Skip to main content
SpringerLink
Log in

Causal Factors for Brain Tumor and Targeted Strategies

  • Conference paper
Universe of Scales: From Nanotechnology to Cosmology

Part of the book series: Springer Proceedings in Physics ((SPPHY,volume 150))

Abstract

Every five-year plan of each advanced country in the World includes major investments toward medical care. Consequently, vast improvements have taken place, bringing in precise robotic assistance in surgery and spectacular tools for the early detection of a large number of diseases. Advanced genomics and proteomics have ushered in promises for personalized medicine for cancer patients. Yet, the most advanced countries in the World still witness the highest proportion of age-adjusted incidence of brain cancer. Here we submit an overview of the reported etiology, genetics, and epigenetics that appear to be causal to cancers, especially for brain cancers. We discuss in some detail the use and usefulness of simple natural products such as curcumin to minimize the probability of developing cancer and to counteract existing cancers, even those as deadly as primary brain tumors. In this context we address the argument that brain cancers are more of a metabolic rather than a genetic disease and then discuss the acute need for new strategies for cancer therapy. Based on the findings from many laboratories including ours, we end this review advocating strongly for an effort to follow the example of Mother Nature and develop therapeutic strategies involving relatively safe food-derived anticancer agents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. J.E. Wolff et al., Preliminary experience with personalized and targeted therapy for pediatric brain tumors. Pediatr. Blood Cancer 59(1), 27–33 (2012)

    Article  Google Scholar 

  2. E.C. Peterson et al., Radiation-induced complications in endovascular neurosurgery: incidence of skin effects and the feasibility of estimating risk of future tumor formation. Neurosurgery (2012)

    Google Scholar 

  3. M.Z. Braganza et al., Ionizing radiation and the risk of brain and central nervous system tumors: a systematic review. Neuro-Oncol. 14(11), 1316–1324 (2012)

    Article  Google Scholar 

  4. K. Hemminki et al., Familial risks in nervous-system tumours: a histology-specific analysis from Sweden and Norway. Lancet Oncol. 10(5), 481–488 (2009)

    Article  Google Scholar 

  5. T. Brown et al., Occupational cancer in Britain. Remaining cancer sites: brain, bone, soft tissue sarcoma and thyroid. Br. J. Cancer 107(Suppl 1), S85–S91 (2012)

    Article  Google Scholar 

  6. J.S. Nelson et al., Potential risk factors for incident glioblastoma multiforme: the Honolulu heart program and Honolulu-Asia aging study. J. Neurooncol. 109(2), 315–321 (2012)

    Article  Google Scholar 

  7. K. Alibek, A. Kakpenova, Y. Baiken, Role of infectious agents in the carcinogenesis of brain and head and neck cancers. Infect. Agents Cancer 8(1), 7 (2013)

    Article  Google Scholar 

  8. S. Cordier et al., Incidence and risk factors for childhood brain tumors in the Ile de France. Int. J. Cancer 59(6), 776–782 (1994)

    Article  Google Scholar 

  9. J.M. Pogoda et al., An international case-control study of maternal diet during pregnancy and childhood brain tumor risk: a histology-specific analysis by food group. Ann. Epidemiol. 19(3), 148–160 (2009)

    Article  Google Scholar 

  10. H. Ohgaki, P. Kleihues, Epidemiology and etiology of gliomas. Acta Neuropathol. 109, 93–108 (2005)

    Article  Google Scholar 

  11. O. Warburg, On the origin of cancer cells. Science 123, 309–314 (1956)

    Article  ADS  Google Scholar 

  12. F. Pistollata, H.-L. Chen, B.R. Rood, H.-Z. Zhang, D. D’Avella, L. Denaro, M. Gardiman, G. Te Kronnie, P.H. Schwartz, E. Favaro, S. Indraccolo, G. Basso, D.M. Panchision, Hypoxia and HIF1alpha repress the differentiative effects of BMPs in high-grade glioma. Cancer Stem Cells 27, 7–17 (2009)

    Article  Google Scholar 

  13. H. Ramsahye et al., Central neurocytoma: radiological and clinico-pathological findings in 18 patients and one additional MRS case. J. Neuroradiol. (2013)

