. The inherent immunocompetent cells and factors in the mucosal surfaces together with the commensal microbiota have pivotal role against pathogens. Immunomodulation is a popular prophylactic strategy in teleost and probiotics possess this beneficial feature. Most of the studies on the immunomodulatory properties of probiotics in fish mainly discussed their impacts on systemic immunity. In contrast, few of these studies discussed the immunomodulatory features of probiotics in mucosal surfaces and are concentrated on the influences in the gut. Significant attention should be devoted in understanding the relationship of mucosal immunity and probiotics as the present knowledge is limited and are mostly based on extrapolations of studies in humans and terrestrial vertebrates. In the course of the advancement of mucosal immunity and probiotics, new perspectives in probiotics research, e.g., probiogenomics have emerged. This review affirms the relevance of probiotics in the mucosal immunity of fish by revisiting and bridging the current knowledge on teleost mucosal immunity, mucosal microbiota and immunomodulation of mucosal surfaces by probiotics. Expanding the knowledge of immunomodulatory properties of probiotics especially on mucosal immunity is essential in advancing the use of probiotics as a sustainable and viable strategy for successful fish husbandry.

  14. Modulation of gut mucosal biofilms.

    Science.gov (United States)

    Kleessen, Brigitta; Blaut, Michael

    2005-04-01

    Non-digestible inulin-type fructans, such as oligofructose and high-molecular-weight inulin, have been shown to have the ability to alter the intestinal microbiota composition in such a way that members of the microbial community, generally considered as health-promoting, are stimulated. Bifidobacteria and lactobacilli are the most frequently targeted organisms. Less information exists on effects of inulin-type fructans on the composition, metabolism and health-related significance of bacteria at or near the mucosa surface or in the mucus layer forming mucosa-associated biofilms. Using rats inoculated with a human faecal flora as an experimental model we have found that inulin-type fructans in the diet modulated the gut microbiota by stimulation of mucosa-associated bifidobacteria as well as by partial reduction of pathogenic Salmonella enterica subsp. enterica serovar Typhimurium and thereby benefit health. In addition to changes in mucosal biofilms, inulin-type fructans also induced changes in the colonic mucosa stimulating proliferation in the crypts, increasing the release of mucins, and altering the profile of mucin components in the goblet cells and epithelial mucus layer. These results indicate that inulin-type fructans may stabilise the gut mucosal barrier. Dietary supplementation with these prebiotics could offer a new approach to supporting the barrier function of the mucosa.

  15. Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells.

    Science.gov (United States)

    Lin, Chih-Yang; Hung, Shih-Ya; Chen, Hsien-Te; Tsou, Hsi-Kai; Fong, Yi-Chin; Wang, Shih-Wei; Tang, Chih-Hsin

    2014-10-15

    Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.

  16. Notch in Pathological Angiogenesis and Lymphangiogenesis

    Science.gov (United States)

    2013-05-01

    Branching of Dopaminergic Axons. Journal of Neuroscience, 29(38): 11973-11981. BOOK CHAPTERS 1. Uh, M.K., Kandel , J., Kitajewski, J. Evaluating Tumor Angiogenesis. 2nd ed. 980. New York: Springer, 2013. 341-51. Print.

  17. WT1 regulates angiogenesis in Ewing Sarcoma

    National Research Council Canada - National Science Library

    Katuri, Varalakshmi; Gerber, Stephanie; Qiu, Xiaofei; McCarty, Gregory; Goldstein, Seth D; Hammers, Hans; Montgomery, Elizabeth; Chen, Allen R; Loeb, David M

    2014-01-01

    Angiogenesis is required for tumor growth. WT1, a protein that affects both mRNA transcription and splicing, has recently been shown to regulate expression of vascular endothelial growth factor (VEGF...

  18. Therapeutic Angiogenesis for Treating Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Lorenzo Deveza, Jeffrey Choi, Fan Yang

    2012-01-01

    Full Text Available Cardiovascular disease is the leading cause of death worldwide and is often associated with partial or full occlusion of the blood vessel network in the affected organs. Restoring blood supply is critical for the successful treatment of cardiovascular diseases. Therapeutic angiogenesis provides a valuable tool for treating cardiovascular diseases by stimulating the growth of new blood vessels from pre-existing vessels. In this review, we discuss strategies developed for therapeutic angiogenesis using single or combinations of biological signals, cells and polymeric biomaterials. Compared to direct delivery of growth factors or cells alone, polymeric biomaterials provide a three-dimensional drug-releasing depot that is capable of facilitating temporally and spatially controlled release. Biomimetic signals can also be incorporated into polymeric scaffolds to allow environmentally-responsive or cell-triggered release of biological signals for targeted angiogenesis. Recent progress in exploiting genetically engineered stem cells and endogenous cell homing mechanisms for therapeutic angiogenesis is also discussed.

  19. Slit-Robo signaling in ocular angiogenesis.

    Science.gov (United States)

    Chen, Haoyu; Zhang, Mingzhi; Tang, Shibo; London, Nyall R; Li, Dean Y; Zhang, Kang

    2010-01-01

    Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the central nervous system. Intense investigation found that this pathway also plays an important role in other biological process including angiogenesis. Robo4 is the vascular endothelial cell specific member of Robo family. It was found that Slit-Robo signaling can inhibit endothelial cell migration, tube formation and vascular permeability. Slit-Robo signaling also plays an important role in embryonic and tumor angiogenesis. In animal model of ocular angiogenesis, addition of Slit inhibited laser induced choroidal neovascularization, oxygen induced retinopathy and VEGF induced retinal permeability in a Robo4 dependent manner. Recent data demonstrates that Robo1 and Robo4 form a heterodimer in endothelial cells, The role of this heterodimer in counteracting VEGF signaling is unknown. Further investigation is required to better understand Slit-Robo signaling and develop novel therapy for angiogenesis.

  20. Galectins in angiogenesis: consequences for gestation.

    Science.gov (United States)

    Blois, Sandra M; Conrad, Melanie L; Freitag, Nancy; Barrientos, Gabriela

    2015-04-01

    Members of the galectin family have been shown to exert several roles in the context of reproduction. They contribute to placentation, maternal immune regulation and facilitate angiogenesis encompassing decidualisation and placenta formation during pregnancy. In the context of neo-vascularisation, galectins have been shown to augment signalling pathways that lead to endothelial cell activation, cell proliferation, migration and tube formation in vitro in addition to angiogenesis in vivo. Angiogenesis during gestation ensures not only proper foetal growth and development, but also maternal health. Consequently, restriction of placental blood flow has major consequences for both foetus and mother, leading to pregnancy diseases. In this review we summarise both the established and the emerging roles of galectin in angiogenesis and discuss the possible implications during healthy and pathological gestation.

  1. Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

    Institute of Scientific and Technical Information of China (English)

    Atsuko Sakurai; Colleen Doci; J Silvio Gutkind

    2012-01-01

    Angiogenesis,the formation of new blood vessels from preexisting vasculature,is essential for many physiological processes,and aberrant angiogenesis contributes to some of the most prevalent human diseases,including cancer.Angiogenesis is controlled by delicate balance between pro- and anti-angiogenic signals.While pro-angiogenic signaling has been extensively investigated,how developmentally regulated,naturally occurring anti-angiogenic molecules prevent the excessive growth of vascular and lymphatic vessels is still poorly understood.In this review,we summarize the current knowledge on how semaphorins and their receptors,plexins and neuropilins,control normal and pathological angiogenesis,with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in vascular and lymphatic endothelial cells.This emerging body of information may afford the opportunity to develop novel anti-angiogenic therapeutic strategies.

  2. Aberrant angiogenesis: The gateway to diabetic complications

    Directory of Open Access Journals (Sweden)

    Sunil K Kota

    2012-01-01

    Full Text Available Diabetes Mellitus is a metabolic cum vascular syndrome with resultant abnormalities in both micro- and macrovasculature. The adverse long-term effects of diabetes mellitus have been described to involve many organ systems. Apart from hyperglycemia, abnormalities of angiogenesis may cause or contribute toward many of the clinical manifestations of diabetes. These are implicated in the pathogenesis of vascular abnormalities of the retina, kidneys, and fetus, impaired wound healing, increased risk of rejection of transplanted organs, and impaired formation of coronary collaterals. A perplexing feature of the aberrant angiogenesis is that excessive and insufficient angiogenesis can occur in different organs in the same individual. The current article hereby reviews the molecular mechanisms including abnormalities in growth factors, cytokines, and metabolic derangements, clinical implications, and therapeutic options of dealing with abnormal angiogenesis in diabetes.

  3. Emerging evidence on the pathobiology of mucositis.

    NARCIS (Netherlands)

    Al-Dasooqi, N.; Sonis, S.T.; Bowen, J.M.; Bateman, E.; Blijlevens, N.M.; Gibson, R.J.; Logan, R.M.; Nair, R.G.; Stringer, A.M.; Yazbeck, R.; Elad, S.; Lalla, R.V.

    2013-01-01

    BACKGROUND: Considerable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely. METHODS: Panel members reviewed th

  4. Biology and mucosal immunity to myxozoans.

    Science.gov (United States)

    Gómez, Daniela; Bartholomew, Jerri; Sunyer, J Oriol

    2014-04-01

    Myxozoans are among the most abundant parasites in nature. Their life cycles involve two hosts: an invertebrate, usually an annelid, and a vertebrate, usually a fish. They affect fish species in their natural habitats but also constitute a menace for fish aquaculture. Using different strategies they are able to parasitize and cause damage in multiple organs, including mucosal tissues, which they use also as portals of entry. In fish, the main mucosal sites include the intestine, skin and gills. Recently the finding of a specific mucosal immunoglobulin in teleost (IgT), analogous to mammalian IgA, and the capacity of fish to develop a specific mucosal immune response against different pathogens, has highlighted the importance of studying immune responses at mucosal sites. In this review, we describe the major biological characteristics of myxozoan parasites and present the data available regarding immune responses for species that infect mucosal sites. As models for mucosal immunity we review the responses to Enteromyxum spp. and Ceratomyxa shasta, both of which parasitize the intestine. The immune response at the skin and gills is also described, as these mucosal tissues are used by myxozoans as attaching surfaces and portal of entry, and some species also parasitize these sites. Finally, the development of immunoprophylactic strategies is discussed.

  5. Nutrition and Gut Mucositis in Pediatric Oncology

    DEFF Research Database (Denmark)

    Pontoppidan, Peter Erik Lotko

    . Unfortunately, effective treatment strategies against mucositis are not in general available. The overall aim of the present PhD was to study interactions between mucositis, inflammation and nutrition. We hypothesized that toxic reactions in the alimentary tract, induced by chemotherapy, followed by release...

  6. Mucosal healing and deep remission: What does it mean?

    Science.gov (United States)

    Rogler, Gerhard; Vavricka, Stephan; Schoepfer, Alain; Lakatos, Peter L

    2013-01-01

    The use of specific terms under different meanings and varying definitions has always been a source of confusion in science. When we point our efforts towards an evidence based medicine for inflammatory bowel diseases (IBD) the same is true: Terms such as “mucosal healing” or “deep remission” as endpoints in clinical trials or treatment goals in daily patient care may contribute to misconceptions if meanings change over time or definitions are altered. It appears to be useful to first have a look at the development of terms and their definitions, to assess their intrinsic and context-independent problems and then to analyze the different relevance in present-day clinical studies and trials. The purpose of such an attempt would be to gain clearer insights into the true impact of the clinical findings behind the terms. It may also lead to a better defined use of those terms for future studies. The terms “mucosal healing” and “deep remission” have been introduced in recent years as new therapeutic targets in the treatment of IBD patients. Several clinical trials, cohort studies or inception cohorts provided data that the long term disease course is better, when mucosal healing is achieved. However, it is still unclear whether continued or increased therapeutic measures will aid or improve mucosal healing for patients in clinical remission. Clinical trials are under way to answer this question. Attention should be paid to clearly address what levels of IBD activity are looked at. In the present review article authors aim to summarize the current evidence available on mucosal healing and deep remission and try to highlight their value and position in the everyday decision making for gastroenterologists. PMID:24282345

  7. Oral health as a predictive factor for oral mucositis

    Directory of Open Access Journals (Sweden)

    Fabio Luiz Coracin

    2013-06-01

    Full Text Available OBJECTIVES: Oral mucositis is a complication frequently associated with hematopoietic stem cell transplantation, decreasing a patient's quality of life and increasing the occurrence of opportunistic infections. The purpose of this study was to determine the incidence and severity of oral mucositis and to assess the correlation of this disease with the oral health of an individual at the time of hematopoietic stem cell transplantation. METHODS: Before transplantation, patients' oral health and inflammatory conditions were determined using the gingival index and the plaque index, which are based on gingival bleeding and the presence of dental plaque, respectively. Additionally, the dental health status was determined using the decayed, missing, and filled teeth index. The monitoring of oral mucositis was based on the World Health Organization grading system and was performed for five periods: from Day 0 to D+5, from D+6 to D+10, from D+11 to D+15, from D+16 to D+20, and from D+21 to D+30. RESULTS: A total of 97 patients (56% male and 44% female who underwent hematopoietic stem cell transplantation at the Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo between January 2008 and July 2009 were prospectively examined. The incidence of ulcerative mucositis was highest from days +6 to +10 and from days +11 to +15 in the patients who underwent autologous and allogeneic hematopoietic stem cell transplantation, respectively. CONCLUSION: The data, including the dental plaque and periodontal status data, showed that these oral health factors were predictive of the incidence and severity of oral mucositis in a cohort of patients with similar conditioning regimens before hematopoietic stem cell transplantation.

  8. Angiogenesis in male breast cancer

    Directory of Open Access Journals (Sweden)

    Kanthan Rani

    2005-03-01

    Full Text Available Abstract Background Male breast cancer is a rare but aggressive and devastating disease. This disease presents at a later stage and in a more advanced fashion than its female counterpart. The immunophenotype also appears to be distinct when compared to female breast cancer. Angiogenesis plays a permissive role in the development of a solid tumor and provides an avenue for nutrient exchange and waste removal. Recent scrutiny of angiogenesis in female breast cancer has shown it to be of significant prognostic value. It was hypothesized that this holds true in invasive ductal carcinoma of the male breast. In the context of male breast cancer, we investigated the relationship of survival and other clinico-pathological variables to the microvascular density of the tumor tissue. Methods Seventy-five cases of primary male breast cancer were identified using the records of the Saskatchewan Cancer Agency over a period of 26 years. Forty-seven cases of invasive ductal carcinoma of the male breast had formalin-fixed paraffin-embedded tissue blocks that were suitable for this study. All cases were reviewed. Immunohistochemical staining was performed for the angiogenic markers (cluster designations 31 (CD31, 34 (CD34 and 105 (CD105, von Willebrand factor (VWF, and vascular endothelial growth factor (VEGF. Microvascular density (MVD was determined using average, centre, and highest microvessel counts (AMC, CMC, and HMC, respectively. Statistical analyses compared differences in the distribution of survival times and times to relapse between levels of MVD, tumor size, node status and age at diagnosis. In addition, MVD values were compared within each marker, between each marker, and were also compared to clinico-pathological data. Results Advanced age and tumor size were related to shorter survival times. There were no statistically significant differences in distributions of survival times and times to relapse between levels of MVD variables. There was no

  9. Mucosal vaccines: a paradigm shift in the development of mucosal adjuvants and delivery vehicles.

    Science.gov (United States)

    Srivastava, Atul; Gowda, Devegowda Vishakante; Madhunapantula, SubbaRao V; Shinde, Chetan G; Iyer, Meenakshi

    2015-04-01

    Mucosal immune responses are the first-line defensive mechanisms against a variety of infections. Therefore, immunizations of mucosal surfaces from which majority of infectious agents make their entry, helps to protect the body against infections. Hence, vaccinization of mucosal surfaces by using mucosal vaccines provides the basis for generating protective immunity both in the mucosal and systemic immune compartments. Mucosal vaccines offer several advantages over parenteral immunization. For example, (i) ease of administration; (ii) non-invasiveness; (iii) high-patient compliance; and (iv) suitability for mass vaccination. Despite these benefits, to date, only very few mucosal vaccines have been developed using whole microorganisms and approved for use in humans. This is due to various challenges associated with the development of an effective mucosal vaccine that can work against a variety of infections, and various problems concerned with the safe delivery of developed vaccine. For instance, protein antigen alone is not just sufficient enough for the optimal delivery of antigen(s) mucosally. Hence, efforts have been made to develop better prophylactic and therapeutic vaccines for improved mucosal Th1 and Th2 immune responses using an efficient and safe immunostimulatory molecule and novel delivery carriers. Therefore, in this review, we have made an attempt to cover the recent advancements in the development of adjuvants and delivery carriers for safe and effective mucosal vaccine production. © 2015 APMIS. Published by John Wiley & Sons Ltd.

  10. Neomycin inhibits angiogenin-induced angiogenesis

    OpenAIRE

    1998-01-01

    A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, an...

  11. Neomycin inhibits angiogenin-induced angiogenesis

    OpenAIRE

    Hu, Guo-fu

    1998-01-01

    A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, an...

  12. Piperine, a dietary phytochemical, inhibits angiogenesis

    OpenAIRE

    2012-01-01

    Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induce...

  13. Mucosal vaccines: novel strategies and applications for the control of pathogens and tumors at mucosal sites.

    Science.gov (United States)

    Nizard, Mevyn; Diniz, Mariana O; Roussel, Helene; Tran, Thi; Ferreira, Luis Cs; Badoual, Cecile; Tartour, Eric

    2014-01-01

    The mucosal immune system displays several adaptations reflecting the exposure to the external environment. The efficient induction of mucosal immune responses also requires specific approaches, such as the use of appropriate administration routes and specific adjuvants and/or delivery systems. In contrast to vaccines delivered via parenteral routes, experimental, and clinical evidences demonstrated that mucosal vaccines can efficiently induce local immune responses to pathogens or tumors located at mucosal sites as well as systemic response. At least in part, such features can be explained by the compartmentalization of mucosal B and T cell populations that play important roles in the modulation of local immune responses. In the present review, we discuss molecular and cellular features of the mucosal immune system as well as novel immunization approaches that may lead to the development of innovative and efficient vaccines targeting pathogens and tumors at different mucosal sites.

  14. Angiogenesis, fibrinogenesis and presence of synechiae after exeresis of a swine vocal fold mucosal microflap and use of topical mitomycin-C Estudo da angiogênese, fibrogênese e presença de sinéquias após exérese de fragmento de mucosa de pregas vocais de suínos utilizando instrumental frio e mitomicina-C tópica

    Directory of Open Access Journals (Sweden)

    Vinicius Ribas de Carvalho Duarte Fonseca

    2010-02-01

    Full Text Available PURPOSE: To evaluate swine vocal fold healing in a period of 30 days after topical mitomycin-C application. METHODS: Twelve swine underwent exeresis of mucosal flaps from the free edge of the anterior third of both vocal folds with a cold instrument (laryngeal scissors. The animals were divided into two groups: EG (Experimental Group, consisting of 6 animals undergoing topical MMC application (4 mg/dL on the operated area for 4 minutes; CG (Control Group, 6 animals undergoing topical saline solution application on the operated area for 4 minutes. After 30 days, the animals were sacrificed and the larynges were collected and examined for the presence of synechiae as well as a histological immunohistochemical assessment of immature and mature collagen deposition, number of blood vessels and myofibroblasts. RESULTS: Mature collagen deposition in the EG was 452.12 μm² and 1332.31μm² in the CG; immature collagen deposition was 1511.73μm² in the EG and 1020.61μm² in the CG. The number of myofibroblasts was 1.556 in the EG and 3.583 in the CG. The number of blood vessels was 2.565 in EG and 6.917 in the CG. There were no synechiae in the two studied groups. CONCLUSIONS: There was an increase in immature collagen deposition in the experimental group when compared with the control group. There was a decrease in mature collagen deposition in the experimental group when compared with the control group. There was a decrease in the number of myofibroblasts in the experimental group when compared with the control group. A decrease in blood vessels was observed in the experimental group when compared with the control group. There was no synechia formation in either studied group.OBJETIVO: Avaliar a cicatrização de pregas vocais de suínos utilizando mitomicina-C tópica, em 30 dias. MÉTODOS: Doze suínos foram submetidos à exérese de mucosa do bordo livre do terço anterior de ambas as pregas vocais com instrumental frio (tesoura curva e divididos

  15. Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons.

    Science.gov (United States)

    Balestra, B; Vicini, R; Cremon, C; Zecchi, L; Dothel, G; Vasina, V; De Giorgio, R; Paccapelo, A; Pastoris, O; Stanghellini, V; Corinaldesi, R; De Ponti, F; Tonini, M; Barbara, G

    2012-12-01

    Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS. © 2012 Blackwell Publishing Ltd.

  16. The effect of chewing gum on oral mucositis in children receiving chemotherapy

    OpenAIRE

    Ocakcı, Ayşe Ferda; Ayverdi, Didem; Ekim, Ayfer

    2014-01-01

    Abstract Background: Oral mucositis is an important clinical problem, resulting in significant patient morbidity, a change in health-related quality of life, and supportive care. The purpose of this study was to assess the efficiency of chewing gum on children, who are receiving chemotherapy regimens, for prevention and treatment of oral mucositis. Method and Material: The study sample consisted of 60 children (30 study group-30 control group) between the ages 6-...

  17. Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models

    OpenAIRE

    Iskra Tuero; Marjorie Robert-Guroff

    2014-01-01

    An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV is transmitted primarily across mucosal surfaces, development of immunity at these sites is critical, but few clinical vaccine trials have targeted these sites or assessed vaccine-elicited mucosal immune responses. Pre-clinic...

  18. Mucosal versus muscle pain sensitivity in provoked vestibulodynia

    Directory of Open Access Journals (Sweden)

    Witzeman K

    2015-08-01

    Full Text Available Kathryn Witzeman,1 Ruby HN Nguyen,2 Alisa Eanes,3 Sawsan As-Sanie,4 Denniz Zolnoun51Department of Obstetrics and Gynecology, Denver Health Medical Center, Denver, CO, 2Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, 3Pelvic Pain Research Unit, Division of Advanced Laparoscopy and Pelvic Pain, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC, 4Department of Obstetrics and Gynecology, Division of Minimally Invasive Gynecologic Surgery, University of Michigan, Ann Arbor, MI, 5Department of Obstetrics and Gynecology and Center for Neurosensory Disorders, University of North Carolina, Chapel Hill, NC, USABackground: An estimated 8.3%–16% of women experience vulvovaginal discomfort during their lifetime. Frequently these patients report provoked pain on contact or with attempted intercourse, commonly referred to as provoked vestibulodynia (PVD. Despite the burden of this condition, little is known about its potential etiologies including pelvic floor muscular dysfunction and mucosal components. This knowledge would be beneficial in developing targeted therapies including physical therapy.Objective: To explore the relative contribution of mucosal versus muscle pain sensitivity on pain report from intercourse among women with PVD.Design: In this proof of concept study, 54 women with PVD underwent a structured examination assessing mucosal and pelvic muscle sensitivity.Methods: We examined three mucosal sites in the upper and lower vestibule. Patients were asked to rate their pain on cotton swab palpation of the mucosa using a 10-point visual analog scale. Muscle pain was assessed using transvaginal application of pressure on right and left puborectalis, and the perineal muscle complex. The Gracely pain scale (0–100 was used to assess the severity of pain with intercourse, with women rating the lowest, average, and highest pain levels; a 100 rating the

  19. Cone-beam computed tomographic evidence of the association between periodontal bone loss and mucosal thickening of the maxillary sinus.

    Science.gov (United States)

    Phothikhun, Sirikarn; Suphanantachat, Supreda; Chuenchompoonut, Vannaporn; Nisapakultorn, Kanokwan

    2012-05-01

    The aim of the present study is to determine the relationship between dental findings and mucosal abnormalities of the maxillary sinus among dental patients, using cone-beam computed tomography (CBCT). Two hundred fifty CBCT scans of dental patients were studied. Dental findings of the upper posterior teeth, including periodontal bone loss, periapical lesions, and root canal fillings, were assessed. The presence of mucosal thickening and mucosal cysts of the maxillary sinus was recorded. Logistic regression analysis was used to determine the influence of periodontal bone loss, periapical lesions, and root canal fillings on these sinus mucosal abnormalities. Mucosal thickening was present in 42% of patients and in 29.2% of sinuses studied. Mucosal cysts were observed in 16.4% of patients and in 10% of sinuses studied. Both abnormalities were present more frequently among males than females. Severe periodontal bone loss was significantly associated with mucosal thickening (odds ratio: 3.02, P maxillary sinus. Sinuses with severe periodontal bone loss were three times more likely to have mucosal thickening. Mucosal cysts were not associated with any dental findings.

  20. Effect of electroacupunture on gastric mucosal intestinal trefoil factor gene expression of stress-induced gastric mucosal injury in rats

    Institute of Scientific and Technical Information of China (English)

    Xi-Ping Li; Jie Yan; Shou-Xiang Yi; Xiao-Rong Chang; Ya-Ping Lin; Zong-Bao Yang; Ai Huang; Rong Hu

    2006-01-01

    AIM: To investigate electroacupunture(EA) at the acupoints of Stomach Meridian of Foot-Yangming(SMFY),Gallbladder Meridian of Foot-Yangming(SMFY) on gastric mucosal intestinal trefoil factor (ITF) gene expression detection in stress-induced rats with gastric mucosal lesion, and to explore the regulatory mechanism and significance of EA-related gastric mucosal protective effect.METHODS: Forty rats were randomly divided into 4 groups: Blank group, Model group, Model group+EA at acupoints of SMFY group("SMFY group"), and Model group+EA at acupoints of GMFY group(GMFY group).All rats (except blank group) were made model by water immersion and restraint stress (WRS). Then the gastric mucosa tissue in each rat was taken off after assessment of gastric mucosal lesion index(GUI), and the expression of ITF mRNA of the tissues was detected by reverse transcription-polymerase chain reaction(RT-PCR) method.RESULTS: Compared with Model group(54.3 ± 1.34),the GUI value in SMFY group (31±2.21) decreased significantly(P 0.05), in SMFY group(0.76± 0.01)with an extremely obvious difference (P<0.01), furthermore the expression in SMFY group was significantly higher than in GMFY group (P< 0.01).CONCLUSION: The gastric mucosal protective effect by EA at the acupoints of SMFY and GMFY was related to the expression variance of ITF, indicating certain meridian specificity exists. It could be one proof for the TCM theory "Relative particularity between SMFY and stomach".

  1. Measuring oral mucositis of pediatric patients with cancer: A psychometric evaluation of chinese version of the oral mucositis daily questionnaire

    Directory of Open Access Journals (Sweden)

    Karis Kin Fong Cheng

    2017-01-01

    Full Text Available Objective: Oral mucositis is a frequent clinical condition that has been shown to affect pediatric cancer patients. Oral Mucositis Daily Questionnaire (OMDQ is one of the few available patient-reported outcome measures to assess the extent and impact of oral mucositis. The objectives of the study were to translate the Mouth and Throat Soreness-Related Questions of the OMDQ into Chinese (OMDQ MTS-Ch for children and adolescents aged 6–18 years receiving chemotherapy and to evaluate its psychometric properties. Methods: This was part of a multicenter, prospective cohort study involving two phases. Phase I involved forward-backward translation to fit the cognitive and linguistic age level of the children and adolescents, followed by face and content validation, together with pretesting. In Phase II, which evaluated the internal consistency, test-retest reliability, and discriminant validity, a total of 140 patients completed the OMDQ MTS-Ch for 14 days. Results: The OMDQ MTS-Ch had satisfactory face and content validities. The Cronbach's alpha coefficient of the OMDQ MTS-Ch was 0.984. All of the corrected item-total correlations were higher than 0.90. The test-retest intraclass correlation coefficient between consecutive days for the OMDQ MTS-Ch items ranged from 0.576 to 0.983; the only value that was not over 0.70 was that for the paired study days 7 and 8 for the item of talking. The mean area-under-the-curve OMDQ MTS-Ch item scores were significantly different among patients with different degrees of mucositis severity (P < 0.001, supporting the discriminant validity. Conclusions: It has been shown that the OMDQ MTS-Ch has a good level of reliability and discriminant validity and can be completed by children aged ≥6 years and adolescents on a daily basis to measure mucositis and its related functional limitations.

  2. Studies on tumor induced angiogenesis.

    Science.gov (United States)

    Ambrus, J L; Ambrus, C M; Forgach, P; Stadler, S; Halpern, J; Sayyid, S; Niswander, P; Toumbis, C

    1992-01-01

    Methods were developed to test angiogenic response to human tumor implants and various biologic agents in the cornea of rabbits and non-human primates (Macaca arctoides). Crude PDGF preparations were found to have significant angiogenic effect. Purified, recombinant PDGF preparations were also effective inhibitors (e.g. pentoxifylline (Px) (which also were found to release PgI2 and t-PA) inhibited human tumor implant induced angiogenesis and reduced spontaneous metastases in 3 transplantable murine tumors (Furth-Columbia Wilms' tumor in Furth-Wistar rats, C-1300 neuroblastoma in A/J mice and HM-Kim mammary carcinoma in Wistar rats) but not in the NIH adenocarcinoma in Balb/c mice. Sodium diethyldithiocarbamate (DDTC), a metal complexing agent with special affinity to copper and anti-thyroid as well as, immune stimulating activity was shown to be anti-angiogenic and to potentiate the effect of Px. The anti-fibrinolytic agents epsilon amino caproic acid (EACA) and tranaxamic acid (t-AMCHA) were anti-angiogenic. DDTC and Px were synergistic from this point of view.

  3. Intestinal mucosal atrophy and adaptation

    Institute of Scientific and Technical Information of China (English)

    Darcy Shaw; Kartik Gohil; Marc D Basson

    2012-01-01

    Mucosal adaptation is an essential process in gut homeostasis.The intestinal mucosa adapts to a range of pathological conditions including starvation,short-gut syndrome,obesity,and bariatric surgery.Broadly,these adaptive functions can be grouped into proliferation and differentiation.These are influenced by diverse interactions with hormonal,immune,dietary,nervous,and mechanical stimuli.It seems likely that clinical outcomes can be improved by manipulating the physiology of adaptation.This review will summarize current understanding of the basic science surrounding adaptation,delineate the wide range of potential targets for therapeutic intervention,and discuss how these might be incorporated into an overall treatment plan.Deeper insight into the physiologic basis of adaptation will identify further targets for intervention to improve clinical outcomes.

  4. Icing oral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant.

    Science.gov (United States)

    Chen, Joey; Seabrook, Jamie; Fulford, Adrienne; Rajakumar, Irina

    2017-03-01

    Background Up to 70% of patients receiving hematopoietic stem cell transplant develop oral mucositis as a side effect of high-dose melphalan conditioning chemotherapy. Oral cryotherapy has been documented to be potentially effective in reducing oral mucositis. The aim of this study was to examine the effectiveness of the cryotherapy protocol implemented within the hematopoietic stem cell transplant program. Methods A retrospective chart review was conducted of adult multiple myeloma patients who received high-dose melphalan conditioning therapy for autologous hematopoietic stem cell transplant. Primary endpoints were incidence and severity of oral mucositis. Secondary endpoints included duration of oral mucositis, duration of hospital stay, parenteral narcotics use and total parenteral nutrition use. Results One hundred and forty patients were included in the study, 70 patients in both no cryotherapy and cryotherapy groups. Both oral mucositis incidence and severity were found to be significantly lower in the cryotherapy group. Fifty (71.4%) experienced mucositis post cryotherapy compared to 67 (95.7%) in the no cryotherapy group (p < 0.001). The median oral mucositis severity, assessed using the WHO oral toxicity scale from grade 0-4, experienced in the no group was 2.5 vs. 2 in the cryotherapy group (p = 0.03). Oral mucositis duration and use of parenteral narcotics were also significantly reduced. Duration of hospital stay and use of parenteral nutrition were similar between the two groups. Conclusion The cryotherapy protocol resulted in a significantly lower incidence and severity of oral mucositis. These results provide evidence for the continued use of oral cryotherapy, an inexpensive and generally well-tolerated practice.

  5. Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats.

    Science.gov (United States)

    Funatsu, Toshiyuki; Chono, Koji; Hirata, Takuya; Keto, Yoshihiro; Kimoto, Aishi; Sasamata, Masao

    2007-01-01

    The mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) suppress gastric mucosal blood flow is not fully understood, although the depletion of mucosal prostaglandin E2 has been proposed as one possible explanation. We investigated the role of gastric acid on gastric mucosal blood flow in NSAID-treated rats. A rat stomach was mounted in an ex vivo chamber, and gastric mucosal blood flow was measured sequentially in a 5-mm2 area of the gastric corpus using a scanning laser Doppler perfusion image system. Results showed that diclofenac (5 mg/kg s.c.) and indomethacin (10 mg/kg s.c.) did not affect gastric mucosal blood flow, although both strongly decreased mucosal prostaglandin E2 when saline was instilled into the gastric chamber. On replacement of the saline in the chamber with 100 mM hydrochloric acid, these drugs caused a decrease in gastric mucosal blood flow levels within 30 min. The specific cyclooxygenase (COX)-2 inhibitors celecoxib (50 mg/kg s.c.) and rofecoxib (25 mg/kg s.c.) did not affect mucosal prostaglandin E2 level, nor did they decrease gastric mucosal blood flow, even when hydrochloric acid was added to the chamber. Furthermore, measurement of vasoconstrictive factors present in the mucosa showed that endothelin-1 levels increased after administration of diclofenac s.c. in the presence of intragastric hydrochloric acid. This indicates that the presence of mucosal hydrochloric acid plays an important role in the NSAID-induced decrease in gastric mucosal blood flow, while the COX-1-derived basal prostaglandin E2, which is unlikely to control gastric mucosal blood flow itself, protects microcirculatory systems from mucosal hydrochloric acid.

  6. Clopidogrel inhibits angiogenesis of gastric ulcer healing via downregulation of vascular endothelial growth factor receptor 2.

    Science.gov (United States)

    Luo, Jiing-Chyuan; Peng, Yen-Ling; Chen, Tseng-Shing; Huo, Teh-Ia; Hou, Ming-Chih; Huang, Hui-Chun; Lin, Han-Chieh; Lee, Fa-Yauh

    2016-09-01

    Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogrel delays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms. Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation. The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK. Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway. Copyright © 2015. Published by Elsevier B.V.

  7. Neonatal Cytokine Profile in the Airway Mucosal Lining Fluid Is Skewed by Maternal Atopy

    DEFF Research Database (Denmark)

    Folsgaard, Nilofar V.; Chawes, Bo L.; Rasmussen, Morten A.;

    2012-01-01

    on the cytokines and chemokines in the upper airway mucosal lining fluid of healthy neonates. Objectives: To study parental atopic imprinting on the cytokines and chemokines in the upper airway mucosal lining fluid of healthy neonates. Methods: Eighteen cytokines and chemokines were quantified in nasal mucosal...... lining fluid in 309 neonates from the novel unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort. Measurements and Main Results: Maternal, but not paternal, atopic status (asthma, hay fever, or eczema with or without sensitization) was associated with general down......-regulation of all 18 mediators assessed by principal component analysis (overall P = 0.015). Conclusions: Maternal atopy, but not paternal atopy, showed a strong linkage with a suppressed mucosal cytokine and chemokine signature in asymptomatic neonates, suggesting imprinting by the maternal milieu in utero...

  8. Brain neuropeptides in gastric mucosal protection.

    Science.gov (United States)

    Gyires, Klára; Zádori, Zoltán S

    2014-12-01

    The centrally induced gastroprotective effect of neuropeptides has been intensively studied. Besides many similarities, however, differences can also be observed in their gastroprotective actions. The gastroprotective dose-response curve proved to be either sigmoid, or bell-shaped. Additional gastrointestinal effects of neuropeptides can contribute to their mucosal protective effect. Part of the neuropeptides induces gastroprotection by peripheral administration as well. Besides vagal nerve the sympathetic nervous system may also be involved in conveying the central effect to the periphery. Better understanding of the complex mechanism of the maintenance of gastric mucosal integrity may result in the development of new strategy to enhance gastric mucosal resistance against injury.

  9. Cancer gene therapy targeting angiogenesis: An updated review

    Institute of Scientific and Technical Information of China (English)

    Ching-Chiu Liu; Zan Shen; Hsiang-Fu Kung; Marie CM Lin

    2006-01-01

    Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971,scientists have made efforts exploring the possibilities in treating cancer by targeting angiogenesis. Inhibition of angiogenesis growth factors and administration of angiogenesis inhibitors are the basics of antiangiogenesis therapy. Transfer of anti-angiogenesis genes has Received attention recently not only because of the advancement of recombinant vectors, but also because of the localized and sustained expression of therapeutic gene product inside the tumor after gene transfer. This review provides the up-to-date information about the strategies and the vectors studied in the field of anti-angiogenesis cancer gene therapy.

  10. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression.

    Directory of Open Access Journals (Sweden)

    Matthew E Hardee

    Full Text Available BACKGROUND: The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad. CONCLUSIONS/SIGNIFICANCE: These data indicate that erythropoietin is an

  11. Angiogenesis is inhibitory for mammalian digit regeneration.

    Science.gov (United States)

    Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D; Leininger, Eric; Han, Manjong; Muneoka, Ken

    2014-06-01

    The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti-angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551-559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium-derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration.

  12. Angiogenesis is inhibitory for mammalian digit regeneration

    Science.gov (United States)

    Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D.; Leininger, Eric; Han, Manjong

    2014-01-01

    Abstract The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti‐angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551–559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium‐derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration. PMID:27499862

  13. Tumor angiogenesis: role in locally aggressive biological behavior of ameloblastoma and keratocystic odontogenic tumor.

    Science.gov (United States)

    Gadbail, Amol Ramchandra; Mankar Gadbail, Mugdha P; Hande, Alka; Chaudhary, Minal S; Gondivkar, Shailesh M; Korde, Sheetal; Gawande, Madhuri N; Patil, Swati; Tekade, Satyjitraje; Sharma, Aparna

    2013-03-01

    The purpose of this study was to assess and compare angiogenesis in ameloblastoma, keratocystic odontogenic tumors, dentigerous cysts, and normal oral mucosa. Angiogenesis was assessed in 28 ameloblastoma-36 keratocystic odontogenic tumors, 28 dentigerous cysts, and 19 normal oral mucosa by measuring the mean vascular density (MVD), total vascular area (TVA) and mean vascular area (MVA). Immunohistochemistry was carried out by using CD105. The nonsignificant difference of MVD was noted between ameloblastoma and keratocystic odontogenic tumors (p = .174). TVA and MVA were significantly higher in ameloblastoma than keratocystic odontogenic tumors, normal oral mucosa, and dentigerous cysts (p ameloblastoma and keratocystic odontogenic tumor. The angiogenesis could be a potent target for developing antiangiogenic therapeutic strategies, particularly in recurrent cases of odontogenic tumors. Copyright © 2012 Wiley Periodicals, Inc.

  14. Exploiting Mucosal Immunity for Antiviral Vaccines.

    Science.gov (United States)

    Iwasaki, Akiko

    2016-05-20

    Mucosal surfaces provide a remarkably effective barrier against potentially dangerous pathogens. Therefore, enhancing mucosal immunity through vaccines-strengthening that first line of defense-holds significant promise for reducing the burden of viral diseases. The large and varied class of viral pathogens, however, continues to present thorny challenges to vaccine development. Two primary difficulties exist: Viruses exhibit a stunning diversity of strategies for evading the host immune response, and even when we understand the nature of effective immune protection against a given virus, eliciting that protection is technically challenging. Only a few mucosal vaccines have surmounted these obstacles thus far. Recent developments, however, could greatly improve vaccine design. In this review, we first sketch out our understanding of mucosal immunity and then compare the herpes simplex virus, human immunodeficiency virus, and influenza virus to illustrate the distinct challenges of developing successful vaccines and to outline potential solutions.

  15. Microbiota and mucosal immunity in amphibians.

    Science.gov (United States)

    Colombo, Bruno M; Scalvenzi, Thibault; Benlamara, Sarah; Pollet, Nicolas

    2015-01-01

    We know that animals live in a world dominated by bacteria. In the last 20 years, we have learned that microbes are essential regulators of mucosal immunity. Bacteria, archeas, and viruses influence different aspects of mucosal development and function. Yet, the literature mainly covers findings obtained in mammals. In this review, we focus on two major themes that emerge from the comparative analysis of mammals and amphibians. These themes concern: (i) the structure and functions of lymphoid organs and immune cells in amphibians, with a focus on the gut mucosal immune system; and (ii) the characteristics of the amphibian microbiota and its influence on mucosal immunity. Lastly, we propose to use Xenopus tadpoles as an alternative small-animal model to improve the fundamental knowledge on immunological functions of gut microbiota.

  16. Microbiota and mucosal immunity in amphibians

    Directory of Open Access Journals (Sweden)

    Bruno M Colombo

    2015-03-01

    Full Text Available We know that animals live in a world dominated by bacteria. In the last twenty years we have learned that microbes are essential regulators of mucosal immunity. Bacterias, archeas and viruses influence different aspects of mucosal development and function. Yet the literature mainly covers findings obtained in mammals. In this review, we focus on two major themes that emerge from the comparative analysis of mammals and amphibians. These themes concern: i the structure and functions of lymphoid organs and immune cells in amphibians, with a focus on the gut mucosal immune system; and ii the characteristics of the amphibian microbiota and its influence on mucosal immunity. Lastly, we propose to use Xenopus tadpoles as an alternative small animal model to improve the fundamental knowledge on immunological functions of gut microbiota.

  17. Effect of ageing on colonic mucosal regeneration

    Institute of Scientific and Technical Information of China (English)

    Ferenc Sipos; Katalin Leiszter; Zsolt Tulassay

    2011-01-01

    The physiologic and pathologic cellular and molecular changes occurring with age in the human colon affect both the inflammatory process leading to mucosal injury and the regenerative capacity of the epithelium. On the one hand, age-related telomere shortening and inflamm-ageing may lead to the development of colonic inflammation, which results in epithelial damage. On the other hand, the altered migration and function of regenerative stem cells, the age-related methylation of mucosal healing-associated genes, together with the alterations of growth factor signaling with age, may be involved in delayed mucosal regeneration. The connections of these alterations to the process of ageing are not fully known. The understanding and customtailored modification of these mechanisms are of great clinical importance with regard to disease prevention and modern therapeutic strategies. Here, we aim to summarize the age-related microscopic and molecular changes of the human colon, as well as their role in altered mucosal healing.

  18. Transgenic Killer Commensal Bacteria as Mucosal Protectants

    Directory of Open Access Journals (Sweden)

    Luciano Polonelli

    2001-01-01

    Full Text Available As first line of defense against the majority of infections and primary site for their transmission, mucosal surfaces of the oral cavity and genitourinary, gastrointestinal, and respiratory tracts represent the most suitable sites to deliver protective agents for the prevention of infectious diseases. Mucosal protection is important not only for life threatening diseases but also for opportunistic infections which currently represent a serious burden in terms of morbidity, mortality, and cost of cures. Candida albicans is among the most prevalent causes of mucosal infections not only in immuno- compromised patients, such as HIV-infected subjects who are frequently affected by oral and esophageal candidiasis, but also in otherwise healthy individuals, as in the case of acute vaginitis. Unfortunately, current strategies for mucosal protection against candidiasis are severely limited by the lack of effective vaccines and the relative paucity and toxicity of commercially available antifungal drugs. An additional option has been reported in a recent

  19. A regenerative approach towards mucosal fenestration closure.

    Science.gov (United States)

    Gandi, Padma; Anumala, Naveen; Reddy, Amarender; Chandra, Rampalli Viswa

    2013-06-06

    Mucosal fenestration is an opening or an interstice through the oral mucosa. A lesion which occurs with greater frequency than generally realised, its occurrence is attributed to a myriad of causes. Mucogingival procedures including connective tissue grafts, free gingival grafts and lateral pedicle grafts are generally considered to be the treatment of choice in the closure of a mucosal fenestration. More often, these procedures are performed in conjunction with other procedures such as periradicular surgery and with bone grafts. However, the concomitant use of gingival grafts and bone grafts in mucosal fenestrations secondary to infections in sites exhibiting severe bone loss is highly debatable. In this article, we report two cases of mucosal fenestrations secondary to trauma and their management by regenerative periodontal surgery with the placement of guided tissue regeneration membrane and bone graft. The final outcome was a complete closure of the fenestration in both the cases.

  20. Targeting the Tumor Microenvironment: Focus on Angiogenesis

    Directory of Open Access Journals (Sweden)

    Fengjuan Fan

    2012-01-01

    Full Text Available Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.

  1. Targeting the tumor microenvironment: focus on angiogenesis.

    Science.gov (United States)

    Fan, Fengjuan; Schimming, Alexander; Jaeger, Dirk; Podar, Klaus

    2012-01-01

    Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.

  2. Mesoscopic and continuum modelling of angiogenesis

    KAUST Repository

    Spill, F.

    2014-03-11

    Angiogenesis is the formation of new blood vessels from pre-existing ones in response to chemical signals secreted by, for example, a wound or a tumour. In this paper, we propose a mesoscopic lattice-based model of angiogenesis, in which processes that include proliferation and cell movement are considered as stochastic events. By studying the dependence of the model on the lattice spacing and the number of cells involved, we are able to derive the deterministic continuum limit of our equations and compare it to similar existing models of angiogenesis. We further identify conditions under which the use of continuum models is justified, and others for which stochastic or discrete effects dominate. We also compare different stochastic models for the movement of endothelial tip cells which have the same macroscopic, deterministic behaviour, but lead to markedly different behaviour in terms of production of new vessel cells. © 2014 Springer-Verlag Berlin Heidelberg.

  3. Angiogenesis and Lymphangiogenesis of Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Yasuhiko Kitadai

    2010-01-01

    Full Text Available Tumor angiogenesis is the result of an imbalance between positive and negative angiogenic factors released by tumor and host cells into the microenvironment of the neoplastic tissue. The stroma constitutes a large part of most solid tumors, and cancer-stromal cell interactions contribute functionally to tumor growth and metastasis. Activated fibroblasts and macrophages in tumor stroma play important roles in angiogenesis and tumor progression. In gastric cancer, tumor cells and stromal cells produce various angiogenic factors, including vascular endothelial growth factor, interleukin-8, platelet-derived endothelial cell growth factor, and angiopoietin. In addition, Helicobacter pylori infection increases tumor cell expression of metastasis-related genes including those encoding several angiogenic factors. We review the current understanding of molecular mechanisms involved in angiogenesis and lymphangiogenesis of human gastric cancer.

  4. COX-2, VEGF and tumour angiogenesis.

    LENUS (Irish Health Repository)

    Toomey, D P

    2009-06-01

    Epidemiological evidence suggests a protective effective of regular NSAID use against developing cancer. Cyclooxygenase-2, a target of NSAIDs, is upregulated in many cancers and has been associated with increased VEGF production and angiogenesis. Angiogenesis is the formation of new vessels from existing vasculature and as an essential process for tumour development represents an important therapeutic target. Following an extensive review of the literature this article details the current knowledge on the role of COX-2 in tumorigenesis focusing on its relationship to angiogenesis and VEGF production by tumour cells. While COX-2 is clearly detrimental to prognosis and NSAIDs have a beneficial effect, the possibility of COX-2 independent effects being partly or wholly responsible for this benefit cannot be excluded.

  5. The development of an AIDS mucosal vaccine

    OpenAIRE

    Xian Tang; Zhiwei Chen

    2010-01-01

    It is well known that mucosal tissues contain the largest surface area of the human body and are the front line of natural host defense against various pathogens. In fact, more than 80% of infectious disease pathogens probably gain entry into the susceptible human hosts through open mucosal surfaces. Human immunodeficiency virus type one (HIV-1), a mainly sexually transmitted virus, also primarily targets the vaginal and gastrointestinal mucosa as entry sites for viral transmission, seeding, ...

  6. Characterization of zofenoprilat as an inducer of functional angiogenesis through increased H2S availability

    Science.gov (United States)

    Terzuoli, E; Monti, M; Vellecco, V; Bucci, M; Cirino, G; Ziche, M; Morbidelli, L

    2015-01-01

    Background and Purpose Hydrogen sulfide (H2S), an endogenous volatile mediator with pleiotropic functions, promotes vasorelaxation, exerts anti-inflammatory actions and regulates angiogenesis. Previously, the SH-containing angiotensin-converting enzyme inhibitor (ACEI), zofenopril, was identified as being effective in preserving endothelial function and inducing angiogenesis among ACEIs. Based on the H2S donor property of its active metabolite zofenoprilat, the objective of this study was to evaluate whether zofenoprilat-induced angiogenesis was due to increased H2S availability. Experimental Approach HUVECs were used for in vitro studies of angiogenesis, whereas the Matrigel plug assay was used for in vivo assessments. Key Results Zofenoprilat-treated HUVECs showed an increase in all functional features of the angiogenic process in vitro. As zofenoprilat induced the expression of CSE (cystathionine-γ-lyase) and the continuous production of H2S, CSE inhibition or silencing blocked the ability of zofenoprilat to induce angiogenesis, both in vitro and in vivo. The molecular mechanisms underlying H2S/zofenoprilat-induced angiogenesis were dependent on Akt, eNOS and ERK1/2 cascades. ATP-sensitive potassium (KATP) channels, the molecular target that mediates part of the vascular functions of H2S, were shown to be involved in the upstream activation of Akt and ERK1/2. Moreover, the up-regulation of fibroblast growth factor-2 was dependent on CSE-derived H2S response to H2S and KATP activation. Conclusions and Implications Zofenoprilat induced a constant production of H2S that stimulated the angiogenic process through a KATP channel/Akt/eNOS/ERK1/2 pathway. Thus, zofenopril can be considered as a pro-angiogenic drug acting through H2S release and production, useful in cardiovascular pathologies where vascular functions need to be re-established and functional angiogenesis induced. PMID:25631232

  7. KSHV-Mediated Angiogenesis in Tumor Progression

    Directory of Open Access Journals (Sweden)

    Pravinkumar Purushothaman

    2016-07-01

    Full Text Available Human herpesvirus 8 (HHV-8, also known as Kaposi’s sarcoma-associated herpesvirus (KSHV, is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL and a plasmablastic variant of multicentric Castleman’s disease (MCD. KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders.

  8. KSHV-Mediated Angiogenesis in Tumor Progression

    Science.gov (United States)

    Purushothaman, Pravinkumar; Uppal, Timsy; Sarkar, Roni; Verma, Subhash C.

    2016-01-01

    Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders. PMID:27447661

  9. Cancer therapy-related oral mucositis.

    Science.gov (United States)

    Redding, Spencer W

    2005-08-01

    Oral mucositis is a common side effect of cancer therapies, particularly radiation therapy for head and neck cancer and various forms of chemotherapy. It commonly results in severe oral pain that can compromise the duration and success of cancer management. Hospitalizations are common because patients lose the ability to take anything by mouth due to severe pain and must have alimentation supported during this period. Pain management usually requires potent narcotic analgesia. Cancer therapy-related oral mucositis is commonly described as the most significant and debilitating acute complication associated with radiation therapy and chemotherapy. Until recently, cancer therapy-induced oral mucositis was thought to be a process involving the epithelium only. Evidence is building that the process of oral mucositis involves far more than just the epithelium, but includes multiple cellular processes of the submucosa as well. Many strategies have been evaluated to prevent oral mucositis, but the data is confusing since it is often conflicting. Therapy with the growth factor, KGF1, appears promising, as it is the only medication currently approved by the FDA. A multifaceted approach that targets the entire mucositis process will probably be needed to optimize overall prevention.

