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Concept: Cervical cancer

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BackgroundThe American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updates on cancer incidence and death rates and trends in these outcomes for the United States. This year’s report includes incidence trends for human papillomavirus (HPV)-associated cancers and HPV vaccination (recommended for adolescents aged 11-12 years).MethodsData on cancer incidence were obtained from the CDC, NCI, and NAACCR, and data on mortality were obtained from the CDC. Long- (1975/1992-2009) and short-term (2000-2009) trends in age-standardized incidence and death rates for all cancers combined and for the leading cancers among men and among women were examined by joinpoint analysis. Prevalence of HPV vaccination coverage during 2008 and 2010 and of Papanicolaou (Pap) testing during 2010 were obtained from national surveys.ResultsDeath rates continued to decline for all cancers combined for men and women of all major racial and ethnic groups and for most major cancer sites; rates for both sexes combined decreased by 1.5% per year from 2000 to 2009. Overall incidence rates decreased in men but stabilized in women. Incidence rates increased for two HPV-associated cancers (oropharynx, anus) and some cancers not associated with HPV (eg, liver, kidney, thyroid). Nationally, 32.0% (95% confidence interval [CI] = 30.3% to 33.6%) of girls aged 13 to 17 years in 2010 had received three doses of the HPV vaccine, and coverage was statistically significantly lower among the uninsured (14.1%, 95% CI = 9.4% to 20.6%) and in some Southern states (eg, 20.0% in Alabama [95% CI = 13.9% to 27.9%] and Mississippi [95% CI = 13.8% to 28.2%]), where cervical cancer rates were highest and recent Pap testing prevalence was the lowest.ConclusionsThe overall trends in declining cancer death rates continue. However, increases in incidence rates for some HPV-associated cancers and low vaccination coverage among adolescents underscore the need for additional prevention efforts for HPV-associated cancers, including efforts to increase vaccination coverage.

Concepts: American Cancer Society, Papillomavirus, Gardasil, Cervical cancer, Anal cancer, Cancer, HPV vaccine, Human papillomavirus

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Cervical cancer is one of the leading causes of cancer death in women worldwide. The causative agents of cervical cancers, high-risk human papillomaviruses (HPVs), cause cancer through the action of two oncoproteins, E6 and E7. The E6 oncoprotein cooperates with an E3 ubiquitin ligase (UBE3A) to target the p53 tumour suppressor and important polarity and junctional PDZ proteins for proteasomal degradation, activities that are believed to contribute towards malignancy. However, the causative link between degradation of PDZ proteins and E6-mediated malignancy is largely unknown. We have developed an in vivo model of HPV E6-mediated cellular transformation using the genetic model organism, Drosophila melanogaster. Co-expression of E6 and human UBE3A in wing and eye epithelia results in severe morphological abnormalities. Furthermore, E6, via its PDZ-binding motif and in cooperation with UBE3A, targets a suite of PDZ proteins that are conserved in human and Drosophila, including Magi, Dlg and Scribble. Similar to human epithelia, Drosophila Magi is a major degradation target. Magi overexpression rescues the cellular abnormalities caused by E6+UBE3A coexpression and this activity of Magi is PDZ domain-dependent. Drosophila p53 was not targeted by E6+UBE3A, and E6+UBE3A activity alone is not sufficient to induce tumorigenesis, which only occurs when E6+UBE3A are expressed in conjunction with activated/oncogenic forms of Ras or Notch. Finally, through a genetic screen we have identified the insulin receptor signaling pathway as being required for E6+UBE3A induced hyperplasia. Our results suggest a highly conserved mechanism of HPV E6 mediated cellular transformation, and establish a powerful genetic model to identify and understand the cellular mechanisms that underlie HPV E6-induced malignancy.

Concepts: Oncology, Drosophila, Proteasome, Cervical cancer, Model organism, Drosophila melanogaster, Human papillomavirus, Cancer

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Purpose: The purpose of this study was to assess ordering of human papillomavirus (HPV) testing for normal cervical cytology among low-risk women aged 30 to 65 years.

