text:
"A recent report that 93 percent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an understatement," due to underdetection. On reanalysis of the specimens, HPV was found in most supposedly HPV-negative cases, and "the worldwide HPV prevalence in cervical carcinomas is 99.7 percent." (Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. JM Walboomers et al. J Pathol 1999 Sep;189(1):12-19).Walboomers - J Pathol 1999 abstract / PubMed
The human papillomavirus type 16 E6 gene alone is sufficient
induce carcinomas in transgenic animals. S Song, HC Pitot, PF Lambert.
J Virol 1999 Jul;73(7):5887-5893. "We generated K14E6 transgenic mice
in which the HPV16 E6 gene was expressed in the basal layer of
epithelia, using the hK14 promoter. Expression of E6 increased cell
proliferation and induced epidermal hyperplasia. Skin tumors developed
in adult K14E6 mice with an incidence of about 7% at 1 year of age. In
contrast to the tumors derived from K14E7 transgenic mice, which were
primarily benign, tumors derived from K14E6 transgenic mice were mostly
malignant, indicating that E6 alone not only is sufficient to induce
tumors but may contribute to the development of malignancy in animals."
"Inactivation of p53, however, may not be the only mechanism for
E6-induced carcinogenesis. The K14E6 mice that developed tumors also
displayed hyperplastic changes in the epidermis, a property that, as
discussed above, cannot be ascribed to E6's inactivation of p53. It is
likely that the hyperproliferation induced by E6 is important for its
carcinogenesis. Another activity that may contribute to E6-associated
carcinogenesis is its apparent inhibition of cellular differentiation.
Cancer cells usually lack the ability to terminally differentiate. In
this study, we found that the suprabasal compartment of the K14E6
transgenic epidermis stained for K14, indicating that E6 may also
perturb cellular differentiation; this perturbation was caused by
p53-independent activities of E6."
A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. M Durst, L Gissmann, H Ikenberg, H Zur Hausen. Proceedings of the National Academy of Sciences 1983 Jun 15;80(12):3812-3815. 61.1% of cervical carcinomas carried an HPV DNA sequence which had little or no resemblance to those of known HPV types. It was designated HPV 16.Durst / PNAS 1983 abstract
The effect of functional inactivation of TP53 by HPV-E6
transformation on the induction of chromosome aberrations by gamma rays
in human tumor cells. JL Schwartz, KJ Russell. Radiat Res 1999
Apr;151(4):385-390. "While aberration frequencies were similar at early
harvest times, there was evidence for a subpopulation of more heavily
damaged cells in the E6-transformed cells that cycled into late
mitosis. Holding cells noncycling for 24 h to allow repair of
potentially lethal damage eliminated this subpopulation of more heavily
damaged cells. The E6-transformed cells also had higher levels of
chromatid-type aberrations and sister chromatid exchanges, consistent
with an additional defect in kinetics of repair of base damage that is
associated with the E6 transformation. Holding cells noncycling for 24
h eliminated the elevated levels of chromatid-type aberrations and
sister chromatid exchanges. These studies demonstrate that E6
transformation of human tumor cells will influence both the frequency
and types of chromosome aberrations observed after radiation exposure,
and that these effects are related to the expression of potentially
lethal damage."
Relationships between 80 human papillomavirus genotypes and
different grades of cervical intraepithelial neoplasia: association and
causality. T Matsukura, M Sugase. Virology 2001 Apr 25;283(1):139-147.
38 skin and 42 genital HPV types were sought in 386 biopsy samples.
"[S]ingle genital, but no skin's HPVs were identified with more than 10
copies per cell in 354 CIN (88 CIN I, 94 CIN II, and 172 CIN III). HPVs
40, 42, 43, 54, 62, or 71 was found in 10 CIN I, while HPVs 18, 30, 39,
51, 56, 59, 66, 68, 69, or 82 was found in 35 CIN I, 20 CIN II, or 8
CIN III. On the other hand, HPVs 16, 31, 33, 35, 52, 58, or 67 was
identified in 43 CIN I, 74 CIN II, or 164 CIN III. The results are
strongly indicative that most genital HPVs have potency to induce CIN
I; however, HPV 16 and its closely related types are able to
efficiently induce CIN III. We discuss the definition of causal HPV for
CIN with regard to viral prevalence and viral load."
Variation in the E2-binding domain of HPV 16 is associated
high-grade squamous intraepithelial lesions of the cervix. A
Gainnoudis, M Duin, PJ Snijders, CS Herrington. Br J Cancer 2001
Apr;84(8):1058-1063. "[D]isruption of the regions of E2 analysed was
significantly more frequent in high-grade lesions, and there was a
significant association between the 3684C-A variant in the E2 DNA
binding domain and high-grade histology suggesting that this variant
may be important in progression to high-grade intraepithelial disease."
Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study. J Berumen, RM Ordonez, E Lazcano, J Salmeron, SC Galvan, RA Estrada, E Yunes, A Garcia-Carranca, G Gonzalez-Lira, A Madrigal De- La Campa. J Natl Cancer Inst 2001 Sep 5;93(17):1325-1330; and: Aggressive HPV variant common among Mexican women with cervical cancer. Medscape - Reuters Health 2001 Sep 4.Berumen - JNCI 2001 abstract / PubMed
CpG Methylation of Human Papillomavirus Type 16 DNA in
Cancer Cell Lines and in Clinical Specimens: Genomic Hypomethylation
Correlates with Carcinogenic Progression. V Badal, LS Chuang, EH Tan, S
Badal, LL Villa, CM Wheeler, BF Li, HU Bernard. J Virol 2003
Jun;77(11):6227-6234. "In 81 patients from two different cohorts, the
LCR and the E6 gene of HPV-16 DNA were found to be hypermethylated in
52% of asymptomatic smears, 21.7% of precursor lesions, and 6.1% of
invasive carcinomas. This suggests that neoplastic transformation may
be suppressed by CpG methylation, while demethylation occurs as the
cause of or concomitant with neoplastic progression... Two speculative
and opposing views might explain this observation. The cell may have an
antiviral defense that senses viral DNA as foreign and targets it for
transcriptional repression. Alternatively, DNA methylation may be yet
another example of the numerous strategies developed by HPVs that favor
a subclinical, long-term maintenance of the viral infection. Such a
model would be reminiscent of the life cycle of Epstein-Barr virus,
which includes DNA methylation-dependent silencing of a specific
promoter during one form of latency."
Human papillomavirus type 16 E6 and E7 genotypes in
carcinomas. M Hoffmann, C Lohrey, A Hunziker, T Kahn, E Schwarz. Oral
Oncol 2004 May;40(5):520-524. "Sequence analysis of the E6-E7 segments
revealed three different HPV16 E6-E7 genotypes: the HPV16 prototype (6
of 21 cases), the E6 variant T350G (8 of 21 cases), and the E6-E7
variant A131G/C712A (7 of 21 cases). The E6 variants T350G and A131G
have been associated with increased oncogenic potential in cervical
cancer patients depending on host genetic factors. Their high
prevalence in the HNSCC samples studied indicates that they may be
important also in HNSCC development."
Enhanced oncogenicity of Asian-American human papillomavirus
16 is
associated with impaired E2 repression of E6/E7 oncogene transcription.
RM Ordonez, AM Espinosa, DJ Sanchez-Gonzalez, J Armendariz-Borunda, J
Berumen. J Gen Virol 2004 Jun;85(Pt 6):1433-1444. "AA variants confer a
nine times higher risk than E variants for cervical cancer... The low
repression activity of E2 suggests that increased expression of E6/E7
oncogenes may occur much earlier in AA tumours. Therefore, the time
period between viral infection and the emergence of a frankly invasive
cancer may be decreased. This hypothesis could explain the association
of the AA-c variant with patients 11 years younger than those with E
variants (Berumen et al., 2001)."
Human papillomaviruses: Some genital-mucosal types. "Known to
be a
human carcinogen. First listed in the Eleventh
Report on Carcinogens (2004)." [In comparison, the IARC
HPV to be a known human carcinogen in 1995.]
DNA aneuploidy and integration of human papillomavirus type 16
oncogenes in intraepithelial neoplasia and invasive squamous cell
carcinoma of the cervix uteri. P Melsheimer, S Vinokurova, N
Wentzensen, G Bastert, M von Knebel Doeberitz. Clin Cancer Res 2004 May
1;10(9):3059-3063. "RESULTS: DNA aneuploidy and viral genome
integration were both associated with increasing dysplasia (P <
0.001, chi(2) test for trend). In addition, DNA aneuploidy was
associated with increased viral integration (P < 0.01, Fisher's
exact test). Nineteen of 20 (95%) lesions with integrated viral genomes
had aneuploid cell lines; however, only 19 of 32 (59%) lesions with
aneuploid cell lines had integrated viral genomes. CONCLUSIONS: These
data support the hypothesis that aneuploidization precedes integration
of HR-HPV genomes in the progression of cervical dysplasia.
Accordingly, deregulated viral oncogene expression appears to result
first in chromosomal instability and aneuploidization and is
subsequently followed by integration of HR-HPV genomes in the affected
cell clones."
The pivotal role of phosphatidylinositol 3-kinase–Akt signal
transduction in virus survival. S Cooray. J Gen Virol
2004;85(5):1065-1076. "A number of viruses including EBV, HPV, HBV
and HCV have the ability to establish long-term infections in the host,
either through the establishment of latent or chronic infections, which
can ultimately lead to cellular transformation. It appears that the
gene products of these viruses stimulate PI3K–Akt-mediated cell
survival and thereby block apoptosis of the cells they infect. This
to both virus survival and oncogenic transformation..."
Mapping and analysis of HPV16 integration sites in a head and
cancer cell line. CC Ragin, SC Reshmi, SM Gollin. Int J Cancer 2004 Jul
10;110(5):701-709. "Disruption of the E2 gene sequence due to viral
integration results in upregulation of E6 and E7, which promote
tumorigenesis by abrogating p53 and pRb functions... Sequential FISH
and spectral karyotyping identified integration sites on chromosomes 3,
6, 9q, 13q and t(1;8)(q;?). Restriction site-polymerase chain reaction
(RS-PCR) was performed to identify the viral-cellular junctions.
Sequence analyses confirmed integration sites at 9q31.1 and 6p21 and
revealed a novel junction at 16p12.3. Subsequent chromosome breakage
studies suggested that the observed viral-cellular integration sites
may have occurred within common fragile sites. Additional studies using
RT-PCR for E6--E7 viral transcripts showed oncoprotein expression from
episomal and integrated viral sequences. Our results suggest that viral
integration of HPV in SCCHN appears to occur nonrandomly through
targeting specific chromosomal sequences prone to breakage."
Mechanisms of
papillomavirus-induced oncogenesis. K Munger, A
Baldwin, KM Edwards, H Hayakawa, CL Nguyen, M Owens, M Grace, KW Huh.
Journal of Virology 2004 Nov;78(21):11451-11460. Minireview.
oncogenic E6 and E7 protein-expressing sequences of human
papillomavirus are integrated into human genes, and continue to express
their proteins; while the E2 protein-expressing sequence, which
supresses transcription, is often lost or its expression is disturbed.
The E6 proteins bind to and degrade the cell's p53 tumor suppressor
protein, and prevent it from causing the death of damaged or mutated
cells. HPV E6 proteins also have independent transforming abilities.
The E7 protein inactivates the cell's pRb protein, which results in
excessive cell proliferation. The E6 and E7 proteins also collaborate
to induce telemerase activity which immortalizes the cell, and they
cause centrosome abnormalities during cell division as well.