  10. Perfusion computed tomography evaluation of angiogenesis in liver cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Han Feng [Xuanwu Hospital, Capital Medical University, Department of Clinical Pain, Beijing (China); Hospital of North Sichuan Medical College, Department of Radiology, Nanchong City, Sichuan Province (China); Du, Yong; Xu, Xiao Xue; Li, Yang [Hospital of North Sichuan Medical College, Department of Radiology, Nanchong City, Sichuan Province (China); Ni, Jia Xiang [Xuanwu Hospital, Capital Medical University, Department of Clinical Pain, Beijing (China); Zhou, Xiang Ping [West China Hospital, Sichuan University, Department of Radiology, Chengdu City, Sichuan Province (China); Li, Jin Dong [Hospital of North Sichuan Medical College, Department of General Surgery, Nanchong City, Sichuan Province (China); Zhang, Qing [Hospital of North Sichuan Medical College, Department of Ultrasound, Nanchong City, Sichuan Province (China)

    2010-06-15

    To investigate the value of computed tomography (CT) perfusion imaging for assessment of angiogenesis in liver cancer. Twenty-one patients with histologically proven liver cancer underwent CT perfusion examination. We compared the following perfusion parameters in the tumour area versus the non-tumour area: total blood flow (TBF), hepatic arterial perfusion (HAP), hepatic portal perfusion (HPP) and hepatic arterial perfusion index (HAPI). Slices of postoperative specimen were stained with haematoxylin-eosin and anti-CD34 immunohistochemistry. The slices were evaluated with emphasis on the CD34-positive neovasculature in the tumour parenchyma. Tumour microvascular density (MVD) was calculated according to the Weidner method. Pearson correlation was used to detect correlations between tumour MVD and tumour perfusion parameters. TBF and HPP in the tumour area were lower than in the non-tumour area (P < 0.05). HAP and HAPI in the tumour area were higher than those of the non-tumour area (P < 0.05). TBF and HAP in the tumour area correlated with MVD in the tumour (P < 0.05), with correlation coefficients of 0.849 and 0.829, respectively. CT perfusion imaging can quantitatively assess the blood supply and its distribution in liver cancer. TBF or HAP may be a useful parameter in assessing angiogenesis of liver cancer. (orig.)

  11. Angiogenesis and vascular targeting: Relevance for hyperthermia

    DEFF Research Database (Denmark)

    Horsman, Michael R

    2008-01-01

    The creation of a functional blood supply from the normal tissue vasculature via the process of angiogenesis is critical for the continued growth and development of solid tumours. This importance has led to the concept of targeting the tumour vasculature as a therapeutic strategy, and two major...... types of vascular targeting agents (VTAs) have developed; those that inhibit the angiogenic process-angiogenesis inhibiting agents (AIAs)-and those that specifically damage the already established neovasculature-vascular disrupting agents (VDAs). The tumour vasculature also plays a critical role...

  12. Monitoring angiogenesis using magnetic resonance methods

    DEFF Research Database (Denmark)

    Holm, David Alberg

    2008-01-01

    and the involved signaling molecules. Subsequently, a short review of contrast agents and perfusion measurements is given. Finally, methods for monitoring angiogenesis using magnetic resonance imaging are reviewed. A method for monitoring early stages of angiogenesis as well as the effect of anti......-angiogenic treatment is presented in the first manuscript. In the second and third manuscript, two separate methods of quantifying perfusion, blood volume and vessel permeability are presented. The methods are used to show that drug delivery to a xenografted tumor is plausible and to show possible vascular maturation...

  13. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Yoon Sun; Jung, Hye Jin [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Seok, Seung Hyeok [Department of Microbiology and Immunology, Institute for Experimental Animals, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Payumo, Alexander Y.; Chen, James K. [Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 (United States); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2013-04-19

    Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases.

  14. Angiogenesis and mast cell density in invasive pulmonary adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Ehsan Ullah

    2012-01-01

    Conclusion: High angiogenesis and MCD predict poor survival and are positively correlated with each other and with the histological grades in pulmonary adenocarcinoma. High angiogenesis is also associated with advance TNM stage of disease.

  15. Randomized phase I: safety, immunogenicity and mucosal antiviral activity in young healthy women vaccinated with HIV-1 Gp41 P1 peptide on virosomes

    OpenAIRE

    Geert Leroux-Roels; Cathy Maes; Frédéric Clement; Frank van Engelenburg; Marieke van den Dobbelsteen; Michael Adler; Mario Amacker; Lucia Lopalco; Morgane Bomsel; Anick Chalifour; Sylvain Fleury

    2013-01-01

    UNLABELLED: Mucosal antibodies harboring various antiviral activities may best protect mucosal surfaces against early HIV-1 entry at mucosal sites and they should be ideally induced by prophylactic HIV-1 vaccines for optimal prevention of sexually transmitted HIV-1. A phase I, double-blind, randomized, placebo-controlled trial was conducted in twenty-four healthy HIV-uninfected young women. The study objectives were to assess the safety, tolerability and immunogenicity of virosomes harboring ...

  16. KIT amplification and gene mutations in acral/mucosal melanoma in Korea.

    Science.gov (United States)

    Yun, Jina; Lee, Jeeyun; Jang, Jiryeon; Lee, Eui Jin; Jang, Kee Taek; Kim, Jung Han; Kim, Kyoung-Mee

    2011-06-01

    Mucosal and acral melanomas have demonstrated different genetic alterations and biological behavior compared with more common cutaneous melanomas. It was recently reported that gain-of-function KIT mutations and/or copy number increases are more common in mucosal and acral melanomas. Thus, we studied the frequency and pattern of KIT aberrations in mucosal and acral melanomas in Korea. We analyzed 97 patients who were pathologically confirmed with mucosal or acral melanoma between 1997 and 2010 at Samsung Medical Center. Of the 97 melanoma patients, 92 were screened for mutations in KIT exons 11, 13, 17, and 18, BRAF and NRAS genes. KIT copy number was assessed by quantitative, real-time PCR. Of the 97 patients, 55 (56.7%) were mucosal, 40 (41.2%) were acral melanoma, and two were of unknown primary origin. Among seven cases with KIT mutation, five (60.0%) occurred in exon 11, one (20.0%) in exon 17, and one (20.0%) in exon 13. Point mutations were the most common, resulting in substitutions in exon 11 (K558R, T574A, L576P, and V559A), exon 13 (N655K), and exon 17 (N822K). A novel Thr574Ala (c.1720A>G) KIT mutation, which has not been reported in melanoma or other tumor types, was identified in one genital melanoma case. Of the 97 mucosal or acral melanoma specimens, 49 were tested for KIT gene copy number changes using quantitative PCR. Increased KIT copy number was identified in 15 patients: seven (40%) of 20 acral melanomas and eight (31%) of 26 mucosal melanomas. Our study implicates that a significant proportion of acral and mucosal melanomas have KIT mutations in Asian population.

  17. Zebrafish as an emerging model organism to study angiogenesis in development and regeneration

    Directory of Open Access Journals (Sweden)

    Myra Noemi Chavez

    2016-03-01

    Full Text Available Angiogenesis is the process through which new blood vessels are formed from preexisting ones and plays a critical role in several conditions including embryonic development, tissue repair and disease. Moreover, enhanced therapeutic angiogenesis is a major goal in the field of regenerative medicine and efficient vascularization of artificial tissues and organs is one of the main hindrances in the implementation of tissue engineering approaches, while, on the other hand, inhibition of angiogenesis is a key therapeutic target to inhibit for instance tumor growth. During the last decades, the understanding of cellular and molecular mechanisms involved in this process has been matter of intense research. In this regard, several in vitro and in vivo models have been established to visualize and study migration of endothelial progenitor cells, formation of endothelial tubules and the generation of new vascular networks, while assessing the conditions and treatments that either promote or inhibit such processes. In this review, we address and compare the most commonly used experimental models to study angiogenesis in vitro and in vivo. In particular, we focus on the implementation of the zebrafish (Danio rerio as a model to study angiogenesis and discuss the advantages and not yet explored possibilities of its use as model organism.

  18. Evaluation of Angiogenesis Using Micro-Computed Tomography in a Xenograft Mouse Model of Lung Cancer

    Directory of Open Access Journals (Sweden)

    Rajkumar Savai

    2009-01-01

    Full Text Available Quantitative evaluation of lung tumor angiogenesis using immunohistochemical techniques has been limited by difficulties in generating reproducible data. To analyze intrapulmonary tumor angiogenesis, we used high-resolution micro-computed tomography (micro-CT of lung tumors of mice inoculated with mouse Lewis lung carcinoma (LLC1 or human adenocarcinoma (A549 cell lines. The lung vasculature was filled with the radiopaque silicone rubber, Microfil, through the jugular vein (in vivo application or pulmonary artery (ex vivo application. In addition, human adenocarcinoma lung tumor-bearing mice treated site-specifically with humanized monoclonal antibody (bevacizumab against vascular endothelial growth factor. Quantitative analysis of lung tumor microvessels imaged with micro-CT showed that more vessels (mainly small, <0.02 mm2 were filled using the in vivo (5.4% compared with the ex vivo (2.1% method. Furthermore, bevacizumab-treated lung tumor-bearing mice showed significantly reduced lung tumor volume and lung tumor angiogenesis compared with untreated mice as assessed by micro-CT. Interestingly, microvascularization of mainly the smaller vessels (<0.02 mm2 was reduced after bevacizumab treatment. This observation with micro-CT was nicely correlated with immunohistochemical measurement of microvessels. Therefore, micro-CT is a novel method for investigating lung tumor angiogenesis, and this might be considered as an additional complementary tool for precise quantification of angiogenesis.

  19. Does angiogenesis play a role in the establishment of mesial temporal lobe epilepsy?

    Science.gov (United States)

    Benini, Ruba; Roth, Raquel; Khoja, Zehra; Avoli, Massimo; Wintermark, Pia

    2016-04-01

    Mesial temporal lobe epilepsy (MTLE) is a focal epileptic disorder that is frequently associated with hippocampal sclerosis. This study investigated whether blocking angiogenesis prevents the development of seizures and hippocampal atrophy in the pilocarpine rat model of MTLE. To block angiogenesis, a subset of animals were given sunitinib orally. Continuous video recordings were performed to identify seizures. Brains were then extracted and sectioned, and hippocampal surfaces and angiogenesis were assessed. After a latent period of 6.6 ± 2.6 days, the sham-treated pilocarpine rats presented convulsive seizures, while the pilocarpine rats treated with sunitinib did not develop seizures. Sham-treated pilocarpine rats but not sunitinib-treated pilocarpine rats had significantly smaller hippocampi. Endothelial cell counts in sham-treated pilocarpine rats were significantly greater than in controls and sunitinib-treated pilocarpine rats. Blocking angiogenesis immediately following the initial insult in this animal model prevented thus angiogenesis and hippocampal atrophy and averted the development of clinical seizures.

  20. Role of endogenous angiogenesis inhibitors in Down syndrome.

    Science.gov (United States)

    Ryeom, Sandra; Folkman, Judah

    2009-03-01

    New blood vessel growth via angiogenesis is a fundamental process in both physiological and pathological conditions. Physiological angiogenesis is critical during embryogenesis and placental development, whereas pathological angiogenesis plays an important role in the progression of many diseases, most notably tumor growth. Tumor angiogenesis is well accepted to be regulated by a balance of proangiogenic and antiangiogenic factors produced both by tumor cells and surrounding stromal cells. For many years, investigation of antiangiogenic therapies for cancer has focused on the proangiogenic cytokine, vascular endothelial growth factor; its receptors; or downstream signaling pathways. However, more recently with the identification of endogenous angiogenesis inhibitors, studies have turned toward understanding the role of endogenous antiangiogenic proteins in preventing disease progression. Clinical clues have suggested that specific populations may have dysregulated angiogenesis due to differential expression of endogenous angiogenesis regulators. For example, individuals with Down syndrome may possess a systemic antiangiogenic state with a significantly decreased incidence of angiogenesis-dependent diseases. Our work suggests that endogenous angiogenesis inhibitors may be the master regulators controlling progression of angiogenesis-dependent diseases such as vascular anomalies and cancer. The molecular regulation of angiogenesis is not yet fully understood; however, the Down syndrome population may give us insights toward novel therapies for controlling angiogenesis in disease.

  1. Inside the mucosal immune system.

    Directory of Open Access Journals (Sweden)

    Jerry R McGhee

    Full Text Available An intricate network of innate and immune cells and their derived mediators function in unison to protect us from toxic elements and infectious microbial diseases that are encountered in our environment. This vast network operates efficiently by use of a single cell epithelium in, for example, the gastrointestinal (GI and upper respiratory (UR tracts, fortified by adjoining cells and lymphoid tissues that protect its integrity. Perturbations certainly occur, sometimes resulting in inflammatory diseases or infections that can be debilitating and life threatening. For example, allergies in the eyes, skin, nose, and the UR or digestive tracts are common. Likewise, genetic background and environmental microbial encounters can lead to inflammatory bowel diseases (IBDs. This mucosal immune system (MIS in both health and disease is currently under intense investigation worldwide by scientists with diverse expertise and interests. Despite this activity, there are numerous questions remaining that will require detailed answers in order to use the MIS to our advantage. In this issue of PLOS Biology, a research article describes a multi-scale in vivo systems approach to determine precisely how the gut epithelium responds to an inflammatory cytokine, tumor necrosis factor-alpha (TNF-α, given by the intravenous route. This article reveals a previously unknown pathway in which several cell types and their secreted mediators work in unison to prevent epithelial cell death in the mouse small intestine. The results of this interesting study illustrate how in vivo systems biology approaches can be used to unravel the complex mechanisms used to protect the host from its environment.

  2. Angiogenesis in gastric mucosa: an important component of gastric erosion and ulcer healing and its impairment in aging.

    Science.gov (United States)

    Tarnawski, Andrzej S; Ahluwalia, Amrita; Jones, Michael K

    2014-12-01

    Angiogenesis (also referred to as neovascularization-formation of new blood vessels from existing vessels) is a fundamental process essential for healing of tissue injury and ulcers because regeneration of blood microvessels is a critical requirement for oxygen and nutrient delivery to the healing site. This review article updates the current views on angiogenesis in gastric mucosa following injury and during ulcer healing, its sequential events, the underlying mechanisms, and the impairment of angiogenesis in aging gastric mucosa. We focus on the time sequence and ultrastructural features of angiogenesis, hypoxia as a trigger, role of vascular endothelial growth factor signaling (VEGF), serum response factor, Cox2 and prostaglandins, nitric oxide, and importin. Recent reports indicate that gastric mucosa of aging humans and experimental animals exhibits increased susceptibility to injury and delayed healing. Gastric mucosa of aging rats has increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin, and other non-steroidal anti-inflammatory drugs because of structural and functional abnormalities including: reduced gastric mucosal blood flow, hypoxia, reduced expression of vascular endothelial growth factor and survivin, and increased expression of early growth response protein 1 (egr-1) and phosphatase and tensin homolog (PTEN). Until recently, postnatal neovascularization was assumed to occur solely through angiogenesis sprouting of endothelial cells and formation of new blood vessels from pre-existing blood vessels. New studies in the last decade have challenged this paradigm and indicate that in some tissues, including gastric mucosa, the homing of bone marrow-derived endothelial progenitor cells to the site of injury can also contribute to neovascularization by a process termed vasculogenesis.

  3. Fibromodulin Enhances Angiogenesis during Cutaneous Wound Healing

    Directory of Open Access Journals (Sweden)

    Zhong Zheng, PhD

    2014-12-01

    Conclusions: Altogether, we demonstrated that in addition to reducing scar formation, FMOD also promotes angiogenesis. As blood vessels organize and regulate wound healing, its potent angiogenic properties will further expand the clinical application of FMOD for cutaneous healing of poorly vascularized wounds.

  4. Angiogenesis and the inception of pregnancy

    NARCIS (Netherlands)

    Kapiteijn, Kitty

    2006-01-01

    Vascular maladaptation prior and during implantation may lead to serious complications during pregnancy, perinatally, but also later in life (Barker hypothesis). The consequences later in life often appear to be related to endothelial dysfunction. Angiogenesis, the formation of new blood vessels fro

  5. Adaptive angiogenesis in placentas of heavy smokers.

    Science.gov (United States)

    Pfarrer, C; Macara, L; Leiser, R; Kingdom, J

    1999-07-24

    Smoking in pregnancy increases perinatal morbidity and mortality, suggesting impaired placental function, though placental weight is increased. We used scanning electron microscopy to show adaptive angiogenesis in term placental villi from smokers (n=4) and non-smokers (n=4). These images may aid communication of the dangers of smoking in pregnancy.

  6. PPAR Gamma and Angiogenesis: Endothelial Cells Perspective

    Directory of Open Access Journals (Sweden)

    Jerzy Kotlinowski

    2016-01-01

    Full Text Available We summarize the current knowledge concerning PPARγ function in angiogenesis. We discuss the mechanisms of action for PPARγ and its role in vasculature development and homeostasis, focusing on endothelial cells, endothelial progenitor cells, and bone marrow-derived proangiogenic cells.

  7. Orchestration of angiogenesis by immune cells

    Directory of Open Access Journals (Sweden)

    Antonino eBruno

    2014-07-01

    Full Text Available It is widely accepted that the tumor microenvironment plays a major role in cancer and is indispensable for tumor progression. The tumor microenvironment involves many players going well beyond the malignant-transformed cells, including stromal, immune and endothelial cells. The non-malignant cells can acquire tumor-promoting functions during carcinogenesis. In particular, these cells can orchestrate the symphony of the angiogenic switch, permitting the creation of new blood vessels that allows rapid expansion and progression toward malignancy.Considerable attention within the context of tumor angiogenesis should focus not only on the endothelial cells, representing a fundamental unit, but also on immune cells and on the inflammatory tumor infiltrate. Immune cells infiltrating tumors typically show a tumor-induced polarization associated with attenuation of anti-tumor functions and generation of pro-tumor activities, among these angiogenesis. Here we propose a scenario suggesting that the angiogenic switch is an immune switch arising from the pro-angiogenic polarization of immune cells. This view links immunity, inflammation and angiogenesis to tumor progression. Here we review the data in the literature and seek to identify the conductors of this orchestra. We also suggest that interrupting the immune -> inflammation -> angiogenesis -> tumor progression process can delay or prevent tumor insurgence and malignant disease.

  8. Mucosal Immunity and the Onset of Allergic Disease

    Directory of Open Access Journals (Sweden)

    Yusei Ohshima

    2013-01-01

    Full Text Available Mucosal barriers encounter an environment that is rich in pathogens that possess mechanisms for invading mucosal tissues. These barriers also encounter innocuous antigens, such as foods, airborne antigens, and microbiota. The mucosa has developed a sophisticated immune system that can mount robust immune responses against pathogenic antigens, while maintaining mucosal tolerance against non-pathogenic antigens. Accumulating evidence indicates that the mucosal epithelium, dendritic cells, and a subtype of T cells with regulatory properties play important roles in the development and maintenance of mucosal tolerance. Moreover, the micribiota also contribute to regulating the mucosal immune system. A failure to develop or the breakdown of mucosal tolerance can result in allergic diseases, such as food allergy and asthma. By taking advantage of the unique characteristics of the mucosal immune system, strategies that induce regulatory cells in vivo and, thereby, reconstitute mucosal tolerance may be used to develop novel therapies that are suitable for treating or preventing of allergic diseases.

  9. Angiogenesis and vascular malformations: Antiangiogenic drugs for treatment of gastrointestinal bleeding

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Treatment of gastrointestinal bleeding in patients with angiodysplasias and Osler's disease (hereditary hemorrhagic teleangiectasia) is clinically challenging.Frequently, vascular malformations occur as multiple disseminated lesions, making local treatment an unfavorable choice or impossible. After local therapy,lesions often recur at other sites of the intestine.However, as there are few therapeutic alternatives,repeated endoscopic coagulations or surgical resections are still performed to prevent recurrent bleeding.Hormonal therapy has been employed for more than 50 years but has recently been shown to be ineffective.Therefore, new therapeutic strategies are required.Understanding of the pathophysiology of angiogenesis and vascular malformations has recently substantially increased. Currently, multiple inhibitors of angiogenesis are under development for treatment of malignant diseases. Experimental and clinical data suggest that antiangiogenic substances, which were originally developed for treatment of malignant diseases, may also represent long-awaited specific drugs for the treatment of vascular malformations. However, antiangiogenics display significantly different actions and side-effects.Although antiangiogenics like thalidomide seem to inhibit gastrointestinal bleeding, other substances like bevacizumab can cause mucosal bleeding. Therefore differential and cautious evaluation of this therapeutic strategy is necessary.

  10. Connexins in respiratory and gastrointestinal mucosal immunity.

    Science.gov (United States)

    Bou Saab, Joanna; Losa, Davide; Chanson, Marc; Ruez, Richard

    2014-04-17

    The mucosal lining forms the physical and chemical barrier that protects against pathogens and hostile particles and harbors its own population of bacteria, fungi and archea, known as the microbiota. The immune system controls tolerance of this population of microorganisms that have proven to be beneficial for its host. Keeping its physical integrity and a correct balance with the microbiota, the mucosa preserves its homeostasis and its protective function and maintains host's health. However, in some conditions, pathogens may succeed in breaching mucosal homeostasis and successfully infecting the host. In this review we will discuss the role the mucosa plays in the defense against bacterial pathogens by considering the gap junction protein connexins. We will detail their implication in mucosal homeostasis and upon infection with bacteria in the respiratory and the gastrointestinal tracts. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  11. Novel vaccine development strategies for inducing mucosal immunity.

    Science.gov (United States)

    Fujkuyama, Yoshiko; Tokuhara, Daisuke; Kataoka, Kosuke; Gilbert, Rebekah S; McGhee, Jerry R; Yuki, Yoshikazu; Kiyono, Hiroshi; Fujihashi, Kohtaro

    2012-03-01

    To develop protective immune responses against mucosal pathogens, the delivery route and adjuvants for vaccination are important. The host, however, strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance, instead of immune activation. Thus, induction of mucosal immunity through vaccination is a rather difficult task, and potent mucosal adjuvants, vectors or other special delivery systems are often used, especially in the elderly. By taking advantage of the common mucosal immune system, the targeting of mucosal dendritic cells and microfold epithelial cells may facilitate the induction of effective mucosal immunity. Thus, novel routes of immunization and antigen delivery systems also show great potential for the development of effective and safe mucosal vaccines against various pathogens. The purpose of this review is to introduce several recent approaches to induce mucosal immunity to vaccines, with an emphasis on mucosal tissue targeting, new immunization routes and delivery systems. Defining the mechanisms of mucosal vaccines is as important as their efficacy and safety, and in this article, examples of recent approaches, which will likely accelerate progress in mucosal vaccine development, are discussed.

  12. Oral mucosal diseases: evaluation and management.

    Science.gov (United States)

    Stoopler, Eric T; Sollecito, Thomas P

    2014-11-01

    Oral mucosal diseases encompass several common conditions that affect the general population. Some of these disorders present with signs and symptoms that are pathognomonic for the condition, whereas others present with similar features that can make clinical diagnosis difficult to achieve. It is important for physicians to have a clear understanding of these disorders to provide appropriate care to patients. This article reviews clinical aspects of common oral mucosal disorders, including candidiasis, herpes simplex viral infections, aphthous stomatitis, lichen planus, pemphigus vulgaris, and mucous membrane pemphigoid.

  13. Endoscopic, assisted, modified turbinoplasty with mucosal flap.

    Science.gov (United States)

    Puterman, M M; Segal, N; Joshua, B-Z

    2012-05-01

    A variety of surgical methods have been developed to reduce the volume of the inferior turbinates, in order to create a more patent nasal airway. We describe a technique used in our department since February 2002 for all patients undergoing inferior turbinectomy. We resect with endoscopic assistance the lateral mucosa and bony inferior turbinate. This technique can reduce a large volume of the turbinate while preserving the mucosal continuity and the submucosa by covering the raw surface with a mucosal flap. We believe our method minimises post-operative side effects and complications such as dryness, infection, bleeding and pain.

  14. Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model.

    Science.gov (United States)

    Kakinuma, Yoshihiko; Furihata, Mutsuo; Akiyama, Tsuyoshi; Arikawa, Mikihiko; Handa, Takemi; Katare, Rajesh G; Sato, Takayuki

    2010-04-01

    Our recent studies have indicated that acetylcholine (ACh) protects cardiomyocytes from prolonged hypoxia through activation of the PI3K/Akt/HIF-1alpha/VEGF pathway and that cardiomyocyte-derived VEGF promotes angiogenesis in a paracrine fashion. These results suggest that a cholinergic system plays a role in modulating angiogenesis. Therefore, we assessed the hypothesis that the cholinergic modulator donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, exhibits beneficial effects, especially on the acceleration of angiogenesis. We evaluated the effects of donepezil on angiogenic properties in vitro and in vivo, using an ischemic hindlimb model of alpha7 nicotinic receptor-deleted mice (alpha7 KO) and wild-type mice (WT). Donepezil activated angiogenic signals, i.e., HIF-1alpha and VEGF expression, and accelerated tube formation in human umbilical vein endothelial cells (HUVECs). ACh and nicotine upregulated signal transduction with acceleration of tube formation, suggesting that donepezil promotes a common angiogenesis pathway. Moreover, donepezil-treated WT exhibited rich capillaries with enhanced VEGF and PCNA endothelial expression, recovery from impaired tissue perfusion, prevention of ischemia-induced muscular atrophy with sustained surface skin temperature in the limb, and inhibition of apoptosis independent of the alpha7 receptor. Donepezil exerted comparably more effects in alpha7 KO in terms of angiogenesis, tissue perfusion, biochemical markers, and surface skin temperature. Donepezil concomitantly elevated VEGF expression in intracardiac endothelial cells of WT and alpha7 KO and further increased choline acetyltransferase (ChAT) protein expression, which is critical for ACh synthesis in endothelial cells. The present study concludes that donepezil can act as a therapeutic tool to accelerate angiogenesis in cardiovascular disease patients.

  15. Rebamipide attenuates 5-Fluorouracil-induced small intestinal mucositis in a mouse model.

    Science.gov (United States)

    Kim, Hyun Jin; Kim, Jin Hyun; Moon, Won; Park, Jongha; Park, Seun Ja; Song, Geun Am; Han, Seung Hee; Lee, Jong Hun

    2015-01-01

    5-Fluorouracil (5-FU)-induced intestinal mucositis is one of the most common morbidities in chemotherapy and involves the reactive oxygen species (ROS) system, apoptosis, and inflammatory cytokines. Rebamipide exerts a mucosal-protective effect, mediated through several mechanisms. The aim of this study was to evaluate the effects of rebamipide in 5-FU-induced mouse small-intestinal mucositis. BALB/c mice were assigned randomly to four groups; (1) control group (n=10; receiving saline orally for 6 d), (2) rebamipide group (n=10; 150 mg/kg rebamipide for 6 d orally), (3) 5-FU group (n=10; 30 mg/kg 5-FU for 5 d, intraperitoneally (i.p.)), and (4) rebamipide +5-FU group (n=10; 150 mg/kg rebamipide for 6 d orally and 30 mg/kg 5-FU for 5 d, i.p.). Body weights and diarrhea scales were assessed. At day 5, the mice were sacrificed. Small intestinal tissue was used for: (1) hematoxylin and eosin (HE) staining for determination of small intestinal villi height, (2) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, (3) immunohistochemistry for inducible nitric oxide synthase (iNOS), F4/80, and transforming growth factor (TGF)-β1, (4) measurement of serum and tissue GSH levels, and (5) measurement of serum tumor necrosis factor (TNF)-α levels. Rebamipide attenuated the severity of mucosal injury reflected by body weight changes, degrees of diarrhea, and heights of villi. Rebamipide reduced the expression of iNOS and TGF-β1, apoptosis, macrophage accumulation, serum TNF-α levels, and prevented reductions in serum and tissue glutathione (GSH) levels by 5-FU administration. These results suggest that rebamipide promotes several mechanisms of mucosal protection and attenuated the 5-FU-induced mucosal injury. In conclusion, administration of rebamipide may have significant protective effects against 5-FU-induced intestinal mucositis.

  16. Vasoinhibins: novel inhibitors of ocular angiogenesis.

    Science.gov (United States)

    Clapp, Carmen; Thebault, Stéphanie; Arnold, Edith; García, Celina; Rivera, José Carlos; de la Escalera, Gonzalo Martínez

    2008-10-01

    Disruption of the quiescent state of blood vessels in the retina leads to aberrant vasopermeability and angiogenesis, the major causes of vision loss in diabetic retinopathy. Prolactin is expressed throughout the retina, where it is proteolytically cleaved to vasoinhibins, a family of peptides (including the 16-kDa fragment of prolactin) with potent antiangiogenic, vasoconstrictive, and antivasopermeability actions. Ocular vasoinhibins act directly on endothelial cells to block blood vessel growth and dilation and to promote apoptosis-mediated vascular regression. Also, vasoinhibins prevent retinal angiogenesis and vasopermeability associated with diabetic retinopathy, and inactivation of endothelial nitric oxide synthase via protein phosphatase 2A is among the various mechanisms mediating their actions. Here, we discuss the potential role of vasoinhibins both in the maintenance of normal retinal vasculature and in the cause and prevention of diabetic retinopathy and other vasoproliferative retinopathies.

  17. Ferrite Nanoparticles in Pharmacological Modulation of Angiogenesis

    Science.gov (United States)

    Deshmukh, Aparna; Radha, S.; Khan, Y.; Tilak, Priya

    2011-07-01

    Nanoparticles are being explored in the targeted drug delivery of pharmacological agents : angiogenesis being one such novel application which involves formation of new blood vessels or branching of existing ones. The present study involves the use of ferrite nanoparticles for precise therapeutic modulation of angiogenesis. The ferrite nanoparticles synthesized by co-precipitation of ferrous and ferric salts by a suitable base, were found to be 10-20 nm from X-ray diffraction and TEM measurements. The magnetization measurements showed superparamagnetic behavior of the uncoated nanoparticles. These ferrite nanoparticles were found to be bio-compatible with lymphocytes and neural cell lines from the biochemical assays. The chick chorioallantoic membrane(CAM) from the shell of fertile white Leghorn eggs was chosen as a model to study angiogenic activity. An enhancement in the angiogenic activity in the CAM due to addition of uncoated ferrite nanoparticles was observed.

  18. Advances and challenges in skeletal muscle angiogenesis

    DEFF Research Database (Denmark)

    Olfert, I Mark; Baum, Oliver; Hellsten, Ylva

    2016-01-01

    during health, but poorly controlled in disease - resulting in either excessive capillary growth (pathological angiogenesis) or losses in capillarity (rarefaction). Given that skeletal muscle comprises nearly 40% of body mass in humans, skeletal muscle capillary density has a significant impact...... on metabolism, endocrine function, and locomotion, and is tightly regulated at many different levels. Skeletal muscle is also high adaptable, and thus one of the few organ systems which can be experimentally manipulated (e.g. by exercise) to study physiologic regulation of angiogenesis. This review will focus...... on 1) the methodological concerns that have arisen in determining skeletal muscle capillarity, and 2) highlight the concepts that are reshaping our understanding of the angio-adaptation process. We also summarize selected new findings (physical influences, molecular changes and ultrastructural...

  19. Monitoring angiogenesis using magnetic resonance methods

    DEFF Research Database (Denmark)

    Holm, David Alberg

    2008-01-01

    -angiogenic treatment is presented in the first manuscript. In the second and third manuscript, two separate methods of quantifying perfusion, blood volume and vessel permeability are presented. The methods are used to show that drug delivery to a xenografted tumor is plausible and to show possible vascular maturation...... and the involved signaling molecules. Subsequently, a short review of contrast agents and perfusion measurements is given. Finally, methods for monitoring angiogenesis using magnetic resonance imaging are reviewed. A method for monitoring early stages of angiogenesis as well as the effect of anti...... in a transgenic mouse model. The last manuscript presents a new method for in vivo cell labeling. This method could find use in studying the metastatic spread of cancer cells throughout the body....

  20. The Role of Intestinal Microbiota in the Development and Severity of Chemotherapy-Induced Mucositis

    NARCIS (Netherlands)

    van Vliet, Michel J.; Harmsen, Hermie J. M.; de Bont, Eveline S. J. M.; Tissing, Wim J. E.

    2010-01-01

    Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment,

  1. Oral mucosal lesions in Indians from Northeast Brazil: cross-sectional study of prevalence and risk indicators.

    Science.gov (United States)

    Cury, Patricia Ramos; Porto, Lia Pontes Arruda; dos Santos, Jean Nunes; Figueiredo e Ribeiro, Livia Silva; de Aquino Xavier, Flavia Caló; Figueiredo, Andreia Leal; Ramalho, Luciana Maria Pedreira

    2014-12-01

    The aim of this cross-sectional study was to evaluate the prevalence of oral mucosal lesions, and their risk indicators in adult Kiriri Indians from Northeast Brazil. Clinical oral examination was performed on a representative sample of 223 Indians (age ≥ 19 years). A systematic evaluation of lips, labial mucosa and sulcus, commissures, buccal mucosa and sulcus, gingiva and alveolar ridge, tongue, floor of the mouth, and soft and hard palate was performed. Bivariate analysis was conducted to assess associations between mucosal conditions and age, gender, income, educational level, diabetic status, and smoking status. Mucosal lesions were found in 50 participants (22.4%). The most prevalent lesions were fistulae (6.2%) and traumatic ulcers (4.48%). Oral mucosal was associated with higher age (≥ 35 years; odds ratio [OR] = 1.99, 95% confidence interval [CI]: 1.05-3.76, P = 0.03) and lower education level (<9 years; OR = 2.13, 95% CI: 0.96-4.71, P = 0.06). Mucosal conditions are prevalent in Kiriri Indians and the presence of mucosal lesions is associated with advanced age and lower education. A public health program aimed at preventing and treating mucosal lesions and targeted toward the high-risk group is vital to improve the oral health status of this population.

  2. Toll-Like Receptors in Angiogenesis

    Directory of Open Access Journals (Sweden)

    Karsten Grote

    2011-01-01

    Full Text Available Toll-like receptors (TLRs are known as pattern-recognition receptors related to the Toll protein of Drosophila. After recognition of pathogen-associated molecular patterns of microbial origin, the TLRs alert the immune system, and initiate innate and adaptive immune responses. The TLR system, though, is not confined solely to the leukocyte-mediated immune defense against exogenous pathogens. Besides myeloid cells, TLR expression has been reported in multiple tissues and cell types, including epithelial and endothelial cells. Moreover, despite the microbial patterns that are commonly accepted as TLR ligands, there is increasing evidence that TLRs also recognize host-derived molecules. In this regard, recent studies point to an involvement of TLRs in various chronic inflammatory disorders and cardiovascular diseases, including atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, and even cancer. A common feature of these disorders is an enhanced so-called inflammation-induced angiogenesis. However, inflammation-induced angiogenesis is not solely a key component of pathogen defense during acute infection or chronic inflammatory disorders, but also plays a critical role in repair mechanisms, e.g., wound healing and subsequent tissue regeneration. Interestingly, the latest research could coincidentally demonstrate that TLR activation promotes angiogenesis in various inflammatory settings in response to both exogenous and endogenous ligands, although the precise mode of action of TLRs in this context still remains ambiguous. The objective of this review is to present evidence for the implication of TLRs in angiogenesis during physiological and pathophysiological processes, and the potential clinical relevance for new treatment regimes involving TLR modulation.

  3. Trisubstituted pyrazolopyrimidines as novel angiogenesis inhibitors.

    Directory of Open Access Journals (Sweden)

    Sabine B Weitensteiner

    Full Text Available Current inhibitors of angiogenesis comprise either therapeutic antibodies (e.g. bevacicumab binding to VEGF-A or small molecular inhibitors of receptor tyrosin kinases like e.g. sunitinib, which inhibits PDGFR and VEGFR. We have recently identified cyclin-dependent kinase 5 (Cdk5 as novel alternative and pharmacologically accessible target in the context of angiogenesis. In the present work we demonstrate that trisubstituted pyrazolo[4,3-d]pyrimidines constitute a novel class of compounds which potently inhibit angiogenesis. All seven tested compounds inhibited endothelial cell proliferation with IC(50 values between 1 and 18 µM. Interestingly, this seems not to be due to cytotoxicity, since none of them showed acute cytotoxic effects on endothelial cells at a concentration of 10 µM,. The three most potent compounds (LGR1404, LGR1406 and LGR1407 also inhibited cell migration (by 27, 51 and 31%, resp., chemotaxis (by 50, 70 and 60% in accumulative distance, resp., and tube formation (by 25, 60 and 30% of total tube length, resp. at the non-toxic concentration of 10 µM. Furthermore, angiogenesis was reduced in vivo in the CAM assay by these three compounds. A kinase selectivity profiling revealed that the compounds prevalently inhibit Cdk2, Cdk5 and Cdk9. The phenotype of the migrating cells (reduced formation of lamellipodia, loss of Rac-1 translocation to the membrane resembles the previously described effects of silencing of Cdk5 in endothelial cells. We conclude that especially LGR1406 and LGR1407 are highly attractive anti-angiogenic compounds, whose effects seem to largely depend on their Cdk5 inhibiting properties.

  4. Angiogenesis and antiangiogenic agents in cervical cancer

    Directory of Open Access Journals (Sweden)

    Tomao F

    2014-12-01

    Full Text Available Federica Tomao,1 Anselmo Papa,2 Luigi Rossi,2 Eleonora Zaccarelli,2 Davide Caruso,2 Federica Zoratto,2 Pierluigi Benedetti Panici,1 Silverio Tomao2 1Department of Gynecology and Obstetrics, Sapienza University of Rome, Policlinico Umberto I, Rome, 2Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Oncology Unit, ICOT, Latina, Italy Abstract: Standard treatment of cervical cancer (CC consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer. The dominant role of angiogenesis in CC seems to be directly related to human papillomavirus-related inhibition of p53 and stabilization of hypoxia-inducible factor-1α. Both of these mechanisms are able to increase expression of vascular endothelial growth factor (VEGF. Activation of VEGF promotes endothelial cell proliferation and migration, favoring formation of new blood vessels and increasing permeability of existing blood vessels. Since bevacizumab, a recombinant humanized monoclonal antibody binding to all isoforms of VEGF, has been demonstrated to significantly improve survival in gynecologic cancer, some recent clinical research has explored the possibility of using novel therapies directed toward inhibition of angiogenesis in CC too. Here we review the main results from studies concerning the use of antiangiogenic drugs that are being investigated for the treatment of CC. Keywords: cervical cancer, angiogenesis, human papillomavirus, bevacizumab, target therapies

  5. Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer.

    Science.gov (United States)

    Sridhar, Srikala S; Shepherd, Frances A

    2003-12-01

    It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.

  6. Treatment of urethral strictures in balanitis xerotica obliterans (BXO) using circular buccal mucosal meatoplasy: Experience of 15 cases

    OpenAIRE

    2014-01-01

    Objectives: Balanitis xerotica obliterans (BXO) related strictures involving the external urethral meatus. We reviewed our result with the use of circular mucosal graft in the reconstruction of strictures. Methods: Between March 1997 and January 2012, 15 patients underwent circular buccal mucosal urethroplasy for BXO related anterior urethral strictures. Urethral catheter was removed within 2 weeks. Follow-up included patient symptoms assessment, cosmetic outcome and uroflowmetry. Results: Me...

  7. Molecular Therapeutic Targets for Glioma Angiogenesis

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    Shingo Takano

    2010-01-01

    Full Text Available Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, v3 integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4 results in a nonfunctioning vasculature and could be another important target distinct from VEGF.

  8. Neomycin inhibits angiogenin-induced angiogenesis.

    Science.gov (United States)

    Hu, G F

    1998-08-18

    A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, and staurosporine, inhibitors of tyrosine kinase, phosphotyrosine phosphatase, and protein kinase C, respectively, do not inhibit nuclear translocation of angiogenin. Neomycin inhibits angiogenin-induced proliferation of human endothelial cells in a dose-dependent manner. At 50 microM, neomycin abolishes angiogenin-induced proliferation but does not affect the basal level of proliferation and cell viability. Other aminoglycoside antibiotics, including gentamicin, streptomycin, kanamycin, amikacin, and paromomycin, have no effect on angiogenin-induced cell proliferation. Most importantly, neomycin completely inhibits angiogenin-induced angiogenesis in the chicken chorioallantoic membrane at a dose as low as 20 ng per egg. These results suggest that neomycin and its analogs are a class of agents that may be developed for anti-angiogenin therapy.

  9. Hypoxia-induced angiogenesis: good and evil.

    Science.gov (United States)

    Krock, Bryan L; Skuli, Nicolas; Simon, M Celeste

    2011-12-01

    The vascular network delivers oxygen (O(2)) and nutrients to all cells within the body. It is therefore not surprising that O(2) availability serves as a primary regulator of this complex organ. Most transcriptional responses to low O(2) are mediated by hypoxia-inducible factors (HIFs), highly conserved transcription factors that control the expression of numerous angiogenic, metabolic, and cell cycle genes. Accordingly, the HIF pathway is currently viewed as a master regulator of angiogenesis. HIF modulation could provide therapeutic benefit for a wide array of pathologies, including cancer, ischemic heart disease, peripheral artery disease, wound healing, and neovascular eye diseases. Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function. Through extensive research, the integral role of hypoxia and HIF signaling in human disease is becoming increasingly clear. Consequently, a thorough understanding of how hypoxia regulates angiogenesis through an ever-expanding number of pathways in multiple cell types will be essential for the identification of new therapeutic targets and modalities.

  10. Pathophysiological mechanisms of angiogenesis in atherogenesis

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    Vučević Danijela

    2013-01-01

    Full Text Available Introduction. Atherosclerosis is a progressive, multifactorial, diffuse, multisystemic, chronic, inflammatory disease, which is manifested by disorders of vascular, immune and metabolic system. Pathogenesis of this disease is not fully understood. Accordingly, angiogenesis represents a special field of research due to its role in atherogenesis. Steps of Angiogenesis. Angiogenesis is a complex biological process, which requires the precise coordination of its four steps (vasodilatation and permeability, vessel destabilization and matrix degradation, endothelial cell proliferation and migration, and lumen formation and vessel stabilization. Mediators of Angiogenic Process. The process of forming new blood vessels is regulated by a delicate balance between proangiogenic and antiangiogenic molecules. Numerous soluble growth factors and inhibitors, cytokines, proteases, extracellular matrix proteins and adhesion molecules, as well as hypoxia, inflammatory process, shear stress, hypertension and interaction between cells and extracellular matrix strictly control the angiogenic process. Neovascularization is halted due to the downregulation of angiogenic factors or the increase of inhibitors of this process. Tumor Vascularization. In the asymptomatic phase of cancerogenesis, cancer rarely exceeds the diameter of 1-2 millimeters. However, when the metabolic demand increases, it leads to tumor vascularization. In this way, tumor switches to an angiogenic phenotype. The molecular basis of angiogenic switch refers to increased production of angiogenic factors and/or loss of angiogenic inhibitors. Conclusion. The contribution of angiogenic process has become increasingly meaningful in understanding the pathogenesis of atherosclerosis. [Projekat Ministarstva nauke Republike Srbije, br. 175015

  11. Statins and angiogenesis: Is it about connections?

    Energy Technology Data Exchange (ETDEWEB)

    Khaidakov, Magomed, E-mail: mkhaidakov@uams.edu [Division of Cardiology, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, AR (United States); Wang, Wenze [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR (United States); Khan, Junaid A.; Kang, Bum-Yong; Hermonat, Paul L. [Division of Cardiology, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, AR (United States); Mehta, Jawahar L., E-mail: Mehtajl@uams.edu [Division of Cardiology, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, AR (United States)

    2009-09-25

    Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, have been shown to induce both angiogenic and angiostatic responses. We attempted to resolve this controversy by studying the effects of two different statins, rosuvastatin and simvastatin, in two different assay systems. In the matrigel angiogenesis assay, both statins enhanced tube formation by human umbilical vein endothelial cells (HUVECs, p < 0.01 vs. control). In the ex vivo mouse aortic ring sprouting assay, both statins virtually abolished new vessel formation (p < 0.01). As a basic difference between the two models of angiogenesis is dispersed state of endothelial cells vs. compact monolayer, we analyzed influence of statins on endothelial junction proteins. RT-PCR analysis and cytoimmunostaining of HUVECs treated with simvastatin revealed increased expression of VE-cadherin (p < 0.05). The blockade of VE-cadherin with a specific antibody reversed simvastatin-induced tube formation (p < 0.002). These data suggest that statins through VE-cadherin stimulation modulate cell-cell adhesion and diminish the ability of cells to proliferate and migrate. The observations of reduced angiogenesis in the intact vessel may relate to anti-atherosclerotic and anti-cancer effects of statins, and provide a feasible explanation for conflicting data under different experimental conditions.

  12. Topical morphine for oral mucositis in children

    DEFF Research Database (Denmark)

    Nielsen, Bettina Nygaard; Aagaard, Gitte; Henneberg, Steen W;

    2012-01-01

    Systemic opioids for painful chemotherapy-induced oral mucositis in children often result in unsatisfactory pain relief and a high frequency of side effects. Opioids applied topically can produce analgesia by binding to opioid receptors on peripheral terminals of sensory neurons. These receptors...

  13. Nutrition and Gut Mucositis in Pediatric Oncology

    DEFF Research Database (Denmark)

    Pontoppidan, Peter Erik Lotko

    and differential regulation of miRNA-155 and -146a. This was sustained during the first three weeks after transplantation, along with increased spontaneous production of inflammatory cytokines by early trafficking of leukocytes. In conclusion, we successfully induced oral and intestinal mucositis in piglets...

  14. Management of mucositis in oral irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Feber, T. [Cookridge Hospital, Leeds (United Kingdom)

    1996-10-01

    Mucositis significantly affects quality of life and tolerance of treatment in oral irradiation. Effective management of this complication is therefore very important. However, there is a scarcity of up-to-date oral care protocols, with most centres using ritualized regimens. The literature on oral rinses in radiation mucositis is at best inconclusive and at worst confusing. In this study, patients undergoing radical radiotherapy treatment (55-60 Gy in 4 weeks) to more than 50% of the oral cavity and oropharynx were randomized to a research based oral care protocol with either saline 0.9% or hydrogen peroxide 3.5 volumes (HP) as rinses. The results of this study show that, on average, the group receiving saline rinses appeared to do better on some outcomes than the group receiving HP. This suggests that frequent mechanical cleansing of the mouth may be more important than the antiseptic properties of a mouthwash. Antiseptic mouthwashes may be contra-indicated in radiation mucositis. In order to determine best practice in mucositis management, multicentre, multidisciplinary trials should be conducted. (Author).

  15. Measuring mucosal damage induced by cytotoxic therapy.

    NARCIS (Netherlands)

    Blijlevens, N.M.A.; Land, B. van 't; Donnelly, J.P.; Rabet, L. M'; Pauw, B.E. de

    2004-01-01

    We scored oral mucositis and gut toxicity and measured sugar permeability testing among 56 recipients of a haematopoietic stem cell transplant (HSCT) given myeloablative conditioning with idarubicin, cyclophosphamide and TBI, and a group of 18 patients given cytotoxic chemotherapy for newly diagnose

  16. Mucosal melanoma of the head and neck.

    Science.gov (United States)

    Ascierto, Paolo Antonio; Accorona, Remo; Botti, Gerardo; Farina, Davide; Fossati, Piero; Gatta, Gemma; Gogas, Helen; Lombardi, Davide; Maroldi, Roberto; Nicolai, Piero; Ravanelli, Marco; Vanella, Vito

    2017-04-01

    Mucosal melanoma of the head and neck is a very rare and aggressive malignancy with a very poor prognosis. The nasal cavity, paranasal sinuses, and oral cavity are the most common locations. One-, 3- and 5-year survival rates between 2000 and 2007 were 63%, 30% and 20%, respectively. Cigarette smoking seems to be a risk factor even though the evidence for this is very low. Clinical signs and symptoms are usually nonspecific. While surgery is considered the mainstay of treatment for most mucosal melanomas of the head and neck region, radiotherapy has a role in local control of the disease after surgery. Many new treatment options in the last years, in particular targeted therapies (i.e. inhibitors of c-KIT, NRAS/MEK or BRAF) and immunotherapies (anti CTLA-4 and anti PD-1/PD-L1 antibodies), have changed the history of cutaneous melanoma. Despite the different biology, mucosal melanoma is currently treated in the same way as cutaneous melanoma; however, patients with mucosal melanoma were excluded from the majority of recent clinical trials. Recent molecular findings offer new hope for the development of more effective systemic therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Mucosal biofilm detection in chronic otitis media

    DEFF Research Database (Denmark)

    Wessman, Marcus; Bjarnsholt, Thomas; Eickhardt-Sørensen, Steffen Robert

    2015-01-01

    The objectives of this study were to examine middle ear biopsies from Greenlandic patients with chronic otitis media (COM) for the presence of mucosal biofilms and the bacteria within the biofilms. Thirty-five middle ear biopsies were obtained from 32 Greenlandic COM patients admitted to ear...

  18. Can the oral microflora affect oral ulcerative mucositis?

    NARCIS (Netherlands)

    Laheij, A.M.G.A.; de Soet, J.J.

    2014-01-01

    Purpose of review: Oral mucositis is one of the most prevalent toxicities after hematopoietic stem cell transplantation. Mucositis is initiated by the chemotherapy or radiotherapy preceding the transplantation. It is commonly accepted that microorganisms play a role in the process of oral mucositis.

  19. Mucosal Vaccination and Therapy with Genetically Modified Lactic Acid Bacteria

    NARCIS (Netherlands)

    Wells, J.

    2011-01-01

    Lactic acid bacteria (LAB) have proved to be effective mucosal delivery vehicles that overcome the problem of delivering functional proteins to the mucosal tissues. By the intranasal route, both live and killed LAB vaccine strains have been shown to elicit mucosal and systemic immune responses that

  20. Concomitant early mucosal and cutaneous leishmaniasis in Brazil.

    Science.gov (United States)

    Boaventura, Viviane S; Cafe, Virginia; Costa, Jackson; Oliveira, Fabiano; Bafica, Andre; Rosato, Andrea; de Freitas, Luiz A R; Brodskyn, Claudia; Barral-Netto, Manoel; Barral, Aldina

    2006-08-01

    Mucosal leishmaniasis (ML) is often clinically silent until reaching a highly advanced state. In this prospective study, 6 of 220 patients with early cutaneous leishmaniasis were diagnosed with mucosal involvement by otorhinolaryngological examination (a rate similar to the reported rate of late ML). Detection of early ML may represent an important strategy in preventing severe mucosal destruction in human leishmaniasis.

  1. Mucosal Vaccination and Therapy with Genetically Modified Lactic Acid Bacteria

    NARCIS (Netherlands)

    Wells, J.

    2011-01-01

    Lactic acid bacteria (LAB) have proved to be effective mucosal delivery vehicles that overcome the problem of delivering functional proteins to the mucosal tissues. By the intranasal route, both live and killed LAB vaccine strains have been shown to elicit mucosal and systemic immune responses that

  2. Cytotoxic Effects of Intranasal Midazolam on Nasal Mucosal Tissue.

    Science.gov (United States)

    Ozbay, I; Kucur, C; Değer, A; Ital, I; Kasim, Cayci M; Oghan, F

    2015-09-01

    The aim of this experimental study was to investigate the cytotoxic effects of intranasal midazolam on nasal mucosal tissue in rats. Forty healthy rats were randomly divided into 5 groups. Group 1 (n = 8) was the control group, group 2 (n = 8) received intranasal saline, group 3 (n = 8) received intranasal midazolam, group 4 (n = 8) received intraperitoneal saline, and group 5 received intraperitoneal midazolam (n = 8). Midazolam and saline were administered via intraperitoneal and intranasal routes at doses of 200 μg/kg. Nasal septal mucosal stripe tissues were removed at the 6th hour. All materials were evaluated according to Ki67 and p53 staining to evaluate proliferation and apoptosis, respectively, and hemotoxylin and eosin staining was performed for histopathology evaluation. Ki67 values and inflammation in group 3 were statistically higher compared to group 1, group 2, and group 4. P53 values in group 3 were statistically higher compared to group 1. Assessment of subepithelial edema between group 3 and the other groups revealed no statistically significant differences. Assessment of cilia loss between group 3 and group 1, group 2, and group 4 revealed no statistically significant difference. The evaluation of goblet cell loss between group 3 and group 1 revealed a statistically significant difference. Intranasal midazolam had adverse effects on nasal mucosa. However, intranasal midazolam is as safe as systemic midazolam administration with respect to nasal mucosa.