Concepts: Harald zur Hausen, Cervarix, Cervical intraepithelial neoplasia, Gardasil, HPV vaccine, Papillomavirus, Cervical cancer, Human papillomavirus

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BACKGROUND: The human papillomavirus (HPV) vaccine offers an opportunity to reduce health inequalities associated with cervical cancer provided the vaccine is delivered equitably at population level.Method We reviewed evidence of inequalities in HPV vaccine uptake in young women after undertaking a comprehensive search of databases from inception to March 2012. Studies that compared HPV vaccination initiation and/or completion by at least one ethnicity or socioeconomic-related variable in adolescent young women were included. There were no language restrictions. Data were extracted by two reviewers and pooled in a meta-analysis using a random-effects model; sub-analyses and meta-regression were undertaken to investigate sources of heterogeneity. RESULTS: In all, 29 publications related to 27 studies were included in the review. Black young women were less likely to initiate HPV vaccination compared with White young women (combined OR: 0.89, 95% CI: 0.82-0.97). In the USA, young women without healthcare insurance were less likely to initiate (combined OR: 0.56, 95% CI: 0.40-0.78). There was no strong evidence that lower family income (combined OR: 1.16, 95% CI: 1.00-1.34) or lower parental education (combined OR 1.06, 95% CI: 0.92-1.22) influenced HPV vaccination initiation. CONCLUSIONS: We found strong evidence for differences in HPV vaccination initiation by ethnicity and healthcare coverage, but did not find a strong association with parental education or family income variables. The majority of studies originated from the USA. Population-based studies reporting both initiation and completion of the HPV vaccination programme are required to establish patterns of uptake in different healthcare contexts.

Concepts: Anal cancer, Papillomavirus, Gardasil, Cervical cancer, Human papillomavirus, HPV vaccine

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OBJECTIVE: Human papillomavirus (HPV) infections remain a leading cause of mortality worldwide. In the U.S. strategies via screening and vaccination prevent HPV-associated cervical neoplasms, but consumes immense healthcare costs. The spice component curcumin has potent anticancer and antiviral properties, which have been difficult to harness as a treatment, due to its poor systemic bioavailability. This project tests the possibility of developing a curcumin-based therapy for cervical cancer. METHODS: Using four HPV(+) cervical cancer cell lines and normal fibroblasts we first tested the selectivity and potency of curcumin in eliminating HPV(+) cells. Subsequently, we developed a curcumin-based cervical cream and tested its efficacy in eliminating apposed HPV(+) cells and also its possible side effects on the vaginal epithelium of healthy mice. RESULTS: Curcumin selectively eliminates a variety of HPV(+) cervical cancer cells (HeLa, ME-180, SiHa, and SW756), suppresses the transforming antigen E6, dramatically inhibits the expression of the pro-cancer protein epidermal growth factor receptor (EGFR), and concomitantly induces p53. Additionally, Vacurin, a uniform colloidal solution of curcumin in a clinically used amphipathic vaginal cream, eliminates apposed HeLa cells while suppressing the expression of EGFR. In mice, daily intravaginal application of Vacurin for three weeks produced no change in body weight and when the mice were sacrificed, the vaginal tract epithelium showed no Vacurin-evoked adverse effects. CONCLUSION: We have developed a curcumin-based vaginal cream, which effectively eradicates HPV(+) cancer cells and does not affect non-cancerous tissue. Our preclinical data support a novel approach for the treatment of cervical HPV infection.

Concepts: Epidermal growth factor receptor, Lung cancer, P53, HPV vaccine, Cervical cancer, Human papillomavirus, Cancer, Immune system

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Late rupture of external iliac artery pseudo-aneurysm is an uncommon complication in patients who undergo extensive gynecologic radical surgeries. A 28-year-old woman with stage IB cervical cancer underwent pelvic lymphadenectomy and extrafascial trachelectomy. Two months after surgery, massive bleeding from ruptured pseudo-aneurysm of the external iliac artery occurred. Endovascular management with covered stent placement was feasible and safe to stop bleeding.

Concepts: Surgery, Hysterectomy, Internal iliac artery, Pelvis, Stent, External iliac artery, Cervical cancer, Radiation therapy

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To evaluate the incidence of leukoencephalopathy after whole-brain radiation therapy (WBRT) in patients with brain metastases.