Papillomavirus capsid mutation to escape dendritic cell-dependent innate immunity in cervical cancer. R Yang, CM Wheeler, X Chen, S Uematsu, K Takeda, S Akira, DV Pastrana, RP Viscidi, RBS Roden. J Virol 2005 Jun;79(11):6741-6750. Mutations occuring in high-grade CIN and cervical cancer evade recognition by the immune system.Yang / J Virol 2005 abstract
The carcinogenicity of human papillomavirus types reflects
evolution. M Schiffman, R Herrero, R Desalle, A Hildesheim, S
Wacholder, AC Rodriguez, MC Bratti, ME Sherman, J Morales, D Guillen, M
Alfaro, M Hutchinson, TC Wright, D Solomon, Z Chen, J Schussler, PE
Castle, RD Burk. Virology 2005 Jun 20;337(1):76-84. Population-based
study of 10,000 women in Costa Rica. "HPV16 was uniquely likely both to
persist and to cause neoplastic progression when it persisted, making
it a remarkably powerful human carcinogen that merits separate clinical
consideration... Other carcinogenic types, many related to HPV16, were
not particularly persistent but could cause neoplastic progression, at
lower rates than HPV16, if they did persist. Some low-risk types were
persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence. Separately, we
that the carcinogenic HPV types code for an E5 protein, whereas most
low-risk types either lack a definable homologous E5 ORF and/or a
translation start codon for E5."
Two distinct activities contribute to human papillomavirus 16
oncogenic potential. SJ Simonson, MJ Difilippantonio, PF Lambert.
Cancer Res 2005 Sep 15;65(18):8266-8273. "A very different finding was
made when we monitored carcinoma development, a measure of progression.
Here, we found that, compared with nontransgenic mice, a significantly
greater percentage of mice in both K14E6WT (P = 0.005) and K14E6146-151
(P = 0.002) groups developed carcinomas (Fig. 2B). This result
indicates that, although E6's interactions with PDZ domain proteins
correlate with E6's ability to act in the promotion stage of
carcinogenesis, these PDZ interactions are not required for E6's
progression activity in carcinogenesis. This is the first evidence
showing that the contribution of E6 to the multiple stages of
carcinogenesis can be mechanistically separated." "This provides the
first direct evidence that distinct activities of E6 contribute to
distinct stages in carcinogenesis. We suspect that this other property
is E6's inactivation of p53, as mice deficient for p53 specifically
show an enhanced rate and incidence of progression but no increase in
initiation or promotion."
Worldwide Genomic Diversity of the High-Risk Human
Types 31, 35, 52, and 58, Four Close Relatives of Human Papillomavirus
Type 16. IE Calleja-Macias, LL Villa, JC Prado, M Kalantari, B Allan,
A-L Williamson, L-P Chung, RJ Collins, RE. Zuna, ST Dunn, T-Y Chu, HA
Cubie, K Cuschieri, M von Knebel-Doeberitz, CR Martins, GI Sanchez, FX
Bosch, N Munoz, H-U Bernard. Journal of Virology, 2005
The Human DEK Proto-Oncogene Is a Senescence Inhibitor and an
Upregulated Target of High-Risk Human Papillomavirus E7. TM
Wise-Draper, HV Allen, MN Thobe, EE Jones, KB Habash, K Münger,
and SI Wells. J Virology, 2005 Nov;79(22): 14309-14317.
Genome wide expression analysis in HPV16 cervical cancer:
Identification of altered metabolic pathways. C Perez-Plasencia, G
Vazquez-Ortiz, R Lopez-Romero, P Pina-Sanchez, J Moreno, M Salcedo.
Infectious Agents and Cancer 2007;2(16): in progress. "We found 2,067
genes significantly up or down-modulated (at least 2-fold) in tumor
clinical samples compared to normal tissues, representing ~ 3.7% of
analyzed genes. Cervical carcinoma was associated with an important
up-regulation of Wnt signaling pathway, which was validated by in situ
hybridization in clinical samples. Other up-regulated pathways were
those of calcium signaling and MAPK signaling, as well as cell
cycle-related genes. There was down-regulation of focal adhesion,
TGF-beta signaling, among other metabolic pathways."
Genomic integration of oncogenic HPV and gain of the human
telomerase gene TERC at 3q26 are strongly associated events in the
progression of uterine cervical dysplasia to invasive cancer. AH
Hopman, W Theelen, PP Hommelberg, MA Kamps, CS Herrington, LE Morrison,
EJ Speel, F Smedts, FC Ramaekers. J Pathol 2006 Dec;210(4):412-419.
"Recently proposed events associated with the progression of cervical
intraepithelial neoplasia (CIN) 2/3 to cervical carcinoma include
integration of human papillomavirus (HPV) into the host genome, genomic
instability, and an increase in chromosome 3q copy number. In
particular, the gene coding for the RNA component of telomerase (TERC)
at 3q26 has been implicated as a possible candidate gene... The TERC
gene was increasingly gained with progression of CIN 2/3 (3 of 17)
through CIN 3&mCA (7 of 13) to invCA (5 of 7). In the lesions
exhibiting gain of TERC, the virus was predominantly integrated. This
was seen in eight of ten diploid lesions, indicating that these events
can occur prior to aneuploidization and are strongly associated with
the progression of CIN 3 to mCA and invCA (p < 0.001). With
progression to carcinoma, a number of these lesions show
polyploidization, resulting in aneuploidy and high TERC gene copy
Human papillomavirus causes an angiogenic switch in
which is sufficient to alter endothelial cell behavior. W Chen, F Li, L
Mead, H White, J Walker, DA Ingram, A Roman. Virology 2007 Oct
10;367(1):168-174. "Here we report that HPV-induced early changes in
the keratinocyte phenotype are sufficient to alter endothelial cell
behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7
expressing HFKs as well as from human cervical keratinocytes containing
the intact HPV16 were able to stimulate proliferation and migration of
human microvascular endothelial cells. In addition, introduction of the
conditioned media into immunocompetent mice using a Matrigel plug model
resulted in a clear angiogenic response. These novel data support the
hypothesis that HPV proteins contribute not only to the uncontrolled
keratinocyte growth seen following HPV infection but also to the
angiogenic response needed for tumor formation."
The Fraud of
IARC Monograph 90,
Human Papillomaviruses: IARC Monographs on the Evaluation
Carcinogenic Risks to Humans,
Volume 90 (2007). Human Papillomaviruses.
Chapter 4. Molecular Mechanisms of HPV-induced Carcinogenesis.
IARC Monographs on the Evaluation of Carcinogenic Risks to
Volume 90 (2007). Human Papillomaviruses. Chapter 5. Summary of Data
Reported and Evaluation. "Cancer of the Cervix: ... Strong
epidemiological evidence confirmed the previous evaluation that HPV
types 16 and 18 are carcinogenic to humans. The evidence for
carcinogenicity was strongest for HPV 16. In addition, a convincing
association, mainly from case–control studies, was found for HPV types
31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66. HPV types 26, 68, 73 and
82 were associated with cervical cancer in some case–control studies
but were rarely found in case series and were not associated with an
increase in risk in prospective studies; overall, the epidemiological
data for these types were not considered to show a consistent
association. Despite a large amount of HPV type-specific data that
failed to demonstrate an association, HPV 6 and 11 have been reported
in very rare cases, but they did not contribute meaningfully to the
burden of cervical cancer. Fewer data were available for other HPV
types." This is not fraudulent. The fraud commences when they deal with
the subject of smoking and cancers caused by HPV.
Note the bias of this report concernign HPV and lung cancer:
claim that "At present, there is a lack of evidence from case–control
studies to support a possible involvement of HPV infections in tumours
of these organs." However, there have been more than fifty laboratory
studies, and the same high-risk HPV types have been implicated in lung
cancer as in cervical cancer; and there is no reason to suppose that
HPV functions any differently in the lung than in the cervix.
Furthermore, the existing studies indicate that HPV is involved in ten
times more lung cancers than the anti-smoking charlatans pretend - on
the basis of nothing but lifestyle questionnaires! - are caused by
secondhand smoke. The lack of case-control studies of HPV and lung
cancer, despite the major health implications of the evidence, in
contrast to the comparatively massive expenditure of resources of
scientifically-specious lifestyle-questionnaire studies whose object is
to serve the political purpose of banning smoking, is proof of
corruption of the scientific process by the anti-smokers, and their
deliberate neglect of research on infection.
They also demonstrate their bias by their shoddy and negligent
handling of the issue of confounding by the extraordinarily high odds
ratios that are associated with infection by high-risk human
paillomaviruses. In cervical cancer, they exceed 300! Odds ratios of
this magnitude must not be handled in the same casual manner as the
trivial odds ratios found in lifestyle questionnaire studies! In
lifestyle questionnaire studies, the inclusion or exclusion of some
purported non-infectious "risk factor" never alters the odds ratio by
more a few tenths of a point. In contrast, the failure to accurately
detect exposure to a causal factor with an odds ratio of 300 is
guaranteed to result in spurious ratios odds of two or more more, any
time that there is a difference between the comparison groups in the
amount and duration of their exposure to the pathogen. Their failure to
cite the mathematical demonstration of Phillips
and Smith, and deal with the issues that it raises, is proof
their negligence, especially on the part of Xavier Bosch, who
corresponded with Phillips and Smith on this subject and confirmed it
in his own data set. Their specious blow-off is an outrage: "The risk
estimates for this association were consistently in the range of 2.0
regardless of the study design (retrospective versus prospective), the
restriction criteria employed (any HPV type-positive versus high-risk
HPV-positive) and the covariates included in the model" (Ch. 5, p.
471), because this subject requires and deserves a detailed analysis of
all the potential routes for confounding, not just a superficial
glance at a pile of inadequate studies which concludes that the
findings are legitimate on the grounds of the height of the pile!
Simply detecting "any HPV" or "high-risk HPV-positive" is not
sufficient because infection by multiple strains multiplies the risk.
Furthermore, the infectious status of the partner influences the amount
of exposure, and the risk of development of cervical cancer. In fact, they have willfully failed to
their claim about smoking and cervical cancer to the same degree of
scrutiny which they applied to HPV,
including "lack of a reliable measurement of lifetime exposure to HPV
infection" (Ch. 2. Studies of Cancer in Humans, (b) Impact of Study Design,
p. 2),
which differs between smokers and non-smokers for socioeconomic
reasons. IN FACT, given that the potential routes for confounding make
it a virtual certainty, any pretense that smoking increases the risk of
cervical cancer ought to have been summarily dismissed, and the burden of proof placed
where it
rightfully belongs, on the anti-smokers, to
convincingly that they have eliminated potential confounding.
p53-independent abrogation of a postmitotic checkpoint
to human papillomavirus E6-induced polyploidy. Y Liu, SA Heilman, D
Illanes, G Sluder, JJ Chen. Cancer Res 2007 Mar 15;67(6):2603-2610.
"Polyploidy is often an early event during cervical carcinogenesis, and
it predisposes cells to aneuploidy, which is thought to play a causal
role in tumorigenesis... We found that E6 expression does not affect
the spindle checkpoint. Instead, we provide direct evidence that E6 is
capable of abrogating the subsequent G(1) arrest after adaptation of
the mitotic stress. E6 targets p53 for degradation, and previous
studies have shown an important role for p53 in modulation of the G(1)
arrest after mitotic stress. Importantly, we have discovered that E6
mutants defective in p53 degradation also induce polyploidy, although
with lower efficiency. These results suggest that E6
is able to
induce polyploidy via both p53-dependent and p53-independent mechanisms."
Genomic instability of the host cell induced by the human
papillomavirus replication machinery. M Kadaja, A Sumerina, T Verst, M
Ojarand, E Ustav, M Ustav. EMBO J 2007 Apr 18;26(8):2180-2191. "We show
that HPV replication proteins E1 and E2 are capable of inducing
overamplification of the genomic locus where HPV origin has been
integrated. Clonal analysis of the cells in which the replication from
integrated HPV origin was induced showed excision, rearrangement and de
novo integration of the HPV containing and flanking cellular sequences."
