scholarly journals Downregulation of Cdc2/CDK1 Kinase Activity Induces the Synthesis of Noninfectious Human Papillomavirus Type 31b Virions in Organotypic Tissues Exposed to Benzo[a]pyrene

2010 ◽  
Vol 84 (9) ◽  
pp. 4630-4645 ◽  
Author(s):  
Samina Alam ◽  
Brian S. Bowser ◽  
Michael J. Conway ◽  
Mohd Israr ◽  
Eric J. Ryndock ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Specific Inhibitor ◽  
Cell Interaction ◽  
Epidemiological Studies ◽  
Cyclin Dependent Kinase ◽  
Hpv Status ◽  
Increased Risk ◽  
Control Virus

ABSTRACT Epidemiological studies suggest that human papillomavirus (HPV)-infected women who smoke face an increased risk for developing cervical cancer. We have previously reported that exposure of HPV-positive organotypic cultures to benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, resulted in enhanced viral titers. Since BaP is known to deregulate multiple pathways of cellular proliferation, enhanced virion synthesis could result from carcinogen/host cell interaction. Here, we report that BaP-mediated upregulation of virus synthesis is correlated to an altered balance between cell cycle-specific cyclin-dependent kinase (CDK) activity profile compared with controls. Specifically, BaP treatment increased accumulation of hyperphosphorylated retinoblastoma protein (pRb) which coincided with increased cdc2/CDK1 kinase activity, but which further conflicted with the simultaneous upregulation of CDK inhibitors p16INK4 and p27KIP1, which normally mediate pRb hypophosphorylation. In contrast, p21WAF1 and p53 levels remained unchanged. Under these conditions, CDK6 and CDK2 kinase activities were decreased, whereas CDK4 kinase activity remained unchanged. The addition of purvalanol A, a specific inhibitor of CDK1 kinase, to BaP-treated cultures, resulted in the production of noninfectious HPV type 31b (HPV31b) particles. In contrast, infectivity of control virus was unaffected by purvalanol A treatment. BaP targeting of CDK1 occurred independently of HPV status, since BaP treatment also increased CDK1 activity in tissues derived from primary keratinocytes. Our data indicate that HPV31b virions synthesized in the presence of BaP were dependent on BaP-mediated alteration in CDK1 kinase activity for maintaining their infectivity.

Meta-analysis of the impact of human papillomavirus on cancer risk and overall survival in head and neck squamous cell carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6080-6080
Author(s):  
F. Dayyani ◽  
C. Etzel ◽  
M. Liu ◽  
C. Ho ◽  
S. M. Lippman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Human Papillomavirus ◽  
Meta Analysis ◽  
Local Therapy ◽  
Forest Plot ◽  
Etiologic Factor ◽  
Hpv Dna ◽  
Hpv Status ◽  
Increased Risk ◽  
The Impact

6080 Background: Human papillomavirus (HPV) is an important etiologic factor in HNSCC and its prevalence has been reported in several independent studies. We conducted a meta-analysis to determine the prevalence of HPV, its impact on risk of developing HNSCC and overall survival (OS). Methods: Pubmed search terms “HPV” and “HNSCC” were used to identify 40 clinical and translational studies between the years 1980–2008 that reported the prevalence of HPV in HNSCC. Statistical software STATA 10.0 was used in the meta-analyses to identify the association of HPV and HNSCC risk and OS. Pooled adjusted odds ratio (OR) or hazard ratio (HR) were obtained using a random-effects model. The amount of heterogeneity between studies was estimated with both the Chi-squared based Q test and the I2 statistic model. Potential sources of publication bias were detected using funnel plots. OS between the trials was compared in forest plot. Results: A total of 6,794 patients (pts) were included. The prevalence of HPV among HNSCC pts was 24.2%; and 86.8% of all HPV(+) tumors were HPV16. Thirteen studies (n = 1933 pts) determined HPV status by serology and the remainder detected HPV DNA in tumor tissue by PCR. Overall, HPV positivity conferred an increased risk for HNSCC (OR = 1.43; 95% CI 1.04–1.82). Risk for HNSCC among HPV16(+) pts was 4.47 times that of HPV16(-) pts. The OS was improved in HPV(+) pts compared to HPV(-) pts (HR = 0.40; 0.27–0.53). In HPV16(+) pts the HR for OS was 0.41 and the survival benefit was even more pronounced in the subgroup of HPV16(+) oropharyngeal cancers (HR = 0.38;0.17–0.58). Conclusions: This meta-analysis provides further evidence supporting the role of HPV as an important causative agent in HNSCC and supports HPV(+) HNSCC as a separate biologic entity which likely should be treated differently than HPV(-) HNSCC. Additional analysis on treatment outcomes to systemic and local therapy is ongoing. No significant financial relationships to disclose.