  3. Long term immunologic consequences of experimental stroke and mucosal tolerance

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    Gee J Michael

    2009-10-01

    Full Text Available Abstract Background An inflammatory insult following middle cerebral artery occlusion (MCAO is associated with a predisposition to develop a deleterious autoimmune response to the brain antigen myelin basic protein (MBP. Induction of immunologic tolerance to brain antigens prior to MCAO prevents this deleterious autoimmune response and is associated with better functional outcome early after stroke. In this study, we sought to determine the long term immunologic consequences of experimental stroke and induction of mucosal tolerance. Methods Male Lewis rats were tolerized to MBP or ovalbumin (OVA by intranasal administration prior to MCAO and administration of lipopolysaccharide (LPS. Neurological outcome was assessed at set points after MCAO and animals sacrificed at 3 months; the immune response to MBP in brain and spleen was determined using ELISPOT assay and degree of cellular inflammatory brain infiltrate assessed by immunocytochemistry. Results Animals that developed a pro-inflammatory (TH1 response to MBP experienced worse outcome, while those that developed a regulatory response (TREG experienced better outcome. A TREG response in spleen was also associated with decreased inflammation and an increase in the number of FoxP3 positive cells in brain. In this study, tolerization to MBP prior to MCAO was associated with a tendency to develop a TH1 response to MBP by 3 months after MCAO. Conclusion These data show that induction of immunological tolerance to MBP is associated with improved outcome after stroke. This study, however, raises concern about the potential for inadvertent induction of detrimental autoimmunity through mucosal administration of antigen.

  4. Changes in the Mucus Barrier during Cisplatin-Induced Intestinal Mucositis in Rats

    Directory of Open Access Journals (Sweden)

    Hajime Yamamoto

    2013-01-01

    Full Text Available Aim. Gastrointestinal mucositis is a frequent complication of antineoplastic chemotherapy, but the effects of chemotherapy on mucosal defense mechanisms remain poorly understood. We studied the effects of cisplatin on mucin, one of the principal defense factors of the gastrointestinal mucosa, and evaluated the efficacy of two different types of H2-receptor antagonists against cisplatin-induced mucositis. Methods. Cisplatin (6 mg/kg was administered intravenously to rats (day 0. The rats were sacrificed 1, 3, 7, and 11 days after treatment, and their stomach, jejunum, ileum, and colon were removed. Immunoreactivity of the mucosa was compared with the use of anti-mucin monoclonal antibody. To evaluate the efficacy of H2-receptor antagonists, either famotidine (3 mg/kg or lafutidine (30 mg/kg was given orally once daily on days 0, 1, and 2. Histological and biochemical findings were compared among the groups to assess effects on cisplatin-induced injury. Results. Cisplatin significantly altered the immunoreactivity and content of mucin in the small intestinal mucosa, especially in the ileum. Lafutidine protected against cisplatin-induced mucosal injury and attenuated decreased mucin accumulation. Conclusion. Cisplatin appears to alter the mucus barrier function in the intestinal mucosa. Lafutidine might effectively prevent chemotherapy-induced mucositis by activating intestinal mucus cells.

  5. Strategies of mucosal immunotherapy for allergic diseases

    Institute of Scientific and Technical Information of China (English)

    Yi-Ling Ye; Ya-Hui Chuang; Bor-Luen Chiang

    2011-01-01

    Incidences of allergic disease have recently increased worldwide.Allergen-specific immunotherapy (SIT) has long been a controversial treatment for allergic diseases.Although beneficial effects on clinically relevant outcomes have been demonstrated in clinical trials by subcutaneous immunotherapy (SCIT),there remains a risk of severe and sometimes fatal anaphylaxis.Mucosal immunotherapy is one advantageous choice because of its non-injection routes of administration and lower side-effect profile.This study reviews recent progress in mucosal immunotherapy for allergic diseases.Administration routes,antigen quality and quantity,and adjuvants used are major considerations in this field.Also,direct uses of unique probiotics,or specific cytokines,have been discussed.Furthermore,some researchers have reported new therapeutic ideas that combine two or more strategies.The most important strategy for development of mucosal therapies for allergic diseases is the improvement of antigen formulation,which includes continuous searching for efficient adjuvants,collecting more information about dominant T-cell epitopes of allergens,and having the proper combination of each.In clinics,when compared to other mucosal routes,sublingual immunotherapy (SLIT) is a preferred choice for therapeutic administration,although local and systemic side effects have been reported.Additionally,not every allergen has the same beneficial effect.Further studies are needed to determine the benefits of mucosal immunotherapy for different allergic diseases after comparison of the different administration routes in children and adults.Data collected from large,well-designed,double-blind,placebo-controlled,and randomized trials,with post-treatment follow-up,can provide robust substantiation of current evidence.

  6. Intragastric inulin as a measure of mucosal damage caused by aspirin

    Energy Technology Data Exchange (ETDEWEB)

    Wittmers, L.E. Jr.; Anderson, L.A.; Fall, M.M.; Alich, A.A. (Univ. of Minnesota-Duluth School of Medicine (USA))

    1990-11-01

    In an attempt to find a method of gastric mucosal damage assessment that yields consistent results, the experiments presented here employed the measurement of the movement of inulin out of the gastric contents into the stomach wall and vascular compartment as an estimate of mucosal damage. Anesthetized male Sprague-Dawley rats were functionally nephrectomized and were administered a control or test solution containing 3H-inulin. The test solutions contained one of three doses of aspirin. Blood samples were taken at 15-min intervals over a 90-min exposure period. The stomach was removed from the animal and full-thickness tissue samples taken for measurement of 3H-inulin content. When the gastric mucosa was exposed to the test agents, there was a significantly greater accumulation of inulin in the body and antrum as well as in the plasma when compared to controls. We conclude that intragastric inulin can be employed to estimate gastric mucosal damage.

  7. Alterations in mucosal immunity identified in the colon of patients with irritable bowel syndrome.

    Science.gov (United States)

    Aerssens, Jeroen; Camilleri, Michael; Talloen, Willem; Thielemans, Leen; Göhlmann, Hinrich W H; Van Den Wyngaert, Ilse; Thielemans, Theo; De Hoogt, Ronald; Andrews, Christopher N; Bharucha, Adil E; Carlson, Paula J; Busciglio, Irene; Burton, Duane D; Smyrk, Thomas; Urrutia, Raul; Coulie, Bernard

    2008-02-01

    Irritable bowel syndrome (IBS) has been associated with mucosal dysfunction, mild inflammation, and altered colonic bacteria. We used microarray expression profiling of sigmoid colon mucosa to assess whether there are stably expressed sets of genes that suggest there are objective molecular biomarkers associated with IBS. Gene expression profiling was performed using Human Genome U133 Plus 2.0 (Affymetrix) GeneChips with RNA from sigmoid colon mucosal biopsy specimens from 36 IBS patients and 25 healthy control subjects. Real-time quantitative polymerase chain reaction was used to confirm the data in 12 genes of interest. Statistical methods for microarray data were applied to search for differentially expressed genes, and to assess the stability of molecular signatures in IBS patients. Mucosal gene expression profiles were consistent across different sites within the sigmoid colon and were stable on repeat biopsy over approximately 3 months. Differentially expressed genes suggest functional alterations of several components of the host mucosal immune response to microbial pathogens. The most strikingly increased expression involved a yet uncharacterized gene, DKFZP564O0823. Identified specific genes suggest the hypothesis that molecular signatures may enable distinction of a subset of IBS patients from healthy controls. By using 75% of the biopsy specimens as a validation set to develop a gene profile, the test set (25%) was predicted correctly with approximately 70% accuracy. Mucosal gene expression analysis shows there are relatively stable alterations in colonic mucosal immunity in IBS. These molecular alterations provide the basis to test the hypothesis that objective biomarkers may be identified in IBS and enhance understanding of the disease.

  8. The efficacy of anti-PD-1 agents in acral and mucosal melanoma.

    Science.gov (United States)

    Shoushtari, Alexander N; Munhoz, Rodrigo R; Kuk, Deborah; Ott, Patrick A; Johnson, Douglas B; Tsai, Katy K; Rapisuwon, Suthee; Eroglu, Zeynep; Sullivan, Ryan J; Luke, Jason J; Gangadhar, Tara C; Salama, April K S; Clark, Varina; Burias, Clare; Puzanov, Igor; Atkins, Michael B; Algazi, Alain P; Ribas, Antoni; Wolchok, Jedd D; Postow, Michael A

    2016-11-15

    Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method. Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity. Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354-3362. © 2016 American Cancer Society. © 2016

  9. Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model

    Science.gov (United States)

    Jiang, Chun-Bin; Cheng, Mei-Lien; Liu, Chia-Yuan; Chang, Szu-Wen; Chiang Chiau, Jen-Shiu; Lee, Hung-Chang

    2015-01-01

    Background and Aims Intestinal mucositis is a frequently encountered side effect in oncology patients undergoing chemotherapy. No well-established or up to date therapeutic strategies are available. To study a novel way to alleviate mucositis, we investigate the effects and safety of probiotic supplementation in ameliorating 5-FU-induced intestinal mucositis in a mouse model. Methods Seventy-two mice were injected saline or 5-Fluorouracil (5-FU) intraperitoneally daily. Mice were either orally administrated daily saline, probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi). Diarrhea score, pro-inflammatory cytokines serum levels, intestinal villus height and crypt depth and total RNA from tissue were assessed. Samples of blood, liver and spleen tissues were assessed for translocation. Results Marked diarrhea developed in the 5-FU groups but was attenuated after oral Lcr35 and LaBi administrations. Diarrhea scores decreased significantly from 2.64 to 1.45 and 0.80, respectively (Pprobiotics administration. We also found TNF-α, IL-1β and IL-6 mRNA expressions were up-regulated in intestinal mucositis tissues following 5-FU treatment (TNF-α: 4.35 vs. 1.18, IL-1β: 2.29 vs. 1.07, IL-6: 1.49 vs. 1.02) and that probiotics treatment suppressed this up-regulation (Pprobiotics Lcr35 and LaBi can ameliorate chemotherapy-induced intestinal mucositis in a mouse model. This suggests probiotics may serve as an alternative therapeutic strategy for the prevention or management of chemotherapy-induced mucositis in the future. PMID:26406888

  10. Effect of DAPT, a gamma secretase inhibitor, on tumor angiogenesis in control mice

    Directory of Open Access Journals (Sweden)

    Elmira Kalantari

    2013-01-01

    Full Text Available Background: Notch signaling is a key factor for angiogenesis in physiological and pathological condition and γ-secretase is the regulator of Notch signaling. The main goal of this study was to assess the effect of (N-[N-(3,5-Diflurophenaacetyl-L-alanyl]-S-phenylglycine t-Butyl Ester DAPT, a γ-secretase inhibitor, on serum angiogenic biomarkers, and tumor angiogenesis in control mice. Materials and Methods: Tumor was induced by inoculation of colon adenocarcinoma cells (CT26 in 12 male Balb/C mice. When tumors size is reached to a 350 ± 50 mm 3 , the animals were randomly divided into two groups: control and DAPT (n = 6/group. DAPT was injected subcutaneously 10 mg/kg/day. After 14 days, blood samples were taken and the tumors were harvested for immunohistochemical staining. Results: Administration of DAPT significantly increased serum nitric oxide concentration and reduced vascular endothelial growth factor receptors-1 (VEGFR1 concentration without changes on serum VEGF concentration. DAPT reduced tumor vascular density in control mice (280.6 ± 81 vs. 386 ± 59.9 CD31 positive cells/mm 2 , although, it was not statistically significant. Conclusion: It seems that γ-secretase inhibitors can be considered for treatment of disorders with abnormal angiogenesis such as tumor angiogenesis.

  11. Photoacoustic imaging of angiogenesis in a subcutaneous islet transplant site in a murine model

    Science.gov (United States)

    Shi, Wei; Pawlick, Rena; Bruni, Antonio; Rafiei, Yasmin; Pepper, Andrew R.; Gala-Lopez, Boris; Choi, Min; Malcolm, Andrew; Zemp, Roger J.; Shapiro, A. M. James

    2016-06-01

    Islet transplantation (IT) is an established clinical therapy for select patients with type-1 diabetes. Clinically, the hepatic portal vein serves as the site for IT. Despite numerous advances in clinical IT, limitations remain, including early islet cell loss posttransplant, procedural complications, and the inability to effectively monitor islet grafts. Hence, alternative sites for IT are currently being explored, with the subcutaneous space as one potential option. When left unmodified, the subcutaneous space routinely fails to promote successful islet engraftment. However, when employing the previously developed subcutaneous "deviceless" technique, a favorable microenvironment for islet survival and function is established. In this technique, an angiocatheter was temporarily implanted subcutaneously, which facilitated angiogenesis to promote subsequent islet engraftment. This technique has been employed in preclinical animal models, providing a sufficient means to develop techniques to monitor functional aspects of the graft such as angiogenesis. Here, we utilize photoacoustic imaging to track angiogenesis during the priming of the subcutaneous site by the implanted catheter at 1 to 4 weeks postcatheter. Quantitative analysis on vessel densities shows gradual growth of vasculature in the implant position. These results demonstrate the ability to track angiogenesis, thus facilitating a means to optimize and assess the pretransplant microenvironment.

  12. Inhibition of angiogenesis and HCT-116 xenograft tumor growth in mice by kallistatin

    Institute of Scientific and Technical Information of China (English)

    Yong Diao; Rui-An Xu; Jian Ma; Wei-Dong Xiao; Jia Luo; Xin-Yan Li; Kin-Wah Chu; Peter WC Fung; Nagy Habib; Farzin Farzaneh

    2007-01-01

    AIM: To investigate the inhibitory effect of kallistatin (KAL) on angiogenesis and HCT-116 xenograft tumor growth.METHODS: Heterotopic tumors were induced by subcutaneous injection of 2 × 106 HCT-11 cells in mice.Seven days later, 2 × 1011 rAAV-GFP or rAAV-KAL was injected intratumorally (n = 5 for each group). The mice were sacrificed at d 28, by which time the tumors in the rAAV-GFP group had grown to beyond 5% of the total body weight. Tumor growth was measured by calipers in two dimensions. Tumor angiogenesis was determined with tumor microvessel density (MVD) by immunohistology. Tumor cell proliferation was assessed by Ki-67 staining.RESULTS: Intratumor injection of rAAV-KAL inhibited tumor growth in the treatment group by 78% (171 ±52 mm3) at d 21 after virus infection compared to the control group (776 ± 241 mm3). Microvessel density was significantly inhibited in tumor tissues treated with rAAV-KAL. rAAV-KAL also decreased the proportion of proliferating cells (Ki-67 positive cells) in tumors compared with the control group.CONCLUSION: rAAV-mediated expression of KAL inhibits the growth of colon cancer by reducing angiogenesis and proliferation of tumor cells, and may provide a promising anti-angiogenesis-based approach to the treatment of metastatic colorectal cancer.

  13. Chemotherapy-Induced and/or Radiation Therapy-Induced Oral Mucositis-Complicating the Treatment of Cancer

    Directory of Open Access Journals (Sweden)

    Maddireddy Umameshwar Rao Naidu

    2004-09-01

    condition, but none of them can completely prevent or treat mucositis. More and more pathological methods are being developed to understand this condition so that better therapeutic regimens can be selected. Emphasis also should be made in assessing the patient's psychologic condition, particular depressive disorders. This is important because treatment with antidepressants will not only contribute in lifting depression but also reduces pain somatization. Although mucositis is rarely life-threatening, it will interfere with treatment of cancer to a great extent.

  14. An open-label, multicenter, phase 2a study to assess the feasibility of imaging metastases in late-stage cancer patients with the {alpha}{sub v}{beta}{sub 3}-selective angiogenesis imaging agent {sup 99m}Tc-NC100692

    Energy Technology Data Exchange (ETDEWEB)

    Axelsson, Rimma [Division of Radiology, Dept. of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Inst., Karolinska Univ. Hospital, Stockholm (Sweden)], e-mail: rimma.axelsson@ki.se; Bach-Gansmo, Tore [The Norwegian Radium Hospital, Oslo (Norway); Castell-Conesa, Juan [Hospital Universitari Vall d' Hebron, Barcelona (Spain); McParland, Brian J. [Research and Development, Medical Diagnostics, GE Healthcare Ltd., Amersham (United Kingdom)

    2010-01-15

    Background: The {alpha}{sub v}{beta}{sub 3} integrin is one of the angiogenesis-related membrane proteins highly expressed on the neovasculature of breast cancer and lung carcinomas. Labeling of the {alpha}{sub v}{beta}{sub 3} integrin with {sup 99m}Tc-NC100692 provides a potential tool for imaging angiogenesis and hence the presence of malignant lesions. Purpose: To determine the feasibility of detecting metastatic lesions in liver, lung, bone, and brain with scintigraphy using the {alpha}{sub v}{beta}{sub 3}-avid imaging agent {sup 99m}Tc-NC100692 in patients with breast or lung cancer, and to assess its safety profile. Material and Methods: Twenty-five patients, 15 with lung cancer and 10 with breast cancer, were recruited at 10 centers. Metastases were newly diagnosed by computed tomography, magnetic resonance imaging, or bone scintigraphy, i.e., the reference standard. Patients underwent whole-body scans of approximately 10-15 min duration beginning at 45 min post-injection and a SPECT acquisition of approximately 30 min beginning at 75 min after injection of up to 1100 MBq {sup 99m}Tc-NC100692. In case of liver metastases, dynamic acquisitions of 15 min were performed starting immediately post-injection. Safety measurements were performed up to 2.5 hours after injection and included hematology, serum biochemistry, coagulation, urine analysis, vital signs, oximetry, 12-lead ECG assessments, and a physical examination. Results: In patients with breast cancer, {sup 99m}Tc-NC100692 scintigraphy detected 1 of 7 liver, 4 of 5 lung, 8 of 17 bone, and 1 of 1 brain metastases. The corresponding numbers for lung cancer patients were 0 of 2, 17 of 18, 2 of 2, and 7 of 9. There was overall stability through the follow-up period for all investigated safety parameters. Conclusion: Scintigraphy with {sup 99m}Tc-NC100692 is feasible for detection of lung and brain metastases from breast and lung cancer, while the detection of liver and bone lesions is poor. The use of {sup

  15. An open-label, multicenter, phase 2a study to assess the feasibility of imaging metastases in late-stage cancer patients with the alpha{sub v}beta{sub 3}-selective angiogenesis imaging agent 99mTc-NC100692

    Energy Technology Data Exchange (ETDEWEB)

    Axelsson, Rimma (Division of Radiology, Dept. of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Inst., Karolinska Univ. Hospital, Stockholm (Sweden)), e-mail: rimma.axelsson@ki.se; Bach-Gansmo, Tore (The Norwegian Radium Hospital, Oslo (Norway)); Castell-Conesa, Juan (Hospital Universitari Vall d' Hebron, Barcelona (Spain)); McParland, Brian J. (Research and Development, Medical Diagnostics, GE Healthcare Ltd., Amersham (United Kingdom))

    2010-01-15

    Background: The alpha{sub v}beta{sub 3} integrin is one of the angiogenesis-related membrane proteins highly expressed on the neovasculature of breast cancer and lung carcinomas. Labeling of the alpha{sub v}beta{sub 3} integrin with 99mTc-NC100692 provides a potential tool for imaging angiogenesis and hence the presence of malignant lesions. Purpose: To determine the feasibility of detecting metastatic lesions in liver, lung, bone, and brain with scintigraphy using the alpha{sub v}beta{sub 3}-avid imaging agent 99mTc-NC100692 in patients with breast or lung cancer, and to assess its safety profile. Material and Methods: Twenty-five patients, 15 with lung cancer and 10 with breast cancer, were recruited at 10 centers. Metastases were newly diagnosed by computed tomography, magnetic resonance imaging, or bone scintigraphy, i.e., the reference standard. Patients underwent whole-body scans of approximately 10-15 min duration beginning at 45 min post-injection and a SPECT acquisition of approximately 30 min beginning at 75 min after injection of up to 1100 MBq 99mTc-NC100692. In case of liver metastases, dynamic acquisitions of 15 min were performed starting immediately post-injection. Safety measurements were performed up to 2.5 hours after injection and included hematology, serum biochemistry, coagulation, urine analysis, vital signs, oximetry, 12-lead ECG assessments, and a physical examination. Results: In patients with breast cancer, 99mTc-NC100692 scintigraphy detected 1 of 7 liver, 4 of 5 lung, 8 of 17 bone, and 1 of 1 brain metastases. The corresponding numbers for lung cancer patients were 0 of 2, 17 of 18, 2 of 2, and 7 of 9. There was overall stability through the follow-up period for all investigated safety parameters. Conclusion: Scintigraphy with 99mTc-NC100692 is feasible for detection of lung and brain metastases from breast and lung cancer, while the detection of liver and bone lesions is poor. The use of 99mTc-NC100692 is safe and well tolerated

  16. Altered Esophageal Mucosal Structure in Patients with Celiac Disease

    Science.gov (United States)

    Pinto-Sánchez, María Inés; Nachman, Fabio D.; Fuxman, Claudia; Iantorno, Guido; Hwang, Hui Jer; Ditaranto, Andrés; Costa, Florencia; Longarini, Gabriela; Wang, Xuan Yu; Huang, Xianxi; Vázquez, Horacio; Moreno, María L.; Niveloni, Sonia; Bercik, Premysl; Smecuol, Edgardo; Mazure, Roberto; Bilder, Claudio; Mauriño, Eduardo C.; Verdu, Elena F.; Bai, Julio C.

    2016-01-01

    Background/Aim. Reflux symptoms (RS) are common in patients with celiac disease (CD), a chronic enteropathy that affects primarily the small intestine. We evaluated mucosal integrity and motility of the lower esophagus as mechanisms contributing to RS generation in patients with CD. Methods. We enrolled newly diagnosed CD patients with and without RS, nonceliac patients with classical reflux disease (GERD), and controls (without RS). Endoscopic biopsies from the distal esophagus were assessed for dilated intercellular space (DIS) by light microscopy and electron microscopy. Tight junction (TJ) mRNA proteins expression for zonula occludens-1 (ZO-1) and claudin-2 and claudin-3 (CLDN-2; CLDN-3) was determined using qRT-PCR. Results. DIS scores were higher in patients with active CD than in controls, but similar to GERD patients. The altered DIS was found even in CD patients without RS and normalized after one year of a gluten-free diet. CD patients with and without RS had lower expression of ZO-1 than controls. The expression of CLDN-2 and CLDN-3 was similar in CD and GERD patients. Conclusions. Our study shows that patients with active CD have altered esophageal mucosal integrity, independently of the presence of RS. The altered expression of ZO-1 may underlie loss of TJ integrity in the esophageal mucosa and may contribute to RS generation. PMID:27446827

  17. [Efficacy of Rebamipide Gargle against Chemotherapy-induced Oral Mucositis].

    Science.gov (United States)

    Shinohara, Akiyoshi; Nakamura, Masato; Onikubo, Toshihide; Nakamura, Kumi

    2015-01-01

    Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy. Toxic free radicals and pro-inflammatory cytokines produced by anticancer drugs have been reported to be associated with CIOM. Rebamipide has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, and to behave as an oxygen free-radical scavenger in addition to other anti-inflammatory actions. We developed a gargle solution of rebamipide, adding ultrahydrogel for mucosal protection and to maintain rebamipide on the oral mucosa. A 300 mL rebamipide gargle solution combines 600 mg rebamipide, 3 g high molecular-weight polyethylene oxide, 1.2 g carrageenan, pineapple flavoring, and water. The efficacy of the rebamipide gargle was evaluated in 175 patients with CIOM from November 2009 to December 2012, each instructed to use the rebamipide gargle 5-6 times daily. The severity of CIOM was assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Their CTCAE scores (3/2/1/0) changed from n=13/64/98/0 to 0/10/103/62, respectively, after initiation of the rebamipide gargle (pRebamipide gargle was well tolerated and demonstrated to have significant therapeutic efficacy against CIOM.

  18. Oral Mucosal Disorders in Pregnant versus Non-Pregnant Women

    Directory of Open Access Journals (Sweden)

    Fahimeh Rezazadeh

    2014-12-01

    Full Text Available The effects of pregnancy on the Oral Mucosa Disorder (OMD have been sporadically documented in some developed countries. Less known is the status of OMD during pregnancy in less developed/developing countries. Iran is no exception. This study assesses the prevalence of OMD in 200 pregnant women and compares the findings with the findings from a 200 non-pregnant woman of similar age distribution in Iran. The participants had been referred to a clinic to receive reproductive age-related services. Participants suffering from systemic chronic diseases, those on medications/drugs, smokers, needing biopsies, and those with urgent Oral Mucosal Lesion (OML treatments were excluded from the study. Oral mucosal of all 400 participants were examined. The participants’ age ranges were from 17 to 47; with the average age of 33.14 for one group; and 30.23 for the other group. Both groups had the same level of formal education. Out of 400 examined women; 62 had lesions, including 47 pregnant (23.5%; and 15 non-pregnant (7.5% women. This result shows that the OMD rate of occurrence was significantly higher among the pregnant women. Higher OML prevalence in pregnant women, as compared to the non-pregnant women, indicates the importance of timely oral examination of pregnant women and subsequent treatment plans for them.

  19. Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke.

    Science.gov (United States)

    Font, M Angels; Arboix, Adriá; Krupinski, Jerzy

    2010-08-01

    Only very little is know about the neurovascular niche after cardioembolic stroke. Three processes implicated in neurorepair: angiogenesis, neurogenesis and synaptic plasticity, would be naturally produced in adult brains, but also could be stimulated through endogen neurorepair phenomena. Angiogenesis stimulation generates new vessels with the aim to increase collateral circulation. Neurogenesis is controlled by intrinsic genetic mechanisms and growth factors but also ambiental factors are important. The leading process of the migrating neural progenitor cells (NPCs) is closely associated with blood vessels, suggesting that this interaction provides directional guidance to the NPCs. These findings suggest that blood vessels play an important role as a scaffold for NPCs migration toward the damaged brain region. DNA microarray technology and blood genomic profiling in human stroke provided tools to investigate the expression of thousands of genes. Critical comparison of gene expression profiles after stroke in humans with those in animal models should lead to a better understanding of the pathophysiology of brain ischaemia. Probably the most important part of early recovery after stroke is limited capacity of penumbra/infarct neurones to recover. It became more clear in the last years, that penumbra is not just passively dying over time but it is also actively recovering. This initial plasticity in majority contributes towards later neurogenesis, angiogenesis and final recovery. Penumbra is a principal target in acute phase of stroke. Thus, the origin of newly formed vessels and the pathogenic role of neovascularization and neurogenesis are important unresolved issues in our understanding of the mechanisms after stroke. Biomaterials for promoting brain protection, repair and regeneration are new hot target. Recently developed biomaterials can enable and increase the target delivery of drugs or therapeutic proteins to the brain, allow cell or tissue transplants to

  20. [Emoxipin as an inhibitor of angiogenesis].

    Science.gov (United States)

    Sologub, A A; Akberova, S I; Ziangirova, G G

    1992-12-01

    The effect of emoxypin on angiogenesis in rabbit cornea in aseptic inflammation induced by intracorneal implantation of a piece of quartz and on the development of the vessels of the chick embryo yolk sac was studied. 1% emoxypin pipetted thrice a day for 10-14 days inhibited corneal neovascularization and reduced the formation of new blood vessels. We observed an inhibitory effect on the development of vascular bed of the embryo yolk sac on incubation hour 64-72. The drug affected neither general growth of the embryos no the number of somites.

  1. Could the biological robustness of low level laser therapy (Photobiomodulation) impact its use in the management of mucositis in head and neck cancer patients.

    Science.gov (United States)

    Sonis, Stephen T; Hashemi, Sepehr; Epstein, Joel B; Nair, Raj G; Raber-Durlacher, Judith E

    2016-03-01

    Low level laser therapy (LLLT) has been noted to be effective in mitigating the development of oral mucositis among patients being treated with chemoradiation for cancers of the head and neck. To explain the biological basis for this observation we performed a comprehensive literature search. Our investigation identified a substantial number of LLLT-activated pathways that have been strongly associated with negative tumor outcomes including proliferation, invasion, angiogenesis, metastases and cancer-treatment resistance. In light of these findings, we suggest an investigational strategy to assure that LLLT's anti-mucositis efficacy is independent of its possible potential to enhance threatening tumor behaviors. Included are appropriate pre-clinical modeling, short- and long-term follow-up of LLLT-treated patients, and the requirement for consistency of LLLT parameters.

  2. Mucosal Schwann cell "Hamartoma": A new entity?

    Institute of Scientific and Technical Information of China (English)

    Paola Pasquini; Andrea Baiocchini; Laura Falasca; Dante Annibali; Guido Gimbo; Francesco Pace; Franca Del Nonno

    2009-01-01

    Schwannoma is a well-described, benign nerve sheath tumor of the soft tissue, but is rare in the gastrointestinal tract. Gastrointestinal schwannomas are often incidentally discovered as small polypoid intraluminal lesions. In this report, we describe the clinicopathologic and immunohistochemical features of a distinctive neural mucosal polyp composed of a diffuse cellular proliferation of uniform bland spindled cells in the lamina propria that entraps the colonic crypts. Immunohistochemical analysis revealed strong and diffuse positivity for the S-100 protein. To avoid confusion of these solitary colorectal polyps containing pure spindled Schwann cell proliferation in the lamina propria with neural lesions that have significant association with inherited syndromes, it is better to use the designation "mucosal Schwann hamartoma".

  3. Age, gender, dentures and oral mucosal disorders.

    Science.gov (United States)

    MacEntee, M I; Glick, N; Stolar, E

    1998-03-01

    The numbers of participants over 75 years of age in previous studies of oral health have not been sufficient to permit a full investigation of the influence of age on the mouth. In this study a disproportionate stratified random sample of 255 independent elders was selected from a list of urban voters to provide similar numbers of men and women in three age groups. The subjects were interviewed and examined, and nearly half of them had mucosal disorders. There was a significant (P angular cheilitis in particular were associated significantly with men and with the use of defective dentures. Logistic regression revealed that neither age alone nor the quality of dentures predispose to mucosal lesions, but that the odds of finding stomatitis, denture-related hyperplasia and angular cheilitis in particular increased about three-fold in denture-users, and almost doubled in men.

  4. The microbiome and regulation of mucosal immunity.

    Science.gov (United States)

    McDermott, Andrew J; Huffnagle, Gary B

    2014-05-01

    The gastrointestinal tract is a mucosal surface constantly exposed to foreign antigens and microbes, and is protected by a vast array of immunologically active structures and cells. Epithelial cells directly participate in immunological surveillance and direction of host responses in the gut and can express numerous pattern recognition receptors, including Toll-like receptor 5 (TLR5), TLR1, TLR2, TLR3, TLR9, and nucleotide oligomerization domain 2, as well as produce chemotactic factors for both myeloid and lymphoid cells following inflammatory stimulation. Within the epithelium and in the underlying lamina propria resides a population of innate lymphoid cells that, following stimulation, can become activated and produce effector cytokines and exert both protective and pathogenic roles during inflammation. Lamina propria dendritic cells play a large role in determining whether the response to a particular antigen will be inflammatory or anti-inflammatory. It is becoming clear that the composition and metabolic activity of the intestinal microbiome, as a whole community, exerts a profound influence on mucosal immune regulation. The microbiome produces short-chain fatty acids, polysaccharide A, α-galactosylceramide and tryptophan metabolites, which can induce interleukin-22, Reg3γ, IgA and interleukin-17 responses. However, much of what is known about microbiome-host immune interactions has come from the study of single bacterial members of the gastrointestinal microbiome and their impact on intestinal mucosal immunity. Additionally, evidence continues to accumulate that alterations of the intestinal microbiome can impact not only gastrointestinal immunity but also immune regulation at distal mucosal sites.

  5. Peptic activity and gastroduodenal mucosal damage.

    OpenAIRE

    Raufman, J P

    1996-01-01

    This contribution reviews briefly the history of the discovery and characterization of peptic activity; secretory models and current concepts regarding the regulation of pepsinogen secretion; and evidence that pepsin is a necessary co-factor for gastroduodenal mucosal injury. Several animal studies indicate that peptic activity is required for acid- and nonsteroidal anti-inflammatory drug-induced gastroduodenal ulceration. A more vigorous approach to the development of anti-peptic drugs for t...

  6. Hitting the mucosal road in tolerance induction.

    Science.gov (United States)

    Wiedermann, Ursula

    2009-01-01

    Within the last decades a dramatic increase in allergic diseases has been recognized in the Westernized societies, leading to the fact that meanwhile 25-30% of the population is afflicted by allergic disorders. Besides a hereditary disposition, other factors, including a reduced microbial contact early in life or changes in nutrition, might also have influenced this epidemiological development. So far the only causative treatment against type-I allergies is specific immunotherapy. In young and monosensitized patients this treatment is highly efficacious, while there are clear limitations in older or multisensitized patients. Allergy research therefore aims at establishing new and more efficacious treatment strategies in prophylactic as well as therapeutic settings. Our research programs focus on the development of novel allergy vaccines based on the induction of mucosal tolerance. In different mouse models of respiratory allergy mucosal treatment with genetically engineered allergen constructs proved to prevent the development of allergic mono- and multisensitivities. The additional use of mucosal adjuvants seems particularly important to improve therapeutic treatment approaches. Recent studies on the inverse relation of certain parasite infections and the development of allergy prompted us to search for selected parasitic molecules with immunosuppressive properties as potential adjuvant systems for novel allergy vaccines. An overview of our recent studies will be given.

  7. Brain-gut axis and mucosal immunity: a perspective on mucosal psychoneuroimmunology.

    LENUS (Irish Health Repository)

    Shanahan, F

    2012-02-03

    The role of the brain-gut axis has traditionally been investigated in relation to intestinal motility, secretion, and vascularity. More recently, the concept of brain-gut dialogue has extended to the relationship between the nervous system and mucosal immune function. There is compelling evidence for a reciprocal or bi-directional communication between the immune system and the neuroendocrine system. This is mediated, in part, by shared ligands (chemical messengers) and receptors that are common to the immune and nervous systems. Although the concept of psychoneuroimmunology and neuroimmune cross-talk has been studied primarily in the context of the systemic immune system, it is likely to have special significance in the gut. The mucosal immune system is anatomically, functionally, and operationally distinct from the systemic immune system and is subject to independent regulatory signals. Furthermore, the intestinal mucosal immune system operates in a local milieu that depends on a dense innervation for its integrity, with juxtaposition of neuroendocrine cells and mucosal immune cells. An overview of evidence for the biologic plausibility of a brain-gut-immune axis is presented and its potential relevance to mucosal inflammatory disorders is discussed.

  8. A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch.

    LENUS (Irish Health Repository)

    Smith, F M

    2012-02-03

    INTRODUCTION: The resolution of pouchitis with metronidazole points to an anaerobic aetiology. Pouchitis is mainly seen in patients with ulcerative colitis pouches (UCP). We have recently found that sulphate reducing bacteria (SRB), a species of strict anaerobe, colonize UCP exclusively. Herein, we aimed to correlate levels of different bacterial species (including SRB) with mucosal inflammation and morphology. METHODS: Following ethical approval, fresh faecal samples and mucosal biopsies were taken from 9 patients with UCP and 5 patients with familial adenomatous polyposis pouches (FAPP). For the purposes of comparison, faecal samples and mucosal biopsies were also taken from the stomas of 7 of the 9 patients with UC (UCS). Colonization by four types of strict anaerobes (SRB, Clostridium perfringens, Bifidobacteria and Bacteroides) as well as by three types of facultative anaerobes (Enterococci, Coliforms and Lactobacilli) was evaluated. Inflammatory scores and mucosal morphology were assessed histologically in a blinded fashion by a pathologist. RESULTS: In general, strict anaerobes predominated over facultative in the UCP (P = 0.041). SRB were present in UCP exclusively. Even after exclusion of SRB from total bacterial counts, strict anaerobes still predominated. In the UCS, facultative anaerobes predominated. Strict and facultative anaerobes were present at similar levels in the FAPP. Enterococci were present at significantly reduced levels in the UCP when compared with the UCS (P = 0.031). When levels of SRB and other anaerobic species were individually correlated with mucosal inflammation and morphology, no trends were observed. CONCLUSION: We have previously identified that SRB exclusively colonize UCP. In addition we have now identified a novel increase in the strict\\/facultative anaerobic ratio within the UCP compared to UCS. These stark differences in bacterial colonization, however, appear to have limited impact on mucosal inflammation or morphology.

  9. Serum zinc levels in 368 patients with oral mucosal diseases: A preliminary study

    Science.gov (United States)

    Bao, Zhe-Xuan; Yang, Xiao-Wen; Shi, Jing

    2016-01-01

    Background The aim of this study was to assess the serum zinc levels in patients with common oral mucosal diseases by comparing these to healthy controls. Material and Methods A total of 368 patients, which consisted of 156 recurrent aphthous stomatitis (RAS) patients, 57 oral lichen planus (OLP) patients, 55 burning mouth syndrome (BMS) patients, 54 atrophic glossitis (AG) patients, 46 xerostomia patients, and 115 sex-and age-matched healthy control subjects were enrolled in this study. Serum zinc levels were measured in all participants. Statistical analysis was performed using a one-way ANOVA, t-test, and Chi-square test. Results The mean serum zinc level in the healthy control group was significantly higher than the levels of all other groups (p < 0.001). No individual in the healthy control group had a serum zinc level less than the minimum normal value. However, up to 24.7% (13/54) of patients with AG presented with zinc deficiency, while 21.2% (33/156) of patients with RAS, 16.4% (9/55) of patients with BMS, 15.2% (7/46) of patients with xerostomia, and 14.0% (8/57) of patients with OLP were zinc deficient. Altogether, the zinc deficiency rate was 19.02% (70/368) in the oral mucosal diseases (OMD) group (all patients with OMD). The difference between the OMD and healthy control group was significant (p <0.001). Gender differences in serum zinc levels were also present, although not statistically significant. Conclusions Zinc deficiency may be involved in the pathogenesis of common oral mucosal diseases. Zinc supplementation may be a useful treatment for oral mucosal diseases, but this requires further investigation; the optimal serum level of zinc, for the prevention and treatment of oral mucosal diseases, remains to be determined. Key words:Oral mucosal diseases, Zinc deficiency, pathogenesis. PMID:27031065

  10. Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Pei-Lin, E-mail: pchen@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Easton, Alexander S., E-mail: alexander.easton@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Division of Neurosurgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Canada)

    2010-01-01

    Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10{sup -5} mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

  11. Galectin-3 in angiogenesis and metastasis

    Science.gov (United States)

    Funasaka, Tatsuyoshi; Raz, Avraham; Nangia-Makker, Pratima

    2014-01-01

    Galectin-3 is a member of the family of β-galactoside-binding lectins characterized by evolutionarily conserved sequences defined by structural similarities in their carbohydrate-recognition domains. Galectin-3 is a unique, chimeric protein consisting of three distinct structural motifs: (i) a short NH2 terminal domain containing a serine phosphorylation site; (ii) a repetitive proline-rich collagen-α-like sequence cleavable by matrix metalloproteases; and (iii) a globular COOH-terminal domain containing a carbohydrate-binding motif and an NWGR anti-death motif. It is ubiquitously expressed and has diverse biological functions depending on its subcellular localization. Galectin-3 is mainly found in the cytoplasm, also seen in the nucleus and can be secreted by non-classical, secretory pathways. In general, secreted galectin-3 mediates cell migration, cell adhesion and cell–cell interactions through the binding with high affinity to galactose-containing glycoproteins on the cell surface. Cytoplasmic galectin-3 exhibits anti-apoptotic activity and regulates several signal transduction pathways, whereas nuclear galectin-3 has been associated with pre-mRNA splicing and gene expression. Its unique chimeric structure enables it to interact with a plethora of ligands and modulate diverse functions such as cell growth, adhesion, migration, invasion, angiogenesis, immune function, apoptosis and endocytosis emphasizing its significance in the process of tumor progression. In this review, we have focused on the role of galectin-3 in tumor metastasis with special emphasis on angiogenesis. PMID:25138305

  12. Safrole oxide inhibits angiogenesis by inducing apoptosis.

    Science.gov (United States)

    Zhao, Jing; Miao, Junying; Zhao, Baoxiang; Zhang, Shangli; Yin, Deling

    2005-06-01

    Our previous studies indicate that 3, 4-(methylenedioxy)-1-(2', 3'-epoxypropyl)-benzene (safrole oxide), a newly synthesized compound, induces apoptosis in vascular endothelial cells (VECs) and A549 lung cancer cells. To our knowledge, the inhibition of angiogenesis by safrole oxide has not been reported yet. We report here that cultured rat aorta treated with safrole oxide exhibited a significant microvessel reduction as determined by counting the number of microvessels in a phase contrast microscope. There were more microvessels formed in the presence of A549 lung cancer cells in rat aorta model, while a dramatic inhibition of angiogenesis was obtained by adding 220-450 micromol l(-1) of safrole oxide to the growth medium (Psafrole oxide produced only some abortive endothelial cells but not microvessels. Furthermore, safrole oxide induced antiangiogenic effect in the chorioallantoic membranes (CAM) as a dose dependent manner. Eggs treated with 2-11 micromol 100 microl(-1) per egg of the safrole oxide for 48 h exhibited a significant reduction in blood vessel area of the CAM, a process likely mediated by apoptosis as demonstrated by DNA fragmentation. Our results suggest that safrole oxide has antiangiogenic activity and this effect might occur by induction of cellular apoptosis.

  13. Comparative Efficacy of Aloe vera and Benzydamine Mouthwashes on Radiation-induced Oral Mucositis: A Triple-blind, Randomised, Controlled Clinical Trial.

    Science.gov (United States)

    Sahebjamee, Mahnaz; Mansourian, Arash; Hajimirzamohammad, Mohammad; Mohammad, Haji Mirza Mohammad; Zadeh, Mohsen Taghi; Bekhradi, Reza; Kazemian, Ali; Manifar, Soheila; Ashnagar, Sajjad; Doroudgar, Kiavash

    2015-01-01

    To compare the efficacy of an Aloe vera mouthwash with a benzydamine mouthwash in the alleviation of radiation- induced mucositis in head and neck cancer patients using a triple-blind, randomised controlled trial. Twenty-six eligible head and neck cancer patients who were to receive conventional radiation therapy at the radiation oncology department were randomised to receive an Aloe vera mouthwash or a benzydamine mouthwash. Mucositis severity was assessed during the course of radiation therapy using the WHO grading system. At baseline, there was no difference in the distribution of mucositis severity between the two groups. The mean interval between radiation therapy and onset of mucositis was similar for both groups (Aloe vera 15.69±7.77 days, benzydamine 15.85±12.96 days). The mean interval between the start of radiation therapy and the maximum severity of mucositis were was also similar in both the Aloe vera and benzydamine groups (Aloe vera 23.38±10.75 days, benzydamine 23.54±15.45 days). Mean changes of mucositis severity over time in both groups were statistically similar and the effect of both treatments did not change signficantly with time (p=0.09). Aloe vera mouthwash was as beneficial as benzydamine mouthwash in alleviating the severity of radiation-induced mucositis and showed no side effects. The Aloe vera mouthwash could be an alternative agent in the treatment of radiation-induced mucositis in patients with head and neck cancers.

  14. Control of Angiogenesis by AIBP-mediated Cholesterol Efflux

    Science.gov (United States)

    Fang, Longhou; Choi, Soo-Ho; Baek, Ji Sun; Liu, Chao; Almazan, Felicidad; Ulrich, Florian; Wiesner, Philipp; Taleb, Adam; Deer, Elena; Pattison, Jennifer; Torres-Vázquez, Jesús; Li, Andrew C.; Miller, Yury I.

    2013-01-01

    Cholesterol is a structural component of the cell, indispensable for normal cellular function, but its excess often leads to abnormal proliferation, migration, inflammatory responses and/or cell death. To prevent cholesterol overload, ATP-binding cassette (ABC) transporters mediate cholesterol efflux from the cells to apolipoprotein A-I (ApoA-I) and to the ApoA-I-containing high-density lipoprotein (HDL)1-3. Maintaining efficient cholesterol efflux is essential for normal cellular function4-6. However, the role of cholesterol efflux in angiogenesis and the identity of its local regulators are poorly understood. Here we show that ApoA-I binding protein (AIBP) accelerates cholesterol efflux from endothelial cells (EC) to HDL and thereby regulates angiogenesis. AIBP/HDL-mediated cholesterol depletion reduces lipid rafts, interferes with VEGFR2 dimerization and signaling, and inhibits VEGF-induced angiogenesis in vitro and mouse aortic neovascularization ex vivo. Remarkably, Aibp regulates the membrane lipid order in embryonic zebrafish vasculature and functions as a non-cell autonomous regulator of zebrafish angiogenesis. Aibp knockdown results in dysregulated sprouting/branching angiogenesis, while forced Aibp expression inhibits angiogenesis. Dysregulated angiogenesis is phenocopied in Abca1/Abcg1-deficient embryos, and cholesterol levels are increased in Aibp-deficient and Abca1/Abcg1-deficient embryos. Our findings demonstrate that secreted AIBP positively regulates cholesterol efflux from EC and that effective cholesterol efflux is critical for proper angiogenesis. PMID:23719382

  15. Relative defects in mucosal immunity predict acute graft-versus-host disease.

    Science.gov (United States)

    August, Keith J; Chiang, K-Y; Qayed, Muna; Dulson, Ashley; Worthington-White, Diana; Cole, Conrad R; Horan, John T

    2014-07-01

    Impairment of gut mucosal immunity by the transplant process could facilitate translocation of commensal bacteria and thereby augment the graft-versus-host response. To begin to assess the influence of gut mucosal immunity on the development of acute graft-versus-host disease (GVHD), we conducted a prospective study in 24 pediatric allogeneic hematopoietic cell transplant recipients, assessing 4 fecal markers of mucosal immunity: calprotectin, soluble CD8 (sCD8), soluble intracellular adhesion molecule 1, and β-defensin-2. Stool samples were collected prospectively on transplant days 0, +5, +10, and +15 and analyzed by ELISA. Lower levels on day +5 (calprotectin and β-defensin-2) and day +10 (calprotectin, β-defensin-2, and sCD8) were associated with subsequent acute GVHD. The most striking difference was with calprotectin on day +10. Patients with levels below 424 mg/kg had an incidence of 77.8%, whereas those with levels above this threshold had a cumulative incidence of 0% (P = .002). Relative defects in gut mucosal immunity may be important in the pathogenesis of acute GVHD.

  16. Perceiving nasal patency through mucosal cooling rather than air temperature or nasal resistance.

    Directory of Open Access Journals (Sweden)

    Kai Zhao

    Full Text Available Adequate perception of nasal airflow (i.e., nasal patency is an important consideration for patients with nasal sinus diseases. The perception of a lack of nasal patency becomes the primary symptom that drives these patients to seek medical treatment. However, clinical assessment of nasal patency remains a challenge because we lack objective measurements that correlate well with what patients perceive. The current study examined factors that may influence perceived patency, including air temperature, humidity, mucosal cooling, nasal resistance, and trigeminal sensitivity. Forty-four healthy subjects rated nasal patency while sampling air from three facial exposure boxes that were ventilated with untreated room air, cold air, and dry air, respectively. In all conditions, air temperature and relative humidity inside each box were recorded with sensors connected to a computer. Nasal resistance and minimum airway cross-sectional area (MCA were measured using rhinomanometry and acoustic rhinometry, respectively. General trigeminal sensitivity was assessed through lateralization thresholds to butanol. No significant correlation was found between perceived patency and nasal resistance or MCA. In contrast, air temperature, humidity, and butanol threshold combined significantly contributed to the ratings of patency, with mucosal cooling (heat loss being the most heavily weighted predictor. Air humidity significantly influences perceived patency, suggesting that mucosal cooling rather than air temperature alone provides the trigeminal sensation that results in perception of patency. The dynamic cooling between the airstream and the mucosal wall may be quantified experimentally or computationally and could potentially lead to a new clinical evaluation tool.

  17. The effect of thalidomide on ethanol-induced gastric mucosal damage in mice: involvement of inflammatory cytokines and nitric oxide.

    Science.gov (United States)

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-01-01

    Excessive ethanol ingestion causes gastric mucosal damage through the inflammatory and oxidative processes. The present study was aimed to evaluate the protective effect of thalidomide on ethanol-induced gastric mucosal damage in mice. The animals were pretreated with vehicle or thalidomide (30 or 60 mg/kg, orally), and one hour later, the gastric mucosal injury was induced by oral administration of acidified ethanol. The animals were euthanized one hour after ethanol ingestion, and gastric tissues were collected to biochemical analyzes. The gastric mucosal lesions were assessed by macroscopic and histopathological examinations. The results showed that treatment of mice with thalidomide prior to the administration of ethanol dose-dependently reduced the gastric ulcer index. Thalidomide pretreatment significantly reduced the levels of pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6], malondialdehyde (MDA) and myeloperoxidase (MPO) activity. In addition, thalidomide significantly inhibited ethanol-induced nitric oxide (NO) overproduction in gastric tissue. Histological observations showed that ethanol-induced gastric mucosal damage was attenuated by thalidomide pretreatment. It seems that thalidomide as an anti-inflammatory agent may have a protective effect against alcohol-induced mucosal damage by inhibition of neutrophil infiltration and reducing the production of nitric oxide and inflammatory cytokines in gastric tissue.

  18. Sacral nerve stimulation enhances early intestinal mucosal repair following mucosal injury in a pig model.

    Science.gov (United States)

    Brégeon, Jérémy; Coron, Emmanuel; Da Silva, Anna Christina Cordeiro; Jaulin, Julie; Aubert, Philippe; Chevalier, Julien; Vergnolle, Nathalie; Meurette, Guillaume; Neunlist, Michel

    2016-08-01

    Reducing intestinal epithelial barrier (IEB) dysfunctions is recognized as being of major therapeutic interest for various intestinal disorders. Sacral nerve stimulation (SNS) is known to reduce IEB permeability. Here, we report in a pig model that SNS enhances morphological and functional recovery of IEB following mucosal injury induced via 2,4,6-trinitrobenzenesulfonic acid. These effects are associated with an increased expression of tight junction proteins such as ZO-1 and FAK. These results establish that SNS enhances intestinal barrier repair in acute mucosal injury. They further set the scientific basis for future use of SNS as a complementary or alternative therapeutic option for the treatment of gut disorders with IEB dysfunctions such as inflammatory bowel diseases or irritable bowel syndrome. Intestinal epithelial barrier (IEB) dysfunctions, such as increased permeability or altered healing, are central to intestinal disorders. Sacral nerve stimulation (SNS) is known to reduce IEB permeability, but its ability to modulate IEB repair remains unknown. This study aimed to characterize the impact of SNS on mucosal repair following 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced lesions. Six pigs were stimulated by SNS 3 h prior to and 3 h after TNBS enema, while sham animals (n = 8) were not stimulated. The impact of SNS on mucosal changes was evaluated by combining in vivo imaging, histological and functional methods. Biochemical and transcriptomic approaches were used to analyse the IEB and mucosal inflammatory response. We observed that SNS enhanced the recovery from TNBS-induced increase in transcellular permeability. At 24 h, TNBS-induced alterations of mucosal morphology were significantly less in SNS compared with sham animals. SNS reduced TNBS-induced changes in ZO-1 expression and its epithelial pericellular distribution, and also increased pFAK/FAK expression compared with sham. Interestingly, SNS increased the mucosal density of neutrophils

  19. Impaired differentiation of macrophage lineage cells attenuates bone remodeling and inflammatory angiogenesis in Ndrg1 deficient mice.