    Google Scholar 

  14. P.Y. Wen, S. Kesari, Malignant gliomas in adults. N. Engl. J. Med. 359(5), 492–507 (2008)

    Article  Google Scholar 

  15. J. Chen et al., A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488(7412), 522–526 (2012)

    Article  ADS  Google Scholar 

  16. FDA Approval for Temozolomide, National Cancer Institute (2010). http://www.cancer.gov/cancertopics/druginfo/fda-temozolomide

  17. L. Ricci-Vitiani et al., Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468(7325), 824–828 (2010)

    Article  ADS  Google Scholar 

  18. R. Stupp et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352(10), 987–996 (2005)

    Article  Google Scholar 

  19. A.K. Anand et al., Survival outcome and neurotoxicity in patients of high-grade gliomas treated with conformal radiation and temozolamide. J. Cancer Res. Ther. 8(1), 50–56 (2012)

    Article  Google Scholar 

  20. S. Sahebjam et al., Bevacizumab use for recurrent high-grade glioma at McGill University Hospital. Can. J. Neurol. Sci. 40(2), 241–246 (2013)

    Google Scholar 

  21. F.B. Furnari et al., Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 21(21), 2683–2710 (2007)

    Article  Google Scholar 

  22. B.E. Stopschinski, C.P. Beier, D. Beier, Glioblastoma cancer stem cells—from concept to clinical application. Cancer Lett. 338, 32–40 (2013)

    Article  Google Scholar 

  23. B.S. Malmer et al., Genetic variation in p53 and ATM haplotypes and risk of glioma and meningioma. J. Neurooncol. 82(3), 229–237 (2007)

    Article  Google Scholar 

  24. L.E. Wang et al., Polymorphisms of DNA repair genes and risk of glioma. Cancer Res. 64(16), 5560–5563 (2004)

    Article  Google Scholar 

  25. D.A. Haas-Kogan et al., p53 function influences the effect of fractionated radiotherapy on glioblastoma tumors. Int. J. Radiat. Oncol. Biol. Phys. 43(2), 399–403 (1999)

    Article  Google Scholar 

  26. I. Zawlik et al., Common polymorphisms in the MDM2 and TP53 genes and the relationship between TP53 mutations and patient outcomes in glioblastomas. Brain Pathol. 19(2), 188–194 (2009)

    Article  Google Scholar 

  27. S.E. Yost et al., High-resolution mutational profiling suggests the genetic validity of glioblastoma patient-derived pre-clinical models. PLoS ONE 8(2), e56185 (2013)

    Article  ADS  Google Scholar 

  28. L. Bethke et al., The common D302H variant of CASP8 is associated with risk of glioma. Cancer Epidemiol. Biomark. Prev. 17(4), 987–989 (2008)

    Article  Google Scholar 

  29. A. Wigertz et al., Allergic conditions and brain tumor risk. Am. J. Epidemiol. 166(8), 941–950 (2007)

    Article  Google Scholar 

  30. K. Ueki et al., CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 56(1), 150–153 (1996)

    Google Scholar 

  31. K. Ichimura et al., Distinct patterns of deletion on 10p and 10q suggest involvement of multiple tumor suppressor genes in the development of astrocytic gliomas of different malignancy grades. Genes Chromosomes Cancer 22(1), 9–15 (1998)

    Article  Google Scholar 

  32. W. Biernat et al., Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. Acta Neuropathol. 94(4), 303–309 (1997)

    Article  Google Scholar 

  33. S. Pfister et al., BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J. Clin. Invest. 118(5), 1739–1749 (2008)

    Article  Google Scholar 

  34. D.T. Jones et al., Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 68(21), 8673–8677 (2008)

    Article  Google Scholar 

  35. A. Kaul et al., Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev. 26(23), 2561–2566 (2012)

    Article  Google Scholar 

  36. C. Wibom et al., EGFR gene variants are associated with specific somatic aberrations in glioma. PLoS ONE 7(12), e47929 (2012)

    Article  ADS  Google Scholar 

  37. B.M. Costa et al., Impact of EGFR genetic variants on glioma risk and patient outcome. Cancer Epidemiol. Biomark. Prev. 20(12), 2610–2617 (2011)

    Article  Google Scholar 

  38. S. Jeon et al., Genetic variants of AICDA/CASP14 associated with childhood brain tumor. Genet. Mol. Res. 12(AOP) (2013)

