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:
. 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
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.
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.
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.
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.
C.97bis -8 ° IAS 2015- Victory of pharmaceutical lobbies - life antiretroviral treatment for all!
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The last conference of the International AIDS Society (IAS) on HIV Pathogenesis, its treatments and prevention was held in Vancouver (Canada) from 19 to 22 July 2015. It brought together over 6000 participants but became over the years a mercantile fair (sponsored by laboratories) whose almost exclusive promotion purposes with questionable arguments, always toxic treatments and broader populations to increasingly numerous to which the utility is far be demonstrated.
All the information presented in this conference can be found on the site
An impressive amount of information at a fundamental level, clinical, prevention and social, has been provided. Unfortunately, nothing essential in terms of what patients are waiting : efficient preventive or therapeutic vaccine , effective ways to eradicate or reduce reservoirs, non-toxic treatments, .... were made.
Let us recall that the long-term antiviral therapies may cause metabolic disorders (lipid abnormalities, diabetes), toxicities of liver , kidney, heart, bone disorders, peripheral neuropathy and even libido problems (erectile dysfunction) . These side effects of antiviral drugs can lead to serious illnesses and deaths, it is imperative that the patient be informed honestly so as not to undergo a medical and media hype and freely choose and accept treatment.
Pre-exposure prophylaxis (PrEP) was one of the main topics of discussion at the IAS 2015: How to take it, who should be able to take and when it will be available to you-Three studies presented show that for some people in some contexts, a less frequent use of PrEP, with doses determined according to sexual activity, was feasible and that a high number of sex remained protected by PrEP. This could offer people who want to use PrEP, and their physicians, additional options, allowing them to find a way to take PrEP that suits them best.
However our association “Positifs” does not wish this prevention which is very marginal, became the majority, except perhaps on groups at very high risk, such as prostitute (e) s. We maintain that the only prevention, safe, easy to implement and a very low cost (should be free) is the condom, which unfortunately does not sufficiently been campaigns by national health systems. PrEP will not serve if it requires only a majority fatten a little lobbies at the expense of the health of users who consume long-term toxic products and further despoiling a little more bloodless medical coverage systems.
One study, still serving the pharmaceutical lobbies, presented by Myron Cohen, revealed that the partner of a HIV patient, having an undetectable viral load avoids the transmission if he uses a PrEP, while it is known for more than an HIV-positive 10 years with undetectable viral load is not contaminant !! PrEP in this case is unnecessary and criminal for all HIV-negative partners that condoms can be used for any occasion.
We believe that the best way to stop transmission is to test authoritarian way the entire population since over 50% of HIV positive are unaware of their status and thus is the major transmission vector, to make free condoms, and empower HIV-positive patients.
The START study considers provide 'definitive' evidence on the benefits of early treatmentT?
Let us recall that the starting threshold of antiviral treatment was for 20 years, under pressure from the pharmaceutical lobbies, and experimenters of complacent trials systematically raised from 200, where the risk of opportunistic infections very minimal, 350, then 500 and now the announcement of seropositivity (with normal values in the range 500-1000).
Emphasize again that the immediate start of treatment, requires that possible non progressors patients , unidentified, suffer for years (5, 10 years sometimes more) toxic treatments of aggression with their train of 'side effects. For the majority of patients starting treatment at CD4 300-350, allows, with a negligible risk, to live many years without the constraint of a daily treatment and calmly await the arrival of less toxic and non-treatment day (which are today possible from the work of J.Leibowitch, father of HAART, but not shockingly implemented) or eradication therapy.
According to the results of the much awaited START study, the risk of disease or death are significantly lower among people who start antiretroviral therapy when their diagnosis when their CD4 count is still high, rather than waiting until 'that it falls below 350 cells / mm3. The latest results of the study were presented at the Congress of IAS 2015 and were published simultaneously in the early edition of the American Journal "New England Journal of Medicine" dated July 20, 2015.
“Positifs” does not share the beliefs of the authors of the study on the merits of early treatment. Indeed the START trial is a statistical study of 4685 patients followed for 3 years. Or recall to the uninitiated that more study is about the number the easier it is to demonstrate what we want. This multicenter trial conducted in 35 countries and funded by the American NIH with a huge budget and the results were taken and recommended, without critical analysis by WHO and UNAIDS show collusion NIH, pharmaceutical lobbies, WHO, UNAIDS.
