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Sample records for 1-integrin reverts prostate

  1. Inhibiting Vimentin or beta 1-integrin Reverts Prostate Tumor Cells in IrECM and Reduces Tumor Growth

    Zhang, Xueping; Fournier, Marcia V.; Ware, Joy L.; Bissell, Mina J.; Zehner, Zendra E.

    2009-07-27

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphological changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional (3D) lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the parental prostate epithelial P69 cell line by selection in nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin or {alpha}6-, {beta}4- and {beta}1-integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via siRNA interference or {beta}1-integrin expression by the addition of the blocking antibody, AIIB2, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by subcutaneous injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in 3D lrECM gels. These studies suggest that the levels of vimentin and {beta}1-integrin play a key role in the homeostasis of the normal acini in prostate and that their dysregulation may lead to tumorigenesis.

  2. Inhibition of vimentin or B1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo

    Zhang, Xueping; Fournier, Marcia V; Ware, Joy L; Bissell, Mina J; Yacoub, Adly; Zehner, Zendra E

    2008-06-12

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphologic changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the immortalized, prostate epithelial P69 cell line by selection in athymic, nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the parental, nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin, or {alpha}6 and {beta}1 integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via small interfering RNA interference or the expression of {alpha}6 and {beta}1 integrins by the addition of blocking antibodies, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by s.c. injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in three-dimensional lrECM gels. These studies suggest that the levels of vimentin and {beta}1 integrin play a key role in the homeostasis of the normal acinus in prostate and that their dysregulation may lead to tumorigenesis. [Mol Cancer Ther 2009;8(3):499-508].

  3. IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels.

    Aejaz Sayeed

    Full Text Available Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer cell migration and invasion. Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization. They also mediate signal transduction to regulate cell proliferation and survival. The type 1 insulin-like growth factor receptor (IGF-IR mediates tumor cell growth, adhesion and inhibition of apoptosis in several types of cancer. We have previously demonstrated that β1 integrins regulate anchorage-independent growth of prostate cancer (PrCa cells by regulating IGF-IR expression and androgen receptor-mediated transcriptional functions. Furthermore, we have recently reported that IGF-IR regulates the expression of β1 integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β1 integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β1 integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β1 integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β1 integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β1 integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β1 cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β1 subunit by protecting it from proteasomal degradation. The α5 subunit, one of the binding partners of β1, is also downregulated along with β1 upon IGF-IR knockdown while no change is observed in the expression of the α2, α3, α4, α6 and α7 subunits. Our results reveal a crucial mechanistic role for the α5β1 integrin, downstream of IGF-IR, in regulating cancer growth.

  4. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T; van der Horst, Geertje; Hemmer, Daniëlle M; Marijt, Koen A; Hwang, Ming S; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M; Meijer, Onno C; Culig, Zoran; van der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa. PMID:26483423

  5. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T.; Van Der Horst, Geertje; Lemhemmer, Daniël; Marijt, Koen A.; Hwang, Ming S.; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M.; Meijer, Onno C.; Culig, Zoran; Van Der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCA). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. I

  6. Gleditsia sinensis Thorn Attenuates the Collagen-Based Migration of PC3 Prostate Cancer Cells through the Suppression of α2β1 Integrin Expression

    Sujin Ryu

    2016-03-01

    Full Text Available Gleditsia sinensis thorns (GST have been used as a traditional medicine for carbuncles and skin diseases. The purpose of this study was to decide whether non-toxicological levels of water extract of GST (WEGST are effective in inhibiting the progress of prostate cancer formation and to identify the target molecule involved in the WEGST-mediated inhibitory process of prostate cancer cell migration and in vivo tumor formation. Through the Boyden chamber migration assay, we found that non-toxic levels of WEGST could not attenuate the PC3 migration to the bottom area coated with serum but significantly inhibited PC3 cell migration to the collagen-coated bottom area. We also found that non-toxic levels of WEGST significantly attenuated collagen against adhesion. Interestingly, ectopic administration of WEGST could not affect the expression of α2β1 integrin, which is known as a receptor of collagen. However, when the PC3 cells adhered to a collagen-coated plate, the expression of α2 integrin but not that of β1 integrin was significantly inhibited by the administration of non-toxic levels of WEGST, leading to the inhibition of focal adhesion kinase (FAK phosphorylation. Furthermore, oral administration of WEGST (25 mg/kg/day significantly inhibited the size of a PC3 cell-xenografted tumor. Taken together, these results suggest a novel molecular mechanism for WEGST to inhibit prostate cancer progression at particular stages, such as collagen-mediated adhesion and migration, and it might provide further development for the therapeutic use of WEGST in the treatment of prostate cancer progression.

  7. Genetic analysis of beta1 integrin "activation motifs" in mice

    Czuchra, Aleksandra; Meyer, Hannelore; Legate, Kyle R;

    2006-01-01

    /beta tails, leading to tail separation and integrin activation. We analyzed mice in which we mutated the tyrosines of the beta1 tail and the membrane-proximal aspartic acid required for the salt bridge. Tyrosine-to-alanine substitutions abolished beta1 integrin functions and led to a beta1 integrin...

  8. EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB.

    Civenni, Gianluca; Longoni, Nicole; Costales, Paula; Dallavalle, Cecilia; García Inclán, Cristina; Albino, Domenico; Nuñez, Luz Elena; Morís, Francisco; Carbone, Giuseppina M; Catapano, Carlo V

    2016-05-01

    Cancer stem cells (CSC) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-κB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124 is a novel chimeric indolocarbazole compound generated by metabolic engineering of the biosynthetic pathways of glycosylated indolocarbazoles, such as staurosporine and rebeccamycin. In vitro kinome analyses revealed that EC-70124 acted as a multikinase inhibitor with potent activity against IKKβ and JAK2. In this study, we show that EC-70124 blocked concomitantly NF-κB and STAT3 in prostate cancer cells and particularly prostate CSCs, which exhibited overactivation of these transcription factors. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKβ and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-κB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro and delayed development of prostate tumor xenografts. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo Thus, EC-70124 is a potent inhibitor of the NF-κB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Mol Cancer Ther; 15(5); 806-18. ©2016 AACR. PMID:26826115

  9. β1 Integrins Mediate Mechanosensitive Signaling Pathways in Osteocytes

    Litzenberger, Julie B.; Tummala, Padmaja; Kim, Jae-Beom; Jacobs, Christopher R.

    2010-01-01

    Integrins are cell-substrate adhesion proteins that initiate intracellular signaling and may serve as mechanosensors in bone. MLO-Y4 cells were stably transfected with a dominant negative form of the β1 integrin subunit (β1DN) containing the transmembrane domain and cytoplasmic tail of β1 integrin. Cells expressing β1DN had reduced vinculin localization to focal contacts but no change in intracellular actin organization. When exposed to oscillatory fluid flow, β1DN cells exhibited a significa...

  10. β1 Integrin Is Essential for Teratoma Growth and Angiogenesis

    Bloch, Wilhelm; Forsberg, Erik; Lentini, Sylvia; Brakebusch, Cord; Martin, Karl; Krell, Hans W.; Weidle, Ulrich H.; Addicks, Klaus; Fässler, Reinhard

    1997-01-01

    Teratomas are benign tumors that form after ectopic injection of embryonic stem (ES) cells into mice and contain derivatives of all primitive germ layers. To study the role of β1 integrin during teratoma formation, we compared teratomas induced by normal and β1-null ES cells. Injection of normal ES cells gave rise to large teratomas. In contrast, β1-null ES cells either did not grow or formed small teratomas with an average weight of

  11. Beta 1 integrin is essential for teratoma growth and angiogenesis

    Bloch, W; Forsberg, E; Lentini, S;

    1997-01-01

    Teratomas are benign tumors that form after ectopic injection of embryonic stem (ES) cells into mice and contain derivatives of all primitive germ layers. To study the role of beta 1 integrin during teratoma formation, we compared teratomas induced by normal and beta1-null ES cells. Injection of...... normal ES cells gave rise to large teratomas. In contrast, beta 1-null ES cells either did not grow or formed small teratomas with an average weight of <5% of that of normal teratomas. Histological analysis of beta 1-null teratomas revealed the presence of various differentiated cells, however, a much...... lower number of host-derived stromal cells than in normal teratomas. Fibronectin, collagen I, and nidogen were expressed but, in contrast to normal teratomas, diffusely deposited in beta1-null teratomas. Basement membranes were present but with irregular shape and detached from the cell surface. Normal...

  12. The involvement of Gab1 and PI 3-kinase in β1 integrin signaling in keratinocytes

    The control of the stem cell compartment in epidermis is closely linked to the regulation of keratinocyte proliferation and differentiation. β1 integrins are expressed 2-fold higher by stem cells than transit-amplifying cells. Signaling from these β1 integrins is critical for the regulation of the epidermal stem cell compartment. To clarify the functional relevance of this differential expression of β1 integrins, we established HaCaT cells with high β1integrin expression by repeated flow cytometric sorting of this population from the parental cell line. In these obtained cells expressing β1 integrins by 5-fold, MAPK activation was markedly increased. Regarding the upstream of MAPK, Gab1 phosphorylation was also higher with high β1 integrin expression, while Shc phosphorylation was not altered. In addition, enhanced phosphatidylinositol 3-kinase activation was also observed. These observations suggest that Gab1 and phosphatidylinositol 3-kinase play pivotal roles in the β1 integrin-mediated regulation of the epidermal stem cell compartment

  13. β1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli

    Li, Na; Zhang, Yu; Naylor, Matthew J.; Schatzmann, Franziska; Maurer, Francisca; Wintermantel, Tim; Schuetz, Gunther; Mueller, Ulrich; Streuli, Charles H; Hynes, Nancy E.

    2005-01-01

    Integrin–extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of β1 integrin in the mammary gland, Itgβ1flox/flox mice were crossed with WAPiCre transgenic mice, which led to specific ablation of β1 integrin in luminal alveolar epithelial cells. In the β1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell–basement membr...

  14. Interactions between the discoidin domain receptor 1 and β1 integrin regulate attachment to collagen

    Lisa A. Staudinger

    2013-09-01

    Collagen degradation by phagocytosis is essential for physiological collagen turnover and connective tissue homeostasis. The rate limiting step of phagocytosis is the binding of specific adhesion receptors, which include the integrins and discoidin domain receptors (DDR, to fibrillar collagen. While previous data suggest that these two receptors interact, the functional nature of these interactions is not defined. In mouse and human fibroblasts we examined the effects of DDR1 knockdown and over-expression on β1 integrin subunit function. DDR1 expression levels were positively associated with enhanced contraction of floating and attached collagen gels, increased collagen binding and increased collagen remodeling. In DDR1 over-expressing cells compared with control cells, there were increased numbers, area and length of focal adhesions immunostained for talin, paxillin, vinculin and activated β1 integrin. After treatment with the integrin-cleaving protease jararhagin, in comparison to controls, DDR1 over-expressing cells exhibited increased β1 integrin cleavage at the cell membrane, indicating that DDR1 over-expression affected the access and susceptibility of cell-surface β1 integrin to the protease. DDR1 over-expression was associated with increased glycosylation of the β1 integrin subunit, which when blocked by deoxymannojirimycin, reduced collagen binding. Collectively these data indicate that DDR1 regulates β1 integrin interactions with fibrillar collagen, which positively impacts the binding step of collagen phagocytosis and collagen remodeling.

  15. Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy

    Tumor development remains one of the major obstacles following organ transplantation. Immunosuppressive drugs such as cyclosporine and tacrolimus directly contribute to enhanced malignancy, whereas the influence of the novel compound mycophenolate mofetil (MMF) on tumor cell dissemination has not been explored. We therefore investigated the adhesion capacity of colon, pancreas, prostate and kidney carcinoma cell lines to endothelium, as well as their beta1 integrin expression profile before and after MMF treatment. Tumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 μM MMF and compared to unstimulated controls. beta1 integrin analysis included alpha1beta1 (CD49a), alpha2beta1 (CD49b), alpha3beta1 (CD49c), alpha4beta1 (CD49d), alpha5beta1 (CD49e), and alpha6beta1 (CD49f) receptors, and was carried out by reverse transcriptase-polymerase chain reaction, confocal microscopy and flow cytometry. Adhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 μM MMF. This effect was accompanied by down-regulation of alpha3beta1 and alpha6beta1 surface expression and of alpha3beta1 and alpha6beta1 coding mRNA. Adhesion of the prostate tumor cell line DU-145 was blocked dose-dependently by MMF. In contrast to MMF's effects on HT-29 cells, MMF dose-dependently up-regulated alpha1beta1, alpha2beta1, alpha3beta1, and alpha5beta1 on DU-145 tumor cell membranes. We conclude that MMF possesses distinct anti-tumoral properties, particularly in colon and prostate carcinoma cells. Adhesion blockage of HT-29 cells was due to the loss of alpha3beta1 and alpha6beta1 surface expression, which might contribute to a reduced invasive behaviour of this tumor entity. The enhancement of integrin beta1 subtypes observed in DU-145 cells possibly causes re-differentiation towards a low-invasive phenotype

  16. Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy

    Beecken Wolf-Dietrich

    2005-01-01

    Full Text Available Abstract Background Tumor development remains one of the major obstacles following organ transplantation. Immunosuppressive drugs such as cyclosporine and tacrolimus directly contribute to enhanced malignancy, whereas the influence of the novel compound mycophenolate mofetil (MMF on tumor cell dissemination has not been explored. We therefore investigated the adhesion capacity of colon, pancreas, prostate and kidney carcinoma cell lines to endothelium, as well as their beta1 integrin expression profile before and after MMF treatment. Methods Tumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 μM MMF and compared to unstimulated controls. beta1 integrin analysis included alpha1beta1 (CD49a, alpha2beta1 (CD49b, alpha3beta1 (CD49c, alpha4beta1 (CD49d, alpha5beta1 (CD49e, and alpha6beta1 (CD49f receptors, and was carried out by reverse transcriptase-polymerase chain reaction, confocal microscopy and flow cytometry. Results Adhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 μM MMF. This effect was accompanied by down-regulation of alpha3beta1 and alpha6beta1 surface expression and of alpha3beta1 and alpha6beta1 coding mRNA. Adhesion of the prostate tumor cell line DU-145 was blocked dose-dependently by MMF. In contrast to MMF's effects on HT-29 cells, MMF dose-dependently up-regulated alpha1beta1, alpha2beta1, alpha3beta1, and alpha5beta1 on DU-145 tumor cell membranes. Conclusion We conclude that MMF possesses distinct anti-tumoral properties, particularly in colon and prostate carcinoma cells. Adhesion blockage of HT-29 cells was due to the loss of alpha3beta1 and alpha6beta1 surface expression, which might contribute to a reduced invasive behaviour of this tumor entity. The enhancement of integrin beta1 subtypes observed in DU-145 cells possibly causes re-differentiation towards a low-invasive phenotype.

  17. Revertant mosaicism in skin: natural gene therapy

    Joey E Lai-Cheong; McGrath, John A; Uitto, Jouni

    2010-01-01

    Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic mutation in a somatic cell. Recent studies suggest that it is not a rare event and that it could be clinically relevant to phenotypic expression and patient treatment. Indeed, revertant cell therapy represents a potential “natural gene therapy” because in vivo reversion obviates the need for further genetic correction. Revertant mosaicism has been observed in several inherited conditions, ...

  18. Beta 1 integrin predicts survival in breast cancer: a clinicopathological and immunohistochemical study

    dos Santos Petra

    2012-08-01

    Full Text Available Abstract Background The main focus of several studies concerned with cancer progression and metastasis is to analyze the mechanisms that allow cancer cells to interact and quickly adapt with their environment. Integrins, a family of transmembrane glycoproteins, play a major role in invasive and metastatic processes. Integrins are involved in cell adhesion in both cell-extracellular matrix and cell-cell interactions, and particularly, β1 integrin is involved in proliferation and differentiation of cells in the development of epithelial tissues. This work aimed to investigate the putative role of β1 integrin expression on survival and metastasis in patients with breast invasive ductal carcinoma (IDC. In addition, we compared the expression of β1 integrin in patients with ductal carcinoma in situ (DCIS. Methods Through tissue microarray (TMA slides containing 225 samples of IDC and 67 samples of DCIS, β1 integrin expression was related with several immunohistochemical markers and clinicopathologic features of prognostic significance. Results β1 integrin was overexpressed in 32.8% of IDC. In IDC, β1 integrin was related with HER-2 (p = 0.019 and VEGF (p = 0.011 expression and it had a significant relationship with metastasis and death (p = 0.001 and p = 0.05, respectively. Kaplan-Meier survival analysis showed that the overexpression of this protein is very significant (p = 0.002 in specific survival (number of months between diagnosis and death caused by the disease. There were no correlation between IDC and DCIS (p = 0.559 regarding β1 integrin expression. Conclusions Considering that the expression of β1 integrin in breast cancer remains controversial, specially its relation with survival of patients, our findings provide further evidence that β1 integrin can be a marker of poor prognosis in breast cancer. Virtual slides The virtual slide(s for this article can be found here: http

  19. Modulation of radiation-induced oral mucositis (mouse) by selective inhibition of β1 integrin

    Introduction: Oral mucositis is a severe side effect of radio(chemo)therapy for head and neck tumors, for which β1 integrins have been proposed as potential therapeutic targets. The present study was initiated to determine the effect of selective inhibition of β1 integrin on the oral epithelial radiation response. Materials and methods: Daily fractionated irradiation was given with 5 × 3 Gy/week over 1 or 2 weeks with/without the β1 integrin-inhibiting monoclonal antibody AIIB2 or an IgG control. Each protocol was terminated by graded test doses to generate full dose–effect curves for mucosal ulceration. The same technique was used for single dose irradiation. Results: Combined single dose irradiation plus AIIB2 resulted in a significant decrease of the ED50 compared to irradiation alone or control IgG. No effect of AIIB2 was found with fractionated irradiation over 1 week. With 2 weeks of fractionation, AIIB2 induced a significant increase in the ED50 for the terminating test irradiation when administered in week 2. The time course of the response was largely unaffected by β1 integrin inhibition. Conclusions: A reduction of mucosal reactions by β1 integrin inhibition later in a course of fractionation was observed, i.e. when epithelial repopulation processes were active. Further mechanistic studies are required.

  20. Discoidin domain receptor 1 is activated independently of beta(1) integrin

    Vogel, W; Brakebusch, C; Fässler, R;

    2000-01-01

    Various types of collagen have been identified as potential ligands for the two mammalian discoidin domain receptor (DDR) tyrosine kinases, DDR1 and DDR2. It is presently unclear whether collagen-induced DDR receptor activation, which occurs with very slow kinetics, involves additional proteins...... blocking antibodies for alpha(2)beta(1) integrin or in cells with a targeted deletion of the beta(1) integrin gene. Finally, we show that overexpression of dominant negative DDR1 in the myoblast cell line C2C12 blocks cellular differentiation and the formation of myofibers....

  1. CD46 and beta1 integrin relocation in the sperm head during capacitation and acrosome reaction

    Šebková, N.; Frolíková, M.; Dvořáková-Hortová, Kateřina

    Madison: Society for the Study of Reproduction, 2015. s. 212. [48th Annual Meeting of the Society for the Study of reproduction. 18.06.2015-22.06.2015, San Juan] R&D Projects: GA ČR(CZ) GA14-05547S Institutional support: RVO:86652036 Keywords : CD46 * beta1 integrin * Proximity Ligation Assay * acrosome reaction Subject RIV: CE - Biochemistry

  2. ADAM12 and alpha9beta1 integrin are instrumental in human myogenic cell differentiation

    Lafuste, Peggy; Sonnet, Corinne; Chazaud, Bénédicte; Dreyfus, Patrick A; Gherardi, Romain K; Wewer, Ulla M; Authier, François-Jérôme

    2005-01-01

    of alpha9 parallels that of ADAM12 and culminates at time of fusion. alpha9 and ADAM12 coimmunoprecipitate and participate to mpc adhesion. Inhibition of ADAM12/alpha9beta1 integrin interplay, by either ADAM12 antisense oligonucleotides or blocking antibody to alpha9beta1, inhibited overall mpc...

  3. Tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates myogenesis and β1 integrin expression in vitro

    Myogenesis in vitro involves myoblast cell cycle arrest, migration, and fusion to form multinucleated myotubes. Extracellular matrix (ECM) integrity during these processes is maintained by the opposing actions of matrix metalloproteinase (MMP) proteases and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs). Here, we report that TIMP-2, MMP-2, and MT1-MMP are differentially expressed during mouse myoblast differentiation in vitro. A specific role for TIMP-2 in myogenesis is demonstrated by altered TIMP-2-/- myotube formation. When differentiated in horse serum-containing medium, TIMP-2-/- myotubes are larger than wild-type myotubes. In contrast, when serum-free medium is used, TIMP-2-/- myotubes are smaller than wild-type myotubes. Regardless of culture condition, myotube size is directly correlated with MMP activity and inversely correlated with β1 integrin expression. Treatment with recombinant TIMP-2 rescues reduced TIMP-2-/- myotube size and induces increased MMP-9 activation and decreased β1 integrin expression. Treatment with either MMP-2 or MMP-9 similarly rescues reduced myotube size, but has no effect on β1 integrin expression. These data suggest a specific regulatory relationship between TIMP-2 and β1 integrin during myogenesis. Elucidating the role of TIMP-2 in myogenesis in vitro may lead to new therapeutic options for the use of TIMP-2 in myopathies and muscular dystrophies in vivo

  4. Beta1 integrin promotes but is not essential for metastasis of ras-myc transformed fibroblasts

    Brakebusch, C; Wennerberg, K; Krell, H W; Weidle, U H; Sallmyr, A; Johansson, S; Fässler, R

    1999-01-01

    integrin-expressing sublines. Tumors were induced by subcutaneous injection of GERM 11 cells and 3 independent beta1 integrin expressing sublines (GERM 116, 1A10, 2F2) into syngeneic mice. After 10 days tumors were surgically removed. While average weights of GERM 11 and GERM 116 tumors were similar...

  5. Beta1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity

    Bauer, Martina; Brakebusch, Cord; Coisne, Caroline;

    2009-01-01

    )-integrin gene either in all hematopoietic cells or selectively in T lymphocytes. Our results show that T cells critically rely on beta(1) integrins to accumulate in the central nervous system (CNS) during EAE, whereas CNS infiltration of beta(1)-deficient myeloid cells remains unaffected, suggesting that T...

  6. Interaction between fibronectin and β1 integrin is essential for tooth development.

    Kan Saito

    Full Text Available The dental epithelium and extracellular matrix interact to ensure that cell growth and differentiation lead to the formation of teeth of appropriate size and quality. To determine the role of fibronectin in differentiation of the dental epithelium and tooth formation, we analyzed its expression in developing incisors. Fibronectin mRNA was expressed during the presecretory stage in developing dental epithelium, decreased in the secretory and early maturation stages, and then reappeared during the late maturation stage. The binding of dental epithelial cells derived from postnatal day-1 molars to a fibronectin-coated dish was inhibited by the RGD but not RAD peptide, and by a β1 integrin-neutralizing antibody, suggesting that fibronectin-β1 integrin interactions contribute to dental epithelial-cell binding. Because fibronectin and β1 integrin are highly expressed in the dental mesenchyme, it is difficult to determine precisely how their interactions influence dental epithelial differentiation in vivo. Therefore, we analyzed β1 integrin conditional knockout mice (Intβ1lox-/lox-/K14-Cre and found that they exhibited partial enamel hypoplasia, and delayed eruption of molars and differentiation of ameloblasts, but not of odontoblasts. Furthermore, a cyst-like structure was observed during late ameloblast maturation. Dental epithelial cells from knockout mice did not bind to fibronectin, and induction of ameloblastin expression in these cells by neurotrophic factor-4 was inhibited by treatment with RGD peptide or a fibronectin siRNA, suggesting that the epithelial interaction between fibronectin and β1 integrin is important for ameloblast differentiation and enamel formation.

  7. Signaling through urokinase and urokinase receptor in lung cancer cells requires interactions with beta1 integrins.

    Tang, Chi-Hui; Hill, Marla L; Brumwell, Alexis N; Chapman, Harold A; Wei, Ying

    2008-11-15

    The urokinase receptor (uPAR) is upregulated upon tumor cell invasion and correlates with poor lung cancer survival. Although a cis-interaction with integrins has been ascribed to uPAR, whether this interaction alone is critical to urokinase (uPA)- and uPAR-dependent signaling and tumor promotion is unclear. Here we report the functional consequences of point mutations of uPAR (H249A-D262A) that eliminate beta1 integrin interactions but maintain uPA binding, vitronectin attachment and association with alphaV integrins, caveolin and epidermal growth factor receptor. Disruption of uPAR interactions with beta1 integrins recapitulated previously reported findings with beta1-integrin-derived peptides that attenuated matrix-dependent ERK activation, MMP expression and in vitro migration by human lung adenocarcinoma cell lines. The uPAR mutant cells acquired enhanced capacity to adhere to vitronectin via uPAR-alphaVbeta5-integrin, rather than through the uPAR-alpha3beta1-integrin complex and they were unable to initiate uPA signaling to activate ERK, Akt or Stat1. In an orthotopic lung cancer model, uPAR mutant cells exhibited reduced tumor size compared with cells expressing wild-type uPAR. Taken together, the results indicate that uPAR-beta1-integrin interactions are essential to signals induced by integrin matrix ligands or uPA that support lung cancer cell invasion in vitro and progression in vivo. PMID:18940913

  8. beta1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury

    Cordes, N; Seidler, J; Durzok, R; Geinitz, H; Brakebusch, C

    2006-01-01

    Integrin-mediated adhesion to extracellular matrix proteins confers resistance to radiation- or drug-induced genotoxic injury. To analyse the underlying mechanisms specific for beta1-integrins, wild-type beta1A-integrin-expressing GD25beta1A cells were compared to GD25beta1B cells, which express...... findings in tumor cells, human A-172 glioma cells were examined under the same conditions after siRNA-mediated silencing of beta1-integrins. We found that beta1A-integrin-mediated adhesion to fibronectin, collagen-III or beta1-IgG was essential for cell survival after radiation-induced genotoxic injury...... central role of beta1-integrins in Akt- and p130Cas/paxillin-mediated prosurvival signaling. These findings suggest beta1-integrins as critical regulators of cell survival after radiation-induced genotoxic injury. Elucidation of the molecular circuitry of prosurvival beta1-integrin-mediated signaling in...

  9. Bidirectional remodeling of β1-integrin adhesions during chemotropic regulation of nerve growth

    Carlstrom Lucas P

    2011-11-01

    Full Text Available Abstract Background Chemotropic factors in the extracellular microenvironment guide nerve growth by acting on the growth cone located at the tip of extending axons. Growth cone extension requires the coordination of cytoskeleton-dependent membrane protrusion and dynamic adhesion to the extracellular matrix, yet how chemotropic factors regulate these events remains an outstanding question. We demonstrated previously that the inhibitory factor myelin-associated glycoprotein (MAG triggers endocytic removal of the adhesion receptor β1-integrin from the growth cone surface membrane to negatively remodel substrate adhesions during chemorepulsion. Here, we tested how a neurotrophin might affect integrin adhesions. Results We report that brain-derived neurotropic factor (BDNF positively regulates the formation of substrate adhesions in axonal growth cones during stimulated outgrowth and prevents removal of β1-integrin adhesions by MAG. Treatment of Xenopus spinal neurons with BDNF rapidly triggered β1-integrin clustering and induced the dynamic formation of nascent vinculin-containing adhesion complexes in the growth cone periphery. Both the formation of nascent β1-integrin adhesions and the stimulation of axon extension by BDNF required cytoplasmic calcium ion signaling and integrin activation at the cell surface. Exposure to MAG decreased the number of β1-integrin adhesions in the growth cone during inhibition of axon extension. In contrast, the BDNF-induced adhesions were resistant to negative remodeling by MAG, correlating with the ability of BDNF pretreatment to counteract MAG-inhibition of axon extension. Pre-exposure to MAG prevented the BDNF-induced formation of β1-integrin adhesions and blocked the stimulation of axon extension by BDNF. Conclusions Altogether, these findings demonstrate the neurotrophin-dependent formation of integrin-based adhesions in the growth cone and reveal how a positive regulator of substrate adhesions can block

  10. Loss of β1-integrin from urothelium results in overactive bladder and incontinence in mice: a mechanosensory rather than structural phenotype

    Kanasaki, Keizo; Yu, Weiqun; von Bodungen, Maximilian; Larigakis, John D.; Kanasaki, Megumi; Ayala de la Pena, Francisco; Kalluri, Raghu; Hill, Warren G.

