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C.102-HUMAN PAPILLOMAVIRUS (HPV) AND PROSTATIC CANCER OSTEOBLASTIC BONE METASTASIS: HPV E6 CONTAINS |
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HUMAN PAPILLOMAVIRUS (HPV) AND PROSTATIC CANCER OSTEOBLASTIC BONE METASTASIS: HPV E6 CONTAINS AN ENDOTHELIN ACTIVE SITE TRYPTOPHAN
ARTP 18 Nov 2015 Paris Porte Maillot
TRAN Guy Mong Ky
Retired, Public Health (Agence Régionale de Santé ARS Auvergne Rhône Alpes), Hospital Hôtel-Dieu, Clermont-Ferrand, FRANCE. Correspondence: 31 Avenue du Bois 92290 Chatenay Malabry. E-mail:
Cette adresse email est protégée contre les robots des spammeurs, vous devez activer Javascript pour la voir.
. Phone: +33 9 81 89 38 70.
BACKKROUND Endothelin (ET-1, 2, 3) (Yanagisawa M, 1989) is mitogenic for 3T3 fibroblasts (Takuwa N, 1989), induces osteoblast proliferation and is involved in osteoblastic bone metastases of Prostatic Cancer (PK) with translocation TMPRSS2:ERG gene fusion (Delliaux C, 2014). We found earlier by centering on the HQLL motif that:
HPV-18 E2 IQTLNHQVL
contains the osteoprotegerin active site ET SHQLL
as well as parathormone (PTH) IQ LMHNL
and PTH-related Protein (PTHrP) S EHQLL
that could explain PK osteoclastic bone metastasis (Tran GMK, 2004). We search for an endothelin in HPV that could explain osteoblastic bone metastasis.
METHODS Amino acid sequences and three dimensional structure (3D) comparison between HPV and ET.
RESULTS By centering on the crucial tryptophan W21, which removal decreases ET potency by a factor > 1000 (Kimura S, 1988), we found that
HPV (cand 89), -150, -160 E6 34-EL-35 48-LDIVW-52 is homologous to the
ET-1,-2,-3/sarafotoxin active site 5-DM-6 17-LDI IW-21
In 3D structure, HPV E6 has 2 separated functional sites, centered on the COOH-terminal tryptophane W 21 and on 5-DM-6 (of sarafotoxine). The homologous sequence LNVVW is found in HPV-3, -28, -29, -68 ME 180. In HPV-18 E6, W was replaced by Y. Burrowing asp Attractaspis engaddensis sarafotoxin, which induces a coronary spasm, differs slightly from ET:QDVIW (where Q replaced L).
Weak but highly selective ET-A Receptor antagonists were isolated from Streptomyces Misakiensis and sp n° 7338 (Miyata S, 1992). Highly potent and selective ET-A Receptor antagonist structures are pentapeptides:
cyclo (D-Asp-Pro-D-Val-Leu-D-Trp) (Ihara M, 1992) and
cyclo (D-Asp-Pro-D-Ile -Leu-D-Trp) (D=Dextrogyre) (Lippton, 1993).
CONCLUSION The molecular homology of HPV E6 with the active site of Endothelin, implicated in PK bone metastasis, supports further the HPV role in KP, not only in the primary tumor, but also specifically in osteoblastic bone metastasis. Interestingly, high doses of Vitamin C has an anti-Endothelin action (Dow C, 2015).
BIBLIOGRAPHY Delliaux C, Endothelin-1, a gene regulated by TMPRSS2:ERG fusion proteins in prostate cancer bone metastases. ARTP, Paris, Nov 19 2014. Ihara M. Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci 1992, 50: 247-55. Dow C.Vitamin C Supplementation Reduces ET-1 System Activity in Overweight and Obese Adults.14th Int Conf on Endothelin: Physiology, Pathophysiology and Therapeutics. Press release of the Am Physiol Soc, 4th September 2015, www.the-aps.org/mm/hp/Audiences/Public-Press/2015/44.html. Kimura S. Structure-activity relationships of endothelin: importance of the C-terminal moiety. Bio Bio Res Com 1988, 156: 1182-6. Miyata S. WS-7338, new endothelin receptor antagonists isolated from Streptomyces sp. No. 7338. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities. J Antibiot (Tokyo) 1992, 45: 74-82; 83-7; 698-703;788-91; 1029-40; 1041-6. Lippton. Am Heart Assoc, 66th Scientific Sessions, Georgia World Congress, Nov 8-11, 1993. Takuwa N. A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts. J Biol Chem 1989, 264: 7856-61. Tran GMK, Role of human papillomavirus type 18 in a subgroup of prostatic cancer with bone metastasis: Its protein E2 contains the osteoprotegerin active site EuroConf Cancer, Pasteur Inst. Jan 15-16 2004. Yanagisawa M. Molecular biology and biochemistry of the endothelins. Trends Pharmacol Sci 1989, 10: 374-8. Review. |
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C.101-PROSTATIC CANCER AND HUMAN PAPILLOMAVIRUS (HPV): MOLECULAR HOMOLOGY OF HPV-18 E2 WITH ONCOGENE |
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PROSTATIC CANCER AND HUMAN PAPILLOMAVIRUS (HPV): MOLECULAR HOMOLOGY OF HPV-18 E2 WITH ONCOGENE CRIPTO-1.