scholarly journals E2f1, E2f2, and E2f3 Control E2F Target Expression and Cellular Proliferation via a p53-Dependent Negative Feedback Loop

2007 ◽  
Vol 27 (1) ◽  
pp. 65-78 ◽  
Author(s):  
Cynthia Timmers ◽  
Nidhi Sharma ◽  
Rene Opavsky ◽  
Baidehi Maiti ◽  
Lizhao Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Cyclin Dependent Kinase ◽  
Control Of Gene Expression ◽  
Target Gene Expression ◽  
Rb Phosphorylation ◽  
P53 Target Genes

ABSTRACT E2F-mediated control of gene expression is believed to have an essential role in the control of cellular proliferation. Using a conditional gene-targeting approach, we show that the targeted disruption of the entire E2F activator subclass composed of E2f1, E2f2, and E2f3 in mouse embryonic fibroblasts leads to the activation of p53 and the induction of p53 target genes, including p21 CIP1 . Consequently, cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation are dramatically inhibited, leading to Rb/E2F-mediated repression of E2F target gene expression and a severe block in cellular proliferation. Inactivation of p53 in E2f1-, E2f2-, and E2f3-deficient cells, either by spontaneous mutation or by conditional gene ablation, prevented the induction of p21 CIP1 and many other p53 target genes. As a result, cyclin-dependent kinase activity, Rb phosphorylation, and E2F target gene expression were restored to nearly normal levels, rendering cells responsive to normal growth signals. These findings suggest that a critical function of the E2F1, E2F2, and E2F3 activators is in the control of a p53-dependent axis that indirectly regulates E2F-mediated transcriptional repression and cellular proliferation.

scholarly journals Direct Activation of Cyclin-Dependent Kinase 2 by Human Papillomavirus E7

2003 ◽  
Vol 77 (19) ◽  
pp. 10566-10574 ◽  
Author(s):  
Wanxia He ◽  
Doug Staples ◽  
Clark Smith ◽  
Chris Fisher
Keyword(s):  
Human Papillomavirus ◽  
Kinase Activity ◽  
Cyclin A ◽  
Cross Linking ◽  
Amino Acid Residues ◽  
Cyclin Dependent Kinase ◽  
Major Activity ◽  
Hpv E7 ◽  
Cdk2 Activity ◽  
High Risk Hpv

ABSTRACT Addition of human papillomavirus (HPV) E7 CDK2/cyclin A or CDK2/cyclin E, purified from either insect cells or bacteria, dramatically upregulates histone H1 kinase activity. Activation is substrate specific, with a smaller effect noted for retinoblastoma protein (Rb). The CDK2 stimulatory activity is equivalent in high-risk (HPV type 16 [HPV16] and HPV31) and low-risk (HPV6b) E7. Mutational analyses of HPV16 E7 indicate that the major activity resides in amino acids 9 to 38, spanning CR1 and CR2, and does not require casein kinase II or Rb-binding domain functions. Synthetic peptides spanning HPV16 amino acid residues 9 to 38 also activate CDK2. Peptides containing this sequence that carry biotin on the carboxy terminus, as well as a photoactivated cross-linking group (benzophenone), also activate the complex and covalently associate with the CDK2/cyclin A complex in a specific manner requiring UV. Cross-linking studies that use protein monomers detect association of the E7 peptides with cyclin A but not CDK2. Together, our results indicate a novel mechanism whereby E7 promotes HPV replication by directly altering CDK2 activity and substrate specificity.

scholarly journals Is Human Papillomavirus Associated with Prostate Cancer Survival?

