Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
April-2017 Volume 15 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
April-2017 Volume 15 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics

  • Authors:
    • Alexandros Tsarouhas
    • Giannoula Soufla
    • Konstantinos Tsarouhas
    • Pavlos Katonis
    • Dritan Pasku
    • Antonis Vakis
    • Aristides M. Tsatsakis
    • Demetrios A. Spandidos
  • View Affiliations / Copyright

    Affiliations: Laboratory of Virology, Medical School, University of Crete, Heraklion 71003, Greece, Cardiological Department, University General Hospital of Larissa, Larissa 41110, Greece, Department of Orthopedics and Traumatology, University Hospital of Heraklion, Heraklion 71110, Greece, Department of Neurosurgery, University Hospital of Heraklion, Heraklion 71110, Greece, Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece
    Copyright: © Tsarouhas et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2195-2203
    |
    Published online on: February 20, 2017
       https://doi.org/10.3892/mmr.2017.6221
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The involvement of growth factors (GFs) in the pathogenesis of lumbar intervertebral disc (ID) herniation and the spontaneous resorption of herniated ID fragments remains only partially elucidated. A simultaneous assessment of the transcript levels of numerous GFs and their association with clinical and epidemiological profiles of human ID herniation would provide valuable insight into the biology and clinical course of the disease. In the present study, we examined simultaneously the transcript levels of vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF‑β1), basic fibroblast growth factor 2 (bFGF2), platelet derived growth factor (PDGF) isoforms and receptors, epidermal growth factor (EGF) and insulin growth factor‑1 (IGF‑1) in herniated and control ID specimens and investigated their correlation with the clinicopathological profiles of patients suffering from symptomatic lumbar ID herniation. GF mRNA expression levels were determined by RT-qPCR in 63 surgical specimens from lumbar herniated discs and 10 control ID specimens. Multiple positive correlations were observed between the transcript levels of the GFs examined in the ID herniation group. VEGF mRNA expression was significantly increased in the protruding compared with the extruded discs. Intense and acute pain significantly upregulated the PDGF transcript levels. Significant negative correlations were observed between the patient body mass index and the transcript levels of VEGF and PDGF receptors. Our findings support the hypothesis of the involvement of GFs in the natural history of ID herniation. GFs synergistically act in herniated IDs. Increased VEGF expression possibly induces the neovascularization process in the earliest stages of ID herniation. PDGF‑C and ‑D play a role in the acute phase of radiculopathy in a metabolic response for tissue healing. A molecular effect, in addition to the biomechanical effect of obesity in the pathogenesis of ID herniation is also implied.
View Figures

Figure 1

Figure 2

Figure 3

View References

1 

Taylor VM, Deyo RA, Cherkin DC and Kreuter W: Low back pain hospitalization. Recent United States trends and regional variations. Spine. 19:1207–1212; discussion 13. 1994. View Article : Google Scholar : PubMed/NCBI

2 

Katz JN: Lumbar disc disorders and low-back pain: Socioeconomic factors and consequences. J Bone Joint Surg Am. 88:21–24. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Komori H, Shinomiya K, Nakai O, Yamaura I, Takeda S and Furuya K: The natural history of herniated nucleus pulposus with radiculopathy. Spine. 21:225–229. 1996. View Article : Google Scholar : PubMed/NCBI

4 

Saal JA, Saal JS and Herzog RJ: The natural history of lumbar intervertebral disc extrusions treated nonoperatively. Spine. 15:683–686. 1990. View Article : Google Scholar : PubMed/NCBI

5 

Tsarouhas A, Soufla G, Katonis P, Pasku D, Vakis A and Spandidos DA: Transcript levels of major MMPs and ADAMTS-4 in relation to the clinicopathological profile of patients with lumbar disc herniation. Eur Spine J. 20:781–790. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Masuda K, Oegema TR Jr and An HS: Growth factors and treatment of intervertebral disc degeneration. Spine. 29:2757–2769. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Alvarez RH, Kantarjian HM and Cortes JE: Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin Proc. 81:1241–1257. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Tolonen J, Grönblad M, Virri J, Seitsalo S, Rytömaa T and Karaharju E: Transforming growth factor beta receptor induction in herniated intervertebral disc tissue: An immunohistochemical study. Eur Spine J. 10:172–176. 2001. View Article : Google Scholar : PubMed/NCBI