    2013-01-01

    Bladder urothelium senses and communicates information about bladder fullness. However, the mechanoreceptors that respond to tissue stretch are poorly defined. Integrins are mechanotransducers in other tissues. Therefore, we eliminated β1-integrin selectively in urothelium of mice using Cre-LoxP targeted gene deletion. β1-Integrin localized to basal/intermediate urothelial cells by confocal microscopy. β1-Integrin conditional-knockout (β1-cKO) mice lacking urothelial β1-integrin exhibited dow...

  11. Fetal and adult hematopoietic stem cells require beta1 integrin function for colonizing fetal liver, spleen, and bone marrow

    Potocnik, A J; Brakebusch, C; Fässler, R

    2000-01-01

    Homing of hematopoietic stem cells (HSCs) into hematopoietic organs is a prerequisite for the establishment of hematopoiesis during embryogenesis and after bone marrow transplantation. We show that beta1 integrin-deficient HSCs from the para-aortic splanchnopleura and the fetal blood had hematoly......Homing of hematopoietic stem cells (HSCs) into hematopoietic organs is a prerequisite for the establishment of hematopoiesis during embryogenesis and after bone marrow transplantation. We show that beta1 integrin-deficient HSCs from the para-aortic splanchnopleura and the fetal blood had...... hematolymphoid differentiation potential in vitro and in fetal organ cultures but were unable to seed fetal and adult hematopoietic tissues. Adult beta1 integrin null HSCs isolated from mice carrying loxP-tagged beta1 integrin alleles and ablated for beta1 integrin expression by retroviral cre transduction...... failed to engraft irradiated recipient mice. Moreover, absence of beta1 integrin resulted in sequestration of HSCs in the circulation and their reduced adhesion to endothelioma cells. These findings define beta1 integrin as an essential adhesion receptor for the homing of HSCs....

  12. Dystrophin Dp71f associates with the beta1-integrin adhesion complex to modulate PC12 cell adhesion

    Cerna, Joel; Cerecedo, Doris; Ortega, Arturo; García-Sierra, Francisco; Centeno, Federico; Garrido, Efrain; Mornet, Dominique; Cisneros, Bulmaro

    2006-01-01

    Dystrophin Dp71 is the main product of the Duchenne muscular dystrophy gene in the brain; however, its function is unknown. To study the role of Dp71 in neuronal cells, we previously generated by antisense treatment PC12 neuronal cell clones with decreased Dp71 expression (antisense-Dp71 cells). PC12 cells express two different splicing isoforms of Dp71, a cytoplasmic variant called Dp71f and a nuclear isoform called Dp71d. We previously reported that antisense-Dp71 cells display deficient adhesion to substrate and reduced immunostaining of β1-integrin in the cell area contacting the substrate. In this study, we isolated additional antisenseDp71 clones to analyze in detail the potential involvement of Dp71f isoform with the β1-integrin adhesion system of PC12 cells. Immunofluorescence analyses as well as immunoprecipitation assays demonstrated that the PC12 cell β1-integrin adhesion complex is composed of β1-integrin, talin, paxillin, α-actinin, FAK and actin. In addition, our results showed that Dp71f associates with most of the β1-integrin complex components (β1-integrin, FAK, α-actinin, talin and actin). In the antisense-Dp71 cells, the deficiency of Dp71 provokes a significant reduction of the β1-integrin adhesion complex and, consequently, the deficient adhesion of these cells to laminin. In vitro binding experiments confirmed the interaction of Dp71f with FAK and β1-integrin. Our data indicate that Dp71f is a structural component of the β1-integrin adhesion complex of PC12 cells that modulates PC12 cell adhesion by conferring proper complex assembly and/or maintenance. PMID:16935300

  13. Alpha9beta1 integrin in melanoma cells can signal different adhesion states for migration and anchorage

    Lydolph, Magnus C; Morgan-Fisher, Marie; Høye, Anette M;

    2009-01-01

    Cell surface integrins are the primary receptors for cell migration on extracellular matrix, and exist in several activation states regulated in part by ectodomain conformation. The alpha9 integrin subunit, which pairs only with beta1, has specific roles in the immune system and may regulate cell......beta1 integrin- and Rho kinase-dependent focal adhesion and stress fibre formation, suggesting that the activation status of alpha9beta1 integrin was altered. The effect of manganese ions in promoting focal adhesion formation was reproduced by beta1 integrin activating antibody. The alpha9beta1...

  14. beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

    Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.

    2008-06-02

    {beta}1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of {beta}1 integrin signaling. We showed previously that {beta}1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and {beta}1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.

  15. PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/β1-Integrin Signaling.

    Liu, Xingfeng; Huai, Jisen; Endle, Heiko; Schlüter, Leslie; Fan, Wei; Li, Yunbo; Richers, Sebastian; Yurugi, Hajime; Rajalingam, Krishnaraj; Ji, Haichao; Cheng, Hong; Rister, Benjamin; Horta, Guilherme; Baumgart, Jan; Berger, Hendrik; Laube, Gregor; Schmitt, Ulrich; Schmeisser, Michael J; Boeckers, Tobias M; Tenzer, Stefan; Vlachos, Andreas; Deller, Thomas; Nitsch, Robert; Vogt, Johannes

    2016-08-01

    Alterations in dendritic spine numbers are linked to deficits in learning and memory. While we previously revealed that postsynaptic plasticity-related gene 1 (PRG-1) controls lysophosphatidic acid (LPA) signaling at glutamatergic synapses via presynaptic LPA receptors, we now show that PRG-1 also affects spine density and synaptic plasticity in a cell-autonomous fashion via protein phosphatase 2A (PP2A)/β1-integrin activation. PRG-1 deficiency reduces spine numbers and β1-integrin activation, alters long-term potentiation (LTP), and impairs spatial memory. The intracellular PRG-1 C terminus interacts in an LPA-dependent fashion with PP2A, thus modulating its phosphatase activity at the postsynaptic density. This results in recruitment of adhesome components src, paxillin, and talin to lipid rafts and ultimately in activation of β1-integrins. Consistent with these findings, activation of PP2A with FTY720 rescues defects in spine density and LTP of PRG-1-deficient animals. These results disclose a mechanism by which bioactive lipid signaling via PRG-1 could affect synaptic plasticity and memory formation. PMID:27453502

  16. Conditional beta1-integrin gene deletion in neural crest cells causes severe developmental alterations of the peripheral nervous system

    Pietri, Thomas; Eder, Olivier; Breau, Marie Anne;

    2004-01-01

    Integrins are transmembrane receptors that are known to interact with the extracellular matrix and to be required for migration, proliferation, differentiation and apoptosis. We have generated mice with a neural crest cell-specific deletion of the beta1-integrin gene to analyse the role of beta1-...... almost complete absence of Schwann cells and sensory axon segregation and defective maturation in neuromuscular synaptogenesis. Thus, beta1-integrins are important for the control of embryonic and postnatal peripheral nervous system development....

  17. A preliminary optical and electron microscopic study of the beta(1) integrin distribution pattern of human osteosarcoma-derived cells.

    Banai, Kiarash; Brady, Ken; McDonald, Fraser

    2004-07-01

    Immunogold labelling was used to study the organisation of the beta(1) integrins on osteosarcoma-derived osteoblasts (Saos-2 and MG-63). Monolayers of cells were prepared in multiwell culture plates on both uncovered and collagen-covered coverslips, and beta(1) integrins were primarily labelled using mouse monoclonal antibodies to beta(1) integrins. Indirect immunofluorescence labels using an anti-mouse fluorescein-conjugated goat antibody showed an even distribution of the beta(1) integrins on the cell membranes of all cell types used. A concentration of 2 microg/ml of the primary antibodies and a 1:100 dilution of the secondary antibodies were determined as the optimal concentration for labelling to use with indirect localisation of the primary antibodies gold conjugated to goat anti-mouse antibodies and viewed under an electron microscope. Ten nanometre gold particles were used for transmission electron microscopy (TEM) and 40 nm gold particles for scanning electron microscopy. TEM showed that beta(1) integrins were mainly clustered on the cell membrane processes with less labelling on the cell membranes themselves. The distribution of beta(1) integrins on osteosarcoma cells supports the concept that integrins may function by forming focal adhesions at the site of the cytoplasmic membrane processes. PMID:15241608

  18. Skin and hair follicle integrity is crucially dependent on beta 1 integrin expression on keratinocytes

    Brakebusch, C; Grose, R; Quondamatteo, F;

    2000-01-01

    developed severe hair loss due to a reduced proliferation of hair matrix cells and severe hair follicle abnormalities. Eventually, the malformed hair follicles were removed by infiltrating macrophages. The epidermis of the back skin became hyperthickened, the basal keratinocytes showed reduced expression of......, the integrity of the basement membrane surrounding the beta 1-deficient hair follicle was not affected. Finally, the dermis became fibrotic. These results demonstrate an important role of beta 1 integrins in hair follicle morphogenesis, in the processing of basement membrane components, in the...

  19. Highly Potent, Water Soluble Benzimidazole Antagonist for Activated (alpha)4(beta)1 Integrin

    Carpenter, R D; Andrei, M; Lau, E Y; Lightstone, F C; Liu, R; Lam, K S; Kurth, M J

    2007-08-29

    The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin, activated constitutively in lymphoma, can be targeted with the bisaryl urea peptidomimetic antagonist 1 (LLP2A). However, concerns on its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzimidazole moiety resulting in improved solubility while maintaining picomolar potency [5 (KLCA4); IC{sub 50} = 305 pM]. With exceptional solubility, this finding has potential for improving PK to help diagnose and treat lymphomas.

  20. Tumor cell adhesion to endothelial cells is increased by endotoxin via an upregulation of beta-1 integrin expression.

    Andrews, E J

    2012-02-03

    BACKGROUND: Recent studies have demonstrated that metastatic disease develops from tumor cells that adhere to endothelial cells and proliferate intravascularly. The beta-1 integrin family and its ligand laminin have been shown to be important in tumor-to-endothelial cell adhesion. Lipopolysaccharide (LPS) has been implicated in the increased metastatic tumor growth that is seen postoperatively. We postulated that LPS increases tumor cell expression of beta-1 integrins and that this leads to increased adhesion. METHODS: The human metastatic colon cancer cell line LS174T was labeled with an enhanced green fluorescent protein (eGFP) using retroviral transfection. Cell cultures were treated with LPS for 1, 2, and 4 h (n = 6 each) and were subsequently cocultured for 30 or 120 min with confluent human umbilical vein endothelial cells (HUVECs), to allow adherence. Adherent tumor cells were counted using fluorescence microscopy. These experiments were carried out in the presence or absence of a functional blocking beta-1 integrin monoclonal antibody (4B4). Expression of beta-1 integrin and laminin on tumor and HUVECs was assessed using flow cytometric analysis. Tumor cell NF-kappaB activation after incubation with LPS was measured. RESULTS: Tumor cell and HUVEC beta-1 integrin expression and HUVEC expression of laminin were significantly (P < 0.05) enhanced after incubation with LPS. Tumor cell adhesion to HUVECs was significantly increased. Addition of the beta-1 integrin blocking antibody reduced tumor cell adhesion to control levels. LPS increased tumor cell NF-kappaB activation. CONCLUSIONS: Exposure to LPS increases tumor cell adhesion to the endothelium through a beta-1 integrin-mediated pathway that is NF-kappaB dependent. This may provide a target for immunotherapy directed at reducing postoperative metastatic tumor growth.

  1. Evaluation of β1-integrin expression on chondrogenically differentiating human adipose-derived stem cells using atomic force microscopy.

    Quisenberry, Chrystal R; Nazempour, Arshan; Van Wie, Bernard J; Abu-Lail, Nehal I

    2016-06-01

    The expression of β1-integrin on human adipose-derived stem cells, differentiating toward a chondrogenic lineage, is hypothesized to decrease when cells are grown under in vivo-like environments due to sufficient extracellular matrix (ECM) buildup in the engineered tissues. The opposite is true when cells are grown in static cultures such as in pellet or micromass. To probe β1-integrin distribution on cellular surfaces, atomic force microscopy cantilevers modified with anti-β1-integrin antibodies were used. Specific antibody-antigen adhesion forces were identified and indicated the locations of β1-integrins on cells. ECM properties were assessed by estimating the Young's modulus of the matrix. Specific single antibody-antigen interactions averaged 78 ± 10 pN with multiple bindings occurring at approximate multiples of 78 pN. The author's results show that upregulated β1-integrin expression coincided with a less robust ECM as assessed by mechanical properties of tissues. In micromass and pellet cultures, transforming growth factor β3(TGF-β3) elicited a decrease in Young's modulus by 3.7- and 4.4-fold while eliciting an increase in β1-integrin count by 1.1- and 1.3-fold, respectively. β1-integrin counts on cells grown in the presence of TGF-β3 with oscillating hydrostatic pressure decreased by a 1.1-fold while the Young's modulus increased by a 1.9-fold. Collectively, our results suggest that cells in insufficiently robust ECM express more integrin perhaps to facilitate cell-ECM adhesion and compensate for a looser less robust ECM. PMID:27106564

  2. LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin.

    Kawamoto, Eiji; Okamoto, Takayuki; Takagi, Yoshimi; Honda, Goichi; Suzuki, Koji; Imai, Hiroshi; Shimaoka, Motomu

    2016-05-13

    LFA-1 (αLβ2) and Mac-1 (αMβ2) integrins regulate leukocyte trafficking in health and disease by binding primarily to IgSF ligand ICAM-1 and ICAM-2 on endothelial cells. Here we have shown that the anti-coagulant molecule thrombomodulin (TM), found on the surface of endothelial cells, functions as a potentially new ligand for leukocyte integrins. We generated a recombinant extracellular domain of human TM and Fc fusion protein (TM-domains 123-Fc), and showed that pheripheral blood mononuclear cells (PBMCs) bind to TM-domains 123-Fc dependent upon integrin activation. We then demonstrated that αL integrin-blocking mAb, αM integrin-blocking mAb, and β2 integrin-blocking mAb inhibited the binding of PBMCs to TM-domains 123-Fc. Furthermore, we show that the serine/threonine-rich domain (domain 3) of TM is required for the interaction with the LFA-1 (αLβ2) and Mac-1 (αMβ2) integrins to occur on PBMCs. These results demonstrate that the LFA-1 and Mac-1 integrins on leukocytes bind to TM, thereby establishing the molecular and structural basis underlying LFA-1 and Mac-1 integrin interaction with TM on endothelial cells. In fact, integrin-TM interactions might be involved in the dynamic regulation of leukocyte adhesion with endothelial cells. PMID:27055590

  3. Vesicle-associated membrane protein 2 mediates trafficking of α5β1 integrin to the plasma membrane

    Integrins are major receptors for cell adhesion to the extracellular matrix (ECM). As transmembrane proteins, the levels of integrins at the plasma membrane or the cell surface are ultimately determined by the balance between two vesicle trafficking events: endocytosis of integrins at the plasma membrane and exocytosis of the vesicles that transport integrins. Here, we report that vesicle-associated membrane protein 2 (VAMP2), a SNARE protein that mediates vesicle fusion with the plasma membrane, is involved in the trafficking of α5β1 integrin. VAMP2 was present on vesicles containing endocytosed β1 integrin. Small interfering RNA (siRNA) silencing of VAMP2 markedly reduced cell surface α5β1 and inhibited cell adhesion and chemotactic migration to fibronectin, the ECM ligand of α5β1, without altering cell surface expression of α2β1 integrin or α3β1 integrin. By contrast, silencing of VAMP8, another SNARE protein, had no effect on cell surface expression of the integrins or cell adhesion to fibronectin. In addition, VAMP2-mediated trafficking is involved in cell adhesion to collagen but not to laminin. Consistent with disruption of integrin functions in cell proliferation and survival, VAMP2 silencing diminished proliferation and triggered apoptosis. Collectively, these data indicate that VAMP2 mediates the trafficking of α5β1 integrin to the plasma membrane and VAMP2-dependent integrin trafficking is critical in cell adhesion, migration and survival.

  4. alpha 11beta 1 integrin recognizes the GFOGER sequence in interstitial collagens.

    Zhang, Wan-Ming; Kapyla, Jarmo; Puranen, J Santeri; Knight, C Graham; Tiger, Carl-Fredrik; Pentikainen, Olli T; Johnson, Mark S; Farndale, Richard W; Heino, Jyrki; Gullberg, Donald

    2003-02-28

    The integrins alpha(1)beta(1), alpha(2)beta(1), alpha(10)beta(1), and alpha(11)beta(1) are referred to as a collagen receptor subgroup of the integrin family. Recently, both alpha(1)beta(1) and alpha(2)beta(1) integrins have been shown to recognize triple-helical GFOGER (where single letter amino acid nomenclature is used, O = hydroxyproline) or GFOGER-like motifs found in collagens, despite their distinct binding specificity for various collagen subtypes. In the present study we have investigated the mechanism whereby the latest member in the integrin family, alpha(11)beta(1), recognizes collagens using C2C12 cells transfected with alpha(11) cDNA and the bacterially expressed recombinant alpha(11) I domain. The ligand binding properties of alpha(11)beta(1) were compared with those of alpha(2)beta(1). Mg(2+)-dependent alpha(11)beta(1) binding to type I collagen required micromolar Ca(2+) but was inhibited by 1 mm Ca(2+), whereas alpha(2)beta(1)-mediated binding was refractory to millimolar concentrations of Ca(2+). The bacterially expressed recombinant alpha(11) I domain preference for fibrillar collagens over collagens IV and VI was the same as the alpha(2) I domain. Despite the difference in Ca(2+) sensitivity, alpha(11)beta(1)-expressing cells and the alpha(11) I domain bound to helical GFOGER sequences in a manner similar to alpha(2)beta(1)-expressing cells and the alpha(2) I domain. Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. Although alpha(10) and alpha(11) chains show the highest sequence identity, alpha(2) and alpha(11) are more similar with regard to collagen specificity. Future studies will reveal whether alpha(2)beta(1) and alpha(11)beta(1

  5. Lack of beta1 integrins in enteric neural crest cells leads to a Hirschsprung-like phenotype

    Breau, Marie A; Pietri, Thomas; Eder, Olivier;

    2006-01-01

    The enteric nervous system arises mainly from vagal and sacral neural crest cells that colonise the gut between 9.5 and 14 days of development in mice. Using the Cre-LoxP system, we removed beta1 integrins in the neural crest cells when they emerge from the neural tube. beta1-null enteric neural...... integrins are required for the villi innervation in the small intestine. Our findings highlight the crucial roles played by beta1 integrins at various steps of enteric nervous system development....

  6. HGF Accelerates Wound Healing by Promoting the Dedifferentiation of Epidermal Cells through β1-Integrin/ILK Pathway

    Jin-Feng Li

    2013-01-01

    Full Text Available Skin wound healing is a critical and complex biological process after trauma. This process is activated by signaling pathways of both epithelial and nonepithelial cells, which release a myriad of different cytokines and growth factors. Hepatocyte growth factor (HGF is a cytokine known to play multiple roles during the various stages of wound healing. This study evaluated the benefits of HGF on reepithelialization during wound healing and investigated its mechanisms of action. Gross and histological results showed that HGF significantly accelerated reepithelialization in diabetic (DB rats. HGF increased the expressions of the cell adhesion molecules β1-integrin and the cytoskeleton remodeling protein integrin-linked kinase (ILK in epidermal cells in vivo and in vitro. Silencing of ILK gene expression by RNA interference reduced expression of β1-integrin, ILK, and c-met in epidermal cells, concomitantly decreasing the proliferation and migration ability of epidermal cells. β1-Integrin can be an important maker of poorly differentiated epidermal cells. Therefore, these data demonstrate that epidermal cells become poorly differentiated state and regained some characteristics of epidermal stem cells under the role of HGF after wound. Taken together, the results provide evidence that HGF can accelerate reepithelialization in skin wound healing by dedifferentiation of epidermal cells in a manner related to the β1-integrin/ILK pathway.

  7. α-Hemolysin enhances Staphylococcus aureus internalization and survival within mast cells by modulating the expression of β1 integrin.

    Goldmann, Oliver; Tuchscherr, Lorena; Rohde, Manfred; Medina, Eva

    2016-06-01

    Mast cells (MCs) are important sentinels of the host defence against invading pathogens. We previously reported that Staphylococcus aureus evaded the extracellular antimicrobial activities of MCs by promoting its internalization within these cells via β1 integrins. Here, we investigated the molecular mechanisms governing this process. We found that S. aureus responded to the antimicrobial mediators released by MCs by up-regulating the expression of α-hemolysin (Hla), fibronectin-binding protein A and several regulatory systems. We also found that S. aureus induced the up-regulation of β1 integrin expression on MCs and that this effect was mediated by Hla-ADAM10 (a disintegrin and metalloproteinase 10) interaction. Thus, deletion of Hla or inhibition of Hla-ADAM10 interaction significantly impaired S. aureus internalization within MCs. Furthermore, purified Hla but not the inactive HlaH35L induced up-regulation of β1 integrin expression in MCs in a dose-dependent manner. Our data support a model in which S. aureus counter-reacts the extracellular microbicidal mechanisms of MCs by increasing expression of fibronectin-binding proteins and by inducing Hla-ADAM10-mediated up-regulation of β1 integrin in MCs. The up-regulation of bacterial fibronectin-binding proteins, concomitantly with the increased expression of its receptor β1 integrin on the MCs, resulted in enhanced S. aureus internalization through the binding of fibronectin-binding proteins to integrin β1 via fibronectin. PMID:26595647

  8. Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity

    Momic T

    2015-01-01

    Full Text Available Tatjana Momic,1 Jehoshua Katzhendler,1 Ela Shai,2 Efrat Noy,3 Hanoch Senderowitz,3 Johannes A Eble,4 Cezary Marcinkiewicz,5 David Varon,2 Philip Lazarovici11School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 2Department of Hematology, Coagulation Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 3Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel; 4Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany; 5Department of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, USAAbstract: Linear peptides containing the sequence WKTSRTSHY were used as lead compounds to synthesize a novel peptidomimetic antagonist of α2β1 integrin, with platelet aggregation-inhibiting activity, named Vipegitide. Vipegitide is a 13-amino acid, folded peptidomimetic molecule, containing two α-aminoisobutyric acid residues at positions 6 and 8 and not stable in human serum. Substitution of glycine and tryptophan residues at positions 1 and 2, respectively, with a unit of two polyethylene glycol (PEG molecules yielded peptidomimetic Vipegitide-PEG2, stable in human serum for over 3 hours. Vipegitide and Vipegitide-PEG2 showed high potency (7×10-10 M and 1.5×10-10 M, respectively and intermediate efficacy (40% and 35%, respectively as well as selectivity toward α2 integrin in inhibition of adhesion of α1/α2 integrin overexpressing cells toward respective collagens. Interaction of both peptidomimetics with extracellular active domain of α2 integrin was confirmed in cell-free binding assay with recombinant α2 A-domain. Integrin α2β1 receptor is found on the platelet membrane and triggers collagen-induced platelet aggregation. Vipegitide and Vipegitide-PEG2 inhibited α2β1 integrin-mediated adhesion of human and murine platelets under the flow condition, by 50%. They efficiently blocked adenosine diphosphate

  9. Cellular microenvironment controls the nuclear architecture of breast epithelia through β1-integrin.

    Maya-Mendoza, Apolinar; Bartek, Jiri; Jackson, Dean A; Streuli, Charles H

    2016-02-01

    Defects in nuclear architecture occur in a variety of diseases, however the fundamental mechanisms that control the internal structure of nuclei are poorly defined. Here we reveal that the cellular microenvironment has a profound influence on the global internal organization of nuclei in breast epithelia. A 3D microenvironment induces a prolonged but reversible form of cell cycle arrest that features many of the classical markers of cell senescence. This unique form of arrest is dependent on signaling from the external microenvironment through β1-integrins. It is concomitant with alterations in nuclear architecture that characterize the withdrawal from cell proliferation. Unexpectedly, following prolonged cell cycle arrest in 3D, the senescence-like state and associated reprogramming of nuclear architecture are freely reversible on altering the dimensionality of the cellular microenvironment. Breast epithelia can therefore maintain a proliferative plasticity that correlates with nuclear remodelling. However, the changes in nuclear architecture are cell lineage-specific and do not occur in fibroblasts, and moreover they are overcome in breast cancer cells. PMID:26818565

  10. Beta1 integrin expression by podocytes is required to maintain glomerular structural integrity.

    Pozzi, Ambra; Jarad, George; Moeckel, Gilbert W; Coffa, Sergio; Zhang, Xi; Gewin, Leslie; Eremina, Vera; Hudson, Billy G; Borza, Dorin-Bogdan; Harris, Raymond C; Holzman, Lawrence B; Phillips, Carrie L; Fassler, Reinhard; Quaggin, Susan E; Miner, Jeffrey H; Zent, Roy

    2008-04-15

    Integrins are transmembrane heteromeric receptors that mediate interactions between cells and extracellular matrix (ECM). beta1, the most abundantly expressed integrin subunit, binds at least 12 alpha subunits. beta1 containing integrins are highly expressed in the glomerulus of the kidney; however their role in glomerular morphogenesis and maintenance of glomerular filtration barrier integrity is poorly understood. To study these questions we selectively deleted beta1 integrin in the podocyte by crossing beta1(flox/flox) mice with podocyte specific podocin-cre mice (pod-Cre), which express cre at the time of glomerular capillary formation. We demonstrate that podocyte abnormalities are visualized during glomerulogenesis of the pod-Cre;beta1(flox/flox) mice and proteinuria is present at birth, despite a grossly normal glomerular basement membrane. Following the advent of glomerular filtration there is progressive podocyte loss and the mice develop capillary loop and mesangium degeneration with little evidence of glomerulosclerosis. By 3 weeks of age the mice develop severe end stage renal failure characterized by both tubulointerstitial and glomerular pathology. Thus, expression of beta1 containing integrins by the podocyte is critical for maintaining the structural integrity of the glomerulus. PMID:18328474

  11. Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

    Wen-Liang Lei; Shi-Ge Xing; Cai-Yun Deng; Xiang-Chun Ju; Xing-Yu Jiang; Zhen-Ge Luo

    2012-01-01

    Axon specification during neuronal polarization is closely associated with increased microtubule stabilization in one of the neurites of unpolarized neuron,but how this increased microtubule stability is achieved is unclear.Here,we show that extracellular matrix (ECM) component laminin promotes neuronal polarization via regulating directional microtubule assembly through β1 integrin (Itgb1).Contact with laminin coated on culture substrate or polystyrene beads was sufficient for axon specification of undifferentiated neurites in cultured hippocampal neurons and cortical slices.Active Itgb1 was found to be concentrated in laminin-contacting neurites.Axon formation was promoted and abolished by enhancing and attenuating Itgbl signaling,respectively.Interestingly,laminin contact promoted plus-end microtubule assembly in a manner that required Itgbl.Moreover,stabilizing microtubules partially prevented polarization defects caused by ltgbl downregulation.Finally,genetic ablation of ltgbl in dorsal telencephalic progenitors caused deficits in axon development of cortical pyramidal neurons.Thus,laminin/Itgb1 signaling plays an instructive role in axon initiation and growth,both in vitro and in vivo,through the regulation of microtubule assembly.This study has established a linkage between an extrinsic factor and intrinsic cytoskeletai dynamics during neuronal polarization.