2013 ◽  
Vol 35 ◽  
pp. 607-613 ◽  
Author(s):  
Mariarosa Pascale ◽  
Danae Pracella ◽  
Renzo Barbazza ◽  
Barbara Marongiu ◽  
Enrico Roggero ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Human Papillomavirus ◽  
Dna Analysis ◽  
Positive Association ◽  
Hpv Infection ◽  
Prognostic Impact ◽  
Prostate Carcinogenesis ◽  
Hpv Status ◽  
Increased Risk

The role of human papillomavirus (HPV) in prostate carcinogenesis is highly controversial: some studies suggest a positive association between HPV infection and an increased risk of prostate cancer (PCa), whereas others do not reveal any correlation. In this study, we investigated the prognostic impact of HPV infection on survival in 150 primary PCa patients. One hundred twelve (74.67%) patients had positive expression of HPV E7 protein, which was evaluated in tumour tissue by immunohistochemistry. DNA analysis on a subset of cases confirmed HPV infection and revealed the presence of genotype 16. In Kaplan-Meier analysis, HPV-positive cancer patients showed worse overall survival (OS) (median 4.59 years) compared to HPV-negative (median 8.24 years,P=0.0381). In multivariate analysis age (P<0.001), Gleason score (P<0.001), nuclear grading (P=0.002), and HPV status (P=0.034) were independent prognostic factors for OS. In our cohort, we observed high prevalence of HPV nuclear E7 oncoprotein and an association between HPV infection and PCa survival. In the debate about the oncogenic activity of HPV in PCa, our results further confirm the need for additional studies to clarify the possible role of HPV in prostate carcinogenesis.

scholarly journals Cyclin-Dependent Kinase Activity Is Required at Early Times for Accurate Processing and Accumulation of the Human Cytomegalovirus UL122-123 and UL37 Immediate-Early Transcripts and at Later Times for Virus Production

2004 ◽  
Vol 78 (20) ◽  
pp. 11219-11232 ◽  
Author(s):  
Veronica Sanchez ◽  
Anita K. McElroy ◽  
Judy Yen ◽  
Sama Tamrakar ◽  
Charles L. Clark ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Viral Replication ◽  
Human Cytomegalovirus ◽  
Kinase Activity ◽  
Hcmv Infection ◽  
Specific Inhibitor ◽  
Early Gene ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases

ABSTRACT Human cytomegalovirus (HCMV) infection leads to dysregulation of multiple cell cycle-regulatory proteins. In this study, we examined the effects of inhibition of cyclin-dependent kinase (cdk) activity on viral replication. With the drug Roscovitine, a specific inhibitor of cyclin-dependent kinases 1, 2, 5, 7, and 9, we have shown that during the first 6 h of infection, cyclin-dependent kinase-dependent events occurred that included the regulated processing and accumulation of the immediate-early (IE) UL122-123 transcripts and UL36-37 transcripts. Altered processing of UL122-123 led to a loss of IE1-72 and an increase in IE2-86. The ratio of spliced to unspliced UL37 transcripts also changed. These effects did not require de novo protein synthesis or degradation of proteins by the proteasome. Addition of Roscovitine at the beginning of the infection was also associated with inhibition of expression of selected viral early gene products, viral DNA replication, and late viral gene expression. When Roscovitine was added after the first 6 h of infection, the effects on IE gene expression were no longer observed and viral replication proceeded through the late phase, but viral titers were reduced. The reduction in viral titer was observed even when Roscovitine was first added at 48 h postinfection, indicating that cyclin-dependent kinase activity is required at both IE and late times. Flavopiridol, another specific inhibitor of cyclin-dependent kinases, had similar effects on IE and early gene expression. These results underscore the importance of accurate RNA processing and reiterate the significant role of cell cycle-regulatory factors in HCMV infection.

scholarly journals Human Papillomavirus and Overall Survival After Progression of Oropharyngeal Squamous Cell Carcinoma

2014 ◽  
Vol 32 (30) ◽  
pp. 3365-3373 ◽  
Author(s):  
Carole Fakhry ◽  
Qiang Zhang ◽  
Phuc Felix Nguyen-Tan ◽  
David Rosenthal ◽  
Adel El-Naggar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Human Papillomavirus ◽  
Disease Progression ◽  
Cancer Progression ◽  
Radiation Therapy Oncology Group ◽  
Treatment Protocol ◽  
Risk Of Death ◽  
Hpv Status ◽  
Increased Risk ◽  
Risk Of Cancer