Présenté à
ARTP 18 Nov 2015 Paris Porte Maillot
TRAN Guy Mong Ky
Retired, Public Health (Agence Régionale de Santé ARS Auvergne Rhône Alpes), Hospital Hôtel-Dieu, Clermont-Ferrand, FRANCE. Correspondence: 31 Avenue du Bois 92290 Chatenay Malabry. E-mail:
Cette adresse email est protégée contre les robots des spammeurs, vous devez activer Javascript pour la voir.
. Phone: +33 9 81 89 38 70.
BACKROUND HPV are found in Prostatic Cancer (PK) by PCR only when the primer is E (=Early) and not L (=Late) (Tran GMK, 2004). This particularity may be explained by L loss during integration (Johansson H, 2013). Cripto-1 (Teratocarcinoma-Derived Growth Factor-1), a member of Epidermal Growth Factor (EGF) family, is involved in PK progression (Terry S, 2013, 2015). It is a co-receptor of TGF-β, induces E-Cadherin loss (Zhong XY, 2008) in Epithelial to Mesenchymal Transition (Thiery JP, 2002) and stimulates the PI3K/Akt pathway. E-Cadherin down regulation can also be induced by HPV E6 (Matthews K, 2003). As HPV contains many oncogenes implicated specifically in PK [HPV-11 E2 = EGF-HRG-TGFα mitogens chimera (Tran MKG, 1997) with a common MHIESL hexapeptide, Osteoprotegerin in bone metastases (Tran GMK, 2004), Nucleophosmin 1 (NPM1) in androgeno-regulation (Tran GMK, 2014)], we search for a molecular homology between Cripto-1 and HPV.
METHODS Amino acid sequences comparison of HPV with Cripto-1 EGF motif
CcxxGGxCxxxxxCxCxxxxxxxxC.
RESULTS
HPV-18 E2 113-CFkKGGqTV 45-YFdGNK D 127-DGNKDNC
Cripto-1 83-CL
HPV-18 E2 96 D W T L 323-PPNN L KCWR Q RC 122-VQVYF
matches with Cripto-1 120-D(W,T)L 124-LPKKcsLcKCWHgQlRC 142-PQAFL
CONCLUSION The discovery of Cripto-1 being a viral HPV-18 E2 oncogene, whereas EGF is a HPV-11 E2, confirms the HPV role in PK, and E-cadherin loss as a factor of metastasis. A safe and efficient vaccine is warranted, as Gardasil and Gardasil 9 based on L1 may be followed by menopause/sterility and multiple sclerosis, and Cervarix by thrombocytopenia. A BT PHARMA vaccine based on a HPV-16 and -18 oncogene E7, instead of L1 as in Gardasil and Cervarix, is in phase II trial at the Pasteur Institute (Paris). E7 is much smaller than L1 and has less worrying epitopes.
BIBLIOGRAPHY Matthews K. Depletion of Langerhans cells in human papillomavirus type 16-infected skin is associated with E6-mediated down regulation of E-cadherin. J Virol 2003, 77: 8378-85. Terry S. Involvement of CRIPTO-1 in progression of prostate tumors. Eurocancer, Paris, June 25-26, 2013. Terry S. CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities. Oncotarget 2015, 6: 11994-2008. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002, 2: 442-54. Tran MKG. Human Papillomavirus (HPV) E2 protein contains a chimera of epidermal growth factor (EGF) and EGF family mitogens: Heregulin and Tumor Growth Factor. 6th Eur HIV Conf, Hamburg 1997, P474. Tran GMK. Role of human papillomavirus type 18 in a subgroup of prostatic cancer with bone metastasis: Its protein E2 contains the osteoprotegerin active site. EuroConf Cancer, Pasteur Inst. Jan 15-16 2004. Tran GMK. Prostatic cancer of viral origin: Homology of human oncogenic papillomavirus (HPV) L1 with nucleophosmin (NPM1), a controller of androgen receptor transcription. ARTP, Nov 19, 2014, Paris. Zhong XY. Positive association of up-regulated Cripto-1 and down-regulated E-cadherin with tumour progression and poor prognosis in gastric cancer. Histopathology. 2008, 52: 560-8.