    Science.gov (United States)

    Watari, Kosuke; Shibata, Tomohiro; Nabeshima, Hiroshi; Shinoda, Ai; Fukunaga, Yuichi; Kawahara, Akihiko; Karasuyama, Kazuyuki; Fukushi, Jun-Ichi; Iwamoto, Yukihide; Kuwano, Michihiko; Ono, Mayumi

    2016-01-18

    N-myc downstream regulated gene 1 (NDRG1) is a responsible gene for a hereditary motor and sensory neuropathy-Lom (Charcot-Marie-Tooth disease type 4D). This is the first study aiming to assess the contribution of NDRG1 to differentiation of macrophage lineage cells, which has important implications for bone remodeling and inflammatory angiogenesis. Ndrg1 knockout (KO) mice exhibited abnormal curvature of the spine, high trabecular bone mass, and reduced number of osteoclasts. We observed that serum levels of macrophage colony-stimulating factor (M-CSF) and macrophage-related cytokines were markedly decreased in KO mice. Differentiation of bone marrow (BM) cells into osteoclasts, M1/M2-type macrophages and dendritic cells was all impaired. Furthermore, KO mice also showed reduced tumor growth and angiogenesis by cancer cells, accompanied by decreased infiltration of tumor-associated macrophages. The transfer of BM-derived macrophages from KO mice into BM-eradicated wild type (WT) mice induced much less tumor angiogenesis than observed in WT mice. Angiogenesis in corneas in response to inflammatory stimuli was also suppressed with decreased infiltration of macrophages. Taken together, these results indicate that NDRG1 deficiency attenuates the differentiation of macrophage lineage cells, suppressing bone remodeling and inflammatory angiogenesis. This study strongly suggests the crucial role of NDRG1 in differentiation process for macrophages.

  20. Strychnine inhibits inflammatory angiogenesis in mice via down regulation of VEGF, TNF-α and TGF-β.

    Science.gov (United States)

    Saraswati, Sarita; Agarwal, S S

    2013-05-01

    Strychnine is known to possess anti-inflammatory and antitumour activity, but its roles in tumour angiogenesis, the key step involved in tumour growth and metastasis, and the involved molecular mechanism are still unknown. We aimed to investigate the effects of strychnine on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and strychnine (0.25, and 0.5 mg/kg/day) was given through installed cannulas for 9 days. The implants collected at day 9 postimplantation were processed for the assessment of haemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen used as indexes for angiogenesis, neutrophil and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Strychnine treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-α and transforming growth factor (TGF-β). A regulatory function of strychnine on multiple parameters of main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic underlying the actions of strychnine. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Targeting angiogenesis with integrative cancer therapies.

    Science.gov (United States)

    Yance, Donald R; Sagar, Stephen M

    2006-03-01

    An integrative approach for managing a patient with cancer should target the multiple biochemical and physiological pathways that support tumor development while minimizing normal tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The authors will focus on natural health products (NHPs) that have a high degree of antiangiogenic activity but also describe some of their many other interactions that can inhibit tumor progression and reduce the risk of metastasis. NHPs target various molecular pathways besides angiogenesis, including epidermal growth factor receptor (EGFR), the HER-2/neu gene, the cyclooxygenase-2 enzyme, the NF-kB transcription factor, the protein kinases, Bcl-2 protein, and coagulation pathways. The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are confirming the knowledge that is already documented in traditional texts. The following herbs are traditionally used for anticancer treatment and are antiangiogenic through multiple interdependent processes that include effects on gene expression, signal processing, and enzyme activities: Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (turmeric), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinale (ginger), Panax ginseng, Rabdosia rubescens (rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking on clinical trials. More data are required on dose response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations

  2. Chitosan-Based Nanoparticles for Mucosal Delivery of RNAi Therapeutics

    DEFF Research Database (Denmark)

    Martirosyan, Alina; Olesen, Morten Jarlstad; Howard, Kenneth A.

    2014-01-01

    of the polysaccharide chitosan have been used to facilitate delivery of siRNA across mucosal surfaces following local administration. This chapter describes the mucosal barriers that need to be addressed in order to design an effective mucosal delivery strategy and the utilization of the mucoadhesive properties...... of chitosan. Focus is given to preparation methods and the preclinical application of chitosan nanoparticles for respiratory and oral delivery of siRNA....

  3. Chitosan-Based Nanoparticles for Mucosal Delivery of RNAi Therapeutics

    DEFF Research Database (Denmark)

    Martirosyan, Alina; Olesen, Morten Jarlstad; Howard, Kenneth A.

    2014-01-01

    of the polysaccharide chitosan have been used to facilitate delivery of siRNA across mucosal surfaces following local administration. This chapter describes the mucosal barriers that need to be addressed in order to design an effective mucosal delivery strategy and the utilization of the mucoadhesive properties...... of chitosan. Focus is given to preparation methods and the preclinical application of chitosan nanoparticles for respiratory and oral delivery of siRNA....

  4. Enhanced gastric mucosal haemostasis after upper gastrointestinal haemorrhage.

    OpenAIRE

    Allison, M C; Fullarton, G M; Brown, I.L.; Crean, G P; McColl, K E

    1991-01-01

    An endoscopic technique for the measurement of gastric mucosal bleeding time has been developed to study gastric haemostasis in patients with acute upper gastrointestinal haemorrhage. The relation of gastric mucosal bleeding time to skin bleeding time and nonsterodial anti-inflammatory drug usage was examined in 61 control patients and in 47 patients presenting with bleeding peptic ulcers or erosions. Gastric mucosal bleeding time was shorter in patients with haemorrhage (median 2 minutes, ra...

  5. Classification of pulmonary airway disease based on mucosal color analysis

    Science.gov (United States)

    Suter, Melissa; Reinhardt, Joseph M.; Riker, David; Ferguson, John Scott; McLennan, Geoffrey

    2005-04-01

    Airway mucosal color changes occur in response to the development of bronchial diseases including lung cancer, cystic fibrosis, chronic bronchitis, emphysema and asthma. These associated changes are often visualized using standard macro-optical bronchoscopy techniques. A limitation to this form of assessment is that the subtle changes that indicate early stages in disease development may often be missed as a result of this highly subjective assessment, especially in inexperienced bronchoscopists. Tri-chromatic CCD chip bronchoscopes allow for digital color analysis of the pulmonary airway mucosa. This form of analysis may facilitate a greater understanding of airway disease response. A 2-step image classification approach is employed: the first step is to distinguish between healthy and diseased bronchoscope images and the second is to classify the detected abnormal images into 1 of 4 possible disease categories. A database of airway mucosal color constructed from healthy human volunteers is used as a standard against which statistical comparisons are made from mucosa with known apparent airway abnormalities. This approach demonstrates great promise as an effective detection and diagnosis tool to highlight potentially abnormal airway mucosa identifying a region possibly suited to further analysis via airway forceps biopsy, or newly developed micro-optical biopsy strategies. Following the identification of abnormal airway images a neural network is used to distinguish between the different disease classes. We have shown that classification of potentially diseased airway mucosa is possible through comparative color analysis of digital bronchoscope images. The combination of the two strategies appears to increase the classification accuracy in addition to greatly decreasing the computational time.

  6. Scoring irradiation mucositis in head and neck cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Spijkervet, F.K.L.; Panders, A.K. (Departments of Oral and Maxillofacial Surgery, University Hospital Groningen (Netherlands)); Saene, H.K.F. van (Medical Microbiology, University of Liverpool (UK)); Vermey, A. (Department of Surgery Oncology Division, University Hospital Groningen (Netherlands)); Mehta, D.M. (Department of Radiotherapy, University Hospital Groningen (Netherlands))

    1989-01-01

    Irradiation mucositis is defined as an inflammatory-like process of the oropharyngeal mucosa following therapeutic irradiation of patients who have head and neck cancer. Clinically, it is a serious side effect because severe mucositis can cause generalized problems (weight loss, nasogastic tube feedings) and interferes with the well-being of the patient seriously. Grading mucositis is important for the evaluation of preventive and therapeutic measures. The object of this study was to develop a scoring method based on local mucositis signs only. Four clinical local signs of mucositis were used in this score: white discoloration, erythema, pseudomembranes and ulceration. Mucositis of the oral cavity was calcualted during conventional irradiation protocol for 8 distinguishable areas using the 4 signs and their extent. A prospective evaluation of this method in 15 irradiated head and neck cancer patients displayed an S-curve reflecting a symptomless first irradiation week, followed by a rapid and steady increase of white discoloration, erythema and pseudomembranes during the second and third week. Oral candidiasis, generalized symptoms such as weight loss and the highest mucositis scores were seen after 3 weeks irradiation. The novel mucositis scoring method may be of value in studying the effect of hygiene programs, topical application of disinfectans or antibiotics on oral mucositis. (author).

  7. Mucosal and systemic adjuvant activity of alphavirus replicon particles

    Science.gov (United States)

    Thompson, Joseph M.; Whitmore, Alan C.; Konopka, Jennifer L.; Collier, Martha L.; Richmond, Erin M. B.; Davis, Nancy L.; Staats, Herman F.; Johnston, Robert E.

    2006-03-01

    Vaccination represents the most effective control measure in the fight against infectious diseases. Local mucosal immune responses are critical for protection from, and resolution of, infection by numerous mucosal pathogens. Antigen processing across mucosal surfaces is the natural route by which mucosal immunity is generated, as peripheral antigen delivery typically fails to induce mucosal immune responses. However, we demonstrate in this article that mucosal immune responses are evident at multiple mucosal surfaces after parenteral delivery of Venezuelan equine encephalitis virus replicon particles (VRP). Moreover, coinoculation of null VRP (not expressing any transgene) with inactivated influenza virions, or ovalbumin, resulted in a significant increase in antigen-specific systemic IgG and fecal IgA antibodies, compared with antigen alone. Pretreatment of VRP with UV light largely abrogated this adjuvant effect. These results demonstrate that alphavirus replicon particles possess intrinsic systemic and mucosal adjuvant activity and suggest that VRP RNA replication is the trigger for this activity. We feel that these observations and the continued experimentation they stimulate will ultimately define the specific components of an alternative pathway for the induction of mucosal immunity, and if the activity is evident in humans, will enable new possibilities for safe and inexpensive subunit and inactivated vaccines. vaccine vector | Venezuelan equine encephalitis virus | viral immunology | RNA virus

  8. Influence of levamisole and other angiogenesis inhibitors on angiogenesis and endothelial cell morphology in vitro.

    Science.gov (United States)

    Friis, Tina; Engel, Anne-Marie; Bendiksen, Christine D; Larsen, Line S; Houen, Gunnar

    2013-01-01

    Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC) receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF) and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI) IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs) results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti-angiogenic activity

  9. Influence of Levamisole and Other Angiogenesis Inhibitors on Angiogenesis and Endothelial Cell Morphology in Vitro

    Science.gov (United States)

    Friis, Tina; Engel, Anne-Marie; Bendiksen, Christine D.; Larsen, Line S.; Houen, Gunnar

    2013-01-01

    Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC) receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF) and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI) IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs) results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti-angiogenic activity

  10. Influence of Levamisole and Other Angiogenesis Inhibitors on Angiogenesis and Endothelial Cell Morphology in Vitro

    Directory of Open Access Journals (Sweden)

    Gunnar Houen

    2013-06-01

    Full Text Available Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti

  11. Influence of Levamisole and Other Angiogenesis Inhibitors on Angiogenesis and Endothelial Cell Morphology in Vitro

    Energy Technology Data Exchange (ETDEWEB)

    Friis, Tina; Engel, Anne-Marie; Bendiksen, Christine D.; Larsen, Line S.; Houen, Gunnar, E-mail: gh@ssi.dk [Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen (Denmark)

    2013-06-24

    Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC) receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF) and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI) IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs) results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti-angiogenic activity

  12. Oral mucosal immunization using glucomannosylated bilosomes.

    Science.gov (United States)

    Jain, Sanyog; Indulkar, Anura; Harde, Harshad; Agrawal, Ashish K

    2014-06-01

    The present study embarks on the feasibility of GM-bilosomes as a rationally designed vehicle for oral mucosal immunization. Bilosomes containing BSA as a model antigen were found to have vesicle size of 157 +/- 3 nm, PDI of 0.287 +/- 0.045, zeta potential of -21.8 +/- 2.01 mV and entrapment efficiency of 71.3 +/- 4.3%. Bilosomal formulations were freeze dried and entrapped BSA in freeze dried formulations was found to retain its structural and conformational stability as evident by SDS-PAGE and CD analysis. The GM-bilosomes were also found stable in different simulated biological fluids and bile salt solutions of different concentrations. In-vitro drug release revealed that GM-bilosomes were able to sustain drug release up to 24 h. In-vitro cell uptake in RAW 264.7 macrophage cells demonstrated significantly higher uptake of GM-bilosomes in comparison with bilosomes and free antigen. Intestinal uptake studies on excised rat intestinal sections further demonstrated higher uptake of vesicular systems throughout the intestinal region in comparison with free antigen. Significantly higher (p alum adsorbed BSA (BSA-AL) following oral administration. The immune response observed in case of GM-bilosomes was comparable to BSA-AL administered through im route without any significant difference (p > 0.05). More importantly, GM-bilosomes were found capable of inducing mucosal immune response as well as cell mediated immune response which was not induced by im BSA-AL. In conclusion, GM-bilosomes could be considered as promising carrier and adjuvant system for oral mucosal immunization and productively exploited for oral delivery of other candidate antigens.

  13. Characteristics of resistin in rheumatoid arthritis angiogenesis.

    Science.gov (United States)

    Su, Chen-Ming; Huang, Chun-Yin; Tang, Chih-Hsin

    2016-06-01

    Adipokines have been reported to be involved in the regulation of various physiological processes, including the immune response. Rheumatoid arthritis (RA) is an example of a systemic immune disease that causes chronic inflammation of the synovium and bone destruction in the joint. Recent therapeutic strategies based on the understanding of the role of cytokines and cellular mechanisms in RA have improved our understanding of angiogenesis. On the other hand, endogenous endothelial progenitor cells, which are a population isolated from peripheral blood monocytes have recently been identified as a homing target for pro-angiogeneic factor and vessel formation. In this review, we summarize the effects of common adipokines, such as adiponectin, leptin and resistin in RA pathogenesis and discuss other potential mechanisms of relevance for the therapeutic treatment of RA.

  14. Tumor angiogenesis in mice and men.

    Science.gov (United States)

    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.

  15. Oral lichen planus and lichenoid mucositis.

    Science.gov (United States)

    De Rossi, Scott S; Ciarrocca, Katharine

    2014-04-01

    Oral lichen planus (OLP) is commonly found in middle-aged women. Although the cause is unknown, research points to several complex immunologic events and cells that are responsible for the inflammatory destruction and chronicity of these lesions. Biopsy for histologic diagnosis is recommended. The mainstay of treatment remains topical corticosteroids; however, newer therapies such as immunomodulating agents are available for recalcitrant lesions. In cases of lichenoid mucositis or reactions, treatment should be directed at identifying and removing the presumed cause. Given the apparent risk of squamous cell carcinoma in these patients, frequent follow-up and repeat biopsy are vital.

  16. Potential of dietary nitrate in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Christos; Rammos; Peter; Luedike; Ulrike; Hendgen-Cotta; Tienush; Rassaf

    2015-01-01

    Endothelial dysfunction with impaired bioavailability of nitric oxide(NO) is the hallmark in the development of cardiovascular disease. Endothelial dysfunction leads to atherosclerosis, characterized by chronic inflammation of the arterial wall and stepwise narrowing of the vessel lumen. Atherosclerosis causes deprivation of adequate tissue blood flow with compromised oxygen supply. To overcome this undersupply, remodeling of the vascular network is necessary to reconstitute and sustain tissue viability. This physiological response is often not sufficient and therapeutic angiogenesis remains an unmet medical need in critical limb ischemia or coronary artery disease. Feasible approaches to promote blood vessel formation are sparse. Administration of pro-angiogenic factors, gene therapy, or targeting of micro RNAs has not yet entered the daily practice. Nitric oxide is an important mediator of angiogenesis that becomes limited under ischemic conditions and the maintenance of NO availability might constitute an attractive therapeutic target. Until recently it was unknown how the organism provides NO under ischemia. In recent years it could be demonstrated that NO can be formed independently of its enzymatic synthesis in the endothelium by reduction of inorganic nitrite under hypoxic conditions. Circulating nitrite derives from oxidation of NO or reduction of inorganic nitrate by commensal bacteria in the oral cavity. Intriguingly, nitrate is a common constituent of our everyday diet and particularly high concentrations are found in leafy green vegetables such as spinach, lettuce, or beetroot. Evidence suggests that dietary nitrate supplementation increases the regenerative capacity of ischemic tissue and that this effect may offer an attractive nutrition-based strategy to improve ischemia-induced revascularization. We here summarize and discuss the regenerative capacity of dietary nitrate on the vascular system.

  17. Tympanomastoid cholesterol granulomas: Immunohistochemical evaluation of angiogenesis.

    Science.gov (United States)

    Iannella, Giannicola; Di Gioia, Cira; Carletti, Raffaella; Magliulo, Giuseppe

    2017-08-01

    This study investigates the immunohistochemical expression of vascular endothelial growth factor (VEGF) and CD34 in patients treated for middle ear and mastoid cholesterol granulomas to evaluate the angiogenesis and vascularization of this type of lesion. A correlation between the immunohistochemical data and the radiological and intraoperative evidence of temporal bone marrow invasion and blood source connection was performed to validate this hypothesis. Retrospective study. Immunohistochemical expression of VEGF and CD34 in a group of 16 patients surgically treated for cholesterol granuloma was examined. Middle ear cholesteatomas with normal middle ear mucosa and external auditory canal skin were used as the control groups. The radiological and intraoperative features of cholesterol granulomas were also examined. In endothelial cells, there was an increased expression of angiogenetic growth factor receptors in all the cholesterol granulomas in this study. The quantitative analysis of VEGF showed a mean value of 37.5, whereas the CD34 quantitative analysis gave a mean value of 6.8. Seven patients presented radiological or intraoperative evidence of bone marrow invasion, hematopoietic potentialities, or blood source connections that might support the bleeding theory. In all of these cases there was computed tomography or intraoperative evidence of bone erosion of the middle ear and/or temporal bone structures. The mean values of VEGF and CD34 were 41.1 and 7.7, respectively. High values of VEGF and CD34 are present in patients with cholesterol granulomas. Upregulation of VEGF and CD34 is indicative of a remarkable angiogenesis and a widespread vascular concentration in cholesterol granulomas. 3b. Laryngoscope, 127:E283-E290, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

  18. Potential of dietary nitrate in angiogenesis.

    Science.gov (United States)

    Rammos, Christos; Luedike, Peter; Hendgen-Cotta, Ulrike; Rassaf, Tienush

    2015-10-26

    Endothelial dysfunction with impaired bioavailability of nitric oxide (NO) is the hallmark in the development of cardiovascular disease. Endothelial dysfunction leads to atherosclerosis, characterized by chronic inflammation of the arterial wall and stepwise narrowing of the vessel lumen. Atherosclerosis causes deprivation of adequate tissue blood flow with compromised oxygen supply. To overcome this undersupply, remodeling of the vascular network is necessary to reconstitute and sustain tissue viability. This physiological response is often not sufficient and therapeutic angiogenesis remains an unmet medical need in critical limb ischemia or coronary artery disease. Feasible approaches to promote blood vessel formation are sparse. Administration of pro-angiogenic factors, gene therapy, or targeting of microRNAs has not yet entered the daily practice. Nitric oxide is an important mediator of angiogenesis that becomes limited under ischemic conditions and the maintenance of NO availability might constitute an attractive therapeutic target. Until recently it was unknown how the organism provides NO under ischemia. In recent years it could be demonstrated that NO can be formed independently of its enzymatic synthesis in the endothelium by reduction of inorganic nitrite under hypoxic conditions. Circulating nitrite derives from oxidation of NO or reduction of inorganic nitrate by commensal bacteria in the oral cavity. Intriguingly, nitrate is a common constituent of our everyday diet and particularly high concentrations are found in leafy green vegetables such as spinach, lettuce, or beetroot. Evidence suggests that dietary nitrate supplementation increases the regenerative capacity of ischemic tissue and that this effect may offer an attractive nutrition-based strategy to improve ischemia-induced revascularization. We here summarize and discuss the regenerative capacity of dietary nitrate on the vascular system.

  19. Characterising the mucosal and systemic immune responses to experimental human hookworm infection.

    Directory of Open Access Journals (Sweden)

    Soraya Gaze

    2012-02-01

    Full Text Available The mucosal cytokine response of healthy humans to parasitic helminths has never been reported. We investigated the systemic and mucosal cytokine responses to hookworm infection in experimentally infected, previously hookworm naive individuals from non-endemic areas. We collected both peripheral blood and duodenal biopsies to assess the systemic immune response, as well as the response at the site of adult worm establishment. Our results show that experimental hookworm infection leads to a strong systemic and mucosal Th2 (IL-4, IL-5, IL-9 and IL-13 and regulatory (IL-10 and TGF-β response, with some evidence of a Th1 (IFN-γ and IL-2 response. Despite upregulation after patency of both IL-15 and ALDH1A2, a known Th17-inducing combination in inflammatory diseases, we saw no evidence of a Th17 (IL-17 response. Moreover, we observed strong suppression of mucosal IL-23 and upregulation of IL-22 during established hookworm infection, suggesting a potential mechanism by which Th17 responses are suppressed, and highlighting the potential that hookworms and their secreted proteins offer as therapeutics for human inflammatory diseases.

  20. Relationship between mucositis and changes in oral microflora during cancer chemotherapy.

    Science.gov (United States)

    Napeñas, Joel J; Brennan, Michael T; Bahrani-Mougeot, Farah K; Fox, Philip C; Lockhart, Peter B

    2007-01-01

    It is thought that the incidence and severity of cancer chemotherapy-associated mucositis is caused in part by changes in the oral bacterial microflora. This systematic review examined the role of oral bacterial microflora changes in the development of oral mucositis during chemotherapy. Thirteen prospective clinical trials were identified, involving 300 patients with 13 different cancer diagnoses. There was great variability in patient populations, bacterial sample collection methodology, and oral sample sites. No clear pattern regarding qualitative and quantitative oral flora changes emerged among these studies. The most frequent Gram-negative species isolated during chemotherapy were from the Enterobacteriaceae family, Pseudomonas sp. and E. coli. The most common Gram-positive species isolated were Staphylococcus sp. and Streptococcus sp. Five studies assessed the role of oral flora changes in the genesis of oral mucosal changes, with no consensus among them. More detailed studies are required to understand the relationship between chemotherapy, alterations in the nature and magnitude of the oral microflora, and the presence of mucositis.

  1. Rhubarb extract partially improves mucosal integrity in chemotherapy-induced intestinal mucositis

    Science.gov (United States)

    Bajic, Juliana E; Eden, Georgina L; Lampton, Lorrinne S; Cheah, Ker Y; Lymn, Kerry A; Pei, Jinxin V; Yool, Andrea J; Howarth, Gordon S

    2016-01-01

    AIM To investigate the effects of orally gavaged aqueous rhubarb extract (RE) on 5-fluorouracil (5-FU)-induced intestinal mucositis in rats. METHODS Female Dark Agouti rats (n = 8/group) were gavaged daily (1 mL) with water, high-dose RE (HDR; 200 mg/kg) or low-dose RE (LDR; 20mg/kg) for eight days. Intestinal mucositis was induced (day 5) with 5-FU (150 mg/kg) via intraperitoneal injection. Intestinal tissue samples were collected for myeloperoxidase (MPO) activity and histological examination. Xenopus oocytes expressing aquaporin 4 water channels were prepared to examine the effect of aqueous RE on cell volume, indicating a potential mechanism responsible for modulating net fluid absorption and secretion in the gastrointestinal tract. Statistical significance was assumed at P < 0.05 by one-way ANOVA. RESULTS Bodyweight was significantly reduced in rats administered 5-FU compared to healthy controls (P < 0.01). Rats administered 5-FU significantly increased intestinal MPO levels (≥ 307%; P < 0.001), compared to healthy controls. However, LDR attenuated this effect in 5-FU treated rats, significantly decreasing ileal MPO activity (by 45%; P < 0.05), as compared to 5-FU controls. 5-FU significantly reduced intestinal mucosal thickness (by ≥ 29% P < 0.001) as compared to healthy controls. LDR significantly increased ileal mucosal thickness in 5-FU treated rats (19%; P < 0.05) relative to 5-FU controls. In xenopus oocytes expressing AQP4 water channels, RE selectively blocked water influx into the cell, induced by a decrease in external osmotic pressure. As water efflux was unaltered by the presence of extracellular RE, the directional flow of water across the epithelial barrier, in the presence of extracellular RE, indicated that RE may alleviate water loss across the epithelial barrier and promote intestinal health in chemotherapy-induced intestinal mucositis. CONCLUSION In summary, low dose RE improves selected parameters of mucosal integrity and reduces ileal

  2. In-vivo three-dimensional Doppler variance imaging for tumor angiogenesis on chorioallantoic membrane

    Science.gov (United States)

    Qi, Wenjuan; Liu, Gangjun; Chen, Zhongping

    2011-03-01

    Non-invasive tumor microvasculature visualization and characterization play significant roles in the detection of tumors and importantly, for aiding in the development of therapeutic strategies. The feasibility and effectiveness of a Doppler variance standard deviation imaging method for tumor angiogenesis on chorioallantoic membrane were tested in vivo on a rat glioma F98 tumor spheroid. Utilizing a high resolution Doppler Variance Optical Coherence Tomography (DVOCT) system with A-line rate of 20 kHz, three-dimensional mapping of a tumor with a total area of 3×2.5mm2 was completed within 15 seconds. The top-view image clearly visualized the complex vascular perfusion with the detection of capillaries as small as approximately 10μm. The results of the current study demonstrate the capability of the Doppler variance standard deviation imaging method as a non-invasive assessment of tumor angiogenesis, with the potential for its use in clinical settings.

  3. Pattern analysis accounts for heterogeneity observed in MRI studies of tumor angiogenesis.

    Science.gov (United States)

    Dominietto, Marco; Lehmann, Steffi; Keist, Ruth; Rudin, Markus

    2013-11-01

    MRI is a method of choice for assessing anatomical structures or angiogenesis-related parameters noninvasively during tumor progression. Typically, tumor tissue displays a high degree of heterogeneity that can be evaluated using pattern analysis (PA), which comprises shape and texture analysis. This work aims at implementing PA methods to study angiogenesis in a murine tumor model and testing its sensitivity with regard to detecting changes elicited by administration of a drug. Twelve balb/c-nude mice were injected subcutaneously with 10(6) C51 cells (colon carcinoma). A first group (N = 6) of animals was treated with dimethyloxalylglycine, a drug known to stabilize hypoxia-inducible-factor-α, which among other functions, is involved in angiogenesis. The second group (N = 6) was treated with saline. MRI experiments assessing tumor blood volume and permeability-maps (K(trans) ) were performed immediately before and 6 days after drug treatment. Data have been analyzed using standard histogram analysis and PA. Standard histogram analysis did not reveal any difference between the two groups, neither before nor after the treatment. In contrast, PA revealed significant differences between drug and placebo treated mice in the texture of the TBV and K(trans) maps after drug treatment, but not with regard to tumors shapes. The results indicated that in view of the heterogeneity of tumor tissue, standard histogram analysis appears insensitive in picking-up differences in response to treatment, while PA appears to be particularly sensitive to changes in texture. Copyright © 2012 Wiley Periodicals, Inc.

  4. Oxygen Tension Regulates the Expression of Angiogenesis Factor by Macrophages

    Science.gov (United States)

    Knighton, David R.; Hunt, Thomas K.; Scheuenstuhl, Heinz; Halliday, Betty J.; Werb, Zena; Banda, Michael J.

    1983-09-01

    When cultured in a hypoxic environment similar to that found in the center of a wound, macrophages secreted active angiogenesis factor into the medium. Under conditions similar to those of well-oxygenated tissue, macrophages did not secrete active angiogenesis factor. Macrophages that secreted the factor at hypoxic conditions stopped secreting it when returned to room air. Thus the control of angiogenesis in wound healing may be the result of macrophages responding to tissue oxygen tension without the necessity of interacting with other cell types or biochemical signals.

  5. Oxygen tension regulates the expression angiogenesis factor by macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Knighton, D.R.; Hunt, T.K.; Scheuenstuhl, H.; Halliday, B.J.; Werb, Z.; Banda, M.J.

    1983-09-23

    When cultured in a hypoxic environment similar to that found in the center of a wound, macrophages secreted active angiogenesis factor into the medium. Under conditions similar to those of well-oxygenated tissue, macrophages did not secrete active angiogenesis factor. Macrophages that secreted the factor at hyposic conditions stopped secreting it when returned to room air. Thus the control of angiogenesis in wound healing may be the result of macrophages responding to tissue oxygen tension without the necessity of interacting with other cell types or biochemical signals.

  6. Oxygen tension regulated the expression of angiogenesis factor by macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Knighton, D.R.; Hunt, T.K.; Scheuenstuhl, H.; Halliday, B.J.; Werb, Z.; Banda, M.J.

    1983-09-23

    When cultured in a hypoxic environment similar to that found in the center of a wound, macrophages secreted active angiogenesis factor into the medium. Under conditions similar to those of well-oxygenated tissue, macrophages did not secrete active angiogenesis factor. Macrophages that secreted the factor at hypoxic conditions stopped secreting it when returned to room air. Thus the control of angiogenesis in wound healing may be the result of macrophages responding to tissue oxygen tension without the necessity of interacting with other cell types or biochemical signals.

  7. Osteochondral plate angiogenesis: a new treatment target in osteoarthritis.

    Science.gov (United States)

    Pesesse, Laurence; Sanchez, Christelle; Henrotin, Yves

    2011-03-01

    Healthy adult joint cartilage contains neither blood vessels nor nerves. Osteoarthritic cartilage, in contrast, may be invaded by blood vessels from the subchondral bone. The mechanisms underlying cartilage angiogenesis in osteoarthritis are unclear but may involve hypertrophic chondrocyte differentiation. Active research is under way to identify the factors involved in cartilage angiogenesis. Here, we discuss the pathophysiological mechanisms of osteoarthritic cartilage angiogenesis based on evidence from a systematic literature review of articles retrieved via PubMed and ISI Web of Knowledge. Our conclusions suggest new research perspectives and treatment options.

  8. Longitudinal Studies of Angiogenesis in Hormone-Dependent Shionogi Tumors

    Directory of Open Access Journals (Sweden)

    Trevor P. Wade

    2007-07-01

    Full Text Available Vessel size imaging was used to assess changes in the average vessel size of Shionogi tumors throughout the tumor growth cycle. Changes in R2 and R2* relaxivities caused by the injection of a superparamagnetic contrast agent (ferumoxtran-10 were measured using a 2.35-T animal magnetic resonance imaging system, and average vessel size index (VSI was calculated for each stage of tumor progression: growth, regression, and relapse. Statistical analysis using Spearman rank correlation test showed no dependence between vessel size and tumor volume at any stage of the tumor growth cycle. Paired Student's t test was used to assess the statistical significance of the differences in average vessel size for the three stages of the tumor growth cycle. The average VSI for regressing tumors (15.1 ± 6.6 wm was significantly lower than that for growing tumors (35.2 ± 25.5 μm; P < .01. Relapsing tumors also had an average VSI (45.4 ± 41.8 μm higher than that of regressing tumors, although the difference was not statistically significant (P = .067. This study shows that VSI imaging is a viable method for the noninvasive monitoring of angiogenesis during the progression of a Shionogi tumor from androgen dependence to androgen independence.

  9. Preventive Effect of Rebamipide Gargle on Chemoradiotherpy-Induced Oral Mucositis in Patients with Oral Cancer: a Pilot Study

    Directory of Open Access Journals (Sweden)

    Takashi Yasuda

    2011-11-01

    Full Text Available Objectives: To assess the efficacy and safety of rebamipide in preventing chemoradiotherapy-induced oral mucositis in patients with oral cancer.Material and Methods: Patients with oral cancer treated with chemoradiotherapy (daily radiotherapy plus docetaxel hydrate once a week were enrolled for this study. They were assigned in a double-blind fashion to receive either rebamipide gargle or placebo on the days of chemoradiotherapy. Oral mucositis was assessed using the WHO grading system. The primary endpoint of this study was the incidence of grade 3 - 4 mucositis after exposure to 40 Gy radiation (4 weeks. The secondary endpoint was the effect of rebamipide gargle on tumour response to chemoradiotherapy.Results: Twenty-four patients were randomly assigned to receive rebamipide gargle (n = 12 or placebo-gargle (n = 12 during chemoradiotherapy. The number of patients with severe mucositis (WHO ≥ 3 was higher in the placebo group than in the rebamipide group (83.3% vs. 33.3%, P = 0.036. In addition, no effect of rebamipide gargle on tumour response to chemoradiotherapy was recognized compared with the placebo group.Conclusions: For patients with oral cancer undergoing chemoradiotherapy, rebamipide gargle may contribute to decrease the severity of oral mucositis.

  10. Preventive effect of rebamipide gargle on chemoradiotherpy-induced oral mucositis in patients with oral cancer: a pilot study.

    Science.gov (United States)

    Yasuda, Takashi; Chiba, Hiroshige; Satomi, Takafumi; Matsuo, Akira; Kaneko, Tadayoshi; Chikazu, Daichi; Miyamatsu, Hironobu

    2012-01-01

    To assess the efficacy and safety of rebamipide in preventing chemoradiotherapy-induced oral mucositis in patients with oral cancer. Patients with oral cancer treated with chemoradiotherapy (daily radiotherapy plus docetaxel hydrate once a week) were enrolled for this study. They were assigned in a double-blind fashion to receive either rebamipide gargle or placebo on the days of chemoradiotherapy. Oral mucositis was assessed using the WHO grading system. The primary endpoint of this study was the incidence of grade 3 - 4 mucositis after exposure to 40 Gy radiation (4 weeks). The secondary endpoint was the effect of rebamipide gargle on tumour response to chemoradiotherapy. Twenty-four patients were randomly assigned to receive rebamipide gargle (n = 12) or placebo-gargle (n = 12) during chemoradiotherapy. The number of patients with severe mucositis (WHO ≥ 3) was higher in the placebo group than in the rebamipide group (83.3% vs. 33.3%, P = 0.036). In addition, no effect of rebamipide gargle on tumour response to chemoradiotherapy was recognized compared with the placebo group. For patients with oral cancer undergoing chemoradiotherapy, rebamipide gargle may contribute to decrease the severity of oral mucositis.

  11. Probiotics as Antifungals in Mucosal Candidiasis.

    Science.gov (United States)

    Matsubara, Victor H; Bandara, H M H N; Mayer, Marcia P A; Samaranayake, Lakshman P

    2016-05-01

    Candidais an opportunistic pathogen that causes mucosal and deep systemic candidiasis. The emergence of drug resistance and the side effects of currently available antifungals have restricted their use as long-term prophylactic agents for candidal infections. Given this scenario, probiotics have been suggested as a useful alternative for the management of candidiasis. We analyzed the available data on the efficacy of probiotics in candidal colonization of host surfaces. A number of well-controlled studies indicate that probiotics, particularly lactobacilli, suppressCandidagrowth and biofilm development in vitro.A few clinical trials have also shown the beneficial effects of probiotics in reducing oral, vaginal, and enteric colonization byCandida; alleviation of clinical signs and symptoms; and, in some cases, reducing the incidence of invasive fungal infection in critically ill patients. Probiotics may serve in the future as a worthy ally in the battle against chronic mucosal candidal infections. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  12. Genistein reduces angiogenesis and apoptosis in women with endometrial hyperplasia

    Directory of Open Access Journals (Sweden)

    Granese R

    2015-01-01

    Full Text Available Roberta Granese,1,* Alessandra Bitto,2,* Francesca Polito,2 Onofrio Triolo,1 Domenico Giordano,1 Angelo Santamaria,1 Francesco Squadrito,2 Rosario D’Anna1 1Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, 2Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Messina, Messina, Italy*These authors contributed equally to this workAbstract: Endometrial hyperplasia without cytological atypia is commonly treated with progestins, but other treatments may be available with equivalent efficacy and reduced side effects. Here, we evaluate the effect of genistein aglycone on angiogenesis and apoptosis-related markers women with endometrial hyperplasia. Premenopausals (n=38 with nonatypical endometrial hyperplasia were administered either genistein aglycone (54 mg/day, n=19 or norethisterone acetate (10 mg/day, n=19 on days 16–25 of the menstrual cycle and evaluated for 6 months. Biopsies were taken during hysteroscopy at baseline and 6 months, and symptoms including excessive uterine bleeding were assessed at baseline and 3 and 6 months following recruitment. The expression of angiogenesis (Vegf, epithelial (Egf and Tgfb, and apoptosis-related (Bax, Bcl-2, and Casp-9 molecules, were assessed in uterine biopsies at baseline and after 6 months of therapy. Follicle-stimulating hormone, luteinizing hormone, estradiol, SHBG, and progesterone levels were also measured. After 6 months, 42% of genistein aglycone-administered patients had a significant improvement of symptoms compared to 47% of norethisterone acetate subjects. No significant differences were noted in hormone levels for any treatment. Gene expression revealed a significant reduction in Vegf, Egf, and Tgfb (P<0.05 versus baseline, and an increase in proapoptotic molecules (Bax and Casp-9, with a concomitant decrease in Bcl-2 values (P<0.05 in both groups. These results suggest that genistein aglycone might be useful for the

  13. Induction of mucosal immunity through systemic immunization: Phantom or reality?

    Science.gov (United States)

    Su, Fei; Patel, Girishchandra B; Hu, Songhua; Chen, Wangxue

    2016-04-02

    Generation of protective immunity at mucosal surfaces can greatly assist the host defense against pathogens which either cause disease at the mucosal epithelial barriers or enter the host through these surfaces. Although mucosal routes of immunization, such as intranasal and oral, are being intensely explored and appear promising for eliciting protective mucosal immunity in mammals, their application in clinical practice has been limited due to technical and safety related challenges. Most of the currently approved human vaccines are administered via systemic (such as intramuscular and subcutaneous) routes. Whereas these routes are acknowledged as being capable to elicit antigen-specific systemic humoral and cell-mediated immune responses, they are generally perceived as incapable of generating IgA responses or protective mucosal immunity. Nevertheless, currently licensed systemic vaccines do provide effective protection against mucosal pathogens such as influenza viruses and Streptococcus pneumoniae. However, whether systemic immunization induces protective mucosal immunity remains a controversial topic. Here we reviewed the current literature and discussed the potential of systemic routes of immunization for the induction of mucosal immunity.

  14. Chemotherapy induced intestinal mucositis; from bench to bed

    NARCIS (Netherlands)

    B.A.E. Koning, de (Barbara)

    2008-01-01

    textabstractPart 1 focuses primarily on the pathophysiology of mucositis, in order to gain more insight different experimental mouse models were used. Chapter 2 describes mucositis induced by high dose doxorubicin (DOX)- treatment. DOX is a frequently used cytostatic drug in childhood cancer,

  15. Minimally invasive treatment of oral ranula with a mucosal tunnel.

    Science.gov (United States)

    Jia, T; Xing, L; Zhu, F; Jin, X; Liu, L; Tao, J; Chen, Y; Gao, Z; Zhang, H

    2015-02-01

    We have developed a new method for minimally-invasive treatment of uncomplicated oral ranulas using a mucosal tunnel, and we report the clinical outcome. We constructed a mucosal tunnel for each of 35 patients who presented with an oral ranula, by making 2 parallel incisions across the top of the protruding ranula 2-3mm apart, and dissected the soft tissue along the incisions to its wall. The fluid was removed and the cavity irrigated with normal saline. The wall of the ranula was not treated. The first mucosal tunnel was made by suturing the base of the mucosal strip to the deepest part of the wall of the ranula. The mucosal base of the tunnel and the deepest part of the base of the ranula were fixed with absorbable sutures. The two external edges of the incisions were sutured together to form the second mucosal tunnel, and apposing sutures were inserted between the two parallel incisions to form two natural mucosal tunnels. The duration of follow-up ranged from 1 to 5 years. One patient was lost to follow-up and 34 patients were cured. Outcomes were satisfactory without relapse during the follow-up period and the patients were satisfied with the outcome. The mucosal tunnel is a safe, effective, simple, and minimally-invasive treatment for oral ranula.

  16. Chemotherapy induced intestinal mucositis; from bench to bed

    NARCIS (Netherlands)

    B.A.E. Koning, de (Barbara)

    2008-01-01

    textabstractPart 1 focuses primarily on the pathophysiology of mucositis, in order to gain more insight different experimental mouse models were used. Chapter 2 describes mucositis induced by high dose doxorubicin (DOX)- treatment. DOX is a frequently used cytostatic drug in childhood cancer,

  17. A Novel Peptide to Treat Oral Mucositis Blocks Endothelial and Epithelial Cell Apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Wu Xiaoyan; Chen Peili [Department of Medicine, University of Chicago, Chicago, Illinois (United States); Sonis, Stephen T. [Division of Oral Medicine, Brigham and Women' s Hospital, Boston, Massachusetts (United States); Biomodels, Watertown, Massachusetts (United States); Lingen, Mark W. [Department of Pathology, University of Chicago, Chicago, Illinois (United States); Berger, Ann [NephRx Corporation, Kalamazoo, Michigan (United States); Toback, F. Gary, E-mail: gtoback@medicine.bsd.uchicago.edu [Department of Medicine, University of Chicago, Chicago, Illinois (United States)

    2012-07-01

    Purpose: No effective agents currently exist to treat oral mucositis (OM) in patients receiving chemoradiation for the treatment of head-and-neck cancer. We identified a novel 21-amino acid peptide derived from antrum mucosal protein-18 that is cytoprotective, mitogenic, and motogenic in tissue culture and animal models of gastrointestinal epithelial cell injury. We examined whether administration of antrum mucosal protein peptide (AMP-p) could protect against and/or speed recovery from OM. Methods and Materials: OM was induced in established hamster models by a single dose of radiation, fractionated radiation, or fractionated radiation together with cisplatin to simulate conventional treatments of head-and-neck cancer. Results: Daily subcutaneous administration of AMP-p reduced the occurrence of ulceration and accelerated mucosal recovery in all three models. A delay in the onset of erythema after irradiation was observed, suggesting that a protective effect exists even before injury to mucosal epithelial cells occurs. To test this hypothesis, the effects of AMP-p on tumor necrosis factor-{alpha}-induced apoptosis were studied in an endothelial cell line (human dermal microvascular endothelial cells) as well as an epithelial cell line (human adult low-calcium, high-temperature keratinocytes; HaCaT) used to model the oral mucosa. AMP-p treatment, either before or after cell monolayers were exposed to tumor necrosis factor-{alpha}, protected against development of apoptosis in both cell types when assessed by annexin V and propidium iodide staining followed by flow cytometry or ligase-mediated polymerase chain reaction. Conclusions: These observations suggest that the ability of AMP-p to attenuate radiation-induced OM could be attributable, at least in part, to its antiapoptotic activity.

  18. Mucosal surface nodularity on upper gastrointestinal series (UGIS) : prospective analysis of its primary cause and prevalence of gastric malignancy

    Energy Technology Data Exchange (ETDEWEB)

    Park, Soo Youn; Kim, Sun Mi; Kim, Ah Young; Kim, Tae Kyoung; Kim, Pyo Nyun; Ha, Hyun Kwon [Univ. of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2001-10-01

    Mucosal surface nodularity was defined as present at UGIS when multiple nodular defects larger than 5 mm were scattered in the gastric mucosa in an area greater than 5 x 5 cm. The purpose of this study was to determine the primary causes of this radiographic finding and to assess the incidence of gastric malignancy in these patients. During a one-year period were prospectively collected among patients who underwent UGIS, data for 51 [aged 30-78 (mean, 51) years] above who met the criteria of mucosal surface nodularity. Whether or not this was present was decided by two radiologists who in reaching a consensus excluded the possibility of erosive gastritis, indicated by central barium collection in the nodular defects. The primary causes of mucosal nodularity and associated gastric pathologies were determined by the histopathological results obtained from the specimens after surgery (n=18) or endoscopic biopsy (n=33). Pathological examinations revealed that the primary causes of the mucosal nodularity in these 51 patients were intestinal metaplasia in 28 (54.9%), MALT lymphoma in seven (13.7%), early gastric cancer in six (11.8%), chronic gastritis in five (9.8%), low grade dysplasia in four (7.8%), and gastritis cystica profunda in one (2%). Gastric malignancy was present either in or outside the area of mucosal nodularity in 34 (66/7%) of the 51 (27 carcinomas and 7 MALT lymphomas). No different patterns of mucosal surface nodularity were noted between the groups of each disease entity. Mucosal surface nodularity is observed at UGIS in various gastric pathologies. Because of the high incidence of gastric malignancy in these patients, close follow-up or gastrofiberscopic biopsy is mandatory.

  19. Angiogenesis,Kaposi's Sarcoma and Kaposi's Sarcomaassociated Herpesvirus

    Institute of Scientific and Technical Information of China (English)

    Tao KANG; Feng-chun Ye; Shou-jiang gao; Lin-ding WANG

    2008-01-01

    Tumor angiogenesis is the uncontrolled growth of blood vessels in tumors,serving to supply nutrients and oxygen,and remove metabolic wastes.Kaposi's sarcoma (KS),a multifocal angioproliferative disorder characterized by spindle cell proliferation,neo-angiogenesis,inflammation,and edema,is associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV).Recent studies indicate that KSHV infection directly promotes angiogenesis and inflammation through an autocrine and paracrine mechanism by inducing pro-angiogenic and pro-inflammatory cytokines.Many of these cytokines are also expressed in KS lesions,implicating a direct role of KSI-IV in the pathogenesis of this malignancy.Several KSHV genes are involved in KSHV-induced angiogenesis.These studies have provided insights into the pathogenesis of KS,and identified potential therapeutic targets for this malignancy.

  20. Molecular targeting of angiogenesis for imaging and therapy

    Energy Technology Data Exchange (ETDEWEB)

    Brack, Simon S.; Neri, Dario [Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology Zurich (Switzerland); Dinkelborg, Ludger M. [Research Laboratories of Schering AG, Berlin (Germany)

    2004-09-01

    Angiogenesis, i.e. the proliferation of new blood vessels from pre-existing ones, is an underlying process in many human diseases, including cancer, blinding ocular disorders and rheumatoid arthritis. The ability to selectively target and interfere with neovascularisation would potentially be useful in the diagnosis and treatment of angiogenesis-related diseases. This review presents the authors' views on some of the most relevant markers of angiogenesis described to date, as well as on specific ligands which have been characterised in pre-clinical animal models and/or clinical studies. Furthermore, we present an overview on technologies which are likely to have an impact on the way molecular targeting of angiogenesis is performed in the future. (orig.)

  1. Tumor-induced remote ECM network orientation steers angiogenesis

    NARCIS (Netherlands)

    Balcioglu, H.E.; Water, van de B.; Danen, E.H.

    2016-01-01

    Tumor angiogenesis promotes tumor growth and metastasis. Here, we use automated sequential microprinting of tumor and endothelial cells in extracellular matrix (ECM) scaffolds to study its mechanical aspects. Quantitative reflection microscopy shows that tumor spheroids induce radial orientation of

  2. Development of the Relationship between Angiogenesis and Tumor Dormancy

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Tumor dormancy, a complex and still poorly understood phenomenon, has been defined by the long-term persistence of occult cancer cells during tumor progression. Recurrence and metastasis may occur just because of an activation of a small portion of the tumor cells. In our view, sustained angiogenesis is considered essential in triggering invasive tumor growth. Here we analyze the correlation between angiogenesis and tumor dormancy, the establishment of tumor dormancy models, the imaging strategies and the new biomarkers for dececting microscopic tumors before or during the angiogenic switch. It imperative to understand the role of angiogenesis in tumor dormancy, as this will accelerate the development of anti-angiogenesis techniques to induce dormancy and/or eradicate dormant disease.

  3. Prostanoids in tumor angiogenesis: therapeutic intervention beyond COX-2.

    Science.gov (United States)

    Salvado, M Dolores; Alfranca, Arántzazu; Haeggström, Jesper Z; Redondo, Juan Miguel

    2012-04-01

    Prostanoids regulate angiogenesis in carcinoma and chronic inflammatory disease progression. Although prostanoid biosynthetic enzymes and signaling have been extensively analyzed in inflammation, little is known about how prostanoids mediate tumor-induced angiogenesis. Targeted cyclooxygenase (COX)-2 inhibition in tumor, stromal and endothelial cells is an attractive antiangiogenic strategy; however, the associated cardiovascular side effects have led to the development of a new generation of nonsteroidal anti-inflammatory drugs (NSAIDs) acting downstream of COX. These agents target terminal prostanoid synthases and prostanoid receptors, which may also include several peroxisome proliferator-activated receptors (PPARs). Here, we discuss the role of prostanoids as modulators of tumor angiogenesis and how prostanoid metabolism reflects complex cell-cell crosstalk that determines tumor growth. Finally, we discuss the potential of new NSAIDs for the treatment of angiogenesis-dependent tumor development.

  4. Aspartame induces angiogenesis in vitro and in vivo models.

    Science.gov (United States)

    Yesildal, F; Aydin, F N; Deveci, S; Tekin, S; Aydin, I; Mammadov, R; Fermanli, O; Avcu, F; Acikel, C H; Ozgurtas, T

    2015-03-01

    Angiogenesis is the process of generating new blood vessels from preexisting vessels and is considered essential in many pathological conditions. The purpose of the present study is to evaluate the effect of aspartame on angiogenesis in vivo chick chorioallantoic membrane (CAM) and wound-healing models as well as in vitro 2,3-bis-2H-tetrazolium-5-carboxanilide (XTT) and tube formation assays. In CAM assay, aspartame increased angiogenesis in a concentration-dependent manner. Compared with the control group, aspartame has significantly increased vessel proliferation (p aspartame group had better healing than control group, and this was statistically significant at p aspartame on human umbilical vein endothelial cells on XTT assay in vitro, but it was not statistically significant; and there was no antiangiogenic effect of aspartame on tube formation assay in vitro. These results provide evidence that aspartame induces angiogenesis in vitro and in vivo; so regular use may have undesirable effect on susceptible cases.

  5. Effect of biomaterials on angiogenesis during vital pulp therapy

    National Research Council Canada - National Science Library

    SAGHIRI, Mohammad Ali; ASATOURIAN, Armen; GARCIA-GODOY, Franklin; SHEIBANI, Nader

    2016-01-01

    This review intended to provide an overview of the effects of dental materials, used in dentin-pulp complex and dental pulp regeneration, on angiogenesis processes during regenerative endodontic procedures...