9 

Tolonen J, Grönblad M, Virri J, Seitsalo S, Rytömaa T and Karaharju EO: Platelet-derived growth factor and vascular endothelial growth factor expression in disc herniation tissue: And immunohistochemical study. Eur Spine J. 6:63–69. 1997. View Article : Google Scholar : PubMed/NCBI

10 

Specchia N, Pagnotta A, Toesca A and Greco F: Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine. Eur Spine J. 11:145–151. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Tolonen J, Grönblad M, Virri J, Seitsalo S, Rytömaa T and Karaharju E: Basic fibroblast growth factor immunoreactivity in blood vessels and cells of disc herniations. Spine. 20:271–276. 1995. View Article : Google Scholar : PubMed/NCBI

12 

Konttinen YT, Kemppinen P, Li TF, Waris E, Pihlajamäki H, Sorsa T, Takagi M, Santavirta S, Schultz GS and Humphreys-Beher MG: Transforming and epidermal growth factors in degenerated intervertebral discs. J Bone Joint Surg Br. 81:1058–1063. 1999. View Article : Google Scholar : PubMed/NCBI

13 

Thompson JP, Oegema TR Jr and Bradford DS: Stimulation of mature canine intervertebral disc by growth factors. Spine. 16:253–260. 1991. View Article : Google Scholar : PubMed/NCBI

14 

Masuda K: Biological repair of the degenerated intervertebral disc by the injection of growth factors. Eur Spine J (Suppl 17). 4:441–451. 2008. View Article : Google Scholar

15 

Milette PC: Classification, diagnostic imaging, and imaging characterization of a lumbar herniated disk. Radiol Clin North Am. 38:1267–1292. 2000. View Article : Google Scholar : PubMed/NCBI

16 

Ahn SH, Cho YW, Ahn MW, Jang SH, Sohn YK and Kim HS: mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine. 27:911–917. 2002. View Article : Google Scholar : PubMed/NCBI

17 

Pepper MS, Ferrara N, Orci L and Montesano R: Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 189:824–831. 1992. View Article : Google Scholar : PubMed/NCBI

18 

Guo P, Hu B, Gu W, Xu L, Wang D, Huang HJ, Cavenee WK and Cheng SY: Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol. 162:1083–1093. 2003. View Article : Google Scholar : PubMed/NCBI

19 

Warren RS, Yuan H, Matli MR, Ferrara N and Donner DB: Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma. J Biol Chem. 271:29483–29488. 1996. View Article : Google Scholar : PubMed/NCBI

20 

Kato T, Haro H, Komori H and Shinomiya K: Sequential dynamics of inflammatory cytokine, angiogenesis inducing factor and matrix degrading enzymes during spontaneous resorption of the herniated disc. J Orthop Res. 22:895–900. 2004. View Article : Google Scholar : PubMed/NCBI

21 

Pratsinis H, Constantinou V, Pavlakis K, Sapkas G and Kletsas D: Exogenous and autocrine growth factors stimulate human intervertebral disc cell proliferation via the ERK and Akt pathways. J Orthop Res. 30:958–964. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Smith RJ, Justen JM, Sam LM, Rohloff NA, Ruppel PL, Brunden MN and Chin JE: Platelet-derived growth factor potentiates cellular responses of articular chondrocytes to interleukin-1. Arthritis Rheum. 34:697–706. 1991. View Article : Google Scholar : PubMed/NCBI

23 

Ferrara N and Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev. 18:4–25. 1997. View Article : Google Scholar : PubMed/NCBI

24 

Koike Y, Uzuki M, Kokubun S and Sawai T: Angiogenesis and inflammatory cell infiltration in lumbar disc herniation. Spine. 28:1928–1933. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Ozaki S, Muro T, Ito S and Mizushima M: Neovascularization of the outermost area of herniated lumbar intervertebral discs. J Orthop Sci. 4:286–292. 1999. View Article : Google Scholar : PubMed/NCBI

26 

Heldin CH and Westermark B: Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 79:1283–1316. 1999.PubMed/NCBI

27 

Digiovanni CW, Baumhauer J, Lin SS, Berberian WS, Flemister AS, Enna MJ, Evangelista P and Newman J: Prospective, randomized, multi-center feasibility trial of rhPDGF-BB versus autologous bone graft in a foot and ankle fusion model. Foot Ankle Int. 32:344–354. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Hee CK, Dines JS, Dines DM, Roden CM, Wisner-Lynch LA, Turner AS, McGilvray KC, Lyons AS, Puttlitz CM and Santoni BG: Augmentation of a rotator cuff suture repair using rhPDGF-BB and a type I bovine collagen matrix in an ovine model. Am J Sports Med. 39:1630–1639. 2011. View Article : Google Scholar : PubMed/NCBI