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C.100-PROSTATIC CANCER AND HUMAN PAPILLOMAVIRUS (HPV): AUTO-IMMUNE THROMBOCYTOPENIA INDUCED BY GARDA |
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PROSTATIC CANCER AND HUMAN PAPILLOMAVIRUS (HPV): AUTO-IMMUNE THROMBOCYTOPENIA INDUCED BY GARDASIL AND CERVARIX VACCINE HPV L1 MIMICKING PLATELET GPV
Présentation
ARTP 18 Nov 2015 Paris Porte Maillot
TRAN Guy Mong Ky
Retired, Public Health (Agence Régionale de Santé ARS Auvergne Rhône Alpes), Hospital Hôtel-Dieu, Clermont-Ferrand, FRANCE. Correspondence: 31 Avenue du Bois 92290 Chatenay Malabry. E-mail:
Cette adresse email est protégée contre les robots des spammeurs, vous devez activer Javascript pour la voir.
. Phone: +33 9 81 89 38 70.
BACKROUND Among the auto-immune complications occurring after anti-HPV vaccination (Gardasil and Cervarix), was reported thrombocytopenia (Pugnet G, 2009). Odds Ratio (OR) for Serious Autoimmune Adverse Events (SAAEs) reported by the Vaccine Adverse Event Reporting System (VAERS) from Jan 2006 through Dec 2012 is OR=1,3 (95% CI=0.48-3.5) (Geier DA, 2015) for thrombocytopenia. If severe, this thrombocytopenia can conduct to cerebral hemorrhage and eventually death.
METHODS Amino acid sequences comparison between HPV L1 and platelet gpV. We centered the alignment on the FP and related LP motifs (Leucine L replaces Proline P). Platelet alloantigen, P1T, on glycoprotein V is associated with neonatal alloimmune thrombocytopenia (Ertem M, 1994). Measles was investigated versus platelet gpIIbIIIa on the FP motif.
RESULTS Platelet gpV was aligned with HPV (types -16,-18, -6, -11,-31,-33,-52,-58) L1 of Gardasil 9.
perfect molecular mimicry ALPDG was found between HPV-61,-72,-81 L1 and platelet gpV.
A common motif LPDT was found between rubella virus nsp and HPV-18 L1. Rubella can induce thrombocytopenia (Okazaki N, 2011). There is a common motif ALPD between gpV, HPV-11 and HPV-6 L1. Anti-gpV specific antibodies are also particularly evident in Varicella virus thrombopenia (Mayer JL, 1996) and are cross-reactive with platelet (Wright JF,1994): Varicella ORF 24 and rubella nsp share the ALPDT motif.
There was a perfect molecular mimicry between Measles P protein strain Mvi/Victoria.AUS/12.99 (Bankamp B, 2008) and platelet gpIIb:
platelet gpIIb 782-RGNSFP-787
Measles P protein strain Mvi/Victoria.AUS/12.99 199-RGNSFP-204
The other Measles virus strains have RGNNFP
CONCLUSION The perfect 100% molecular mimicry ALPDG, centered on a Proline, between HPV-61,-72,-81 L1 and platelet gpV raises the question of the etiology of the so-called "idiopathic" thrombocytopenic purpura. It is advocated to research HPV-61,-72,-81 as possible culprits, either by PCR or Metagenomics (Johansson H, 2013). HLA-DR3 may be a risk factor. The alimentation must be strictly controlled, avoiding in particular aspirin and alliaceous. The obligatory vaccination by Measles Mumps Rubella vaccine, associated with Zoster-Varicella vaccine (Okazaki N, 2011) and 3 doses of Gardasil or Gardasil 9 or Cervarix, may enhance further the auto-immune response against platelet gpV and induce autoimmune thrombocytopenia. Gardasil 9 is particularly worrying.