Purpose Risk of cancer progression is reduced for patients with human papillomavirus (HPV) –positive oropharynx cancer (OPC) relative to HPV-negative OPC, but it is unknown whether risk of death after progression is similarly reduced. Patients and Methods Patients with stage III-IV OPC enrolled onto Radiation Therapy Oncology Group trials 0129 or RTOG 0522 who had known tumor p16 status plus local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy were eligible for a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression. Rates were estimated by Kaplan-Meier method and compared by log-rank; hazard ratios (HRs) were estimated by Cox models. Tests and models were stratified by treatment protocol. Results A total of 181 patients with p16-positive (n = 105) or p16-negative (n = 76) OPC were included in the analysis. Patterns of failure and median time to progression (8.2 v 7.3 months; P = .67) were similar for patients with p16-positive and p16-negative tumors. After a median follow-up period of 4.0 years after disease progression, patients with p16-positive OPC had significantly improved survival rates compared with p16-negative patients (2-year OS, 54.6% v 27.6%; median, 2.6 v 0.8 years; P < .001). p16-positive tumor status (HR, 0.48; 95% CI, 0.31 to 0.74) and receipt of salvage surgery (HR, 0.48; 95% CI; 0.27 to 0.84) reduced risk of death after disease progression whereas distant versus locoregional progression (HR, 1.99; 95% CI, 1.28 to 3.09) increased risk, after adjustment for tumor stage and cigarette pack-years at enrollment. Conclusion Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

Epidemiological Trends in Attempted Suicide in Adolescents and Young Adults Between 1996 and 2004

Crisis ◽  
2009 ◽  
Vol 30 (3) ◽  
pp. 115-119 ◽  
Author(s):  
Stephanie De Munck ◽  
Gwendolyn Portzky ◽  
Kees Van Heeringen
Keyword(s):  
Young Adults ◽  
Attempted Suicide ◽  
Suicide Attempts ◽  
Epidemiological Studies ◽  
Adolescents And Young Adults ◽  
University Hospital ◽  
International Studies ◽  
Suicide Attempters ◽  
Increased Risk ◽  
Epidemiological Trends

Background: Notwithstanding the epidemiological studies indicating an increased risk of attempted suicide among adolescents and young adults, there is a scarcity of international studies that examine long-term epidemiological trends in rates and characteristics of this vulnerable group. Aims: This article describes the results of a 9-year monitoring study of suicide attempts in adolescents and young adults referred to the Accident and Emergency Department of the Gent University Hospital (Belgium). Methods: Between January 1996 and December 2004, trends, sociodemographic, and methodrelated characteristics of suicide attempts were assessed by a psychiatrist on data sheets. Results: Attempted suicide rates declined from 1996 to 2001 and then rose until 2004, but did not exceed previous rates. During the 9 years of monitoring, there was a preponderance of female suicide attempters, except for 1997. Rates of attempts and of fatal suicide were negatively correlated. Significantly more males than females deliberately injured themselves. Younger attempters, especially females, significantly more often poisoned themselves with analgesics. In nearly one in five attempts, alcohol was used in combination with other methods, and alcohol intake was more commonly observed in older suicide attempters. Nearly half of the adolescents were identified as repeaters. Conclusions: The results of this study warrant further monitoring of trends and characteristics of young suicide attempters.

scholarly journals Persistent Human Papillomavirus Infection

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 321
Author(s):  
Ashley N. Della Fera ◽  
Alix Warburton ◽  
Tami L. Coursey ◽  
Simran Khurana ◽  
Alison A. McBride
Keyword(s):  
Human Papillomavirus ◽  
Dna Replication ◽  
Cellular Proliferation ◽  
Basal Cells ◽  
Viral Dna ◽  
Viral Dna Replication ◽  
Viral Genomes ◽  
Cellular Environment ◽  
E6 And E7 ◽  
Cellular Replication

Persistent infection with oncogenic human papillomavirus (HPV) types is responsible for ~5% of human cancers. The HPV infectious cycle can sustain long-term infection in stratified epithelia because viral DNA is maintained as low copy number extrachromosomal plasmids in the dividing basal cells of a lesion, while progeny viral genomes are amplified to large numbers in differentiated superficial cells. The viral E1 and E2 proteins initiate viral DNA replication and maintain and partition viral genomes, in concert with the cellular replication machinery. Additionally, the E5, E6, and E7 proteins are required to evade host immune responses and to produce a cellular environment that supports viral DNA replication. An unfortunate consequence of the manipulation of cellular proliferation and differentiation is that cells become at high risk for carcinogenesis.