    Google Scholar 

  39. V.E. Clark et al., Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339(6123), 1077–1080 (2013)

    Article  ADS  Google Scholar 

  40. L.M. Dyer, K.P. Schooler, L. Ai, C. Klop, J. Qiu, K.D. Robertson, D. Kevin, The transglutaminase 2 gene is aberrantly hypermethylated in glioma. J. Neurooncol. 101(3), 429 (2010)

    Article  Google Scholar 

  41. A. Restrepo et al., Epigenetic regulation of glial fibrillary acidic protein by DNA methylation in human malignant gliomas. Neuro-Oncol. 13(1), 42–50 (2011)

    Article  MathSciNet  Google Scholar 

  42. C. Piperi et al., High incidence of MGMT and RARbeta promoter methylation in primary glioblastomas: association with histopathological characteristics, inflammatory mediators and clinical outcome. Mol. Med. 16(1–2), 1–9 (2010)

    Article  Google Scholar 

  43. S.A. Kim et al., Promoter methylation of WNT inhibitory factor-1 and expression pattern of WNT/beta-catenin pathway in human astrocytoma: pathologic and prognostic correlations. Mod. Pathol. (2013)

    Google Scholar 

  44. N. Syed et al., Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma. Cell Death Dis. 4, e458 (2013)

    Article  Google Scholar 

  45. P. Vaitkiene et al., GATA4 and DcR1 methylation in glioblastomas. Diagn. Pathol. 8(1), 7 (2013)

    Article  Google Scholar 

  46. M. Martini et al., Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis. Cancer 119(5), 1004–1012 (2013)

    Article  Google Scholar 

  47. A.P. Chou et al., Identification of retinol binding protein 1 promoter hypermethylation in isocitrate dehydrogenase 1 and 2 mutant gliomas. J. Natl. Cancer Inst. 104(19), 1458–1469 (2012)

    Article  Google Scholar 

  48. A. von dem Knesebeck et al., RANK (TNFRSF11A) is epigenetically inactivated and induces apoptosis in gliomas. Neoplasia 14(6), 526–534 (2012)

    Google Scholar 

  49. D. Skiriute et al., MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma. BMC Cancer 12, 218 (2012)

    Article  Google Scholar 

  50. A. Waha et al., Frequent epigenetic inactivation of the chaperone SGNE1/7B2 in human gliomas. Int. J. Cancer 131(3), 612–622 (2012)

    Article  Google Scholar 

  51. M. Kadowaki et al., DNA methylation-mediated silencing of nonsteroidal anti-inflammatory drug-activated gene (NAG-1/GDF15) in glioma cell lines. Int. J. Cancer 130(2), 267–277 (2012)

    Article  Google Scholar 

  52. M. Wetzel et al., Effect of trichostatin A, a histone deacetylase inhibitor, on glioma proliferation in vitro by inducing cell cycle arrest and apoptosis. J. Neurosurg. 103(6 Suppl), 549–556 (2005)

    Google Scholar 

  53. A. Bangert et al., Chemosensitization of glioblastoma cells by the histone deacetylase inhibitor MS275. Anticancer Drugs 22(6), 494–499 (2011)

    Article  Google Scholar 

  54. A. Bangert et al., Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP. Oncogene 31(44), 4677–4688 (2012)

    Article  Google Scholar 

  55. S. Hacker et al., Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation. Oncogene 30(19), 2275–2281 (2011)

    Article  Google Scholar 

  56. R.A. Gatenby, R.J. Gillies, Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4(11), 891–899 (2004)

    Article  Google Scholar 

  57. R.J. DeBerardinis et al., The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism 7(1), 11–20 (2008)

    Article  Google Scholar 

  58. D. Hanahan, R.A. Weinberg, The hallmarks of cancer. Cell 100(1), 57–70 (2000)

    Article  Google Scholar 

  59. D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011)

    Article  Google Scholar 

  60. A. Ramanathan, C. Wang, S.L. Schreiber, Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc. Natl. Acad. Sci. 102(17), 5992–5997 (2005)

    Article  ADS  Google Scholar 

  61. I. Marin-Valencia et al., Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metabolism 15(6), 827–837 (2012)

    Article  Google Scholar 

  62. T.N. Seyfried, L.M. Shelton, P. Mukherjee, Does the existing standard of care increase glioblastoma energy metabolism? Lancet Oncol. 11, 811–813 (2010)