Overall after 3 years, if we consider the non-serious and serious events related to HIV and the deaths were 1.8% of patients in the early group and 4.1% in the delayed group representing a 57% reduction. The most common events being tuberculosis and cancer. These high percentages of events for patients still having a well-preserved immunity seems to us suspect and casts doubt on the conclusions of the START study
If we honestly consider the START study, and which is taken up in detail the results of the test, we realize that there is no significant difference in the number of deaths (12 and 21 respectively) . Even if the reasons for these deaths are not explained, it seems surprising that apart from various accidents and suicides, today we can still die of HIV given the existing therapeutic arsenal. These deaths rather bad sign monitoring patients and poor therapeutic strategies.
Concerning tumoral pathologies were observed 0.20 cases / 100 patients / year in the early group and 0.56 event / 100patients / year in the delayed group, but the difference is significant after one year. For Kaposi's sarcoma were 11 cases in the delayed group and 1 in the early group. These figures seem overstated us in relation to all the data already published for HIV + patients still having a well-preserved immunity (CD4> 350).
Regarding serious cardiovascular events there is no significant difference between the 2 groups (14 and 12 cases).
In summary, even assuming that this study has not been tampered with, only the well-informed patient is entitled to decide whether or not to start antiviral treatment as soon as he knows his HIV status when he had CD4 high and normal (600-1000) and low viral load, taking a risk of 5.6 / 1000par year instead of 2/1000 per year of contracting a tumor pathology.
Note that the only interest to the community of early treatment is the lack of contamination of the partners as soon as viral load falls below 1000copies while condom use has the same effect but with a very low cost and without toxicity. Moreover, it seems to us wanting indecent to treat patients who do not really need, so that we do not have the financial means to deal with tens of millions of HIV around the world that we really need!
For eradication, Asier Sáez-Cirion presented the case of a girl who was infected at birth and was immediately treated with antiretroviral therapy when she was a child. She has not taken antiretroviral therapy for twelve years, since the age of six years, with a viral load well below the limits of detectability of standard tests. People in this type of unusual situation (also called post-processing controllers), represent a functional model of healing, one of the objectives of the research on treatment. It appears to us that such indecent case is presented as a useful model in the search for healing, while healing not only functional but real exists. It has been paid there are already two years by Dr. Prakask (see on this site C.92- Revolution hidden in the eradication of the virus HIV-treatment of Dr Prakash), with some patients cured since 5 years. This work which is known by our scientific authorities (F.Barré-Sinoussi, Luc Montagnier, C.Katlama, JF Delfraissy ...), are beautifully obscured. It is lamentable and criminal Dr. Prakask was not the guest of honor at the conference!
Among the many works presented include:
-the association Long-term non-progressors and alteration in the metabolism of cholesterol (MOPEA013 G.Rappocciolo et al)
-the antibodies against 3S motif of gp41 protects the fall in CD4 (MOPEA014-V. Old Man et al). Indicate that the therapeutic vaccine VAC-3S, which is one of C.Katlama responsible! Is based on this result. - IPROTECT1 MULTICENTRE EUROPEAN TEST VACCINE 6 therapeutically VAC-3S tested on patients with undetectable viral load after 12 weeks it shows an increase in the CD4 / CD8 0,48au starting at 0.49 or 0.57 depending on the dose injected.
- Zinc Deficiency in HIV + and inflammatory reaction. Inverse correlation between CRP and Zn concentration. Interest of supplementation (KC MOPEB184- Poudel et al)
-Interest of supplementation of lactobacillus casei (TUPEB295- H. Ichimura et al). The effect of lactobacillus casei, Shirota strain, was tested on 60 children, 31 on HAART and 29 without HAART for 8 weeks and 20 HIV-. CXCR3CCR6-CD4 and CD4 + significantly increases and the percentage of CD4 in the 3 groups . The activation of CD8 + greatly decreases in HIV + without HAART, weakly in HIV-. Viral load decreases slightly but significantly in the group without HAART .The concentration of lactobacillus and bifidobacterium increases significantly in the stool. It might be recommended to supplement with Lactobacillus casei for HIV for which CD4 capped at an insufficient level, but also to accelerate the fall of viral load.
-the doravine, a new NNRTI is as effective as efavirenz but with fewer side effects
C.97- IAS 2015- Victoire des lobbys- le traitement pour tous
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C.96-PROSTATE CANCER AND CADMIUM : A SILENT INODORE TOXIC PENETRATING BY INHALATION.