Phosphoinositide kinase-3 status associated with presence or
of human papillomavirus in head and neck squamous cell carcinomas. WG
Yarbrough, A Whigham, B Brown, M Roach, R Slebos. Int J Radiat Oncol
Biol Phys 2007;69(2 Suppl):S98-101. "PIK3CA gene expression was
confirmed by quantitative reverse transcriptase-polymerase chain
reaction in seven HPV(+) and seven HPV(-) primary HNSCCs. PIK3CA
mutation status in three HPV(+) and nine HPV(-) cell lines was
determined by polymerase chain reaction amplification of hot spot exons
(1, 9, 20) followed by direct sequencing. RESULTS: PIK3CA
overexpressed in HPV(+)-associated HNSCC compared with
expression in HPV(-) HNSCC. Activation of PIK3CA by mutation was found
in 1 of the 12 tested HNSCC cell lines. CONCLUSION: Activation of PI3K
by mutation of PIK3CA is rare in HNSCC cell lines and was not found in
three HPV(+) cell lines. One mechanism by which HPV-associated HNSCC
might activate PI3K is increased expression of PIK3CA."
Activation of AKT and nuclear accumulation of wild type TP53
MDM2 in anal squamous cell carcinoma. H Patel, G Polanco-Echeverry, S
Segditsas, E Volikos, A McCart, C Lai, T Guenther, A Zaitoun, O Sieber,
M Ilyas, J Northover, A Silver. Int J Cancer 2007 Dec
15;121(12):2668-2673. 73%, 94/128 of anal squamous cell carcinomas were
infected by HPV, 86%, 81/94 by HPV16. "Cellular accumulation of
phosphorylated-AKT was observed in 66% (82/125) of ASCCs and an
association demonstrated between nuclear accumulation of MDM2 and
activated AKT (p < 0.001). We observed a high
frequency of copy number gain
at PIK3CA (47%), and some coding sequence mutations
Amplification of PIK3CA was associated with presence of
phosphorylated-AKT (p= 0.008). There was no association between virus
infection and TP53 nuclear accumulation (p = 0.5). However, a
significant association was found between infection and MDM2 nuclear
staining, and between infection and activated AKT (p = 0.04, p = 0.01,
respectively). We propose that activation of AKT, possibly through the
PI3K-AKT pathway, is an important component of ASCC tumorigenesis that
contributes to MDM2 and TP53 accumulation in the nucleus."
The Human Papillomavirus E7 Protein Deregulates Mitosis via an
Association with the Nuclear Mitotic Apparatus Protein-1 (NuMA). CL
Nguyen, K Münger. J Virol 2009 Feb;83(4):1700-1707. "We previously
observed that high-risk human papillomavirus type 16 (HPV16) E7
expression leads to the delocalization of dynein from mitotic spindles
(C. L. Nguyen, M. E. McLaughlin-Drubin, and K. Munger, Cancer Res.
68:8715-8722, 2008). Here, we show that HPV16 E7 associates with
nuclear mitotic apparatus protein 1 (NuMA) and that NuMA binding and
the ability to induce dynein delocalization map to similar
carboxyl-terminal sequences of E7. Additionally, we show that the
delocalization of dynein from mitotic spindles by HPV16 E7 and the
interaction between HPV16 E7 and NuMA correlate with the induction
defects in chromosome alignment during prometaphase even in cells with
normal centrosome numbers. Furthermore, low-risk HPV6b and HPV11 E7s
also associate with NuMA and also induce a similar mitotic defect.
is possible that the disruption of mitotic events by HPV E7, via
targeting of the NuMA/dynein complex and potentially other
NuMA-containing complexes, contributes to viral maintenance and
propagation potentially through abrogating the differentiation program
of the infected epithelium. Furthermore, in concert with activities
specific to high-risk HPV E6 and E7, such as the inactivation of the
p53 and pRB tumor suppressors, respectively, the disruption of the
NuMA/dynein network may result in mitotic errors that would make an
infected cell more prone to the accumulation of aneuploidy even in the
absence of supernumerary centrosomes."
Abrogation of the Postmitotic Checkpoint Contributes to
Polyploidization in HPV E7 Expressing Cells. SA Heilman, JJ Nordberg, Y
Liu, G Sluder, JJ Chen. J Virol. 2009 Mar;83(6):2756-2764. "Cells
expressing the oncogene E7 from high-risk HPVs have a high incidence of
polyploidy, which has been shown to occur as an early event in cervical
carcinogenesis and predisposes the cells to aneuploidy... We find that
E7 expressing cells undergo normal mitoses with an intact spindle
assembly checkpoint, and that they are able to complete cytokinesis.
Our results also exclude DNA re-replication as a major mechanism of
polyploidization in E7 expressing cells upon microtubule disruption.
Instead, we have shown that while normal cells arrest at the
postmitotic checkpoint after adaptation to the spindle assembly
checkpoint, E7 expressing cells replicate their DNA and propagate as
polyploid cells. Thus, abrogation of the postmitotic checkpoint leads
to polyploidy formation in E7 expressing human epithelial cells. Our
results suggest that down-regulation of pRb is important for E7 to
induce polyploidy and abrogation of the postmitotic checkpoint."
Mechanism of genomic instability in cells infected with the
high-risk human papillomaviruses. M Kadaja, H Isok-Paas, T Laos, E
Ustav, M Ustav. PLoS Pathogens 2009 Apr;5(4). "We used
immunofluorescence analysis to show that the DNA repair/recombination
centers are assembled at the sites of the integrated HPV replication.
These centers recruit viral and cellular replication proteins, the MRE
complex, Ku70/80, ATM, Chk2, and, to some extent, ATRIP and Chk1
(S317). In addition, the synthesis of histone γH2AX, which is a
hallmark of DNA double strand breaks, is induced, and Chk2 is activated
by phosphorylation in the HPV–replicating cells... We show that HPV
replication proteins expressed at the physiological level from the
viral extrachromosomal genome are capable of replicating episomal and
integrated HPV simultaneously. Unscheduled replication of the
integrated HPV induces a variety of changes in the host genome, such as
excision, repair, recombination, and amplification, which also involve
the flanking cellular DNA."
Association of p73 G4C14-to-A4T14 polymorphism with human
papillomavirus type 16 status in squamous cell carcinoma of the head
and neck in non-Hispanic whites. X Ji, EM Sturgis, C Zhao, CJ Etzel, Q
Wei, G Li. Cancer 2009 Apr 15;115(8):1660-1668. 202 non-Hispanic white
patients with squamous cell carcinoma of the head and neck . "Compared
with the p73 GC/GC genotype, the AT/AT and combined GC/AT + AT/AT
variant genotypes were associated significantly with HPV-16-positive
tumor status among patients with SCCHN (adjusted OR, 5.32; 95% CI,
1.32-21.4; adjusted OR, 1.91; 95% CI, 1.03-3.53, respectively)."
Compromised Spindle Assembly Checkpoint due to altered
expression of
Ubch10 and Cdc20 in HPV16 E6 and E7 expressing keratinocytes. D Patel,
DJ McCance. J Virol 2010 Nov;84(21):10956-10964. How E6/E7 expressing
cells have the capability to enter and exit mitosis in the presence of
DNA damage and continue with the next round of cell cycle.
Nuclear Accumulation of the Papillomavirus E1 Helicase Blocks
S-Phase Progression and Triggers an ATM-Dependent DNA Damage Response.
A Fradet-Turcotte, F Bergeron-Labrecque, CA Moody, M Lehoux, LA
Laimins, J Archambault. J Virol 2011 Sep;85(17):8996-9012. "Here we
have shown that nuclear accumulation of E1 from different
papillomavirus types blocks cell cycle progression in early S phase and
triggers the activation of a DNA damage response (DDR) and of the ATM
pathway in a manner that requires both the origin-binding and ATPase
activities of E1. Complex formation with E2 reduces the ability of E1
to induce a DDR but does not prevent cell cycle arrest... We propose
that nuclear export of E1 prevents cell cycle arrest and the induction
of a DDR during the episomal maintenance phase of the viral life cycle
and that complex formation with E2 further safeguards undifferentiated
cells from undergoing a DDR when E1 is in the nucleus."
Quantitative Measurement of HPV-16 E5 Oncoprotein Levels in
Epithelial Cell Lines by Mass Spectrometry. Z Sahab, SR Sudarshan, X
Liu, Y Zhang, A Kirilyuk, CM Kamonjoh, V Simic, Y Dai, SW Byers, J
Doorbar, FA Suprynowicz, R Schlegel. J Virol 2012 Sep;86(17):9465-9473.
"In the present study, we show that trypsin cleavage of 16E5 generates
a unique four-amino acid C-terminal peptide (FLIT) that serves as a
marker for E5 expression in transfected cells and epithelial cell lines
containing integrated and episomal HPV-16 DNA. Following trypsin
cleavage, reversed-phase chromatography and mass spectrometry (MS) were
used to detect FLIT. Immunoprecipitation assays using a newly generated
anti-16E5 antibody confirmed that 16E5 was solely responsible for the
FLIT signal, and deuterated FLIT peptide provided an internal standard
that enabled us to quantify the number of 16E5 molecules per cell. We
show that 16E5 is expressed in the Caski, but not in the SiHa cervical
cancer cell line, suggesting that 16E5 may contribute to the malignant
phenotype of some cervical cancers, even in cells exclusively
containing an integrated HPV genome."