    Article  Google Scholar 

  63. T.N. Seyfried, L.M. Shelton, Cancer as a metabolic disease. Nutr. Metab. 7, 7 (2010)

    Article  Google Scholar 

  64. T.N. Seyfried, M.A. Kiebish, J. Marsh, L.M. Shelton, L.C. Huysentruyt, P. Mukherjee, Metabolic management of brain cancer. Biochim. Biophys. Acta 1807, 577–594 (2011)

    Article  Google Scholar 

  65. E.A. Maher et al., Metabolism of [U-13C] glucose in human brain tumors in vivo. NMR Biomed. 25(11), 1234–1244 (2012)

    Article  Google Scholar 

  66. E.A. Maher, F.B. Furnari, R.M. Bachoo, D.H. Rowitch, D.N. Louis, W.K. Cavenee, R.A. DePinho, Malignant glioma: genetics and biology of a grave matter. Genes Dev. 15, 1311–1333 (2001)

    Article  Google Scholar 

  67. K.M. Egan et al., Cancer susceptibility variants and the risk of adult glioma in a US case-control study. J. Neurooncol. 104(2), 535–542 (2011)

    Article  Google Scholar 

  68. D. Hanahan, R.A. Weinberg, In search of cancer’s common ground: a next-generation view. ScienceDaily (2011). http://www.sciencedaily.com/releases/2011/03/110303132300.htm

  69. A. Carter, Curry compound fights cancer in the clinic. J. Natl. Cancer Inst. 100, 616–617 (2008)

    Article  Google Scholar 

  70. J. Ravindran, S. Prasad, B.B. Aggarwal, Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J. 11, 495–510 (2009)

    Article  Google Scholar 

  71. W.-Y. Huang, Y.-Z. Cai, Y. Zhang, Natural phenolic compounds from medicinal herbs and dietary plants: potential use for cancer prevention. Nutr. Cancer 62(1), 1–20 (2009)

    Article  Google Scholar 

  72. S. Purkayastha et al., Curcumin blocks brain tumor formation. Brain Res. (2009)

    Google Scholar 

  73. S. Shishodia, G. Sethi, B.B. Aggarwal, Curcumin: getting back to the roots. Ann. N.Y. Acad. Sci. 1056(1), 206–217 (2005)

    Article  ADS  Google Scholar 

  74. J. Weissenberger et al., Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3 signaling pathway. Clin. Cancer Res. 16(23), 5781–5795 (2010)

    Article  Google Scholar 

  75. W. Zhuang et al., Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Sci. 103(4), 684–690 (2012)

    Article  Google Scholar 

  76. C. Senft et al., The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas. BMC Cancer 10, 491 (2010)

    Article  Google Scholar 

  77. T.Y. Huang et al., Curcuminoids suppress the growth and induce apoptosis through caspase-3-dependent pathways in glioblastoma multiforme (GBM) 8401 cells. J. Agric. Food Chem. 58(19), 10639–10645 (2010)

    Article  Google Scholar 

  78. M.C. Perry et al., Curcumin inhibits tumor growth and angiogenesis in glioblastoma xenografts. Mol. Nutr. Food Res. 54(8), 1192–1201 (2010)

    Google Scholar 

  79. S. Karmakar, N.L. Banik, S.K. Ray, Curcumin suppressed anti-apoptotic signals and activated cysteine proteases for apoptosis in human malignant glioblastoma U87MG cells. Neurochem. Res. 32(12), 2103–2113 (2007)

    Article  Google Scholar 

  80. A.K. Khaw et al., Curcumin inhibits telomerase and induces telomere shortening and apoptosis in brain tumour cells. J. Cell Biochem. (2012)

    Google Scholar 

  81. A. Goel, S. Jhurani, B.B. Aggarwal, Multi-targeted therapy by curcumin: how spicy is it? Mol. Nutr. Food Res. 52, 1010–1030 (2008)

    Article  Google Scholar 

  82. P. Langone, G.M. Curcio, K. Kashfi, S. Dolai, K. Raja, P. Banerjee, Drug targeting to eliminate breast and brain tumors, in Joint AACR and ACS Meeting—Chemistry in Cancer Research: The Biological Chemistry of Inflammation as a Cause of Cancer, San Diego, CA (2011)