scholarly journals AB1158 VACCINATION BARRIERS IN PATIENTS WITH RHEUMATIC DISEASES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1869.2-1870
Author(s):  
G. Figueroa-Parra ◽  
A. Moreno-Salinas ◽  
L. Santoyo-Fexas ◽  
C. M. Gamboa-Alonso ◽  
A. L. De-Leon-Ibarra ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Herpes Zoster ◽  
Hepatitis B ◽  
Adverse Events ◽  
Rheumatic Diseases ◽  
Demographic Characteristics ◽  
Specific Patient ◽  
Increased Risk ◽  
Rheumatic Patients ◽  
Vaccination Barriers

Background:Patients with rheumatic diseases (RD) are at increased risk of infections, attributed to the underlying RD, comorbidities and immunosuppressive therapy, including glucocorticoids, disease-modifying antirheumatic drugs, etc. (1). While many infectious diseases can generally be prevented by vaccines, immunization rates in this specific patient population remain suboptimal (2). Despite being recognized as one of the most successful public health measures, vaccination is perceived as unsafe and unnecessary by a growing number of individuals. Lack of confidence in vaccines is now considered a threat to the success of vaccination programs (3).Objectives:To describe the main causes of non-vaccination in patients with RD.Methods:A self-questionnaire was applied to a sample of patients with RD in the rheumatology clinic of the university hospital “Dr. Jose Eleuterio Gonzalez” in Monterrey, Mexico between September and December 2019. The questionnaire evaluated demographic characteristics (age, gender, diagnosis) and the vaccination status for Influenza (last year), pneumococcal (last 5 years), Herpes zoster (ever), Human papillomavirus (any dose) and Hepatitis B (any dose). It also includes a question asking: If you didn’t receive any of the previous vaccines, what was the reason? (multiple-choice are shown in Table 2). Results are shown in frequencies and percentages.Table 2.Vaccination barriersN=82If you didn’t receive any of the previous vaccines,what was the reason? n (%)1)Did not was recommended22 (26.8)2) Lack of availability21 (25.6)3) Vaccines don’t work13 (15.8)4) Fear of adverse events8 (9.7)5) Previous adverse event3 (3.6)6) Other reason- Own decision8 (9.7)- Disinformation7 (8.5)Results:102 patients were evaluated: Mean age was 51.27 (SD 14.68) years; 84 (82.4%) were females; 71 (69.6%) had rheumatoid arthritis, 13 (12.7%) had systemic lupus erythematosus, 6 (5.8%) had other autoimmune diseases and 12 (11.8%) had osteoarthritis. The rate of vaccination for Influenza was 49 (48%), for pneumococcal 25 (24.5%), for Herpes zoster 5 (4.9%), for Human papillomavirus 9 (8.8%), for Hepatitis B 14 (13.7%) (Table 1). 82 (80.3%) patients reported some barriers in vaccination, from these: 22 (26.8%) did not get the recommendation from the rheumatologist, 21 (25.6%) did not found available the vaccine, 13 (15.8%) believes that vaccines don’t work, 8 (9.7%) had fear of adverse events, 3 (3.6%) reported previous adverse events, and 15 (18.2%) reported other reasons, that we classified as own decision 8 (9.7%) and disinformation 7 (8.5%) (Table 2).Table 1.Demographic characteristicsN= 102Age, years, mean (SD)51.27 (14.68)Female, n (%)84 (82.4)Diagnosis, n (%)-RA71 (69.6)-SLE13 (12.7)-OA12 (11.8)-Other AID6 (5.8)Conclusion:The main barriers in vaccination of rheumatic patients reported were the lack of availability of the indicated vaccines and the medical and patient disinformation. This problem must be combated to ensure the complete vaccination of rheumatic patients.References:[1]Ann Rheum Dis. 2020;79:39-52.[2]J Rheumatol. 2019;46(7):751-754[3]Hum Vaccin Immunother. 2013;9(8):1763-73.Disclosure of Interests:None declared

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