Concepts: Cervical cancer, Chemotherapy, Oncology, Melanoma, Prostate cancer, Cancer, Medicine

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Cervical cancer is the third most common cancer affecting women worldwide and it is an important cause of death, especially in developing countries. Cervical cancer is caused by human papillomavirus (HPV) and can be prevented by HPV vaccine. The challenge is to expand vaccine availability to countries where it is most needed. In 2008 Peru’s Ministry of Health implemented a demonstration project involving 5(th) grade girls in primary schools in the Piura region. We designed and conducted a qualitative study of the decision-making process among parents of girls, and developed a conceptual model describing the process of HPV vaccine acceptance.

Concepts: Cervarix, Cervical intraepithelial neoplasia, Anal cancer, Papillomavirus, Gardasil, Cervical cancer, HPV vaccine, Human papillomavirus

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SELDI-TOF mass spectrometer’s compact size and automated, high throughput design have been attractive to clinical researchers, and the platform has seen steady-use in biomarker studies. Despite new algorithms and preprocessing pipelines that have been developed to address reproducibility issues, visual inspection of the results of SELDI spectra preprocessing by the best algorithms still shows miscalled peaks and systematic sources of error. This suggests that there continues to be problems with SELDI preprocessing. In this work, we study the preprocessing of SELDI in detail and introduce improvements. While many algorithms, including the vendor supplied software, can identify peak clusters of specific mass (or m/z) in groups of spectra with high specificity and low false discover rate (FDR), the algorithms tend to underperform estimating the exact prevalence and intensity of peaks in those clusters. Thus group differences that at first appear very strong are shown, after careful and laborious hand inspection of the spectra, to be less than significant. Here we introduce a wavelet/neural network based algorithm which mimics what a team of expert, human users would call for peaks in each of several hundred spectra in a typical SELDI clinical study. The wavelet denoising part of the algorithm optimally smoothes the signal in each spectrum according to an improved suite of signal processing algorithms previously reported (the LibSELDI toolbox under development). The neural network part of the algorithm combines those results with the raw signal and a training dataset of expertly called peaks, to call peaks in a test set of spectra with approximately 95% accuracy. The new method was applied to data collected from a study of cervical mucus for the early detection of cervical cancer in HPV infected women. The method shows promise in addressing the ongoing SELDI reproducibility issues.

Concepts: Clinical research, Mass spectrometry software, Mass-to-charge ratio, Cervical cancer, Human papillomavirus, Ion source, Soft laser desorption, Mass spectrometry

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BACKGROUND: The female genital tract is an important bacterial habitat of the human body, and vaginal microbiota plays a crucial role in vaginal health. The alteration of vaginal microbiota affects millions of women annually, and is associated with numerous adverse health outcomes, including human papillomavirus (HPV) infection. However, previous studies have primarily focused on the association between bacterial vaginosis and HPV infection. Little is known about the composition of vaginal microbial communities involved in HPV acquisition. The present study was performed to investigate whether HPV infection was associated with the diversity and composition of vaginal microbiota. METHODS: A total of 70 healthy women (32 HPV-negative and 38 HPV-positive) with normal cervical cytology were enrolled in this study. Culture-independent polymerase chain reaction-denaturing gradient gel electrophoresis was used to measure the diversity and composition of vaginal microbiota of all subjects. RESULTS: We found significantly greater biological diversity in the vaginal microbiota of HPV-positive women (p < 0.001). Lactobacillus, including L. gallinarum, L. iners and L. gasseri, was the predominant genus and was detected in all women. No significant difference between HPV-positive and HPV-negative women was found for the frequency of detection of L. gallinarum (p = 0.775) or L. iners (p = 0.717), but L. gasseri was found at a significantly higher frequency in HPV-positive women (p = 0.005). Gardnerella vaginalis was also found at a significantly higher frequency in HPV-positive women (p = 0.031). Dendrograms revealed that vaginal microbiota from the two groups had different profiles. CONCLUSIONS: Our study is the first systematic evaluation of an association between vaginal microbiota and HPV infection, and we have demonstrated that compared with HPV-negative women, the bacterial diversity of HPV-positive women is more complex and the composition of vaginal microbiota is different.

Concepts: Gardnerella vaginalis, Genital wart, Immune system, Cervical cancer, Papillomavirus, Bacteria, Bacterial vaginosis, Human papillomavirus