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Poster présenté à
Association de la Recherche contre les Tumeurs de la Prostate ARTP 2014, 19 November, Paris Palais des Congrès
Most important, as Cadmium half-life is as long as 30 years (Leblanc JC, 2006), it is not eliminated spontaneously and accumulates in the prostate with time, which corresponds to an increased PK risk with age. Cadmium vapours, even in the solid state, penetrate insidiously, are odorless and tasteless. Molluscs (mussels, oysters), crustaceans organism. Tobacco contains Cadmium, [but also dioxine TCDD (→ Ha-Ras mutations), nitrosamines (→ Ki-Ras mutations)]. The Hazard Ratio for PK specific mortality is 1.82 if the patient smokes (Kenfield SA, 2011). Occupational studies show a correlation with the professional work in contact with Cadmium (Kjellstrom T, 1979, in Sweden).
Cadmium increases the oncogene c-Myc in renal (Tang N, 1991) and RWPE-1 prostatic cells (Achanzar WE, 2000). C-Myc stimulates telomerase promoter (high levels in PK). C-Myc up-regulates the androgen receptor messenger RNA (Grad J, 1999). Myc confers androgen-independent prostate cancer cell growth (Bernard D, 2003; Kokontis J, 1994). C-myc transgenic mice develop prostatic intra-epithelial neoplasia (Zhang X, 2000).
Loss Of Heterozygosity (LOH) of Bin-1(Bridging integrator 1) located at chromosome 2q14, an anti-Myc tumor suppressor is found in 42% of KP, in metastatic tumors and androgen-independent tumor cell lines (Ge K, 2000; Sakamuro D, 1996; Schmidt EV ). Subjects with Bin-1 LOH are likely to be more vulnerable to Cadmium oncogenicity.
Cadmium is a risk factor in a PK subgroup; 3 high-quality studies of toenail selenium and PK risk indicated a reduction in PK risk (Relative Risk = 0.29) with a toenail selenium concentration 0.85-0.94 μg/g (Hurst R, 2012).
TheUS Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that a long term supranutritional supplemental dose of selenomethionine (200 μg/d) in a selenium-replete population did not signiﬁcantly reduce the risk of developing prostate cancer. However no data on the cadmium level were presented (Lippman SM, 2009).
ALA, thioctic acid) are Cadmium chelators (El-Maraghy SA,2011). Some soils are rich in Cadmium: in the surrounding area of discharges, gold mines (Orbiel valley, where snails have a Cadmium level 30 times the normal value), dams funds (Sauviat); professionally, workers at risk are those of Cadmium-Nickel battery (Sahmoun AE, 2005), anti-corrosion coating, plastic paints, luminescent materials, metalworking (INRS toxicological card, 1992).
A systematic study of toenail Cadmium levels by graphite-furnace atomic absorption spectrometer is advocated in PK. For this subgroup, Cadmium chelation by Selenium (+ vitamine E) and ALA is logical. Heavy metal detoxification by parsley, coriander, garlic (allium ursinum) may be useful (Willem JP, 2014).
Achanzar WE et al. Cadmium induces c-myc, p53, and c-jun expression in normal human prostate epithelial cells as a prelude to apoptosis. Toxicol Appl Pharmacol 2000, 164: 291-300. Bernard D et al. Myc confers androgen-independent prostate cancer cell growth. J Clin Invest 2003, 112: 1724-31. Bryś M et al. Zinc and cadmium analysis in human prostate neoplasms. Biol Trace Elem Res 1997, 59:145-52. Ekman P. Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. Eur Urol 1999, 35: 362-9. El-Maraghy SA, Nassar NN. Modulatory effects of lipoic acid and selenium against cadmium-induced biochemical alterations in testicular steroidogenesis. J Biochem Mol Toxicol 2011, 25: 15-25. Ge K et al. Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma. Int J Cancer 2000, 86: 155-61. Goyer RA, Liu J, Waalkes MP. Cadmium and cancer of prostate and testis. Biometals 2004,17: 555-8. Grad JM et al. Multiple androgen response elements and a Myc consensus site in the androgen receptor (AR) coding region are involved in androgen-mediated up-regulation of AR messenger RNA. Mol Endocrinol 1999, 13: 1896-911. Hurst R et al. Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr 2012, 96:111-22. Julin B et al. Dietary cadmium exposure and prostate cancer incidence: a population-based prospective cohort study. Br J Cancer 2012, 107: 895-900. INRS toxicological card, 1992 Kenfield SA et al. Smoking and prostate cancer survival and recurrence. JAMA 2011, 305: 2548-55. Kjellström T et al. Mortality and cancer morbidity among cadmium-exposed workers. Environ Health Perspect 1979, 28:199-204. Kokontis J. Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long term androgen deprivation. Cancer Res 1994, 54: 1566–73 Leblanc JC et al. CALIPSO. Etude des consommations alimentaires de produits de la mer et imprégnation aux éléments traces, polluants et oméga 3 . Rapport d'étude Afssa, Ministère de l'Agriculture et de la Pêche, INRA . 2006 Oct, 106 p. Lippman SM. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009, 301:39-51. Morganti G et al. [Clinico-statistical and genetic research on neoplasms of the prostate]. Acta Genet Stat Med 1956-1957, 6: 304-5. French. Ogunlewe JO, Osegbe DN. Zinc and cadmium concentrations in indigenous blacks with normal, hypertrophic, and malignant prostate. Cancer 1989, 63:1388-92. Sahmoun AE et al. Cadmium and prostate cancer: a critical epidemiologic analysis. Cancer Invest 2005, 23: 256-63. Sakamuro D et al. BIN1 is a novel MYC-interacting protein with features of a tumour suppressor. Nat Genet 1996,14: 69-77. Sanchez Garcia A et al. Geochemical prospection of cadmium in a high incidence area of prostate cancer, Sierra de Gata, Salamanca, Spain. Sci Total Environ 1992,116: 243-51. Schmidt EV. MYC family ties. Nat Genet 1996, 14: 8-10. Schöpfer J. Selenium and cadmium levels and ratios in prostates, livers, and kidneys of nonsmokers and smokers. Biol Trace Elem Res. 2010,134:180-7. Tang N, Enger MD. Cadmium induces hypertrophy accompanied by increased myc mRNA accumulation in NRK-49F cells. Cell Biol Toxicol 1991, 7: 401-11. Tang N, Clapper JA, Enger MD. Cd++ inhibits EGF induced DNA synthesis but not EGF induced myc mRNA accumulation in serum starved NRK-49F cells. Cell Biol Toxicol 1991, 7: 35-47. Vinceti M et al. Case-control study of toenail cadmium and prostate cancer risk in Italy. Sci Total Environ 2007, 373: 77-81. Waalkes MP et al. Carcinogenic effects of cadmium in the noble (NBL/Cr) rat: induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions of the dorsolateral prostate. Toxicol Sci 1999, 52: 154-61. West DW et al. Adult dietary intake and prostate cancer risk in Utah: a case-control study with special emphasis on aggressive tumors. Cancer Causes Control 1991, 2: 85-94. Willem Jean-Pierre. Les dégâts des métaux lourds. Sept 2014 (Guy Trédaniel Ed.) 268 pages. Yoshizawa K. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998, 90: 1219-24. Zhang X et al. Prostatic neoplasia in transgenic mice with prostate-directed overexpression of the c-myc oncoprotein. Prostate 2000, 43: 278-85
C.95- PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS (HPV) L1 WITH NU
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PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS (HPV) L1 WITH NUCLEOPHOSMIN (NPM1), A CONTROLLER OF ANDROGEN RECEPTOR TRANSCRIPTION
Association de la Recherche contre les Tumeurs de la Prostate ARTP 2014, 19 November, Paris
Background: We showed previously that HPV contained Prostatic Cancer (PC) related oncogenic proteins:
1°) HPV E2 (51-112) is homologous to an Epidermal Growth Factor (Tran MKG, 1997).
2°) E1 to PTEN, E6 and L1 to the c-Myc inhibitor Bin-1 (Bridging integrator 1 or amphiphysin II), a tumor suppressor deleted in 42% of PC (Tran GMK, 2008).
3°) HPV-18 E2 mimics Osteoprotegerin and ParaTHormone related Protein (PTHrP) active site (explaining bone metastasis). Anwar K (1992) found 80% HPV-18 in metastatic PC in Japan. Our meta-analysis concluded to a frequency of about 30%-40% (21-80%) oncogenic HPV (-16, -18, -33) in PC (EuroConf Cancer Pasteur Inst, 2004). The most important point is the PCR (E6 primer and fresh tissue); L1 primer and formalin-fixed, paraffin-embedded yielded negative results. For example, Terris MK (1997) obtained 21% positivity with E6 and 0% with L1 primer, in the same patients. Recent results confirm that use of paraffin-embedded tissues (Groom HCT, 2012; Ghasemian E, 2013) or L1 primer (Sylvestre RV, 2009) or both (13/104 versus 8/104 Aghakhani A, 2011) were unsuccessful. Positive results were reported (in 10.5% Jalilvand S, 2014; worse overal survival, Pascale M, 2013).
Noda S (1975) described papillomavirus-like particles in electron microscopy of prostate cancer tissue. Whitaker NJ (2013) found koilocytes in HPV-18 infected prostate cancer.
Our aim is to link HPV to Androgen Receptor (AR). Another hormonal cancer linked to virus is breast cancer, as the virus integration site is Aromatase, the estrogen synthetizing enzyme (Tekmal RR, 1995).