  12. Dynamic expression of alpha 1 beta 1 and alpha 2 beta 1 integrin receptors by human vascular smooth muscle cells. Alpha 2 beta 1 integrin is required for chemotaxis across type I collagen-coated membranes.

    Skinner, M P; Raines, E W; Ross, R.

    1994-01-01

    Vascular smooth muscle cells (SMCs) in the media of normal arteries express alpha 1 beta 1 integrin with no detectable alpha 2 beta 1 as determined by immunocytochemistry. In contrast, immunoprecipitation of integrins expressed by human SMCs cultured from medial explants shows strong expression of alpha 2 beta 1 and no expression of alpha 1 beta 1. The apparent reciprocal expression of these two collagen and laminin receptors was confirmed by flow cytometric analysis of fluorescent labeled ce...

  13. Increasing α7β1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

    LIU, Jianming; Burkin, Dean J.; Kaufman, Stephen J.

    2007-01-01

    The dystrophin-glycoprotein complex maintains the integrity of skeletal muscle by associating laminin in the extracellular matrix with the actin cytoskeleton. Several human muscular dystrophies arise from defects in the components of this complex. The α7β1-integrin also binds laminin and links the extracellular matrix with the cytoskeleton. Enhancement of α7-integrin levels alleviates pathology in mdx/utrn−/− mice, a model of Duchenne muscular dystrophy, and thus the integrin may functionally...

  14. Mechanotransduction molecules in the plant gravisensory response: amyloplast/statolith membranes contain a beta 1 integrin-like protein

    Lynch, T. M.; Lintilhac, P. M.; Domozych, D.

    1998-01-01

    It has been hypothesized that the sedimentation of amyloplasts within root cap cells is the primary event in the plant gravisensory-signal transduction cascade. Statolith sedimentation, with its ability to generate weighty mechanical signals, is a legitimate means for organisms to discriminate the direction of the gravity vector. However, it has been demonstrated that starchless mutants with reduced statolith densities maintain some ability to sense gravity, calling into question the statolith sedimentation hypothesis. Here we report on the presence of a beta 1 integrin-like protein localized inside amyloplasts of tobacco NT-1 suspension culture, callus cells, and whole-root caps. Two different antibodies to the beta 1 integrin, one to the cytoplasmic domain and one to the extracellular domain, localize in the vicinity of the starch grains within amyloplasts of NT-1. Biochemical data reveals a 110-kDa protein immunoprecipitated from membrane fractions of NT-1 suspension culture indicating size homology to known beta 1 integrin in animals. This study provides the first direct evidence for the possibility of integrin-mediated signal transduction in the perception of gravity by higher plants. An integrin-mediated pathway, initiated by starch grain sedimentation within the amyloplast, may provide the signal amplification necessary to explain the gravitropic response in starch-depleted cultivars.

  15. RECK-Mediated β1-Integrin Regulation by TGF-β1 Is Critical for Wound Contraction in Mice

    Gutiérrez, Jaime; Droppelmann, Cristian A.; Contreras, Osvaldo; Takahashi, Chiaki; Brandan, Enrique

    2015-01-01

    Fibroblasts are critical for wound contraction; a pivotal step in wound healing. They produce and modify the extracellular matrix (ECM) required for the proper tissue remodeling. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a key regulator of ECM homeostasis and turnover. However, its role in wound contraction is presently unknown. Here we describe that Transforming growth factor type β1 (TGF-β1), one of the main pro-fibrotic wound-healing promoting factors, decreases RECK expression in fibroblasts through the Smad and JNK dependent pathways. This TGF-β1 dependent downregulation of RECK occurs with the concomitant increase of β1-integrin, which is required for fibroblasts adhesion and wound contraction through the activation of focal adhesion kinase (FAK). Loss and gain RECK expression experiments performed in different types of fibroblasts indicate that RECK downregulation mediates TGF-β1 dependent β1-integrin expression. Also, reduced levels of RECK potentiate TGF-β1 effects over fibroblasts FAK-dependent contraction, without affecting its cognate signaling. The above results were confirmed on fibroblasts derived from the Reck+/- mice compared to wild type-derived fibroblasts. We observed that Reck+/- mice heal dermal wounds more efficiently than wild type mice. Our results reveal a critical role for RECK in skin wound contraction as a key mediator in the axis: TGF-β1—RECK- β1-integrin. PMID:26247610

  16. Rhodocytin (aggretin) activates platelets lacking alpha(2)beta(1) integrin, glycoprotein VI, and the ligand-binding domain of glycoprotein Ibalpha

    Bergmeier, W; Bouvard, D; Eble, J A;

    2001-01-01

    collagen may activate platelets by a similar mechanism. In contrast to these findings, we provided evidence that rhodocytin does not bind to alpha(2)beta(1) integrin. Here we show that the Cre/loxP-mediated loss of beta(1) integrin on mouse platelets has no effect on rhodocytin-induced platelet activation......Although alpha(2)beta(1) integrin (glycoprotein Ia/IIa) has been established as a platelet collagen receptor, its role in collagen-induced platelet activation has been controversial. Recently, it has been demonstrated that rhodocytin (also termed aggretin), a snake venom toxin purified from the......, excluding an essential role of alpha(2)beta(1) integrin in this process. Furthermore, proteolytic cleavage of the 45-kDa N-terminal domain of glycoprotein (GP) Ibalpha either on normal or on beta(1)-null platelets had no significant effect on rhodocytin-induced platelet activation. Moreover, mouse platelets...

  17. The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to beta1 integrin-dependent cell spreading

    Iba, K; Albrechtsen, R; Gilpin, B;

    2000-01-01

    spread on ADAM 12. However, spreading could be efficiently induced by the addition of either 1 mM Mn(2+) or the beta1 integrin-activating monoclonal antibody 12G10, suggesting that in these carcinoma cells, the ADAM 12-syndecan complex fails to modulate the function of beta1 integrin.......-dependent manner attach to ADAM 12 via members of the syndecan family. After binding to syndecans, mesenchymal cells spread and form focal adhesions and actin stress fibers. Integrin beta1 was responsible for cell spreading because function-blocking monoclonal antibodies completely inhibited cell spreading, and...... chondroblasts lacking beta1 integrin attached but did not spread. These data suggest that mesenchymal cells use syndecans as the initial receptor for the ADAM 12 cysteine-rich domain-mediated cell adhesion, and then the beta1 integrin to induce cell spreading. Interestingly, carcinoma cells attached but did not...

  18. Loss of β1-integrin from urothelium results in overactive bladder and incontinence in mice: a mechanosensory rather than structural phenotype.

    Kanasaki, Keizo; Yu, Weiqun; von Bodungen, Maximilian; Larigakis, John D; Kanasaki, Megumi; Ayala de la Pena, Francisco; Kalluri, Raghu; Hill, Warren G

    2013-05-01

    Bladder urothelium senses and communicates information about bladder fullness. However, the mechanoreceptors that respond to tissue stretch are poorly defined. Integrins are mechanotransducers in other tissues. Therefore, we eliminated β1-integrin selectively in urothelium of mice using Cre-LoxP targeted gene deletion. β1-Integrin localized to basal/intermediate urothelial cells by confocal microscopy. β1-Integrin conditional-knockout (β1-cKO) mice lacking urothelial β1-integrin exhibited down-regulation and mislocalization of α3- and α5-integrins by immunohistochemistry but, surprisingly, had normal morphology, permeability, and transepithelial resistance when compared with Cre-negative littermate controls. β1-cKO mice were incontinent, as judged by random urine leakage on filter paper (4-fold higher spotting, Pbladder overfilling with 80% longer intercontractile intervals (Phyperactivity (3-fold more prevoid contractions, Pbladder due to abnormal mechanotransduction; more broadly, our findings indicate that urothelium itself directly modulates voiding. PMID:23395910

  19. The dermatan sulfate proteoglycan decorin modulates α2β1 integrin and the vimentin intermediate filament system during collagen synthesis.

    Oliver Jungmann

    Full Text Available Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn(-/- mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn(-/- mice could be rescued in vitro by decorin but not with decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn(-/- fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, we identified vimentin as one of the proteins that was differentially upregulated by the presence of decorin. We discovered that a decorin-deficient matrix leads to abnormal nuclear morphology in the Dcn(-/- fibroblasts. This phenotype could be rescued by the decorin proteoglycan but less efficiently by the decorin protein core. Decorin treatment led to a significant reduction of the α2β1 integrin at day 6 in Dcn(-/- fibroblasts, whereas the protein core had no effect on β1. Interestingly, only the decorin core induced mRNA synthesis, phosphorylation and de novo synthesis of vimentin indicating that the proteoglycan decorin in the extracellular matrix stabilizes the vimentin intermediate filament system. We could support these results in vivo, because the dermis of wild-type mice have more vimentin and less β1 integrin compared to Dcn(-/-. Furthermore, the α2β1 null fibroblasts also showed a reduced amount of vimentin compared to wild-type. These data show for the first time that decorin has an impact on the biology of α2β1 integrin and the vimentin intermediate filament system. Moreover, our findings provide a mechanistic explanation for the reported defects in wound healing associated with the Dcn(-/- phenotype.

  20. Identification of inhibitors of α2β1 integrin, members of C-lectin type proteins, in Echis sochureki venom

    Jakubowski, Piotr [Temple University, Department of Biology, Philadelphia, PA 19122 (United States); Calvete, Juan J. [Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientificas, 46010 Valencia (Spain); Eble, Johannes A. [Excellence Cluster Cardio-Pulmonary System, Center for Molecular Medicine, Vascular Matrix Biology, Frankfurt University Hospital, Frankfurt am Main 60590 (Germany); Lazarovici, Philip [The Hebrew University of Jerusalem, School of Pharmacy, Institute for Drug Research, Jerusalem 91120 (Israel); Marcinkiewicz, Cezary, E-mail: cmarcink@temple.edu [Temple University, Department of Biology, Philadelphia, PA 19122 (United States)

    2013-05-15

    Snake venom antagonists of α2β1 integrin have been identified as members of a C-lectin type family of proteins (CLP). In the present study, we characterized three new CLPs isolated from Echis sochureki venom, which interact with this integrin. These proteins were purified using a combination of gel filtration, ion exchange chromatography and reverse phase HPLC. Sochicetin-A and sochicetin-B potently inhibited adhesion of cells expressing α2β1 integrin and binding of isolated α2β1 ectodomain to collagen I, as well as bound to recombinant GST-α2A domain in ELISA, whereas activity of sochicetin-C in these assays was approximately two orders of magnitude lower. Structurally, sochicetin-B and sochicetin-C are typical heterodimeric αβ CLPs, whereas sochicetin-A exhibits a trimer of its subunits (αβ){sub 3} in the quaternary structure. Immobilized sochicetins supported adhesion of glioma cell lines, LN18 and LBC3, whereas in a soluble form they partially inhibited adhesion of these cells to collagen I. Glioma cells spread very poorly on sochicetin-A, showing no cytoskeleton rearrangement typical for adhesion to collagen I or fibronectin. Adhesion on CLP does not involve focal adhesion elements, such as vinculin. Sochicetin-A also inhibited collagen-induced platelet aggregation, similar to other CLPs' action on the blood coagulation system. - Highlights: • Isolation of three novel snake venom CLPs inhibiting α2β1 integrin • Reporting hexameric CLP, sochicetin-A with anti-collagen receptor activity • CLPs antagonize the interaction of glioma cells with collagen matrix. • Sochicetin-A does not support glioma cell spreading.

  1. Identification of inhibitors of α2β1 integrin, members of C-lectin type proteins, in Echis sochureki venom

    Snake venom antagonists of α2β1 integrin have been identified as members of a C-lectin type family of proteins (CLP). In the present study, we characterized three new CLPs isolated from Echis sochureki venom, which interact with this integrin. These proteins were purified using a combination of gel filtration, ion exchange chromatography and reverse phase HPLC. Sochicetin-A and sochicetin-B potently inhibited adhesion of cells expressing α2β1 integrin and binding of isolated α2β1 ectodomain to collagen I, as well as bound to recombinant GST-α2A domain in ELISA, whereas activity of sochicetin-C in these assays was approximately two orders of magnitude lower. Structurally, sochicetin-B and sochicetin-C are typical heterodimeric αβ CLPs, whereas sochicetin-A exhibits a trimer of its subunits (αβ)3 in the quaternary structure. Immobilized sochicetins supported adhesion of glioma cell lines, LN18 and LBC3, whereas in a soluble form they partially inhibited adhesion of these cells to collagen I. Glioma cells spread very poorly on sochicetin-A, showing no cytoskeleton rearrangement typical for adhesion to collagen I or fibronectin. Adhesion on CLP does not involve focal adhesion elements, such as vinculin. Sochicetin-A also inhibited collagen-induced platelet aggregation, similar to other CLPs' action on the blood coagulation system. - Highlights: • Isolation of three novel snake venom CLPs inhibiting α2β1 integrin • Reporting hexameric CLP, sochicetin-A with anti-collagen receptor activity • CLPs antagonize the interaction of glioma cells with collagen matrix. • Sochicetin-A does not support glioma cell spreading

  2. Laminin isoforms differentially regulate adhesion, spreading, proliferation, and ERK activation of β1 integrin-null cells

    The presence of many laminin receptors of the β1 integrin family on most cells makes it difficult to define the biological functions of other major laminin receptors such as integrin α6β4 and dystroglycan. We therefore tested the binding of a β1 integrin-null cell line GD25 to four different laminin variants. The cells were shown to produce dystroglycan, which based on affinity chromatography bound to laminin-1, -2/4, and -10/11, but not to laminin-5. The cells also expressed the integrin α6Aβ4A variant. GD25 β1 integrin-null cells are known to bind poorly to laminin-1, but we demonstrate here that these cells bind avidly to laminin-2/4, -5, and -10/11. The initial binding at 20 min to each of these laminins could be inhibited by an integrin α6 antibody, but not by a dystroglycan antibody. Hence, integrin α6Aβ4A of GD25 cells was identified as a major receptor for initial GD25 cell adhesion to three out of four tested laminin isoforms. Remarkably, cell adhesion to laminin-5 failed to promote cell spreading, proliferation, and extracellular signal-regulated kinase (ERK) activation, whereas all these responses occurred in response to adhesion to laminin-2/4 or -10/11. The data establish GD25 cells as useful tools to define the role integrin α6Aβ4A and suggest that laminin isoforms have distinctly different capacities to promote cell adhesion and signaling via integrin α6Aβ4A

  3. Staged stromal extracellular 3D matrices differentially regulate breast cancer cell responses through PI3K and beta1-integrins

    Interactions between cancer cells and stroma are critical for growth and invasiveness of epithelial tumors. The biochemical mechanisms behind tumor-stromal interactions leading to increased invasiveness and metastasis are mostly unknown. The goal of this study was to analyze the direct effects of staged stroma-derived extracellular matrices on breast cancer cell behavior. Early and late three-dimensional matrices were produced by NIH-3T3 and tumor-associated murine fibroblasts, respectively. After removing fibroblasts, extracted matrices were re-cultured with breast epithelial cells of assorted characteristics: MCF-10A (non-tumorigenic), MCF-7 (tumorigenic, non-invasive), and MDA-MB-231 (tumorigenic, invasive). Effects prompted by staged matrices on epithelial cell's growth, morphology and invasion were determined. Also, matrix-induced velocity, directionality and relative track orientation of invasive cells were assessed in the presence or absence of inhibitors of phosphoinositide-3 kinase (PI3K) and/or beta-1 integrin. We observed that assorted breast epithelial cells reacted differently to two-dimensional vs. staged, control (early) and tumor-associated (late), three-dimensional matrices. MCF-10A had a proliferative advantage on two-dimensional substrates while MCF-7 and MDA-MB-231 showed no difference. MCF-10A and MCF-7 formed morphologically distinguishable aggregates within three-dimensional matrices, while MDA-MB-231 exhibited increased spindle-shape morphologies and directional movements within three-dimensional matrices. Furthermore, MDA-MB-231 acquired a pattern of parallel oriented organization within tumor-associated, but not control matrices. Moreover, tumor-associated matrices induced PI3K and beta1-integrin dependent Akt/PKB activity in MDA-MB-231 cells. Interestingly, beta1-integrin (but not PI3K) regulated tumor-associated matrix-induced mesenchymal invasion which, when inhibited, resulted in a change of invasive strategy rather than impeding

  4. Insulin-like Growth Factor I Controls Adhesion Strength Mediated by α5β1 Integrins in Motile Carcinoma Cells

    Lynch, Laura; Vodyanik, Pavel I.; Boettiger, David; Guvakova, Marina A

    2005-01-01

    One of the intriguing questions regarding cell motility concerns the mechanism that makes stationary cells move. Here, we provide the first physical evidence that the onset of breast cancer cell motility in response to insulin-like growth factor I (IGF-I) correlates with lowering of adhesion strength from 2.52 ± 0.20 to 1.52 ± 0.13 μdynes/μm2 in cells attached to fibronectin via α5β1 integrin. The adhesion strength depends on the dose of IGF-I and time of IGF-I treatment. Weakening of cell-ma...

  5. Ofloxacin induces apoptosis via β1 integrin-EGFR-Rac1-Nox2 pathway in microencapsulated chondrocytes

    Sheng, Zhi-Guo [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Huang, Wei [Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 1000191 (China); Liu, Yu-Xiang [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Yuan, Ye [Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850 (China); Zhu, Ben-Zhan, E-mail: bzhu@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States)

    2013-02-15

    Quinolones (QNs)-induced arthropathy is an important toxic side-effect in immature animals leading to the restriction of their therapeutic use in pediatrics. Ofloxacin, a typical QN, was found to induce the chondrocytes apoptosis in the early phase (12–48 h) of arthropathy in our previous study. However, the exact mechanism(s) is unclear. Microencapsulated juvenile rabbit joint chondrocytes, a three-dimensional culture system, is utilized to perform the present study. Ofloxacin, at a therapeutically relevant concentration (10 μg/ml), disturbs the interaction between β1 integrin and activated intracellular signaling proteins at 12 h, which is inhibited when supplementing Mg{sup 2+}. Intracellular reactive oxygen species (ROS) significantly increases in a time-dependent manner after exposure to ofloxacin for 12–48 h. Furthermore, ofloxacin markedly enhances the level of activated Rac1 and epidermal growth factor receptor (EGFR) phosphorylation, and its inhibition in turn reduces the ROS production, apoptosis and Rac1 activation. Silencing Nox2, Rac1 or supplementing Mg{sup 2+} inhibits ROS accumulation, apoptosis occurrence and EGFR phosphorylation induced by ofloxacin. However, depletion of Nox2, Rac1 and inhibition of EGFR do not affect ofloxacin-mediated loss of interaction between β1 integrin and activated intracellular signaling proteins. In addition, ofloxacin also induces Vav2 phosphorylation, which is markedly suppressed after inactivating EGFR or supplementing Mg{sup 2+}. These results suggest that ofloxacin causes Nox2-mediated intracellular ROS production by disrupting the β1 integrin function and then activating the EGFR-Vav2-Rac1 pathway, finally resulting in apoptosis within 12–48 h exposure. The present study provides a novel insight regarding the potential role of Nox-driven ROS in QNs-induced arthropathy. - Highlights: ► Ofloxacin induces Nox2-driven ROS in encapsulated chondrocyte at 12–48 h. ► Ofloxacin stimulates ROS production via

  6. The NLRP3 Inflammasome Is a Pathogen Sensor for Invasive Entamoeba histolytica via Activation of α5β1 Integrin at the Macrophage-Amebae Intercellular Junction.

    Leanne Mortimer

    2015-05-01

    Full Text Available Entamoeba histolytica (Eh is an extracellular protozoan parasite of humans that invades the colon to cause life-threatening intestinal and extra-intestinal amebiasis. Colonized Eh is asymptomatic, however, when trophozoites adhere to host cells there is a considerable inflammatory response that is critical in the pathogenesis of amebiasis. The host and/or parasite factors that trigger the inflammatory response to invading Eh are not well understood. We recently identified that Eh adherence to macrophages induces inflammasome activation and in the present study we sought to determine the molecular events upon contact that coordinates this response. Here we report that Eh contact-dependent activation of α5β1 integrin is critical for activation of the NLRP3 inflammasome. Eh-macrophage contact triggered recruitment of α5β1 integrin and NLRP3 into the intercellular junction, where α5β1 integrin underwent activation by an integrin-binding cysteine protease on the parasite surface, termed EhCP5. As a result of its activation, α5β1 integrin induced ATP release into the extracellular space through opening of pannexin-1 channels that signalled through P2X7 receptors to deliver a critical co-stimulatory signal that activated the NLRP3 inflammasome. Both the cysteine protease activity and integrin-binding domain of EhCP5 were required to trigger α5β1 integrin that led to ATP release and NLRP3 inflammasome activation. These findings reveal engagement of α5β1 integrin across the parasite-host junction is a key regulatory step that initiates robust inflammatory responses to Eh. We propose that α5β1 integrin distinguishes Eh direct contact and functions with NLRP3 as pathogenicity sensor for invasive Eh infection.

  7. Airway Hyperresponsiveness in Asthma Model Occurs Independently of Secretion of β1 Integrins in Airway Wall and Focal Adhesions Proteins Down Regulation.

    Álvarez-Santos, Mayra; Carbajal, Verónica; Tellez-Jiménez, Olivia; Martínez-Cordero, Erasmo; Ruiz, Victor; Hernández-Pando, Rogelio; Lascurain, Ricardo; Santibañez-Salgado, Alfredo; Bazan-Perkins, Blanca

    2016-10-01

    The extracellular domains of some membrane proteins can be shed from the cell. A similar phenomenon occurs with β1 integrins (α1β1 and α2β1) in guinea pig. The putative role of β1 integrin subunit alterations due to shedding in airway smooth muscle (ASM) in an allergic asthma model was evaluated. Guinea pigs were sensitized and challenged with antigen. Antigenic challenges induced bronchoobstruction and hyperresponsiveness at the third antigenic challenge. Immunohistochemistry and immunoelectronmicroscopy studies showed that the cytosolic and extracellular domains of the β1 integrin subunit shared the same distribution in airway structures in both groups. Various polypeptides with similar molecular weights were detected with both the cytosolic and extracellular β1 integrin subunit antibodies in isolated airway myocytes and the connective tissue that surrounds the ASM bundle. Flow cytometry and Western blot studies showed that the expression of cytosolic and extracellular β1 integrin subunit domains in ASM was similar between groups. An increment of ITGB1 mRNA in ASM was observed in the asthma model group. RACE-PCR of ITGB1 in ASM did not show splicing variants. The expression levels of integrin-linked kinase (ILK) and paxillin diminished in the asthma model, but not talin. The levels of phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at Thr(696) increased in asthma model. Our work suggests that β1 integrin is secreted in guinea pig airway wall. This secretion is not altered in asthma model; nevertheless, β1 integrin cytodomain assembly proteins in focal cell adhesions in which ILK and paxillin are involved are altered in asthma model. J. Cell. Biochem. 117: 2385-2396, 2016. © 2016 Wiley Periodicals, Inc. PMID:26969873

  8. α2β1 integrin affects metastatic potential of ovarian carcinoma spheroids by supporting disaggregation and proteolysis

    Ackland Margaret

    2007-01-01

    Full Text Available Abstract Background Ovarian cancer is characterized by a wide-spread intra-abdominal metastases which represents a major clinical hurdle in the prognosis and management of the disease. A significant proportion of ovarian cancer cells in peritoneal ascites exist as multicellular aggregates or spheroids. We hypothesize that these cellular aggregates or spheroids are invasive with the capacity to survive and implant on the peritoneal surface. This study was designed to elucidate early inherent mechanism(s of spheroid survival, growth and disaggregation required for peritoneal metastases Methods In this study, we determined the growth pattern and adhesive capacity of ovarian cancer cell lines (HEY and OVHS1 grown as spheroids, using the well established liquid overlay technique, and compared them to a normal ovarian cell line (IOSE29 and cancer cells grown as a monolayer. The proteolytic capacity of these spheroids was compared with cells grown as a monolayer using a gelatin zymography assay to analyze secreted MMP-2/9 in conditioned serum-free medium. The disaggregation of cancer cell line spheroids was determined on extracellular matrices (ECM such as laminin (LM, fibronectin (FN and collagen (CI and the expression of α2, α3, αv, α6 and β1 interin was determined by flow cytometric analysis. Neutralizing antibodies against α2, β1 subunits and α2β1 integrin was used to inhibit disaggregation as well as activation of MMPs in spheroids. Results We demonstrate that ovarian cancer cell lines grown as spheroids can sustain growth for 10 days while the normal ovarian cell line failed to grow beyond 2 days. Compared to cells grown as a monolayer, cancer cells grown as spheroids demonstrated no change in adhesion for up to 4 days, while IOSE29 cells had a 2–4-fold loss of adhesion within 2 days. Cancer cell spheroids disaggregated on extracellular matrices (ECM and demonstrated enhanced expression of secreted pro-MMP2 as well as activated MMP2

  9. THE α4β1 INTEGRIN AND THE EDA DOMAIN OF FIBRONECTIN REGULATE A PROFIBROTIC PHENOTYPE IN DERMAL FIBROBLASTS*

    Shinde, Arti V.; Kelsh, Rhiannon; Peters, John H.; Sekiguchi, Kiyotoshi; Van De Water, Livingston; McKeown-Longo, Paula J.

    2015-01-01

    Prompt deposition of fibronectin-rich extracellular matrix is a critical feature of normal development and the host-response to injury. Fibronectin isoforms that include the EDA and EDB domains are prominent in these fibronectin matrices. We now report using human dermal fibroblast cultures that the EDA domain of fibronectin or EDA-derived peptides modeled after the C-C’ loop promote stress fiber formation and myosin-light chain phosphorylation. These changes are accompanied by an increase in fibronectin synthesis and fibrillogenesis. These effects are blocked by pretreating cells with either siRNA or blocking antibody to the α4 integrin. Our data indicate that the interaction between the α4β1 integrin and the EDA domain of fibronectin helps to drive tissue fibrosis by promoting a contractile phenotype and an increase in fibronectin synthesis and deposition. PMID:25433338

  10. The α4β1 integrin and the EDA domain of fibronectin regulate a profibrotic phenotype in dermal fibroblasts.

    Shinde, Arti V; Kelsh, Rhiannon; Peters, John H; Sekiguchi, Kiyotoshi; Van De Water, Livingston; McKeown-Longo, Paula J

    2015-01-01

    Prompt deposition of fibronectin-rich extracellular matrix is a critical feature of normal development and the host-response to injury. Fibronectin isoforms that include the EDA and EDB domains are prominent in these fibronectin matrices. We now report using human dermal fibroblast cultures that the EDA domain of fibronectin or EDA-derived peptides modeled after the C-C' loop promote stress fiber formation and myosin-light chain phosphorylation. These changes are accompanied by an increase in fibronectin synthesis and fibrillogenesis. These effects are blocked by pretreating cells with either siRNA or blocking antibody to the α4 integrin. Our data indicate that the interaction between the α4β1 integrin and the EDA domain of fibronectin helps to drive tissue fibrosis by promoting a contractile phenotype and an increase in fibronectin synthesis and deposition. PMID:25433338

  11. The Activation of β1-integrin by Type I Collagen Coupling with the Hedgehog Pathway Promotes the Epithelial-Mesenchymal Transition in Pancreatic Cancer.