BIBLIOGRAPHY Bankamp B. Genetic variability and mRNA editing frequencies of the phosphoprotein genes of wild-type measles viruses. Virus Res 2008, 135: 298-306. Ertem M. A new platelet alloantigen, P1T, on glycoprotein V associated with neonatal alloimmune thrombocytopenia. Pediatr Res 1994, 35: 160A. Geier DA. A case-control study of quadrivalent human papillomavirus vaccine-associated autoimmune adverse events. Clin Rheumatol 2015, 34: 1225-31. Johansson H. Metagenomic sequencing of "HPV-negative" condylomas detects novel putative HPV types. Virology 2013, 440: 1-7. Mayer JL. Varicella-associated thrombocytopenia: autoantibodies against platelet surface glycoprotein V. Pediatr Res 1996, 40: 615-9. Meenaghan M. Antibodies to platelet glycoprotein V in polytransfused patients with haematologic diseases. Vox Sang 1993, 64:167–70. Okazaki N. Detection of platelet-binding anti-measles and anti-rubella virus IgG antibodies in infants with vaccine-induced thrombocytopenic purpura. Vaccine 2011, 29: 4878–80. Pugnet G. Immune thrombocytopenic purpura following human papillomavirus vaccination. Vaccine 2009, 27: 3690. Wright JF. Virus-reactive antibodies cross-react with autologous platelets in a patient with varicella zoster virus (VZV)-associated idiopathic thrombocytopenic purpura (ITP). Blood 1994, 84 (suppl):185a
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C.98-GARDASIL ANTI-PAPILLOMAVIRUS VACCINE: MOLECULAR MIMICRY OF HPV L1 WITH GONADOLIBERIN GNRH EXPLA |
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GARDASIL ANTI-PAPILLOMAVIRUS VACCINE: MOLECULAR MIMICRY OF HPV L1 WITH GONADOLIBERIN GNRH EXPLAINING PRECOCIOUS MENOPAUSE AND STERILITY
TRAN Guy Mong Ky
Retired, Public Health (Agence Régionale de Santé Auvergne Rhône Alpes), Hospital Hôtel Dieu, Clermont-Ferrand FRANCE. Correspondence: 31 Avenue du Bois 92290 Chatenay Malabry. E-mail:
Cette adresse email est protégée contre les robots des spammeurs, vous devez activer Javascript pour la voir.
. Phone: +33 9 81 89 38 70.
Association pour la Recherche sur les Tumeurs de la Prostate (ARTP)
18 Nov 2015 . Palais des Congrès, Porte Maillot, Paris
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BACKGROUND
After Gardasil vaccination, a 16 years old Australian (Little DT, 2012) and a 18 years old French Jennifer Sellier (Carrère d'Encausse M, 2015) developped a premature menopause and sterility. Four more Australians were further reported (Little DT, 2014). In September 2015, the Vaccine Adverse Event Reporting System (VAERS) reported 95 irreversible cases among 104 early menopauses. This number did not reflect the reality, as only <1% to 10% are declared, owing to the fact that menopause is unknown from the general practionner as a Gardasil complication (NVIC). Therefore, in reality, there is 10 000 cases of sterility, a number which will grow continuously with time. The September 2015 French pharmacovigilance ANSM/CNAMTS report followed 14 auto-immune diseases, but did not include menopause/sterility among them, despite the fact that infertility can be induced by an immune mechanism, for example by woman antibodies against husband sperm, and fertility recovered by deletion of these antibodies. A FDA cohort began in Sweden with 3000 patients, this number fell to 1700 after 6 years, to 500 after 8 years, then the study was never terminated and simply burried. Gardasil was licensed in the market without any released data on the ovaries of the Sprague-Dawley female rats. Furthermore, Sprague-Dawley rats are prone to cancer, and are not the species of choice in the case of auto-imune disease. The data on male rats were stopped prematurely at the second injection. Tween 80 (polysorbate 80) containing ethylene glycol can provoke severe ovary deformities, degenerative follicles, sterility (Gajdova M, 1992) and anaphylactic shock. Some countries such as Japan, Denmark or Western European countries have yet a worrying decline of fertility. We investigated the auto-immune mechanism of sterility induced by Gardasil.
METHODS We compared the amino acid (AA) sequences of the Gardasil 9 vaccine HPV L1 and Gonadotropin Releasing Hormone GnRH, mumps virus (ovaritis, orchitis and sterility if during post-puberty). Mycoplasma and Enteroviruses [Coxsackie A6 (Foot Mouth Hand Disease or FMHD), Echovirus, Enterovirus E or Bovine Enterovirus (BEV)] were included, because Coxsackievirus A6 orchitis was reported in Finland; and in bull, orchitis, loss of libido, testicular degeneration, aspermatogenesis and sterility occurred after a BEV-1 infection (Weldon SL,1979). BEV has a large spectra and can infect humans.