29 

Uutela M, Wirzenius M, Paavonen K, Rajantie I, He Y, Karpanen T, Lohela M, Wiig H, Salven P, Pajusola K, et al: PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Blood. 104:3198–3204. 2004. View Article : Google Scholar : PubMed/NCBI

30 

Rubin K, Tingström A, Hansson GK, Larsson E, Rönnstrand L, Klareskog L, Claesson-Welsh L, Heldin CH, Fellström B and Terracio L: Induction of B-type receptors for platelet-derived growth factor in vascular inflammation: Possible implications for development of vascular proliferative lesions. Lancet. 1:1353–1356. 1988. View Article : Google Scholar : PubMed/NCBI

31 

Weiler C, Lopez-Ramos M, Mayer HM, Korge A, Siepe CJ, Wuertz K, Weiler V, Boos N and Nerlich AG: Histological analysis of surgical lumbar intervertebral disc tissue provides evidence for an association between disc degeneration and increased body mass index. BMC Res Notes. 4:4972011. View Article : Google Scholar : PubMed/NCBI

32 

Pye SR, Reid DM, Adams JE, Silman AJ and O'Neill TW: Influence of weight, body mass index and lifestyle factors on radiographic features of lumbar disc degeneration. Ann Rheum Dis. 66:426–427. 2007. View Article : Google Scholar : PubMed/NCBI

33 

Hangai M, Kaneoka K, Kuno S, Hinotsu S, Sakane M, Mamizuka N, Sakai S and Ochiai N: Factors associated with lumbar intervertebral disc degeneration in the elderly. Spine J. 8:732–740. 2008. View Article : Google Scholar : PubMed/NCBI

34 

Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R and Simsolo RB: The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 95:2111–2119. 1995. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Tsarouhas A, Soufla G, Tsarouhas K, Katonis P, Pasku D, Vakis A, Tsatsakis AM and Spandidos DA: Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics. Mol Med Rep 15: 2195-2203, 2017.
APA
Tsarouhas, A., Soufla, G., Tsarouhas, K., Katonis, P., Pasku, D., Vakis, A. ... Spandidos, D.A. (2017). Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics. Molecular Medicine Reports, 15, 2195-2203. https://doi.org/10.3892/mmr.2017.6221
MLA
Tsarouhas, A., Soufla, G., Tsarouhas, K., Katonis, P., Pasku, D., Vakis, A., Tsatsakis, A. M., Spandidos, D. A."Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics". Molecular Medicine Reports 15.4 (2017): 2195-2203.
Chicago
Tsarouhas, A., Soufla, G., Tsarouhas, K., Katonis, P., Pasku, D., Vakis, A., Tsatsakis, A. M., Spandidos, D. A."Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics". Molecular Medicine Reports 15, no. 4 (2017): 2195-2203. https://doi.org/10.3892/mmr.2017.6221
Copy and paste a formatted citation
x
Spandidos Publications style
Tsarouhas A, Soufla G, Tsarouhas K, Katonis P, Pasku D, Vakis A, Tsatsakis AM and Spandidos DA: Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics. Mol Med Rep 15: 2195-2203, 2017.
APA
Tsarouhas, A., Soufla, G., Tsarouhas, K., Katonis, P., Pasku, D., Vakis, A. ... Spandidos, D.A. (2017). Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics. Molecular Medicine Reports, 15, 2195-2203. https://doi.org/10.3892/mmr.2017.6221
MLA
Tsarouhas, A., Soufla, G., Tsarouhas, K., Katonis, P., Pasku, D., Vakis, A., Tsatsakis, A. M., Spandidos, D. A."Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics". Molecular Medicine Reports 15.4 (2017): 2195-2203.
Chicago
Tsarouhas, A., Soufla, G., Tsarouhas, K., Katonis, P., Pasku, D., Vakis, A., Tsatsakis, A. M., Spandidos, D. A."Molecular profile of major growth factors in lumbar intervertebral disc herniation: Correlation with patient clinical and epidemiological characteristics". Molecular Medicine Reports 15, no. 4 (2017): 2195-2203. https://doi.org/10.3892/mmr.2017.6221
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team