    Duan, Wanxing; Ma, Jiguang; Ma, Qingyong; Xu, Qinhong; Lei, Jianjun; Han, Liang; Li, Xuqi; Wang, Zheng; Wu, Zheng; Lv, Shifang; Ma, Zhenhua; Liu, Mouzhu; Wang, Fengfei; Wu, Erxi

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by the excessive deposition of extracellular matrix (ECM), which is thought to contribute to this tumor's malignant behavior. However, the detailed mechanism and the contribution of excessive deposition of ECM in PDAC progression remain unclear. A better understanding of the mechanism involved in this process is essential for the design of new effective therapies. In this study, we demonstrated that pancreatic cancer cells exhibited increased proliferation and decreased apoptosis in response to type I collagen. In addition, PDAC cells exposed to type I collagen lost the expression of E-cadherin and increased expression of mesenchymal markers, including N-cadherin and vimentin. This epithelial- mesenchymal transition (EMT) was correlated with enhanced cell migration and invasiveness. Knockdown of β1-integrin abolished the effects induced by type I collagen, and further investigation revealed that type I collagen activates β1-integrin (marked by phosphorylation of β1 integrin downstream effectors, focal adhesion kinase [FAK], AKT, and ERK) accompanied by markedly up-regulation of Gli-1, a component of the Hedgehog (HH) pathway. Knockdown of Gli-1 reversed the effects of type I collagen on PDAC invasion and EMT. These results suggest that there is cross-talk between the β1-integrin signaling pathway and the HH pathway in pancreatic cancer and that activation of the HH pathway plays a key role in the type I collagen-induced effects on pancreatic cancer. PMID:24720337

  12. Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism.

    Wang, Jiang Huai

    2012-02-03

    Beta(1) integrins play a crucial role in supporting tumor cell attachment to and invasion into the extracellular matrix. Endotoxin\\/LPS introduced by surgery has been shown to enhance tumor metastasis in a murine model. Here we show the direct effect of LPS on tumor cell adhesion and invasion in extracellular matrix proteins through a beta(1) integrin-dependent pathway. The human colorectal tumor cell lines SW480 and SW620 constitutively expressed high levels of the beta(1) subunit, whereas various low levels of alpha(1), alpha(2), alpha(4), and alpha(6) expression were detected. SW480 and SW620 did not express membrane-bound CD14; however, LPS in the presence of soluble CD14 (sCD14) significantly up-regulated beta(1) integrin expression; enhanced tumor cell attachment to fibronectin, collagen I, and laminin; and strongly promoted tumor cell invasion through the Matrigel. Anti-beta(1) blocking mAbs (4B4 and 6S6) abrogated LPS- plus sCD14-induced tumor cell adhesion and invasion. Furthermore, LPS, when combined with sCD14, resulted in NF-kappaB activation in both SW480 and SW620 cells. Inhibition of the NF-kappaB pathway significantly attenuated LPS-induced up-regulation of beta(1) integrin expression and prevented tumor cell adhesion and invasion. These results provide direct evidence that although SW480 and SW620 cells do not express membrane-bound CD14, LPS in the presence of sCD14 can activate NF-kappaB, up-regulate beta(1) integrin expression, and subsequently promote tumor cell adhesion and invasion. Moreover, LPS-induced tumor cell attachment to and invasion through extracellular matrix proteins is beta(1) subunit-dependent.

  13. Unique DNA repair properties of a xeroderma pigmentosum revertant.

    Cleaver, J.E.; Cortés, F; Lutze, L H; Morgan, W F; Player, A N; D. L. Mitchell

    1987-01-01

    A group A xeroderma pigmentosum revertant with normal sensitivity was created by chemical mutagenesis. It repaired (6-4) photoproducts normally but not pyrimidine dimers and had near normal levels of repair replication, sister chromatid exchange, and mutagenesis from UV light. The rate of UV-induced mutation in a shuttle vector, however, was as high as the rate in the parental xeroderma pigmentosum cell line.

  14. The Interaction of CD154 with the α5β1 Integrin Inhibits Fas-Induced T Cell Death.

    Bachsais, Meriem; Naddaf, Nadim; Yacoub, Daniel; Salti, Suzanne; Alaaeddine, Nada; Aoudjit, Fawzi; Hassan, Ghada S; Mourad, Walid

    2016-01-01

    CD154, a critical regulator of the immune response, is usually associated with chronic inflammatory, autoimmune diseases as well as malignant disorders. In addition to its classical receptor CD40, CD154 is capable of binding other receptors, members of the integrin family, the αIIbβ3, αMβ2 and α5β1. Given the role attributed to integrins and particularly the β1 integrins in inhibiting apoptotic events in normal as well as malignant T cells, we were highly interested in investigating the role of the CD154/α5β1 interaction in promoting survival of malignant T cells contributing as such to tumor development and/or propagation. To support our hypothesis, we first show that soluble CD154 binds to the T-cell acute lymphoblastic leukemia cell line, Jurkat E6.1 in a α5β1-dependent manner. Binding of soluble CD154 to α5β1 integrin of Jurkat cells leads to the activation of key survival proteins, including the p38 and ERK1/2 mitogen-activated protein kinases (MAPKs), phosphoinositide 3 kinase (PI-3K), and Akt. Interestingly, soluble CD154 significantly inhibits Fas-mediated apoptosis in T cell leukemia-lymphoma cell lines, Jurkat E6.1 and HUT78 cells, an important hallmark of T cell survival during malignancy progression. These anti-apoptotic effects were mainly mediated by the activation of the PI-3K/Akt pathway but also involved the p38 and the ERK1/2 MAPKs cascades. Our data also demonstrated that the CD154-triggered inhibition of the Fas-mediated cell death response was dependent on a suppression of caspase-8 cleavage, but independent of de novo protein synthesis or alterations in Fas expression on cell surface. Together, our results highlight the impact of the CD154/α5β1 interaction in T cell function/survival and identify novel targets for the treatment of malignant disorders, particularly of T cell origin. PMID:27391025

  15. α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3

    Paul, Nikki R.; Allen, Jennifer L.; Chapman, Anna; Morlan-Mairal, Maria; Zindy, Egor; Jacquemet, Guillaume; Fernandez del Ama, Laura; Ferizovic, Nermina; Green, David M.; Howe, Jonathan D.; Ehler, Elisabeth; Hurlstone, Adam

    2015-01-01

    Invasive migration in 3D extracellular matrix (ECM) is crucial to cancer metastasis, yet little is known of the molecular mechanisms that drive reorganization of the cytoskeleton as cancer cells disseminate in vivo. 2D Rac-driven lamellipodial migration is well understood, but how these features apply to 3D migration is not clear. We find that lamellipodia-like protrusions and retrograde actin flow are indeed observed in cells moving in 3D ECM. However, Rab-coupling protein (RCP)-driven endocytic recycling of α5β1 integrin enhances invasive migration of cancer cells into fibronectin-rich 3D ECM, driven by RhoA and filopodial spike-based protrusions, not lamellipodia. Furthermore, we show that actin spike protrusions are Arp2/3-independent. Dynamic actin spike assembly in cells invading in vitro and in vivo is regulated by Formin homology-2 domain containing 3 (FHOD3), which is activated by RhoA/ROCK, establishing a novel mechanism through which the RCP–α5β1 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo. PMID:26370503

  16. Production of IL1-beta by ovarian cancer cells induces mesothelial cell beta1-integrin expression facilitating peritoneal dissemination

    Watanabe Takafumi

    2012-02-01

    Full Text Available Abstract Background A crucial step in the metastatic spread of ovarian cancer (OC is the adhesion and implantation of tumor cells to the peritoneal mesothelium. In order to study this step in the cascade, we derived a pro-metastatic human ovarian carcinoma cell line (MFOC3 from the non-metastatic FOC3 line. Methods Molecular profiling of the isogeneic lines identified differentially expressed genes, and investigation for a role in dissemination for specific factors was achieved by development of a co-culture adhesion assay utilizing monolayers of human mesothelial cells. Results After murine intraperitoneal inoculation, the FOC3 cell line formed no metastases, but the MFOC3 subline formed metastases in > 80% of SCID mice. MFOC3 cells also adhered 2-3 times more avidly to mesothelial monolayers. This adhesion was inhibited by neutralizing antibodies to IL-1β and enhanced by recombinant IL-1β (p in vitro and significantly reduced metastases in vivo. Immunohistochemical analysis of a cohort of 96 ovarian cancer cases showed that negative IL-1β expression was significantly associated with an improved overall survival rate. Conclusions These results suggest that a IL-1β/β1-integrin axis plays a role in ovarian tumor cell adhesion to mesothelia, a crucial step in ovarian cancer dissemination.

  17. SNARE-mediated trafficking of α5β1 integrin is required for spreading in CHO cells

    In this study, the role of SNARE-mediated membrane traffic in regulating integrin localization was examined and the requirement for SNARE function in cellular spreading was quantitatively assessed. Membrane traffic was inhibited with the VAMP-specific catalytic light chain from tetanus toxin (TeTx-LC), a dominant-negative form (E329Q) of N-ethylmaleimide-sensitive fusion protein (NSF), and brefeldin A (BfA). Inhibition of membrane traffic with either E329Q-NSF or TeTx-LC, but not BfA, significantly inhibited spreading of CHO cells on fibronectin. Spreading was rescued in TeTx-LC-expressing cells by co-transfection with a TeTx-resistant cellubrevin/VAMP3. E329Q-NSF, a general inhibitor of SNARE function, was a more potent inhibitor of cell spreading than TeTx-LC, suggesting that tetanus toxin-insensitive SNAREs contribute to adhesion. It was found that E329Q-NSF prevented trafficking of α5β1 integrins from a central Rab11-containing compartment to sites of protrusion during cell adhesion, while TeTx-LC delayed this trafficking. These results are consistent with a model of cellular adhesion that implicates SNARE function as an important component of integrin trafficking during the process of cell spreading

  18. Plumieribetin, a Fish Lectin Homologous to Mannose-binding B-type Lectins, Inhibits the Collagen-binding α1β1 Integrin*

    de Santana Evangelista, Karla; Andrich, Filipe; Figueiredo de Rezende, Flávia; Niland, Stephan; Cordeiro, Marta N.; Horlacher, Tim; Castelli, Riccardo; Schmidt-Hederich, Alletta; Peter H. Seeberger; Sanchez, Eladio F.; Richardson, Michael; Gomes de Figueiredo, Suely; Eble, Johannes A.

    2009-01-01

    Recently, a few fish proteins have been described with a high homology to B-type lectins of monocotyledonous plants. Because of their mannose binding activity, they have been ascribed a role in innate immunity. By screening various fish venoms for their integrin inhibitory activity, we isolated a homologous protein from the fin stings and skin mucus of the scorpionfish (Scorpaena plumieri). This protein inhibits α1β1 integrin binding to basement membrane collagen IV. By protein chemical and s...

  19. Endorepellin, the C-terminal angiostatic module of perlecan, enhances collagen-platelet responses via the α2β1-integrin receptor

    Bix, Gregory; Iozzo, Rex A.; Woodall, Ben; Burrows, Michelle; McQuillan, Angela; Campbell, Shelly; Fields, Gregg B.; Iozzo, Renato V.

    2007-01-01

    Endorepellin, a C-terminal fragment of the vascular basement membrane proteoglycan perlecan, inhibits angiogenesis via the α2β1-integrin receptor. Because this integrin is also implicated in platelet-collagen responses and because endorepellin or its fragments are generated in response to injury and inflammation, we hypothesized that endorepellin could also affect platelet biology. We discovered that endorepellin supported α2β1-dependent platelet adhesion, without appreciably activating or ag...

  20. Treatment of marrow stroma with interferon-alpha restores normal beta 1 integrin-dependent adhesion of chronic myelogenous leukemia hematopoietic progenitors. Role of MIP-1 alpha.

    R Bhatia; McGlave, P B; Verfaillie, C M

    1995-01-01

    The mechanisms by which interferon-alpha (IFN-alpha) restores normal hematopoiesis in chronic myelogenous leukemia (CML) are not well understood. We have recently demonstrated that IFN-alpha acts directly on CML hematopoietic progenitors to restore their adhesion to marrow stroma by modulating beta 1 integrin receptor function. In the present study we examined the effect of IFN-alpha treatment of marrow stroma on subsequent adhesion of CML progenitors. Stromal layers were preincubated with IF...

  1. Tauroursodeoxycholate Protects Rat Hepatocytes from Bile Acid-Induced Apoptosis via β1-Integrin- and Protein Kinase A-Dependent Mechanisms

    Annika Sommerfeld

    2015-05-01

    Full Text Available Background/Aims: Ursodeoxycholic acid, which in vivo is rapidly converted into its taurine conjugate, is frequently used for the treatment of cholestatic liver disease. Apart from its choleretic effects, tauroursodeoxycholate (TUDC can protect hepatocytes from bile acid-induced apoptosis, but the mechanisms underlying its anti-apoptotic effects are poorly understood. Methods: These mechanisms were investigated in perfused rat liver and isolated rat hepatocytes. Results: It was found that TUDC inhibited the glycochenodeoxycholate (GCDC-induced activation of the CD95 death receptor at the level of association between CD95 and the epidermal growth factor receptor. This was due to a rapid TUDC-induced β1-integrin-dependent cyclic AMP (cAMP signal with induction of the dual specificity mitogen-activated protein (MAP kinase phosphatase 1 (MKP-1, which prevented GCDC-induced phosphorylation of mitogen-activated protein kinase kinase 4 (MKK4 and c-jun-NH2-terminal kinase (JNK activation. Furthermore, TUDC induced a protein kinase A (PKA-mediated serine/threonine phosphorylation of the CD95, which was recently identified as an internalization signal for CD95. Furthermore, TUDC inhibited GCDC-induced CD95 targeting to the plasma membrane in a β1-integrin-and PKA-dependent manner. In line with this, the β1-integrin siRNA knockdown in sodium taurocholate cotransporting polypeptide (Ntcp-transfected HepG2 cells abolished the protective effect of TUDC against GCDC-induced apoptosis. Conclusion: TUDC exerts its anti-apoptotic effect via a β1-integrin-mediated formation of cAMP, which prevents CD95 activation by hydrophobic bile acids at the levels of JNK activation and CD95 serine/threonine phosphorylation.

  2. Cellular partitioning of beta-1 integrins and their phosphorylated forms is altered after transformation by Rous sarcoma virus or treatment with cytochalasin D.

    Haimovich, B; Aneskievich, B J; Boettiger, D

    1991-01-01

    A sequential extraction procedure of 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate (CHAPS) buffer followed by RIPA or Laemmli sample buffer was developed to define two distinct subpopulations of beta-1 integrins in primary chicken embryo fibroblasts. Extraction of cells in culture revealed an association of adhesion plaque-localized integrin with the CHAPS-insoluble fraction. Phosphorylated integrins were found in both fractions, but the specific phosphorylation was 12-fold high...

  3. Bone marrow-derived mesenchymal stem cells enhance angiogenesis via their α6β1 integrin receptor

    Bone marrow-derived mesenchymal stem cells (BMSCs) facilitate the angiogenic response of endothelial cells (ECs) within three-dimensional (3D) matrices in vivo and in engineered tissues in vitro in part through paracrine mediators and by acting as stabilizing pericytes. However, the molecular interactions between BMSCs and nascent tubules during the process of angiogenesis are not fully understood. In this study, we have used a tractable 3D co-culture model to explore the functional role of the α6β1 integrin adhesion receptor on BMSCs in sprouting angiogenesis. We report that knockdown of the α6 integrin subunit in BMSCs significantly reduces capillary sprouting, and causes their failure to associate with the nascent vessels. Furthermore, we demonstrate that the BMSCs with attenuated α6 integrin proliferate at a significantly lower rate relative to either control cells expressing non-targeting shRNA or wild type BMSCs; however, despite adding more cells to compensate for this deficit in proliferation, deficient sprouting persists. Collectively, our findings demonstrate that the α6 integrin subunit in BMSCs is important for their ability to stimulate vessel morphogenesis. This conclusion may have important implications in the optimization of cell-based strategies to promote angiogenesis. Highlights: • BMSCs stimulate angiogenesis, but the mechanisms remain unclear. • We silenced the expression of the α6 integrin subunit in BMSCs. • Silencing this receptor subunit significantly inhibited angiogenic sprouting. • Knocking down α6 integrin affected laminin and αSMA expression. • Silencing α6 integrin expression also reduced BMSC proliferation

  4. Differential β3 and β1 Integrin Expression in Bone Marrow and Cortical Bone of Estrogen Deficient Rats.

    Voisin, Muriel; McNamara, Laoise M

    2015-09-01

    Integrin-based (β3 ) attachments to the extracellular matrix (ECM) on osteocyte cell processes have recently been proposed to play an important role in facilitating osteocyte mechanosensation. However, it is not yet known whether integrin expression is altered in the mechanoregulatory osteocytes during osteoporosis. The objective of this study was to test the hypothesis that the expression of integrin-based mechanosensory complexes (β1 and β3 integrins) is altered as a direct response to estrogen deficiency, in an estrogen deficient animal model of osteoporosis. Four weeks post-operatively, immunohistochemistry was used to detect for β1 and β3 integrin subunits in bone tissue and marrow of ovariectomized (OVX; N = 4) and SHAM (N = 4) operated animals. A tartrate resistant acid phosphatase (TRAP) control stain was performed to quantify the presence of osteoclasts in the bone marrow and bone surfaces. Image analysis was performed to quantify expression patterns in different biological compartments, that is, bone marrow, endosteum, and cortical bone. Our results showed that β1 integrins were ubiquitously expressed throughout the bone and marrow, for both OVX and SHAM groups. β3 integrin subunit expression was lower in bone cells from osteoporotic animals compared to controls, whereas β3 expression in marrow cells did not differ significantly between groups. At the endosteum no difference was observed in β3 integrin subunit expression. As expected, the number of osteoclasts was higher in the OVX group validating an imbalance in bone remodeling. We propose that a reduction in β3 integrin expression in osteocytes might impair mechanosensation by bone cells during estrogen deficiency. PMID:25974241

  5. Bone marrow-derived mesenchymal stem cells enhance angiogenesis via their α6β1 integrin receptor

    Carrion, Bita; Kong, Yen P. [Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109 (United States); Kaigler, Darnell [Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109 (United States); Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109 (United States); Putnam, Andrew J., E-mail: putnam@umich.edu [Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109 (United States)

    2013-11-15

    Bone marrow-derived mesenchymal stem cells (BMSCs) facilitate the angiogenic response of endothelial cells (ECs) within three-dimensional (3D) matrices in vivo and in engineered tissues in vitro in part through paracrine mediators and by acting as stabilizing pericytes. However, the molecular interactions between BMSCs and nascent tubules during the process of angiogenesis are not fully understood. In this study, we have used a tractable 3D co-culture model to explore the functional role of the α6β1 integrin adhesion receptor on BMSCs in sprouting angiogenesis. We report that knockdown of the α6 integrin subunit in BMSCs significantly reduces capillary sprouting, and causes their failure to associate with the nascent vessels. Furthermore, we demonstrate that the BMSCs with attenuated α6 integrin proliferate at a significantly lower rate relative to either control cells expressing non-targeting shRNA or wild type BMSCs; however, despite adding more cells to compensate for this deficit in proliferation, deficient sprouting persists. Collectively, our findings demonstrate that the α6 integrin subunit in BMSCs is important for their ability to stimulate vessel morphogenesis. This conclusion may have important implications in the optimization of cell-based strategies to promote angiogenesis. Highlights: • BMSCs stimulate angiogenesis, but the mechanisms remain unclear. • We silenced the expression of the α6 integrin subunit in BMSCs. • Silencing this receptor subunit significantly inhibited angiogenic sprouting. • Knocking down α6 integrin affected laminin and αSMA expression. • Silencing α6 integrin expression also reduced BMSC proliferation.

  6. Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type I collagen.

    Fishman, D A; Kearns, A; Chilukuri, K; Bafetti, L M; O'Toole, E A; Georgacopoulos, J; Ravosa, M J; Stack, M S

    1998-01-01

    Metastatic dissemination of epithelial ovarian carcinoma is thought to be mediated via tumor cell exfoliation into the peritoneal cavity, followed by adhesion to and invasion through the mesothelium which overlies the contents of the peritoneal cavity. In this study, we have utilized short-term primary cultures to analyze the effect of specific extracellular matrix proteins on properties of human ovarian epithelial carcinoma cells which contribute to the invasive phenotype. Analysis of cell:matrix adhesive profiles indicated that ovarian carcinoma cells adhere preferentially to type I collagen. Immunoprecipitation analyses demonstrated the presence of the collagen-binding alpha2beta1 integrin in biotin-labeled ovarian carcinoma cell membranes, and cellular adhesion was inhibited by blocking antibodies directed against the alpha2 and beta1 integrin subunits. The alpha2beta1-binding peptide Asp-Gly-Glu-Ala (DGEA) was also moderately effective at blocking adhesion to collagen relative to the control peptide Ala-Gly-Glu-Ala (AGEA). Analysis of cell motility on protein-coated colloidal gold coverslips demonstrated that ovarian carcinoma cells migrate preferentially on type I collagen coated surfaces. Type I collagen promoted migration in a concentration-dependent, saturable manner, with maximal migration observed at a collagen-coating concentration of 50 microg/ml. Migration on collagen was inhibited by antibodies directed against the alpha2 and beta1 integrin subunits and by DGEA peptide, providing evidence for the role of the alpha2beta1 integrin in ovarian carcinoma cell motility. Culturing ovarian carcinoma cells on type I collagen gels led to a significant increase in conversion of the matrix metalloproteinase 2 zymogen to the 66-kD form, suggesting that adhesion to collagen also influences matrix-degrading proteinases. These data suggest that alpha2beta1-integrin-mediated interaction of ovarian carcinoma cells with type I collagen, a protein prevalent both in the

  7. A vortex venturi for reverting antimisting fuel properties

    Szetela, E. J.; Tevelde, J.

    1983-01-01

    The level of degradation of antimisting fuel polymers such as FM-9 which must be accomplished in order to use antimisting fuel in existing engines may require the use of cavitation. The hydrodynamic shear produced by the collapse of vapor bubbles is capable of producing more splitting of polymeric molecules than mechanically-induced shear. A program has been carried out to investigate the possibility of using a cavitating venturi with rotating flow as a fuel reverter. This investigation included the effects of a swirl-inducing twisted tape upstream of the throat, inlet pressure, recovery pressure ratio and a pintle for varying throat area. A correlation of the data was produced, system concepts for using the vortex venturi were investigated and problem areas were delineated.

  8. Cellular growth and survival are mediated by beta 1 integrins in normal human breast epithelium but not in breast carcinoma

    Howlett, Anthony R; Bailey, Nina; Damsky, Caroline; Petersen, Ole W; Bissell, Mina J

    1994-11-28

    capacity to form colonies. Thus under our culture conditions breast acinar formation is at least a two-step process involving {beta}1-integrin-dependent cellular growth followed by polarization of the cells into organized structures. The regulation of this pathway appears to be impaired or lost in the tumor cells, suggesting that tumor colony formation occurs by independent mechanisms and that loss of proper integrinmediated cell-ECM interaction may be critical to breast tumor formation.

  9. Essential function for PDLIM2 in cell polarization in three-dimensional cultures by feedback regulation of the β1-integrin-RhoA signaling axis.

    Deevi, Ravi Kiran; Cox, Orla T; O'Connor, Rosemary

    2014-05-01

    PDLIM2 is a cytoskeletal and nuclear PDZ-LIM domain protein that regulates the stability of Nuclear Factor kappa-B (NFκB) and other transcription factors, and is required for polarized cell migration. PDLIM2 expression is suppressed by methylation in different cancers, but is strongly expressed in invasive breast cancer cells that have undergone an Epithelial Mesenchymal Transition (EMT). PDLIM2 is also expressed in non-transformed breast myoepithelial MCF10A cells and here we asked whether it is important for maintaining the polarized, epithelial phenotype of these cells. Suppression of PDLIM2 in MCF10A cells was sufficient to disrupt cell polarization and acini formation with increased proliferation and reduced apoptosis in the luminal space compared to control acini with hollow lumina. Spheroids with suppressed PDLIM2 exhibited increased expression of cell-cell and cell-matrix adhesion proteins including beta 1 (β1) integrin. Interestingly, levels of the Insulin-like growth factor 1 receptor (IGF-1 R) and Receptor of activated protein kinase C 1 (RACK1), which scaffolds IGF-1R to β1 integrin, were also increased, indicating a transformed phenotype. Focal Adhesion Kinase (FAK) and cofilin phosphorylation, and RhoA Guanosine Triphosphatase (GTPase) activity were all enhanced in these spheroids compared to control acini. Importantly, inhibition of either FAK or Rho Kinase (ROCK) was sufficient to rescue the polarity defect. We conclude that PDLIM2 expression is essential for feedback regulation of the β1-integrin-RhoA signalling axis and integration of cellular microenvironment signals with gene expression to control the polarity of breast epithelial acini structures. This is a mechanism by which PDLIM2 could mediate tumour suppression in breast epithelium. PMID:24863845

  10. Prostate cancer

    Murphy, G.P.; Kuss, R., Khoury, S.; Chatelain, C.; Denis, L.

    1987-01-01

    This book contains over 70 selections. Some of the titles are: Place of the Computed Tomography in the Staging of Prostatic Cancer; Magnetic Resonance Imaging (MRI) in Staging of the Prostatic Cancer; Magnetic Resonance Imaging of the Prostate; Long-Term Results in Radiotherapy of Prostatic Cancer; Interstitial Irradiation Using I-125 Seeds; and Treatment of Cancer of the Prostate by Use of Physiotherapy: Long-Term Results.

  11. Prostate cancer

    This book contains over 70 selections. Some of the titles are: Place of the Computed Tomography in the Staging of Prostatic Cancer; Magnetic Resonance Imaging (MRI) in Staging of the Prostatic Cancer; Magnetic Resonance Imaging of the Prostate; Long-Term Results in Radiotherapy of Prostatic Cancer; Interstitial Irradiation Using I-125 Seeds; and Treatment of Cancer of the Prostate by Use of Physiotherapy: Long-Term Results

  12. Discovery, SAR, and Radiolabeling of Halogenated Benzimidazole Carboxamide Antagonists as Useful Tools for (alpha)4(beta)1 Integrin Expressed on T- and B-cell Lymphomas

    Carpenter, R D; Natarajan, A; Lau, E Y; Andrei, M; Solano, D M; Lightstone, F C; DeNardo, S J; Lam, K S; Kurth, M J

    2010-02-08

    The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin is an attractive yet poorly understood target for selective diagnosis and treatment of T- and B-cell lymphomas. This report focuses on the rapid microwave preparation of medicinally pertinent benzimidazole heterocycles, structure-activity relationships (SAR) of novel halobenzimidazole carboxamide antagonists 3-6, and preliminary biological evaluation of radioiodinated agents 7, 8, and 18. The I-125 derivative 18 had good tumor uptake (12 {+-} 1% ID/g at 24 h; 4.5 {+-} 1% ID/g at 48 h) and tumor:kidney ratio ({approx}4:1 at 24 h; 2.5:1 at 48 h) in xenograft murine models of B-cell lymphoma. Molecular homology models of {alpha}{sub 4}{beta}{sub 1} integrin have predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. These high affinity ({approx} pM binding) halogenated ligands are attractive tools for medicinal and biological use; the fluoro and iodo derivatives are potential radiodiagnostic ({sup 18}F) or radiotherapeutic ({sup 131}I) agents, whereas the chloro and bromo analogues could provide structural insight into integrin-ligand interactions through photoaffinity cross-linking/mass spectroscopy experiments, as well as co-crystallization X-ray studies.