Comprehensive analysis of host cellular interactions with human papillomavirus e6 proteins identifies new e6 binding partners and reflects viral diversity. EA White, RE Kramer, MJ Tan, SD Hayes, JW Harper, PM Howley. J Virol 2012 Dec;86(24):13174-13186. "The viruses included represent high-risk, low-risk, and non-cancer-associated types from genus alpha as well as viruses from four different species in genus beta. The E6 interaction data set consists of 153 cellular proteins, including several previously reported HPV E6 interactors such as p53, E6AP, MAML1, and p300/CBP and proteins containing PDZ domains. We report the genus-specific binding of E6s to either E6AP or MAML1, define the specific HPV E6s that bind to p300, and demonstrate several new features of interactions involving beta HPV E6s. In particular, we report that several beta HPV E6s bind to proteins containing PDZ domains and that at least two beta HPV E6s bind to p53. Finally, we report the newly discovered interaction of proteins of E6 of beta genus, species 2, with the Ccr4-Not complex, the first report of a viral protein binding to this complex."White - J Virol 2012 abstract / PubMed
Human papillomavirus e7 induces rereplication in response to DNA damage. X Fan, Y Liu, SA Heilman, JJ Chen. J Virol 2013 Jan;87(2):1200-1210. "Here we present evidence demonstrating that HPV-16 E7-expressing cells have an intact G(2) checkpoint. Upon DNA damage, HPV-16 E7-expressing cells arrest at the G(2) checkpoint and then undergo rereplication, a process of successive rounds of host DNA replication without entering mitosis. Interestingly, the DNA replication initiation factor Cdt1, whose uncontrolled expression induces rereplication in human cancer cells, is upregulated in E7-expressing cells. Moreover, downregulation of Cdt1 impairs the ability of E7 to induce rereplication."Fan - J Virol 2013 abstract / PubMed
Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway and inhibition of autophagy. Z Surviladze, RT Sterk, SA DeHaro, MA Ozbun. J Virol 2013 Mar;87(5):2508-2517. "We detected activation of Akt and mTOR several minutes following exposure of human keratinocytes to HPV type 16 (HPV16) pseudovirions. Activated mTOR induced phosphorylation of the mTOR complex 1 substrates 4E-BP1 and S6K, which led to induction of the functional protein translational machinery. Blockade of epidermal GFR (EGFR) signaling revealed that each of these events is at least partially dependent upon EGFR activation. Importantly, activation of PI3K/Akt/mTOR signaling inhibited autophagy in the early stages of virus-host cell interaction."Surviladze - J Virol 2013 abstract / PubMed
Human Papillomavirus community in healthy persons, defined by metagenomics analysis of HMP (human microbiome project) shotgun sequencing datasets. Y Ma, R Madupu, U Karaoz, CW Nossa, L Yang, S Yooseph, PS Yachimski, EL Brodie, KE Nelson, Z Pei. J Virol 2014 May;88(9):4786-4797. 103 subjects. "The overall HPV prevalence was 68.9%, highest in the skin (61.3%), followed by vagina (41.5%), mouth (30%), and gut (17.3%). Of 109 HPV types as well as unclassified types detected, most were undetectable by the widely used commercial kits targeting the vaginal/cervical HPV types. These HPVs likely represent true HPV infections rather than transitory exposure because of strong organ tropism and persistence of same HPV types in repeat samples. Co-existence of multiple HPV types was found in 48.1% HPV-positive samples. Networking between HPV types, co-occurrence or exclusion, was detected in vaginal and skin samples. Large contigs assembled from short HPV reads were obtained from several samples, confirming their genuine HPV origin." "The importance of non-oncogenic viruses in a mixed HPV infection could be stimulating or inhibiting a co-existing oncogenic virus via viral interference or immune cross-reaction."Ma - J Virol 2014 abstract / PubMed
Human Papillomavirus Type 16 E6* Induces Oxidative Stress and DNA Damage. VM Williams, M Filippova, V Filippov, KJ Payne, P Duerksen-Hughes. J Virol 2014 Jun 15;88(12):6751-6761. "The E6 oncoprotein is expressed as several isoforms: a full-length variant referred to as E6 and a few shorter isoforms collectively referred to as E6*. In this study, we found that expression of E6* increased the level of reactive oxygen species (ROS) in both HPV-positive and HPV-negative cells. This increased oxidative stress led to higher levels of DNA damage, as assessed by the comet assay, quantification of 8-oxoguanine, and poly(ADP-ribose) polymerase 1. The observed increase in ROS may be due to a decrease in cellular antioxidant activity, as we found that E6* expression also led to decreased expression of superoxide dismutase isoform 2 and glutathione peroxidase."Williams - J Virol 2014 abstract / PubMed
High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins. JW Park, MK Shin, PF Lambert. Oncogene 2014 Jun 26;33(26):3383-3391. "FA deficiency specifically increased the incidence of cancers in mice expressing E7; but this effect was not observed in mice just expressing E6. We also observed that E7, but not E6, induced DNA damage as scored by induction of γ-H2AX and 53BP1 (p53 binding protein 1) nuclear foci, and this induction was heightened in FA-deficient tissue. Finally, we discovered that this induction of DNA damage responses was recapitulated in mice deficient in expression of 'pocket' proteins, pRb, p107 and p130, which are established targets of E7."Park - Oncogene 2014 abstract / PubMed
Global genomic diversity of human papillomavirus type 6 (HPV6) based on 724 isolates and 190 complete genome sequences. MM Jelen, Z Chen, BJ Kocjan, FJ Burt, PK Chan, D Chouhy, CE Combrinck, F Coutlée, C Estrade, A Ferenczy, A Fiander, EL Franco, SM Garland, AA Giri, JV González, A Gröning, K Heidrich, S Hibbitts, L Hošnjak, TN Luk, K Marinic, T Matsukura, A Neumann, A Oštrbenk, MA Picconi, H Richardson, M Sagadin, R Sahli, RY Seedat, K Seme, A Severini, JL Sinchi, J Smahelova, SN Tabrizi, R Tachezy, S Tohme, V Uloza, A Vitkauskiene, YW Wong, S Zidovec Lepej, RD Burk, M Poljak. J Virol 2014 Jul;88(13):7307-7316. "[T]wo variant lineages: A and B, and five B sublineages: B1, B2, B3, B4 and B5. HPV6 (sub)lineage-specific SNPs and a 960-bp representative region for whole-genome-based phylogenetic clustering within L2 open reading frame were identified. Multivariate logistic regression analysis revealed that lineage B predominated globally. Sublineage B3 was more common in Africa and North and South America and lineage A in Asia. Sublineages B1 and B3 were associated with anogenital infections, indicating a potential lesion-specific predilection of some HPV6 sublineages. Females had higher odds for infection with sublineage B3 than males."Jelen - J Virol 2014 abstract / PubMed
HPV16-associated tumors control myeloid cell homeostasis in lymphoid organs, generating a suppressor environment for T cells. SC Stone, RA Rossetti, A Bolpetti, E Boccardo, PS Souza, AP Lepique. J Leukoc Biol 2014 Oct;96(4):619-631. In mice. "We show evidence of constitutive activation of the IL-6/STAT3 signaling pathway in the tumor, including TAMs, and in APCs in the spleen. We also observed that IL-10 is a central molecule in the tolerance toward tumor antigens through control of NF-κB activation, costimulatory molecule expression, and T cell proliferation."Stone - J Leukoc Biol 2014 abstract / PubMed
Human Papillomavirus E6 Triggers Upregulation of the Antiviral and Cancer Genomic DNA Deaminase APOBEC3B. VC Vieira, B Leonard, EA White, GJ Starrett, NA Temiz, LD Lorenz, D Lee, MA Soares, PF Lambert, PM Howley, RS Harris. MBio 2014 Dec 23;5(6):e02234-14. "Transduction experiments showed that the E6 oncoprotein alone was sufficient to cause A3B upregulation, and a panel of high-risk E6 proteins triggered higher A3B levels than did a panel of low-risk or noncancer E6 proteins."Vieira / MBio 2014 full article
Longitudinal assessment of DNA methylation changes during HPVE6E7-induced immortalization of primary keratinocytes. DM Schütze, JM Kooter, SM Wilting, CJ Meijer, W Quint, PJ Snijders, RD Steenbergen. Epigenetics 2015 Jan 12:1-9. "A significant increase in overall methylation levels was seen with progression through each stage of immortalization. At stage 1 (pre-immortalization), a significant increase in methylation of hTERT, mir124-2, and PRDM14 was already apparent, which continued over time. Methylation of ROBO3 was significantly increased at stage 2 (early immortal), followed by CYGB (stage 3) and FAM19A4, MAL, PHACTR3, and SFRP2 (stage 4). Methylation patterns were mostly growth behavior independent. Yet, hTERT methylation levels were significantly increased in cells that just escaped from crisis. Bisulfite sequencing of hTERT confirmed increased methylation in immortal cells compared to controls, with the transcription core and known repressor sites remaining largely unmethylated."Schütze - Epigenetics 2015 abstract / PubMed
Cancer-Causing Human Papillomavirus E6 Proteins Display Major Differences in the Phospho-Regulation of their PDZ Interactions. SS Boon, V Tomaić, M Thomas, S Roberts, L Banks. J Virol 2015 Feb 1;89(3):1579-1586. "We show that, depending on the HPV type, PDZ binding activity can be regulated by phosphorylation with PKA or AKT, which in turn inhibits PDZ recognition. Such regulation is highly conserved between E6 proteins derived from HPV-16, HPV-18 and HPV-58, whilst being somewhat weaker or absent from other types such as HPV-31, 33 and 51. In the case of HPV31, PKA phosphorylation occurs within the core of the E6 protein and has no effect on PDZ interactions, and this demonstrates a surprising degree of heterogeneity amongst the different high risk HPV E6 oncoproteins in how they are regulated by different cellular signaling pathways."Boon - J Virol 2015 abstract / PubMed
Role of Cdk1 in the p53-independent abrogation of the postmitotic checkpoint by human papillomavirus E6. W Zhang, Y Liu, N Zhao, H Chen, L Qiao, W Zhao, JJ Chen. J Virol 2015 Mar;89(5):2553-2562. The HPV E6 oncoprotein up-regulates Cdk1, "attenuating the postmitotic G1-like checkpoint that can lead to polyploidy, an early event during cervical carcinogenesis that predisposes cells to aneuploidy."Zhang - J Virol 2015 abstract / PubMed
Human Papillomavirus Carcinogenesis: an Identity Crisis in the Retinoblastoma Tumor Suppressor Pathway. K Munger, DL Jones. J Virol 2015 May 1;89(9):4708-4711. "The revised model suggests that HPV E7 expression triggers a p16INK4A-mediated cellular defense response that is reminiscent of RAS oncogene-induced senescence (OIS). De novo p16INK4A expression is triggered by removal of repressive trimethyl marks on lysine 27 of histone H3 (H3K27me3) by the KDM6B histone demethylase. High-risk HPV E7 proteins have evolved to degrade RB1 to short-circuit the p16INK4A-mediated activation of RB1 tumor suppressor activity that is designed to trigger G1 cell cycle arrest and senescence (see also panel C). E7 expression also causes epigenetic derepression of the p14ARF promoter through a KDM6B-independent mechanism. As a consequence of removal of H3K27me3 repressive marks, HPV E7-expressing cells show dysregulated homeobox (HOX) gene expression, suggestive of loss of Polycomb-mediated repression and epigenetic reprogramming. HPV E7-expressing cells rapidly acquire an "addiction" to the KDM6A and KDM6B H3K27 demethylases and to p16INK4A tumor suppressor expression."Munger & Jones 2015 full article / J Virol
HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis. L Mirabello, M Yeager, K Yu, GM Clifford, Y Xiao, B Zhu, M Cullen, JF Boland, N Wentzensen, CW Nelson, T Raine-Bennett, Z Chen, S Bass, L Song, Q Yang, M Steinberg, L Burdett, M Dean, D Roberson, J Mitchell, T Lorey, S Franceschi, PE Castle, J Walker, R Zuna, AR Kreimer, DC Beachler, A Hildesheim, P Gonzalez, C Porras, RD Burk, M Schiffman. Cell 2017 Sep 7;170(6):1164-1174.e6. 5,570 HPV16-infected case-control samples. "Strikingly, E7 was devoid of variants in precancers/cancers compared to higher levels in the controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research."Mirabello - Cell 2017 abstract / PubMed
Human papillomavirus 58E7 T20I/G63S variant isolated from an East Asian population possesses high oncogenicity. SS Boon, C Xia, JY Lim, Z Chen, PTY Law, ACM Yeung, M Thomas, L Banks, PKS Chan. J Virol 2020 Mar 31;94(8). pii: e00090-20. Type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Natural variant T20I/G63S "possesses a greater ability to immortalise and transform primary cells, as well as degrading pRB more effectively than the prototype and other common variants."Boon - J Virol 2020 full article / PubMed Central
Development of a sensitive and specific assay combining
PCR and DNA microarray primer extension to detect high-risk mucosal
human papillomavirus types. T Gheit, S Landi, F Gemignani, PJ Snijders,
S Vaccarella, S Franceschi, F Canzian, M Tommasino. J Clin Microbiol
2006 Jun;44(6):2025-2031. "The importance of assays for the detection
and typing of human papillomaviruses (HPVs) in clinical and
epidemiological studies has been well demonstrated. Several accurate
methods for HPV detection and typing have been developed. However,
comparative studies showed that several assays have different
sensitivities for the detection of specific HPV types, particularly in
the case of multiple infections. Here, we describe a novel one-shot
method for the detection and typing of 19 mucosal high-risk (HR) HPV
types (types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59,
66, 68, 70, 73, and 82). This assay combines two different techniques:
multiplex PCR with HPV type-specific primers for amplification of viral
DNA and array primer extension (APEX) for typing. This novel method has
been validated with artificial mixtures of HPV DNAs and clinical
samples that were already analyzed for the presence of mucosal HPV
types by a different consensus PCR method, i.e., GP5+/GP6+. Our data
showed a very good agreement between the results from the multiplex
PCR/APEX assay and those from the GP5+/GP6+ PCR (overall rates of HPV
positivity, 63.0 and 60.9%, respectively). Whereas the GP5+/GP6+ PCR
was slightly more sensitive for the detection of HPV type 16 (HPV-16),
multiplex PCR-APEX found a higher number of infections with HPV-33,
HPV-53, and multiple HPV types."