    Google Scholar 

  83. S.J. Lee et al., Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo. BMC Cancer 11, 144 (2011)

    Article  Google Scholar 

  84. S.K. Kang, S.H. Cha, H.G. Jeon, Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. Stem Cells Dev. 15(2), 165–174 (2006)

    Article  Google Scholar 

  85. J. Kang et al., Curcumin-induced histone hypoacetylation: the role of reactive oxygen species. Biochem. Pharmacol. 69(8), 1205–1213 (2005)

    Article  Google Scholar 

  86. K. Balasubramanyam et al., Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J. Biol. Chem. 279(49), 51163–51171 (2004)

    Article  Google Scholar 

  87. J. Fang, J. Lu, A. Holmgren, Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. J. Biol. Chem. 280, 25284–25290 (2005)

    Article  Google Scholar 

  88. C. Syng-Ai, A.L. Kumari, A. Khar, Effect of curcumin on normal and tumor cells: role of glutathione and bcl-2. Mol. Cancer Ther. 3, 1101–1108 (2004)

    Google Scholar 

  89. B.B. Aggarwal, B. Sung, Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol. Sci. 30, 85–94 (2009)

    Article  Google Scholar 

  90. S. Manju, K. Sreenivasan, Enhanced drug loading on magnetic nanoparticles by layer-by-layer assembly using drug conjugates: blood compatibility evaluation and targeted drug delivery in cancer cells. Langmuir 27(23), 14489–14496 (2011)

    Article  Google Scholar 

  91. J. Shao et al., Curcumin delivery by methoxy polyethylene glycol-poly(caprolactone) nanoparticles inhibits the growth of C6 glioma cells. Acta Biochim. Biophys. Sin. (Shanghai) 43(4), 267–274 (2011)

    Article  Google Scholar 

  92. P. Langone, P.R. Debata, S. Dolai, G.M. Curcio, J.D. Inigo, K. Raja, P. Banerjee, Coupling to a cancer cell-specific antibody potentiates tumoricidal properties of curcumin. Int. J. Cancer 131, E569–E578 (2012)

    Article  Google Scholar 

  93. Drug Record: Temozolomide, in Clinical and Research Information on Drug-Induced Liver Injury (2012). NIDDK, http://livertox.nih.gov/Temozolomide.htm#overview

  94. T. Takano, J.H. Lin, G. Arcuino, Q. Gao, J. Yang, M. Nedergaard, Glutamata release promotes growth of malignant gliomas. Nat. Med. 7, 1010–1015 (2001)

    Article  Google Scholar 

  95. R. Grondin, Z. Zhang, Y. Ai, D.M. Gash, G.A. Gerhardt, Intracranial delivery of proteins and peptides as a therapy for neurodegenerative diseases. Prog. Drug Res. 61, 101–123 (2003)

    Google Scholar 

  96. D. Grady, A direct hit of drugs to treat brain cancer (2010). Available from http://www.nytimes.com/2010/11/09/health/09avastin.html

Download references

Acknowledgements

A fellowship support for Sumit Mukherjee from the CUNY Graduate Center is gratefully acknowledged here.

Author information

Authors and Affiliations

  1. Department of Chemistry and the Center for Developmental Neuroscience, The City University of New York at The College of Staten Island, Staten Island, NY, 10314, USA

    Priya Ranjan Debata, Gina Marie Curcio & Probal Banerjee

  2. CUNY Doctoral Programs in Biochemistry, The City University of New York at The College of Staten Island, Staten Island, NY, 10314, USA

    Sumit Mukherjee

Authors
  1. Priya Ranjan Debata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gina Marie Curcio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sumit Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Probal Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Probal Banerjee .

Editor information

Editors and Affiliations

  1. SETI Institute, Mountain View, California, USA

    Friedemann Freund

  2. NASA Ames Research Center, Moffet Field, California, USA

    Stephanie Langhoff

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this paper

Cite this paper

Debata, P.R., Curcio, G.M., Mukherjee, S., Banerjee, P. (2014). Causal Factors for Brain Tumor and Targeted Strategies. In: Freund, F., Langhoff, S. (eds) Universe of Scales: From Nanotechnology to Cosmology. Springer Proceedings in Physics, vol 150. Springer, Cham. https://doi.org/10.1007/978-3-319-02207-9_19

Download citation

Publish with us

Policies and ethics

Search

Navigation