  13. Recruitment of focal adhesion kinase and paxillin to β1 integrin promotes cancer cell migration via mitogen activated protein kinase activation

    Integrin-extracellular matrix interactions activate signaling cascades such as mitogen activated protein kinases (MAPK). Integrin binding to extracellular matrix increases tyrosine phosphorylation of focal adhesion kinase (FAK). Inhibition of FAK activity by expression of its carboxyl terminus decreases cell motility, and cells from FAK deficient mice also show reduced migration. Paxillin is a focal adhesion protein which is also phosphorylated on tyrosine. FAK recruitment of paxillin to the cell membrane correlates with Shc phosphorylation and activation of MAPK. Decreased FAK expression inhibits papilloma formation in a mouse skin carcinogenesis model. We previously demonstrated that MAPK activation was required for growth factor induced in vitro migration and invasion by human squamous cell carcinoma (SCC) lines. Adapter protein recruitment to integrin subunits was examined by co-immunoprecipitation in SCC cells attached to type IV collagen or plastic. Stable clones overexpressing FAK or paxillin were created using the lipofection technique. Modified Boyden chambers were used for invasion assays. In the present study, we showed that FAK and paxillin but not Shc are recruited to the β1 integrin cytoplasmic domain following attachment of SCC cells to type IV collagen. Overexpression of either FAK or paxillin stimulated cancer cell migration on type IV collagen and invasion through reconstituted basement membrane which was dependent on MAPK activity. We concluded that recruitment of focal adhesion kinase and paxillin to β1 integrin promoted cancer cell migration via the mitogen activated protein kinase pathway

  14. Recruitment of focal adhesion kinase and paxillin to β1 integrin promotes cancer cell migration via mitogen activated protein kinase activation

    Ohannessian Arthur

    2004-05-01

    Full Text Available Abstract Background Integrin-extracellular matrix interactions activate signaling cascades such as mitogen activated protein kinases (MAPK. Integrin binding to extracellular matrix increases tyrosine phosphorylation of focal adhesion kinase (FAK. Inhibition of FAK activity by expression of its carboxyl terminus decreases cell motility, and cells from FAK deficient mice also show reduced migration. Paxillin is a focal adhesion protein which is also phosphorylated on tyrosine. FAK recruitment of paxillin to the cell membrane correlates with Shc phosphorylation and activation of MAPK. Decreased FAK expression inhibits papilloma formation in a mouse skin carcinogenesis model. We previously demonstrated that MAPK activation was required for growth factor induced in vitro migration and invasion by human squamous cell carcinoma (SCC lines. Methods Adapter protein recruitment to integrin subunits was examined by co-immunoprecipitation in SCC cells attached to type IV collagen or plastic. Stable clones overexpressing FAK or paxillin were created using the lipofection technique. Modified Boyden chambers were used for invasion assays. Results In the present study, we showed that FAK and paxillin but not Shc are recruited to the β1 integrin cytoplasmic domain following attachment of SCC cells to type IV collagen. Overexpression of either FAK or paxillin stimulated cancer cell migration on type IV collagen and invasion through reconstituted basement membrane which was dependent on MAPK activity. Conclusions We concluded that recruitment of focal adhesion kinase and paxillin to β1 integrin promoted cancer cell migration via the mitogen activated protein kinase pathway.

  15. Dietary Cholesterol and Prostate Cancer Risk: Inhibition of prostate Cancer in Rats by the Administration of some Antioxidants

    The present work was carried out to illuminate the relation between high cholesterol diet and incidence of prostate caner. Also, in this study, the effect of DHEA, selenium or oxygen therapy were tested in order to show to what extent they are valid to ameliorate the deleterious effects of prostate cancer. The obtained results revealed that prostate cancer caused a significant (p4 and FT3 were decreased significantly as compared with the corresponding levels in control rats in both normal and high cholesterol diet. Supplementation of DHEA, selenium or oxygen therapy ameliorated all variables recorded herein but, their values did not revert to normal. Any how, the results of this investigation showed that the above mentioned antioxidants possess potential benefits in lessening number of risk factors in blood associated with induced prostate cancer in rats. The underlying mechanisms through which DHEA, selenium and oxygen therapy counteracted prostate cancer were discussed

  16. Prostate Cancer

    ... man's bladder that produces fluid for semen. Prostate cancer is common among older men. It is rare ... younger than 40. Risk factors for developing prostate cancer include being over 65 years of age, family ...

  17. Prostate Cancer

    ... a man's bladder that produces fluid for semen. Prostate cancer is common among older men. It is rare ... men younger than 40. Risk factors for developing prostate cancer include being over 65 years of age, family ...

  18. Prostate biopsy

    ... from the prostate through the scope. Perineal - through perineum (the skin between the anus and the scrotum). ... pain. A small cut is made in the perineum. A needle is inserted to collect prostate tissue.

  19. Prostate brachytherapy

    Implant therapy - prostate cancer; Radioactive seed placement; Internal radiation therapy - prostate; High dose radiation (HDR) ... Brachytherapy takes 30 minutes or more, depending on the type of therapy you have. Before the procedure, ...

  20. Prostatitis - bacterial

    Any bacteria that can cause a urinary tract infection can cause acute bacterial prostatitis. Infections spread through sexual contact can cause prostatitis. These include chlamydia and gonorrhea . Sexually transmitted ...

  1. Chronic prostatitis

    Erickson, Bradley A.; Schaeffer, Anthony J.; Le, Brian

    2008-01-01

    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome, CP/CPPS). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  2. Stability of the tumor suppressor merlin depends on its ability to bind paxillin LD3 and associate with β1 integrin and actin at the plasma membrane

    Maria Elisa Manetti

    2012-08-01

    The NF2 gene encodes a tumor suppressor protein known as merlin or schwannomin whose loss of function causes Neurofibromatosis Type 2 (NF2. NF2 is characterized by the development of benign tumors, predominantly schwannomas, in the peripheral nervous system. Merlin links plasma membrane receptors with the actin cytoskeleton and its targeting to the plasma membrane depends on direct binding to the paxillin scaffold protein. Exon 2 of NF2, an exon mutated in NF2 patients and deleted in a mouse model of NF2, encodes the merlin paxillin binding domain (PBD1. Here, we sought to determine the role of PBD1 in regulation of merlin stability and association with plasma membrane receptors and the actin cytoskeleton in Schwann cells. Using a fluorescence-based pulse-chase technique, we measured the half-life of Halo-tagged merlin variants carrying PBD1, exon 2, and exons 2 and 3 deletions in transiently transfected Schwann cells. We found that PBD1 alone was necessary and sufficient to increase merlin's half-life from approximately three to eleven hours. Merlin lacking PBD1 did not form a complex with surface β1 integrins or associate with the actin cytoskeleton. In addition, direct binding studies using purified merlin and paxillin domains revealed that merlin directly binds paxillin LD3 (leucine-aspartate 3 domain as well as the LD4 and LD5 domains. Together these results demonstrate that a direct interaction between merlin PBD1 and the paxillin LD3–5 domains targets merlin to the plasma membrane where it is stabilized by its association with surface β1 integrins and cortical actin.

  3. Influence of reverted austenite on the texture and magnetic properties of 350 maraging steel

    Abreu, Hamilton F.G., E-mail: hamilton@ufc.br [Universidade Federal do Ceará, Campus do Pici-Bloco 729, CEP 60440-554 Fortaleza, CE (Brazil); Silva, Jean J. [Universidade Federal do Ceará, Campus do Pici-Bloco 729, CEP 60440-554 Fortaleza, CE (Brazil); Silva, Manoel R. [Universidade Federal de Itajubá, Campus Sede Itajubá/IFQ- Instituto de Física e Química, Itajubá, MG (Brazil); Gomes da Silva, Marcelo J., E-mail: mgsilva@ufc.br [Universidade Federal do Ceará, Campus do Pici-Bloco 729, CEP 60440-554 Fortaleza, CE (Brazil)

    2015-11-01

    The aging temperature to improve magnetic properties in Maraging-350 steel (Mar-350) is limited by the onset of austenite reversion. The traditional process of cooling after aging is to remove the piece from the oven and then to air cool it. The purpose of this research was to characterize the reverted austenite and to investigate the effect of cooling below the martensite start temperature (M{sub s}) on the magnetic properties. The Mar350 samples aged at temperatures above 550 °C, and subsequently cooled in liquid nitrogen presented less austenite than samples cooled in air, resulting in higher magnetization saturation and a lower coercive force. A combination of optical microscopy (OM), X-ray diffraction (XRD) and electron backscatter diffraction (EBSD) techniques were used to characterize the presence of reverted austenite. The crystallographic texture of both martensite and reverted austenite were analyzed. The texture of the reverted austenite coincides with the texture of the parent austenite indicating that a phenomenon of texture memory is present. - Highlights: • Cooling maraging samples in liquid nitrogen reduces reverted austenite fraction. • Retained austenite increases coercive force and decreases saturation magnetization. • Reverted and parent austenites have the same crystallographic texture. • Memory effect found during reversion transformation.

  4. Influence of reverted austenite on the texture and magnetic properties of 350 maraging steel

    The aging temperature to improve magnetic properties in Maraging-350 steel (Mar-350) is limited by the onset of austenite reversion. The traditional process of cooling after aging is to remove the piece from the oven and then to air cool it. The purpose of this research was to characterize the reverted austenite and to investigate the effect of cooling below the martensite start temperature (Ms) on the magnetic properties. The Mar350 samples aged at temperatures above 550 °C, and subsequently cooled in liquid nitrogen presented less austenite than samples cooled in air, resulting in higher magnetization saturation and a lower coercive force. A combination of optical microscopy (OM), X-ray diffraction (XRD) and electron backscatter diffraction (EBSD) techniques were used to characterize the presence of reverted austenite. The crystallographic texture of both martensite and reverted austenite were analyzed. The texture of the reverted austenite coincides with the texture of the parent austenite indicating that a phenomenon of texture memory is present. - Highlights: • Cooling maraging samples in liquid nitrogen reduces reverted austenite fraction. • Retained austenite increases coercive force and decreases saturation magnetization. • Reverted and parent austenites have the same crystallographic texture. • Memory effect found during reversion transformation

  5. Progress against Prostate Cancer

    ... this page please turn Javascript on. Feature: Prostate Cancer Progress Against Prostate Cancer Past Issues / Winter 2010 Table of Contents ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  6. Learning about Prostate Cancer

    ... of Information on Prostate Cancer What is prostate cancer? Prostate cancer is the most common cancer in American ... of page Additional Resources of Information on Prostate Cancer Prostate Cancer [nlm.nih.gov] From Medline Plus Medical ...

  7. Stages of Prostate Cancer

    ... Renal Cell) Cancer Leukemia Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All ... Cancer Treatment Prostate Cancer Prevention Genetics of Prostate Cancer Prostate Cancer Screening Research Prostate Cancer Treatment (PDQ®)–Patient ...

  8. Prostate cancer

    This work is about diagnosis, treatment and monitoring of prostate cancer. The techniques used are: transrectal ultrasound, laparascopy, bone scan, chest x-ray, radiography, chemoterapy and radiotherapy

  9. Isolation and genetic characterization of a fertility-restoring revertant induced from cytoplasmic male sterile rice

    A male fertile revertant was isolated from M1 of a cytoplasmic male sterile indica rice line II-32A, the dry seeds of which were treated with 60Co-γ rays at a dose of 290 Gy. The acquired revertant T24 was morphologically and agronomically similar to II-32B, the maintainer of II-32A. Testcrosses of the revertant with II-32A and Zhenshan 97A showed that the revertant was able to restore the fertility of CMS lines. Genetic analysis of the progenies between T24 and II-32A, Zhenshan 97A XieqingzaoA and DZhenshan 97A, which have different cytoplasms, showed that the fertility restoration of four CMS lines by T24 involved one nuclear gene, indicating that T24 was a result of the mutation of one nuclear gene. The mechanism of the restoration of CMS line by T24 was obviously different from other restorers such as Minghui 63 and 20964, which were shown to behave in two gene mode in fertility restoration. The discovery of the revertant T24 contributes to the understanding of CMS and fertility restoration of CMS in rice. The T24 and its parent II-32A may constitute a pair of near isogenic lines for the restoring gene, which should be valuable materials for molecular genetic analysis of CMS

  10. Revertants of a Transcription Termination Mutant of Yeast Contain Diverse Genetic Alterations

    Kotval, Jeroo; Zaret, Kenneth S.; Consaul, Sandra; Sherman, Fred

    1983-01-01

    Revertants of the cyc1-512 transcription termination mutant of the yeast Saccharomyces cerevisiae were isolated and subjected to a detailed genetic analysis. The cyc1-512 mutation previously was shown to be a 38-base pair deletion that causes only 10% of the normal steady-state levels of CYC1 mRNA and of the CYC1 gene product, iso-1-cytochrome c. Forty-one cyc1-512 revertants were classified by their content of iso-1-cytochrome c and by their genetic properties in meiotic crosses. Many of the...

  11. Blood platelets contain and secrete laminin-8 (alpha4beta1gamma1) and adhere to laminin-8 via alpha6beta1 integrin.

    Geberhiwot, T; Ingerpuu, S; Pedraza, C; Neira, M; Lehto, U; Virtanen, I; Kortesmaa, J; Tryggvason, K; Engvall, E; Patarroyo, M

    1999-12-15

    Laminins, a family of heterotrimeric proteins with cell adhesive/signaling properties, are characteristic components of basement membranes of vasculature and tissues. In the present study, permeabilized platelets were found to react with a monoclonal antibody to laminin gamma1 chain by immunofluorescence. In Western blot analysis of platelet lysates, several monoclonal antibodies to gamma1 and beta1 laminin chains recognized 220- to 230-kDa polypeptides, under reducing conditions, and a structure with much slower electrophoretic mobility under nonreducing conditions. Immunoaffinity purification on a laminin beta1 antibody-Sepharose column yielded polypeptides of 230, 220, 200, and 180 kDa from platelet lysates. In the purified material, mAbs to beta1 and gamma1 reacted with the two larger polypeptides, while affinity-purified rabbit antibodies to laminin alpha4 chain recognized the smallest polypeptide. Identity of the polypeptides was confirmed by microsequencing. One million platelets contained on average 1 ng of laminin (approximately 700 molecules per cell), of which 20-35% was secreted within minutes after stimulation with either thrombin or phorbol ester. Platelets adhered to plastic surfaces coated with the purified platelet laminin, and this process was largely inhibited by antibodies to beta1 and alpha6 integrin chains. We conclude that platelets contain and, following activation, secrete laminin-8 (alpha4beta1gamma1) and that the cells adhere to the protein by using alpha6beta1 integrin. PMID:10585296

  12. Prostate Cancer (Radiation Therapy)

    ... Physician Resources Professions Site Index A-Z Prostate Cancer Treatment Prostate cancer overview? What are my treatment options? What ... any new developments in treating my disease? Prostate cancer overview Prostate cancer is the most common form of cancer ...

  13. What is Prostate Cancer?

    ... Research Get Involved Find Local ACS Learn About Cancer » Prostate Cancer » Detailed Guide » What is prostate cancer? Share ... how cancers start and spread, see What Is Cancer? Prostate cancer begins when cells in the prostate gland ...

  14. Cryotherapy for prostate cancer

    Cryosurgery-prostate cancer; Cryoablation-prostate cancer ... Prostate Cancer. American Cancer Society. www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-cryosurgery. Accessed August 31, 2015. Horwich ...

  15. Prostatic melanosis

    Kemal DENİZ

    2007-09-01

    Full Text Available Prostatic melanosis is a rare lesion that is characterized by melanin-containing spindle cells mainly located in the stroma of the prostate gland. This lesion is certainly benign and not a precursor of malignant melanoma. However, differential diagnosis of melanosis with primary and metastatic malignant melanoma is extremely important because of the different biological nature and clinical behavior of these two entities. Recognition of the spectrum of pigmented lesions in the prostate gland is essential to take into consideration of the diagnosis of melanocytic lesions.In this paper, a case of melanosis

  16. Ibuprofen reverts antifungal resistance on Candida albicans showing overexpression of CDR genes.

    Ricardo, Elisabete; Costa-de-Oliveira, Sofia; Dias, Ana Silva; Guerra, José; Rodrigues, Acácio Gonçalves; Pina-Vaz, Cidália

    2009-06-01

    Several mechanisms may be associated with Candida albicans resistance to azoles. Ibuprofen was described as being able to revert resistance related to efflux activity in Candida. The aim of this study was to uncover the molecular base of antifungal resistance in C. albicans clinical strains that could be reverted by ibuprofen. Sixty-two clinical isolates and five control strains of C. albicans were studied: the azole susceptibility phenotype was determined according to the Clinical Laboratory for Standards Institute, M27-A2 protocol and minimal inhibitory concentration values were recalculated with ibuprofen (100 microg mL(-1)); synergistic studies between fluconazole and FK506, a Cdr1p inhibitor, were performed using an agar disk diffusion assay and were compared with ibuprofen results. Gene expression was quantified by real-time PCR, with and without ibuprofen, regarding CDR1, CDR2, MDR1, encoding for efflux pumps, and ERG11, encoding for azole target protein. A correlation between susceptibility phenotype and resistance gene expression profiles was determined. Ibuprofen and FK506 showed a clear synergistic effect when combined with fluconazole. Resistant isolates reverting to susceptible after incubation with ibuprofen showed CDR1 and CDR2 overexpression especially of the latter. Conversely, strains that did not revert displayed a remarkable increase in ERG11 expression along with CDR genes. Ibuprofen did not alter resistance gene expression significantly (P>0.05), probably acting as a Cdrp blocker. PMID:19416368

  17. Induction of cell scattering by expression of beta1 integrins in beta1-deficient epithelial cells requires activation of members of the rho family of GTPases and downregulation of cadherin and catenin function

    Gimond, C; van Der Flier, A; van Delft, S;

    1999-01-01

    was required for a complete morphological transition towards the spindle-shaped fibroblast-like phenotype. The expression of an interleukin-2 receptor (IL2R)-beta1A chimera and its incorporation into focal adhesions also induced the disruption of cadherin-based adhesions and the reorganization of ECM......Adhesion receptors, which connect cells to each other and to the surrounding extracellular matrix (ECM), play a crucial role in the control of tissue structure and of morphogenesis. In this work, we have studied how intercellular adhesion molecules and beta1 integrins influence each other using two......-catenin protein levels accompanied by their redistribution from the cytoskeleton-associated fraction to the detergent-soluble fraction. Regulation of alpha-catenin protein levels by beta1 integrins is likely to play a role in the morphological transition, since overexpression of alpha-catenin in GE11 cells before...

  18. Prostatitis - acute

    ... bladder, such as alcohol, caffeinated foods and drinks, citrus juices, and hot or spicy foods. Drink more ... A.D.A.M. Editorial team. Related MedlinePlus Health Topics Prostate Diseases Browse the Encyclopedia A.D. ...

  19. Prostate cancer

    Chabanova, Elizaveta; Balslev, Ingegerd; Logager, Vibeke;

    2011-01-01

    To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data....

  20. Prostate cancer

    Chabanova, Elizaveta; Balslev, Ingegerd; Logager, Vibeke;

    2011-01-01

    To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data.......To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data....

  1. Adenovirus E1A gene autorepression: revertants of an E1A promoter mutation encode altered E1A proteins

    Larsen, P.L.; Tibbetts, C.

    1987-12-01

    Revertants have been isolated from Ad3hr15, a mutant of human adenovirus type 3 that carries a defective E1A promoter. Transcription of these revertant E1A genes is restored - from nil for Ad3hr15 mutant to levels exceeding that of the wild-type virus. The mutant Ad3hr15 virus and the revertants all have an aberrant E1A promoter that contains two short tandem duplications of viral DNA sequence. The E1A gene-coding region of the mutant is the same as that for wild-type adenovirus type 3, whereas the revertants are characterized by short in-frame deletions within the 5' exon region of their E1A genes. Location of these reverting, second-site deletions is discussed in relation to E1A gene autoregulation and the evolved diversity of E1A-related oncogenic potential among different human adenoviruses.

  2. Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells

    Invasion is an important early step in the metastatic cascade and is the primary cause of death of prostate cancer patients. In order to invade, cells must detach from the primary tumor. Cell-cell and cell-ECM interactions are important regulators of cohesion - a property previously demonstrated to mediate cell detachment and invasion. The studies reported here propose a novel role for α5β1 integrin - the principle mediator of fibronectin matrix assembly (FNMA) - as an invasion suppressor of prostate cancer cells. Using a combination of biophysical and cell biological methods, and well-characterized prostate cancer cell lines of varying invasiveness, we explore the relationship between cohesion, invasiveness, and FNMA. We show that cohesion is inversely proportional to invasive capacity. We also show that more invasive cells express lower levels of α5β1 integrin and lack the capacity for FNMA. Cells were generated to over-express either wild-type α5 integrin or an integrin in which the cytoplasmic domain of α5 was replaced with that of α2. The α2 construct does not promote FNMA. We show that only wild-type α5 integrin promotes aggregate compaction, increases cohesion, and reduces invasion of the more aggressive cells, and that these effects can be blocked by the 70-kDa fibronectin fragment. We propose that restoring capacity for FNMA in deficient cells can increase tumor intercellular cohesion to a point that significantly reduces cell detachment and subsequent invasion. In prostate cancer, this could be of therapeutic benefit by blocking an early key step in the metastatic cascade

  3. Evaluation of the Revertant Phenomenon in Patients with DMD by Immunostaining and Molecular Biology

    Yu Wen; Wu Hua-Chen; Xie Jun; Fan Ji-Shi; Song Yong-Jian; Chen Sheng-Di

    2000-01-01

    Objective To evaluate the significance of revertant phenomenon in patients with Duchunnes muscular dystrophy(DMD). Methods In the present study, the muscles from the patients with DMD were detected by immunofluoresce staining and anti dystrophin antibody, and the 25 pairs of exons in the serum of patients were measured by repetitive PCR test. Results Fifty-one patients had progressive general weakness, especially in proximal and trunk, and hypertrophy calves. Four of them had absent reaction for sarcolemma, which was called as rcvertant phenomenon. The finding was unique and quite rare. The measurement of molecular biology showed no dystrophin deletion in these 4 cases. Conclusions The revertant phenomenon may involve the different mechanism from the conventional medical wisdom. The symptoms and signs of these patients might be improved by a newly therapeutic approach.

  4. ON THE SINGULARITY OF LEAST SQUARES ESTIMATOR FOR MEAN-REVERTING Α-STABLE MOTIONS

    Hu Yaozhong; Long Hongwei

    2009-01-01

    We study the problem of parameter estimation for mean-reverting α-stable motion, dXt= (a0- θ0Xt)dt + dZt, observed at discrete time instants.A least squares estimator is obtained and its asymptotics is discussed in the singular case (a0, θ0)=(0,0).If a0=0, then the mean-reverting α-stable motion becomes Ornstein-Uhlenbeck process and is studied in [7] in the ergodie case θ0 > 0.For the Ornstein-Uhlenbeck process, asymptoties of the least squares estimators for the singular case (θ0 = 0) and for ergodic case (θ0 > 0) are completely different.

  5. Non-invasive Brain Stimulation, a Tool to Revert Maladaptive Plasticity in Neuropathic Pain.

    Naro, Antonino; Milardi, Demetrio; Russo, Margherita; Terranova, Carmen; Rizzo, Vincenzo; Cacciola, Alberto; Marino, Silvia; Calabro, Rocco S; Quartarone, Angelo

    2016-01-01

    Neuromodulatory effects of non-invasive brain stimulation (NIBS) have been extensively studied in chronic pain. A hypothetic mechanism of action would be to prevent or revert the ongoing maladaptive plasticity within the pain matrix. In this review, the authors discuss the mechanisms underlying the development of maladaptive plasticity in patients with chronic pain and the putative mechanisms of NIBS in modulating synaptic plasticity in neuropathic pain conditions. PMID:27512368

  6. Has organic farming modernized itself out of business? - Reverting to conventional methods in Denmark

    Kaltoft, Pernille; Risgaard, Marie-Louise

    2005-01-01

    This case study illustrates that reversion to conventional farming does not take place due to technical problems related to production but that farmers in general decided to stop farming organically due to economic problems – primarily marketing problems – and because of changes in regulations. Almost none of the reverters wished to start using pesticides again and most of them also considered organic farming to be a professional challenge. In general, however, organic and conventional produc...

  7. Has organic farming modernised itself out of business? An analysis of reverting organic farmers

    Kaltoft, Pernille; Risgaard, Marie-Louise

    2004-01-01

    In Denmark organic farming presently experiences a recession with 500 organic farmers leaving the organic sector this year (out of a total of 3500 farmers) and a lot more are considering to revert. A range of earlier studies has reported on the process of modernisation of organic farming. Not at least in Denmark where a lot of conventional farmers have converted to the organic mode of production and where conventional/traditional production and distribution channels have adopted a line of org...

  8. Mutation types and aging differently affect revertant fiber expansion in dystrophic mdx and mdx52 mice.

    Yusuke Echigoya

    Full Text Available Duchenne muscular dystrophy (DMD, one of the most common and lethal genetic disorders, and the mdx mouse myopathies are caused by a lack of dystrophin protein. These dystrophic muscles contain sporadic clusters of dystrophin-expressing revertant fibers (RFs, as detected by immunohistochemistry. RFs are known to arise from muscle precursor cells with spontaneous exon skipping (alternative splicing and clonally expand in size with increasing age through the process of muscle degeneration/regeneration. The expansion of revertant clusters is thought to represent the cumulative history of muscle regeneration and proliferation of such precursor cells. However, the precise mechanisms by which RFs arise and expand are poorly understood. Here, to test the effects of mutation types and aging on RF expansion and muscle regeneration, we examined the number of RFs in mdx mice (containing a nonsense mutation in exon 23 and mdx52 mice (containing deletion mutation of exon 52 with the same C57BL/6 background at 2, 6, 12, and 18months of age. Mdx mice displayed a significantly higher number of RFs compared to mdx52 mice in all age groups, suggesting that revertant fiber expansion largely depends on the type of mutation and/or location in the gene. A significant increase in the expression and clustering levels of RFs was found beginning at 6months of age in mdx mice compared with mdx52 mice. In contrast to the significant expansion of RFs with increasing age, the number of centrally nucleated fibers and embryonic myosin heavy chain-positive fibers (indicative of cumulative and current muscle regeneration, respectively decreased with age in both mouse strains. These results suggest that mutation types and aging differently affect revertant fiber expansion in mdx and mdx52 mice.

  9. Exophytic benign prostatic hyperplasia.

    Blaschko, Sarah D; Eisenberg, Michael L

    2011-08-01

    A 60-year-old man had incidental finding of a multilobular 8 × 7 × 7-cm mass identified posterior to the urinary bladder in continuity with the prostate. The man's prostate-specific antigen was 1.87, and he denied any lower urinary tract symptoms. A transrectal ultrasound-guided biopsy demonstrated benign prostatic tissue. A computed tomography-guided needle aspiration demonstrated a benign epithelium-lined cyst, likely prostatic in origin. Benign prostatic hyperplasia is a proliferation of prostatic epithelial and stromal cells. Although prostatic hyperplasia is usually restricted to the prostate gland, hyperplastic nodules occasionally protrude outside the prostate and rarely form exophytic pelvic masses. PMID:20869104

  10. Simultaneous changes in the function and expression of beta 1 integrins during the growth arrest of poorly differentiated colorectal cells (LISP-1

    R.A. Roela

    2003-08-01

    Full Text Available Cells usually lose adhesion and increase proliferation and migration during malignant transformation. Here, we studied how proliferation can affect the other two characteristics, which ultimately lead to invasion and metastasis. We determined the expression of ß1 integrins, as well as adhesion and migration towards laminin-1, fibronectin, collagens type I and type IV presented by LISP-1 colorectal cancer cells exposed to 2.5% dimethyl sulfoxide (DMSO, an agent capable of decreasing proliferation in this poorly differentiated colorectal cell line. Untreated cells (control, as shown by flow cytometry and monoclonal antibodies, expressed alpha2 (63.8 ± 11.3% positive cells, alpha3 (93.3 ± 7.0%, alpha5 (50.4 ± 12.0% and alpha6 (34.1 ± 4.9% integrins but not alpha1, alpha4, alphav or ß4. Cells adhered well to laminin-1 (73.4 ± 6.0% and fibronectin (40.0 ± 2.0% substrates but very little to collagens. By using blocking monoclonal antibodies, we showed that alpha2, alpha3 and alpha6 mediated laminin-1 adhesion, but neither alpha3 nor alpha5 contributed to fibronectin adherence. DMSO arrested cells at G0/G1 (control: 55.0 ± 2.4% vs DMSO: 70.7 ± 2.5% while simultaneously reducing alpha5 (24.2 ± 19% and alpha6 (14.3 ± 10.8% expression as well as c-myc mRNA (7-fold, the latter shown by Northern blotting. Although the adhesion rate did not change after exposure to DMSO, alpha3 and alpha5 played a major role in laminin-1 and fibronectin adhesion, respectively. Migration towards laminin-1, which was clearly increased upon exposure to DMSO (control: 6 ± 2 cells vs DMSO: 64 ± 6 cells, was blocked by an antibody against alpha6. We conclude that the effects of DMSO on LISP-1 proliferation were accompanied by concurrent changes in the expression and function of integrins, consequently modulating adhesion/migration, and revealing a complex interplay between function/expression and the proliferative state of cells.