Modified General Primer PCR System for Sensitive Detection of
Multiple Types of Oncogenic Human Papillomavirus. A
Söderlund-Strand, J Carlson, J Dillner. J Clin Microbiol 2009
Mar;47(3):541-546. "The reference method (GP5+/6+) had the desirable
high sensitivity (five copies/PCR) for five oncogenic HPV types (HPV
type 16 [HPV-16], HPV-18, HPV-56, HPV-59, and HPV-66). The MGP
[modified general primer] system was able to detect all 14 oncogenic
HPV types at five copies/PCR. In the clinical samples, the MGP system
detected a significantly higher proportion of women with more than two
concomitant HPV infections than did the GP5+/6+ system (102/592 women
compared to 42/592 women [17.2% vs 7.1%]). MGP detected a significantly
greater number of infections with HPV-16, -18, -31, -33, -35, -39, -42,
-43, -45, -51, -52, -56, -58, and -70 than did GP5+/6+."
Comparison of a Polymer-Based DNA Biochip Platform with a
PCR Followed by Reverse Hybridization for the Detection and Genotyping
of Human Papilloma Virus (HPV) in Clinical Samples. T Schenk, T
Brandstetter, A Zur Hausen, J Alt-Mörbe, D Huzly, J Rühe. J
Clin Microbiol 2009 May;47(5):1428-1435. Comparison of a new
hydrogel-based HPV genotyping biochip assay (Biochip) to a commercially
available and CE-marked conventional PCR followed by reverse
hybridization (GenID-PCR), in 123 samples (101 gynecological, 8 genital
warts, 7 otorhinolaryngeal, 5 skin warts, 2 orolabial.) "These
molecular methods for HPV genotyping showed comparable sensitivity and
specificity. However, 19/123 of the results were discrepant.
Specifically, Biochip showed better performance in the detection of
multiple infections, especially when more than one high-risk genotype
was present. Due to the different probe configurations used in the two
assays, GenID-PCR achieves only group-specific detection of many HPV
genotypes, whereas Biochip allows for specific identification."
Performance of the APTIMA high-risk HPV mRNA assay in a
population in comparison with Hybrid Capture 2 and cytology. A Clad, M
Reuschenbach, J Weinschenk, R Grote, J Rahmsdorf, N Freudenberg. J Clin
Microbiol 2011 Mar;49(3):1071-1076. The sensitivity
(specificity) of cytology, HC2, and AHPV for the detection of CIN2+ was
84.9% (66.3%), 91.3% (61.0%), and 91.7% (75.0%), and for the detection
of CIN3+ 93.9% (54.4%), 95.7% (46.0%), and 98.2% (56.3%), respectively.
Of the disease positive specimens containing high risk HPV DNA as
determined by Linear Array (Roche Diagnostics) the AHPV missed 3 CIN2
and 1 microfocal CIN3 while the HC2 test missed 6 CIN2, 4 CIN3 and 1
cervical carcinoma. The AHPV assay had a similar sensitivity, but a
significantly higher specificity (p<0.0001) than the HC2 test
the detection of CIN2+. The AHPV assay was significantly more sensitive
(p=0.0041) and significantly more specific (p=0.0163) than cytology for
the detection of disease (CIN2+)."
HPV group- and type-specific concordance in HPV infected
couples. L Giovannelli, C Bellavia, G Capra, MC Migliore, M Caleca, M
Giglio, A Perino, D Matranga, P Ammatuna. J Med Virol 2007
Dec;79(12):1882-1888. 45 sexual couples with both partners HPV
infected. "Examining individual HPV types, using samples from any male
site, concordance was found in 29 (64.4%; P = 0.036) couples;
significant concordance was evident for 16 HPV genotypes, the most
frequent being HPV-6, -66, -31, -51, and -53."
Transmission of Human Papillomavirus in Heterosexual Couples.
Hernandez, LR Wilkens, X Zhu, P Thompson, K McDuffie, YB Shvetsov, LE
Kamemoto, JK Kileen, L Ning, MT Goodman. Emerg Infect Dis 2008
Jun;14(6):888. "We examined the transmission of human papillomavirus
(HPV) in 25 heterosexual, monogamous couples (25 men, 25 women),
followed up over an average of 7.5 months. A total of 53 heterosexual
transmission events were observed among 16 couples (14 male-to-female
and 39 female-to-male). Sexual transmission involved 13 different
oncogenic and nononcogenic HPV types; 8% were vaccine-covered types
transmitted between partners. The overall rate of HPV transmission from
the penis to the cervix was 4.9/100 person-months, which was
substantially lower than that from the cervix to the penis (17.4/100
person-months). Transmission between the hands and genitals, as well as
apparent self-inoculation events (primarily in men), were also
observed. Couples who transmitted HPV were more sexually active and
used condoms less frequently." Cervical specimens were taken from the
women, and anal, oral, hand, and urine specimens from both sexes.
Concerning attempts to implicate chemical carcinogens from cigarette smoke as cofactors with HPV: "Attempts to determine the importance of cofactors utilizing in vitro models with human cells and recombinant HPV have been frustrating. In general, there is a marked contrast between the effects of a carcinogen on rodent and human cells. Whereas a number of chemical and physical viral agents are effective in transforming normal rodent cells to the malignant state, they are for the most part ineffective when applied to human cells. The same can be said for cells that have been immortalized with HPV-16 or -18. The addition of diverse chemical carcinogens to HPV-16 immortalized cells has consistently failed to induce malignancy; however, evidence of effects has been obtained as reflected by new chromosomal rearrangements." (Immortalization of keratinocytes by human papillomaviruses. CD Woodworth, JA DiPaolo. In: DNA tumor viruses. Oncogenic mechanisms. G Barbanti-Brodano, M Bendinelli, H Friedman, eds. Plenum Press, 1995, Ch 6, pp 91-109.) Author DiPaolo has been a prominent anti-smoker, and both authors are from the National Cancer Institute. And, since enormous resources are always devoted to attempting to blame chemical carcinogens from tobacco, this failure would not be due to lack of trying. Animal cancers that were blamed on chemical carcinogens in bracken ferns have turned out to be caused by HPV, which resulted from immunosuppression from the toxicity of the substances.Chemicals
Efficient repair of bulky anti-BPDE DNA adducts from
DNA strand requires functional p53 but not p21(waf1/cip1) and pRb. MA
Wani, MA El-Mahdy, FM Hamada, G Wani, Q Zhu, QE Wang, AA Wani. Mutat
Res 2002 Aug 29;505(1-2):13-25. "[T]he removal of anti-BPDE DNA adducts
from the genome overall and NTS by GGR was significantly reduced in
HPV-16E6 protein expressing cells as compared to that in normal and
HPV-16E7 protein expressing cells, indicating the role of p53 and not
pRb in nucleotide excision repair (NER)... the modulation of NER by
p53 may be independent of its function in the regulation of cell cycle
arrest upon chemically induced DNA damage."
Drug resistance argues against mutation theory of cancer. By
Sanders. Press Release, UC-Berkeley News, Jun. 26, 2007. Peter
Duesberg, professor of molecular and cell biology at the University of
California, Berkeley: "'The mutation theory of cancer says that a
limited number of genes causes cancer, so cancers should all be more or
less the same,' Duesberg said. The chromosomal theory, which he laid
out in an article in the May 2007 issue of Scientific American, implies
instead that, 'even if cancers are from the same tissue, and are
generated with the same carcinogen, they are never the same. There is
always a cytogenetic and a biochemical individuality in every cancer.'
...Duesberg proposed in 2000 that the assumption underlying most cancer
research today is wrong. That assumption, that cancer results from a
handful of genetic mutations that drive a cell into uncontrolled
growth, has failed to explain many aspects of cancer, he said, and has
led researchers down the wrong path. His alternative theory is that
cancer results from aneuploidy - that is, duplication or sometimes loss
of one or more of our 46 chromosomes, which throws thousands of genes
out of whack. This condition, generated by a defect in the mechanism
that duplicates chromosomes during cell growth, leads to more and more
chromosomal disorder as the cells divide and proliferate, disrupting
even more genes and providing ample opportunity for the development of
resistance to drugs being used to control the cancer. 'In this new
study and in one published in 2005, we have proved that only
chromosomal rearrangements, rather than mutations, can explain the high
rates and wide ranges of drug resistance in cancer cells,' he said...
'The fundamental problem these conventional theories don't address is
why it (drug resistance) doesn't happen in normal cells," he said. "Why
aren't we all getting resistant to any toxic drug we are exposed to?
Why does it happen only in cancer cells? Why do cancer cells become
resistant and the patients don't?... They see now, more and more, that
aneuploidy cannot be ignored. It is a big elephant compared to their
little mutations,' he said."
3. Studies of Animal Papillomaviruses. In: IARC Monographs on
Evaluation of Carcinogenic Risks to Humans. Volume 90, Human
Papillomaviruses, 2007.
Papillomavirus-Associated Cutaneous Neoplasia in Mammals. JS
M Kiupel. Vet Pathol 2010 Mar;47(2):254-264. Review.
Papillomavirus infection in association with feline cutaneous
squamous cell carcinoma in situ. SM LeClerc, EG Clark, DM Haines. Proc
Am Assoc Vet Derm/Am Coll Vet Derm 1997;13:125-126. As reported
in Sundberg 2000: "In a large case series of cutaneous squamous cell
carcinoma in situ in domestic cats, 30 of 63 biopsies were positive for
PV antigens. It is possible that negative tumors in this and other
studies were not associated with papillomavirus infections or that they
were intermittently productively infected, a phenomenon described for
other PV-induced lesions."
Feline papillomas and papillomaviruses. JP Sundberg, M Van
Ranst, R
Montali, BL Homer, WH Miller, PH Rowland, DW Scott, JJ England, RW
Dunstan, I Mikaelian, AB Jenson. Vet Pathol 2000 Jan;37(1):1-10.
Review. "In general, the cat lesions, like their human counterparts
[epidermodysplasia verruciformis], are planar or flat warts with the
clinical appearance of plaques. In the human lesions, those associated
with HPV-5 and HPV-8 undergo conversion to malignancy in the presence
of ultraviolet light in approximately 30% of individuals. This may be
significant because cats frequently develop basal and squamous cell
Clinical, histological and immunohistochemical study of feline
plaques and bowenoid in situ carcinomas. S Wilhelm, F Degorce-Rubiales,
D Godson, C Favrot. Vet Dermatol 2006 Dec;17(6):424-431. "Of the seven
cases in the FVP group, six were deemed positive by immunohistology as
were all 10 cats in the FVP + BISC group. On the other hand, only one
of the nine BISC cats was positive. The presence of both FVP and BISC
lesions in some cats and the high detection rate of PV antigens in the
FVP and FVP + BISC groups suggest that both conditions might have the
same viral cause and that some BISC may evolve from FVP. The low rate
of viral antigen detection in the BISC group indicates another cause or
a loss of viral replication during the cancerogenesis."
Detection of novel papillomaviruslike sequences in
specimens of invasive and in situ squamous cell carcinomas from cats. G
Nespeca, P Grest, WS Rosenkrantz, M Ackermann, C Favrot. Am J Vet Res
2006 Dec;67(12):2036-2041. "5 of 21 BISC specimens and 4 of 22 invasive
SCC specimens were positive for PV DNA on the basis of broad-range PCR
assay results. Sequence analysis revealed that only 1 specimen was
infected by a virus closely related to classic FePV. In the 8 other
specimens positive for PV DNA, DNA of unknown PVs was uncovered.
CONCLUSIONS AND CLINICAL RELEVANCE: Bowenoid in situ SCC and invasive
SCC of cats may be associated with PVs of genetic diversity."
Detection of papillomaviral sequences in feline Bowenoid in situ carcinoma using consensus primers. JS Munday, M Kiupel, AF French, L Howe, RA Squires. Vet Dermatol 2007 Aug;18(4):241-245. Papillomaviral DNA was amplified from 11 of 18 formalin-fixed samples of BISC, but no controls. "Six amplicons were sequenced; one was homologous with a papillomavirus from a human patient with multiple cutaneous squamous cell carcinomas and the other five showed weak homology to human papillomavirus type 17. These five sequences were > 96% homologous over a 235 bp sequence, indicating the presence in all five BISCs of one papillomavirus type distinct from any previously sequenced and more closely related to human than animal papillomaviruses. The results confirm an association between BISC and papillomaviruses, and as all six papillomavirus sequences identified are closely related to human papillomaviruses, it is possible that the virus is transmitted from humans to cats or vice versa."Munday - Vet Dermatol 2007 abstract / PubMed
Amplification of papillomaviral DNA sequences from a high
of feline cutaneous in situ and invasive squamous cell carcinomas using
a nested polymerase chain reaction. JS Munday, M Kiupel, AF French, L
Howe. Vet Dermatol 2008 Oct;19(5):259-263. "Papillomaviral
DNA was amplified from 20 of 20 BISC, 17 of 20 invasive SCC and 3 of 17
non-SCC controls. The rate of PV amplification from feline cutaneous
SCCs was significantly higher than from non-SCC lesions."