Methods: Amino Acid (AA) sequence comparison between HPV (Lowe J, 2008) and NPM1 (nucleophosmin), which controls AR transcriptional activity by promoting S-phase entry and hyperproliferation (cyclin switch D1 to E1 and p27kip1 loss) (Boudra R, ARTP 2013). Clinically, high p27kip1 is a correlate of better survival after prostatectomy at 5 years.
Results: HPV L1 chimera (types 16, 18, 31, 33, 44, 56, 66, 115) [type-16, AA 167-219] is homologous to NPM1 chimera (human, duck, alligator, sheep, rhinoceros, turtle,…)[AA 1-48]
NPM1 MEDSMDMDSMQPLRPQMFLFGC- - - SGAHWARISPCSLLGGFFAGCELKSD
HPV L1 VEDSMDV – SMDPKQIQMFLI GCKPPTGEHWAR-SPCSPVG- --AGDCELKSD
Conclusion: Anti-androgen escape may be explained by AR mutations, but also in a PC subset (about perhaps 30%-40%, depending on the number of HPV serotypes screened) by a viral infection (oncogenic HPV), as HPV L1 is a viral NPM1 mimetic, enhancing AR transcriptional activity and inducing lethal p27kip1 loss. Japanese mushroom Shiitake is a non toxic and highly efficient anti-HPV (Smith JA, 2014). Indole 3 carbinol from cruciferous vegetables (Brussels sprouts, broccoli) are efficient against HPV-16 by viral transcription inhibition (Bradlow HL, 1999; Rieck GC, 2006). Anti-cancer drugs discovered by HPV-18 infected KB cells screening (Perdue RE Jr, 1982) may act, by serenpidity, as anti-HPV: Taxol (Paclitaxel, Docetaxel, Cabazitaxel), topotecan, Vinca Alkaloids (Vinorelbine, Vinflunine) . HPV vaccination of young men could protect against PC.
Bibliography Aghakhani A. Scand J Infect Dis 2011, 43: 64-9.Anwar K et al. Presence of ras oncogene mutations and human papillomavirus DNA in human prostate carcinomas. Cancer Res 1992, 52: 5991-6. Boudra R et al. Nucleophosmin overexpression down-regulates p27Kip1 and induces hyperproliferation in the prostate gland of transgenic mice. ARTP 2013. Bradlow HL. Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent. Ann N Y Acad Sci 1999, 889: 204-13. Review. De Villiers EM. Breast Cancer Res 2005, 7: R1-R11 Ghasemian E. Asian Pacific J Cancer Prev 14: 3305-8 Groom HCT. PLoS ONE 2012, 7(3): e34221. Jalilvand S. Asian Pac J Cancer Prev 15 (17), 7029-35 Lowe J et al. Evolutionary and structural analyses of alpha-papillomavirus capsid proteins yields novel insights into L2 structure and interaction with L1. Virol J 2008, 5: 150. Noda S. The Kurume Med J 1975, 22: 261-8 Pascale M Disease Markers 2013, 35: 607–13 Perdue RE Jr. KB cell culture I. Role in discovery of antitumor agents from higher plants. J Nat Prod 1982, 45: 418-26. Rieck GC. Mol Nutr Food Res 2006, 52: 105-13. Smith JA et al. Evaluation of active hexose correlated compound (AHCC) for the eradication of HPV infections in women with HPV positive Pap smears. Int Conf Soc Integrative Oncology, Houston, Oct 28, 2014. Tekmal RR, Durgam VR. The overexpression of int-5/Aromatase, a novel MMTV integration locus gene, is responsible for D2 mammary tumor cell proliferation. Cancer Lett 1995, 88: 147-55. Terris MK Urology 1997, 50: 150-6. Tran GMK et al. Role of human papillomavirus type 18 in a subgroup of prostatic cancer with bone metastases: Its protein E2 contains the osteoprotegerin active site. EuroConf. Cancer, Pasteur Institute, Jan 15-16 2004, Paris. (Free on: Positifs.org C.53) Tran MKG et al. Human papillomavirus (HPV) E2 protein contains a chimera of epidermal growth factor (EGF) and EGF family mitogens: Heregulin and tumor growth factor. 6th Europ Conf Clin Aspects Treatment HIV infection, Hamburg, Germany, Oct 11-15,1997: P474. Tran GMK et al. Cancer de la prostate métastatique: Le suppresseur de tumeur Bin1, inhibiteur de c-Myc, est homologue aux protéines E6 et L1 des papillomavirus humains oncogènes et PTEN à la protéine E1. Bull Cancer 2008, 95: 592. P33. Whitaker NJ. Prostate 2013, 73: 236-41