  11. Prostate cancer - treatment

    ... this page: //medlineplus.gov/ency/patientinstructions/000403.htm Prostate cancer - treatment To use the sharing features on this ... a combination of drugs is recommended. References National Cancer Institute. Prostate cancer treatment (PDQ): Stages of prostate cancer. Updated ...

  12. Cancer of the Prostate

    ... will die of this disease. Who Gets This Cancer? Prostate cancer occurs only in men, and it is ... Percent of New Cases by Age Group: Prostate Cancer Prostate cancer is most frequently diagnosed among men aged ...

  13. What Is Prostate Cancer?

    Full Text Available ... no such thing as one type of prostate cancer. Prostate cancer is really a spectrum of diseases where on ... very benevolent in its behavior. Men will develop prostate cancer and live the rest of their lives -- 20, ...

  14. Localized Prostate Cancer

    ... a decision aid for men with clinically localized prostate cancer (available at http://effectivehealthcare.ahrq.gov/prostate_da) ... A Decision Aid for Men With Clinically Localized Prostate Cancer Page 1 of 24 Introduction Men with clinically ...

  15. What Is Prostate Cancer?

    Full Text Available ... in their lifetime. Age is the most important risk factor in prostate cancer -- the longer a man ... M.D.: There's no such thing as one type of prostate cancer. Prostate cancer is really a ...

  16. Irradiation and various cytotoxic drugs enhance tyrosine phosphorylation and {beta}{sub 1}-integrin clustering in human A549 lung cancer cells in a substratum-dependent manner in vitro

    Cordes, N.; Beinke, C.; Beuningen, D. van [Inst. of Radiobiology, German Armed Forces, Munich (Germany); Plasswilm, L. [Dept. of Radiation Oncology, Univ. Hospital Basel (Swaziland)

    2004-03-01

    Background and purpose: interactions of cells with a substratum, especially extracellular matrix proteins, initiate clustering of integrin receptors in the cell membrane. This process represents the initial step for the activation of signaling pathways regulating survival, proliferation, differentiation, adhesion, and migration, and could, furthermore, be important for cellular resistance-mediating mechanisms against radiation or cytotoxic drugs. The lack of data elucidating the impact of irradiation or cytotoxic drugs on this important phenomenon led to this study on human A549 lung cancer cells in vitro. Material and methods: the human lung carcinoma cell line A549 grown on polystyrene or fibronectin (FN) was irradiated with 0-8 Gy or treated with cisplatin (0.1-50 {mu}M), paclitaxel (0.1-50 nM), or mitomycin (0.1-50 {mu}M). Colony formation assays, immunofluorescence staining in combination with activation of integrin clustering using anti-{beta}{sub 1}-integrin antibodies (K20), and Western blotting for tyrosine phosphorylation under treatment of cells with the IC{sub 50} for irradiation (2 Gy; IC{sub 50} = 2.2 Gy), cisplatin (2 {mu}M), paclitaxel (5 nM), or mitomycin (7 {mu}M) were performed. Results: attachment of cells to FN resulted in a significantly reduced radio- and chemosensitivity compared to polystyrene. The clustering of {beta}{sub 1}-integrins examined by immunofluorescence staining was only stimulated by irradiation, cisplatin, paclitaxel, or mitomycin in case of cell attachment to FN. By contrast, tyrosine phosphorylation, as one of the major events following {beta}{sub 1}-integrin clustering, showed a 3.7-fold, FN-related enhancement, and treatment of cells with the IC{sub 50} of radiation, cisplatin, paclitaxel, or mitomycin showed a substratum-dependent induction. Conclusion: for the first time, a strong influence of irradiation and a variety of cytotoxic drugs on the clustering of {beta}{sub 1}-integrins could be shown. This event is a

  17. User's guide to REVERT. A CDC 7600 program for converting Spent Fuel Test - Climax data to engineering units, with corrections

    A CDC 7600 computer program, REVERT, can revise Spent Fuel Test - Climax data files using one of several algorithms, depending on the type of data. The algorithms use coefficients from a separate file organized by data type identifiers. REVERT can also make that file of coefficients, using data from tapes made by Hewlett-Packard equipment employed for data acquisition on the spent Fuel Test - Climax at NTS. 12 references

  18. Isolation and characterization of revertants from four different classes of aryl hydrocarbon hydroxylase-deficient hepa-1 mutants.

    Van Gurp, J R; Hankinson, O

    1984-01-01

    Revertants were selected from aryl hydrocarbon hydroxylase (AHH)-deficient recessive mutants belonging to three complementation groups and from a dominant mutant of the Hepa-1 cell line. The recessive mutants had low spontaneous reversion frequencies (less than 4 X 10(-7] that were increased by mutagenesis. The majority of these revertants also had reacquired only partial AHH activity. Revertants of group A mutants were identical to the wild type with respect to both in vivo and in vitro enzyme stability and the Km for the substrate, benzo [alpha]pyrene, and therefore failed to provide evidence that gene A is the AHH structural gene. Group B and group C mutants are defective in the functioning of the Ah receptor required for AHH induction. Revertants of these groups were normal with respect to in vivo temperature sensitivity for AHH induction and for the 50% effective dose for the inducer, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and thus provided no evidence that the B and C genes code for components of the receptor. Two rare group C revertants possessed AHH activity in the absence of induction. The phenotype of one of these was shown to be recessive to the wild type. Spontaneous revertants of the dominant mutant occurred at a frequency 300-fold greater than those of the recessive mutants, and this frequency was not increased by mutagenesis. These revertants all displayed complete restoration of AHH activity to wild type levels. These observations and the results from cell hybridization studies suggest that the dominant revertants arose by a high frequency event leading to functional elimination of the dominant mutation. PMID:6493230

  19. Revertant seedlings from crown gall tumors retain a portion of the bacterial Ti plasmid DNA sequences*

    Yang, Funmei; Simpson, Robert B.

    1981-01-01

    BT37 is a crown gall teratoma incited on tobacco by Agrobacterium tumefaciens containing pTi-T37, a nopaline-type Ti plasmid. Treatment of this cloned tumor tissue with kinetin at 1 mg/liter results in the formation of relatively normal-appearing shoots. These shoots can be induced to root and set viable seed. In contrast to BT37 tissue, the derived tissues are not phytohormone independent and do not produce nopaline. The reverted plants, like normal tobacco plants, are susceptible to infecti...

  20. Is financial leverage mean-reverting? Unit root tests and corporate financing models

    M. E. Bontempi; R. Golinelli

    2001-01-01

    In this paper we use the unit root test at both individual company (Dickey-Fuller) and panel (Im-Pesaran-Shin) level, in order to provide some quantitative evidence of the univariate behaviour of Italian companies’ debt-ratio. If it is mean-reverting, then at least a share of companies are going to behave according to the trade-off model, whereas if it is non-stationary, then companies may behave according to pecking order theory. Individual company test results support the pecking order theo...

  1. Significance of prostatic weight in prostatism

    Jensen, K M; Bruskewitz, R C; Iversen, P; Madsen, P O

    1983-01-01

    In addition to routine evaluation, 68 patients with prostatism underwent blinded urodynamic testing prior to transurethral prostatectomy and were reexamined symptomatologically and urodynamically at 3 and 12 months after surgery to determine if prostatic weight could predict postoperative outcome...

  2. IL-10+ Innate-like B Cells Are Part of the Skin Immune System and Require α4β1 Integrin To Migrate between the Peritoneum and Inflamed Skin.

    Geherin, Skye A; Gómez, Daniela; Glabman, Raisa A; Ruthel, Gordon; Hamann, Alf; Debes, Gudrun F

    2016-03-15

    The skin is an important barrier organ and frequent target of autoimmunity and allergy. In this study, we found innate-like B cells that expressed the anti-inflammatory cytokine IL-10 in the skin of humans and mice. Unexpectedly, innate-like B1 and conventional B2 cells showed differential homing capacities with peritoneal B1 cells preferentially migrating into the inflamed skin of mice. Importantly, the skin-homing B1 cells included IL-10-secreting cells. B1 cell homing into the skin was independent of typical skin-homing trafficking receptors and instead required α4β1-integrin. Moreover, B1 cells constitutively expressed activated β1 integrin and relocated from the peritoneum to the inflamed skin and intestine upon innate stimulation, indicating an inherent propensity to extravasate into inflamed and barrier sites. We conclude that innate-like B cells migrate from central reservoirs into skin, adding an important cell type with regulatory and protective functions to the skin immune system. PMID:26851219

  3. Patient-specific naturally gene-reverted induced pluripotent stem cells in recessive dystrophic epidermolysis bullosa.

    Tolar, Jakub; McGrath, John A; Xia, Lily; Riddle, Megan J; Lees, Chris J; Eide, Cindy; Keene, Douglas R; Liu, Lu; Osborn, Mark J; Lund, Troy C; Blazar, Bruce R; Wagner, John E

    2014-05-01

    Spontaneous reversion of disease-causing mutations has been observed in some genetic disorders. In our clinical observations of severe generalized recessive dystrophic epidermolysis bullosa (RDEB), a currently incurable blistering genodermatosis caused by loss-of-function mutations in COL7A1 that results in a deficit of type VII collagen (C7), we have observed patches of healthy-appearing skin on some individuals. When biopsied, this skin revealed somatic mosaicism resulting in the self-correction of C7 deficiency. We believe this source of cells could represent an opportunity for translational 'natural' gene therapy. We show that revertant RDEB keratinocytes expressing functional C7 can be reprogrammed into induced pluripotent stem cells (iPSCs) and that self-corrected RDEB iPSCs can be induced to differentiate into either epidermal or hematopoietic cell populations. Our results give proof-of-principle that an inexhaustible supply of functional patient-specific revertant cells can be obtained--potentially relevant to local wound therapy and systemic hematopoietic cell transplantation. This technology may also avoid some of the major limitations of other cell therapy strategies, e.g., immune rejection and insertional mutagenesis, which are associated with viral- and nonviral-mediated gene therapy. We believe this approach should be the starting point for autologous cellular therapies using 'natural' gene therapy in RDEB and other diseases. PMID:24317394

  4. Sleep reverts changes in human gray and white matter caused by wake-dependent training.

    Bernardi, Giulio; Cecchetti, Luca; Siclari, Francesca; Buchmann, Andreas; Yu, Xiaoqian; Handjaras, Giacomo; Bellesi, Michele; Ricciardi, Emiliano; Kecskemeti, Steven R; Riedner, Brady A; Alexander, Andrew L; Benca, Ruth M; Ghilardi, M Felice; Pietrini, Pietro; Cirelli, Chiara; Tononi, Giulio

    2016-04-01

    Learning leads to rapid microstructural changes in gray (GM) and white (WM) matter. Do these changes continue to accumulate if task training continues, and can they be reverted by sleep? We addressed these questions by combining structural and diffusion weighted MRI and high-density EEG in 16 subjects studied during the physiological sleep/wake cycle, after 12h and 24h of intense practice in two different tasks, and after post-training sleep. Compared to baseline wake, 12h of training led to a decline in cortical mean diffusivity. The decrease became even more significant after 24h of task practice combined with sleep deprivation. Prolonged practice also resulted in decreased ventricular volume and increased GM and WM subcortical volumes. All changes reverted after recovery sleep. Moreover, these structural alterations predicted cognitive performance at the individual level, suggesting that sleep's ability to counteract performance deficits is linked to its effects on the brain microstructure. The cellular mechanisms that account for the structural effects of sleep are unknown, but they may be linked to its role in promoting the production of cerebrospinal fluid and the decrease in synapse size and strength, as well as to its recently discovered ability to enhance the extracellular space and the clearance of brain metabolites. PMID:26812659

  5. Prostate cancer stem cells

    Tu, Shi-Ming; Lin, Sue-Hwa

    2011-01-01

    Stem cells have long been implicated in prostate glandular formation. The prostate undergoes regression after androgen deprivation and regeneration after testosterone replacement. Regenerative studies suggest that these cells are found in the proximal ducts and basal layer of the prostate. Many characteristics of prostate cancer indicate that it originates from stem cells. For example, the putative AR− status of prostate stem cells renders them inherently insensitive to androgen blockade ther...

  6. Can Prostate Cancer Be Found Early?

    ... Research Get Involved Find Local ACS Learn About Cancer » Prostate Cancer » Detailed Guide » Can prostate cancer be found ... and symptoms of prostate cancer Tests for prostate cancer Prostate cancer stages Survival rates for prostate cancer Previous ...

  7. Interferon-induced revertants of ras-transformed cells: resistance to transformation by specific oncogenes and retransformation by 5-azacytidine.

    Samid, D; Flessate, D M; Friedman, R M

    1987-01-01

    Prolonged alpha/beta interferon (IFN-alpha/beta) treatment of NIH 3T3 cells transformed by a long terminal repeat-activated Ha-ras proto-oncogene resulted in revertants that maintained a nontransformed phenotype long after IFN treatment had been discontinued. Cloned persistent revertants (PRs) produced large amounts of the ras-encoded p21 and were refractile to transformation by EJras DNA and by transforming retroviruses which carried the v-Ha-ras, v-Ki-ras, v-abl, or v-fes oncogene. Transient treatment either in vitro or in vivo with cytidine analogs that alter gene expression by inhibiting DNA methylation resulted in transformation of PR, but not of NIH 3T3, cells. The PR retransformants reverted again with IFN, suggesting that DNA methylation is involved in IFN-induced persistent reversion. Images PMID:2439904

  8. Investigation on the crystallography of the transformation products of reverted austenite in intercritically reheated coarse grained heat affected zone

    Highlights: ► Area of reverted austenite is traced out by crystallographic information. ► Bainite and martensite regions were confirmed within it. ► The martensite region is considered as the blocky MA particles. ► Martensite region has high deformation to initiate fracture. ► More uniform transformation of the reverted austenite is good for toughness. -- Abstract: In present study the intercritically reheated coarse grained heat affected zone (ICCGHAZ) showing the worst impact toughness in the heat affected zone of multi-pass welding was simulated by Gleeble-1500, and its microstructure was investigated in detail by means of scanning electron microscope (SEM) and electron backscattering diffraction (EBSD). With the crystallographic information from EBSD scanning the area of a single reverted austenite grain which formed during the thermal cycles of second pass simulation was traced out. Within it two regions with different characteristic both in morphology and crystallography were found out, showing an un-uniform transformation of the reverted austenite. The region I is a bainitic region containing larger bainitic ferrite grains, while the region II is made up of several clusters containing tiny grains. Based on the crystallographic information each cluster was determined as martensite island thereby should be considered as blocky Martensite/Austenite constituent (M/A), which is hard phase and harmful for toughness. Analysis on the level of deformation shows that the region II is much higher deformed than the region I, indicating there is high stress concentration within the region II. The possible influence of the region I and the region II on fracture is discussed under the early proposed M/A’s fracture-initiating mechanisms. It suggests that the main cause of the toughness reduction is the un-uniform transformation of the reverted austenite, and the toughness performance of the ICCGHAZ could be improved if the transformation of the reverted

  9. [Prostate cancer].

    Morote, Joan; Maldonado, Xavier; Morales-Bárrera, Rafael

    2016-02-01

    The Vall d'Hebron multidisciplinary prostate cancer (PC) team reviews recent advances in the management of this neoplasm. Screening studies with long follow-up show a reduction in mortality, whereas active surveillance is emerging as a therapeutic approach of non-aggressive cancers. New markers increase the specificity of PSA and also allow targeting suspected aggressive cancers. Multiparametric magnetic resonance (mMRI) has emerged as the most effective method in the selection of patients for biopsy and also for local tumor staging. The paradigm of random prostatic biopsy is changing through the fusion techniques that allow guiding ultrasonography-driven biopsy of suspicious areas detected in mMRI. Radical prostatectomy (RP) and radiotherapy (RT) are curative treatments of localized PC and both have experienced significant technological improvements. RP is highly effective and the incorporation of robotic surgery is reducing morbidity. Modern RT allows the possibility of high tumor dose with minimal adjacent dose reducing its toxicity. Androgen deprivation therapy with LHRH analogues remains the treatment of choice for advanced PC, but should be limited to this indication. The loss of bone mass and adverse metabolic effects increases the frequency of fractures and cardiovascular morbimortality. After castration resistance in metastatic disease, new hormone-based drugs have demonstrated efficacy even after chemotherapy resistance. PMID:25727526

  10. Nonlinear Filters for Hidden Markov Models of Regime Change with Fast Mean-Reverting States

    Papanicolaou, Andrew

    2012-01-01

    We consider filtering for a hidden Markov model that evolves with multiple time scales in the hidden states. In particular, we consider the case where one of the states is a scaled Ornstein-Uhlenbeck process with fast reversion to a shifting-mean that is controlled by a continuous time Markov chain modeling regime change. We show that the nonlinear filter for such a process can be approximated by an averaged filter that asymptotically coincides with the true nonlinear filter of the regime-changing Markov chain as the rate of mean reversion approaches infinity. The asymptotics exploit weak converge of the state variables to an invariant distribution, which is significantly different from the strong convergence used to obtain asymptotic results in "Filtering for Fast Mean-Reverting Processes" (19).

  11. Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3

    Pasmooij, Anna M. G.; Pas, Hendri H.; Bolling, Maria C.; Jonkman, Marcel F

    2007-01-01

    Revertant mosaicism due to in vivo reversion of an inherited mutation has been described in the genetic skin disease epidermolysis bullosa (EB) for the genes KRT14 and COL17A1. Here we demonstrate the presence of multiple second-site mutations, all correcting the germline mutation LAMB3:c.628G→A;p.E210K, in 2 unrelated non-Herlitz junctional EB patients with revertant mosaicism. Both probands had a severe reduction in laminin-332 expression in their affected skin. Remarkably, the skin on the ...

  12. Different Phenotypes in Human Prostate Cancer: α6 or α3 Integrin in Cell-extracellular Adhesion Sites

    Monika Schmelz

    2002-01-01

    Full Text Available The distribution of α6/α3 integrin in adhesion complexes at the basal membrane in human normal and cancer prostate glands was analyzed in 135 biopsies from 61 patients. The levels of the polarized α6/α3 integrin expression at the basal membrane of prostate tumor glands were determined by quantitative immunohistochemistry. The α6/α3 integrin expression was compared with Gleason sum score, pathological stage, and preoperative serum prostate-specific antigen (PSA. The associations were assessed by statistical methods. Eighty percent of the tumors expressed the α6 or α3 integrin and 20% was integrin-negative. Gleason sum score, but not serum PSA, was associated with the integrin expression. Low Gleason sum score correlated with increased integrin expression, high Gleason sum score with low and negative integrin expression. Three prostate tumor phenotypes were distinguished based on differential integrin expression. Type I coexpressed both α6 and α3 subunits, type II exclusively expressed a6 integrin, and type III expressed α3 integrin only. Fifteen cases were further examined for the codistribution of vinculin, paxillin, and CD 151 on frozen serial sections using confocal laser scanning microscopy. The α6/α3 integrins, CD151, paxillin, and vinculin were present within normal glands. In prostate carcinoma, α6 integrin was colocalized with CD 151, but not with vinculin or paxillin. In tumor phenotype I, the α6 subunit did not colocalize with the α3 subunit indicating the existence of two different adhesion complexes. Human prostate tumors display on their cell surface the α6β1 and/or α3β1 integrins. Three tumor phenotypes associated with two different adhesion complexes were identified, suggesting a reorganization of cell adhesion structures in prostate cancer.

  13. Prostate carcinoma

    Prostate cancer is the most common malignancy in men in Europe, North America, and in some African states. Early diagnosis in an asymptomatic stage is possible through the combination of digitorectal examination, PSA serum testing, and systematic biopsy. However, general screening is so far not recommended by the Urologic Societies, because the efficiency is not yet proved. Imaging is also not recommended for first-line screening. Novel functional methods of transrectal ultrasound (TRUS) and endorectal MRI can improve accuracy of tumor detection to more than 90% and can be used for TRUS- and now also MRI-guided biopsy leading to two- to threefold higher tumor detection rates. There is general agreement that all men over 50 years of age should be informed about the possibilities, benefits, and risks of the available methods for early tumor detection. (orig.)

  14. What Is Prostate Cancer?

    Full Text Available ... United States, one in ten men will develop prostate cancer in their lifetime. Age is the most important risk factor in prostate cancer -- the longer a man lives the more likely ...

  15. Screening for Prostate Cancer

    ... of Internal Medicine Summaries for Patients Screening for Prostate Cancer: A Guidance Statement From the Clinical Guidelines Committee ... Physicians The full report is titled “Screening for Prostate Cancer: A Guidance Statement From the Clinical Guidelines Committee ...

  16. Detecting Prostate Cancer

    Full Text Available ... such as a trans-rectal ultrasound and a biopsy. Physician: Now, just relax -- the best thing to ... prostate gland. Usually these are accompanied by a biopsy -- a sampling of the prostate tissue with a ...

  17. Prostate cancer staging

    ... this page: //medlineplus.gov/ency/patientinstructions/000397.htm Prostate cancer staging To use the sharing features on this ... trials you may be able to join How Prostate Cancer Staging is Done Initial staging is based on ...

  18. Prostate cancer screenings

    ... this page: //medlineplus.gov/ency/patientinstructions/000846.htm Prostate cancer screenings To use the sharing features on this ... Intern Med . 2011;155(11):762-71. National Cancer Institute. Prostate Cancer Screening -- for health professionals. Revised April 2, ...

  19. Cryotherapy for prostate cancer

    Cryotherapy uses very cold temperatures to freeze and kill prostate cancer cells. The goal of cryosurgery is ... Possible short-term side effects of cryotherapy for prostate ... of the penis or scrotum Problems controlling your bladder (more ...

  20. What Is Prostate Cancer?

    Full Text Available ... In the United States, one in ten men will develop prostate cancer in their lifetime. Age is ... disease that's very benevolent in its behavior. Men will develop prostate cancer and live the rest of ...

  1. Prostate resection - minimally invasive

    ... microwave thermotherapy; TUMT; BPH - resection; Benign prostatic hyperplasia (hypertrophy) - resection; Prostate - enlarged - resection ... passing an instrument through the opening in your penis (meatus). You will be given general anesthesia (asleep ...

  2. Detecting Prostate Cancer

    Full Text Available ... like to do is just do a rectal examination and feel that prostate. Narrator: The other necessary ... they do have an abnormality in their rectal examination does not mean that they have prostate cancer. ...

  3. Prostate cancer in Denmark

    Brasso, K; Friis, S; Kjaer, S K;

    1998-01-01

    To review the trends in prostate cancer (PC) incidence and mortality rates in Denmark during a 50-year period.......To review the trends in prostate cancer (PC) incidence and mortality rates in Denmark during a 50-year period....

  4. What Is Prostate Cancer?

    Full Text Available ... important risk factor in prostate cancer -- the longer a man lives the more likely he is to ... men confront the reality of prostate cancer on a visit to their urologist. John Bertini, M.D.: ...

  5. Enlarged prostate - after care

    BPH - self-care; Benign prostatic hypertrophy - self-care; Benign prostatic hyperplasia - self-care ... exercises ( Kegel exercises ) that strengthen the pelvic floor muscles. Doing these exercise may help with leaking or ...

  6. About the Prostate

    ... DRE) is a useful screening test. Benign prostatic hypertrophy ( BPH ), a non-cancerous prostate condition, typically develops ... Under normal circumstances, the urinary sphincters (bands of muscle at the base of the bladder and at ...

  7. Prostate Cancer Screening

    ... treat. There is no standard screening test for prostate cancer. Researchers are studying different tests to find those ... PSA level may be high if you have prostate cancer. It can also be high if you have ...

  8. Prostate Cancer Prevention

    ... prostate cancer increases as men get older. Family history of prostate cancer A man whose father, brother, ... some foods, such as green vegetables, beans and orange juice. Folic acid is a man-made form ...

  9. Prostate Cancer Foundation

    ... News Faces of Prostate Cancer [4] Survivors Everyday Heroes PCF Researchers Share your story About PCF [1] ... in advanced prostate cancer patients regardless of family history, and are associated with poorer responses to hormonal ...

  10. Can the state of cancer chemotherapy resistance be reverted by epigenetic therapy?

    Duenas-Gonzalez Alfonso

    2006-07-01

    Full Text Available Abstract Background Transcriptome analysis shows that the chemotherapy innate resistance state of tumors is characterized by: poorly dividing tumor cells; an increased DNA repair; an increased drug efflux potential by ABC-transporters; and a dysfunctional ECM. Because chemotherapy resistance involves multiple genes, epigenetic-mediated changes could be the main force responsible of this phenotype. Our hypothesis deals with the potential role of epigenetic therapy for affecting the chemotherapy resistant phenotype of malignant tumors. Presentation of the hypothesis Recent studies reveal the involvement of DNA methylation and histone modifications in the reprogramming of the genome of mammalian cells in cancer. In this sense, it can be hypothesized that epigenetic reprogramming can participate in the establishment of an epigenetic mark associated with the chemotherapy resistant phenotype. If this were correct, then it could be expected that agents targeting DNA methylation and histone deacetylation would by reverting the epigenetic mark induce a global expression profile that mirror the observed in untreated resistant cells. Testing the hypothesis It is proposed to perform a detailed analysis using all the available databases where the gene expression of primary tumors was analyzed and data correlated with the therapeutic outcome to determine whether a transcriptome profiling of "resistance" is observed. Assuming an epigenetic programming determines at some level the intrinsic resistant phenotype, then a similar pattern of gene expression dictated by an epigenetic mark should also be found in cell acquiring drug resistance. If these expectations are meet, then it should be further investigated at the genomic level whether these phenotypes are associated to certain patterns of DNA methylation and chromatin modification. Once confirmed the existence of an epigenetic mark associated to either the intrinsic or acquired chemotherapy resistant phenotype

  11. Energy-Saving Melting and Revert Reduction Technology (E-SMARRT): Final Summary Report

    White, Thornton C [SCRA Appiled R& D

    2014-03-31

    Energy-Saving Melting and Revert Reduction Technology (E-SMARRT) is a balanced portfolio of R&D tasks that address energy-saving opportunities in the metalcasting industry. E-SMARRT was created to: • Improve important capabilities of castings • Reduce carbon footprint of the foundry industry • Develop new job opportunities in manufacturing • Significantly reduce metalcasting process energy consumption and includes R&D in the areas of: • Improvements in Melting Efficiency • Innovative Casting Processes for Yield Improvement/Revert Reduction • Instrumentation and Control Improvement • Material properties for Casting or Tooling Design Improvement The energy savings and process improvements developed under E-SMARRT have been made possible through the unique collaborative structure of the E-SMARRT partnership. The E-SMARRT team consisted of DOE’s Office of Industrial Technology, the three leading metalcasting technical associations in the U.S: the American Foundry Society; the North American Die Casting Association; and the Steel Founders’ Society of America; and SCRA Applied R&D, doing business as the Advanced Technology Institute (ATI), a recognized leader in distributed technology management. This team provided collaborative leadership to a complex industry composed of approximately 2,000 companies, 80% of which employ less than 100 people, and only 4% of which employ more than 250 people. Without collaboration, these new processes and technologies that enable energy efficiencies and environment-friendly improvements would have been slow to develop and had trouble obtaining a broad application. The E-SMARRT R&D tasks featured low-threshold energy efficiency improvements that are attractive to the domestic industry because they do not require major capital investment. The results of this portfolio of projects are significantly reducing metalcasting process energy consumption while improving the important capabilities of metalcastings. Through June

  12. Activation of vanadium nitrogenase expression in Azotobacter vinelandii DJ54 revertant in the presence of molybdenum.