Clinical, histologic, and immunohistochemical analyses of
squamous cell carcinoma in situ. C Favrot, M Welle, M Heimann, DL
Godson, F Guscetti. Vet Pathol 2009 Jan;46(1):25-33. "P53
immunoreactivity was observed in 11/14 (79%) confirmed AK cases and in
4/22 (18%) BISC cases, while papillomavirus antigen was not detected in
any confirmed AK case but was detected in 11/23 (48%) BISC cases."
Detection of papillomaviral DNA sequences in a feline oral
cell carcinoma. JS Munday, L Howe, A French, RA Squires, H Sugiarto.
Res Vet Sci 2009 Apr;86(2):359-361. A papillomavirus similar to human
PV type 76 was found in 1/20 feline OSCCs.
The Nasal Mucosa Contains a Large Spectrum of Human Papillomavirus Types from the Betapapillomavirus and Gammapapillomavirus Genera. O Forslund, H Johansson, KG Madsen, K Kofoed. J Infect Dis 2013 Oct 15;208(8):1335-1341. "A putative subtype of HPV76, originally isolated from a feline oral squamous cell carcinoma, was detected in 7 nasal samples."Forslund - J Infect Dis 2013 abstract / PubMed
Felis catus papillomavirus type 2 E6 oncogene enhances mitogen-activated protein kinases and Akt activation but not EGFR expression in an in vitro feline model of viral pathogenesis. G Altamura, A Corteggio, G Borzacchiello. Vet Microbiol 2016 Nov 15;195:96-100. "The activated molecules MEK (pMEK), ERK (pERK) and Akt (pAkt) are signaling transduction effectors regulating cell proliferation and inhibition of apoptosis, which are critical steps towards tumour formation. Here, we show by Western blotting (WB) that expression of FcaPV2 E6 in feline epithelial cells enhances pMEK, pERK and pAkt levels compared to control cells."Altamura - Vet Microbiol 2016 abstract / PubMed
Detection of DNA sequences from a novel papillomavirus in a feline basal cell carcinoma. JS Munday, A French, N Thomson. Vet Dermatol 2017 Apr;28(2):236-e60. "PCR using consensus primers and primers specific for Felis catus papillomavirus types 2 and 3 (FcaPV-2 and -3) was used to amplify papillomaviral DNA. The same papillomaviral DNA sequence was present in the BCC and the BISC. This sequence was most similar to FcaPV-3, but with just 70.5% similarity, was from a novel papillomavirus type."Munday - Vet Dermatol 2017 abstract / PubMed
Localization of Felis catus Papillomavirus Type 2 E6 and E7 RNA in Feline Cutaneous Squamous Cell Carcinoma. N Hoggard, JS Munday, J Luff. Vet Pathol 2018 May;55(3):409-416. "[W]ithin the 5 SCCs, punctate signals were present within all layers of the epidermis, with progressive loss of intense nuclear signals within the superficial epidermis. This hybridization pattern is consistent with unregulated E6 and E7 transcription and decreased viral replication and is similar to the pattern observed in human papillomavirus-induced cancers as they progress from hyperplastic lesions containing productive infections to nonproductive neoplasms."Hoggard - Vet Pathol 2018 full article / PubMed Central
Detection of Felis catus papillomavirus type-2 DNA and viral gene expression suggest active infection in feline oral squamous cell carcinoma. G Altamura, G Cardeti, A Cersini, C Eleni, C Cocumelli, LE Bartolomé Del Pino, E Razzuoli, M Martano, P Maiolino, G Borzacchiello. Vet Comp Oncol 2020 Jan 28 [Epub ahead of print]. Felis catus PV type-2 viral DNA was found in 10/32 (31%) of feline oral squamous cell carcinomas by PCR.Altamura - Vet Comp Oncol 2020 abstract / PubMed
Bovine papillomavirus E5 oncoprotein binds to the activated
form of
the platelet-derived growth factor beta receptor in naturally occurring
bovine urinary bladder tumours. G Borzacchiello, V Russo, F Gentile, F
Roperto, A Venuti, L Nitsch, MS Campo, S Roperto. Oncogene 2006 Feb
23;25(8):1251-1260. "We have shown that BPV-2 DNA is present in the
majority of naturally occurring urinary bladder tumours of cattle and
that E5 is expressed in the cancer cells. Here we show that the
interaction between the platelet-derived growth factor (PDGF) beta
receptor and BPV E5, described in vitro in cultured cells, takes place
in vivo in bovine urinary bladder cancers. In these cancers, E5 and
PDGF beta receptor colocalize, as shown by confocal microscopy, and
physically interact, as shown by coimmunoprecipitation. Furthermore,
the PDGF beta receptor associated with E5 is highly phosphorylated,
suggesting the functional activation of the receptor upon E5
interaction. Our results demonstrate, for the first time, that E5-PDGF
beta receptor interaction occurs during the natural history of bovine
urinary bladder tumours, suggesting an important role for E5 in
Bovine papillomavirus type-2 DNA and expression of E5 and E7
oncoproteins in vascular tumours of the urinary bladder in cattle. G
Borzacchiello, V Russo, C Spoleto, S Roperto, I Balcos, C Rizzo, A
Venuti, F Roperto. Cancer Lett 2007 May 18;250(1):82-91. "BPV-2 is
present in 100% of the vascular tumours of the urinary bladder
examined. Twenty-six out of twenty-seven tumour samples (96%) expressed
E5 while 20 out of 27 (74%) tumour samples expressed E7. The two viral
oncoproteins were not expressed in normal endothelial cells.
Additionally, they co-localize in neoplastic endothelial cells as
demonstrated by confocal immunofluorescence. PDGFbeta receptor was also
shown to be expressed and co-localizes with E5 in neoplastic blood
Association of bovine papillomavirus type-2 and urinary
tumours in cattle from Romania. LG Balcos, G Borzacchiello, V
Russo, O Popescu, S Roperto, F Roperto. Res Vet Sci 2008
Aug;85(1):145-148. Bovine papillomavirus type 2 (BPV-2) DNA was
detected by polymerase chain reaction (PCR) in 68% of 90 urinary
bladders from slaughtered cows in an area where chronic enzootic
hematuria is endemic. E5 expression was not observed in normal mucosa.
Bovine papillomaviruses: their role in the aetiology of
tumours of bovids and equids. L Nasir, MS Campo. Vet Dermatol 2008
Oct;19(5):243-254. Review. "Cattle papillomas are benign tumours and
generally regress without eliciting any serious clinical problems in
the host, but occasionally persist and provide the focus for malignant
transformation to squamous cell carcinoma, as in the case of cancer of
the urinary bladder and cancer of the upper alimentary canal. BPV is
the only papillomavirus that jumps species: the virus also infects
equids, and gives rise to fibroblastic tumours called sarcoids.
Sarcoids very rarely regress, more often they persist and can be
locally aggressive. These tumours are the most common dermatological
tumour of equids worldwide."
Detection of bovine papillomavirus type 2 in the peripheral
blood of
cattle with urinary bladder tumours: possible biological role. S
Roperto, R Brun, F Paolini, C Urraro, V Russo, G Borzacchiello, U
Pagnini, C Raso, C Rizzo, F Roperto, A Venuti. J Gen Virol 2008
Dec;89(Pt 12):3027-3033. "Peripheral blood samples were collected from
78 cattle clinically suffering from a severe chronic enzootic
haematuria. Circulating BPV-2 DNA was detected in 61 of them and in two
blood samples from healthy cows. Fifty of the affected animals were
slaughtered at public slaughterhouses and neoplastic proliferations in
the urinary bladder were detected in all of them. BPV-2 DNA was
amplified and sequenced in 78 % of urinary bladder tumour samples and
in 38.9 % of normal samples as a control. Circulating episomal BPV-2
DNA was detected in 78.2 % of the blood samples. Simultaneous presence
of BPV-2 DNA in neoplastic bladder and blood samples was detected in 37
Association of bovine papillomavirus type 2 (BPV-2) and
bladder tumours in cattle from the Azores archipelago. AR Resendes, S
Roperto, F Trapani, C Urraro, F Roperto, G Borzacchiello. Res Vet Sci
2011 Jun;90(3):526-529. "We found a 28% incidence rate of
BPV-2 DNA in different types of tumours and cystitis cases (13 out of
46 samples). Tested positive samples for PCR were also positive for the
viral E5 oncoprotein; protein immunolabeling was mainly detected within
the cytoplasm of urothelial cells, displaying a juxtanuclear
Epithelial neoplasms of the skin, the cutaneous mucosa and the transitional epithelium in dogs: an immunolocalization study for papillomavirus antigen. K Schwegler, JH Walter, R Rudolph. Zentralbl Veterinarmed A 1997 Apr;44(2):115-123. 44.2% of 95 papillomas and 27% of 100 diagnosed squamous cell carcinomas reacted with antiserum. "Papillomavirus antigen was detectable in 54.2% of all oral and ocular papillomas and in 37.0% of all cutaneous papillomas. The majority of the squamous cell carcinomas with detectable papillomavirus antigen were considered positive but not without restrictions. The average age of dogs with viral oral and ocular papillomas was 2.3 years, with viral cutaneous papillomas it was 3.2 years. The average age of dogs with virus-positive squamous cell carcinomas was nearly 11 years. Papillomavirus-like particles were demonstrated by means of transmission electron microscopy in three positive oral papillomas, in the positive squamous cell carcinomas virion detection failed."Schwegler - Zentralbl Veterinarmed A 1997 abstract / PubMed
Detection of canine oral papillomavirus-DNA in canine oral
cell carcinomas and p53 overexpressing skin papillomas of the dog using
the polymerase chain reaction and non-radioactive in situ
hybridization. JP Teifke, CV Löhr, H Shirasawa. Vet Microbiol 1998
Feb 28;60(2-4):119-30. 29 oral and 25 non-oral squamous cell carcinomas
of dogs. Fragments of the E6, E7 and L1 gene were amplified by
polymerase chain reaction (PCR) from five of eight oral and from five
of eight cutaneous papillomas as well as from three oral squamous cell
carcinomas. "In three squamous cell carcinomas COPV-DNA was located in
nests of the epithelial tumor cells surrounding 'horn pearls' or
disseminated in the carcinoma tissue. These observations support the
view that COPV may also induce non-oral papillomas in the dog and
confirm the opinion that a progression of viral papillomas into
carcinomas in dogs may occur."
Detection of novel papillomaviruses in canine mucosal,
cutaneous and
in situ squamous cell carcinomas. N Zaugg, G Nespeca, B Hauser, M
Ackermann, C Favrot. Vet Dermatol 2005 Oct;16(5):290-298. "While
approximately 100 human PVs are known, only one single canine oral PV
(COPV) has been identified and studied extensively. Therefore, we
applied a narrow-range polymerase chain reaction (PCR) suitable for the
detection of classical canine and feline PVs, as well as a broad-range
PCR, which has been used for the detection of various novel PVs in
humans, in order to analyse 42 paraffin-embedded samples, representing
three different forms of canine SCCs. Ten samples of skin tissues with
various non-neoplastic conditions served as controls. While none of the
negative controls reacted positively, PV DNA was discovered in 21% of
the tested SCC samples. Interestingly, the classical COPV was amplified
from only one sample, while the other positive cases were associated
with a variety of thus far unknown PVs. This study suggests that a
fraction of canine SCC is infected with PVs and that a genetic variety
of canine PVs exists."