  6. HIV and mucosal barrier interactions: consequences for transmission and pathogenesis.

    Science.gov (United States)

    Burgener, Adam; McGowan, Ian; Klatt, Nichole R

    2015-10-01

    The mucosal barrier plays an integral function in human health as it is the primary defense against pathogens, and provides a critical transition between the external environment and the human internal body. In the context of HIV infection, the most relevant mucosal surfaces include those of the gastrointestinal (GI) and genital tract compartments. Several components help maintain the effectiveness of this mucosal surface, including the physical anatomy of the barrier, cellular immunity, soluble factors, and interactions between the epithelial barrier and the local microenvironment, including mucus and host microbiota. Any defects in barrier integrity or function can rapidly lead to an increase in acquisition risk, or with established infection may result in increased pathogenesis, morbidities, or mortality. Indeed, a key feature to all aspects of HIV infection from transmission to pathogenesis is disruption and/or dysfunction of mucosal barriers. Herein, we will detail the host-pathogen relationship of HIV and mucosal barriers in both of these scenarios.

  7. Erythropoietin-induced proliferation of gastric mucosal cells

    Institute of Scientific and Technical Information of China (English)

    Kazuro Itoh; Masato Higuchi; Fumio Ishihata; Yushi Sudoh; Soichiro Miura; Yoshio Sawasaki; Kyoko Takeuchi; Shingo Kato; Nobuhiro Imai; Yoichiro Kato; Noriyuki Shibata; Makio Kobayashi; Yoshiyuki Moriguchi

    2006-01-01

    AIM: To analyze the localization of erythropoietin receptor on gastric specimens and characterize the effects of erythropoietin on the normal gastric epithelial proliferation using a porcine gastric epithelial cell culture model.METHODS: Erythropoietin receptor was detected by RT-PCR, Western blotting and immunohistochermistry.Growth stimulation effects of erythropoietin on cultured gastric mucosal cells were determined by ELISA using bromodeoxyuridine (BrdU).RESULTS: Erythropoietin receptor was detected on cultured porcine gastric mucosal epithelial cells.Erythropoietin receptor was also detected histochemically at the base of gastric mucosal epithelium. BrdU assay demonstrated a dose-dependent increase in growth potential of cultured porcine gastric mucosal epithelial cells by administration of erythropoietin, as well as these effects were inhibited by administration of antierythropoietin antibody (P< 0.01).CONCLUSION: These findings indicate that erythropoietin has a potential to proliferate gastric mucosal epithelium via erythropoietin receptor.

  8. Palifermin and Chlorhexidine Mouthwashes in Prevention of Chemotherapy-Induced Mucositis in Children with Acute Lymphocytic Leukemia: a Randomized Controlled Trial.

    Science.gov (United States)

    Gholizadeh, Narges; Mehdipoor, Masoumeh; Sajadi, Hasan; Moosavi, Mahdieh-Sadat

    2016-12-01

    Over the past three decades, significant improvements have been achieved in the survival of children with cancer. However, the considerable morbidity which occurs as a result of chemotherapy often restricts the treatment intensity. One of the important dose-limiting and costly adverse effects of cancer therapy is mucositis. Children with hematological malignancies are greatly at risk of developing mucositis. This study aimed to assess the effectiveness of palifermin in preventing mucositis in children with acute lymphocytic leukemia (ALL) who undergo chemotherapy. In this clinical trial, 90 children with ALL were randomized to receive chlorhexidine (n=45) or palifermin (n=45). One group received 60 μg/ kg/ day palifermin as an intravenous bolus once daily for 3 days before and 3 days after the chemotherapy. Chlorhexidine mouthwash was administered once daily for 3 days before and 3 days after the chemotherapy. The world health organization (WHO) oral toxicity scale was employed for grading the mucositis. The data were analyzed by using two-way ANOVA. The two groups were matched for age and gender. The study groups were significantly different in terms of mucositis grading (P values after 1 and 2 week therapy were 0.00). Palifermin decreased the incidence and severity of chemotherapy-induced mucositis. Palifermin reduces the oral mucositis in children with ALL. Several mechanisms of action are suggested for keratinocyte growth factor (such as palifermin) including promotion of cell proliferation and cytoprotection, restraining the apoptosis, and changing the cytokine profile.

  9. Semaphorin 6A regulates angiogenesis by modulating VEGF signaling

    OpenAIRE

    Segarra, Marta; Ohnuki, Hidetaka; Maric, Dragan; Salvucci, Ombretta; Hou, Xu; Kumar, Anil; Li, Xuri; Tosato, Giovanna

    2012-01-01

    Formation of new vessels during development and in the mature mammal generally proceeds through angiogenesis. Although a variety of molecules and signaling pathways are known to underlie endothelial cell sprouting and remodeling during angiogenesis, many aspects of this complex process remain unexplained. Here we show that the transmembrane semaphorin6A (Sema6A) is expressed in endothelial cells, and regulates endothelial cell survival and growth by modulating the expression and signaling of ...

  10. Design and application of peptide nanofibers for modulating angiogenesis

    OpenAIRE

    Şentürk, Berna

    2016-01-01

    Cataloged from PDF version of article. Thesis (Ph.D.): Bilkent University, Department of Materials Science and Nanotechnology, İhsan Doğramacı Bilkent University, 2016. Includes bibliographical references (leaves 168-181). Angiogenesis is important in many diseases, such as diabetic wound healing, cancer and corneal neovascularization. Angiogenesis can be induced or inhibited by complex biological systems. Mimicking the complexity in natural systems requires smart supramolecular arch...

  11. Mechanism and its regulation of tumor-induced angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Manoj Kumar Gupta; Ren-Yi Qin

    2003-01-01

    Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into cancerous growths, supplying nutrients and oxygen and removing waste products. The process of angiogenesis plays an important role in many physiological and pathological conditions. Solid tumors depend on angiogenesis for growth and metastasis in a hostile environment. In the prevascular phase, the tumor is rarely larger than 2 to 3 mm3 and may contain a million or more cells. Up to this size, tumor cells can obtain the necessary oxygen and nutrient supplies required for growth and survival by simple passive diffusion. The properties of tumors to release and induce several angiogenic and antiangiogenic factors which play crucial roles in regulating endothelial cell (EC) proliferation, migration, apoptosis or survival, cell-cell and cell-matrix adhesion through different intracellular signaling are thought to be the essential mechanisms during tumor-induced angiogenesis. Tumor angiogenesis actually starts with tumor cells releasing molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage growth of new blood vessels. In this review, we focus the mechanisms of tumor-induced angiogenesis, with an emphasis on the regulatory role of several angiogenic and anti-angiogenic agents during the angiogenic process in tumors. Advances in understanding the mechanisms of tumor angiogenesis have led to the development of several most effective antiangiogenic and anti-metastatic therapeutic agents and also have provided several techniques for the regulation of cancer's angiogenic switch. The suggestion is made that standard cytotoxic chemotherapy and angiogenesis inhibitors used in combination may produce complementary therapeutic benefits in the treatment of cancer.

  12. Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1α and Notch1 in head neck squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Wei-Ming Wang

    Full Text Available Angiogenesis, a marker of cancer development, affects response to radiotherapy sensibility. This preclinical study aims to understand the receptor tyrosine kinase-mediated angiogenesis in head neck squamous cell carcinoma (HNSCC. The receptor tyrosine kinase activity in a transgenic mouse model of HNSCC was assessed. The anti-tumorigenetic and anti-angiogenetic effects of cetuximab-induced epidermal growth factor receptor (EGFR inhibition were investigated in xenograft and transgenic mouse models of HNSCC. The signaling transduction of Notch1 and hypoxia-inducible factor-1α (HIF-1α was also analyzed. EGFR was overexpressed and activated in the Tgfbr1/Pten deletion (2cKO mouse model of HNSCC. Cetuximab significantly delayed tumor onset by reducing tumor angiogenesis. This drug exerted similar effects on heterotopic xenograft tumors. In the human HNSCC tissue array, increased EGFR expression correlated with increased HIF-1α and micro vessel density. Cetuximab inhibited tumor-induced angiogenesis in vitro and in vivo by significantly downregulating HIF-1α and Notch1. EGFR is involved in the tumor angiogenesis of HNSCC via the HIF-1α and Notch1 pathways. Therefore, targeting EGFR by suppressing hypoxia- and Notch-induced angiogenesis may benefit HNSCC therapy.

  13. Differential modulation of angiogenesis by erythropoiesis-stimulating agents in a mouse model of ischaemic retinopathy.

    Directory of Open Access Journals (Sweden)

    Carmel M McVicar

    Full Text Available BACKGROUND: Erythropoiesis stimulating agents (ESAs are widely used to treat anaemia but concerns exist about their potential to promote pathological angiogenesis in some clinical scenarios. In the current study we have assessed the angiogenic potential of three ESAs; epoetin delta, darbepoetin alfa and epoetin beta using in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDINGS: The epoetins induced angiogenesis in human microvascular endothelial cells at high doses, although darbepoetin alfa was pro-angiogenic at low-doses (1-20 IU/ml. ESA-induced angiogenesis was VEGF-mediated. In a mouse model of ischaemia-induced retinopathy, all ESAs induced generation of reticulocytes but only epoetin beta exacerbated pathological (pre-retinal neovascularisation in comparison to controls (p<0.05. Only epoetin delta induced a significant revascularisation response which enhanced normality of the vasculature (p<0.05. This was associated with mobilisation of haematopoietic stem cells and their localisation to the retinal vasculature. Darbepoetin alfa also increased the number of active microglia in the ischaemic retina relative to other ESAs (p<0.05. Darbepoetin alfa induced retinal TNFalpha and VEGF mRNA expression which were up to 4 fold higher than with epoetin delta (p<0.001. CONCLUSIONS: This study has implications for treatment of patients as there are clear differences in the angiogenic potential of the different ESAs.

  14. Immunohistochemical evaluation of mast cells and angiogenesis in oral squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Sharma Bhushan

    2010-01-01

    Full Text Available Objectives : Angiogenesis is a complex event mediated by angiogenic factors released from cancer cells and immune cells. It has been reported to be associated with progression, aggressiveness and metastases of various malignant tumors including oral squamous cell carcinoma (OSCC. Similarly, mast cells have also been reported to play a role in tumor progression and metastases by promoting angiogenesis. The present study aims at comparison of microvascular density (MVD and mast cell density (MCD in normal oral mucosa (NM and among various grades of OSCC. Materials and Methods : MVD was assessed immunohistochemically using anti-Factor VIII related von Willebrand factor, and MCD using anti-mast cell tryptase in a study sample of 30 cases of OSCC and 10 cases of clinically normal oral mucosa. Results : The mast cells in normal oral mucosa and oral squamous cell carcinoma strongly expressed mast cell tryptase. The density of mast cells and micro vessels were significantly higher in OSCC compared to normal oral mucosa. The MCD and MVD were higher in moderately differentiated OSCC than in well differentiated OSCC ( P > 0.05 and normal oral mucosa ( P < 0.05. Pearson′s correlation revealed a positive correlation between MCD and MVD ( r=0.33; P=0.077. Conclusion : These findings indicate that mast cells may play a role in up regulation of tumor angiogenesis in OSCC probably through mast cell tryptase.

  15. Low-intensity vibration improves angiogenesis and wound healing in diabetic mice.

    Science.gov (United States)

    Weinheimer-Haus, Eileen M; Judex, Stefan; Ennis, William J; Koh, Timothy J

    2014-01-01

    Chronic wounds represent a significant health problem, especially in diabetic patients. In the current study, we investigated a novel therapeutic approach to wound healing--whole body low-intensity vibration (LIV). LIV is anabolic for bone, by stimulating the release of growth factors, and modulating stem cell proliferation and differentiation. We hypothesized that LIV improves the delayed wound healing in diabetic mice by promoting a pro-healing wound environment. Diabetic db/db mice received excisional cutaneous wounds and were subjected to LIV (0.4 g at 45 Hz) for 30 min/d or a non-vibrated sham treatment (controls). Wound tissue was collected at 7 and 15 d post-wounding and wound healing, angiogenesis, growth factor levels and wound cell phenotypes were assessed. LIV increased angiogenesis and granulation tissue formation at day 7, and accelerated wound closure and re-epithelialization over days 7 and 15. LIV also reduced neutrophil accumulation and increased macrophage accumulation. In addition, LIV increased expression of pro-healing growth factors and chemokines (insulin-like growth factor-1, vascular endothelial growth factor and monocyte chemotactic protein-1) in wounds. Despite no evidence of a change in the phenotype of CD11b+ macrophages in wounds, LIV resulted in trends towards a less inflammatory phenotype in the CD11b- cells. Our findings indicate that LIV may exert beneficial effects on wound healing by enhancing angiogenesis and granulation tissue formation, and these changes are associated with increases in pro-angiogenic growth factors.

  16. Essential Role of Interleukin-12 in Angiogenesis in Type 2 Diabetes.

    Science.gov (United States)

    Ali, Maha; Mali, Vishal; Haddox, Samuel; AbdelGhany, Soad M; El-Deek, Sahar E M; Abulfadl, Atif; Matrougui, Khalid; Belmadani, Souad

    2017-08-21

    Recently interleukin-12 (IL-12) emerged as a critical player in type 2 diabetes complications. We previously reported that ischemia-induced angiogenesis is compromised in type 2 diabetic mice. In this study, we determined that IL-12 disruption rescued angiogenesis and arteriogenesis in type 2 diabetic mice. To induce type 2 diabetes, Wild type (WT); p40IL-12(-/-) (p40-/-) and p35IL-12(-/-) (p35-/-) mice were fed high-fat diet (HFD) for 12 weeks. Body weight, glucose test tolerance, and insulin test tolerance were assessed. After 12 weeks of HFD, femoral artery was ligated and blood flow recovery was measured every week for four weeks. WT, p40(-/-) and p35(-/-) mice fed HFD become obese after 12 weeks and exhibit glucose intolerance and insulin resistance. Blood flow recovery was fully restored in 2 to 3 weeks after femoral artery ligation in all group of mice fed normal diet. However, after 12 weeks of HFD, blood flow recovery was compromised in WT mice while it was fully recovered in p40(-/-) and p35(-/-). The mechanism of blood flow recovery involves an increase in capillaries/ arterioles density, eNOS/Akt/VEGFR2 signaling, and a reduction in oxidative stress and inflammation. The disruption of IL-12 promotes angiogenesis and increases blood flow recovery in obese type 2 diabetic mice by eNOS/Akt/VEGFR2/Oxidative stress-inflammation dependent mechanism. Copyright © 2017. Published by Elsevier Inc.

  17. Quantiifcation of angiogenesis by CT perfusion imaging in liver tumor of rabbit

    Institute of Scientific and Technical Information of China (English)

    Hui-Jie Jiang; Zai-Ren Zhang; Bao-Zhong Shen; Yong Wan; Hong Guo; Jin-Ping Li

    2009-01-01

    BACKGROUND: Tumor angiogenesis is essential for primary and metastatic tumor growth. Computed tomography perfusion (CTP) is a new imaging method, made possible by the recent development of fast CT scanners and improved data analysis techniques, which allows measurement of the physiologic and hemodynamic properties of tissue vasculature. This study aimed to evaluate CTP in the quantiifcation of angiogenesis and to assess the relationship between tissue perfusion parameters and microvascular density (MVD) and vascular endothelial growth factor (VEGF), attempting to detect the physiologic properties of angiogenesis. METHODS: Sixteen rabbits with VX2 liver tumors underwent multi-slice CT perfusion (MSCTP) on day 14 after tumor inoculation. CTP parameters included hepatic blood lfow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic artery index (HAI), hepatic artery perfusion (HAP), and hepatic portal perfusion (HPP). The border of the tumor was stained with CD34 and VEGF immunohistochemical stains, and MVD was measured by anti-CD34. Then, CTP parameters were determined whether they were correlated with MVD and VEGF using Pearson’s correlation coefifcient. RESULTS: The positive expression of MVD was different in the center and border of the tumor (P0.05). CONCLUSIONS: Signiifcant correlations were found between perfusion parameters and MVD and VEGF. Therefore, MSCTP can be used to evaluate tumor angiogenesisin vivo.

  18. Evaluation of tumor angiogenesis in patients with non-small cell lung carcinoma

    Directory of Open Access Journals (Sweden)

    Suciu B.A.

    2015-05-01

    Full Text Available The aim of this study is to evaluate tumor angiogenesis in patients with non-small cell lung carcinoma. A total of 20 patients with pulmonary adenocarinoma have been included in the study. In order to evaluate tumor angiogenesis we studied the importance of CD34 expression. Evaluation of vascular density was performed with a semiautomated method using the dedicated software called ImageJ. We introduced in our study 20 patients with lung adenocarcinoma. We were able to identify tumor angiogenesis in 19 cases (95%. Immunolabeling of CD34 positive endothelial cells provided a good overview of tumor vascularization. Immunohistochemical staining of CD34 positive endothelium cells provided a good basis for tumor vascularity assessment, and also an excellent contrast for computer assisted morphometric measurements. Also we studied the intensity of the immunohistochemical staining of CD34 in the tumoral cells. We obtained the following results: a minor expression in 4 cases (20%, a moderate expression in 9 cases (45% and an intense expression in 6 cases (30%. The histological type of adenocarcinomas influences the architecture and branching of the vessels. The density of newly developed vessels is higher in patients with papillary pulmonary adenocarcinomas, which may indicate a possible relationship between the histological type and development of vascular supply.

  19. H-Ras Oncogene Expression and Angiogenesis in Experimental Liver Cirrhosis

    Directory of Open Access Journals (Sweden)

    Gülsüm Özlem Elpek

    2013-01-01

    Full Text Available Background. Proto-oncogenes, particularly ras, may not only affect cell proliferation but also contribute to angiogenesis by influencing both proangiogenic and antiangiogenic mediators. The aim of this study was to investigate whether any relationship exists between ras expression and angiogenesis during diethylnitrosamine- (DEN- induced experimental liver fibrosis. Materials and Methods. Liver cirrhosis was induced in rats by intraperitoneal injections of DEN. The animals were sacrificed 2 weeks after the last administrations and a hepatectomy was performed. Masson’s trichrome staining was used in the evaluation of the extent of liver fibrosis. The vascular density in portal and periportal areas was assessed by determining the count of CD34 labeled vessel sections. For quantitative evaluation of H-ras expression, in each section positive and negative cells were counted. Results. In fibrotic group H-ras expression was higher than that in nonfibrotic group and was more widespread in cirrhotic livers. Friedman’s test showed that there was a significant correlation between H-ras expression and VD (P<0.01. Conclusion. The results of this descriptive study reveal that H-ras expression gradually increases according to the severity of fibrosis and strongly correlates with angiogenesis.

  20. Absorption and tolerability of fentanyl buccal soluble film (FBSF in patients with cancer in the presence of oral mucositis

    Directory of Open Access Journals (Sweden)

    Finn AL

    2011-09-01

    Full Text Available Andrew L Finn1, WD Charlie Hill2, Ignacio Tagarro3, Larry N Gever41Product Development, BioDelivery Sciences International, Inc, Raleigh, NC, USA; 2Co-founding partner, InVisions Consultants, LLC, San Antonio, TX, USA; 3Marketing Centre CIP CNS, Meda Pharma S.A.U., Madrid, Spain; 4Medical Affairs, Meda Pharmaceuticals, Inc, Somerset, NJ, USAPurpose: Fentanyl buccal soluble film (FBSF consists of a small, bilayered, water-soluble polymer film that adheres to the buccal mucosa and rapidly delivers fentanyl into the systemic circulation. The purpose of this study was to evaluate the absorption of fentanyl from FBSF in patients with cancer, with and without grade 1 oral mucositis, and to assess the tolerability of FBSF in this patient population.Patients and methods: In an open-label, single-dose study, two groups of opioid-naive patients (ie, not receiving opioids on a regular basis with cancer received a 200 µg dose of FBSF. Patients in cohort I (n = 7 had grade 1 mucositis, and patients in cohort II (n = 7 were age- and gender-matched controls without mucositis. The FBSF dose was placed on the area of mucositis in cohort I and on a matching location in cohort II. Blood samples were collected up to 4 hours after administration, and safety assessments were made throughout the study.Results: Peak plasma concentration and area under the concentration–time curve from time 0 to 4 hours post-dose values of patients in the grade 1 mucositis cohort were lower than those observed in patients without mucositis. There was no application site irritation reported in any patient, regardless of mucositis status. Mild somnolence was reported by two patients with mucositis. There were no deaths or serious adverse events reported in this study.Conclusion: The results of this study indicate that application of FBSF to an area of grade 1 mucositis does not result in increased fentanyl exposure or irritation of the mucosa. The 200 µg dose of FBSF was well

  1. Lentivirus-Mediated Nox4 shRNA Invasion and Angiogenesis and Enhances Radiosensitivity in Human Glioblastoma

    Directory of Open Access Journals (Sweden)

    Yongsheng Li

    2014-01-01

    Full Text Available Radioresistance remains a significant therapeutic obstacle in glioblastoma. Reactive oxygen species (ROS are associated with multiple cellular functions such as cell proliferation and apoptosis. Nox4 NADPH oxidase is abundantly expressed and has proven to be a major source of ROS production in glioblastoma. Here we investigated the effects of Nox4 on GBM tumor cell invasion, angiogenesis, and radiosensitivity. A lentiviral shRNA vector was utilized to stably knockdown Nox4 in U87MG and U251 glioblastoma cells. ROS production was measured by flow cytometry using the fluorescent probe DCFH-DA. Radiosensitivity was evaluated by clonogenic assay and survival curve was generated. Cell proliferation activity was assessed by a cell counting proliferation assay and invasion/migration potential by Matrigel invasion assay. Tube-like structure formation assay was used to evaluate angiogenesis ability in vitro and VEGF expression was assessed by MTT assay. Nox4 knockdown reduced ROS production significantly and suppressed glioblastoma cells proliferation and invasion and tumor associated angiogenesis and increased their radiosensitivity in vitro. Our results indicate that Nox4 may play a crucial role in tumor invasion, angiogenesis, and radioresistance in glioblastoma. Inhibition of Nox4 by lentivirus-mediated shRNA could be a strategy to overcome radioresistance and then improve its therapeutic efficacy for glioblastoma.

  2. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients.

    NARCIS (Netherlands)

    Saunders, D.P.; Epstein, J.B.; Elad, S.; Allemano, J.; Bossi, P.; Wetering, M.D. van de; Rao, N.G.; Potting, C.M.J.; Cheng, K.K.; Freidank, A.; Brennan, M.T.; Bowen, J.; Dennis, K.; Lalla, R.V.

    2013-01-01

    PURPOSE: The aim of this project was to develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis (OM) in cancer patients. METHODS: A systematic review of the available literature was

  3. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients.

    NARCIS (Netherlands)

    Saunders, D.P.; Epstein, J.B.; Elad, S.; Allemano, J.; Bossi, P.; Wetering, M.D. van de; Rao, N.G.; Potting, C.M.J.; Cheng, K.K.; Freidank, A.; Brennan, M.T.; Bowen, J.; Dennis, K.; Lalla, R.V.

    2013-01-01

    PURPOSE: The aim of this project was to develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis (OM) in cancer patients. METHODS: A systematic review of the available literature was con

  4. Accelerated coronary angiogenesis by vegfr1-knockout endocardial cells.

    Directory of Open Access Journals (Sweden)

    Zheng Zhang

    Full Text Available During mouse heart development, ventricular endocardial cells give rise to the coronary arteries by angiogenesis. Myocardially-derived vascular endothelial growth factor-a (Vegfa regulates embryonic coronary angiogenesis through vascular endothelial growth factor-receptor 2 (Vegfr2 expressed in the endocardium. In this study, we investigated the role of endocardially-produced soluble Vegfr1 (sVegfr1 in the coronary angiogenesis. We deleted sVegfr1 in the endocardium of the developing mouse heart and found that this deletion resulted in a precocious formation of coronary plexuses. Using an ex vivo coronary angiogenesis assay, we showed that the Vegfr1-null ventricular endocardial cells underwent excessive angiogenesis and generated extensive endothelial tubular networks. We also revealed by qPCR analysis that expression of genes involved in the Vegf-Notch pathway was augmented in the Vegfr1-null hearts. We further showed that inhibition of Notch signaling blocked the formation of coronary plexuses by the ventricular endocardial cells. These results establish that Vegfr1 produced in the endocardium negatively regulates embryonic coronary angiogenesis, possibly by limiting the Vegf-Notch signaling.

  5. Emerging Roles of ADAMTSs in Angiogenesis and Cancer

    Directory of Open Access Journals (Sweden)

    Ruowen Ge

    2012-11-01

    Full Text Available A Disintegrin-like And Metalloproteinase with ThromboSpondin motifs—ADAMTSs—are a multi-domain, secreted, extracellular zinc metalloproteinase family with 19 members in humans. These extracellular metalloproteinases are known to cleave a wide range of substrates in the extracellular matrix. They have been implicated in various physiological processes, such as extracellular matrix turnover, melanoblast development, interdigital web regression, blood coagulation, ovulation, etc. ADAMTSs are also critical in pathological processes such as arthritis, atherosclerosis, cancer, angiogenesis, wound healing, etc. In the past few years, there has been an explosion of reports concerning the role of ADAMTS family members in angiogenesis and cancer. To date, 10 out of the 19 members have been demonstrated to be involved in regulating angiogenesis and/or cancer. The mechanism involved in their regulation of angiogenesis or cancer differs among different members. Both angiogenesis-dependent and -independent regulation of cancer have been reported. This review summarizes our current understanding on the roles of ADAMTS in angiogenesis and cancer and highlights their implications in cancer therapeutic development.

  6. Adipose tissue angiogenesis: impact on obesity and type-2 diabetes.

    Science.gov (United States)

    Corvera, Silvia; Gealekman, Olga

    2014-03-01

    The growth and function of tissues are critically dependent on their vascularization. Adipose tissue is capable of expanding many-fold during adulthood, therefore requiring the formation of new vasculature to supply growing and proliferating adipocytes. The expansion of the vasculature in adipose tissue occurs through angiogenesis, where new blood vessels develop from those pre-existing within the tissue. Inappropriate angiogenesis may underlie adipose tissue dysfunction in obesity, which in turn increases type-2 diabetes risk. In addition, genetic and developmental factors involved in vascular patterning may define the size and expandability of diverse adipose tissue depots, which are also associated with type-2 diabetes risk. Moreover, the adipose tissue vasculature appears to be the niche for pre-adipocyte precursors, and factors that affect angiogenesis may directly impact the generation of new adipocytes. Here we review recent advances on the basic mechanisms of angiogenesis, and on the role of angiogenesis in adipose tissue development and obesity. A substantial amount of data points to a deficit in adipose tissue angiogenesis as a contributing factor to insulin resistance and metabolic disease in obesity. These emerging findings support the concept of the adipose tissue vasculature as a source of new targets for metabolic disease therapies. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

  7. Role of ROBO4 Signalling in Developmental and Pathological Angiogenesis

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    Suresh Singh Yadav

    2014-01-01

    Full Text Available Transmembrane roundabout receptor family members (ROBO1–ROBO4 principally orchestrate the neuronal guidance mechanism of the nervous system. Secreted glycoprotein SLITs are the most appreciated ligands for ROBOs. Recently identified ROBO4 is the key mediator of SLIT-ROBO mediated developmental and pathological angiogenesis. Although SLIT2 has been shown to interact with ROBO4 as ligand, it remains an open question whether this protein is the physiologic partner of ROBO4. The purpose of this review is to summarise how reliable SLIT2 as ligand for ROBO4 is, if not what the other possible mechanisms demonstrated till date for ROBO4 mediated developmental and pathological angiogenesis are. We conclude that ROBO4 is expressed specially in vascular endothelial cells and maintains the vascular integrity via either SLIT2 dependent or SLIT2 independent manner. On the contrary, it promotes the pathological angiogenesis by involving different signalling arm(s/unknown ligand(s. This review explores the interactions SLIT2/ROBO1, SLIT2/ROBO1–ROBO4, ROBO1/ROBO4, and ROBO4/UNC5B which can be promising and potential therapeutic targets for developmental angiogenesis defects and pathological angiogenesis. Finally we have reviewed the ROBO4 signalling pathways and made an effort to elaborate the insight of this signalling as therapeutic target of pathological angiogenesis.

  8. Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

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    Zeng, Yi; Zhang, Le; Hu, Zhiping

    2016-01-01

    Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

  9. Micro-CT imaging of tumor angiogenesis: quantitative measures describing micromorphology and vascularization.

    Science.gov (United States)

    Ehling, Josef; Theek, Benjamin; Gremse, Felix; Baetke, Sarah; Möckel, Diana; Maynard, Juliana; Ricketts, Sally-Ann; Grüll, Holger; Neeman, Michal; Knuechel, Ruth; Lederle, Wiltrud; Kiessling, Fabian; Lammers, Twan

    2014-02-01

    Angiogenesis is a hallmark of cancer, and its noninvasive visualization and quantification are key factors for facilitating translational anticancer research. Using four tumor models characterized by different degrees of aggressiveness and angiogenesis, we show that the combination of functional in vivo and anatomical ex vivo X-ray micro-computed tomography (μCT) allows highly accurate quantification of relative blood volume (rBV) and highly detailed three-dimensional analysis of the vascular network in tumors. Depending on the tumor model, rBV values determined using in vivo μCT ranged from 2.6% to 6.0%, and corresponds well with the values assessed using IHC. Using ultra-high-resolution ex vivo μCT, blood vessels as small as 3.4 μm and vessel branches up to the seventh order could be visualized, enabling a highly detailed and quantitative analysis of the three-dimensional micromorphology of tumor vessels. Microvascular parameters such as vessel size and vessel branching correlated very well with tumor aggressiveness and angiogenesis. In rapidly growing and highly angiogenic A431 tumors, the majority of vessels were small and branched only once or twice, whereas in slowly growing A549 tumors, the vessels were much larger and branched four to seven times. Thus, we consider that combining highly accurate functional with highly detailed anatomical μCT is a useful tool for facilitating high-throughput, quantitative, and translational (anti-) angiogenesis and antiangiogenesis research.

  10. Calycosin promotes angiogenesis involving estrogen receptor and mitogen-activated protein kinase (MAPK signaling pathway in zebrafish and HUVEC.

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    Jing Yan Tang

    Full Text Available BACKGROUND: Angiogenesis plays an important role in a wide range of physiological processes, and many diseases are associated with the dysregulation of angiogenesis. Radix Astragali is a Chinese medicinal herb commonly used for treating cardiovascular disorders and has been shown to possess angiogenic effect in previous studies but its active constituent and underlying mechanism remain unclear. The present study investigates the angiogenic effects of calycosin, a major isoflavonoid isolated from Radix Astragali, in vitro and in vivo. METHODOLOGY: Tg(fli1:EGFP and Tg(fli1:nEGFP transgenic zebrafish embryos were treated with different concentrations of calycosin (10, 30, 100 microM from 72 hpf to 96 hpf prior morphological observation and angiogenesis phenotypes assessment. Zebrafish embryos were exposed to calycosin (10, 100 microM from 72 hpf to 78 hpf before gene-expression analysis. The effects of VEGFR tyrosine kinase inhibitor on calycosin-induced angiogenesis were studied using 72 hpf Tg(fli1:EGFP and Tg(fli1:nEGFP zebrafish embryos. The pro-angiogenic effects of calycosin were compared with raloxifene and tamoxifen in 72 hpf Tg(fli1:EGFP zebrafish embryos. The binding affinities of calycosin to estrogen receptors (ERs were evaluated by cell-free and cell-based estrogen receptor binding assays. Human umbilical vein endothelial cell cultures (HUVEC were pretreated with different concentrations of calycosin (3, 10, 30, 100 microM for 48 h then tested for cell viability and tube formation. The role of MAPK signaling in calycosin-induced angiogenesis was evaluated using western blotting. CONCLUSION: Calycosin was shown to induce angiogenesis in human umbilical vein endothelial cell cultures (HUVEC in vitro and zebrafish embryos in vivo via the up-regulation of vascular endothelial growth factor (VEGF, VEGFR1 and VEGFR2 mRNA expression. It was demonstrated that calycosin acted similar to other selective estrogen receptor modulators (SERMs, such

  11. Mucosal immunity to pathogenic intestinal bacteria.

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    Perez-Lopez, Araceli; Behnsen, Judith; Nuccio, Sean-Paul; Raffatellu, Manuela

    2016-03-01

    The intestinal mucosa is a particularly dynamic environment in which the host constantly interacts with trillions of commensal microorganisms, known as the microbiota, and periodically interacts with pathogens of diverse nature. In this Review, we discuss how mucosal immunity is controlled in response to enteric bacterial pathogens, with a focus on the species that cause morbidity and mortality in humans. We explain how the microbiota can shape the immune response to pathogenic bacteria, and we detail innate and adaptive immune mechanisms that drive protective immunity against these pathogens. The vast diversity of the microbiota, pathogens and immune responses encountered in the intestines precludes discussion of all of the relevant players in this Review. Instead, we aim to provide a representative overview of how the intestinal immune system responds to pathogenic bacteria.

  12. Mucosal Immunity and acute viral gastroenteritis.

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    Rose, Markus A

    2014-01-01

    Acute gastroenteritis is a major killer of the very young worldwide. Rotavirus is the most common intestinal virus, causing acute gastroenteritis and extra-intestinal complications especially in young and chronically ill subjects. As early as 1991, the WHO recommended as high priority the development of a vaccine against rotavirus, the major pathogen causing enteric infections. Since the introduction of rotavirus vaccines for infant immunization programmes in different parts of the world in 2006, vaccination against rotavirus has resulted in substantial declines in severe gastroenteritis. The oral rotavirus vaccines RotaTeq(®) and Rotarix(®) are excellent examples for their unique features and principles of mucosal immunization. We elaborate on rotavirus immunity and the success of rotavirus vaccination and aspects also beyond infants' acute gastroenteritis.

  13. Oral mucosal involvement in visceral leishmaniasis

    Institute of Scientific and Technical Information of China (English)

    Sunny Garg; Richik Tripathi; Kamlakar Tripathi

    2013-01-01

    Leishmaniasis affects both the visceral and cutaneous tissues in body.OralMucosal involvement in leishmaniasis is rare and is often overlooked.We present a case17 year old boy from the north east region ofBihar who has a history of visceral leishmaniasis one year back, came to the department of oral surgery for treatment of persistent oral ulcers.Oral examination did not give any diagnostic information while systemic examination revealed enlarged spleen and low grade fever.Patient was screened for leishmaniasis by rK39 based immunochromatographic strip test which came to be positive.Biopsy of the ulcer as well as splenic and bone marrow aspirate confirmed the presence of leishmaniasis.Patient was administeredAmphotericinB for20 days following which significant clinical and haematological improvement followed.

  14. Molecular imaging of angiogenesis with SPECT

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    Dijkgraaf, Ingrid; Boerman, Otto C. [Radboud University Nijmegen Medical Center, Department of Nuclear Medicine, P.O. Box 9101, HB Nijmegen (Netherlands)

    2010-08-15

    Single-photon emission computed tomography (SPECT) and position emission tomography (PET) are the two main imaging modalities in nuclear medicine. SPECT imaging is more widely available than PET imaging and the radionuclides used for SPECT are easier to prepare and usually have a longer half-life than those used for PET. In addition, SPECT is a less expensive technique than PET. Commonly used gamma emitters are: {sup 99m}Tc (E{sub max} 141 keV, T{sub 1/2} 6.02 h), {sup 123}I (E{sub max} 529 keV, T{sub 1/2} 13.0 h) and {sup 111}In (E{sub max} 245 keV, T{sub 1/2} 67.2 h). Compared to clinical SPECT, PET has a higher spatial resolution and the possibility to more accurately estimate the in vivo concentration of a tracer. In preclinical imaging, the situation is quite different. The resolution of microSPECT cameras (<0.5 mm) is higher than that of microPET cameras (>1.5 mm). In this report, studies on new radiolabelled tracers for SPECT imaging of angiogenesis in tumours are reviewed. (orig.)

  15. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

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    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically. Diffuse HIF-1α was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p < 0.001. Conclusion: HIF-1α and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1α in endometrial carcinogenesis.

  16. VASCULAR REMODELING IN HYPERTENSION: ANGIOGENESIS FEATURES

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    L. A. Haisheva

    2014-07-01

    Full Text Available Aim — cross-sectional study of changes in various segments of the vascular bed in arterial hypertension (AH, defining the role of inducers and inhibitors of angiogenesis in these processes.Materials and methods. The study included 99 patients with arterial hypertension of I–II degree, average age of 63.2 ± 2.6 years, diseaseduration 9.2 ± 7.2 years.Results. It was found that patients with arterial hypertension have disorders in all segments of vascular bed: endothelial dysfunction (highvWF, microcirculatory disorders, and increased pulse wave velocity (PWV of elastic-type vessels. The level of angioginesis factors doesnot depend on such parameters as gender, age, body mass index. Smoking and duration of hypertension influence on vascular endothelialgrowth factor raise and endostatin levels are higher in patients with family history of cardiovascular diseases. Duration of disease is directlycorrelated with microcirculatory disorders and the PWV, correlation between microcirculatory disorders and pulse wave velocity indicatetheir common processes.

  17. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.

    Science.gov (United States)

    Iozzo, Renato V; Sanderson, Ralph D

    2011-05-01

    Proteoglycans, key molecular effectors of cell surface and pericellular microenvironments, perform multiple functions in cancer and angiogenesis by virtue of their polyhedric nature and their ability to interact with both ligands and receptors that regulate neoplastic growth and neovascularization. Some proteoglycans such as perlecan, have pro- and anti-angiogenic activities, whereas other proteoglycans, such as syndecans and glypicans, can also directly affect cancer growth by modulating key signalling pathways. The bioactivity of these proteoglycans is further modulated by several classes of enzymes within the tumour microenvironment: (i) sheddases that cleave transmembrane or cell-associated syndecans and glypicans, (ii) various proteinases that cleave the protein core of pericellular proteoglycans and (iii) heparanases and endosulfatases which modify the structure and bioactivity of various heparan sulphate proteoglycans and their bound growth factors. In contrast, some of the small leucine-rich proteoglycans, such as decorin and lumican, act as tumour repressors by physically antagonizing receptor tyrosine kinases including the epidermal growth factor and the Met receptors or integrin receptors thereby evoking anti-survival and pro-apoptotic pathways. In this review we will critically assess the expanding repertoire of molecular interactions attributed to various proteoglycans and will discuss novel proteoglycan functions modulating cancer progression, invasion and metastasis and how these factors regulate the tumour microenvironment.

  18. Role of polyamines in gastrointestinal mucosal growth

    Institute of Scientific and Technical Information of China (English)

    Zhao Xiang Bian; Jian Hua Wang

    2000-01-01

    The polyamines [putrescine (PU), spermidine (SPD) and spermine (SPM)] are ubiquitous polycationiccompounds found in all prokaryotic and eukaryotic cells, are essentially involved in a variety of regulatorysteps during normal, adaptive, and malignant cell proliferation. Nearly four decades investigation about thepolyamines contributed to the synthesis and decomposition of polyamines and the active and passive enzymeswhich regulate them at different levels. This review focuses on the sources and homeostasis of intracellularpolyamines, the transport and role of the polyamines in the growth of the gastrointestinal mucosa and theirpossible mechanism. We tried to point out the gaps remaining in the story and give a working hypothesis forthe role of polyamines in gastrointestinal mucosal growth. We propose in the hypothesis that polyamine is a“key”to unlock the “door”of cell proliferation. How many “doors” between the “polyamine key” and the“real start” of proliferation? The polyamine might be the only key for cell proliferation. Another possibilityis that polyamine is the first key and its “unlocking-effect” resulting in getting another key for the next doorin the proliferation chain, for example, proto-oncogenes. To decide whether polyamine is an intermediatestep or just only one step of cell proliferation, the possible way is to keep polyamine to be a stimulus and finda way to deprive the function of proto-oncogene protein (or other possible gene expression product) to checkthe effect on the cell proliferation. Another important question is how polyamine can trigger the synthesis ofDNA in virtual. Arabinose operon model may give us some ideas to investigate about that. And furthermore,it is necessary to pay attention to the relationship between polyamine and other cell proliferation regulator,like growth factor, chalone, cAMP, cGMP, etc. Further studies are needed to investigate the mechanism ofpolyamine acted on the gastrointestinal mucosal

  19. Prevalence based epigrammatic study of oral cancer and other mucosal disorders in elderly patients visiting dental institution of Northern India

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    Basavaraj T Bhagawati

    2013-01-01

    Full Text Available Objective : This report provides the descriptive information about the oral health among the elderly population. The objective is to assess the association of age, medical status, recent use of dental services, habits and dentures with that of oral cancer, and other mucosal disorders. Materials and Methods: Data from the interviews and clinical examination of 285 persons aged above 60 years were obtained. Patients were divided into three groups of 75 patients each with age group of 60-65 years, 66-70 years, and 71 years above, respectively. Patients were examined and questioned regarding the oral health complaints and the presence of cancer and other mucosal disorders. Results: There are no statistically significant differentiates between the three groups in terms of oral health complaint, medical status. The patients in all the three groups gave the history of consumption of betel quid/alcohol/smoking. About 22.1% patients in Group A, 18.9% in Group B, and 37.9% in Group C had associated mucosal lesion like oral cancer, growth, pigmentation, red lesion, ulcer, and white lesions. Association between deleterious habits and oral mucosal lesions was seen in 12, 15, and 16 patients in Groups A, B, and C, respectively. Conclusion: The oral cancer and oral mucosal lesions were associated with oral habits and the use of faulty dentures. Age had minimal influence but coexistence of multiple conditions might further complicate the oral health.

  20. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis.

    Science.gov (United States)

    van der Velden, Walter J F M; Herbers, Alexandra H E; Netea, Mihai G; Blijlevens, Nicole M A

    2014-11-01

    Infection remains one of the most prominent complications after cytotoxic treatment for cancer. The connection between neutropenia and both infections and fever has long been designated as 'febrile neutropenia', but treatment with antimicrobial agents and haematopoietic growth factors has failed to significantly reduce its incidence. Moreover, emerging antimicrobial resistance is becoming a concern that necessitates the judicious use of available antimicrobial agents. In addition to neutropenia, patients who receive cytotoxic therapy experience mucosal barrier injury (MBI) or 'mucositis'. MBI creates a port-de-entrée for resident micro-organisms to cause blood stream infections and contributes directly to the occurrence of fever by disrupting the highly regulated host-microbe interactions, which, even in the absence of an infection, can result in strong inflammatory reactions. Indeed, MBI has been shown to be a pivotal factor in the occurrence of inflammatory complications after cytotoxic therapy. Hence, the concept 'febrile neutropenia' alone may no longer suffice and a new concept 'febrile mucositis' should be recognized as the two are at least complementary. This review we summarizes the existing evidence for both paradigms and proposes new therapeutic approaches to tackle the perturbed host-microbe interactions arising from cytotoxic therapy-induced tissue damage in order to reduce fever in neutropenic patients with cancer.

  1. Mucosal patterns of Helicobacter pylori-related gastritis without atrophy in the gastric corpus using standard endoscopy

    Institute of Scientific and Technical Information of China (English)

    Shwu-Tzy; Wu; Chien-Hua; Chen; Yeh-Huang; Hung; Tsung-Hsun; Yang; Vun-Siew; Pang; Yung-Hsiang; Yeh

    2010-01-01

    AIM:To identify the mucosal patterns of Helicobacter pylori(H.pylori )-related gastritis in the gastric corpus using standard endoscopy and to evaluate their reproducibility.METHODS:A total of 112 consecutive patients underwent upper gastrointestinal endoscopy.The endoscopists classified the endoscopic findings into 4 patterns.In the second part of the study,90 images were shown to 3 endoscopists in order to evaluate the inter-observer and intra-observer variability in image assessment.RESULTS:The mucosal p...

  2. Mucosal exposure to cockroach extract induces allergic sensitization and allergic airway inflammation

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    Arizmendi Narcy G

    2011-12-01

    Full Text Available Abstract Background Allergic sensitization to aeroallergens develops in response to mucosal exposure to these allergens. Allergic sensitization may lead to the development of asthma, which is characterized by chronic airway inflammation. The objective of this study is to describe in detail a model of mucosal exposure to cockroach allergens in the absence of an exogenous adjuvant. Methods Cockroach extract (CE was administered to mice intranasally (i.n. daily for 5 days, and 5 days later mice were challenged with CE for 4 consecutive days. A second group received CE i.n. for 3 weeks. Airway hyperresponsiveness (AHR was assessed 24 h after the last allergen exposure. Allergic airway inflammation was assessed by BAL and lung histology 48 h after the last allergen exposure. Antigen-specific antibodies were assessed in serum. Lungs were excised from mice from measurement of cytokines and chemokines in whole lung lysate. Results Mucosal exposure of Balb/c mice to cockroach extract induced airway eosinophilic inflammation, AHR and cockroach-specific IgG1; however, AHR to methacholine was absent in the long term group. Lung histology showed patchy, multicentric damage with inflammatory infiltrates at the airways in both groups. Lungs from mice from the short term group showed increased IL-4, CCL11, CXCL1 and CCL2 protein levels. IL4 and CXCL1 were also increased in the BAL of cockroach-sensitized mice in the short-term protocol. Conclusions Mucosal exposure to cockroach extract in the absence of adjuvant induces allergic airway sensitization characterized by AHR, the presence of Th2 cytokines in the lung and eosinophils in the airways.

  3. Treatment of urethral strictures in balanitis xerotica obliterans (BXO using circular buccal mucosal meatoplasy: Experience of 15 cases

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    Abdulmuttalip Simsek

    2014-03-01

    Full Text Available Objectives: Balanitis xerotica obliterans (BXO related strictures involving the external urethral meatus. We reviewed our result with the use of circular mucosal graft in the reconstruction of strictures. Methods: Between March 1997 and January 2012, 15 patients underwent circular buccal mucosal urethroplasy for BXO related anterior urethral strictures. Urethral catheter was removed within 2 weeks. Follow-up included patient symptoms assessment, cosmetic outcome and uroflowmetry. Results: Median follow-up was 20.5 months (range 4 to 96. Mean postoperative peak urinary flow rate obtained 1 month after catheter removal was 22.4 ml per second. All patients had a normal meatus and none had recurrent stricture, chordee or erectile dysfunction. A functional and cosmetic outcome was achieved in 100% of the patients. Conclusions: Circular mucosal graft technique for treatment of meatal strictures is an efficient method for the restoration of a functional and cosmetic penis.

  4. Modeling mucosal candidiasis in larval zebrafish by swimbladder injection.

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    Gratacap, Remi L; Bergeron, Audrey C; Wheeler, Robert T

    2014-01-01

    Early defense against mucosal pathogens consists of both an epithelial barrier and innate immune cells. The immunocompetency of both, and their intercommunication, are paramount for the protection against infections. The interactions of epithelial and innate immune cells with a pathogen are best investigated in vivo, where complex behavior unfolds over time and space. However, existing models do not allow for easy spatio-temporal imaging of the battle with pathogens at the mucosal level. The model developed here creates a mucosal infection by direct injection of the fungal pathogen, Candida albicans, into the swimbladder of juvenile zebrafish. The resulting infection enables high-resolution imaging of epithelial and innate immune cell behavior throughout the development of mucosal disease. The versatility of this method allows for interrogation of the host to probe the detailed sequence of immune events leading to phagocyte recruitment and to examine the roles of particular cell types and molecular pathways in protection. In addition, the behavior of the pathogen as a function of immune attack can be imaged simultaneously by using fluorescent protein-expressing C. albicans. Increased spatial resolution of the host-pathogen interaction is also possible using the described rapid swimbladder dissection technique. The mucosal infection model described here is straightforward and highly reproducible, making it a valuable tool for the study of mucosal candidiasis. This system may also be broadly translatable to other mucosal pathogens such as mycobacterial, bacterial or viral microbes that normally infect through epithelial surfaces.

  5. Roles of Mucosal Immunity against Mycobacterium tuberculosis Infection.

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    Li, Wu; Deng, Guangcun; Li, Min; Liu, Xiaoming; Wang, Yujiong

    2012-01-01

    Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is one of the world's leading infectious causes of morbidity and mortality. As a mucosal-transmitted pathogen, Mtb infects humans and animals mainly through the mucosal tissue of the respiratory tract. Apart from providing a physical barrier against the invasion of pathogen, the major function of the respiratory mucosa may be to serve as the inductive sites to initiate mucosal immune responses and sequentially provide the first line of defense for the host to defend against this pathogen. A large body of studies in the animals and humans have demonstrated that the mucosal immune system, rather than the systemic immune system, plays fundamental roles in the host's defense against Mtb infection. Therefore, the development of new vaccines and novel delivery routes capable of directly inducing respiratory mucosal immunity is emphasized for achieving enhanced protection from Mtb infection. In this paper, we outline the current state of knowledge regarding the mucosal immunity against Mtb infection, including the development of TB vaccines, and respiratory delivery routes to enhance mucosal immunity are discussed.

  6. Roles of Mucosal Immunity against Mycobacterium tuberculosis Infection

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    Wu Li

    2012-01-01

    Full Text Available Mycobacterium tuberculosis (Mtb, the causative agent of tuberculosis (TB, is one of the world's leading infectious causes of morbidity and mortality. As a mucosal-transmitted pathogen, Mtb infects humans and animals mainly through the mucosal tissue of the respiratory tract. Apart from providing a physical barrier against the invasion of pathogen, the major function of the respiratory mucosa may be to serve as the inductive sites to initiate mucosal immune responses and sequentially provide the first line of defense for the host to defend against this pathogen. A large body of studies in the animals and humans have demonstrated that the mucosal immune system, rather than the systemic immune system, plays fundamental roles in the host’s defense against Mtb infection. Therefore, the development of new vaccines and novel delivery routes capable of directly inducing respiratory mucosal immunity is emphasized for achieving enhanced protection from Mtb infection. In this paper, we outline the current state of knowledge regarding the mucosal immunity against Mtb infection, including the development of TB vaccines, and respiratory delivery routes to enhance mucosal immunity are discussed.

  7. HIV infection and specific mucosal immunity: workshop 4B.

    Science.gov (United States)

    Challacombe, S J; Fidel, P L; Tugizov, S; Tao, L; Wahl, S M

    2011-04-01

    Most HIV infections are transmitted across mucosal epithelium. An area of fundamental importance is understanding the role of innate and specific mucosal immunity in susceptibility or protection against HIV infection, as well as the effect of HIV infection on mucosal immunity, which leads to increased susceptibility to bacterial, fungal, and viral infections of oral and other mucosae. This workshop attempted to address 5 basic issues-namely, HIV acquisition across mucosal surfaces, innate and adaptive immunity in HIV resistance, antiviral activity of breast milk as a model mucosal fluid, neutralizing immunoglobulin A antibodies against HIV, and progress toward a mucosal vaccine against HIV. The workshop attendants agreed that progress had been made in each area covered, with much recent information. However, these advances revealed how little work had been performed on stratified squamous epithelium compared with columnar epithelium, and the attendants identified several important biological questions that had not been addressed. It is increasingly clear that innate immunity has an important biological role, although basic understanding of the mechanisms of normal homeostasis is still being investigated. Application of the emerging knowledge was lacking with regard to homeostatic mucosal immunity to HIV and its role in changing this homeostasis. With regard to breast milk, a series of studies have demonstrated the differences between transmitters and nontransmitters, although whether these findings could be generalized to other secretions such as saliva was less clear. Important progress toward an oral mucosal HIV vaccine has been made, demonstrating proof of principle for administering vaccine candidates into oral lymphoid tissues to trigger anti-HIV local and systemic immune responses. Similarly, experimental data emphasized the central role of neutralizing antibodies to prevent HIV infection via mucosal routes.