    Lei, S; Pulakat, L; Gavini, N

    2000-09-29

    Azotobacter vinelandii carries three different and genetically distinct nitrogenase systems on its chromosome. Expression of all three nitrogenases is repressed by high concentrations of fixed nitrogen. Expression of individual nitrogenase systems is under the control of specific metal availability. We have isolated a novel type of A. vinelandii DJ54 revertant, designated A. vinelandii BG54, which carries a defined deletion in the nifH gene and is capable of diazotrophic growth in the presence of molybdenum. Inactivation of nifDK has no effect on growth of this mutant strain in nitrogen-free medium suggesting that products of the nif system are not involved in supporting diazotrophic growth of A. vinelandii BG54. Similar to the wild type, A. vinelandii BG54 is also sensitive to 1 mM tungsten. Tn5-B21 mutagenesis to inactivate the genes specific to individual systems revealed that the structural genes for vnf nitrogenase are required for diazotrophic growth of A. vinelandii BG54. Analysis of promoter activity of different nif systems revealed that the vnf promoter is activated in A. vinelandii BG54 in the presence of molybdenum. Based on these data we conclude that A. vinelandii BG54 strain utilizes vnf nitrogenase proteins to support its diazotrophic growth. PMID:11018539

  13. Prostate Cancer: Symptoms, Diagnosis and Treatment

    ... this page please turn Javascript on. Feature: Prostate Cancer Prostate Cancer: Symptoms, Diagnosis and Treatment Past Issues / Winter ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  14. Co-expression of α9β1 integrin and VEGF-D confers lymphatic metastatic ability to a human breast cancer cell line MDA-MB-468LN.

    Mousumi Majumder

    Full Text Available INTRODUCTION AND OBJECTIVES: Lymphatic metastasis is a common occurrence in human breast cancer, mechanisms remaining poorly understood. MDA-MB-468LN (468LN, a variant of the MDA-MB-468GFP (468GFP human breast cancer cell line, produces extensive lymphatic metastasis in nude mice. 468LN cells differentially express α9β1 integrin, a receptor for lymphangiogenic factors VEGF-C/-D. We explored whether (1 differential production of VEGF-C/-D by 468LN cells provides an autocrine stimulus for cellular motility by interacting with α9β1 and a paracrine stimulus for lymphangiogenesis in vitro as measured with capillary-like tube formation by human lymphatic endothelial cells (HMVEC-dLy; (2 differential expression of α9 also promotes cellular motility/invasiveness by interacting with macrophage derived factors; (3 stable knock-down of VEGF-D or α9 in 468LN cells abrogates lymphangiogenesis and lymphatic metastasis in vivo in nude mice. RESULTS: A comparison of expression of cyclo-oxygenase (COX-2 (a VEGF-C/-D inducer, VEGF-C/-D and their receptors revealed little COX-2 expression by either cells. However, 468LN cells showed differential VEGF-D and α9β1 expression, VEGF-D secretion, proliferative, migratory/invasive capacities, latter functions being stimulated further with VEGF-D. The requirement of α9β1 for native and VEGF-D-stimulated proliferation, migration and Erk activation was demonstrated by treating with α9β1 blocking antibody or knock-down of α9. An autocrine role of VEGF-D in migration was shown by its impairment by silencing VEGF-D and restoration with VEGF-D. 468LN cells and their soluble products stimulated tube formation, migration/invasiveness of HMVEC-dLy cell in a VEGF-D dependent manner as indicated by the loss of stimulation by silencing VEGF-D in 468LN cells. Furthermore, 468LN cells showed α9-dependent stimulation of migration/invasiveness by macrophage products. Finally, capacity for intra-tumoral lymphangiogenesis and

  15. Vaccine Treatment for Prostate Cancer

    ... Preventing and treating prostate cancer spread to bones Vaccine treatment for prostate cancer Sipuleucel-T (Provenge) is ... less advanced prostate cancer. Possible side effects of vaccine treatment Side effects from the vaccine tend to ...

  16. Hormone therapy for prostate cancer

    ... this page: //medlineplus.gov/ency/patientinstructions/000908.htm Hormone therapy for prostate cancer To use the sharing ... helps slow the growth of prostate cancer. Male Hormones and Prostate Cancer Androgens are male sex hormones. ...

  17. 6 Common Cancers - Prostate Cancer

    ... Bar Home Current Issue Past Issues 6 Common Cancers - Prostate Cancer Past Issues / Spring 2007 Table of Contents ... early screening. Photo: AP Photo/Danny Moloshok Prostate Cancer The prostate gland is a walnut-sized structure that makes ...

  18. Clinical and demographic features of vertigo: findings from the REVERT registry

    Sam eAgus

    2013-05-01

    Full Text Available IntroductionDespite being a common disease, data on vertigo management in a real-world setting are scarce. AimsTo provide information on the vertigo and its management in a real-world setting.Materials and MethodsData were collected from 4,294 patients with vertigo in 13 countries over 28 months via a multi-national, non-interventional observational study (the so-called REVERT registry. Data included medical history and details of anti-vertigo therapy. ‘Clinical global impression’ (CGI of severity (CGI-S was assessed at baseline (V1 and then at 6 months follow-up (V2 along with CGI change (CGI-C. All variables were analysed descriptively. ResultsThe majority of patients were female, >40 years of age, and almost half had co-morbid cardiovascular disease. Diagnoses were split into 4 categories: 37.2% ‘other vertigo of peripheral vestibular origin’, 26.9% benign paroxysmal positional vertigo (BPPV, 20.5% ‘peripheral vestibular vertigo of unknown origin’ and 15.4% Menière’s disease (MD. Betahistine was the most commonly prescribed therapy prior to and after enrolment, and was followed by piracetam, ginkgo biloba and diuretics. MD had the highest proportion of betahistine treated patients. Almost half of patients were ‘moderately ill’ at V1 based on CGI-S. At V2, patient distribution moved towards ‘less severe illness’ (91.0% improved.The greatest improvements were in the more severely ill, and those with BPPV or ‘other vertigo of peripheral origin’. ConclusionsThere was a reduction in illness severity over the course of the study, some of which is likely to be due to pharmacological intervention. Further studies are needed to confirm these results.

  19. The burden and impact of vertigo: findings from the REVERT patient registry

    Heike eBenecke

    2013-10-01

    Full Text Available Objective: Despite the high prevalence of vertigo globally and an acknowledged, but underreported, effect on an individual’s wellbeing, few studies have evaluated the burden on healthcare systems and society. This study was aimed to quantitatively determine the impact of vertigo on healthcare resource use and work productivity. Methods: The economic burden of vertigo was assessed through a multi-country, non-interventional, observational registry of vertigo patients: the Registry to Evaluate the Burden of Disease in Vertigo (REVERT. Patients included were those with a new diagnosis of Meniere’s disease (MD, benign paroxysmal positional vertigo (BPPV, other vertigo of peripheral vestibular origin or peripheral vestibular vertigo of unknown origin. Results: A total of 4,294 patients at 618 centers in 13 countries were included during the registry. Of the 4,105 patients analyzed, only half were in employment. Among this working patient population, 69.8% had reduced their workload, 63.3% had lost working days and 4.6% had changed and 5.7% had quit their jobs, due to vertigo symptoms. Use of healthcare services among patients was high. In the 3 months preceding Visit 1, patients used emergency services 0.4 ± 0.9 times, primary care consultations 1.6 ± 1.8 times and specialist consultations 1.4 ± 2.0 times (all mean ± SD. A mean of 2.0 ± 5.4 days/patient was also spent in hospital due to vertigo.Conclusions: In addition to the negative impact on the patient from a humanistic perspective, vertigo has considerable impact on work productivity and healthcare resource use.

  20. Promising genomic transfectant into Xeroderma pigmentosum group A with highly amplified mouse DNA and intermediate UV resistance turns revertant

    Following transfection of genomic mouse DNA into an SV40 transformed fibroblast cell line from a patient with Xeroderma pigmentosum (complementation group A, XPA), a single UV resistant cell clone was isolated out of a total of 10(4) independent transfectants. The recipient XPA cell line has as yet not produced spontaneous revertants among 2.2 x 10(8) cells. The isolated cell clone contains 50-70 kb of mouse sequences which are heavily amplified (500-fold), and has acquired both intermediate resistance to UV killing and intermediate unscheduled DNA synthesis (UDS) capacity. By continued passage without selective pressure, cells were generated, which had lost both the dominant marker gene and repetitive mouse sequences. Single colonies of these cells were still intermediately resistant to UV suggesting that either undetected unique mouse DNA had segregated from the bulk of repetitive DNA, or, more likely, that the initially isolated transfectant was a spontaneous revertant. This documents that a persuasive clone isolated can still be a false positive (spontaneous revertant) and that an extremely laborious approach may lead into a dead end

  1. THE DIALECTICS OF HUMANISM AND A POSTMODERN PLAY IN THE WORKS BY A.PEREZ-REVERTE ( THE SIEGE

    Blinova M. P.

    2014-11-01

    Full Text Available The analysis of the philosophical and narrative structure’s features in the novels by modern Spanish writer A. Pérez-Reverte has been reviewed in this article. His works present an example of the postmodern double coding, that is the compound a mass and elite, playing and moral. It allows to avoid the text’s tendentiousness and to keep the content. In the novel “The Siege” A. Pérez-Reverte uses the detective story, but he deconstructs it: keeping the traditional plot’s scheme the writer changes the images’ interpretation, the meaning of the finale, adds the intertext and the conceptual metaphors (the chess, the net, the herbarium. They code some philosophical ideas about human life. At the same time A. Pérez-Reverte asks the traditional classic literature’s questions and shows how war influences the person, what is love and so on. He also makes a psychological analysis of actions’ reasons and reveal the feelings’ contradictory. As a result, the multilayer, nonlinear and metaphorical narrative has been viewed as a particular tool of the author’s opinion realization and the philosophical implication’s creation. And with it the postmodern polysemic text associates with a psychological analysis and humanism

  2. Marine bromophenol bis (2,3-dibromo-4,5-dihydroxy-phenyl)-methane inhibits the proliferation, migration, and invasion of hepatocellular carcinoma cells via modulating β1-integrin/FAK signaling.

    Wu, Ning; Luo, Jiao; Jiang, Bo; Wang, Lijun; Wang, Shuaiyu; Wang, Changhui; Fu, Changqing; Li, Jian; Shi, Dayong

    2015-02-01

    Bis (2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a natural bromophenol compound derived from marine algae. Previous reports have shown that BDDPM possesses antimicrobial activity. In the present study, we found that BDDPM has cytotoxic activity on a wide range of tumor cells, including BEL-7402 cells (IC50 = 8.7 μg/mL). Further studies have shown that prior to the onset of apoptosis, the BDDPM induces BEL-7402 cell detachment by decreasing the adherence of cells to the extracellular matrix (ECM). Detachment experiments have shown that the treatment of BEL-7402 cells with low concentrations of BDDPM (5.0 μg/mL) significantly inhibits cell adhesion to fibronectin and collagen IV as well as cell migration and invasion. High doses of BDDPM (10.0 μg/mL) completely inhibit the migration of BEL-7402 cells, and the expression level of MMPs (MMP-2 and MMP-9) is significantly decreased. Moreover, the expression of β1-integrin and focal adhesion kinase (FAK) is found to be down-regulated by BDDPM. This study suggests that BDDPM has a potential to be developed as a novel anticancer therapeutic agent due to its anti-metastatic activity and also indicates that BDDPM, which has a unique chemical structure, could serve as a lead compound for rational drug design and for future development of anticancer agents. PMID:25689564

  3. Marine Bromophenol Bis (2,3-Dibromo-4,5-dihydroxy-phenyl-methane Inhibits the Proliferation, Migration, and Invasion of Hepatocellular Carcinoma Cells via Modulating β1-Integrin/FAK Signaling

    Ning Wu

    2015-02-01

    Full Text Available Bis (2,3-dibromo-4,5-dihydroxy-phenyl-methane (BDDPM is a natural bromophenol compound derived from marine algae. Previous reports have shown that BDDPM possesses antimicrobial activity. In the present study, we found that BDDPM has cytotoxic activity on a wide range of tumor cells, including BEL-7402 cells (IC50 = 8.7 μg/mL. Further studies have shown that prior to the onset of apoptosis, the BDDPM induces BEL-7402 cell detachment by decreasing the adherence of cells to the extracellular matrix (ECM. Detachment experiments have shown that the treatment of BEL-7402 cells with low concentrations of BDDPM (5.0 μg/mL significantly inhibits cell adhesion to fibronectin and collagen IV as well as cell migration and invasion. High doses of BDDPM (10.0 μg/mL completely inhibit the migration of BEL-7402 cells, and the expression level of MMPs (MMP-2 and MMP-9 is significantly decreased. Moreover, the expression of β1-integrin and focal adhesion kinase (FAK is found to be down-regulated by BDDPM. This study suggests that BDDPM has a potential to be developed as a novel anticancer therapeutic agent due to its anti-metastatic activity and also indicates that BDDPM, which has a unique chemical structure, could serve as a lead compound for rational drug design and for future development of anticancer agents.

  4. Venom gland EST analysis of the saw-scaled viper, Echis ocellatus, reveals novel alpha9beta1 integrin-binding motifs in venom metalloproteinases and a new group of putative toxins, renin-like aspartic proteases.

    Wagstaff, Simon C; Harrison, Robert A

    2006-08-01

    Echis ocellatus is the most medically important snake in West Africa. However, the composition of its venom and the differential contribution of these venom components to the severe haemorrhagic and coagulopathic pathology of envenoming are poorly understood. To address this situation we assembled a toxin transcriptome based upon 1000 expressed sequence tags (EST) from a cDNA library constructed from pooled venom glands of 10 individual E. ocellatus. We used a variety of bioinformatic tools to construct a fully annotated venom-toxin transcriptome that was interrogated with a combination of BLAST annotation, gene ontology cataloguing and disintegrin-motif searching. The results of these analyses revealed an unusually abundant and diverse expression of snake venom metalloproteinases (SVMP) and a broad toxin-expression profile including several distinct isoforms of bradykinin-potentiating peptides, phospholipase A(2), C-type lectins, serine proteinases and l-amino oxidases. Most significantly, we identified for the first time a conserved alpha(9)beta(1) integrin-binding motif in several SVMPs, and a new group of putative venom toxins, renin-like aspartic proteases. PMID:16713134

  5. Estrogen receptors in the human male prostatic urethra and prostate in prostatic cancer and benign prostatic hyperplasia

    Bødker, A; Bruun, J; Balslev, E;

    1999-01-01

    Estrogen receptors (ERs) in the prostate and prostatic urethra were examined in 33 men with benign prostatic hyperplasia (BPH) and in 11 with prostate cancer (PC). The Abbot monoclonal ER-ICA assay was used for immunohistochemical investigation. In the BPH group, ERs were revealed in the prostatic...... stroma in eight cases and in the glandular epithelium in one. In four cases ERs were seen in the prostatic stroma and in the glandular epithelium. In the prostatic urethra, ERs were found in 19 cases located in the urothelium, lamina propria and/or periurethral glands. In the PC group, ERs were...... demonstrated in the prostatic stroma and/or prostatic urethra in 6 out of 11 cases. In both BPH and PC patients, immunoreactivity was weak and confined to few cells, indicating low ER content in the prostate as well as in the prostatic urethra. Dextran-coated charcoal (DCC) analysis was used for detection and...

  6. The experience of using sonoelastography of prostate in prostatic diseases

    P. S. Zubeev

    2014-11-01

    Full Text Available Objective. To assess sonoelastography opportunities in differential diagnosis of prostatic diseases; to place sonoelastography in general algorithm of prostatic diseases diagnostics.Materials and methods. 91 patients under examination were divided into three groups. The first group included 21 patients (23.1 % with suspected prostate carcinoma, later they underwent puncture multifocal biopsy of prostate with morphological verification of prostate carcinoma. The second group consisted of 51 patients (56.0 % with benign prostatic hyperplasia, and in the third group there were 19 patients (20.9 % with acute and chronic prostatitis.Results. 91 patients with different prostatic diseases were examined. There were defined PSA (prostate specific antigen level, and performed TRUS (transrectal ultrasound, biopsy and sonoelastography of prostate. In 72 patients SEG (sonoelastography-picture of prostate was compared to morphological diagnosis. According to SEG findings, 43 (81.1 % patients were revealed to have the areas of reduced compliance due to what malignancy in prostate gland (PG was excluded. Morphological diagnosis of prostate carcinoma was confirmed in 21 patients. In 51 patients SEG-picture corresponded to benign process confirmed by histology.Conclusion. Sonoelastography is a modern diagnostic technique of prostatic diseases, seminal vesicles, paraprostatic space. The distinguished mapping types enable to make differential diagnosis of different prostatic pathological processes. Sonoelastography improves prostate carcinoma diagnostics and staging, and also has economic significance value when compared to MRP (magnetic resonance tomography with bolus contrast.

  7. Prostate-Specific Antigen (PSA) Test

    ... Understanding Laboratory Tests Prostate Cancer—Patient Version Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Tumor Markers Understanding Prostate Changes: A Health Guide for Men ...

  8. Detecting Prostate Cancer

    Full Text Available ... rectal examination does not mean that they have prostate cancer. It means that we're concerned about it and they should go on to have other tests, such as a trans-rectal ultrasound ... made of the prostate gland. Usually these are accompanied by a biopsy -- ...

  9. Detecting Prostate Cancer

    ... rectal examination does not mean that they have prostate cancer. It means that we're concerned about it and they should go on to have other tests, such as a trans-rectal ultrasound ... made of the prostate gland. Usually these are accompanied by a biopsy -- ...

  10. Optimizing prostate biopsy for repeat transrectal prostate biopsies patients

    Xiaojun Deng; Jianwei Cao; Feng Liu; Weifeng Wang; Jidong Hao; Jiansheng Wan; Hui Liu

    2014-01-01

    Objective:Diagnosis of patients with negative prostate biopsy and persistent suspicion of prostate cancer re-mains a serious problem. In this study, we investigated the application of optimizing prostate biopsy for patients who need repeat prostate biopsy. Methods:In this prospective, non-randomized phase-I clinical trial, the prostate cancer detection rate of initial detection scheme was compared with optimizing prostate biopsy scheme. The number of punctures of initial detection scheme was the same as that of optimizing prostate biopsy scheme. The puncture direction of optimizing prostate biopsy was a 45° angle to the sagittal plane from front, middle, and back. The two cores from each lateral lobe were horizontal y inwardly inclined 45°. Results:A total of 45 patients with initial negative biopsy for cancer were received the optimizing prostate biopsy scheme. The cancer detection rate was 17.8%(8/45), and prostate intraepithelial neoplasm (PIN) was 6.7%(3/45). The pa-tients receiving repeat transrectal prostate biopsies were pathological y diagnosed as lower Gleason grade prostate cancers. Conclusion:The cancer detection rate of repeat biopsy prostate cancer is lower than that of initial biopsy. Our study showed that the optimizing prostate biopsy is important to improve the detection rate of repeat transrectal prostate biopsies patients.

  11. El Club Dumas de Arturo Pérez-Reverte como paradigma de la narrativa posmoderna española

    Isaac Gómez Laguna

    2015-06-01

    Full Text Available El presente artículo ofrece un análisis de los diferentes rasgos posmodernistas que aparecen de manera explícita en El Club Dumas, novela insignia de la narrativa posmoderna en España, en torno a tres ejes centrales: a género de la obra e intertextualidad, b indeterminación e irrealidad, y c individuo y sociedad. Mediante esta reflexión pretendemos evidenciar que su autor, Arturo Pérez-Reverte, no solo crea una novela puramente posmoderna, sino que su obra le sirve para teorizar acerca del posmodernismo.

  12. Prostate cancer; Cancer de la prostate

    Vieillot, S.; Fenoglietto, P.; Ailleres, N.; Hay, M.H.; Dubois, J.B.; Azria, D. [Departement de cancerologie radiotherapie, Universite Montpellier I, CRLC Val d' Aurelle, 34 - Montpellier (France)

    2010-07-01

    Radiation therapy is now widely accepted as an efficacious treatment of localized prostate cancer. The technical developments of recent years have enabled the evolution of a three-dimensional conformal radiotherapy, offering a better adaptation of the dose distribution, and leading therefore to preserve organs at risk. In addition, the required dose delivered to the target volume permit physician to increase the total dose if necessary. This requires a thorough knowledge of the radio-anatomy of the prostate, the natural history of the disease but also the ballistics and dosimetry. The objectives of this work were to detail epidemiology and radio-anatomy of the prostate cancer. In addition, conformal radiation modalities are illustrated by a case report. (authors)

  13. What Tests Can Detect Prostate Cancer?

    ... saved articles window. My Saved Articles » My ACS » Prostate Cancer Prevention and Early Detection + - Text Size Download Printable Version [ ... coverage for prostate cancer screening Additional resources for prostate cancer prevention and early detection References: Prostate cancer prevention and ...

  14. Ultrasound- and MRI-Guided Prostate Biopsy

    ... Index A-Z Ultrasound- and MRI-Guided Prostate Biopsy Ultrasound- and MRI-guided prostate biopsy uses imaging ... Biopsy? What is Ultrasound- and MRI-guided Prostate Biopsy? Ultrasound- and MRI-guided prostate biopsies are performed ...

  15. Prostate Cancer Screening (Beyond the Basics)

    ... best in your individual situation. WHAT IS PROSTATE CANCER? — Prostate cancer is a cancer of the prostate, a ... most of them do not die from their cancer. Prostate cancer often grows so slowly that many men ...

  16. The link between benign prostatic hyperplasia and prostate cancer.

    Ørsted, David D; Bojesen, Stig E

    2013-01-01

    Benign prostatic hyperplasia (BPH) and prostate cancer are among the most common diseases of the prostate gland and represent significant burdens for patients and health-care systems in many countries. The two diseases share traits such as hormone-dependent growth and response to antiandrogen therapy. Furthermore, risk factors such as prostate inflammation and metabolic disruption have key roles in the development of both diseases. Despite these commonalities, BPH and prostate cancer exhibit important differences in terms of histology and localization. Although large-scale epidemiological studies have shown that men with BPH have an increased risk of prostate cancer and prostate-cancer-related mortality, it remains unclear whether this association reflects a causal link, shared risk factors or pathophysiological mechanisms, or detection bias upon statistical analysis. Establishing BPH as a causal factor for prostate cancer development could improve the accuracy of prognostication and expedite intervention, potentially reducing the number of men who die from prostate cancer. PMID:23165396

  17. The Lifestyle Carbon Dividend: Assessment of the Carbon Sequestration Potential of Grasslands and Pasturelands Reverted to Native Forests

    Rao, S.; Jain, A. K.; Shu, S.

    2015-12-01

    What is the potential of a global transition to a vegan lifestyle to sequester carbon and mitigate climate change? To answer this question, we use an Earth System Model (ESM), the Integrated Science Assessment Model (ISAM). ISAM is a fully coupled biogeochemistry (carbon and nitrogen cycles) and biogeophysics (hydrology and thermal energy) ESM, which calculates carbon sources and sinks due to land cover and land use change activities, such as reforestation and afforestation. We calculate the carbon sequestration potential of grasslands and pasturelands that can be reverted to native forests as 265 GtC on 1.96E+7 km2 of land area, just 41% of the total area of such lands on Earth. The grasslands and pasturelands are assumed to revert back to native forests which existed prior to any human intervention and these include tropical, temperate and boreal forests. The results are validated with above ground regrowth measurements. Since this carbon sequestration potential is greater than the 240 GtC of that has been added to the atmosphere since the industrial era began, it shows that such global lifestyle transitions have tremendous potential to mitigate and even reverse climate change.

  18. Methods for Prostate Biopsy

    M. Ghafoori

    2008-01-01

    Prostate cancer is currently the most prevalent form of cancer in men and the second leading cause of can-cer death in the United States, and the third most common cancer in men worldwide. Increasing mor-tality rates due to prostate carcinoma have been ob-served worldwide. This disease usually progresses im-perceptibly; thus, patients are unlikely to seek medi-cal help during the early stages. For these reasons, screening programs aimed at early detection have been developed. The prostate-spe...

  19. Detecting Prostate Cancer

    Full Text Available ... M.D.: PSA stands for Prostate Specific Antigen. It is a test that men have by having ... detection is the digital rectal exam. Barry Trevithick: It doesn't make sense to be afraid of ...

  20. What Is Prostate Cancer?

    Full Text Available ... visit to their urologist. John Bertini, M.D.: It's a wide variety of reasons why they might ... have a prostate. Most men don't pronounce it correctly and wouldn't know where it's located ...

  1. Prostate brachytherapy - discharge

    ... into your prostate. They were inserted through your perineum (the area between the scrotum and the anus). ... feel the urge to urinate more often. Your perineum may be tender and bruised. You can use ...

  2. Prostate cancer staging

    ... effects of treatment The chance that treatment can cure your cancer or help you in other ways With stage ... III prostate cancer, the main goal is to cure the cancer by treating it and keeping it from coming ...

  3. Detecting Prostate Cancer

    Full Text Available ... have other tests, such as a trans-rectal ultrasound and a biopsy. Physician: Now, just relax -- the ... exam or PSA test indicates an abnormality, an ultrasound image is made of the prostate gland. Usually ...

  4. Prostate radiation - discharge

    ... day. Avoid orange juice, grapefruit juice, and other citrus juices if they make the bowel or bladder ... A.D.A.M. Editorial team. Related MedlinePlus Health Topics Prostate Cancer Browse the Encyclopedia A.D. ...

  5. What Is Prostate Cancer?

    Full Text Available ... the more likely he is to develop the disease. Physician: Come on back, first room. Narrator: Most ... cancer. Prostate cancer is really a spectrum of diseases where on one end of the spectrum there ...

  6. Detecting Prostate Cancer

    Full Text Available ... have by having their blood sampled and what we look for is a particular glyco-protein that's ... that they have prostate cancer. It means that we're concerned about it and they should go ...

  7. Detecting Prostate Cancer

    Full Text Available ... abnormal and raises the index of suspicion that cancer may be present. Narrator: While the use of ... examination does not mean that they have prostate cancer. It means that we're concerned about it ...

  8. Detecting Prostate Cancer

    Full Text Available ... stands for Prostate Specific Antigen. It is a test that men have by having their blood sampled ... be present. Narrator: While the use of the test remains controversial, a normal PSA level is considered ...

  9. Epigenetics in Prostate Cancer

    Costantine Albany

    2011-01-01

    Full Text Available Prostate cancer (PC is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  10. Detecting Prostate Cancer

    Full Text Available ... PSA stands for Prostate Specific Antigen. It is a test that men have by having their blood sampled and what we look for is a particular glyco-protein that's found in the blood. ...

