Nicotinamide Improves Delayed Tooth Eruption in Runx2+/- Mice.

Patients with cleidocranial dysplasia (CCD) caused by mutations in RUNX2 have severe dental anomalies, including delayed or absent eruption of permanent teeth. This requires painful and expensive surgical/orthodontic intervention because of the absence of medicine for this condition. Here, we demonstrate that nicotinamide, a vitamin B3 and class III histone deacetylase inhibitor, significantly improves delayed tooth eruption in Runx2+/- mice, a well-known CCD animal model, through the restoration of decreased osteoclastogenesis. We also found that Csf1 mRNA and protein levels were significantly reduced in Runx2+/- osteoblasts as compared with wild type whereas RANKL and OPG levels had no significant difference between wild type and Runx2+/- osteoblasts. The nicotinamide-induced restoration of osteoclastogenesis of bone marrow-derived macrophages in Runx2+/- mice was due to the increased expression of RUNX2 and CSF1 and increased RANKL/OPG ratio. RUNX2 directly regulated Csf1 mRNA expression via binding to the promoter region of the Csf1 gene. In addition, nicotinamide enhanced the RUNX2 protein level and transacting activity posttranslationally with Sirt2 inhibition. Taken together, our study shows the potential and underlying molecular mechanism of nicotinamide for the treatment of delayed tooth eruption by using the Runx2+/- murine model, suggesting nicotinamide as a candidate therapeutic drug for dental abnormalities in patients with CCD.

PIN1 is a new therapeutic target of craniosynostosis.

Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.

Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples.

AIM: This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide. METHODS: We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16(INK4a) expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance. RESULTS: HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16(INK4a) overexpression was found in 87% of HPV DNA positive vaginal cancer cases. CONCLUSIONS: HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.

Cancer survival in Busan, Republic of Korea, 1996-2001.

The Busan cancer registry was established in 1996; cancer registration is done by passive and active methods. The registry contributed survival data for 48 cancer sites or types registered during 1996-2001. Follow-up information has been gleaned predominantly by passive methods with median follow-up ranging between 1-57 months for various cancers. The proportion with histologically verified diagnosis for different cancers ranged between 20-100%; death certificates only (DCOs) comprised 0-53%; 47-100% of total registered cases were included for survival analysis. The top-ranking cancers on 5-year age-standardized relative survival rates were penis (94%), thyroid (91%), non-melanoma skin (89%), placenta (86%), breast (76%), Hodgkin lymphoma (75%) and testis (72%). Five-year relative survival by age group showed a decreasing trend with increasing age groups for cancers of the nasopharynx, gall bladder, lung, bone, soft tissue, breast, cervix, corpus uteri, thyroid, multiple myeloma, lymphoid leukaemia and myeloid leukaemia or was fluctuating for other cancers.

Population attributable fraction of infection-related cancers in Korea.

BACKGROUND: A number of infectious agents have been classified as human carcinogens. The purpose of the current study was to provide an evidence-based assessment of the burden of infection-related cancers in the Korean population. MATERIALS AND METHODS: The population attributable fraction was calculated using infection prevalence data from 1990 or earlier, relative risk estimates from meta-analyses using mainly Korean studies and national data on cancer incidence and mortality for the year 2007. RESULTS: The fractions of all cancers attributable to infection were 25.1% and 16.8% for cancer incidence in men and women, and 25.8% and 22.7% of cancer mortality in men and women, respectively. Among infection-related cancers, Helicobacter pylori was responsible for 56.5% of cases and 45.1% of deaths, followed by hepatitis B virus (HBV) (23.9% of cases and 37.5% of deaths) and human papillomavirus (HPV) (11.3% of cases and 6% of deaths) and then by hepatitis C virus (HCV) (6% of cases and 9% of deaths). Over 97% of infection-related cancers were attributable to infection with H. pylori, HBV, HCV and HPV. CONCLUSION: Up to one-quarter of cancer cases and deaths would be preventable through appropriate control of infectious agents in Korea.