  8. Macroscopic extent of gastric mucosal atrophy: increased risk factor for esophageal squamous cell carcinoma in Japan

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    Kobayashi Noritoshi

    2009-05-01

    Full Text Available Abstract Background We aimed to estimate whether the macroscopic extent of gastric mucosal atrophy is associated with a risk for esophageal squamous cell carcinoma using a case-control study in Japanese subjects, a population known to have a high prevalence of CagA-positive H. pylori infection. Methods Two hundred and fifty-three patients who were diagnosed as having esophageal squamous cell carcinoma, and 253 sex- and age-matched controls were enrolled in the present study. The macroscopic extent of gastric mucosal atrophy was evaluated based on the Kimura and Takemoto Classification. A conditional logistic regression model with adjustment for potential confounding factors was used to assess the associations. Results Body gastritis, defined endoscopically, was independently associated with an increased risk for esophageal squamous cell carcinoma. Conclusion Our findings suggest that macroscopic body gastritis may be a risk factor for esophageal squamous cell carcinoma in Japan. Further studies are needed to confirm these findings.

  9. Increased angiogenesis in portal hypertensive rats: role of nitric oxide.

    Science.gov (United States)

    Sumanovski, L T; Battegay, E; Stumm, M; van der Kooij, M; Sieber, C C

    1999-04-01

    Systemic and especially splanchnic arterial vasodilation accompany chronic portal hypertension. Different soluble mediators causing this vasodilation have been proposed, the strongest evidence being for nitric oxide (NO). No data exist if structural vascular changes may partly account for this vasodilatory state. Here, we developed a new in vivo quantitative angiogenesis assay in the abdominal cavity and determined if: 1) portal hypertensive rats show increased angiogenesis; and 2) angiogenesis is altered by inhibiting NO formation. Portal hypertension was induced by partial portal vein ligation (PVL). Sham-operated rats served as controls (CON). During the index operation (day 0), a teflon ring filled with collagen I (Vitrogen 100) was sutured in the mesenteric cavity. After 16 days, rings were explanted, embedded in paraffin, and ingrown vessels counted using a morphometry system. The role of NO was tested by adding an antagonist of NO formation (Nomega-nitro-L-arginine [NNA], 3.3 mg/kg/d) into the drinking water. The mean number of ingrown vessels per implant was significantly higher in PVL rats compared with CON rats, i.e., 1,453 +/- 187 versus 888 +/- 116, respectively (P <.05; N = 5 per group). NNA significantly (P <.01) inhibited angiogenesis in PVL (202 +/- 124; N = 5) and in CON (174 +/- 25; N = 6) rats, respectively. In contrast, the beta-adrenergic blocker, propranolol, did not prevent angiogenesis either in PVL or CON rats in a separate set of experiments (data not shown). The conclusions drawn from this study are that: 1) rats with portal hypertension show increased angiogenesis; and 2) inhibition of NO formation significantly prevents angiogenesis in both PVL and CON rats. Therefore, splanchnic vasodilation in chronic portal hypertension may also be a result of structural changes.

  10. Opioids Inhibit Angiogenesis in a Chorioallantoic Membrane Model.

    Science.gov (United States)

    Karaman, Haktan; Tufek, Adnan; Karaman, Evren; Tokgoz, Orhan

    2017-02-01

    Angiogenesis is an important characteristic of cancer. Switching from the avascular phase to the vascular phase is a necessary process for tumor growth. Therefore, research in cancer treatment has focused on angiogenesis as a drug target. Despite the widespread use of opioids to treat pain in patients with cancer, little is known about the effect of these drugs on vascular endothelium and angiogenesis. We aimed to investigate the efficacies of morphine, codeine, and tramadol in 3 different concentrations on angiogenesis in hens' eggs. This is a prospective, observational, controlled, in-vivo animal study. Single academic medical center. This study was conducted on the chorioallantoic membrane (CAM) of fertilized hens' eggs. The efficacies of morphine, codeine, and tramadol in 3 different concentrations were evaluated on angiogenesis in a total of 165 hens' eggs. Statistically significant differences were found between drug-free agarose used as a negative control and concentrations of morphine of 10 µM and 1 µM, a concentration of tramadol of 10 µM, and concentrations of codeine of 10 µM and 1 µM. Concentrations of morphine of 10 µM and 1 µM showed strong antiangiogenic effects. While codeine had strong antiangiogenic effects at high concentrations, at 0.1 µM it was shown to have weak antiangiogenic effects. However, tramadol at a concentration of 10 µM had only weak antiangiogenic effects. This is just a CAM model study. In this study, we tested the effects of 3 different opioid drugs on angiogenesis in 3 different concentrations, and we observed that morphine was a good anti-angiogenic agent, but tramadol and codeine only had anti-angiogenic effects at high doses.Key Words: Morphine, codeine, tramadol, opioid, bevacizumab, chorioallantoic membrane (CAM), angiogenesis.

  11. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

    Science.gov (United States)

    Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

    2003-01-01

    Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.

  12. Copper and angiogenesis: unravelling a relationship key to cancer progression.

    Science.gov (United States)

    Finney, Lydia; Vogt, Stefan; Fukai, Tohru; Glesne, David

    2009-01-01

    1. Angiogenesis, the formation of new capillaries from existing vasculature, is a critical process in normal physiology as well as several physiopathologies. A desire to curb the supportive role angiogenesis plays in the development and metastasis of cancers has driven exploration into anti-angiogenic strategies as cancer therapeutics. Key to this, angiogenesis additionally displays an exquisite sensitivity to bioavailable copper. Depletion of copper has been shown to inhibit angiogenesis in a wide variety of cancer cell and xenograft systems. Several clinical trials using copper chelation as either an adjuvant or primary therapy have been conducted. Yet, the biological basis for the sensitivity of angiogenesis remains unclear. Numerous molecules important to angiogenesis regulation have been shown to be either directly or indirectly influenced by copper, yet a clear probative answer to the connection remains elusive. 2. Measurements of copper in biological systems have historically relied on techniques that, although demonstrably powerful, provide little or no information as to the spatial distribution of metals in a cellular context. Therefore, several new approaches have been developed to image copper in a biological context. One such approach relies on synchrotron-derived X-rays from third-generation synchrotrons and the technique of high resolution X-ray fluorescence microprobe (XFM) analysis. 3. Recent applications of XFM approaches to the role of copper in regulating angiogenesis have provided unique insight into the connection between copper and cellular behaviour. Using XFM, copper has been shown to be highly spatially regulated, as it is translocated from perinuclear areas of the cell towards the tips of extending filopodia and across the cell membrane into the extracellular space during angiogenic processes. Such findings may explain the heightened sensitivity of this cellular process to this transition metal and set a new paradigm for the kinds of

  13. Angiogenesis-regulating microRNAs and Ischemic Stroke.

    Science.gov (United States)

    Yin, Ke-Jie; Hamblin, Milton; Chen, Y Eugene

    2015-01-01

    Stroke is a leading cause of death and disability worldwide. Ischemic stroke is the dominant subtype of stroke and results from focal cerebral ischemia due to occlusion of major cerebral arteries. Thus, the restoration or improvement of reduced regional cerebral blood supply in a timely manner is very critical for improving stroke outcomes and poststroke functional recovery. The recovery from ischemic stroke largely relies on appropriate restoration of blood flow via angiogenesis. Newly formed vessels would allow increased cerebral blood flow, thus increasing the amount of oxygen and nutrients delivered to affected brain tissue. Angiogenesis is strictly controlled by many key angiogenic factors in the central nervous system, and these molecules have been well-documented to play an important role in the development of angiogenesis in response to various pathological conditions. Promoting angiogenesis via various approaches that target angiogenic factors appears to be a useful treatment for experimental ischemic stroke. Most recently, microRNAs (miRs) have been identified as negative regulators of gene expression in a post-transcriptional manner. Accumulating studies have demonstrated that miRs are essential determinants of vascular endothelial cell biology/angiogenesis as well as contributors to stroke pathogenesis. In this review, we summarize the knowledge of stroke-associated angiogenic modulators, as well as the role and molecular mechanisms of stroke-associated miRs with a focus on angiogenesis-regulating miRs. Moreover, we further discuss their potential impact on miR-based therapeutics in stroke through targeting and enhancing post-ischemic angiogenesis.

  14. Organoarsenic Roxarsone Promotes Angiogenesis In Vivo.

    Science.gov (United States)

    Zhang, Yumei; Wang, Yujing; Lu, Qianqian; Xin, Wenfang; Cui, Weibo; Zhu, Jiaqiao

    2016-04-01

    Roxarsone, an organoarsenic feed additive, is widely used worldwide to promote animal growth. It has been found to exhibit a higher angiogenic index than As(III) at lower concentrations and to promote angiogenic phenotype in human endothelial cell in vitro. Little research has focused on the potential angiogenic effect of roxarsone in vitro or in vivo. Here, we investigated the pro-angiogenic effect of roxarsone in vivo. The effects of 0.1-10.0 μM roxarsone were tested in the rat endothelial cell Matrigel plug assay, chicken chorioallantoic membrane (CAM) model and MCF-7 cell xenograft tumour model; 10 ng/mL vascular endothelial growth factor (VEGF) was used as a positive control and PBS as a negative control. Roxarsone significantly increased the volume, weight and haemoglobin content of the Matrigel plugs compared to PBS group (p roxarsone exerted the most significant effects. H&E staining and CD31 immunochemistry revealed obviously more new vessels or capillary-like structures in the plugs of the roxarsone and VEGF groups. Roxarsone significantly increased the numbers of primary/secondary vessels and area of vessels in the CAM assay and obviously increased tumour weight and volume in the xenograft model compared to PBS (p roxarsone groups, with less necrosis apparent in the VEGF-treated tumours. The growth of endothelial cells and VEGF level was obviously affected at blockade of VEGF and its receptor Flt-1/Flk-1 by SU5416 or its antibody in vitro. This study demonstrates roxarsone promotes angiogenesis in vivo, and a VEGF/VEGFR mechanism may be involved.

  15. Anatomical and microstructural imaging of angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kiessling, Fabian [University of Aachen (RWTH), Experimental Molecular Imaging, Aachen (Germany); Razansky, Daniel [Technical University of Munich and Helmholtz Center Munich, Institute for Biological and Medical Imaging, Munich (Germany); Alves, Frauke [University Medical Center, Department of Haematology and Oncology, Goettingen (Germany); Max-Planck-Institute for Experimental Medicine, Department of Molecular Biology of Neuronal Signals, Goettingen (Germany)

    2010-08-15

    This article reviews and discusses different options for visualizing the microarchitecture of vessels ex vivo and in vivo with respect to reliability, practicability and availability. The investigation of angiogenesis by standard histological methods, like microvessel density counts, is limited since the three-dimensional (3-D) architecture and the functionality of vessels cannot be considered properly. Coregistration of immunostained images of vessels may be performed but is time consuming and often not sufficiently accurate. Confocal fluorescence microscopy is an alternative, but only enables 3-D stacks of less than 500 nm in thickness. Multiphoton microscopy and other advanced technologies, such as optical coherence tomography and optical frequency domain imaging, provide a deeper view into tissues and allow for in vivo imaging of microvessels, which is a precondition for longitudinal studies. Besides these microscopic techniques, the vascularization in larger tissue samples can be investigated using corrosion casts in combination with scanning electron microscopy, or microcomputed tomography ({mu}CT). Furthermore, recent improvements in {mu}CT technology open up new perspectives for in vivo scans with high resolution and tolerable X-ray doses. Also 3-D contrast-enhanced high-frequency ultrasound has been shown to be sensitive for angiogenic vessels and even distinguishing between mature and immature vessels appears feasible. Microvessel architecture can also be visualized by MRI. Here, T1-weighted angiography techniques after injection of blood pool contrast agents appear preferable. Optoacoustic tomographic imaging has more recently shown promise for high-resolution in vivo mapping of the microvasculature in rodents using intrinsic haemoglobin-based contrast and exogenous contrast agents. (orig.)

  16. The effect of three mouthwashes on radiation-induced oral mucositis in patients with head and neck malignancies: A randomized control trial

    Directory of Open Access Journals (Sweden)

    Madan Kumar P

    2008-01-01

    Full Text Available Aims: The present study was done to assess the effect of three alcohol-free mouthwashes on radiation-induced oral mucositis in patients with head and neck malignancies. Materials and Methods: Eighty patients with head and neck malignancies, scheduled to undergo curative radiotherapy, were randomly assigned to receive one of the three alcohol-free test mouthwashes (0.12% chlorhexidine, 1% povidone-iodine, or salt/soda or a control. The patients were instructed to rinse with 10 ml of the mouthwash, twice a day, for a period of 6 weeks. Mucositis was assessed at baseline and at weekly intervals during radiation therapy, using the World Health Organization criteria for grading of mucositis. The baseline demography of the four groups was matched for age, sex, stage of cancer, and whether the patient had cancer of oral or extraoral regions. A post hoc test for repeated measures was used to find the difference of mean mucositis scores between the groups at various week intervals. Results: Among the 76 patients who completed the study, patients in the povidone-iodine group had significantly lower mucositis scores when compared to the control group from the first week of radiotherapy. Their scores were also significantly lower when compared to the salt/soda and chlorhexidine groups from the fourth and fifth week, respectively, after radiotherapy. Conclusions: This study demonstrates that use of alcohol-free povidone-iodine mouthwash can reduce the severity and delay the onset of oral mucositis due to antineoplastic radiotherapy.

  17. A randomized, double-blind, placebo-controlled study of rebamipide for gastric mucosal injury taking aspirin with or without clopidogrel.

    Science.gov (United States)

    Tozawa, Katsuyuki; Oshima, Tadayuki; Okugawa, Takuya; Ogawa, Tomohiro; Ohda, Yoshio; Tomita, Toshihiko; Hida, Nobuyuki; Fukui, Hirokazu; Hori, Kazutoshi; Watari, Jiro; Nakamura, Shiro; Miwa, Hiroto

    2014-08-01

    Antithrombotic drugs, such as low-dose aspirin (LDA) and clopidogrel, can cause upper gastrointestinal complications. The goal of the present study was to investigate whether a mucosal-protective agent, rebamipide, could prevent gastric mucosal injuries induced by LDA with or without clopidogrel in healthy subjects. A randomized, double-blind, placebo-controlled trial was performed with 32 healthy male volunteers. Subjects were randomly assigned to a 14-day course of one of the following regimens: group A, placebo (tid) + LDA; group B, rebamipide (100 mg tid) + LDA (100 mg once-daily); group C, placebo + LDA + clopidogrel (75 mg once-daily); or group D, rebamipide + LDA + clopidogrel. The grade of gastric mucosal injuries was evaluated by esophagogastroduodenoscopy before and after dosing (on day 0 and day 14), and the grade of gastric mucosal injury was assessed according to the modified Lanza score. Subjective symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS). A rapid urease test was performed on day 0, and blood tests were performed on day 0 and day 14. Rebamipide significantly inhibited gastric mucosal injury induced by LDA alone or by LDA plus clopidogrel when compared with placebo in healthy subjects. GSRS score and hemoglobin level were not significantly different among the four groups. Rebamipide is useful for the primary prevention of gastric mucosal injury induced by LDA alone or by LDA plus clopidogrel in healthy subjects.

  18. Angiogenesis related genes NOS3, CD14, MMP3 and IL4R are associated to VEGF gene expression and circulating levels in healthy adults

    OpenAIRE

    Saleh, Abdelsalam; Stathopoulou, Maria G.; Dadé, Sébastien; Ndiaye, Ndeye Coumba; Azimi-Nezhad, Mohsen; Murray, Helena; Masson, Christine; Lamont, John; Fitzgerald, Peter; Visvikis-Siest, Sophie

    2015-01-01

    Background Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. The aim was to assess the genetic connections between the angiogenesis-related NOS3, CD14, MMP3, IL4R, IL4 genes and VEGF expression and plasma levels. Methods The associations between VEGF plasma levels with the polymorphisms of NOS3, CD14, MMP3, IL4R, and IL4 were assessed in 403 healthy unrelated adults. The epistatic and environmental interactions were explored, including four VEGF-related polymorphisms...

  19. Measurement of Mucosal Thickness in Denture-bearing Area of Edentulous Mandible

    Directory of Open Access Journals (Sweden)

    Jian Dong

    2015-01-01

    Full Text Available Background: The thickness of the alveolar mucosa influences the probability of the occurrence of denture-induced irritations. Thick denture-supporting tissues offer relief from mucosal tenderness and ulcers; however, the uniformity of the thickness across the entire mandibular alveolar mucosa cannot be accurately determined in edentulous patients. This study aimed to assess the mucosal thickness of the denture-bearing area in the edentulous mandible. Methods: Twenty-seven edentulous patients underwent cone-beam computed tomography scanning, wherein the patients wore a record base to retract soft tissues away from the alveolar mucosa. The measured regions were the central incisor (IC, lateral incisor (IL, canine (Ca, first premolar (P1, second premolar (P2, first molar (M1, and second molar (M2 regions. The thickness was measured in the alveolar ridge crest (T, buccal (B1-B4, and lingual (L1-L4 alveolar ridge mucosa. The average thickness of the mucosa at buccal sides (B and lingual sides (L were also assessed. Results: The differences in the mucosal thickness between the left and right sides were not significant. In the Ca-M2 regions, T was the thickest, and L3 was the thinnest of all the measured points in the same regions. L was significantly less than B in posterior regions (P < 0.01. On the other hand, M2 at L4 was thinnest of all the measured regions from Ca to M2 (P < 0.01, and was thicker than IC, IL, P1, and P2 at B2. Conclusions: Since the mucosal thickness of denture-bearing area in the edentulous mandible is not uniform; the tissue surface of the denture base or custom tray should be selectively relieved, which may reduce the risk of denture-induced irritations.

  20. Subclinical mucosal inflammation in diarrhea-predominant irritable bowel syndrome (IBS) in a tropical setting.

    Science.gov (United States)

    De Silva, Arjuna Priyadarsin; Nandasiri, Shanika Dulanjalee; Hewavisenthi, Janaki; Manamperi, Aresha; Ariyasinghe, Madurangi Prasadi; Dassanayake, Anuradha Supun; Jewell, Derek P; de Silva, Hithanadura Janaka

    2012-06-01

    There is evidence for low-grade inflammation in the pathophysiology of post-infectious irritable bowel syndrome (IBS). We assessed the degree of subclinical intestinal mucosal inflammation in diarrhea-predominant IBS (IBS-D) in a tropical setting. In a prospective study over 1 year, we investigated 49 patients with IBS-D (cases; median age 34 years (range 18-59); M:F 36:13), diagnosed on Rome III criteria. 14 individuals with a family history of colon cancer (median age 46.5 years (range 23-56); M:F 6:8) were selected as controls. Stools of cases and controls were tested for calprotectin. During colonoileoscopy, serial biopsies were obtained. Mucosal mast cells, neutrophils, eosinophils and lymphocytes/plasma cell infiltrate were quantified. Tissue expression of IL-8 and IL-10 was assessed in biopsies by semi-quantitative RT-PCR. A history suggestive of an episode of infectious diarrhea (ID) was present in 16/49 cases and 0/14 controls (p = 0.013). In cases, there were significantly more mucosal mast cells in the ileum and all segments of colon and significantly more eosinophils in the cecum. Tissue expression of IL-8 was significantly higher and IL-10 significantly lower in cases compared with controls (target/standard cDNA ratio, median (range) IL-8: 1.25 (0.75-2) vs. 0.85 (0.63-1.3), p < 0.0001, Mann-Whitney U test; IL-10: 0.33 (0-0.63) vs. 0.55 (0.5-0.7), p < 0.0001). There was a significant inverse correlation between IL-8 and IL-10 expression (Pearson correlation, (-) 0.509; p < 0.01). There was evidence of subclinical intestinal mucosal inflammation in patients with IBS-D. The finding of increased eosinophils is novel, and may be of special relevance to IBS-D in the tropics.

  1. Measurement of Mucosal Thickness in Denture-bearing Area of Edentulous Mandible

    Institute of Scientific and Technical Information of China (English)

    Jian Dong; Fei-Yu Zhang; Guang-Hui Wu; Wei Zhang; Jian Yin

    2015-01-01

    Background:The thickness of the alveolar mucosa influences the probability of the occurrence of denture-induced irritations.Thick denture-supporting tissues offer relief from mucosal tenderness and ulcers; however,the uniformity of the thickness across the entire mandibular alveolar mucosa cannot be accurately determined in edentulous patients.This study aimed to assess the mucosal thickness of the denture-bearing area in the edentulous mandible.Methods:Twenty-seven edentulous patients underwent cone-beam computed tomography scanning,wherein the patients wore a record base to retract soft tissues away from the alveolar mucosa.The measured regions were the central incisor (IC),lateral incisor (IL),canine (Ca),first premolar (P 1),second premolar (P2),first molar (M1),and second molar (M2) regions.The thickness was measured in the alveolar ridge crest (T),buccal (B 1-B4),and lingual (L1-L4) alveolar ridge mucosa.The average thickness of the mucosa at buccal sides (B) and lingual sides (L) were also assessed.Results:The differences in the mucosal thickness between the left and right sides were not significant.In the Ca-M2 regions,T was the thickest,and L3 was the thinnest of all the measured points in the same regions.L was significantly less than B in posterior regions (P < 0.01).On the other hand,M2 at L4 was thinnest of all the measured regions from Ca to M2 (P < 0.01),and was thicker than IC,IL,P1,and P2 at B2.Conclusions:Since the mucosal thickness of denture-bearing area in the edentulous mandible is not uniform; the tissue surface of the denture base or custom tray should be selectively relieved,which may reduce the risk of denture-induced irritations.

  2. Helicobacter pylori coinfection is a confounder, modulating mucosal inflammation in oral submucous fibrosis

    Directory of Open Access Journals (Sweden)

    Rajendran R

    2009-01-01

    Full Text Available The oral cavity has been considered a potential reservoir for Helicobacter pylori (H pylori , from where the organism causes recurrent gastric infections. Aim: With this case-control study we tried to evaluate the role of H pylori in the etiology of mucosal inflammation, a condition that compounds the morbid state associated with oral submucous fibrosis (OSF. Materials and Methods : Subjects ( n = 150 were selected following institutional regulations on sample collection and grouped into test cases and positive and negative controls based on the presence of mucosal fibrosis and inflammation. The negative controls had none of the clinical signs. All patients underwent an oral examination as well as tests to assess oral hygiene/periodontal disease status; a rapid urease test (RUT of plaque samples was also done to estimate the H pylori bacterial load. We used univariate and mutivariate logistic regression for statistical analysis of the data and calculated the odds ratios to assess the risk posed by the different variables. Results : The RUT results differed significantly between the groups, reflecting the variations in the bacterial loads in each category. The test was positive in 52% in the positive controls (where nonspecific inflammation of oral mucosa was seen unassociated with fibrosis, in 46% of the test cases, and in 18% of the negative controls (healthy volunteers (χ2 = 13.887; P < 0.01. A positive correlation was seen between the oral hygiene/periodontal disease indices and RUT reactivity in all the three groups. Conclusions: The contribution of the H pylori in dental plaque to mucosal inflammation and periodontal disease was significant. Logistic regression analysis showed gastrointestinal disease and poor oral hygiene as being the greatest risk factors for bacterial colonization, irrespective of the subject groups. A positive correlation exists between RUT reactivity and the frequency of mucosal inflammation.

  3. Angiogenesis and blood vessel stability in inflammatory arthritis.

    LENUS (Irish Health Repository)

    Kennedy, Aisling

    2012-02-01

    OBJECTIVE: To assess blood vessel stability in inflammatory synovial tissue (ST) and to examine neural cell adhesion molecule (NCAM), oxidative DNA damage, and hypoxia in vivo. METHODS: Macroscopic vascularity and ST oxygen levels were determined in vivo in patients with inflammatory arthritis who were undergoing arthroscopy. Vessel maturity\\/stability was quantified in matched ST samples by dual immunofluorescence staining for factor VIII (FVIII)\\/alpha-smooth muscle actin (alpha-SMA). NCAM and 8-oxo-7,8-dihydro-2\\'-deoxyguanosine (8-oxodG) were examined by immunohistochemistry. Angiogenesis was assessed in vitro, using human dermal endothelial cells (HDECs) in a Matrigel tube formation assay. RESULTS: A significant number of immature vessels (showing no pericyte recruitment) was observed in tissue from patients with inflammatory arthritis (P < 0.001), in contrast to osteoarthritic and normal tissue, which showed complete recruitment of pericytes. Low in vivo PO(2) levels in the inflamed joint (median [range] 22.8 [3.2-54.1] mm Hg) were inversely related to increased macroscopic vascularity (P < 0.04) and increased microscopic expression of FVIII and alpha-SMA (P < 0.04 and P < 0.03, respectively). A significant proportion of vessels showed focal expression of NCAM and strong nuclear 8-oxodG expression, implicating a loss of EC-pericyte contact and increased DNA damage, levels of which were inversely associated with low in vivo PO(2) (P = 0.04 for each comparison). Circulating cells were completely negative for 8-oxodG. Exposure of HDEC to 3% O(2) (reflecting mean ST in vivo measurements) significantly increased EC tube formation (P < 0.05). CONCLUSION: Our findings indicate the presence of unstable vessels in inflamed joints associated with hypoxia, incomplete EC-pericyte interactions, and increased DNA damage. These changes may further contribute to persistent hypoxia in the inflamed joint to further drive this unstable microenvironment.

  4. Mucosal healing in UC%浅谈溃疡性结肠炎中的黏膜愈合

    Institute of Scientific and Technical Information of China (English)

    张双喜

    2013-01-01

    Not currently recognized UC endpoints to assess the effectiveness of treatment. The most representative of remission of clinical symptoms and endoscopic recently defined mucosal healing. However, mucosal healing as well as the main treatment goal importance in predicting recurrence are inconclusive. In the assessment of mucosal healing as an indicator of disease activity is still facing a lot of problems before. This paper will discuss these issues, an objective assessment of mucosal healing in ulcerative colitis value.%  目前并无公认的终点用以评估UC治疗的有效性。最具代表性的为临床症状的缓解以及最近被内镜所定义的黏膜愈合。但是,黏膜愈合作为主要的治疗目标以及在预测复发中的重要性仍未有定论。在将黏膜愈合作为评估疾病活动性的指标之前仍面临很多问题。本文将就这些问题展开讨论,客观评估黏膜愈合在溃疡性结肠炎中的价值。

  5. Risk analysis, diagnosis and management of gastrointestinal mucositis in pediatric cancer patients

    NARCIS (Netherlands)

    Kuiken, Nicoline S. S.; Rings, Edmond H. H. M.; Tissing, Wim J. E.

    2015-01-01

    Mucositis is a complex inflammatory reaction of the mucous membranes of the alimentary tract upon chemotherapy and radiotherapy treatment in oncology patients. Mucositis can be subdivided in oral and gastrointestinal mucositis (GI mucositis). The damage to the gastrointestinal tract compromises the

  6. Module-based multiscale simulation of angiogenesis in skeletal muscle

    Directory of Open Access Journals (Sweden)

    Mac Gabhann Feilim

    2011-04-01

    Full Text Available Abstract Background Mathematical modeling of angiogenesis has been gaining momentum as a means to shed new light on the biological complexity underlying blood vessel growth. A variety of computational models have been developed, each focusing on different aspects of the angiogenesis process and occurring at different biological scales, ranging from the molecular to the tissue levels. Integration of models at different scales is a challenging and currently unsolved problem. Results We present an object-oriented module-based computational integration strategy to build a multiscale model of angiogenesis that links currently available models. As an example case, we use this approach to integrate modules representing microvascular blood flow, oxygen transport, vascular endothelial growth factor transport and endothelial cell behavior (sensing, migration and proliferation. Modeling methodologies in these modules include algebraic equations, partial differential equations and agent-based models with complex logical rules. We apply this integrated model to simulate exercise-induced angiogenesis in skeletal muscle. The simulation results compare capillary growth patterns between different exercise conditions for a single bout of exercise. Results demonstrate how the computational infrastructure can effectively integrate multiple modules by coordinating their connectivity and data exchange. Model parameterization offers simulation flexibility and a platform for performing sensitivity analysis. Conclusions This systems biology strategy can be applied to larger scale integration of computational models of angiogenesis in skeletal muscle, or other complex processes in other tissues under physiological and pathological conditions.

  7. Growth factors for therapeutic angiogenesis in hypercholesterolemic erectile dysfunction

    Institute of Scientific and Technical Information of China (English)

    Donghua Xie; Brian H. Annex; Craig F. Donatucci

    2008-01-01

    The past decade has seen an explosion of new information on the physiology of penile erection, and pathophysiology of erectile dysfunction (ED). Hypercholesterolemia is a chronic condition that can lead to degeneration in the vasculature bed and can result in ED if the penile vasculature is involved. Angiogenesis is the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion, such as coronary artery disease and ED. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future.Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm for the treatment of ischemic heart and/or peripheral vascular disease, though clinical studies have not achieved similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, novel therapies which target multiple different angiogenic pathways are also being developed and tested. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the development of growth factors for hypercholesterolemic ED, the use of various growth factors for ED therapy, their routes of delivery, and the results in animal studies.

  8. Tumour angiogenesis regulation by the miR-200 family

    Science.gov (United States)

    Pecot, Chad V.; Ivan, Cristina; Lu, Chunhua; Wu, Sherry; Han, Hee-Dong; Shah, Maitri Y.; Rodriguez-Aguayo, Cristian; Bottsford-Miller, Justin; Liu, Yuexin; Kim, Sang Bae; Unruh, Anna; Gonzalez-Villasana, Vianey; Huang, Li; Zand, Behrouz; Moreno-Smith, Myrthala; Mangala, Lingegowda S.; Taylor, Morgan; Dalton, Heather J.; Sehgal, Vasudha; Wen, Yunfei; Kang, Yu; Baggerly, Keith A.; Lee, Ju-Seog; Ram, Prahlad T.; Ravoori, Murali K.; Kundra, Vikas; Zhang, Xinna; Ali-Fehmi, Rouba; Gonzalez-Angulo, Ana-Maria; Massion, Pierre P.; Calin, George A.; Lopez-Berestein, Gabriel; Zhang, Wei; Sood, Anil K.

    2013-01-01

    The miR-200 family is well known to inhibit the epithelial–mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent. PMID:24018975

  9. The functional role of platelets in the regulation of angiogenesis.

    Science.gov (United States)

    Walsh, Tony G; Metharom, Pat; Berndt, Michael C

    2015-01-01

    Functionally, platelets are primarily recognized as key regulators of thrombosis and hemostasis. Upon vessel injury, the typically quiescent platelet interacts with subendothelial matrix to regulate platelet adhesion, activation and aggregation, with subsequent induction of the coagulation cascade forming a thrombus. Recently, however, newly described roles for platelets in the regulation of angiogenesis have emerged. Platelets possess an armory of pro- and anti-angiogenic proteins, which are actively sequestered and highly organized in α-granule populations. Platelet activation facilitates their release, eliciting potent angiogenic responses through mechanisms that appear to be tightly regulated. In conjunction, the release of platelet-derived phospholipids and microparticles has also earned merit as synergistic regulators of angiogenesis. Consequently, platelets have been functionally implicated in a range of angiogenesis-dependent processes, including physiological roles in wound healing, vascular development and blood/lymphatic vessel separation, whilst facilitating aberrant angiogenesis in a range of diseases including cancer, atherosclerosis and diabetic retinopathy. Whilst the underlying mechanisms are only starting to be elucidated, significant insights have been established, suggesting that platelets represent a promising therapeutic strategy in diseases requiring angiogenic modulation. Moreover, anti-platelet therapies targeting thrombotic complications also exert protective effects in disorders characterized by persistent angiogenesis.

  10. Robo 4 Counteracts Angiogenesis in Herpetic Stromal Keratitis.

    Directory of Open Access Journals (Sweden)

    Fernanda Gimenez

    Full Text Available The cornea is a complex tissue that must preserve its transparency to maintain optimal vision. However, in some circumstances, damage to the eye can result in neovascularization that impairs vision. This outcome can occur when herpes simplex virus type 1 (HSV-1 causes the immunoinflammatory lesion stromal keratitis (SK. Potentially useful measures to control the severity of SK are to target angiogenesis which with herpetic SK invariably involves VEGF. One such way to control angiogenesis involves the endothelial receptor Robo4 (R4, which upon interaction with another protein activates an antiangiogenic pathway that counteracts VEGF downstream signaling. In this study we show that mice unable to produce R4 because of gene knockout developed significantly higher angiogenesis after HSV-1 ocular infection than did infected wild type (WT controls. Moreover, providing additional soluble R4 (sR4 protein by subconjunctival administration to R4 KO HSV-1 infected mice substantially rescued the WT phenotype. Finally, administration of sR4 to WT HSV-1 infected mice diminished the extent of corneal angiogenesis compared to WT control animals. Our results indicate that sR4 could represent a useful therapeutic tool to counteract corneal angiogenesis and help control the severity of SK.

  11. Angiogenesis-Related Pathways in the Pathogenesis of Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Aristotle Bamias

    2013-07-01

    Full Text Available Ovarian Cancer represents the most fatal type of gynecological malignancies. A number of processes are involved in the pathogenesis of ovarian cancer, especially within the tumor microenvironment. Angiogenesis represents a hallmark phenomenon in cancer, and it is responsible for tumor spread and metastasis in ovarian cancer, among other tumor types, as it leads to new blood vessel formation. In recent years angiogenesis has been given considerable attention in order to identify targets for developing effective anti-tumor therapies. Growth factors have been identified to play key roles in driving angiogenesis and, thus, the formation of new blood vessels that assist in “feeding” cancer. Such molecules include the vascular endothelial growth factor (VEGF, the platelet derived growth factor (PDGF, the fibroblast growth factor (FGF, and the angiopoietin/Tie2 receptor complex. These proteins are key players in complex molecular pathways within the tumor cell and they have been in the spotlight of the development of anti-angiogenic molecules that may act as stand-alone therapeutics, or in concert with standard treatment regimes such as chemotherapy. The pathways involved in angiogenesis and molecules that have been developed in order to combat angiogenesis are described in this paper.

  12. Perspectives of SLIT/ROBO signaling in placental angiogenesis.

    Science.gov (United States)

    Liao, Wu-xiang; Wing, Deborah A; Geng, Jian-Guo; Chen, Dong-bao

    2010-09-01

    A novel family of evolutionally conserved neuronal guidance cues, including ligands (i.e., Slit, netrin, epherin, and semaphorin) and their corresponding receptors (i.e., Robo, DCC/Unc5, Eph and plexin/ neuropilin), has been identified to play a crucial role in axon pathfinding and branching as well as neuronal cell migration. The presence of commonalities in both neural and vascular developments has led to some exciting discoveries recently, which have extended the functions of these systems to vascular formation (vasculogenesis) and development (angiogenesis). Some of these ligands and receptors have been found to be expressed in the vasculature and surrounding tissues in physiological and pathological conditions. It is postulated that they regulate the formation and integrity of blood vessels. In particular, it has been shown that the Slit/Robo pair plays a novel role in angiogenesis during tumorigenesis and vascular formation during embryogenesis. Herein we summarize briefly the characteristics of this family of neuronal guidance molecules and discuss the extra-neural expression and function of the Slit/Robo pair in angiogenesis in physiological and pathological settings. We report expression of Robo1 protein in capillary endothelium and co-expression of Slit2 and Robo1 proteins in syncytiotrophoblast in healthy term human placental villi. These cellular expression patterns implicate that the Slit/Robo signaling plays an autocrine and/or paracrine role in angiogenesis and trophoblast functions. We also speculate a possible role of this system in pathophysiological placental angiogenesis.

  13. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice.

    Science.gov (United States)

    Li, Yanli; Gao, Rufei; Liu, Xueqing; Chen, Xuemei; Liao, Xinggui; Geng, Yanqing; Ding, Yubin; Wang, Yingxiong; He, Junlin

    2015-08-04

    The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34) immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA), placental growth factor (PLGF), and VEGF receptor 2 (VEGFR2) were also tested. Serum levels of homocysteine (Hcy), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2) were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR) and estrogen receptor α (ERα) were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone.

  14. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

    Directory of Open Access Journals (Sweden)

    Yanli Li

    2015-08-01

    Full Text Available The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34 immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA, placental growth factor (PLGF, and VEGF receptor 2 (VEGFR2 were also tested. Serum levels of homocysteine (Hcy, follicle stimulating hormone (FSH, luteinizing hormone (LH, prolactin (PRL, progesterone (P4, and estradiol (E2 were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR and estrogen receptor α (ERα were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone.

  15. Role of laminins in physiological and pathological angiogenesis.

    Science.gov (United States)

    Simon-Assmann, Patricia; Orend, Gertraud; Mammadova-Bach, Elmina; Spenlé, Caroline; Lefebvre, Olivier

    2011-01-01

    The interaction of endothelial cells and pericytes with their microenvironment, in particular with the basement membrane, plays a crucial role during vasculogenesis and angiogenesis. In this review, we focus on laminins, a major family of extracellular matrix molecules present in basement membranes. Laminins interact with cell surface receptors to trigger intracellular signalling that shapes cell behaviour. Each laminin exerts a distinct effect on endothelial cells and pericytes which largely depends on the adhesion receptor profile expressed on the cell surface. Moreover, proteolytic cleavage of laminins may affect their role in angiogenesis. We report in vitro and in vivo data on laminin-111, -411, -511 and -332 and their associated signalling that regulates cell behaviour and angiogenesis under normal and pathological conditions. We also discuss how tissue-specific deletion of laminin genes affects the behaviour of endothelial cells and pericytes and thus angiogenesis. Finally, we examine how coculture systems with defined laminin expression contribute to our understanding of the roles of laminins in normal and pathological vasculogenesis and angiogenesis.

  16. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

    Science.gov (United States)

    Li, Yanli; Gao, Rufei; Liu, Xueqing; Chen, Xuemei; Liao, Xinggui; Geng, Yanqing; Ding, Yubin; Wang, Yingxiong; He, Junlin

    2015-01-01

    The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34) immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA), placental growth factor (PLGF), and VEGF receptor 2 (VEGFR2) were also tested. Serum levels of homocysteine (Hcy), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2) were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR) and estrogen receptor α (ERα) were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone. PMID:26247969

  17. How can probiotics and prebiotics impact mucosal immunity?

    National Research Council Canada - National Science Library

    O'Flaherty, Sarah; Saulnier, Delphine; Pot, Bruno; Versalovic, James

    2010-01-01

    ...? These questions were part of a discussion entitled "How Can Probiotics and Prebiotics Impact Mucosal Immunity" at the 2009 annual meeting of the International Scientific Association for Probiotics and Prebiotics (ISAPP...

  18. Prevention of acute gastric mucosal lesions by Solcoseryl.

    Science.gov (United States)

    Brzozowski, T; Radecki, T; Sendur, R; Gustaw, P; Konturek, S J

    1987-04-01

    Solcoseryl, a deproteinized extract from calf blood containing various biologically active substances, has been reported to promote the healing of skin wounds and gastric ulceration In this study, the gastroprotective effects of Solcoseryl vis-a-vis acute gastric mucosal damage were examined in rats. Solcoseryl significantly reduced the formation of acute lesions induced by intragastric application of absolute ethanol or acidified taurocholate and by water immersion and restraint stress, but failed to affect those caused by acidified aspirin. Since Solcoseryl did not offer protection in the absence of mucosal prostaglandins (PG) e.g. in aspirin-induced gastric damage, it is likely that PG may be involved in the observed gastroprotective activity of the drug. Solcoseryl failed to affect gastric acid or pepsin secretion, but increased mucosal blood flow. Thus PG generated by Solcoseryl might contribute to the maintenance of the observed mucosal microcirculation and the prevention of lesion formation by corrosive substances and stress conditions.

  19. Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey

    DEFF Research Database (Denmark)

    Mikkelsen, Lauge H; Larsen, Ann-Cathrine; von Buchwald, Christian

    2016-01-01

    melanoma must be excluded. Mutations in KIT are frequently found, while BRAF and NRAS mutations are rarely found - except in conjunctival melanomas that carry BRAF mutations. Mutations in the TERT promotor region are also found in mucosal melanomas. Complete surgical resection with free margins......Mucosal melanomas constitute 1.3% of all melanomas and they may develop in any mucosal membrane. Conjunctival melanomas (0.5/million/year) and melanomas in the sinonasal cavity (0.5/million/year) are the most common, followed by anorectal melanomas (0.4/million/year) and melanomas in the oral...... cavity (0.2/million/year). Anorectal melanoma occurs slightly more often in females, whereas oral melanoma has a male predilection. Mucosal melanoma most commonly develops in a patient's sixth or seventh decade of life, and no differences between races have been found except for sinonasal melanoma...

  20. Mucosal environmental sensors in the pathogenesis of dry eye.

    Science.gov (United States)

    Pflugfelder, Stephen C; Stern, Michael E

    2014-09-01

    The 4th Cullen Symposium, held April 17 and 18, 2014, included expert researchers in mucosal immunity of the eye and other mucosal surfaces, particularly the gut. The theme of the meeting was environmental sensing mechanisms in mucosal tissues and their relevance for initiating ocular surface inflammation in dry eye. There are a number of shared features between the ocular surface and other mucosal surfaces, but distinct differences may exist in the type and distribution of mucins and microbiota. Mechanisms to regulate DC maturation and prevent tissue-damaging inflammation are shared among these sites. Epithelial and dendritic cells are key environmental sensors participating in initiation of innate and adaptive immune responses in response to a variety of environmental stresses.

  1. Chamomile Mouth Rinse Effects on Mucositis Reduction After Radiotherapy

    Directory of Open Access Journals (Sweden)

    Talaipour AR

    2000-05-01

    Full Text Available In recent years many patients have been received radiotherapy for head and neck tumors and"na large number of them have been survived for some years."nThe side effects of radiotherapy in oral region are mucositis, ulcers, fungal and viral infections and"nsalivary glands dysfunction. Among these, mucositis is the most important one."nA randomized double blind clinical trial was performed in radiotherapy department of Tehran Imam"nKhomeini Hospital to determine chamomile mouth rinse effects on mucositis after radiotherapy."nThe patients are selected randomly from those with oral oropharyngeal or nasopharyngeal cancers."nData showed that chamomile administration could decrease mucositis rate significantly,

  2. [Mucositis in head and neck cancer patients undergoing radiochemotherapy].

    Science.gov (United States)

    Santos, Renata Cristina Schmidt; Dias, Rodrigo Souza; Giordani, Adelmo José; Segreto, Roberto Araújo; Segreto, Helena Regina Comodo

    2011-12-01

    The objective of present study was to classify oral mucositis according to the Common Toxicity Criterion (CTC) international parameters in head and neck tumor patients simultaneously treated with radio and chemotherapy, and characterize a patient profile in our area, observing the individuals' habits, tumor characteristics, treatment protocol and acute reaction intensity. Fifty patients undergoing simultaneous 66 to 70 Gy megavoltage radiotherapy and cisplatin/carboplatin chemotherapy were evaluated in this study. Weekly evaluations of the degree of mucositis were perfoemed according to CTC, a four-degree ordinal scale; 36% of all patients and 100% of those with diabetes discontinued treatment due to mucositis, showing that this pathology contributes to the severity of mucositis.

  3. A DETAILED REVIEW ON ORAL MUCOSAL DRUG DELIVERY SYSTEM

    Directory of Open Access Journals (Sweden)

    Radha Bhati

    2012-03-01

    Full Text Available Oral mucosal drug delivery system is widely applicable as novel site for administration of drug for immediate and controlled release action by preventing first pass metabolism and enzymatic degradation due to GI microbial flora. Oral mucosal drug delivery system provides local and systemic action. In this review, attention is focused to give regarding physiology of oral mucosal including tissue permeability, barriers to permeation and route of permeation, biopharmaceutics of buccal and sublingual absorption, factors affecting drug absorption, detailed information of penetration enhancers, design of oral mucosal drug delivery system and role of mucoadhesion and various theories of bioadhesion. Evaluation techniques and selection of animal model for in-vivo studies are also discussed.

  4. (CGRP) on gastric mucosal barrier in stress induced rats

    African Journals Online (AJOL)

    STORAGESEVER

    2009-04-20

    Apr 20, 2009 ... phospholipids (Kao et al., 1987), mucosal blood flow. (Stein, 1989 .... in blood vessels of tunica mucosa. A diffuse ... improve and there were signs of regeneration in lamina epitelialis ... The dilatation and edema of the vessels.

  5. MUCOSAL MALIGNANT MELANOMA OF NASOPHARYNX: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Chandrasekhar

    2015-06-01

    Full Text Available Primary mucosal malignant melanomas of sinonasal tract are uncommon tumors comprising 0.3-2% of all malignant melanomas and 4% of all head and Neck melanomas. We are reporting a rare case of mucosal malignant melanoma in a 45 year old female arising from nasopharynx which was excised completely by trans palatal approach followed by irradiation. This case is being reported because of its isolated involvement of nasopharynx, and early age of presentation.

  6. Mucosal Inflammatory Response to Salmonella Typhimurium Infection

    Directory of Open Access Journals (Sweden)

    Samir ePatel

    2014-07-01

    Full Text Available The human intestinal epithelium consists of a single layer of epithelial cells that forms a barrier against food antigens and the resident microbiota within the lumen. This delicately balanced organ functions in a highly sophisticated manner to uphold the fidelity of the intestinal epithelium and to eliminate disease-causing microorganisms. On the luminal side, this barrier is fortified by a thick mucus layer, and on the serosal side exists the lamina propria containing a resident population of immune cells. Pathogens that are able to breach this barrier disrupt the healthy epithelial lining by interfering with the regulatory mechanisms that govern the normal balance of intestinal architecture and function. This disruption results in a coordinated innate immune response deployed to eliminate the intruder that includes the release of antimicrobial peptides, activation of pattern recognition receptors, and recruitment of a variety of immune cells. In the case of Salmonella enterica serovar Typhimurium (S. Typhimurium infection, induction of an inflammatory response has been linked to its virulence mechanism, the type III secretion system (T3SS. The T3SS secretes protein effectors that exploit the host’s cell biology to facilitate bacterial entry and intracellular survival, and to modulate the host immune response. As the role of the intestinal epithelium in initiating an immune response has been increasingly realized, this review will highlight recent research that details progress made in understanding mechanisms underlying the mucosal inflammatory response to Salmonella infection, and how such inflammatory responses impact pathogenic fitness of this organism.

  7. Evaluation of TLR agonists as potential mucosal adjuvants for HIV gp140 and tetanus toxoid in mice.

    Directory of Open Access Journals (Sweden)

    Viviana Buffa

    Full Text Available In the present study we investigate the impact of a range of TLR ligands and chitosan as potential adjuvants for different routes of mucosal immunisation (sublingual (SL, intranasal (IN, intravaginal (IVag and a parenteral route (subcutaneous (SC in the murine model. We assess their ability to enhance antibody responses to HIV-1 CN54gp140 (gp140 and Tetanus toxoid (TT in systemic and vaginal compartments. A number of trends were observed by route of administration. For non-adjuvanted antigen, SC>SL>IN immunisation with respect to systemic IgG responses, where endpoint titres were greater for TT than for gp140. In general, co-administration with adjuvants increased specific IgG responses where IN = SC>SL, while in the vaginal compartment IN>SL>SC for specific IgA. In contrast, for systemic and mucosal IgA responses to antigen alone SL>IN = SC. A number of adjuvants increased specific systemic IgA responses where in general IN>SL>SC immunisation, while for mucosal responses IN = SL>SC. In contrast, direct intravaginal immunisation failed to induce any detectable systemic or mucosal responses to gp140 even in the presence of adjuvant. However, significant systemic IgG responses to TT were induced by intravaginal immunisation with or without adjuvant, and detectable mucosal responses IgG and IgA were observed when TT was administered with FSL-1 or Poly I∶C. Interestingly some TLRs displayed differential activity dependent upon the route of administration. MPLA (TLR4 suppressed systemic responses to SL immunisation while enhancing responses to IN or SC immunisation. CpG B enhanced SL and IN responses, while having little or no impact on SC immunisation. These data demonstrate important route, antigen and adjuvant effects that need to be considered in the design of mucosal vaccine strategies.

  8. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

    Directory of Open Access Journals (Sweden)

    Sabrina Bimonte

    2015-01-01

    Full Text Available Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.

  9. “Decoding” angiogenesis: new facets controlling endothelial cell behavior

    Directory of Open Access Journals (Sweden)

    Massimo Mattia Santoro

    2016-07-01

    Full Text Available Angiogenesis, the formation of new blood vessels, is a unique and crucial biological process occurring during both development and adulthood. A better understanding of the mechanisms that regulates such process is mandatory to intervene in pathophysiological conditions. Here we highlight some recent argument on new players that are critical in endothelial cells, by summarizing novel discoveries that regulate notorious vascular pathways such as Vascular Endothelial Growth Factor (VEGF, Notch and Planar Cell Polarity, and by discussing more recent findings that put metabolism, redox signaling and hemodynamic forces as novel unforeseen facets in angiogenesis. These new aspects, that critically regulate angiogenesis and vascular homeostasis in health and diseased, represent unforeseen new ground to develop anti-angiogenic therapies.

  10. Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer

    Science.gov (United States)

    Reusser, Nicole M; Dalton, Heather J; Pradeep, Sunila; Gonzalez-Villasana, Vianey; Jennings, Nicholas B; Vasquez, Hernan G; Wen, Yunfei; Rupaimoole, Rajesh; Nagaraja, Archana S; Gharpure, Kshipra; Miyake, Takahito; Huang, Jie; Hu, Wei; Lopez-Berestein, Gabriel; Sood, Anil K

    2014-01-01

    Purpose Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations. Experimental Design Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis. Results Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density. Conclusions Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer. PMID:24841852

  11. Acetazolamide inhibits aquaporin-1 protein expression and angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Yang XIANG; Bing MA; Tao LI; Jun-wei GAO; He-ming YU; Xue-jun LI

    2004-01-01

    AIM: To study effects of acetazolamide on aquaporin-1 (AQP1) protein expression and angiogenesis. METHODS:Establishing Lewis-lung-carcinoma model, the localization of AQP1 in tumor tissues was investigated by immunohistochemical methods; The biological activity of acetazolamide was detected by endothelial cells proliferation test (MTT) assay and chorioallantoic membrane (CAM) vascular inhibition test. RESULTS: Immunohistochemical localization of AQP1 in mice tumor was labeled in capillaries, post capillary venules endothelial cells. After being treated with acetazolamide, the number of capillaries and post capillary venules was significantly decreased in tumor tissue. Acetazolamide showed significant inhibitory effect on angiogenesis in CAM and endothelial cell proliferation.CONCLUSION: Acetazolamide might be identified and developed as one of potential lead compounds for a new therapeutic intervention in inhibiting cancer angiogenesis.

  12. Antisense oligonucleotide targeting midkine suppresses in vivo angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Li-Cheng Dai; Xiang Wang; Xing Yao; Yong-Liang Lu; Jin-Liang Ping; Jian-Fang He

    2007-01-01

    AIM: To evaluate the effect of antisense oligonucleotide targeting midkine (MK-AS) on angiogenesis in chick chorioallantoic membrane (CAM) andin situ human hepatocellular carcinoma (HCC).METHODS: An in situ human hepatocellular carcinoma (HCC) model and CAM assay were used in this experiment. The effect of MK-AS on angiogenesis was evaluated by cell proliferation assay and hematoxylineosin (HE) staining.RESULTS: MK-AS significantly inhibited human umbilical vein endothelial cells (HUVEC) and in situ human HCC growth. At the same time, MK-AS suppressed the angiogenesis both in human hepatocellular carcinoma cell line (HEPG2)-induced CAM and in situ human HCC tissues.CONCLUSION: MK-AS is an effective antiangiogenesis agent in vivo.

