Sharon J.B. Hanley

HPV vaccination crisis in Japan

www.thelancet.com Vol 385 June 27, 2015 2571 Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/ similar adverse event crises, are already documenting substantial reductions in precancerous cervical lesions in those vaccinated. No vaccine safety signal has been recorded in Japan. Instead, individuals who have the misfortune to be unwell with rare or diffi cult to treat disorders have been encouraged by antivaccination advocates to blame the HPV vaccine, especially in an unrestrained media environment and with little reassurance and systematic addressing of these events by the government. According to the Global Advisory Committee on Vaccine Safety, “Allegations of harm from vaccination based on weak evidence can lead to real harm when, as a result, safe and eff ective vaccines cease to be used.” Sadly, this is what has transpired in Japan.

Tracking the global spread of vaccine sentiments: The global response to Japan's suspension of its HPV vaccine recommendation

In June 2013 the Japanese Ministry of Health, Labor, and Welfare (MHLW) suspended its HPV vaccination recommendation after a series of highly publicized alleged adverse events following immunization stoked public doubts about the vaccines safety. This paper examines the global spread of the news of Japans HPV vaccine suspension through online media, and takes a retrospective look at non-Japanese media sources that were used to support those claiming HPV vaccine injury in Japan. Methods: Two searches were conducted. One searched relevant content in an archive of Google Alerts on vaccines and vaccine preventable diseases. The second search was conducted using Google Search on January 6th 2014 and on July 18th 2014, using the keywords, “HPV vaccine Japan” and “cervical cancer vaccine Japan.” Both searches were used as Google Searches render more (and some different) results than Google Alerts. Results: Online media collected and analyzed totalled 57. Sixty 3 percent were published in the USA, 23% in Japan, 5% in the UK, 2% in France, 2% in Switzerland, 2% in the Philippines, 2% in Kenya and 2% in Denmark. The majority took a negative view of the HPV vaccine, the primary concern being vaccine safety. Discussion: The news of Japans suspension of the HPV vaccine recommendation has traveled globally through online media and social media networks, being applauded by anti-vaccination groups but not by the global scientific community. The longer the uncertainty around the Japanese HPV vaccine recommendation persists, the further the public concerns are likely to travel.

MiR-137 and miR-34a directly target Snail and inhibit EMT, invasion and sphere-forming ability of ovarian cancer cells.

BackgroundIn ovarian cancer (OC) cells, Snail was reported to induce the epithelial-to-mesenchymal transition (EMT), which is a critical step in OC metastasis. At present little is known about controlling Snail expression in OC cells by using specific microRNAs (miRNAs).MethodsWe first used a computational target prediction analysis to identify 6 candidate miRNAs that bind to the 3′-untranslated region (3′-UTR) region of the Snail mRNA. Among these miRNAs, two miRNAs (miR-137 and miR-34a) with a potential to regulate Snail were validated by quantitative real-time PCR, Western blot analysis, and Snail 3′-UTR reporter assays. We assessed the effects of miR-137 and miR-34a on EMT, invasion and sphere formation in OC cells. We also evaluated the expression of miR-137 and miR-34a in OC tissues and adjacent normal tissues and analyzed the relationship between their expression and patient survival.ResultsWe report that OC tissues possess significantly decreased levels of miR-137 and miR-34a and increased expression of Snail when compared to their adjacent normal tissues, and lower miR-137 and miR-34a expression correlates with worse patient survival. Using luciferase constructs containing the 3′-UTR region of Snail mRNA combined with miRNA overexpression and mutagenesis, we identified miR-137 and miR-34a as direct suppressors of Snail in OC cells. The introduction of miR-137 and miR-34a resulted in the suppression of Snail at both the transcript and protein levels, and effectively suppressed the EMT phenotype and sphere formation of OC cells. However, the inhibition of miR-137 and miR-34a with antisense oligonucleotides promoted EMT and OC cell invasion. Moreover, ectopic expression of Snail significantly reversed the inhibitory effects of miR-137 and miR-34a on OC cell invasion and sphere formation.ConclusionsThese findings suggest that both miR-137 and miR-34a act as Snail suppressors to negatively regulate EMT, invasive and sphere-forming properties of OC cells.

Acceptance of and attitudes towards human papillomavirus vaccination in Japanese mothers of adolescent girls.