RESULTS There is a molecular mimicry EHWS between HPV-57, -2, -27 L1 and the catfish, dogfish GnRH active site, Mycoplasma Salivarium (WP_024544007), extending to 6 AAs EHWSKG and pEHWSHG (p=pyrrolidone).
We found a molecular mimicry between HPV-16, -18, -11, -6 L1 163-EHW and the GnRH active site 24-pEHW-26, prolonged upstream to 2 Cys 153-CMVGC-157 and 17-CVVGC-21. GnRH (homo, teleost) 31-SPGGKRNAE-39 matches with HPV (-3, -34 chimera) 198-TPCGKQNAgE-207 (Span=28 AA).
Hypogonadotropic Hypogonadism 12 mutation R → C C
GnRH CV VGC SSpEHWS HGLSPGGKRNA E
PVH L1 CMVGCapplgEHWGKGLSPCGKQNAgE
Mumps virus F EQWS YPAKNC
Coxsakievirus A6 ALVFP (Q,H)WINLRTNNCA
Enterovirus E VP2 LIYP (Q,H)WINLRTNNS A
Mycoplasma Salivarium 80-EHWSKG
Glutamine Q and Histidine H are cross-reactive, owing to their chemical similarities. A length of only 3 AAs is enough for a hypothalamic hormonal activity (i.e. TSH Releasing Factor pGln-His-Pro, Melanostatin Pro-Leu-Gly). The mutation R31C of GnRH 24-pEHWSYGLRPG-33 induces a Hypogonadotropic Hypogonadism 12 (HH12). C31 almost aligned with C171 of L1 163-EHWGKGKQC-171 and C324 of mumps virus F (Fusion) protein 315-EQWSYPAKNC-324. The most worrying is the discovery that Gardasil 9 contains 9 times the EHW motif, highly conserved in 71/75 (94,7%) studied HPV types.
CONCLUSION
Gardasil L1 mimics the GnRH active site pEHWxxG and is homologous to mumps virus F, Coxsackie A6 (FMHD) and Mycoplasma, all three responsible of sterility. This is coherent with an auto-immune disease directed against GnRH which is destroyed by anti-GnRH auto-antibodies cross-reactive with vaccine L1, in particular L1 of HPV-6 and -11, absent in Cervarix. Japan has suspended Gardasil in June 2013, India in 2010. As for mumps virus, pubescent adults are susceptible to have complications conducting to a definitve sterility, particularly in the feminine sex very prone to auto-immunity (they have a more reactive HLA system). One third of young women take oral contraceptives that can mask this complication during all the time they take the pill, so infertility may only develop when stopping contraception, about 15 years later, in the 2030s. The 3 intra-muscular injections provoke a powerful, durable and aggravating anamnestic response [induced by Aluminium-DNA complex (Lee SH, 2012)], which is 10 times more powerful than the natural infection. The Gardasil 4 HPV types possess the pEHWxxG motif, and more dramatically the Gardasil 9 have it 9 times. The obligatory Measles Mumps Rubella vaccine may enhance the auto-antibodies. Undetected enterovirus E infection on a background of selenium deficiency may aggravate the situation. Mycoplasma Salivarium contains also a GnRH epitope.
Plasmapheresis may be a possible solution to delete anti-GnRH auto-antibodies. Selenium levels must be determined and corrected. Selenium has an antiviral activity against enteroviruses.
BIBLIOGRAPHY
ANSM/CNAM report Sept 2015
Carrère d'Encausse M. Les médicaments sont-ils parfois dangereux pour notre santé? French TV 5, 10.2.2015.
Gajdova M. Food Chem Toxicol 1992, 31:180-90.
Lee SH. Detection of human papillomavirus L1 gene DNA fragments in postmortem blood and spleen after Gardasil® vaccination—A case report. Adv Biosc Biotech, 2012, 3: 1214-24
Little DT. Premature ovarian failure 3 years after menarche in a 16-year-old girl following human papilloma-virus vaccination. BMJ Case Rep 2012. 10.1136/bcr-2012-006879.
Little DT. Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus Vaccination. A Case Series Seen in General Practice. J Investig Med High Impact Case Rep 2014, 2: 2324709614556129.
Little DT. Human papillomavirus vaccine and the ovary: the need for research. Paper presented at: Proceedings of the 18th World Congress on Controversies in Obstetrics, Gynecology and Infertility; October 24-27, 2013; Vienna, Austria.
NVIC.Org
SANEVAX
Weldon SL. Isolation of picornavirus from feces and semen from an infertile bull. J Am Vet Med Assoc 1979, 174:168-9.
Aknowlegments to Caprani A., President of Positifs Association, Positifs.org for financial support.
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