An epidermotropic canine papillomavirus with malignant
contains an E5 gene and establishes a unique genus. H Yuan, S Ghim, J
Newsome, T Apolinario, V Olcese, M Martin, H Delius, P Felsburg, B
Jenson, R Schlegel. Virology 2007 Mar 1;359(1):28-36. "CfPV-2
establishes a new PV genus, with its closest phylogenetic relatives
being amongst the Xi and Gamma genuses. CfPV-2 also has unique
biological features; it induces papillomas on footpads and interdigital
regions which, if infection is persistent, can progress to highly
metastatic squamous cell carcinoma. CfPV-2 does not induce oral
papillomas in immunocompetent animals and antibodies generated against
COPV and CfPV-2 are type-specific."
A retrospective investigation on canine papillomavirus 1 (CPV1) in oral oncogenesis reveals dogs are not a suitable animal model for high-risk HPV-induced oral cancer. I Porcellato, C Brachelente, G Guelfi, A Reginato, M Sforna, L Bongiovanni, L Mechelli. PLoS One 2014 Nov 17;9(11):e112833. "In 3/33 (10%) SCCs, viral DNA was demonstrated but no viral RNA could be found. No positivity was observed both with immunohistochemistry and Real-Time PCR in the other hyperplastic and neoplastic lesions of the oral cavity of dogs."Porcellato - PLoS One 2014 full article / PubMed Central
Molecular and immunohistochemical studies do not support a role for papillomaviruses in canine oral squamous cell carcinoma development. JS Munday, A French, CJ Harvey. Vet J 2015 May;204(2):223-225. 0/28 canine OSCCs were positive by PCR.Munday - Vet J 2015 abstract / PubMed
Genomic characterisation of canine papillomavirus type 17, a possible rare cause of canine oral squamous cell carcinoma. JS Munday, M Dunowska, RE Laurie, S Hills. Vet Microbiol 2016;182:135-140. "Phylogenetic analysis of ORF L1 revealed greater than 70% similarity to CPV-2 and CPV-7 and we propose that CPV-17 also be classified as a Taupapillomavirus 1."Munday - Vet Microbiol 2016 abstract / PubMed
Evaluation of equine papillomas, aural plaques, and sarcoids
for the
presence of Equine papillomavirus DNA and Papillomavirus antigen. RC
Postey, GD Appleyard, BA Kidney. Can J Vet Res 2007 Jan;71(1):28-33.
"With IHC testing, 23 of 38 papillomas, 4 of 9 aural plaques, and 0 of
10 sarcoids were positive for PV antigen; EPV DNA was found in 20 of
the 38 papillomas and 1 of the 10 sarcoids but 0 of the 9 aural
High prevalence of bovine papillomaviral DNA in the normal
skin of
equine sarcoid-affected and healthy horses. L Bogaert, A Martens, M Van
Poucke, R Ducatelle, H De Cock, J Dewulf, C De Baere, L Peelman, F
Gasthuys. Vet Microbiol 2008 May 25;129(1-2):58-68. "BPV DNA was found
in the normal skin of 24 of 42 horses (57%). Mainly sarcoid-affected
horses and horses living in contact with cattle were carriers (73%),
but BPV DNA was also detected in 50% of the horses living in contact
with sarcoid-affected horses and in 30% of the control population. BPV
mRNA was detected in 58% of the samples positive for BPV DNA, although
in a much lower quantity compared to sarcoids."
Bovine papillomaviruses: their role in the aetiology of
tumours of bovids and equids. L Nasir, MS Campo. Vet Dermatol 2008
Oct;19(5):243-254. Review. "Cattle papillomas are benign tumours and
generally regress without eliciting any serious clinical problems in
the host, but occasionally persist and provide the focus for malignant
transformation to squamous cell carcinoma, as in the case of cancer of
the urinary bladder and cancer of the upper alimentary canal. BPV is
the only papillomavirus that jumps species: the virus also infects
equids, and gives rise to fibroblastic tumours called sarcoids.
Sarcoids very rarely regress, more often they persist and can be
locally aggressive. These tumours are the most common dermatological
tumour of equids worldwide."
Expression of platelet-derived growth factor-beta receptor and
bovine papillomavirus E5 and E7 oncoproteins in equine sarcoid. G
Borzacchiello, V Russo, L Della Salda, S Roperto, F Roperto. J Comp
Pathol 2008 Nov;139(4):231-237. "BPV DNA was demonstrated in 12/15
tumours collected from different areas of Italy. Nine of these 12
tumours expressed the BPV oncoproteins E5 and E7, but these
oncoproteins were not expressed by normal equine cells."
Detection of bovine papillomavirus DNA in sarcoid-affected and
healthy free-roaming zebra (Equus zebra) populations in South Africa. E
van Dyk, MC Oosthuizen, AM Bosman, PJ Nel, D Zimmerman, EH Venter. J
Virol Methods 2009 Jun;158(1-2):141-151. "BPV-1 and -2 DNA (either
single or mixed infections) are present in sarcoid tumour, healthy skin
and blood of sarcoid-affected and healthy zebras from sarcoid-affected
parks as well as in the blood of zebras from parks where no sarcoid has
been observed before."
BPV-1 infection is not confined to the dermis but also
involves the
epidermis of equine sarcoids. S Brandt, R Tober, A Corteggio, S Burger,
S Sabitzer, I Walter, C Kainzbauer, R Steinborn, L Nasir, G
Borzacchiello. Vet Microbiol 2011 May 12;150(1-2):35-40. "BPV-1
DNA was demonstrated in all sarcoid epidermis samples, with viral DNA
loads ranging between 2 and 195copies/cell. Identical BPV-1 E5 genes
were identified in epidermis and dermis of each of two sarcoids, yet
different E5 variants were found in individual lesions. IHC/IF revealed
the presence of E5 and E7 protein in sarcoid epidermis, and L1
capsomers in the squamous layer of one lesion."
Bovine papillomavirus type 1 and Equus caballus papillomavirus 2 in equine squamous cell carcinoma of the head and neck in a Connemara mare. C Kainzbauer, J Rushton, R Tober, T Scase, B Nell, S Sykora, S Brandt. Equine Vet J 2012 Jan;44(1):112-115. "Whereas PBMCs from 2008 scored negative, EcPV-2 DNA was present in PBMCs and SCCs from 2010. Furthermore, reverse transcription PCR revealed EcPV-2 E6 transcripts in these samples. BPV-1/2 DNA, but not RNA, was demonstrated in the periorbital/parotideal mass, the SCC of the jugular groove, vulval mucosa and intact skin, but not in the pharyngeal SCC and PBMCs."Kainzbauer - Equine Vet J 2012 abstract / PubMed
Bovine papillomavirus type 13 DNA in equine sarcoids. M Lunardi, BK de Alcântara, RA Otonel, WB Rodrigues, AF Alfieri, AA Alfieri. J Clin Microbiol 2013 Jul;51(7):2167-2171. 2 horses. "The FAP59/FAP64, MY09/MY11, and AR-E1F2/AR-E1R4 sequences generated from the sarcoids were shown to present 99 to 100% identity with bovine papillomavirus 13, a new bovine papillomavirus type previously described in cattle."Lunardi - J Clin Microbiol 2013 abstract / PubMed
Equine papillomavirus type 2: An equine equivalent to human papillomavirus 16? S Sykora, C Jindra, M Hofer, R Steinborn, S Brandt. Vet J 2017 Jul;225:3-8. "Four of 15 HSCC tested positive for EcPV2 DNA and harboured known or novel genetic variants of E6, E7, E2 and the LCR."Sykora - Vet J 2017 abstract / PubMed
Presence of a novel hamster oral papillomavirus in dysplastic
lesions of hamster lingual mucosa induced by application of
dimethylbenzanthracene and excisional wounding: molecular cloning and
complete nucleotide sequence. T Iwasaki, H Maeda, Y Kameyama, M
Moriyama, S Kanai, T Kurata. J Gen Virol 1997 May;78 ( Pt 5):1087-1093.
"All dysplastic lesions induced by this combination of DMBA application
and excisional wounding contained viral DNA. Although Southern blot
hybridization analysis could not detect the HOPV genome, PCR analysis
demonstrated the latent
HOPV genome in the tongue and skin of an untreated hamster. These
results suggest that latently present HOPV genome is reactivated by the
DMBA/wounding procedures." Viral particles resembling papillomavirus
were detected in the nuclei as far back as 1986.
DNA vaccine against hamster oral papillomavirus-associated
cancer. H Maeda, K Kubo, Y Sugita, Y Miyamoto, S Komatsu, S Takeuchi, T
Umebayashi, S Morikawa, K Kawanishi, Y Kameyama. J Int Med Res 2005
Nov-Dec;33(6):647-653. "Previously we developed a carcinogenesis model
involving the combination of 9,10-dimethyl-1,2-benzanthracene (DMBA)
application with physical wounding of hamster lingual mucosa. The
presence of a novel hamster oral papillomavirus (HOPV) was demonstrated
and its genome sequenced... All control hamsters developed lingual
carcinoma, whereas 12 of the L1-vaccinated hamsters showed no lesions."
There were 20 vaccinated and 20 control animals.
Cloning and characterization of a papillomavirus associated
papillomas and carcinomas in the European harvest mouse (Micromys
minutus). MK O'Banion, ME Reichmann, JP Sundberg. J Virol 1988
Jan;62(1):226-233. "All 17 tumors examined contained large amounts of
viral DNA in a supercoiled, unintegrated form as revealed by Southern
blot hybridization. Furthermore, many extracts (25 of 35) from normal
organs and skin of individuals with lesions elsewhere on their bodies
contained viral DNA." "[H]igh copy numbers and the presence of viral
antigens indicate that productive infection was occurring in many of
these tissues. Although insufficient sample numbers preclude a final
conclusion, the observations that no viral antigens were detected in
two sebaceous carcinomas and that the viral DNA copy number was low
(100 copies) in the one carcinoma examined
suggest that productive infection was not occurring in these lesions."
Viral DNAs were also detected in many apparently normal tissues from
affected individuals.
Rodent Papillomaviruses. A Uberoi, PF Lambert. Viruses 2017 Nov 27;9(12):E362. Review.Uberoi & Lambert / Viruses 2017 full article
Mouse papillomavirus infections spread to cutaneous sites with progression to malignancy. NM Cladel, LR Budgeon, TK Cooper, KK Balogh, ND Christensen, R Myers, V Majerciak, D Gotte, ZM Zheng, J Hu. Gen Virol 2017 Oct;98(10):2520-2529.Cladel - Gen Virol 2017 full article / PubMed Central
Mouse papillomavirus infection persists in mucosal tissues of an immunocompetent mouse strain and progresses to cancer. NM Cladel, LR Budgeon, KK Balogh, TK Cooper, SA Brendle, ND Christensen, TD Schell, J Hu. Sci Rep 2017 Dec 5;7(1):16932.Cladel - Sci Rep 2017 full article / PubMed Central
A transactivator function of cottontail rabbit papillomavirus
e2 is
essential for tumor induction in rabbits. S Jeckel, E Huber, F
Stubenrauch, T Iftner. J Virol 2002 Nov;76(22):11209-11215. "In
contrast to the productive virus infection observed in the cottontail
rabbit, which is the natural host, infection of New Zealand White
rabbits with CRPV causes an abortive infection. As many as 80% of the
initially benign epithelial tumors progress to carcinomas within the
next 6 to 14 months, and these finally metastasize without the need for
Cutaneous papillomavirus E6 proteins must interact with p300
block p53-mediated apoptosis for cellular immortalization and
tumorigenesis. P Muench, S Probst, J Schuetz, N Leiprecht, M Busch, S
Wesselborg, F Stubenrauch, T Iftner. Cancer Res 2010 Sep
1;70(17):6913-6924. "[T]he cottontail rabbit papillomavirus (CRPV)
rapidly induces skin cancer without additional cofactors, and CRPVE6
and E7 immortalize rabbit keratinocytes in vitro. However, CRPVE6
neither interacts with E6AP and p53 nor does it induce p53
degradation... In this study, we show that the interaction of CRPVE6,
or HPV38E6, with the histone acetyltransferase p300 is crucial to
inhibit the ability of p53 to induce apoptosis."