  13. Microfluidic traction force microscopy to study mechanotransduction in angiogenesis.

    Science.gov (United States)

    Boldock, Luke; Wittkowske, Claudia; Perrault, Cecile M

    2017-07-01

    The formation of new blood vessels from existing vasculature, angiogenesis, is driven by coordinated endothelial cell migration and matrix remodeling in response to local signals. Recently, a growing body of evidence has shown that mechanotransduction, along with chemotransduction, is a major regulator of angiogenesis. Mechanical signals, such as fluid shear stress and substrate mechanics, influence sprouting and network formation, but the mechanisms behind this relationship are still unclear. Here, we present cellular traction forces as possible effectors activated by mechanosensing to mediate matrix remodeling, and encourage the use of TFM to study mechanotransduction in angiogenesis. We also suggest that deciphering the response of EC to mechanical signals could reveal an optimal angiogenic mechanical environment, and provide insight into development, wound healing, the initiation and growth of tumors, and new strategies for tissue engineering. © 2017 John Wiley & Sons Ltd.

  14. [New routes of administration: epidermal, transcutaneous mucosal ways of vaccination].

    Science.gov (United States)

    Denis, François; Alain, Sophie; Ploy, Marie-Cécile

    2007-04-01

    A successful vaccine triggers the interaction of various cells of the immune system as does a regular immune response. It is thus necessary to introduce the vaccine antigens into an anatomic site where they will contact immune cells. The route of administration is thus critical for the outcome of vaccination. Intramuscular or subcutaneous injections are the most popular. Antigens injected intramuscularly can form persistent precipitates that are dissolved and re-absorbed relatively slowly. If injecting antigens is a quick, easy and reproducible way to vaccination, it requires trained personnel. Alternatives exist, through non-invasive formulations which allow administration by the patient or a third party with no particular expertise. The skin, especially its epidermal layer, is an accessible and competent immune environment and an attractive target for vaccine delivery, through transcutaneous delivery or immunostimulant patches. Mucosal immunization is another strategy: its major rationale is that organisms invade the body via mucosal surfaces. Therefore, local protection at mucosal surface as well as systemic defense is beneficial. Various formulations of mucosal vaccines have been developed, such as the Sabin oral polio vaccine (OPV), rotavirus vaccines, cold-adapted influenza vaccines or vaccine against typhoid fever. Thus we are entering in an era where mucosal and transcutaneous immunisation will play an important role in disease management. However, it has not been so easy to obtain regulatory approval for mucosal or transcutaneous formulations and needle-based vaccines continue to dominate the market.

  15. Sodium alginate inhibits methotrexate-induced gastrointestinal mucositis in rats.

    Science.gov (United States)

    Yamamoto, Atsuki; Itoh, Tomokazu; Nasu, Reishi; Kajiwara, Eiji; Nishida, Ryuichi

    2013-01-01

    Gastrointestinal mucositis is one of the most prevalent side effects of chemotherapy. Methotrexate is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukemia and other malignancies. Through its effects on normal tissues with high rates of proliferation, methotrexate treatment leads to gastrointestinal mucositis. In rats, methotrexate-induced gastrointestinal mucositis is histologically characterized by crypt loss, callus fusion and atrophy, capillary dilatation, and infiltration of mixed inflammatory cells. The water-soluble dietary fiber sodium alginate (AL-Na) is derived from seaweed and has demonstrated muco-protective and hemostatic effects on upper gastrointestinal ulcers. In the present study, we evaluated the effects of AL-Na on methotrexate-induced small intestinal mucositis in rats. Animals were subcutaneously administered methotrexate at a dosage of 2.5 mg/kg once daily for 3 d. Rats were treated with single oral doses of AL-Na 30 min before and 6 h after methotrexate administration. On the 4th day, small intestines were removed and weighed. Subsequently, tissues were stained with hematoxylin-eosin and bromodeoxyuridine. AL-Na significantly prevented methotrexate-induced small intestinal mucositis. Moreover, AL-Na prevented decreases in red blood cell numbers, hemoglobin levels, and hematocrit levels. These results suggest the potential of AL-Na as a therapy for methotrexate-induced small intestinal mucositis.

  16. Differential Apoptosis in Mucosal and Dermal Wound Healing

    Science.gov (United States)

    Johnson, Ariel; Francis, Marybeth; DiPietro, Luisa Ann

    2014-01-01

    Objectives: Dermal and mucosal healing are mechanistically similar. However, scarring and closure rates are dramatically improved in mucosal healing, possibly due to differences in apoptosis. Apoptosis, nature's preprogrammed form of cell death, occurs via two major pathways, extrinsic and intrinsic, which intersect at caspase3 (Casp3) cleavage and activation. The purpose of this experiment was to identify the predominant pathways of apoptosis in mucosal and dermal wound healing. Approach: Wounds (1 mm biopsy punch) were made in the dorsal skin (n=3) or tongue (n=3) of female Balb/C mice aged 6 weeks. Wounds were harvested at 6 h, 24 h, day 3 (D3), D5, D7, and D10. RNA was isolated and analyzed using real time reverse transcriptase–polymerase chain reaction. Expression levels for genes in the intrinsic and extrinsic apoptotic pathways were compared in dermal and mucosal wounds. Results: Compared to mucosal healing, dermal wounds exhibited significantly higher expression of Casp3 (at D5; pwound healing compared to skin. Conclusion: Expression patterns of key regulators of apoptosis in wound healing indicate that apoptosis occurs predominantly through the intrinsic pathway in the healing mucosa, but predominantly through the extrinsic pathway in the healing skin. The identification of differences in the apoptotic pathways in skin and mucosal wounds may allow the development of therapeutics to improve skin healing. PMID:25493209

  17. Nabumetone induces less gastrointestinal mucosal changes than diclofenac retard.

    Science.gov (United States)

    Becvár, R; Urbanová, Z; Vlasáková, V; Vítová, J; Rybár, I; Maldyk, H; Filipowicz-Sosnowska, A; Bernacka, K; Mackiewicz, S; Gömör, B; Rojkovich, B; Siro, B; Bereczki, J; Toth, K; Sukenik, S; Green, L; Ehrenfeld, M; Pavelka, K

    1999-01-01

    The aim of the study was to compare the efficacy and the effects on the mucosa of the gastrointestinal tract (GIT) of nabumetone and diclofenac retard in patients with osteoarthritis (OA). An open, multicentre, randomised, comparative, endoscopy-blind parallel group study included 201 patients with nabumetone and 193 patients with diclofenac retard suffering from moderate to severe OA of the knee or hip joint. Twelve clinical efficacy variables were assessed and a portion of the population underwent gastroduodenoscopy. All patients exhibited significant improvement in pain severity and pain relief (p nabumetone and 19% on diclofenac experienced GIT side-effects. Sixty-nine patients with nabumetone and 61 with diclofenac underwent gastroduodenoscopy. The differences in the mucosal grade for the oesophagus, stomach and duodenum at baseline were not significant. In the oesophagus there were significantly less changes after treatment with nabumetone (p = 0.007) than with diclofenac; there were similar findings in the stomach (p nabumetone and diclofenac retard have similar efficacy in the treatment of OA, but nabumetone has significantly fewer GIT side-effects.

  18. Angiogenesis related gene expression profiles of EA.hy926 cells induced by irbesartan: a possible novel therapeutic approach

    Institute of Scientific and Technical Information of China (English)

    MA Cong; LU Xue-chun; LUO Yun; CAO Jian; YANG Bo; GAO Yan; LIU Xian-feng; FAN Li

    2012-01-01

    Background Angiogenesis occurs commonly in various physiological and pathological processes.Improving blood supply through promoting angiogenesis is a novel approach for treating ischemic diseases.Angiotensin Ⅱ type 1 receptor blockers (ARBs) dominate the management of hypertension,but evidence of their role in angiogenesis is contradictory.Here we explored the angiogenic effects of ARBs through characterizing gene expression of the human umbilical vein endothelial cell line EA.hy926 exposed to irbesartan.Methods The human umbilical vein endothelial cell line EA.hy926 was grown for 72 hours after treatment with different concentrations of irbesartan.The cell proliferative capacity was assessed by CCK8 assay at 24,48 and 72 hours.Gene expression levels in EA.hy926 cells responding to irbesartan were measured under optimal proliferation conditions by microarray analysis using Affymetrix U133 plus 2.0.The differential expression of genes involved in angiogenesis was identified through cluster analysis of the resulting microarray data.Quantitative RT-PCR and Western blotting analyses were used to validate differential gene expression related to the angiogenesis process.Results In the 10-4,10-5,10-6 mol/L treatment groups,cell proliferation studies revealed significantly increased proliferation in EA.hy926 cells after 24 hours of irbesartan treatment.However,after 48 and 72 hours of treatment with different concentrations of irbesartan,there was no significant difference in cell proliferation observed in any treatment group.We selected the group stimulated with irbersartan at a concentration of 10-6 mol/L for microarray experiments.Statistical analysis of the microarray data resulted in the identification of 56 gene transcripts whose expression patterns were significantly correlated,negatively or positively,with irbesartan treatment.Cluster analysis showed that these genes were involved in angiogenesis,extracellular stimulus,binding reactions and skeletal system

  19. Impact of aging on allergy and mucosal immunity in upper respiratory tract

    Directory of Open Access Journals (Sweden)

    Seyyed Abbas Hashemi

    2016-01-01

    Full Text Available Objectives: Although age-associated alterations on immune system are well described and aging is a subject of different investigations but studies did not discuss about the effect of advanced age on immunity in upper respiratory tract disorders. Therefore in this trial, we elucidated how aging imposes allergic reactions and mucosal immune responses mediated by salivary IgA and serum Total IgE in patients suffered from upper respiratory tract diseases. Study Design: Experimental study. Place and Duration of Study: Department of Otorhinolaringology, microbiology and immunology, Mazandaran university of medical sciences, sari, Iran, from September 2010 to august 2011. Methods: In this study, 140 patients in 7 age groups with upper respiratory tract infections underwent salivary IgA assessment by direct immunoenzymatic determination and serum Total IgE by enzyme linked immunoabsorbent assay. We compared each study arm to the youngest subjects. Results: There was no significant difference in salivary IgA level for patients younger than 60 but a significant change observed for patients older than 60 (p=0.01. Likewise, there was no significant change for total IgE. Conclusion: This research didn’t provide any evidence about the minus impact of aging on allergic reactions in upper respiratory tract infections .There was an up regulation in mucosal immunity mediated by salivary IgA in patients aged over sixty which revealed secretory IgA plays an important role in mucosal defense of aged subjects.

  20. Efficacy and toxicity of Samen-ista emulsion on treatment of cutaneous and mucosal bleeding.

    Science.gov (United States)

    Hosseini, Mousalreza; Pourakbar, Ali; Forouzanfar, Fatemeh; Arian, Amirali; Ghaffarzadegan, Kamran; Salehi, Maryam; Esfandiari, Samaneh; Rakhshandeh, Hassan

    2016-10-01

    Despite new treatment methods, upper gastrointestinal bleeding remains challenging. Samen-ista emulsion is a new agent based on traditional medicine with coagulant properties. The efficacy and safety of Samen-ista were assessed in cutaneous and mucosal bleeding animal models. Coagulant properties of Samen-ista were evaluated using mice tail bleeding assay, marginal ear vein and upper gastrointestinal mucosal bleeding times in rabbits. After 7 days, clinical signs, mortality and end-organ (kidney, liver, lung, brain and gastric mucosa) histopathological changes were also examined. Samen-ista dose-dependently decreased mean cutaneous tail (128 vs. 14 s) and marginal ear vein (396 vs. 84 s) bleeding times. Rabbit's upper gastrointestinal bleeding time was also significantly decreased (214 vs. 15.8 s) upon Samen-ista local endoscopic application. Treatment with Samen-ista for 7 days did not cause any mortality, abnormal signs of bleeding, changes in appetite or significant histopathologicl changes. Samen-ista emulsion is well tolerated and highly effective in achieving hemostasis in cutaneous and mucosal bleeding animal models.

  1. Acute effects of Helicobacter pylori extracts on gastric mucosal blood flow in the mouse

    Institute of Scientific and Technical Information of China (English)

    Johanna Henriksn(a)s; Christer Atuma; Mia Phillipson; Stellan Sandler; Lars Engstrand; Lena Holm

    2009-01-01

    AIM: To investigate the mechanisms underlying the reduction in gastric blood flow induced by a luminal water extract of Helicobacter pylori (HPE). METHODS: The stomachs of isoflurane-anesthetized mice were exteriorized, and the mucosal surface exposed. Blood flow was measured with the laser Doppler technique, and systemic arterial blood pressure monitored. C57BL/6 mice were exposed to water extract produced from H pylori strain 88-23. To investigate the role of a nerve- or iNOS-mediated pathway, we used intraluminal lidocaine and iNOS-/-mice. Blood flow response to the endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine (ADMA) was also assessed. RESULTS: In wild-type mice, HPE decreased mucosal blood flow by approximately 30%. This reduction was abolished in iNOS-deficient mice, and by pre-treatment with lidocaine. Luminally applied ADMA resulted in reduction in blood flow similar to that observed in wildtype mice exposed to HPE. CONCLUSION: A H pylori water extract reduces gastric mucosal blood flow acutely through iNOS- and nerve-mediated pathways.

  2. Identification of anaplastic lymphoma kinase break points and oncogenic mutation profiles in acral/mucosal melanomas.

    Science.gov (United States)

    Niu, Hai-Tao; Zhou, Qi-Ming; Wang, Fang; Shao, Qiong; Guan, Yuan-Xiang; Wen, Xi-Zhi; Chen, Li-Zhen; Feng, Qi-Sheng; Li, Wei; Zeng, Yi-Xin; Zhang, Xiao-Shi

    2013-09-01

    Acral and mucosal melanomas, the two most common subtypes of melanoma in China, exhibit different genetic alterations and biologic behavior compared with other subtypes of melanomas. The purpose of this study was to identify the genetic alterations in patients with acral or mucosal melanomas in southern China. Fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) analysis, polymerase chain reaction (PCR), and quantitative real-time reverse transcriptase PCR (qRT-PCR) were used to assess the anaplastic lymphoma kinase (ALK) break points. Furthermore, a mass spectrometry-based genotyping platform was used to analyze 30 acral melanomas and 28 mucosal melanomas to profile 238 known somatic mutations in 19 oncogenes. ALK break points were identified in four acral cases (6.9%). Eight (13.8%) cases harbored BRAF mutations, six (10.3%) had NRAS mutations, four (6.9%) had KIT mutations, two (3.5%) had EGFR mutations, two (3.5%) had KRAS mutations, two (3.5%) had MET mutations, one (1.7%) had an HRAS mutation, and one (1.7%) had a PIK3CA mutation. Two cases exhibited co-occurring mutations, and one case with a BRAF mutation had a translocation in ALK. This study represents a comprehensive and concurrent analysis of the major recurrent oncogenic mutations involved in melanoma cases from southern China. These data have implications for both clinical trial designs and therapeutic strategies.

  3. Syndecan-4 shedding impairs macrovascular angiogenesis in diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Li, Ran; Xie, Jun; Wu, Han; Li, Guannan; Chen, Jianzhou; Chen, Qinhua; Wang, Lian; Xu, Biao, E-mail: xubiao@medmail.com.cn

    2016-05-20

    Purpose: Syndecan-4 (synd4) is a ubiquitous heparan sulfate proteoglycan cell surface receptor that modulates cell proliferation, migration, mechanotransduction, and endocytosis. The extracellular domain of synd4 sheds heavily in acute inflammation, but the shedding of synd4 in chronic inflammation, such as diabetes mellitus (DM), is still undefined. We investigated the alterations of synd4 endothelial expression in DM and the influence of impaired synd4 signaling on angiogenesis in human umbilical vein endothelial cells (HUVECs), diabetic rats, synd4 null mice, and db/db mice. Material and methods: HUVECs were incubated with advanced glycation end products (AGEs). Western blot analysis was used to determine synd4 protein expression and ELISA was used to detect soluble synd4 fragments. The concentration of synd4 in the aortic endothelia of diabetic rats was detected by immunohistochemical staining. Aortic ring assays were performed to study the process of angiogenesis in the diabetic rats and in synd4 null and db/db mice. Recombinant adenoviruses containing the synd4 gene or null were constructed to enhance synd4 aortic expression in db/db mice. Results: Western blot analysis showed decreased expression of the synd4 extracellular domain in HUVECs, and ELISA detected increased soluble fragments of synd4 in the media. Synd4 endothelial expression in the aortas of diabetic rats was decreased. Aortic ring assay indicated impaired angiogenesis in synd4 null and db/db mice, which was partially reversed by synd4 overexpression in db/db mice. Conclusion: Synd4 shedding from vascular endothelial cells played an important role in the diabetes-related impairment of angiogenesis. -- Highlights: •Synd4 shedding from endothelial cells is accelerated under the stimulation of AGEs. •Extracellular domain of synd4 is diminished in the endothelium of DM rats. •Aortic rings of synd4 null mice showed impaired angiogenesis. •Overexpression of synd4 partly rescues macrovascular

  4. Endothelial Progenitor Cells in Sprouting Angiogenesis: Proteases Pave the Way.

    Science.gov (United States)

    Laurenzana, A; Fibbi, G; Margheri, F; Biagioni, A; Luciani, C; Del Rosso, M; Chillà, A

    2015-01-01

    Sprouting angiogenesis consists of the expansion and remodelling of existing vessels, where the vascular sprouts connect each other to form new vascular loops. Endothelial Progenitor Cells (EPCs) are a subtype of stem cells, with high proliferative potential, able to differentiate into mature Endothelial Cells (ECs) during the neovascularization process. In addition to this direct structural role EPCs improve neovascularization, also secreting numerous pro-angiogenic factors able to enhance the proliferation, survival and function of mature ECs, and other surrounding progenitor cells. While sprouting angiogenesis by mature ECs involves resident ECs, the vasculogenic contribution of EPCs is a high hurdle race. Bone marrowmobilized EPCs have to detach from the stem cell niche, intravasate into bone marrow vessels, reach the hypoxic area or tumour site, extravasate and incorporate into the new vessel lumen, thus complementing the resident mature ECs in sprouting angiogenesis. The goal of this review is to highlight the role of the main protease systems able to control each of these steps. The pivotal protease systems here described, involved in vascular patterning in sprouting angiogenesis, are the matrix-metalloproteinases (MMPs), the serineproteinases urokinase-type plasminogen activator (uPA) associated with its receptor (uPAR) and receptorassociated plasminogen/plasmin, the neutrophil elastase and the cathepsins. Since angiogenesis plays a critical role not only in physiological but also in pathological processes, such as in tumours, controlling the contribution of EPCs to the angiogenic process, through the regulation of the protease systems involved, could yield new opportunities for the therapeutic prospect of efficient control of pathological angiogenesis.

  5. Tumor angiogenesis--a new therapeutic target in gliomas

    DEFF Research Database (Denmark)

    Lund, E L; Spang-Thomsen, M; Skovgaard-Poulsen, H

    1998-01-01

    Tumor growth is critically dependent on angiogenesis, which is sprouting of new vessels from pre-existing vasculature. This process is regulated by inducers and inhibitors released from tumor cells, endothelial cells, and macrophages. Brain tumors, especially glioblastoma multiforme, have...... significant angiogenic activity primarily by the expression of the angiogenic factor VEGF Anti-angiogenic therapy represents a new promising therapeutic modality in solid tumors. Several agents are currently under evaluation in clinical trials. The present review describes the principal inducers...... and inhibitors of angiogenesis in tumors and summarizes what is known about their mechanisms of action in relation to CNS tumors. Potential areas for clinical use are also discussed....

  6. Roxarsone induces angiogenesis via PI3K/Akt signaling

    OpenAIRE

    2016-01-01

    Background 3-Nitro-4-hydroxy phenyl arsenic acid, roxarsone, is widely used as an organic arsenic feed additive for livestock and poultry, which may increase the level of arsenic in the environment and the risk of exposure to arsenic in human. Little information is focused on the angiogenesis roxarsone-induced and its mechanism at present. This paper aims to study the role of PI3K/Akt signaling in roxarsone-induced angiogenesis in rat vascular endothelial cells and a mouse B16–F10 melanoma xe...

  7. Sphingosine-1-phosphate signaling in vasculogenesis and angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Kelley; M; Argraves; Brent; A; Wilkerson; W; Scott; Argraves

    2010-01-01

    Blood vessels either form de novo through the process of vasculogenesis or through angiogenesis that involves the sprouting and proliferation of endothelial cells in pre-existing blood vessels. A complex interactive network of signaling cascades downstream from at least three of the nine known G-protein-coupled sphingosine-1-phosphate (S1P) receptors act as a prime effector of neovascularization that occurs in embryonic development and in association with various pathologies. This review focuses on the current knowledge of the roles of S1P signaling in vasculogenesis and angiogenesis, with particular emphasis on vascular cell adhesion and motility responses.

  8. An interesting case of angiogenesis in cavernous hemangioma

    Directory of Open Access Journals (Sweden)

    Dipankar Das

    2016-01-01

    Full Text Available Cavernous hemangioma is the most common orbital tumor in adult. There is lot of literatures for clinicopathological features of this tumor. These tumors had been studied for the model of angiogenesis in many of the experimental setups. We present a case of 34-year-old male with this tumor in the left eye with computerized tomography evidence. Postsurgical laboratory findings gave interesting evidence of tumor angiogenesis with tumor endothelial cells and sprouting of the small vessels endothelial cells. Podosome rosette could be conceptualized from the characteristic patterns seen in the tumor.

  9. Angiogenesis factors involved in the pathogenesis of colorectal cancer.

    Science.gov (United States)

    Mihalache, A; Rogoveanu, I

    2014-01-01

    Colorectal cancer stands at the top of oncologic pathology in the world, and in the same measure in Romania because is the third most frequent cancer diagnosed in men and women. Colorectal cancer develops as a result of mutations in genes that control proliferation and cell death. It was established that in the development of a tumor there is originally a prevascular phase followed by a phase of tumor angiogenesis. In the future it is necessary to develop new clinical protocols that angiogenesis inhibitors are associated with chemo or radiotherapy, conventional or other methods such as immunotherapy and gene therapy.

  10. Effect of Curcumin on Angiogenesis in Aortic Ring Model of the Wistar Rat

    Directory of Open Access Journals (Sweden)

    J Baharara

    2014-08-01

    Conclusion: The results proposed that the Curcumin had dose-dependent inhibitory effects on angiogenesis in rat aortic ring Therefore, it can be introduced as an appropriate candidate in order to study angiogenesis and related diseases.

  11. Celecoxib treatment reduces peritoneal fibrosis and angiogenesis and prevents ultrafiltration failure in experimental peritoneal dialysis

    NARCIS (Netherlands)

    Fabbrini, Paolo; Schilte, Margot N.; Zareie, Mammad; ter Wee, Piet M.; Keuning, Eelco D.; Beelen, Robert H. J.; van den Born, Jaap

    2009-01-01

    Background. Daily peritoneal exposure to peritoneal dialysis fluid (PDF) induces severe morphological alterations including fibrosis and angiogenesis that lead to a loss of peritoneal ultrafiltration (UF) capacity. Since cyclooxygenase (COX)-2 is involved in fibrosis and angiogenesis, we investigate

  12. Cardiovascular, renal and thyroid toxicity during angiogenesis inhibition: A translational approach

    NARCIS (Netherlands)

    M.H.W. Kappers (Mariette)

    2011-01-01

    textabstractInhibition of angiogenesis with humanized monoclonal antibodies to vascular endothelial growth factor (VEGF) or with tyrosine kinase inhibitors targeting VEGF receptors has become an established treatment for various tumor types. Contrary to expectations, angiogenesis inhibition by block

  13. Efficacy of Sucralfate Mouth Wash in Prevention of 5-fluorouracil Induced Oral Mucositis: A Prospective, Randomized, Double-Blind, Controlled Trial.

    Science.gov (United States)

    Ala, Shahram; Saeedi, Majid; Janbabai, Ghasem; Ganji, Reza; Azhdari, Elham; Shiva, Afshin

    2016-01-01

    Sucralfate has been used for the prevention and treatment of radiotherapy- and chemotherapy-induced stomatitis and mucositis in a number of studies, but the results are contradictory. To answer such discrepancies, the present study was designed to evaluate the efficacy of sucralfate mouthwash in prevention of 5-fluorouracil (5-FU)-induced oral mucositis in patients with gastrointestinal malignancies. Patients with gastrointestinal cancers receiving 5-FU-based chemotherapy regimens were included in this randomized, blinded, controlled trial and were randomly allocated to either sucralfate mouthwash (every 6 h) or placebo. The patients were visited at fifth and tenth day of trial; the presence and severity of oral mucositis and the intensity of pain were assessed. The patients receiving sucralfate experienced lower frequency and severity of mucositis (76% vs. 38.5%, P = 0.005 and 84 vs. 38.5%, P oral mucositis in patients with gastrointestinal malignancies compared with placebo, indicating its efficacy in the prevention of chemotherapy-induced mucositis.

  14. Comparison of the chloride channel activator lubiprostone and the oral laxative Polyethylene Glycol 3350 on mucosal barrier repair in ischemic-injured porcine intestine

    Institute of Scientific and Technical Information of China (English)

    Adam J Moeser; Prashant K Nighot; Birgit Roerig; Ryuji Ueno; Anthony T Blikslager

    2008-01-01

    AIM: To investigate the effects of lubiprostone and Polyethylene Glycol 3350 (PEG) on mucosal barrier repair in ischemic-injured porcine intestine.METHODS: Ileum from 6 piglets (approximately 15 kg body weight) was subjected to ischemic conditions by occluding the local mesenteric circulation for 45 min in vivo. Ileal tissues from each pig were then harvested and mounted in Ussing chambers and bathed in oxygenated Ringer's solution in vitro. Intestinal barrier function was assessed by measuring transepithelial electrical resistance (TER) and mucosal-to-serosal fluxes of 3H-mannitol and 14C-inulin. Statistical analyses of data collected over a 120-min time course included 2-way ANOVA for the effects of time and treatment on indices of barrier function.RESULTS: Application of 1 μmol/L lubiprostone to the mucosal surface of ischemic-injured ileum in vitro induced significant elevations in TER compared to non-treated tissue. Lubiprostone also reduced mucosal-to-serosal fluxes of 3H-mannitol and 14C-inulin. Alternatively, application of a polyethylene laxative (PEG, 20 mmol/L) to the mucosal surface of ischemic tissues significantly increased flux of 3H-mannitol and 14C-inulin.CONCLUSION: This experiment demonstrates that lubiprostone stimulates recovery of barrier function in ischemic intestinal tissues whereas the PEG laxative had deleterious effects on mucosal repair. These results suggest that, unlike osmotic laxatives, lubiprostone stimulates repair of the injured intestinal barrier.

  15. Palifermin and Chlorhexidine Mouthwashes in Prevention of Chemotherapy-Induced Mucositis in Children with Acute Lymphocytic Leukemia: a Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Narges Gholizadeh

    2016-12-01

    Full Text Available Statement of the Problem: Over the past three decades, significant improvements have been achieved in the survival of children with cancer. However, the considerable morbidity which occurs as a result of chemotherapy often restricts the treatment intensity. One of the important dose-limiting and costly adverse effects of cancer therapy is mucositis. Children with hematological malignancies are greatly at risk of developing mucositis. Purpose: This study aimed to assess the effectiveness of palifermin in preventing mucositis in children with acute lymphocytic leukemia (ALL who undergo chemotherapy. Materials and Method: In this clinical trial, 90 children with ALL were randomized to receive chlorhexidine (n=45 or palifermin (n=45. One group received 60 μg/ kg/ day palifermin as an intravenous bolus once daily for 3 days before and 3 days after the chemotherapy. Chlorhexidine mouthwash was administered once daily for 3 days before and 3 days after the chemotherapy. The world health organization (WHO oral toxicity scale was employed for grading the mucositis. The data were analyzed by using two-way ANOVA. Results: The two groups were matched for age and gender. The study groups were significantly different in terms of mucositis grading (P values after 1 and 2 week therapy were 0.00. Palifermin decreased the incidence and severity of chemotherapy-induced mucositis. Conclusion: Palifermin reduces the oral mucositis in children with ALL. Several mechanisms of action are suggested for keratinocyte growth factor (such as palifermin including promotion of cell proliferation and cytoprotection, restraining the apoptosis, and changing the cytokine profile. Keywords ● Oral Mucositis ● Palifermin ● Leukemia

  16. Protein energy malnutrition alters mucosal IgA responses and reduces mucosal vaccine efficacy in mice.

    Science.gov (United States)

    Rho, Semi; Kim, Heejoo; Shim, Seung Hyun; Lee, Seung Young; Kim, Min Jung; Yang, Bo-Gie; Jang, Myoung Ho; Han, Byung Woo; Song, Man Ki; Czerkinsky, Cecil; Kim, Jae-Ouk

    2017-08-30

    Oral vaccine responsiveness is often lower in children from less developed countries. Childhood malnutrition may be associated with poor immune response to oral vaccines. The present study was designed to investigate whether protein energy malnutrition (PEM) impairs B cell immunity and ultimately reduces oral vaccine efficacy in a mouse model. Purified isocaloric diets containing low protein (1/10 the protein of the control diet) were used to determine the effect of PEM. PEM increased both nonspecific total IgA and oral antigen-specific IgA in serum without alteration of gut permeability. However, PEM decreased oral antigen-specific IgA in feces, which is consistent with decreased expression of polymeric Immunoglobulin receptor (pIgR) in the small intestine. Of note, polymeric IgA was predominant in serum under PEM. In addition, PEM altered B cell development status in the bone marrow and increased the frequency of IgA-secreting B cells, as well as IgA secretion by long-lived plasma cells in the small intestinal lamina propria. Moreover, PEM reduced the protective efficacy of the mucosally administered cholera vaccine and recombinant attenuated Salmonella enterica serovar Typhimurium vaccine in a mouse model. Our results suggest that PEM can impair mucosal immunity where IgA plays an important role in host protection and may partly explain the reduced efficacy of oral vaccines in malnourished subjects. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  17. Comparison of systemic and mucosal immunization with helper-dependent adenoviruses for vaccination against mucosal challenge with SHIV.

    Directory of Open Access Journals (Sweden)

    Eric A Weaver

    Full Text Available Most HIV-1 infections are thought to occur at mucosal surfaces during sexual contact. It has been hypothesized that vaccines delivered at mucosal surfaces may mediate better protection against HIV-1 than vaccines that are delivered systemically. To test this, rhesus macaques were vaccinated by intramuscular (i.m. or intravaginal (ivag. routes with helper-dependent adenoviral (HD-Ad vectors expressing HIV-1 envelope. Macaques were first immunized intranasally with species C Ad serotype 5 (Ad5 prior to serotype-switching with species C HD-Ad6, Ad1, Ad5, and Ad2 vectors expressing env followed by rectal challenge with CCR5-tropic SHIV-SF162P3. Vaccination by the systemic route generated stronger systemic CD8 T cell responses in PBMC, but weaker mucosal responses. Conversely, mucosal immunization generated stronger CD4 T cell central memory (Tcm responses in the colon. Intramuscular immunization generated higher levels of env-binding antibodies, but neither produced neutralizing or cytotoxic antibodies. After mucosal SHIV challenge, both groups controlled SHIV better than control animals. However, more animals in the ivag. group had lower viral set points than in in the i.m. group. These data suggest mucosal vaccination may have improve protection against sexually-transmitted HIV. These data also demonstrate that helper-dependent Ad vaccines can mediate robust vaccine responses in the face of prior immunity to Ad5 and during four rounds of adenovirus vaccination.

  18. Clotrimazole nanoparticle gel for mucosal administration

    Energy Technology Data Exchange (ETDEWEB)

    Esposito, Elisabetta, E-mail: ese@unife.it [Department of Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara (Italy); Ravani, Laura [Department of Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara (Italy); Contado, Catia [Department of Chemistry, University of Ferrara, Ferrara (Italy); Costenaro, Andrea [Department of Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara (Italy); Drechsler, Markus [Macromolecular Chemistry II, University of Bayreuth (Germany); Rossi, Damiano [Department of Biology and Evolution, LT Terra and Acqua Tech UR7, University of Ferrara, Ferrara (Italy); Menegatti, Enea [Department of Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara (Italy); Grandini, Alessandro [Department of Biology and Evolution, LT Terra and Acqua Tech UR7, University of Ferrara, Ferrara (Italy); Cortesi, Rita [Department of Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara (Italy)

    2013-01-01

    In this study a formulation suitable to be applied on oral and/or vaginal mucosa has been developed for the treatment of fungal infections. The aim of the research is a comparison between clotrimazole (CLO) containing semisolid formulations based on monoolein aqueous dispersion (MAD) or nanostructured lipid carrier (NLC). MAD and NLC have been characterized in terms of morphology and dimensional distribution by cryogenic Transmission Electron Microscopy (cryo-TEM) and Photon Correlation Spectroscopy (PCS). CLO was encapsulated with high entrapment efficiency both in MAD and in NLC, according to Sedimentation Field Flow Fractionation (SdFFF) combined with HPLC. CLO recovery in MAD and NLC has been investigated by time. In order to obtain formulations with suitable viscosity for mucosal application, MAD was diluted with a carbomer gel, while NLC was directly viscosized by the addition of poloxamer 407 in the dispersion. The rheological properties of MAD and NLC after viscosizing have been investigated. Franz cell has been employed to study CLO diffusion from the different vehicles, evidencing diffusion rates from MAD and NLC superimposable to that obtained using Canesten{sup Registered-Sign }. An anticandidal activity study demonstrated that both CLO-MAD and CLO-NLC were more active against Candida albicans with respect to the pure drug. Highlights: Black-Right-Pointing-Pointer Comparison between monoolein aqueous dispersion (MAD) and nanostructured lipid carrier (NLC). Black-Right-Pointing-Pointer Clotrimazole (CLO) encapsulated with high entrapment efficiency both in MAD and in NLC. Black-Right-Pointing-Pointer The solid matrix of NLC controls CLO degradation better than MAD. Black-Right-Pointing-Pointer CLO containing MAD and NLC exhibits a higher anticandidal activity than the free drug. Black-Right-Pointing-Pointer Simple production of CLO-NLC based poloxamer gel, suitable for industry scaling up.

  19. Gastric mucosal damage in water immersion stress:Mechanism and prevention with GHRP-6

    Institute of Scientific and Technical Information of China (English)

    Shu Guo; Qian Gao; Qing Jiao; Wei Hao; Xue Gao; Ji-Min Cao

    2012-01-01

    AIM:To investigate the mechanism of gastric mucosal demage induced by water immersion restraint stress (WRS) and its prevention by growth hormone releasing peptide-6 (GHRP-6).METHODS:Male Wistar rats were subjected to conscious or unconscious (anesthetized) WRS,simple restraint (SR),free swimming (FS),non-water fluid immersion,immersion without water contact,or rats were placed in a cage surrounded by sand.To explore the sensitivity structures that influence the stress reaction besides skin stimuli,a group the rats had their eyes occluded.Cervical bilateral trunk vagotomy or atropine injection was performed in some rats to assess the parasympathetic role in mucosal damage.Gastric mucosal lesions,acid output and heart rate variability were measured.Plasma renin,endothelin-1 and thromboxane B2 and gastric heat shock protein 70 were also assayed.GHRP-6 was injected [intraperitoneal (IP) or intracerebroventricular (ICV)]2 h before the onset of stress to observe its potential prevention of the mucosal lesion.RESULTS:WRS for 6 h induced serious gastric mucosal lesion [lesion area,WRS 81.8 ± 6.4 mm2 vs normal control 0.0 ± 0.0 mm2,P < 0.01],decreased the heart rate,and increased the heart rate variability and gastric acid secretion,suggesting an increase in vagal nervecarrying stimuli.The mucosal injury was inversely correlated with water temperature (lesion area,WRS at 35 ℃ 56.4 ± 5.2 mm2 vs WRS at 23 ℃ 81.8 ± 6.4 mm2,P < 0.01) and was consciousness-dependent.The injury could not be prevented by eye occlusion,but could be prevented by avoiding contact of the rat body with the water by dressing it in an impermeable plastic suit.When water was replaced by vegetable oil or liquid paraffin,there were gastric lesions in the same grade of water immersion.When rat were placed in a cage surrounded by sand,there were no gastric lesions.All these data point to a remarkable importance of cutenuous information transmitted to the high neural center that by vagal nerves

  20. Liposomal targeting of glucocorticoids to inhibit tumor angiogenesis

    NARCIS (Netherlands)

    Banciu, M.

    2007-01-01

    Glucocorticoids (GC) have inhibitory actions on solid tumor growth due to suppressive effects on tumor angiogenesis and inflammation. When evaluating the preclinical studies on solid tumor growth inhibition, it appears that GC-induced antitumor effects are achieved by using substantially higher dose

  1. Targeting Angiogenesis in Biliary Tract Cancers: An Open Option

    Directory of Open Access Journals (Sweden)

    Valeria Simone

    2017-02-01

    Full Text Available Biliary tract cancers (BTCs are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF and fibroblast growth factor (FGF, are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2, are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.

  2. Imbalance of angiogenesis in diabetic complications: The mechanisms

    Directory of Open Access Journals (Sweden)

    Zoya Tahergorabi

    2012-01-01

    Full Text Available Type 2 diabetes mellitus is a complex disease and a chronic health-care problem. Nowadays, because of alteration of lifestyle such as lack of exercise, intake of high fat diet subsequently obesity and aging population, the prevalence of diabetes mellitus is increasing quickly in around the world. The international diabetes federation estimated in 2008, that 246 million adults in worldwide suffered from diabetes mellitus and the prevalence of disease is expected to reach to 380 million by 2025. Although, mainly in management of diabetes focused on hyperglycemia, however, it is documented that abnormalities of angiogenesis may contribute in the pathogenesis of diabetes complications. Angiogenesis is the generation of new blood vessels from pre-existing ones. Normal angiogenesis depends on the intricate balance between angiogenic factors (such as VEGF, FGF 2 , TGF-β, angiopoietins and angiostatic factors (angiostatin, endostatin, thrombospondins. Vascular abnormalities in different tissues including retina and kidney can play a role in pathogenesis of micro-vascular complications of diabetes; also vascular impairment contributes in macrovascular complications e.g., diabetic neuropathy and impaired formation of coronary collaterals. Therefore, identifying of different mechanisms of the diabetic complications can give us an opportunity to prevent and/or treat the following complications and improves quality of life for patients and society. In this review, we studied the mechanisms of angiogenesis in micro-vascular and macro-vascular complications of diabetes mellitus.

  3. The enigmatic role of angiopoietin-1 in tumor angiogenesis

    Institute of Scientific and Technical Information of China (English)

    LINDA J METHENY-BARLOW; LU YUAN LI

    2003-01-01

    A tumor vasculature is highly unstable and immature, characterized by a high proliferation rate of endothelial cells,hyper-permeability, and chaotic blood flow. The dysfunctional vasculature gives rise to continual plasma leakage and hypoxia in the tumor, resulting in constant on-sets of inflammation and angiogenesis. Tumors are thus likened to wounds that will not heal. The lack of functional mural cells, including pericytes and vascular smooth muscle cells,in tumor vascular structure contributes significantly to the abnormality of tumor vessels. Angiopoietin- 1 (Angl) is a physiological angiogenesis promoter during embryonic development. The function of Ang 1 is essential to endothelial cell survival, vascular branching, and pericyte recruitment. However, an increasing amount of experimental data suggest that Ang 1-stimulated association of mural cells with endothelial cells lead to stabilization of newly formed blood vessels. This in turn may limit the otherwise continuous angiogenesis in the tumor, and consequently give rise to inhibition of tumor growth. We discuss the enigmatic role of Ang1 in tumor angiogenesis in this review.

  4. Semaphorin 6A regulates angiogenesis by modulating VEGF signaling

    Science.gov (United States)

    Segarra, Marta; Maric, Dragan; Salvucci, Ombretta; Hou, Xu; Kumar, Anil; Li, Xuri; Tosato, Giovanna

    2012-01-01

    Formation of new vessels during development and in the mature mammal generally proceeds through angiogenesis. Although a variety of molecules and signaling pathways are known to underlie endothelial cell sprouting and remodeling during angiogenesis, many aspects of this complex process remain unexplained. Here we show that the transmembrane semaphorin6A (Sema6A) is expressed in endothelial cells, and regulates endothelial cell survival and growth by modulating the expression and signaling of VEGFR2, which is known to maintain endothelial cell viability by autocrine VEGFR signaling. The silencing of Sema6A in primary endothelial cells promotes cell death that is not rescued by exogenous VEGF-A or FGF2, attributable to the loss of prosurvival signaling from endogenous VEGF. Analyses of mouse tissues demonstrate that Sema6A is expressed in angiogenic and remodeling vessels. Mice with null mutations of Sema6A exhibit significant defects in hyaloid vessels complexity associated with increased endothelial cell death, and in retinal vessels development that is abnormally reduced. Adult Sema6A-null mice exhibit reduced tumor, matrigel, and choroidal angiogenesis compared with controls. Sema6A plays important roles in development of the nervous system. Here we show that it also regulates vascular development and adult angiogenesis. PMID:23007403

  5. Angiogenesis in calcium phosphate scaffolds by inorganic copper ion release

    NARCIS (Netherlands)

    Barralet, Jake E.; Gbureck, Uwe; Habibovic, Pamela; Vorndran, Elke; Gerard, Catherine; Doillon, Charles J.

    2009-01-01

    Angiogenesis in a tissue-engineered device may be induced by incorporating growth factors (e.g., vascular endothelial growth factor [VEGF]), genetically modified cells, and/or vascular cells. It represents an important process during the formation and repair of tissue and is essential for

  6. Visualising and quantifying angiogenesis in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Hansen, Torben Frøstrup; Nielsen, Boye Schnack; Jakobsen, Anders

    2013-01-01

    Angiogenesis plays an important role in tumour growth and dissemination. We have recently shown that blood vessel density, determined by image analysis based on microRNA-126 (miRNA-126) in situ hybridization (ISH) in the primary tumours of metastatic colorectal cancers (mCRC), is predictive...

  7. Protein Structure in Context: The Molecular Landscape of Angiogenesis

    Science.gov (United States)

    Span, Elise A.; Goodsell, David S.; Ramchandran, Ramani; Franzen, Margaret A.; Herman, Tim; Sem, Daniel S.

    2013-01-01

    A team of students, educators, and researchers has developed new materials to teach cell signaling within its cellular context. Two nontraditional modalities are employed: physical models, to explore the atomic details of several of the proteins in the angiogenesis signaling cascade, and illustrations of the proteins in their cellular environment,…

  8. Epo is involved in angiogenesis in human glioma.

    Science.gov (United States)

    Nico, Beatrice; Annese, Tiziana; Guidolin, Diego; Finato, Nicoletta; Crivellato, Enrico; Ribatti, Domenico

    2011-03-01

    In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreactivity of tumor cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human glioma specimens, and the effect of anti-Epo antibody on glioma-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane (CAM) has been investigated. Results show that: (1) Epo/EpoR expression correlates with angiogenesis, (2) in the CAM assay, tumor bioptic specimens induce a strong angiogenic response, comparable to that induced by VEGF, and (3) an anti-Epo antibody co-administered with tumor bioptic specimens significantly inhibits the angiogenic response. These findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by glioma tumor cells and it affects glioma vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner. Moreover, as demonstrated by in vivo experiments, Epo is responsible for the strong angiogenic response induced by human glioma bioptic specimens, because an anti-Epo antibody is able to significantly inhibit this response.

  9. Protein Structure in Context: The Molecular Landscape of Angiogenesis

    Science.gov (United States)

    Span, Elise A.; Goodsell, David S.; Ramchandran, Ramani; Franzen, Margaret A.; Herman, Tim; Sem, Daniel S.

    2013-01-01

    A team of students, educators, and researchers has developed new materials to teach cell signaling within its cellular context. Two nontraditional modalities are employed: physical models, to explore the atomic details of several of the proteins in the angiogenesis signaling cascade, and illustrations of the proteins in their cellular environment,…

  10. THE ANGIOGENESIS ASPECTS IN COLO-RECTAL CARCINOMAS

    OpenAIRE

    C. Ivascu; Alice Chirana

    2006-01-01

    Angiogenesis represents the formation and differentiation of blood vessels and is implicated in fisiological processes (embriogenesis, reproductive function, wound curing) as well as in pathological processes (retinian macular degeneration, reumathoid arthrithis, psoriazis, as well as the neoplazic progression and metastasis).The solid tumors need neovascularisation for growth, invasion, and metastasis. The neovascularisation (determined by using Anti CD34 antybod

  11. Advances in the cellular and molecular biology of angiogenesis.

    Science.gov (United States)

    Egginton, Stuart; Bicknell, Roy

    2011-12-01

    Capillaries have been recognized for over a century as one of the most important components in regulating tissue oxygen transport, and their formation or angiogenesis a pivotal element of tissue remodelling during development and adaptation. Clinical interest stems from observations that both excessive and inadequate vascular growth plays a major role in human diseases, and novel developments in treatments for cancer and eye disease increasingly rely on anti-angiogenic therapies. Although the discovery of VEGF (vascular endothelial growth factor) provided the first clue for specificity of signalling in endothelial cell activation, understanding the integrative response that drives angiogenesis requires a much broader perspective. The Advances in the Cellular and Molecular Biology of Angiogenesis meeting brought together researchers at the forefront of this rapidly moving field to provide an update on current understanding, and the most recent insights into molecular and cellular mechanisms of vascular growth. The plenary lecture highlighted the integrative nature of the angiogenic process, whereas invited contributions from basic and clinician scientists described fundamental mechanisms and disease-associated issues of blood vessel formation, grouped under a number of themes to aid discussion. These articles will appeal to academic, clinical and pharmaceutical scientists interested in the molecular and cellular basis of angiogenesis, their modulation or dysfunction in human diseases, and application of these findings towards translational medicine.

  12. Angiogenesis effects of adenovirus-mediated gene transfer of VEGF-B on chronic ischemic myocardium

    Institute of Scientific and Technical Information of China (English)

    DONG Shu-qiang; ZHANG Bao-ren; MEI Ju; XU Zhi-yun; ZOU Liang-jian; HUANG Sheng-dong

    2002-01-01

    Objective: To study the angiogenesis effects of adenovirus-mediated gene transfer of VEGF-B on chronic ischemic myocardium. Methods: Domestic pigs underwent thoracotomy and placement of an ameroid constrictor on the circumflex coronary artery. Four weeks later, Ad. VEGF-B, Ad. LacZ or PBS were administrated directly into the myocardium at 10 sites in the circumflex distribution (109 PFU or 100 μl) according to groups. Echocardiography and ex vivo coronary angiography were performed. The injection sites around myocardium were harvested and subjected to histological analysis and immunochemical staining. Results: Echocardiography assessment 4 weeks after vector administration demonstrated significant improvement of regional wall systolic function. Collateral vesseldevelopment assessed by angiography was also significantly greater in Ad. VEGF-B animals than that in control animals. Vascular density analysis revealed a mean of 43±5 neovessels per high-power field in Ad.VEGF-B group versus 19±4 and 17±6 in Ad.LacZ and PBS group. Conclusion:Direct intramyocardial administration of Ad.VEGF-B can induce focal angiogenesis and result in improvement in regional myocardial function, which may be useful in patients with ischemic heart disease who are not eligible for conventional therapies.

  13. Oral ingestion of Streptococcus thermophilus does not affect mucositis severity or tumor progression in the tumor-bearing rat.

    Science.gov (United States)

    Tooley, Katie L; Howarth, Gordon S; Lymn, Kerry A; Lawrence, Andrew; Butler, Ross N

    2011-07-15

    Preventative or adjunctive agents for the amelioration of small intestinal chemotherapy-induced mucositis are not currently available for clinical use. We have previously demonstrated that oral ingestion of Streptococcus thermophilus (TH-4) partially attenuated chemotherapy-induced mucositis in the rat. Here we assess the effects of TH-4 on small intestinal damage and tumor progression in tumor-bearing rats with experimentally-induced mucositis. Female Dark Agouti tumor-bearing (mammary adenocarcinoma) rats (n = 36; 139 ± 1 g) had small intestinal damage induced via the administration of methotrexate (MTX). Rats were administered MTX; (1.5 mg/kg intramuscular) or saline at 0 and 24 h; with daily gavage administration of TH-4 (109 cfu/mL) or skim milk from -48 to +96 h post-MTX. Rats were allocated to groups (n=9): saline control, TH-4 control, MTX control or TH-4+MTX. The non-invasive ( 13) C-sucrose breath test (SBT) was conducted prior to tumor inoculation, pre-MTX (-24 h) and prior to sacrifice (96 h) to monitor gut function. At sacrifice small intestinal segments were excised and assessed for sucrase and myeloperoxidase activity as well as histological damage. Irrespective of TH-4 treatment, MTX-treated rats had a significant decrease in bodyweight, SBT levels, sucrase and myeloperoxidase activity, and histological damage score (p 0.05) but failed to alleviate mucositis indices. Although TH-4, at a dose of 109 cfu/mL, yielded neither protection nor amelioration of chemotherapy-induced mucositis, progression of mammary adenocarcinoma was unaffected.

  14. Local glutathione redox status does not regulate ileal mucosal growth after massive small bowel resection in rats.

    Science.gov (United States)

    Tian, Junqiang; Washizawa, Naohiro; Gu, Li H; Levin, Marc S; Wang, Lihua; Rubin, Deborah C; Mwangi, Simon; Srinivasan, Shanthi; Jones, Dean P; Ziegler, Thomas R

    2007-02-01

    Glutathione (GSH) concentration affects cell proliferation and apoptosis in intestinal and other cell lines in vitro. However, in vivo data on gut mucosal GSH redox status and cell turnover are limited. We investigated the effect of altered GSH redox status on the ileal mucosa in a rat model of short bowel syndrome following massive small bowel resection (SBR). Rats underwent 80% mid-jejunoileal resection (RX) or small bowel transection (TX; as operative controls), with administration of either saline or D, L-buthionine-sulfoximine (BSO), a specific inhibitor of cellular GSH synthesis. Ileal mucosal redox, morphology, and indices of cell proliferation and apoptosis were determined at different days after surgery. Ileal GSH redox status was assessed by GSH and GSH disulfide (GSSG) concentrations and the redox potential of GSH/GSSG (Eh). Ileal lipid peroxidation [free malondialdehyde (MDA)] was measured as an index of lipid peroxidation. BSO markedly decreased ileal mucosal GSH, oxidized GSH/GSSG Eh, and increased MDA content without inducing morphological damage as assessed by light or electron microscopy. As expected, SBR stimulated adaptive growth of ileal villus height and total mucosal height at 7 d after surgery, but this response was unaffected by BSO treatment despite a modest increase in crypt cell apoptosis. Ileal cell proliferation (crypt cell bromodeoxyuridine incorporation) increased at 2 d after SBR but was unaffected by BSO. Collectively, our in vivo data show that marked depletion of ileal GSH and oxidation of the GSH redox pool does not alter indices of ileal epithelial proliferation or SBR-induced ileal mucosal adaptive growth.