  11. Screening for Prostate Cancer

    ... absolute reduction in mortal- ity. Preliminary results from PIVOT (Prostate Cancer In- tervention Versus Observation Trial), in ... early PSA screening era, prelim- inary findings from PIVOT show that, after 12 years, in- tention to ...

  12. Prostate Cancer Screening

    ... man's bladder that produces fluid for semen. Cancer screening is looking for cancer before you have any ... be easier to treat. There is no standard screening test for prostate cancer. Researchers are studying different ...

  13. Prostatitis - eine endlose Geschichte?

    Riedl CR

    2001-01-01

    Full Text Available Aktuelle epidemiologische Daten aus den USA zeigen, daß der urogenitale Symptomenkomplex, der langläufig als "Prostatitis" bezeichnet wird, ein nicht unbeträchtliches volksgesundheitliches und volkswirtschaftliches Problem darstellt: dieses Krankheitsbild ist jährlich für 2 Millionen Arztbesuche und für 8% aller urologischen Konsulationen in den USA verantwortlich. Umgekehrt sieht jeder Urologe im Jahr zwischen 150 und 250 Patienten mit "Prostatitis".

  14. Drugs Approved for Prostate Cancer

    ... Ask about Your Treatment Research Drugs Approved for Prostate Cancer This page lists cancer drugs approved by the ... that are not listed here. Drugs Approved for Prostate Cancer Abiraterone Acetate Bicalutamide Cabazitaxel Casodex (Bicalutamide) Degarelix Docetaxel ...

  15. Understanding Prostate Cancer: Newly Diagnosed

    ... Wellness PCF Spotlight Glossary African American Men Understanding Prostate Cancer Newly Diagnosed Newly Diagnosed Staging the Disease Issues ... you care about has recently been diagnosed with prostate cancer, this section will help guide you through the ...

  16. New Prostate Cancer Treatment Target

    Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

  17. Methods for Prostate Biopsy

    M. Ghafoori

    2008-01-01

    Full Text Available Prostate cancer is currently the most prevalent form of cancer in men and the second leading cause of can-cer death in the United States, and the third most common cancer in men worldwide. Increasing mor-tality rates due to prostate carcinoma have been ob-served worldwide. This disease usually progresses im-perceptibly; thus, patients are unlikely to seek medi-cal help during the early stages. For these reasons, screening programs aimed at early detection have been developed. The prostate-specific antigen (PSA test is among the best screening tools available in medicine today and is recognized as the best marker for its early detection. Prostate cancers detected by DRE method alone are clinically localized only 50% to 60% of the time, whereas PSA-detected tumors are clinically localized 90% of the time and pathologi-cally confined to the prostate as determined at prostatectomy about two thirds of the time. Recently, the detection of localized prostate cancers has improved, owing to the development of various new biopsy methods. However, a standard biopsy method, including number of cores, has not yet been established at present. When screening results indi-cate the possibility of prostate cancer, a pathologic diagnosis may be pursued by ultrasound guided trans-rectal needle biopsy. Prostate biopsy is usually ad-vised if serum PSA is >4 ng/mL, and this procedure remains the gold standard for prostate cancer diagno-sis. Fine needle biopsy is less painful than core bi-opsy, but also less diagnostically accurate. Systematic biopsy protocols: In 1989, Hodge et al. coined the sextant biopsy method that is still the standard of reference in prostate cancer detection. The prostate is bilaterally divided into three regions (apex, midgland, and base, all of which are system-atically biopsied once. Although Hodge et al. first proposed sextant biopsy under transrectal ultrasound guidance, some recent reports have indicated that systematic sextant biopsy

  18. Multidrug reverting activity toward leukemia cells in a group of new verapamil analogues with low cardiovascular activity

    Biscardi, Monica; Teodori, Elisabetta; Caporale, Roberto;

    2005-01-01

    designed and synthesized to improve their MDR-reverting activity and reduce cardiovascular effects. Cytotoxicity (WST-1 methods) and functional (calcein-acetoxymethyl (Calcein-AM)) assays were performed on a resistant cell line K-562/doxR and on the mononuclear cells (MNCs) of patients with AML...... strongest activity. Results obtained from the MNCs were superimposible to K-562/doxR. Further studies on pump functional analysis confirmed the cytotoxic test results: MM 36, CTS 27 and CTS 41 showed a striking inhibition of P-glycoprotein (Pgp) efflux in K-562/doxR and MNCs. Cardiovascular activity of MM...... 36, CTS 27 and CTS 41, that are the most interesting compounds as MDR inhibitors, followed this course: MM 36>CTS 27>CTS 41, the last one presenting no cardiovascular activity. Chemosensivity to IDA in K-562/doxR cells and AML blasts could be enhanced in vitro by the adjuvant use of the six new VRP...

  19. Focal therapy in prostate cancer

    Bos, van den, G.A.M.

    2016-01-01

    Interesting developments took place in the treatment of prostate cancer including focal therapy for less aggressive organ-confined prostate cancer. Fortunately, curative treatment is often still an option for patients suffering from the lower staged tumors. In carefully selected patients, the prostate cancer may be focally treated followed by careful post-treatment evaluation, and if necessary by focal re-treatment. During the past decades, the age of men at prostate cancer detection has decr...

  20. Genetic epidemiology of prostate cancer

    Wiklund, Fredrik

    2004-01-01

    Prostate cancer is a major health burden throughout the world, yet the etiology of prostate cancer is poorly understood. Evidence has accumulated supporting the existence of a hereditary form of this disease. Improved understanding of the genetic mechanisms underlying the development and progression of prostate cancer would be a major advance for improved prevention, detection and treatment strategies. This thesis evaluates different aspects of the genetic epidemiology of prostate cancer. In ...

  1. Prostate cancer: emerging pharmacotherapeutic modalities

    Pratap Shankar; Anoop Kumar Verma; Rakesh Kumar Dixit; Amod Kumar Sachan

    2013-01-01

    Prostate cancer is the most common cancer in the world due to factors like old age, family history, ethnicity, diet and some elements exposure, with lot of controversies regarding prevention of prostate cancer. Though the exact pathogenesis is not clear, epidemiological evidence supports a relationship between prostate cancer and hormone levels. In this review article we are focusing on the advances in different pharmacotherapeutic modalities i.e. Chemoprevention, Prostate-Specific Antigen, H...

  2. BPH and prostate cancer risk

    Miah, Saiful; Catto, James

    2014-01-01

    Introduction: With the exclusion of non-melanomatous skin malignancy, prostate cancer (PCa) is the second most prevalent cancer in men globally. It has been reported that the majority of men will develop benign prostatic hyperplasia (BPH) by the time they reach their 60s. Together, these prostatic diseases have a significant morbidity and mortality affecting over a billion men throughout the world. The risk of developing prostate cancer of men suffering BPH is one that has resulted in a healt...

  3. Metastaze raka prostate u penis

    Krpina, Kristian; Markić, Dean; Španjol, Josip; Valenčić, Maksim; Fučkar, Željko

    2011-01-01

    Metastaziranje adenokarcinoma prostate u penis je rijetko. Prikazuje se slučaj adenokarcinoma prostate s metastazama u glans penis. U ovom slučaju metastaze u penis razvile su se devet godina nakon dijagnosticiranja raka prostate s metastazama u regionalne limfne čvorove.

  4. Cholesterol and benign prostate disease.

    Freeman, Michael R; Solomon, Keith R

    2011-01-01

    The origins of benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), are poorly understood. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign prostate conditions and prostate cancer is uncertain. Epidemiologic data for BPH and CP/CPPS are limited, however an apparent association between BPH symptoms and cardiovascular disease (CVD) has been consistently reported. The prostate synthesizes and stores large amounts of cholesterol and prostate tissues may be particularly sensitive to perturbations in cholesterol metabolism. Hypercholesterolemia, a major risk factor for CVD, is also a risk factor for BPH. Animal model and clinical trial findings suggest that agents that inhibit cholesterol absorption from the intestine, such as the class of compounds known as polyene macrolides, can reduce prostate gland size and improve lower urinary tract symptoms (LUTS). Observational studies indicate that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while prostate cancer cell growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. Here we review the evidence that cholesterol metabolism plays a role in the incidence of benign prostate disease and we highlight possible therapeutic approaches based on this concept. PMID:21862201

  5. Biomarkers for the diagnosis of prostatic inflammation in benign prostatic hyperplasia

    Robert, G.Y.M.; Smit, F.; Hessels, D.; Jannink, S.A.; Karthaus, H.F.M.; Aalders, T.; Jansen, K.; Taille, A. De La; Mulders, P.F.A.; Schalken, J.A.

    2011-01-01

    BACKGROUND: Chronic prostatic inflammation could be a central mechanism in benign prostatic hyperplasia (BPH) progression. Currently, the histological examination of prostate biopsies remains the only way to diagnose prostatic inflammation. Our objective was to find new noninvasive biomarkers for th

  6. Steroid hormone receptors in prostatic hyperplasia and prostatic carcinoma.

    Khalid, B A; Nurshireen, A; Rashidah, M; Zainal, B Y; Roslan, B A; Mahamooth, Z

    1990-06-01

    One hundred and six prostatic tissue samples obtained from transurethral resection were analysed for androgen and estrogen receptors. In 62 of these, progesterone and glucocorticoid receptors were also assayed. Steroid receptors were assayed using single saturation dose 3H-labelled ligand assays. Ninety percent of the 97 prostatic hyperplasia tissues and six of the nine prostatic carcinoma tissues were positive for androgen receptors. Estrogen receptors were only present in 19% and 33% respectively. Progesterone receptors were present in 70% of the tissues, but glucocorticoid receptors were present in only 16% of prostatic hyperplasia and none in prostatic carcinoma. PMID:1725553

  7. Glycogen synthase kinase-3β inhibition depletes the population of prostate cancer stem/progenitor-like cells and attenuates metastatic growth

    Kroon, Jan; in 't Veld, Lars S.; Buijs, Jeroen T.; Cheung, Henry; van der Horst, Geertje; van der Pluijm, Gabri

    2014-01-01

    Cancer cells with stem or progenitor properties play a pivotal role in the initiation, recurrence and metastatic potential of solid tumors, including those of the human prostate. Cancer stem cells are generally more resistant to conventional therapies thus requiring the characterization of key pathways involved in the formation and/or maintenance of this malignant cellular subpopulation. To this end, we identified Glycogen Synthase Kinase-3β (GSK-3β) as a crucial kinase for the maintenance of prostate cancer stem/progenitor-like cells and pharmacologic inhibition of GSK-3β dramatically decreased the size of this cellular subpopulation. This was paralleled by impaired clonogenicity, decreased migratory potential and dramatic morphological changes. In line with our in vitro observations, treatment with a GSK-3β inhibitor leads to a complete loss of tumorigenicity and a decrease in metastatic potential in preclinical in vivo models. These observed anti-tumor effects appear to be largely Wnt-independent as simultaneous Wnt inhibition does not reverse the observed antitumor effects of GSK-3β blockage. We found that GSK-3β activity is linked to cytoskeletal protein F-actin and inhibition of GSK-3β leads to disturbance of F-actin polymerization. This may underlie the dramatic effects of GSK-3β inhibition on prostate cancer migration. Furthermore, GSK-3β inhibition led to strongly decreased expression of several integrin types including the cancer stem cell-associated α2β1 integrin. Taken together, our mechanistic observations highlight the importance of GSK-3β activity in prostate cancer stemness and may facilitate the development of novel therapy for advanced prostate cancer. PMID:25344861

  8. The link between benign prostatic hyperplasia and prostate cancer

    Ørsted, David Dynnes; Bojesen, Stig E

    2013-01-01

    Benign prostatic hyperplasia (BPH) and prostate cancer are among the most common diseases of the prostate gland and represent significant burdens for patients and health-care systems in many countries. The two diseases share traits such as hormone-dependent growth and response to antiandrogen...... therapy. Furthermore, risk factors such as prostate inflammation and metabolic disruption have key roles in the development of both diseases. Despite these commonalities, BPH and prostate cancer exhibit important differences in terms of histology and localization. Although large-scale epidemiological...... studies have shown that men with BPH have an increased risk of prostate cancer and prostate-cancer-related mortality, it remains unclear whether this association reflects a causal link, shared risk factors or pathophysiological mechanisms, or detection bias upon statistical analysis. Establishing BPH as a...

  9. Osteoporosis and prostate cancer

    Poulsen, Mads Hvid; Nielsen, Morten Frost Munk; Abrahamsen, Bo;

    2014-01-01

    Abstract Objective. The aim of this study was to analyse the prevalence of osteoporosis and risk factors of osteoporotic fractures before androgen deprivation in Danish men. Treatment and prognosis of prostate cancer necessitate management of long-term consequences of androgen deprivation therapy...... (ADT), including accelerated bone loss resulting in osteoporosis. Osteoporotic fractures are associated with excess morbidity and mortality. Material and methods. Patients with prostate cancer awaiting initiation of ADT were consecutively included. Half of the patients had localized disease and were......-specific antigen level was 30.5 g/l (1-5714 g/l). The average Gleason score was 7.8 (range 5-10, SD 1.1). Fifty patients had localized prostate cancer and the other 55 patients had disseminated disease. The prevalence of osteoporosis was 10% and the prevalence of osteopenia was 58% before ADT. There was no...

  10. Clinical Perspective of Prostate Cancer.

    Patil, Nilesh; Gaitonde, Krishnanath

    2016-06-01

    Prostate cancer is the most common noncutaneous cancer affecting men today. It largely affects men in the fifth and sixth decade of life. Screening for prostate cancer, though controversial, is still the only way to detect early prostate cancer. Multiple newer options such as blood tests and genetic markers are being used in the clinical domain today to improve cancer detection and avoid unnecessary biopsies. To date, biopsy of the prostate remains the only modality to stratify the grade of cancer. Significant improvements in the imaging technology have improved localizing and detecting the disease. Treatment of prostate cancer is stratified on the basis of the grade and volume of the disease. There are multiple treatment options involved in the management of prostate cancer. Treatment of localized prostate cancer still continues to have very high cure rates and long-term cancer-specific survival rates. PMID:27187167

  11. Chemotherapy in Prostate Cancer.

    Hurwitz, Michael

    2015-10-01

    For approximately a decade, chemotherapy has been shown to prolong life in patients with metastatic castration-resistant prostate cancer (mCRPC). Since that time, however, only two agents have proven to prolong life (docetaxel and cabazitaxel). However, in the last year, the addition of chemotherapy to primary hormonal therapy became a standard of care for high-volume castration-sensitive metastatic disease. Here I will review current prostate cancer chemotherapies, mechanisms of resistance to those therapies, and ongoing clinical studies of chemotherapy combinations and novel chemotherapeutics. PMID:26216506

  12. Prostate Cancer Research Trial Helps John Spencer Treat His Cancer

    ... this page please turn Javascript on. Feature: Prostate Cancer Prostate Cancer Research Trial Helps John Spencer Treat His ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  13. Benign Prostatic Hyperstatic Hyperplasia (BPH) (Beyond the Basics)

    ... names for benign prostatic hyperplasia include benign prostatic hypertrophy, an enlarged prostate, and BPH. BPH occurs only ... prostatic hyperplasia" .) Alpha blockers — These medications relax the muscle of the prostate and bladder neck, which allows ...

  14. Survival in prostate cancer prevention trial detailed

    In the NCI-sponsored Prostate Cancer Prevention Trial, initial findings from a decade ago showed that the drug finasteride significantly reduced the risk of prostate cancer, but among those who did develop prostate cancer, paradoxically, the drug was asso

  15. Prostate Cancer Rates by Race and Ethnicity

    ... HPV-Associated Lung Ovarian Skin Uterine Cancer Home Prostate Cancer Rates by Race and Ethnicity Language: English Español ( ... Tweet Share Compartir The rate of men getting prostate cancer or dying from prostate cancer varies by race ...

  16. Prostate Cancer: Take Time to Decide

    ... PDF for professional printing [PDF-983KB] Cancer Home Prostate Cancer: Take Time to Decide Infographic Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir Prostate Cancer: Take Time to Decide Most prostate cancers grow ...

  17. Detecting Prostate Cancer

    Full Text Available Roger Babaian, M.D.: PSA stands for Prostate Specific Antigen. It is a test that men have by having their blood sampled and ... testing may be required. Physician: OK, what I'd like to do is just do a rectal ...

  18. Detecting Prostate Cancer

    Full Text Available ... an abnormality in their rectal examination does not mean that they have prostate cancer. It means that we're concerned about it and they ... tissue with a needle. Physician: Now there's a little pressure -- you can probably feel that. Then you' ...

  19. Comparability of prostate trials

    Suciu, S; Sylvester, R; Iversen, P;

    1993-01-01

    The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type...

  20. Comparability of prostate trials

    Suciu, S; Sylvester, R; Iversen, P; Christensen, I; Denis, L

    The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type...

  1. Common Questions About Chronic Prostatitis.

    Holt, James D; Garrett, W Allan; McCurry, Tyler K; Teichman, Joel M H

    2016-02-15

    Chronic prostatitis is relatively common, with a lifetime prevalence of 1.8% to 8.2%. Risk factors include conditions that facilitate introduction of bacteria into the urethra and prostate (which also predispose the patient to urinary tract infections) and conditions that can lead to chronic neuropathic pain. Chronic prostatitis must be differentiated from other causes of chronic pelvic pain, such as interstitial cystitis/bladder pain syndrome and pelvic floor dysfunction; prostate and bladder cancers; benign prostatic hyperplasia; urolithiasis; and other causes of dysuria, urinary frequency, and nocturia. The National Institutes of Health divides prostatitis into four syndromes: acute bacterial prostatitis, chronic bacterial prostatitis (CBP), chronic nonbacterial prostatitis (CNP)/chronic pelvic pain syndrome (CPPS), and asymptomatic inflammatory prostatitis. CBP and CNP/CPPS both lead to pelvic pain and lower urinary tract symptoms. CBP presents as recurrent urinary tract infections with the same organism identified on repeated cultures; it responds to a prolonged course of an antibiotic that adequately penetrates the prostate, if the urine culture suggests sensitivity. If four to six weeks of antibiotic therapy is effective but symptoms recur, another course may be prescribed, perhaps in combination with alpha blockers or nonopioid analgesics. CNP/CPPS, accounting for more than 90% of chronic prostatitis cases, presents as prostatic pain lasting at least three months without consistent culture results. Weak evidence supports the use of alpha blockers, pain medications, and a four- to six-week course of antibiotics for the treatment of CNP/CPPS. Patients may also be referred to a psychologist experienced in managing chronic pain. Experts on this condition recommend a combination of treatments tailored to the patient's phenotypic presentation. Urology referral should be considered when appropriate treatment is ineffective. Additional treatments include pelvic

  2. Prostate brachytherapy in patients with prior evidence of prostatitis

    Purpose: To refute a misconception that a prior history of prostatitis is a contraindication to prostate brachytherapy. Methods and Materials: Five patients with clinical or pathologic evidence of prior prostatitis were treated with transperineal brachytherapy. Four of the patients received a single i.v. dose of ciprofloxacin (500 mg) intraoperatively. Postimplant antibiotics were not given. The pretreatment biopsy slides were reviewed. Results: Two of the five patients developed postimplant urinary retention requiring short-term catheterization, and both resolved spontaneously. One patient developed what appeared to be an exacerbation of his chronic prostatitis. Conclusion: We continue to recommend prostate brachytherapy for the treatment of clinically organ-confined cancer, with no concern about prior clinical or pathologic evidence of prostatitis

  3. Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism.

    Kim, Kyung Eun; Jung, Youngae; Min, Soonki; Nam, Miso; Heo, Rok Won; Jeon, Byeong Tak; Song, Dae Hyun; Yi, Chin-Ok; Jeong, Eun Ae; Kim, Hwajin; Kim, Jeonghyun; Jeong, Seon-Yong; Kwak, Woori; Ryu, Do Hyun; Horvath, Tamas L; Roh, Gu Seob; Hwang, Geum-Sook

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver disease and its prevalence is a serious and growing clinical problem. Caloric restriction (CR) is commonly recommended for improvement of obesity-related diseases such as NAFLD. However, the effects of CR on hepatic metabolism remain unknown. We investigated the effects of CR on metabolic dysfunction in the liver of obese diabetic db/db mice. We found that CR of db/db mice reverted insulin resistance, hepatic steatosis, body weight and adiposity to those of db/m mice. (1)H-NMR- and UPLC-QTOF-MS-based metabolite profiling data showed significant metabolic alterations related to lipogenesis, ketogenesis, and inflammation in db/db mice. Moreover, western blot analysis showed that lipogenesis pathway enzymes in the liver of db/db mice were reduced by CR. In addition, CR reversed ketogenesis pathway enzymes and the enhanced autophagy, mitochondrial biogenesis, collagen deposition and endoplasmic reticulum stress in db/db mice. In particular, hepatic inflammation-related proteins including lipocalin-2 in db/db mice were attenuated by CR. Hepatic metabolomic studies yielded multiple pathological mechanisms of NAFLD. Also, these findings showed that CR has a therapeutic effect by attenuating the deleterious effects of obesity and diabetes-induced multiple complications. PMID:27439777

  4. Smaller is less stable: Size effects on twinning vs. transformation of reverted austenite in TRIP-maraging steels

    Steels containing reverted nanoscale austenite (γRN) islands or films dispersed in a martensitic matrix show excellent strength, ductility and toughness. The underlying microstructural mechanisms responsible for these improvements are not yet understood, but are observed to be strongly connected to the γRN island or film size. Two main micromechanical effects are conceivable in this context, namely: (i) interaction of γRN with microcracks from the matrix (crack blunting or arresting); and (ii) deformation-induced phase transformation of γRN to martensite (TRIP effect). The focus here is on the latter phenomenon. To investigate size effects on γRN transformation independent of other factors that can influence austenite stability (composition, crystallographic orientation, defect density, surrounding phase, etc.), a model (TRIP-maraging steel) microstructure is designed with support from diffusion simulations (using DICTRA software) to have the same, homogeneous chemical composition in all γRN grains. Characterization is conducted by in-situ tension and bending experiments in conjunction with high-resolution electron backscatter diffraction mapping and scanning electron microscopy imaging, as well as post-mortem transmission electron microscopy and synchrotron X-ray diffraction analysis. Results reveal an unexpected “smaller is less stable” effect due to the size-dependent competition between mechanical twinning and deformation-induced phase transformation

  5. Energy Saving Melting and Revert Reduction Technology (Energy SMARRT): Manufacturing Advanced Engineered Components Using Lost Foam Casting Technology

    Littleton, Harry; Griffin, John

    2011-07-31

    This project was a subtask of Energy Saving Melting and Revert Reduction Technology (Energy SMARRT) Program. Through this project, technologies, such as computer modeling, pattern quality control, casting quality control and marketing tools, were developed to advance the Lost Foam Casting process application and provide greater energy savings. These technologies have improved (1) production efficiency, (2) mechanical properties, and (3) marketability of lost foam castings. All three reduce energy consumption in the metals casting industry. This report summarizes the work done on all tasks in the period of January 1, 2004 through June 30, 2011. Current (2011) annual energy saving estimates based on commercial introduction in 2011 and a market penetration of 97% by 2020 is 5.02 trillion BTU's/year and 6.46 trillion BTU's/year with 100% market penetration by 2023. Along with these energy savings, reduction of scrap and improvement in casting yield will result in a reduction of the environmental emissions associated with the melting and pouring of the metal which will be saved as a result of this technology. The average annual estimate of CO2 reduction per year through 2020 is 0.03 Million Metric Tons of Carbon Equivalent (MM TCE).

  6. MRI diagnosis for prostate cancer

    Recently, in Japan, both the Westernization of life styles and the advent of an aged-society have led to an increase in the incidence of prostate cancer. In making a localizing diagnosis of prostate cancer, magnetic resonance imaging (MRI), which has excellent contrast resolution, and transrectal ultrasonography, are used clinically, and their usefulness is being established. MRI is employed in the diagnosis of prostate cancer to detect tumors, and to determine the stage of such tumors. For the visualization of prostate cancer by MRI, T2-weighted axial images are used exclusively. After becoming familiar with normal prostate images, it is important to evaluate the localization of a tumor, and the invasion of the capsule and seminal vesicles. Future applications of new techniques for MRI will undoubtedly be found. In this paper, the present state of MRI diagnosis of prostate cancer at Kawasaki Medical School Hospital will be reviewed. (author)

  7. MRI diagnosis for prostate cancer

    Tamada, Tsutomu; Nagai, Kiyohisa; Imai, Shigeki; Kajihara, Yasumasa; Jo, Yoshimasa; Tanaka, Hiroyoshi; Fukunaga, Masao (Kawasaki Medical School, Kurashiki, Okayama (Japan)); Matsuki, Takakazu

    1998-01-01

    Recently, in Japan, both the Westernization of life styles and the advent of an aged-society have led to an increase in the incidence of prostate cancer. In making a localizing diagnosis of prostate cancer, magnetic resonance imaging (MRI), which has excellent contrast resolution, and transrectal ultrasonography, are used clinically, and their usefulness is being established. MRI is employed in the diagnosis of prostate cancer to detect tumors, and to determine the stage of such tumors. For the visualization of prostate cancer by MRI, T2-weighted axial images are used exclusively. After becoming familiar with normal prostate images, it is important to evaluate the localization of a tumor, and the invasion of the capsule and seminal vesicles. Future applications of new techniques for MRI will undoubtedly be found. In this paper, the present state of MRI diagnosis of prostate cancer at Kawasaki Medical School Hospital will be reviewed. (author)

  8. MRI diagnosis for prostate cancer

    Tamada, Tsutomu; Nagai, Kiyohisa; Imai, Shigeki; Kajihara, Yasumasa; Jo, Yoshimasa; Tanaka, Hiroyoshi; Fukunaga, Masao [Kawasaki Medical School, Kurashiki, Okayama (Japan); Matsuki, Takakazu

    1998-12-31

    Recently, in Japan, both the Westernization of life styles and the advent of an aged-society have led to an increase in the incidence of prostate cancer. In making a localizing diagnosis of prostate cancer, magnetic resonance imaging (MRI), which has excellent contrast resolution, and transrectal ultrasonography, are used clinically, and their usefulness is being established. MRI is employed in the diagnosis of prostate cancer to detect tumors, and to determine the stage of such tumors. For the visualization of prostate cancer by MRI, T2-weighted axial images are used exclusively. After becoming familiar with normal prostate images, it is important to evaluate the localization of a tumor, and the invasion of the capsule and seminal vesicles. Future applications of new techniques for MRI will undoubtedly be found. In this paper, the present state of MRI diagnosis of prostate cancer at Kawasaki Medical School Hospital will be reviewed. (author)

  9. BENIGN PROSTATIC HYPERPLASIA: UPDATED REVIEW

    Praveen.R

    2013-01-01

    Benign Prostatic Hyperplasia (BPH) is one of the commonest medical conditions affecting the geriatric male population. The enlargement of prostate can lead to various clinical symptoms like difficulty in voiding, urinary retention etc. The symptoms are varied depending on the size of enlargement. The International Prostatic Symptom Score (IPSS) is the gold standard and first step in understanding and diagnosing the disease clinically, but in the recent past there are various other newer tools...

  10. Culture of mouse prostate organoids

    sprotocols

    2014-01-01

    Authors: Chee Wai Chua, Maho Shibata, Ming Lei, Roxanne Toivanen, LaMont Barlow & Michael Shen ### Abstract This protocol describes a novel three-dimensional “organoid” culture for prostate epithelial cells. We describe the digestion and dissociation of prostate tissue into single-cell suspensions containing both prostatic epithelial and stromal cells, the isolation of epithelial cells from the parental population via fluorescence activated cell sorting, and the plating condition...