The Mastomys natalensis papillomavirus: nucleotide sequence,
organization, and phylogenetic relationship of a rodent papillomavirus
involved in tumorigenesis of cutaneous epithelia. CH Tan, R Tachezy, M
Van Ranst, SY Chan, HU Bernard, RD Burk. Virology 1994
Feb;198(2):534-541. "Mastomys natalensis is a rodent of African origin
afflicted with a very high incidence of skin tumors (keratoacanthomas
and squamous carcinomas), which are associated with a papillomavirus,
M. natalensis papillomavirus (MnPV)." It is similar to several HPV
types that are associated with epidermodysplasia verruciformis.
cast 05-09-20


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Manchester Athletic Club recently updated our fitness floor with improved, more functional equipment. Watch the transformation!
Informational sessions will be held to help our members familiarize themselves with the new equipment and make sure they are still getting the workout they are looking for. Ask for schedule of sessions or request a personal demonstration

subset: commoncrawl


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You're Invited to Celebrate Our 70th
on July 16, 2017!
While registration is now closed – you can still sponsor our event!
To see our current list of sponsors, click here!
To be added to our Wait List for the 70th, register below.
Add Your Name to the Wait List
Whether you went to Camp Saratoga, Camp Swig or Camp Newman, Camp has been a magical home to tens of thousands of campers, faculty and staff for decades. Come celebrate our anniversary as one community on Sunday, July 16, 2017, from 2pm-7:30pm, at URJ Camp Newman! For the schedule of events, click here.
In the 70 years since our first west coast Jewish camp was established and in the 20 years since Camp Newman began, we have shared unforgettable moments, made precious friendships, and started new traditions that continue to this day.
We hope you can join us for this special event to commemorate seven decades of Jewish camping, and to recognize and honor the camp alumni who have impacted our lives.
Who is honored? One who honors others. – Pirkei Avot
A Special Invitation from Rabbi Rick Jacobs…
Festivities to include:
- time to reconnect with your camp friends and community
- special song sessions with past song leaders
- a BBQ & beer garden
- a special art project
- favorite camp activities
- CIT reunions for 10 year, 20 year, 30 year classes
- and more…
For the full schedule, click here.
If you plan to stay overnight in our region, accommodations sell out far in advance. For a list of local places, see our resource – Your Guide to Our Region.
Help Us Spread the Word
Let your fellow alumni know about the event! "Like" and "share" our posts on our Facebook and Alumni pages. Post that you're attending on Facebook, Instagram or Twitter!


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Are you still one of the many doctors or patients who worry that statins hurt the liver? As posted here 9 months ago, this concern is nonsense.
And now the Food and Drug Administration (FDA) finally had the courage to state so.
The FDA stated in a recent safety announcement: "the available scientific evidence does not support the routine monitoring of liver biochemistries in asymptomatic patients receiving statins … because (1) irreversible liver damage resulting from statins is exceptionally rare and is likely idiosyncratic in nature, and (2) no data exist to show that routine periodic monitoring of liver biochemistries is effective in identifying the very rare individual who may develop significant liver injury from ongoing statin therapy."
In other words, there is no need to be worried that statins hurt the liver and there is no need to do routine blood tests to check for liver damage from statins.
There is actually no good evidence that statins cause liver damage.
And for years, there was no good evidence that any of the statins hurt the liver.
How much harm and untold anxiety were caused by the previous FDA requirement to monitor liver tests in people on statins?
How many people had their statin stopped inappropriately and suffered a cardiovascular event because blood tests worried the doctor that the statin hurt the liver?
How much time and money were wasted on making patients go for unnecessary blood tests to monitor their liver?
Look, I admit knowledge is not fixed. We learn over time.
New evidence becomes available.
But our regulatory authorities seem very predisposed to send out scary warnings and alerts about dubious harms. Of course, in so doing, they cannot be blamed because of failure to warn. They "cover" themselves.
But there is real harm caused when these authorities scare people unnecessarily or when they fail to withdraw warnings, cautions or alerts that are no longer supported by the evidence.
Similar considerations and politics affect FDA drug approvals.
For now, as pointed out here last year, if you have been prescribed a statin there is no worry it may hurt your liver.
Check back soon for more evidence based updates, not influenced by politics.


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Atletico Madrid have hired Abel Resino as coach to replace Javier Aguirre, who stepped down after agreeing to end his contract, the Primera Liga club's president Enrique Cerezo said on Tuesday.
Cerezo said in an interview with Cadena Ser radio that the club had reached an agreement with former Atletico goalkeeper Resino, who is coach of second division Castellon.
"We have chosen Abel because we believe he is the right solution for the current situation," Cerezo said.
Atletico have not won a match this year and slipped to seventh in the standings after a 2-1 home defeat by Real Valladolid on Sunday.
The 49-year-old Resino also had brief spells as coach of Levante and Ciudad de Murcia, and takes charge just over three weeks before the first leg of the club's Champions League last 16 tie against Porto.
Earlier on Tuesday, Aguirre said he had stepped down after agreeing with Cerezo to end his two-and-a-half year term as coach.
"We have reached a good agreement," the Mexican told Cadena Ser. "I am the first to understand that I am a fundamental part of the problem the team finds itself in.
"We are adults, it doesn't matter. It's the easiest for everyone and the least traumatic."
Aguirre joined the Madrid side from Osasuna in 2006 and became the first coach since they returned to the top flight in 2002 to last more than one campaign.
The former Mexico coach steered the club into the Champions League with a fourth-placed finish last term, their first appearance in the competition since the 1996-7 season.
Feb 3, 2009
Sport - Football;Atletico hire Resino as coach to replace Aguirre
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Careers Exhibition
Meet leading employers
& training providers
Proudly supported by
Supercharge your skills & jumpstart your career!
Brent Civic Centre BRENT CIVIC CENTRE, ENGINEERS WAY, WEMBLEY, HA9 0FJ
19th March
3pm - 7pm
London is one of the world's leading cities for technology, entrepreneurship and digital creativity. Over 1.25 million people work in technology-related industries in London but the demand for digital skills is constantly increasing. On 19th MARCH, Techmix is hosting Brent Careers Exhibition at Brent Civic Centre, Engineers Way, Wembley, HA9 0FJ.
Come along to meet top local and national employers and learn about careers in their companies. Find out about apprenticeships on offer and discover courses from local training providers that can help you get your dream job. Bring your CV and your best self and discover new opportunities in your area!
This event is focussed on careers in the Digital, Creative and Technology sectors and is hosted in partnership with Brent Local Council.
Before the event, teams of young, talented tech entrepreneurs will be pitching their ideas for the high street of the future. Coming from different schools, colleges and career paths, these teams will face a judging panel of local residents, top employers and council leaders to find the best idea in the borough. Come along to find out about their ideas and vote for the idea you support.


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|Website logo ideas. It was a tough call.
|Thumbnail for berserker.
|Three adventurers.
|Two chicks hangin' out.
|Some amazon attempts.
|Some sketches for a painting I've yet to start. Plus Santa.
|A couple of landscapes from my head.
|Spear dude.
|Working out a pose & costume for a painting.
|Tree sketch from last summer up the mountain from Woodstock.
|Some folks.
|My son's work, actually.
|My daughter checking out the snow.


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Will MS go down the Apple road?
..of only allowing reinstallation of the OS from the cloud? That way they can make a 'clean' <ahem> image available to all who have an activated legit OS installed. Big draw back: they pay for the hosting infrastructure and if your line in the boondocks is too slow you'll never get the image (Oh yeah, trying reinstalling OS X over the web on less than 2Mbps and see you connection disappear into a black hole somewhere in the US)
Why stop there? When your data is on One Drive and your use Office online (or whatever it is called this week) all you need is a browser. Oh yes, that's the Surface / Windease phone isn't it?


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House Always Wins?
This story appears in the March 2006 issue of Entrepreneur. Subscribe »
There are two schools of thought on last year's 12.02 percent rise in home prices: Either it means the market is healthy and mortgage rates are low enough that homes remain in high demand, or it means home prices are inflated and buyers cannot continue to support such increases.
The uncertainty of whether a housing bubble even exists leaves many entrepreneurs hanging in the balance while they wait to see how changes in the real estate market might affect the economy and their businesses. To help sort out the dilemma are Bill Fleckenstein, president of Fleckenstein Capital in Issaquah, Washington, and author of the "Market Rap" column at www.fleckensteincapital.com, and James F. Smith, chief economist with Parsec Financial and a University of North Carolina, Chapel Hill, finance professor.
Entrepreneur: What do you think of the current housing bubble, and what are its implications?
James F. Smith: If [you think] it means prices rising at an unsustainable rate, then true, prices will not continue to grow at double-digit rates, but they will continue to rise. If you think it means the demand for houses will collapse, you're absolutely crazy. There is no housing bubble.
Bill Fleckenstein: Inflated housing prices are not what created the real estate bubble. It was lending standards that allowed people to finance homes they could not afford. Never before have lending standards dropped so low to allow no down payment and 100 percent financing. In addition, the serial extraction of equity via home equity loans has allowed people to live beyond their means. It's the financing mania that will cause grief [to entrepreneurs]. That is what has made this cycle so dangerous.
Entrepreneur: Will the market soften?
Smith: The national average home ownership rate was 68.8 percent as of third quarter 2005. Homeownership rises steadily-past 83 percent-until the age of 75, and 77 million baby boomers are just approaching age 60, so [the market impact] hasn't peaked.
Fleckenstein: There will be a nasty fall in the real estate market. If the average consumer is tapped out, then my contention is they are going to cut back on their spending, and most businesses will be nega-tively affected. That is going to [cause] a recession.
Entrepreneur: What do you think entrepreneurs should be doing now?
Smith: If you want to be in a business that's likely to be very good for a very long time, then do anything you can think of related to housing. There is plenty of opportunity. Remember, in Florida they are still trying to rebuild everything that was destroyed from Hurricane Ivan, so I imagine that Wilma, Katrina and Rita will generate lots of income for some time to come.
Fleckenstein: What entrepreneurs need to understand is that people who were using their homes as ATMs will no longer be able to do so. When our real estate bubble bursts, we'll be left with a financial system riddled with bad loans and consumers who owe more on their homes than they're worth. This will not be good for business, and entrepreneurs need to figure out what that means to them and the industries they're in.


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Tealady preserves and pickles are handmade in Norfolk, where sweeping fields, unspoilt beaches and dramatic sunsets in huge open skies are the norm. And it is the natural rhythms of this glorious setting that inspire the ethos of TheTealady – buying and gathering fruit and vegetables in season to make simple, tasty products that are full of robust countryside flavours. Using traditional methods, we hand-cut and hand-stir every batch to reflect a truly homemade product for you to enjoy.
Our delicious handmade jams, jellies, marmalades and chutneys are, primarily made from locally sourced ingredients, in small batches in the heart of Breckland, creating a unique range of products which we're sure you'll enjoy. Of course, we sometimes need ingredients from further afield e.g. citrus and cranberries, we always buy from trusted local businesses so we are able to ensure we're using the freshest quality ingredients.
If you're looking for something different, or you've bought from us before and you'd like something not listed in our online shop, then please do contact us
A selection of our homemade jams, chutneys and marmalades are stocked by a growing number of local retailers including those on our Stockists page and of course, you can buy from our stand at one of the many events we enjoy visiting throughout the year. Find out where we'll be here. We look forward to serving you very soon!
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Handmade in Norfolk. Sweeping fields, unspoilt beaches and sunsets in huge open skies inspire simple, tasty jars packed with countryside flavour.