  15. SNP-SNP interaction network in angiogenesis genes associated with prostate cancer aggressiveness.

    Directory of Open Access Journals (Sweden)

    Hui-Yi Lin

    Full Text Available Angiogenesis has been shown to be associated with prostate cancer development. The majority of prostate cancer studies focused on individual single nucleotide polymorphisms (SNPs while SNP-SNP interactions are suggested having a great impact on unveiling the underlying mechanism of complex disease. Using 1,151 prostate cancer patients in the Cancer Genetic Markers of Susceptibility (CGEMS dataset, 2,651 SNPs in the angiogenesis genes associated with prostate cancer aggressiveness were evaluated. SNP-SNP interactions were primarily assessed using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM approach in the CGEMS group, and were then re-evaluated in the Moffitt group with 1,040 patients. For the identified gene pairs, cross-evaluation was applied to evaluate SNP interactions in both study groups. Five SNP-SNP interactions in three gene pairs (MMP16+ ROBO1, MMP16+ CSF1, and MMP16+ EGFR were identified to be associated with aggressive prostate cancer in both groups. Three pairs of SNPs (rs1477908+ rs1387665, rs1467251+ rs7625555, and rs1824717+ rs7625555 were in MMP16 and ROBO1, one pair (rs2176771+ rs333970 in MMP16 and CSF1, and one pair (rs1401862+ rs6964705 in MMP16 and EGFR. The results suggest that MMP16 may play an important role in prostate cancer aggressiveness. By integrating our novel findings and available biomedical literature, a hypothetical gene interaction network was proposed. This network demonstrates that our identified SNP-SNP interactions are biologically relevant and shows that EGFR may be the hub for the interactions. The findings provide valuable information to identify genotype combinations at risk of developing aggressive prostate cancer and improve understanding on the genetic etiology of angiogenesis associated with prostate cancer aggressiveness.

  16. Liver angiogenesis as a risk factor for hepatocellular carcinoma development in hepatitis C virus cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To evaluate the predictive value of hepatocyte proliferation and hepatic angiogenesis for the occurrence of Hepatocellular carcinoma (HCC) in hepatitis C virus(HCV) cirrhotic patients.METHODS: One hundred-five patients (69 males,36 females; age range, 51-90 year; median 66 year)with biopsy proven HCV cirrhosis were prospectively monitored for HCC occurrence for a median time of 64 mo. Angiogenesis was assessed by using microvessel density (MVD), hepatocyte turnover by MIB1 and PCNA indexes at inclusion in liver biopsies.RESULTS: Forty six patients (43.8%) developed HCC after a median time of 55 (6-120) mo while 59 (56.2%)did not. Patients were divided into two groups according to the median value of each index. The difference between patients with low (median MVD = 3; range 0-20) and high (median MVD = 7; range 1-24) MVD was statistically significant (χ2 = 22.06; P < 0.0001) which was not the case for MIB1 or PCNA (MIB-1: χ2 = 1.41;P = 0.2351; PCNA: χ2 = 1.27; P = 0.2589). The median MVD was higher in patients who developed HCC than in those who did not. HCC-free interval was significantly longer in patients with the MVD ≤ 4 (P = 0.0006).No relationship was found between MIB1 or PCNA and MVD (MIB-1 r2 = 0.00007116, P = 0.9281; PCNA: r2 =0.001950; P = 0.6692). MVD only was able to predict the occurrence of HCC in these patients. Among other known risk factors for HCC, only male sex was statistically associated with an increased risk.CONCLUSION: Liver angiogenesis has a role for in HCVrelated liver carcinogenesis and for defining patients at higher risk.

  17. Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb.

    Science.gov (United States)

    Silvestre, Jean-Sébastien; Tamarat, Radia; Senbonmatsu, Takaaki; Icchiki, Toshihiro; Ebrahimian, Teni; Iglarz, Marc; Besnard, Sandrine; Duriez, Micheline; Inagami, Tadashi; Lévy, Bernard I

    2002-05-31

    This study examined the potential role of angiotensin type 2 (AT(2)) receptor on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by femoral artery ligature in both wild-type and AT(2) gene-deleted mice (Agtr2(-)/Y). After 28 days, angiogenesis was quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. Protein levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), Bax, and Bcl-2 were determined by Western blot analysis in hindlimbs. The AT(2) mRNA level (assessed by semiquantitative RT-PCR) was increased in the ischemic hindlimb of wild-type mice. Angiographic vessel density and laser Doppler perfusion data showed significant improvement in ischemic/nonischemic leg ratio, 1.9- and 1.7-fold, respectively, in Agtr2(-)/Y mice compared with controls. In ischemic leg of Agtr2(-)/Y mice, revascularization was associated with an increase in the antiapoptotic protein content, Bcl-2 (211% of basal), and a decrease (60% of basal) in the number of cell death, determined by TUNEL method. Angiotensin II treatment (0.3 mg/kg per day) raised angiogenic score, blood perfusion, and both VEGF and eNOS protein content in ischemic leg of wild-type control but did not modulate the enhanced angiogenic response observed in untreated Agtr2(-)/Y mice. Finally, immunohistochemistry analysis revealed that VEGF was mainly localized to myocyte, whereas eNOS-positive staining was mainly observed in the capillary of ischemic leg of both wild-type and AT(2)-deficient mice. This study demonstrates for the first time that the AT(2) receptor subtype may negatively modulate ischemia-induced angiogenesis through an activation of the apoptotic process.

  18. Intestinal colonization with Candida albicans and mucosal immunity

    Institute of Scientific and Technical Information of China (English)

    Xiao-Dong Bai; Xian-Hua Liu; Qing-Ying Tong

    2004-01-01

    AIM: To observe the relationship between intestinal lumen colonization with Candida albicans and mucosal secretory IgA (sIgA).METHODS: A total of 82 specific-pathogen-free mice were divided randomly into control and colonization groups. After Candida albicans were inoculated into specific-pathogenfree mice, the number of Candida albicans adhering to cecum and mucosal membrane was counted. The lymphocyte proliferation in Peyer's patch and in lamina propria was shown by BrdU incorporation, while mucosal sIgA (surface membrane) isotype switch in Peyer's patch was investigated. IgA plasma cells in lamina propria were observed by immunohistochemical staining. Specific IgA antibodies to Candida albicans were measured with ELISA.RESULTS: From d 3 to d 14 after Candida albicans gavaging to mice, the number of Candida albicans colonizing in lumen and adhering to mucosal membrane was sharply reduced.Candida albicans translocation to mesenteric lymph nodes occurred at early time points following gavage administration and disappeared at later time points. Meanwhile, the content of specific IgA was increased obviously. Proliferation and differentiation of lymphocytes in lamina propria were also increased.CONCLUSION: Lymphocytes in lamina propria play an important role in intestinal mucosal immunity of specificpathogen-free mice when they are first inoculated with Candida albicans. The decreasing number of Candida albicans in intestine is related to the increased level of specific IgA antibodies in the intestinal mucus.

  19. Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants.

    Science.gov (United States)

    Suzuki, M; Miura, S; Mori, M; Kai, A; Suzuki, H; Fukumura, D; Suematsu, M; Tsuchiya, M

    1994-01-01

    The effect of rebamipide, a novel antiulcer compound, on Helicobacter pylori activated neutrophil dependent in vitro gastric epithelial cell injury was investigated. Luminol dependent chemiluminescence (ChL), which detects toxic oxidants from neutrophils exhibited a 12-fold increase when the bacterial suspension of H pylori was added to the isolated human neutrophils. This change was significantly attenuated by rebamipide at a concentration less than 1 mM, showing that rebamipide may inhibit oxidant production from H pylori elicited neutrophils. To assess whether rebamipide attenuates gastric mucosal injury, we tested its inhibitory action on H pylori induced gastric mucosal damage associated with neutrophils in vitro. Rabbit gastric mucosal cells were monolayered in culture wells and coincubated with human neutrophils and H pylori, and the cytotoxicity index was then calculated. Cultured gastric cells were significantly damaged when they were incubated with human neutrophils activated by H pylori. This cellular damage was attenuated by rebamipide in a dose-dependent manner. Furthermore, spectrophotometrical measurement showed that rebamipide (1 mM) inhibits urease activity by 21.7%. As monochloramine (an oxidant yielded by reaction of neutrophil derived chlorinated oxidant and ammonia) is proposed as an important toxic molecule in this model, the current findings suggest that the preventive effect of rebamipide on H pylori elicited neutrophil induced gastric mucosal injury may result from its inhibitory actions on the neutrophilic oxidative burst as well as H pylori derived urease activity. PMID:7959190

  20. Fucoidan inhibits angiogenesis induced by multiple myeloma cells.

    Science.gov (United States)

    Liu, Fen; Luo, Guoping; Xiao, Qing; Chen, Liping; Luo, Xiaohua; Lv, Jinglong; Chen, Lixue

    2016-10-01

    Multiple myeloma (MM) remains an incurable hematological neoplasms. Our previous studies showed that Fucoidan possessed anti-myeloma effect by inducing apoptosis and inhibiting invasion of myeloma cells. In this study, we evaluated the effect of Fucoidan on angiogenesis induced by human myeloma cells and elucidated its possible mechanisms. Multiple myeloma cells were treated with Fucoidan at different concentrations, then the conditioned medium (CM) was collected. The levels of VEGF in the CM were tested by ELISA. The results showed that Fucoidan significantly decreased VEGF secretion by RPMI-8226 and U266 cells. The tube formation assay and migration test on human umbilical vein endothelial cells (HUVECs) were used to examine the effect of Fucoidan on angiogenesis induced by human myeloma cells. The results showed that Fucoidan decreased HUVECs formed tube structures and inhibited HUVECs migration, and suppressed the angiogenic ability of multiple myeloma RPMI-8226 and U266 cells in a dose-dependent manner. The study also showed that Fucoidan downregulated the expression of several kinds of proteins, which may be correlated with the reduction of angiogenesis induced by myeloma cells. Moreover, results were compared from normoxic and hypoxic conditions, they showed that Fucoidan had anti-angiogenic activity. Furthermore, in a multiple myeloma xenograft mouse model, it indicated that Fucoidan negatively affected tumor growth and angiogenesis in vivo. In conclusion, our results demonstrate that Fucoidan was able to interfere with angiogenesis of multiple myeloma cells both in vitro and in vivo and may have a substantial potential in the treatment of MM.

  1. Angiogenesis dysregulation in term asphyxiated newborns treated with hypothermia.

    Directory of Open Access Journals (Sweden)

    Henna Shaikh

    Full Text Available Neonatal encephalopathy following birth asphyxia is a major predictor of long-term neurological impairment. Therapeutic hypothermia is currently the standard of care to prevent brain injury in asphyxiated newborns but is not protective in all cases. More robust and versatile treatment options are needed. Angiogenesis is a demonstrated therapeutic target in adult stroke. However, no systematic study examines the expression of angiogenesis-related markers following birth asphyxia in human newborns.This study aimed to evaluate the expression of angiogenesis-related protein markers in asphyxiated newborns developing and not developing brain injury compared to healthy control newborns.Twelve asphyxiated newborns treated with hypothermia were prospectively enrolled; six developed eventual brain injury and six did not. Four healthy control newborns were also included. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study the plasma concentration of 49 angiogenesis-related proteins. Mean protein concentrations were compared between each group of newborns.Compared to healthy newborns, asphyxiated newborns not developing brain injury showed up-regulation of pro-angiogenic proteins, including fatty acid binding protein-4, glucose-6-phosphate isomerase, neuropilin-1, and receptor tyrosine-protein kinase erbB-3; this up-regulation was not evident in asphyxiated newborns eventually developing brain injury. Also, asphyxiated newborns developing brain injury showed a decreased expression of anti-angiogenic proteins, including insulin-growth factor binding proteins -1, -4, and -6, compared to healthy newborns.These findings suggest that angiogenesis pathways are dysregulated following birth asphyxia and are putatively involved in brain injury pathology and recovery.

  2. Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies

    Science.gov (United States)

    Cheeseman, Hannah M.; Olejniczak, Natalia J.; Rogers, Paul M.; Evans, Abbey B.; King, Deborah F. L.; Ziprin, Paul; Liao, Hua-Xin; Haynes, Barton F.

    2016-01-01

    tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies. PMID:27795431

  3. Selective tissue elevation by pressure injection (STEP) facilitates endoscopic mucosal resection (EMR).

    Science.gov (United States)

    Kähler, Georg F B A; Sold, Moritz S; Post, Stefan; Fischer, Klaus; Enderle, Markus D

    2007-01-01

    Endoscopic mucosal resection and endoscopic submucosal dissection have become more common in treatment of flat superficial tumors of the gastrointestinal tract. Submucosal injection is used to try to avoid complications and improve the technical feasibility of the procedure. However, the method has its limitations, particularly when treating extensive flat tumors in the colon. The water-jet dissector has already demonstrated its capacity for selective cutting with the dissection of parenchymatous. This chapter addresses a new indication, transmucosal mucosal elevation, together with first clinical results. After carrying out animal experiments into the physical properties using animal preparations and freshly resected human specimens from operations, our work group investigated and compared the applicability of the procedure using different carrier fluids. Six test substances-hydroxyethyl starch (HES), Gelafusal, Infukoll, Glucose 50 und isotonic saline solution-were injected into six anesthetized pigs; the height of the submucosal fluid cushion created by the injection was measured endosonographically over a period of 45 minutes. Endoscopic mucosal resection was subsequently carried out, and the resected specimen together with the area it was taken from were assessed histologically. Using commercially available NaCl cartridges, applied by the way of endocapillaries, 18 lesions were elevated in a series of 12 patients and subsequently resected endoscopically. All investigated substances could be applied without difficulty using the Helix HydroJet (Erbe Elektromedizin GmbH, Waldhörnle-Str., Tübingen, Germany). The plasma expanders (HES and Gelafundin 4%, B. Braun Melsungen AG, Melsungen, Germany) produced longer lasting fluid cushions than the isotonic solutions. Mucosal resections could be carried out in all cases with all of the solutions. Histological investigation confirmed the selective nature of the fluid accumulation in the submucosal tissue, which spared

  4. Oral mucosal alterations among the institutionalized elderly in Brazil

    Directory of Open Access Journals (Sweden)

    Raquel Conceição Ferreira

    2010-09-01

    Full Text Available This study determined the prevalence of oral mucosal alterations and associated factors among the institutionalized elderly in Brazil. Data were collected through a structured questionnaire, a review of their medical records and an intra-oral examination. A sample of 335 individuals over 60 years of age was randomly selected. In total, 646 alterations were diagnosed; 59.1% were variations of the normal oral mucosa. The most frequent variation consisted of sublingual varicosities (51.6%. Denture stomatitis (15.2% and denture hyperplasia (12.8% were the most frequent lesions. Elderly patients who wore dentures had a significantly higher prevalence of oral mucosal lesions (p = 0.00 than those that didn't wear dentures. There was a high prevalence of variations of the normal oral mucosa and of mucosal lesions, especially denture-induced lesions, among the institutionalized elderly.

  5. Mucosal immunity in the gut: the non-vertebrate perspective.

    Science.gov (United States)

    Garcia-Garcia, Erick; Galindo-Villegas, Jorge; Mulero, Victor

    2013-01-01

    Much is now known about the vertebrate mechanisms involved in mucosal immunity, and the requirement of commensal microbiota at mucosal surfaces for the proper functioning of the immune system. In comparison, very little is known about the mechanisms of immunity at the barrier epithelia of non-vertebrate organisms. The purpose of this review is to summarize key experimental evidence illustrating how non-vertebrate immune mechanisms at barrier epithelia compare to those of higher vertebrates, using the gut as a model organ. Not only effector mechanisms of gut immunity are similar between vertebrates and non-vertebrates, but it also seems that the proper functioning of non-vertebrate gut defense mechanisms requires the presence of a resident microbiota. As more information becomes available, it will be possible to obtain a more accurate picture of how mucosal immunity has evolved, and how it adapts to the organisms' life styles.

  6. Potential Benefits of Oral Cryotherapy for Chemotherapy-Induced Mucositis.

    Science.gov (United States)

    Wodzinski, Amelia

    2016-10-01

    Mucositis is a common side effect of cancer therapies that causes painful, erythematous lesions to develop in the gastrointestinal tract. These lesions can lead to malnutrition, increased risk for serious infection, prolonged hospital stays, and reduced quality of life. Oral cryotherapy, or the use of ice chips to cool the mucous membranes during bolus chemotherapy infusions (e.g., 5-fluorouracil [Adrucil®] and melphalan [Alkeran®]), is the most readily accessible and cost-effective intervention available. Although many factors may contribute to the development of mucositis during cancer treatment, studies have found a reduction in the incidence and the severity of mucositis with the use of oral cryotherapy.


  7. Peptic ulcer pathophysiology: acid, bicarbonate, and mucosal function

    DEFF Research Database (Denmark)

    Højgaard, L; Mertz Nielsen, A; Rune, S J

    1996-01-01

    The previously accepted role of gastric acid hypersecretion in peptic ulcer disease has been modified by studies showing no correlation between acid output and clinical outcome of ulcer disease, or between ulcer recurrence rate after vagotomy and preoperative acid secretion. At the same time......, studies have been unable to demonstrate increased acidity in the duodenal bulb in patients with duodenal ulcer, and consequently more emphasis has been given to the mucosal protecting mechanisms. The existence of an active gastric and duodenal mucosal bicarbonate secretion creates a pH gradient from...... cell removal and repair regulated by epidermal growth factor. Sufficient mucosal blood flow, including a normal acid/base balance, is important for subepithelial protection. In today's model of ulcer pathogenesis, gastric acid and H. pylori work in concert as aggressive factors, with the open question...

  8. Prediction of Acute Radiation Mucositis using an Oral Mucosal Dose Surface Model in Carbon Ion Radiotherapy for Head and Neck Tumors.

    Directory of Open Access Journals (Sweden)

    Atsushi Musha

    Full Text Available To evaluate the dose-response relationship for development of acute radiation mucositis (ARM using an oral mucosal dose surface model (OMDS-model in carbon ion radiotherapy (C-ion RT for head and neck tumors.Thirty-nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0, and the Radiation Therapy Oncology Group (RTOG scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient.The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2-3 ARM in the palate and tongue were 43.0 Gy(RBE and 54.3 Gy(RBE, respectively.The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2-3 ARM.

  9. Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Xiaohai; Li, Jinfeng; Zhuo, Jianxin [Department of General Surgery, The Second People' s Hospital of Yueqing, Yueqing 325608 (China); Cai, Liuxin, E-mail: liuxcai08@googlemail.com [Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Linhai 317000 (China)

    2010-12-17

    Research highlights: {yields} Reconstitution of ARHI suppresses the growth of HCC xenografts. {yields} ARHI reexpression impairs tumor angiogenesis in vivo. {yields} Inhibition of the mTOR/VEGF signaling by forced expression of ARHI. {yields} Manipulating ARHI may be of therapeutic benefit in treatment of ARHI-negative HCCs. -- Abstract: The Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI) is frequently downregulated in many types of cancer, including hepatocellular carcinoma (HCC). In this study, we sought to explore the therapeutic implications of ARHI reconstitution in the treatment of HCC. We generated stable cell lines overexpressing ARHI in Hep3B and SK-Hep1 cells, both of which lack endogenous ARHI. The effects of ARHI reexpression on tumor growth and angiogenesis were assessed. Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway. Forced expression of ARHI resulted in a significant inhibition of the proliferation of both Hep3B and SK-Hep1 cells compared to control cells (P < 0.01). Cell cycle analysis revealed a G0-G1 arrest induced by ARHI reexpression. Moreover, ARHI reexpression significantly retarded Hep3B xenograft growth in vivo, and caused a marked reduction in tumor angiogenesis assessed by CD31-stained microvessel count. Western blot analysis of the xenografts showed that ARHI overexpression substantially reduced the phosphorylation of two mTOR substrates, S6K1 and 4E-BP1, indicative of an inactivation of the mTOR pathway. Accompanying with the mTOR inactivation, the angiogenic factors, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, were significantly downregulated. These data highlighted an important role for ARHI in controlling HCC growth and angiogenesis, therefore offering a possible therapeutic strategy against this malignancy.

  10. Enhanced mucosal reactions in AIDS patients receiving oropharyngeal irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Watkins, E.B.; Findlay, P.; Gelmann, E.; Lane, H.C.; Zabell, A.

    1987-09-01

    The oropharynx and hypopharynx are common sites of involvement in AIDS patients with mucocutaneous Kaposi's sarcoma. The radiotherapist is often asked to intervene with these patients due to problems with pain, difficulty in swallowing, or impending airway obstruction. We have noted an unexpected decrease in normal tissue tolerance of the oropharyngeal mucosa to irradiation in AIDS patients treated in our department. Data on 12 patients with AIDS and Kaposi's sarcoma receiving oropharyngeal irradiation are presented here. Doses ranged from 1000 cGy to 1800 cGy delivered in 150-300 cGy fractions. Seven of eight patients receiving doses of 1200 cGy or more developed some degree of mucositis, four of these developed mucositis severe enough to require termination of treatment. All patients in this study received some form of systemic therapy during the course of their disease, but no influence on mucosal response to irradiation was noted. Four patients received total body skin electron treatments, but no effect on degree of mucositis was seen. Presence or absence of oral candidiasis was not an obvious factor in the radiation response of the oral mucosa in these patients. T4 counts were done on 9 of the 12 patients. Although the timing of the T4 counts was quite variable, no correlation with immune status and degree of mucositis was found. The degree of mucositis seen in these patients occurred at doses much lower than expected based on normal tissue tolerances seen in other patient populations receiving head and neck irradiations. We believe that the ability of the oral mucosa to repair radiation damage is somehow altered in patients with AIDS.

  11. Evaluation of Mucosal and Systemic Immune Responses Elicited by GPI-0100-Adjuvanted Influenza Vaccine Delivered by Different Immunization Strategies

    NARCIS (Netherlands)

    Liu, Heng; Patil, Harshad P.; de Vries-Idema, Jacqueline; Wilschut, Jan; Huckriede, Anke

    2013-01-01

    Vaccines for protection against respiratory infections should optimally induce a mucosal immune response in the respiratory tract in addition to a systemic immune response. However, current parenteral immunization modalities generally fail to induce mucosal immunity, while mucosal vaccine delivery

  12. Esophageal sensitivity to acid in patients with Barrett's esophagus is not related to preserved esophageal mucosal integrity.

    Science.gov (United States)

    Weijenborg, P W; Smout, A J P M; Krishnadath, K K; Bergman, J G H M; Verheij, J; Bredenoord, A J

    2017-07-01

    Patients with Barrett's esophagus (BE) usually have severe gastroesophageal reflux. However, they often have surprisingly few reflux symptoms. We hypothesized that BE patients are less sensitive to acid than gastroesophageal reflux disease (GERD) patients without Barrett and that this is due to an unusual preservation of mucosal integrity of the squamous epithelium prohibiting transepithelial acid diffusion. We prospectively analyzed esophageal sensitivity and esophageal mucosal integrity in GERD patients with and without BE and healthy subjects. An acid perfusion test was performed and mucosal integrity was assessed in vivo by electrical tissue impedance spectroscopy and ex vivo by Ussing chamber experiments with biopsy specimens. Gastroesophageal reflux disease patients with BE were less sensitive to acid than GERD patients without BE, but more sensitive to acid than healthy controls (time to perception Barrett's 14.0 minutes, GERD 4.6 minutes, controls 17.5 minutes). However, extracellular impedance (6.2 and 5.7 vs 8.4×10(3)  Ω/m) and transepithelial resistance (94.0 and 89 vs 118 Ω/cm(2) ) was similar in BE and GERD patients and significantly lower than in healthy subjects. Transepithelial fluorescein flux was equally increased in GERD patients with and without BE (1.6 and 1.7×10(3) vs 0.6×10(3)  nmol/cm(2) /h). Esophageal hypersensitivity to acid is less pronounced in BE patients than in GERD patients without Barrett. However, mucosal integrity of the squamous epithelium is equally impaired in GERD patients with and without Barrett, indicating that factors other than esophageal mucosal barrier integrity explain the difference in acid sensitivity between those with BE and those without. © 2017 John Wiley & Sons Ltd.

  13. Synthesis and biological evaluation of salicylic acid conjugated isoxazoline analogues on immune cell proliferation and angiogenesis.

    Science.gov (United States)

    Puttaswamy, Naveen; Pavan Kumar, G S; Al-Ghorbani, Mohammed; Vigneshwaran, V; Prabhakar, B T; Khanum, Shaukath Ara

    2016-05-23

    Mitogenicity is the ability of the natural or synthetic compounds to induce cell division or proliferation. A series of salicylic acid derivatives containing isoxazoline moiety (8a-j) were synthesized and their immunopharmacological activities targeting lymphocyte proliferation and angiogenesis were evaluated. The compounds 8a-j mitogenicity were investigated on immunological cells that include human peripheral blood lymphocytes and murine splenocytes in-vitro. The results implicate that among the series of 8a-j, compound 8e showed a potent proliferative response on both human and murine lymphocytes. The proliferative index of the compound 8e was comparable to the reference mitogen Con A and mitogenecity is due to increased secretion IL-2. In -vivo CAM and rat corneal angiogenesis assays were performed to assess the compound's effect on endothelial cell migration and proliferation which inferred that 8e also induces the proliferation of endothelial cells. The study reports the synthetic immunostimulatory and pro-angiogenic activity of novel mitogen 8e which could be translated into new drug in future.

  14. Functional CT imaging of angiogenesis in rabbit VX2 soft-tissue tumour

    Science.gov (United States)

    Purdie, Thomas G.; Henderson, Elizabeth; Lee, Ting-Yim

    2001-12-01

    Functional parameters such as blood flow (BF), microvessel permeability surface area product (PS), blood volume (BV) and mean transit time (MTT) are physiological markers related to the changes associated with angiogenesis. In the current study we present a functional CT technique for the simultaneous measurement of these four functional parameters and the display of each parameter as a functional image over an entire tissue slice. New Zealand White rabbits with implanted VX2 thigh tumours were scanned using CT with contrast media injection. The ex vivo method of radioactive microspheres was used to evaluate the accuracy of BF measurements with the functional CT technique. There was a significant linear correlation (R = 0.96) between regional CT and microsphere-measured BF values, with a slope not significantly different from unity (0.98 +/- 0.02, P precision of our CT technique was determined by the repeated scanning under steady-state conditions. The precision of CT-measured BF, PS, BV and MTT was 14%, 18%, 20% and 24%, respectively. In conclusion, BF can be measured accurately and BF, PS, BV and MTT reproducibly using our functional CT technique. Functional CT can be readily incorporated into existing imaging protocols to assess tumour angiogenesis.

  15. Brazilian Green Propolis Inhibits Inflammatory Angiogenesis in a Murine Sponge Model

    Directory of Open Access Journals (Sweden)

    Sandra Aparecida Lima de Moura

    2011-01-01

    Full Text Available Angiogenesis and inflammation are persistent features of several pathological conditions. Propolis, a sticky material that honeybees collect from living plants, has been reported to have multiple biological effects including anti-inflammatory and anti-neoplasic activities. Here, we investigated the effects of water extract of green propolis (WEP on angiogenesis, inflammatory cell accumulation and endogenous production of cytokines in sponge implants of mice over a 14-day period. Blood vessel formation as assessed by hemoglobin content and by morphometric analysis of the implants was reduced by WEP (500 mg kg−1 orally compared to the untreated group. The levels of vascular endothelial growth factor (VEGF increased progressively in the treated group but decreased after Day 10 in the control group. Accumulation of neutrophils and macrophages was determined by measuring myeloperoxidase (MPO and N-acetyl-β-D-glucosaminidase (NAG activities, respectively. Neutrophil accumulation was unaffected by propolis, but NAG activity was reduced by the treatment at Day 14. The levels TGF-β1 intra-implant increased progressively in both groups but were higher (40% at Day 14 in the control implants. The pro-inflammatory levels of TNF-α peaked at Day 7 in the control implants, and at Day 14 in the propolis-treated group. Our results indicate that the anti-inflammatory/anti-angiogenic effects of propolis are associated with cytokine modulation.

  16. Identification of Target Genes Involved in Wound Healing Angiogenesis of Endothelial Cells with the Treatment of a Chinese 2-Herb Formula.

    Science.gov (United States)

    Tam, Jacqueline Chor Wing; Ko, Chun Hay; Koon, Chi Man; Cheng, Zhang; Lok, Wong Hing; Lau, Ching Po; Leung, Ping Chung; Fung, Kwok Pui; Chan, Wai Yee; Lau, Clara Bik San

    2015-01-01

    Angiogenesis is vitally important in diabetic wound healing. We had previously demonstrated that a Chinese 2-herb formula (NF3) significantly stimulated angiogenesis of HUVEC in wound healing. However, the molecular mechanism has not yet been elucidated. In line with this, global expression profiling of NF3-treated HUVEC was performed so as to assess the regulatory role of NF3 involved in the underlying signaling pathways in wound healing angiogenesis. The microarray results illustrated that different panels of differentially expressed genes were strictly governed in NF3-treated HUVEC in a time-regulated manner. The microarray analysis followed by qRT-PCR and western blotting verification of NF3-treated HUVEC at 6 h revealed the involvement of various genes in diverse biological process, e.g., MAP3K14 in anti-inflammation; SLC5A8 in anti-tumorogenesis; DNAJB7 in protein translation; BIRC5, EPCAM, INSL4, MMP8 and NPR3 in cell proliferation; CXCR7, EPCAM, HAND1 and MMP8 in migration; CXCR7, EPCAM and MMP8 in tubular formation; and BIRC5, CXCR7, EPCAM, HAND1, MMP8 and UBD in angiogenesis. After 16 h incubation of NF3, other sets of genes were shown with differential expression in HUVEC, e.g., IL1RAPL2 and NR1H4 in anti-inflammation; miR28 in anti-tumorogenesis; GRIN1 and LCN1 in anti-oxidation; EPB41 in intracellular signal transduction; PRL and TFAP2A in cell proliferation; miR28, PRL and SCG2 in cell migration; PRL in tubular formation; and miR28, NR1H4 and PRL in angiogenesis. This study provided concrete scientific evidence in support of the regulatory role of NF3 on endothelial cells involved in wound healing angiogenesis.

  17. Identification of Target Genes Involved in Wound Healing Angiogenesis of Endothelial Cells with the Treatment of a Chinese 2-Herb Formula.

    Directory of Open Access Journals (Sweden)

    Jacqueline Chor Wing Tam

    Full Text Available Angiogenesis is vitally important in diabetic wound healing. We had previously demonstrated that a Chinese 2-herb formula (NF3 significantly stimulated angiogenesis of HUVEC in wound healing. However, the molecular mechanism has not yet been elucidated. In line with this, global expression profiling of NF3-treated HUVEC was performed so as to assess the regulatory role of NF3 involved in the underlying signaling pathways in wound healing angiogenesis. The microarray results illustrated that different panels of differentially expressed genes were strictly governed in NF3-treated HUVEC in a time-regulated manner. The microarray analysis followed by qRT-PCR and western blotting verification of NF3-treated HUVEC at 6 h revealed the involvement of various genes in diverse biological process, e.g., MAP3K14 in anti-inflammation; SLC5A8 in anti-tumorogenesis; DNAJB7 in protein translation; BIRC5, EPCAM, INSL4, MMP8 and NPR3 in cell proliferation; CXCR7, EPCAM, HAND1 and MMP8 in migration; CXCR7, EPCAM and MMP8 in tubular formation; and BIRC5, CXCR7, EPCAM, HAND1, MMP8 and UBD in angiogenesis. After 16 h incubation of NF3, other sets of genes were shown with differential expression in HUVEC, e.g., IL1RAPL2 and NR1H4 in anti-inflammation; miR28 in anti-tumorogenesis; GRIN1 and LCN1 in anti-oxidation; EPB41 in intracellular signal transduction; PRL and TFAP2A in cell proliferation; miR28, PRL and SCG2 in cell migration; PRL in tubular formation; and miR28, NR1H4 and PRL in angiogenesis. This study provided concrete scientific evidence in support of the regulatory role of NF3 on endothelial cells involved in wound healing angiogenesis.

  18. The pleiotropic role of vitamin A in regulating mucosal immunity.

    Science.gov (United States)

    Sirisinha, Stitaya

    2015-06-01

    The effect of vitamin A on mucosal immunity has never been subjected to extensive studies until recently. We started to work in this area in the early 1970s when we observed that children with protein-calorie malnutrition (PCM) often had defective mucosal immunity, judging from the incidence of respiratory tract infections and diarrhea. We reported that these children had depressed secretory IgA (sIgA) levels in their nasal wash fluids. The IgA level in specimens collected from those superimposed with some degrees of vitamin A deficiency state appeared to be more severely affected. In order to better understand the underlying mechanism associated with this condition, we started to study more detail the deficiency state using experimental vitamin A-deficient rats. From a series of experiments using this animal model, we proposed that vitamin A was needed for transport and/or secretion of sIgA across the mucosa. This conclusion was based on the observation that the secretory component of sIgA synthesized by the epithelial cells of these vitamin A deficient animals was adversely affected as compared to the control animals. From that time onward, much progress has been made by several other groups showing that other mechanisms could also influence the integrity and immune function of the mucosa. For instance, recent studies demonstrated that retinoic acid which is a biologically active form of vitamin A has an essential role in mucosal homeostasis, controlling tolerance and immunity in these non-lymphoid tissues. Such a conclusion was made possible by the availability of sophisticated new molecular biology and genetic engineering techniques together with advances in the field of immunoregulation, e.g., the discovery of dendritic cells (DCs) and T helper cell subsets in 1980s, and the role of Toll-like receptors (TLRs) together with other innate immune regulators in controlling adaptive immune response in the early 1990s. These advances provided considerable new

  19. Effects of omeprazole and eradication of Helicobacter pylori on gastric and duodenal mucosal enzyme activities and DNA in duodenal ulcer patients.

    Science.gov (United States)

    Vetvik, K; Schrumpf, E; Mowinckel, P; Aase, S; Andersen, K J

    1994-11-01

    Duodenal and gastric content of mucosal enzymes in duodenal ulcer (DU) patients differs from that of controls. The purpose of this study has been to examine the effect of omeprazole and eradication of Helicobacter pylori on mucosal enzymes in DU patients. The enzyme activities of seven gastric and duodenal mucosal marker enzymes from the brush border, lysosomes, and mitochondria have been studied. In study I the measurements were made in 29 patients with an active DU before and after 14 days of omeprazole treatment. In study II 22 duodenal ulcer patients were given bismuth subnitrate, oxytetracycline, and metronidazole (triple therapy) for 2 weeks to eradicate H. pylori. Biopsy specimens were taken from the duodenum and the stomach for enzyme measurements and histologic assessment. In study II additional specimens were obtained from the prepyloric region for urease tests and culture of H. pylori. The ulcer healing rates were more than 90% after both omeprazole and triple therapy. H. pylori was eradicated in 86% after triple therapy. The activities of the brush-border enzymes lactase, neutral-alpha-glucosidase, alkaline phosphatase, leucyl-beta-naphthylamidase, and gamma-glutamyltransferase (gamma-GT) increased significantly in the duodenal bulb and the descending duodenum during treatment with omeprazole. No changes in duodenal enzyme activity were detected after triple therapy, whereas a significant fall in gamma-GT and acid phosphatase activities was seen in the stomach. The mucosal DNA in the gastric antrum decreased both after treatment with omeprazole and after triple therapy. A similar decrease in mucosal DNA of the gastric antrum was demonstrated after both omeprazole and triple therapy with bismuth subnitrate, oxytetracycline, and metronidazole. Omeprazole also affects the content of duodenal mucosal enzymes, whereas triple therapy particularly affects the gastric mucosal enzyme activity.

  20. Polymer nanomicelles for efficient mucus delivery and antigen-specific high mucosal immunity.

    Science.gov (United States)

    Noh, Young-Woock; Hong, Ji Hyun; Shim, Sang-Mu; Park, Hye Sun; Bae, Hee Ho; Ryu, Eun Kyoung; Hwang, Jung Hwan; Lee, Chul-Ho; Cho, Seong Hun; Sung, Moon-Hee; Poo, Haryoung; Lim, Yong Taik

    2013-07-22

    Micelles for mucosal immunity: A mucosal vaccine system based on γ-PGA nanomicelles and viral antigens was synthesized. The intranasal administration of the vaccine system induces a high immune response both in the humoral and cellular immunity (see picture).

  1. Mucosal delivery routes for optimal immunization: targeting immunity to the right tissues.

    Science.gov (United States)

    Czerkinsky, C; Holmgren, J

    2012-01-01

    The mucosal immune system exhibits a high degree of anatomic compartmentalization related to the migratory patterns of lymphocytes activated at different mucosal sites. The selective localization of mucosal lymphocytes to specific tissues is governed by cellular "homing" and chemokine receptors in conjunction with tissue-specific addressins and epithelial cell-derived chemokines that are differentially expressed in "effector" tissues. The compartmentalization of mucosal immune responses imposes constraints on the selection of vaccine administration route. Traditional routes of mucosal immunization include oral and nasal routes. Other routes for inducing mucosal immunity include the rectal, vaginal, sublingual, and transcutaneous routes. Sublingual administration is a new approach that results in induction of mucosal and systemic T cell and antibody responses with an exceptionally broad dissemination to different mucosae, including the gastrointestinal and respiratory tracts, and the genital mucosa. Here, we discuss how sublingual and different routes of immunization can be used to generate immune responses in the desired mucosal tissue(s).

  2. Clinical investigation of mucosal thickness stability after soft tissue grafting around implants: A 3-year retrospective study

    OpenAIRE

    Speroni Stefano; Cicciù Marco; Maridati Paolo; Grossi Giovanni; Maiorana Carlo

    2010-01-01

    Purpose: To assess the long-term stability of gingival grafts placed around dental implants at the time of second surgery uncovering and to further investigate the association between mucosal thickness (MTh) by demographic variables and clinical investigation. Materials and Methods: Fourteen patients with submerged dental implants covered by inadequate keratinized mucosa were studied. The subjects underwent a periimplant plastic surgery (PPS) at the second-stage dental implant surgery and fr...

  3. Correlation between {sup 99m}Tc-MIBI uptake and angiogenesis in MIBI-positive breast lesions

    Energy Technology Data Exchange (ETDEWEB)

    Bekis, Recep [Department of Nuclear Medicine, Dokuz Eyluel University School of Medicine, Inciralti-Izmir 35340 (Turkey)]. E-mail: recep.bekis@deu.edu.tr; Degirmenci, Berna [Department of Nuclear Medicine, Dokuz Eyluel University School of Medicine, Inciralti-Izmir 35340 (Turkey); Aydin, Aysel [Department of Nuclear Medicine, Dokuz Eyluel University School of Medicine, Inciralti-Izmir 35340 (Turkey); Ozdogan, Ozhan [Department of Nuclear Medicine, Dokuz Eyluel University School of Medicine, Inciralti-Izmir 35340 (Turkey); Canda, Tulay [Department of Pathology, Dokuz Eyluel University School of Medicine, Inciralti-Izmir 35340 (Turkey); Durak, Hatice [Department of Nuclear Medicine, Dokuz Eyluel University School of Medicine, Inciralti-Izmir 35340 (Turkey)

    2005-07-01

    This study was undertaken to assess the correlation between the degree of accumulation and the washout of 99m technetium methoxyisobutylisonitrile ({sup 99m}Tc-MIBI) and angiogenesis in MIBI-positive breast lesions. Twenty-eight patients (mean age, 51{+-}11 years) with 31 breast lesions who underwent scintimammography were studied. Anterior, left and right prone lateral images were obtained 20 min and 3 h after the injection of 740 MBq {sup 99m}Tc-MIBI. All breast lesions showed increased {sup 99m}Tc-MIBI uptake. Early and delayed tumor to background activity ratios (T/BG) and washout index (early tumor uptake-delayed tumor uptake divided by early tumor uptake) were calculated. Vascular endothelium was immunohistochemically labeled using a biotinylated monoclonal antibody directed against the factor-VIII-associated antigen using standard biotin-avidin technique. Angiogenesis was evaluated by assessing the vascular surface density (VSD) and the microvessel number (NVES) within 10 randomly chosen areas. All pathological data were compared with early and delayed T/BG activity ratios and washout index of {sup 99m}Tc-MIBI. Statistical analysis was performed using Spearman correlation test. There was no statistically significant correlation between the degree of angiogenesis and early T/BG (r=.287, P>.05 with VSD, r=.351, P>.05 with NVES), delayed T/BG (r=.277, P>.05 with VSD, r=.315, P>.05 with NVES) and the washout index (r=.268, P>.05 with VSD, r=.285, P>.05 with NVES) of {sup 99m}Tc-MIBI in all breast lesions. There was no statistically significant correlation between the degree of angiogenesis and early T/BG (r=.235, P>.05 with VSD, r=.356, P>.05 with NVES), delayed T/BG (r=.181, P>.05 with VSD, r=.285, P>.05 with NVES) and the washout index (r=.158, P>.05 with VSD, r=.187, P>.05 with NVES) of {sup 99m}Tc-MIBI in 24 invasive breast lesions. No statistically significant correlation was found between the degree of angiogenesis and early T/BG (r=-.036, P>.05 with VSD

  4. The Effect of Brain-derived Neurotrophic Factor on Angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Chunyan SUN; Yu HU; Zhangbo CHU; Jing HUANG; Lu ZHANG

    2009-01-01

    To investigate the in vitro and in vivo proangiogenic effects of brain-derived ncurotrophic factor (BDNF),human umbilical vein endothelial cells (HUVECs) were isolated and cultured in primary culture.The effect of BDNF on the proliferation of HUVECs was examined by MTT assay.The effects of BDNF on HUVEC migration and tube formation were studied by modified Boyden chamber assay and tube formation assay,respectively.Matrigel plug assay and chorioaUantoic membrane assay were used to evaluate the effects of BDNF on angiogencsis in vivo.Our results showed that BDNF substantially stimulated the migration and tube formation of HUVECs in vitro,although it did not induce HUVEC proliferation.BDNF also induced angiogenesis both in matrigcl plug of mouse model and in chick chorioallantoic membrane.In conclusion,BDNF can promote angiogenesis both in vitro and in vivo,and may be a proangiogenic factor.

  5. Newly discovered angiogenesis inhibitors and their mechanisms of action

    Institute of Scientific and Technical Information of China (English)

    Ze-hong MIAO; Jian-ming FENG; Jian DING

    2012-01-01

    In the past decade,the success of angiogenesis inhibitors in clinical contexts has established the antiangiogenic strategy as an important part of cancer therapy,During that time period,we have discovered and reported 17 compounds that exert potent inhibition on angiogenesis.These compounds exhibit tremendous diversity in their sources,structures,targets and mechanisms.These studies have generated new models for further modification and optimization of inhibitory compounds,new information for mechanistic studies and a new drug candidate for clinical development.In particular,through studies on the antiangiogenic mechanism of pseudolaric acid B,we discovered a novel mechanism by which the stability of hypoxia-irducible factor 1α is regulated by the transcription factor c-Jun.We also completed a preclinical study of AL3810,a compound with the potential to circumvent tumor drug resistance to a certain extent.All of these findings will be briefly reviewed in this article.

  6. Ramucirumab (IMC-1121B): a novel attack on angiogenesis.

    Science.gov (United States)

    Spratlin, Jennifer L; Mulder, Karen E; Mackey, John R

    2010-07-01

    Angiogenesis is a critical hallmark of malignancy, and attempts to inhibit this process have characterized the age of biologic anticancer therapies for solid tumors. VEGF receptor-2 is the premier receptor responsible for many of the cancer-driven VEGF-induced spectrum of biologic changes, including modification of blood vessel structure and function, proliferation and migration. Unlike all clinically approved angiogenesis inhibitors, the fully human monoclonal antibody ramucirumab (IMC-1121B) specifically and potently inhibits VEGF receptor-2. Phase I clinical trials have shown safety across a wide range of ramucirumab doses with impressive, albeit early, evidence of both stable disease and partial responses in a variety of tumor types. In this article, we review the current data on ramucirumab and make comparisons with commercially available antiangiogenic agents.

  7. Gene therapy and angiogenesis in patients with coronary artery disease

    DEFF Research Database (Denmark)

    Kastrup, Jens

    2010-01-01

    Not all patients with severe coronary artery disease can be treated satisfactorily with current recommended medications and revascularization techniques. Various vascular growth factors have the potential to induce angiogenesis in ischemic tissue. Clinical trials have only evaluated the effect...... of VEGF and FGF in patients with coronary artery disease. The initial small and unblinded studies with either recombinant growth factor proteins or genes encoding growth factors were encouraging, demonstrating both clinical improvement and evidence of angiogenesis. However, subsequent larger double...... an improvement in clinical results can be obtained with a cocktail of growth factors or by a combination of gene and stem cell therapy in patients with severe coronary artery disease, which cannot be treated effectively with current treatment strategies....

  8. Molecular and hormonal regulation of angiogenesis in proliferative endometrium

    Directory of Open Access Journals (Sweden)

    Yousef Rezaei Chianeh

    2014-02-01

    Full Text Available Angiogenesis is a hallmark of wound healing, the menstrual cycle, cancer, and various ischemic and inflammatory diseases. A rich variety of pro and anti-angiogenic molecules have already been identified. Vascular endothelial growth factor (VEGF is an interesting inducer of angiogenesis and lymphangiogenesis, because it is a highly specific mitogen for endothelial cells. Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation, migration, and new vessel formation. In this article, the role of VEGF and other growth factors in the pathology of dysfunctional uterine bleeding is reviewed. We also discuss the role of VEGF expression and interaction with extracellular matrix that lead to possible inhibition or stimulation of Angiogenic factor on endometrium of dysfunctional uterine bleeding patients. [Int J Res Med Sci 2014; 2(1.000: 1-9

  9. Preliminary study in a new protocol for the treatment of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and chemotherapy (CT).

    Science.gov (United States)

    Vitale, Marina Consuelo; Modaffari, Carola; Decembrino, Nunzia; Zhou, Feng Xiao; Zecca, Marco; Defabianis, Patrizia

    2017-08-01

    Oral mucositis (OM) is a debilitating and serious side effect in patients undergoing hematopoietic stem cell transplantation (HSCT) and chemotherapy (CT). Laser therapy is becoming a promising treatment option in these patients, avoiding the necessity of enteral/parenteral nutrition. The aim of this study was to evaluate the efficacy of laser therapy in patients affected by oral mucositis induced by chemotherapy and HSCT. Sixteen onco-hematological pediatric patients receiving chemotherapy and hematopoietic stem cell transplantation, affected by oral mucositis, were enrolled in this study. They were divided in two randomized groups: the laser group and the placebo-control group. Patients in the laser group were treated with HPLT (970 ± 15 nm, 3.2 W (50%), 35-6000 Hz, 240 s) for four consecutive days, once a day; and placebo group underwent sham treatment. The assessment of mucositis was recorded through WHO Oral Mucositis Grading Objective Scale, and pain was evaluated through Visual Analogue Scale (VAS). Patients were monitored and evaluated 3, 7, and 11 days after the first day of laser therapy. Once OM was diagnosed, the patients had mucositis grading assessments before laser or sham application at day 3, 7, and 11 after first application. All patients of laser group demonstrated improvement in pain sensation from day 3 after first application of laser (p < 0.05), ulcerations reduced their dimensions and erythema disappeared. The patients of placebo group had improvement from day 7. In laser group, all mucositis were fully resolved from day 7 (p < 0.05). Oral mucositis negatively impacts on nutritional intake, oral hygiene, and quality of life. Laser therapy appears to be a safe and innovative approach in the management of oral mucositis. In this preliminary study, HPLT encourages to consider laser therapy as a part of onco-hematological protocol, providing to decrease pain and duration of OM induced by CT and HSCT. Further researches will be needed

  10. Angiogenesis, Proliferative Activity and DNA Ploidy in Oral Verrucous Carcinoma: A Comparative Study Including Verrucous Hyperplasia and Squamous Cell Carcinoma.

    Science.gov (United States)

    Mallick, Saumyaranjan; Breta, Monika; Gupta, Siddhartha Datta; Dinda, Amit Kumar; Mohanty, Biddhu K; Singh, Manoj K

    2015-09-01

    Verrucous carcinoma (VC) is a rare and distinct clinicopathologic variant of well-differentiated squamous cell carcinoma (SCC). This study aims to evaluate the histomorphology, proliferative activity, level of angiogenesis, and DNA ploidy of these pathological entities. This was a retrospective-prospective study of 18 cases of verrucous hyperplasia (VH), 41 cases of VC, and 44 cases of SCC. Immunohistochemical analysis for Ki-67 (MIB-1) and CD34 were performed. The tumor proliferative index, endothelial proliferative index and microvascular density were calculated. DNA ploidy was determined using image cytometry. The age range and gender ratio were similar in all three groups. The differences in MIB-1 labeling index (p = 0.0001), microvascular density (p = 0.01), and endothelial proliferative index (p = 0.001) between VC and SCC were found to be statistically significant. A non-significant increasing trend was observed in all of these parameters between VH and VC. On ploidy analysis, 100 % of SCC cases were aneuploid, compared to 39 % of VH and 86 % of VC cases. Our study demonstrates a significant difference in tumor proliferation, microvessel density, and ploidy between VC and SCC while increasing trend between VH and VC. These parameters, along with morphological findings, may be useful in differentiating these entities in small mucosal biopsies.

  11. Angiogenesis: An improved in vitro biological system and automated image-based workflow to aid identification and characterization of angiogenesis and angiogenic modulators

    NARCIS (Netherlands)

    Santos, A.F.; Zaltsman, A.B.; Martin, R.C.; Kuzmin, A.; Alexandrov, Y.; Roquemore, E.P.; Jessop, R.A.; Erck, M.G.M.V.; Verheijen, J.H.

    2008-01-01

    Angiogenesis is a general term describing formation of new tube-like microvessel sprouts that are the size of capillary blood vessels. Angiogenesis is fundamental in key stages of embryonic development, organ formation, and wound repair and is also involved in the development and progression of a va

  12. SHORT PEDF-DERIVED PEPTIDE INHIBITS ANGIOGENESIS AND TUMOR GROWTH

    Science.gov (United States)

    Mirochnik, Yelena; Aurora, Arin; Schulze-Hoepfner, Frank T.; Deabes, Ahmed; Shifrin, Victor; Beckmann, Richard; Polsky, Charles; Volpert, Olga V.

    2010-01-01

    Purpose Pigment epithelial-derived factor (PEDF) is a potent angiogenesis inhibitor with multiple other functions, some of which enhance tumor growth. Our previous studies mapped PEDF anti-angiogenic and pro-survival activities to distinct epitopes. This study was aimed to determine the minimal fragment of PEDF, which maintains anti-angiogenic and anti-tumor efficacy. Experimental Design We analyzed antigenicity, hydrophilicity, and charge distribution of the angioinhibitory epitope (the 34-mer) and designed three peptides covering its C-terminus, P14, P18 and P23. We analyzed their ability to block endothelial cell (EC) chemotaxis and induce apoptosis in vitro and their anti-angiogenic activity in vivo. The selected peptide was tested for the anti-tumor activity against mildly aggressive xenografted prostate carcinoma and highly aggressive renal cell carcinoma. To verify that P18 acts in the same manner as PEDF, we used immunohistochemistry to measure PEDF targets, VEGFR2 and CD95L expression in P18-treated vasculature. Results P14 and P18 blocked endothelial cell chemotaxis; P18 and P23 induced apoptosis. P18 showed the highest IC50 and blocked angiogenesis in vivo: P23 was inactive and P14 was pro-angiogenic. P18 increased the production of CD95L and reduced the expression of VEGFR-2 by the endothelial cells in vivo. In tumor studies, P18 was more effective in blocking the angiogenesis and growth of the prostate cancer then parental 34-mer; in the renal cell carcinoma P18 strongly decreased angiogenesis and halted the progression of established tumors. Conclusions P18 is a novel and potent anti-angiogenic biotherapeutic agent, which has potential to be developed for the treatment of prostate and renal cancer. PMID:19223494

  13. Sprouty2 downregulates angiogenesis during mouse skin wound healing

    Science.gov (United States)

    Wietecha, Mateusz S.; Chen, Lin; Ranzer, Matthew J.; Anderson, Kimberly; Ying, Chunyi; Patel, Tarun B.

    2011-01-01

    Angiogenesis is regulated by signals received by receptor tyrosine