To better understand how to achieve high uptake rates of human papillomavirus (HPV) vaccination in Japan, we investigated acceptance of and attitudes towards HPV vaccination in 2192 mothers of girls aged 11-14 yrs. A school-based survey was conducted in five elementary and fourteen junior high schools in Sapporo, Japan. Responses from 862 participants were analyzed. Ninety-three percent of mothers would accept the vaccine for their daughter if free, but only 1.5% was willing to pay the minimum recommended price of ¥ 40,000. Vaccine acceptance was higher in mothers who had heard of HPV vaccine (adjusted odds ratio, aOR=2.58, confidence interval, CI=1.47-4.53), and who believed susceptibility to (aOR=2.30, CI=1.34-3.92) and severity of (aOR=3.73, CI=1.41-9.88) HPV to be high. Recommendations from a doctor (aOR=12.60, CI=7.06-21.48) and local health board (aOR=27.80, CI=13.88-55.86) were also positively associated with increased HPV vaccine acceptance. Concerns about side effects of both the HPV vaccine (aOR=0.03, CI=0.01-0.08) and routine childhood vaccines in general (aOR=0.11, CI=0.02-0.78) emerged as barriers to vaccination. Not participating in routine cervical screening also emerged as a deterrent (aOR=0.49, CI=0.27-0.91). While most mothers (66.8%) agreed that 10-14 yr was an appropriate age for vaccination, a further 30.6% believed >15 yr to be more appropriate. In conclusion, attitudes of Japanese mothers toward HPV vaccination are encouraging. While lower vaccine acceptance in mothers who do not undergo regular cervical screening needs further investigation, this study indicates that high uptake may be possible in a publically funded HPV vaccination program if physicians actively address safety concerns and justify why the vaccine is needed at a particular age.

Epidemic of charcoal burning suicide in Japan

BACKGROUND The charcoal burning suicide epidemics in both Hong Kong and Taiwan have been well documented. However, little is known about the situation in Japan. AIMS To examine the impact of charcoal burning suicide on the overall and other method-specific suicide rates between 1998 and 2007 in Japan. METHOD Using data obtained from the Vital Statistics of Japan, negative binomial regression analyses were performed to investigate the impact of the charcoal burning method. RESULTS In males and females aged 15-24 and 25-44 years, the charcoal burning epidemic led to a substantial increase in overall suicides, without a decrease in other methods. In all other age groups, no such trend was observed. CONCLUSIONS In young Japanese, the charcoal burning method may have appealed to individuals who might not have chosen other highly or relatively lethal methods, and consequently led to an increase in overall suicides.

Reactivation of epigenetically silenced miR-124 reverses the epithelial-to-mesenchymal transition and inhibits invasion in endometrial cancer cells via the direct repression of IQGAP1 expression

Overexpression of IQGAP1 and microRNA (miRNA) dysregulation are frequent in human tumors, but little is known about the role of IQGAP1 and its relationship to miRNA in endometrial carcinogenesis. We demonstrate that IQGAP1 activates the epithelial–mesenchymal transition (EMT) program and that miR-124 directly represses IQGAP1 expression in endometrial cancer (EC) cells. The overexpression of IQGAP1 stimulates EMT features and enhances migration, invasion and proliferation of EC cells, whereas knocking down IQGAP1 expression reverses EMT and inhibits these malignant properties. Using miRNA microarray profiling, we identified 29 miRNAs (let-7b, let-7f, miR-10b, miR-15b, miR-23a, miR-24, miR-25, miR-27a, miR-29b, miR-30a-5p, miR-34a, miR-124, miR-127, miR-130b, miR-148a, miR-155, miR-191*, miR-194, miR-224, miR-362, miR-409-3p, miR-422b, miR-424, miR-453, miR-497, miR-518d, miR-518f*, miR-526a and miR-656) that are significantly down-regulated in an in vitro-selected highly invasive derivative cell line (HEC-50-HI) relative to the parental HEC-50 cells. We further identified miR-124 as a direct regulator of IQGAP1 in EC cells. Enforced expression of miR-124 suppresses EC cell invasion and proliferation. The expression of IQGAP1 mRNA was significantly elevated in EC tissues, while the expression of miR-124 was decreased. The downregulation of miR-124 correlates with a poor survival outcome for patients with EC. Treating EC cells with the demethylating agent 5-aza-2′-deoxycytidine increased miR-124 expression and down-regulated IQGAP1 levels. Our data suggest that IQGAP1 promotes EMT, migration and invasion of EC cells. MiR-124, a novel tumor suppressor miRNA that is epigenetically silenced in EC, can reverse EMT and the invasive properties, by attenuating the expression of the IQGAP1 oncogene.

High HPV vaccination uptake rates for adolescent girls after regional governmental funding in Shiki City, Japan.

BACKGROUND In Japan, the bivalent HPV vaccine was approved in October, 2009 and became available as a non-routine vaccine from December, 2009. While routine vaccinations are free, the cost and responsibility for non-routine vaccinations are left to the individual. In exceptional circumstances regional governments fund non-routine vaccinations. This was the case in Shiki City, Saitama Prefecture, where a high uptake rate for individual (non-school based) HPV vaccination was obtained. MATERIALS On January 20, 2010, the mayor of Shiki City announced to the media his decision to vaccinate adolescent girls in Shiki City against HPV. A project team for HPV vaccination was set up in the citys Health Promotion Center. To gain mutual consent for HPV vaccination, senior health professionals, city officials, the head of the board of education, school principals and health-care teachers met several times. The cohort to be vaccinated was 1254 girls aged 12-15 years. Individual notifications were mailed to each girl on April 23, 2010, along with information about the HPV vaccine. CONCLUSIONS As of April 10th, 2011, the uptake rate for girls aged 15 years old was 90.7% for the 1st dose. The vaccine registry is managed by the health care system of the city. The success of the HPV vaccination program and high uptake rates in Shiki City is a good model for the nationwide HPV vaccination program that started in February, 2011.

EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis

EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2′-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.

Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124

Derepression of wild-type p53 by suppressing its negative inhibitor iASPP (Inhibitor of apoptosis-stimulating protein of p53) represents a potential therapeutic option for cervical cancer (CC). Here, we reported a novel functional significance of iASPP upregulation in cervical tumorigenesis: iASPP acts as a key promoter of CC cell proliferation, epithelial-mesenchymal transition, invasion and cancer stemness, by interacting with p53 to suppress p53-mediated transcription of target genes and reducing p53-responsive microRNA-34a levels. Moreover, we demonstrate that miR-124, directly targeting iASPP, reduces expression of iASPP and attenuates CC cell growth and invasiveness. Low miR-124 expression is inversely correlated with increased expression of iASPP mRNA in CC tissues. In a cohort of 40 patients with CC, the low miR-124 expression was correlated with poor 5-year overall survival (P = 0.0002) and shorter disease-free survival 5-year (P = 0006). Treatment with the DNA methyltransferase inhibitor Zebularine increases miR-124 expression and retards CC cell growth and invasion with minimal toxicity to normal cells. Even at a non-toxic concentration, Zebularine was effective in suppressing CC cell invasion and migration. Altogether, the restoration of miR-124 reduces iASPP expression and leads to p53-dependent tumor suppression, suggesting a therapeutic strategy to treat iASPP-associated CC.

Incidence risk of cervical intraepithelial neoplasia 3 or more severe lesions is a function of human papillomavirus genotypes and severity of cytological and histological abnormalities in adult Japanese women

We examined incidence probabilities of cervical intraepithelial neoplasia 3 (CIN3) or more severe lesions (CIN3+) in 1,467 adult Japanese women with abnormal cytology in relation to seven common human papillomavirus (HPV) infections (16/18/31/33/35/52/58) between April 2000 and March 2008. Sixty‐seven patients with multiple HPV infection were excluded from the risk factor analysis. Incidence of CIN3+ in 1,400 patients including 68 with ASCUS, 969 with low grade squamous intraepithelial lesion (LSIL), 132 with HSIL without histology‐proven CIN2 (HSIL/CIN2(−)) and 231 with HSIL with histology‐proven CIN2 (HSIL/CIN2(+)) was investigated. In both high grade squamous intraepithelial lesion (HSIL)/CIN2(−) and HSIL/CIN2(+), HPV16/18/33 was associated with a significantly earlier and higher incidence of CIN3+ than HPV31/35/52/58 (p = 0.049 and p = 0.0060, respectively). This association was also observed in LSIL (p = 0.0002). The 1‐year cumulative incidence rate (CIR) of CIN3+ in HSIL/CIN2(−) and HSIL/CIN2(+) according to HPV genotypes (16/18/33 vs. 31/35/52/58) were 27.1% vs. 7.5% and 46.6% vs. 19.2%, respectively. In contrast, progression of HSIL/CIN2(+) to CIN3+ was infrequent when HPV DNA was undetected: 0% of 1‐year CIR and 8.1% of 5‐year CIR. All cervical cancer occurred in HSIL cases of seven high‐risk HPVs (11/198) but not in cases of other HPV or undetectable/negative‐HPV (0/165) (p = 0.0013). In conclusion, incidence of CIN3+ depends on HPV genotypes, severity of cytological abnormalities and histology of CIN2. HSIL/CIN2(+) associated with HPV16/18/33 may justify early therapeutic intervention, while HSIL/CIN2(−) harboring these HPV genotypes needs close observation to detect incidence of CIN3+. A therapeutic intervention is not indicated for CIN2 without HPV DNA.