The need for public education on HPV and cervical cancer prevention in Asia. Opinions of experts at the AOGIN conference.

Asia accounts for more than half of all cases of cervical cancer registered globally and improving prevention is urgently needed. A range of tools and strategies is now available to effectively prevent this disease, including two new prophylactic HPV vaccines approved and recommended for adolescents and young women. However, without communication these tools may have little impact on disease burden. The conferences of the Asia Oceania Research Organisation in Genital Infection and Neoplasia (AOGIN) bring together clinicians and scientists whose work is related to genital infections, particularly HPV, cervical dysplasia and neoplasia, as well as other anogenital cancers, with the aim of improving communication on prevention through human papillomavirus (HPV) vaccination and screening in Asian countries. The scope of this year's AOGIN conference was to extend education to include health workers, family doctors, paediatricians, governmental health agencies, and the general public through patients' testimonials that can reach out to women raising awareness of this silent disease. Community based initiatives and awareness campaigns were also reported, and can empower the people to engage in a dialog with local governments towards prioritization of cancer prevention programs, achieving more for the public than isolated actions. Parents and teachers are encouraged to communicate about these issues within families and schools. Evidence was discussed that males can participate in cervical cancer control as well, and prevention programs involving men should not be neglected as they may reduce genital disease burden in women. Opinion leaders proposed prevention measures to be considered for governmental decisions. While each country develops a locally appropriate policy for cervical cancer control there is a need to revise these programs regularly, as knowledge increases in response to public need, as well as to gather evidence about disease burden and the effectiveness of education and interventions. In conclusion, AOGIN is committed to improve communication with patients, health authorities, professional organizations and opinion leaders towards strengthening cervical cancer prevention in Asia, to achieve a timely steep reduction in this cancer.

The economic burden of cancer in Korea in 2002.

Cancer is the leading cause of death and one of the most significant healthcare expenses in Korea. The purpose of this study was to estimate the economic burden of cancer on Korean society. We studied the medical, non-medical, morbidity and mortality costs related to cancer treatment, lost productivity and premature death. Healthcare claims for 2002 obtained from the Health Insurance Review Agency were used to estimate medical expenditures; these were linked with the Korean Central Cancer Registry database to identify cancer patients. The number of deaths used to estimate mortality costs was obtained from the Annual Report of Mortality from the National Statistics Office of Korea. Moreover, data from the Korean National Statistics Office and Ministry of Labor were used to calculate life expectancy at the age of death, labour force participation, and average age- and gender-specific earnings. In 2002, the estimated total economic cost of cancer amounted to $9.4 billion (1.72% of GDP) at a 3% discount rate. Medical care costs amounted to 13.7% of total costs, non-medical costs 6.5%, morbidity costs 14.5%, and mortality costs accounted for 65.3%. Increased prevention, earlier diagnosis, new therapies and effective cancer control policies are needed to reduce the economic burden of cancer in Korea.

Smoking, alcohol and gastric cancer risk in Korean men: the National Health Insurance Corporation Study.

We investigated the risk of gastric cancer by subsite in relation to cigarette smoking and alcohol in a large population-based cohort of 669 570 Korean men in an insurance plan followed for an average 6.5 years, yielding 3452 new cases of gastric cancer, of which 127 were cardia and upper-third gastric cancer, 2409 were distal gastric cancer and 1007 were unclassified. A moderate association was found between smoking, cardia and upper-third (adjusted relative risk (aRR) 2.2; 95% confidence interval (CI) 1.4-3.5) and distal cancers (aRR=1.4; 95% CI=1.3-1.6). We also found a positive association between alcohol consumption and distal (aRR=1.3; 95% CI=1.2-1.5) and total (aRR=1.2; 95% CI=1.1-1.4) gastric cancer. Combined exposure to high levels of tobacco and alcohol increased the risk estimates further; cardia and upper-third gastric cancers were more strongly related to smoking status than distal gastric cancer.British Journal of Cancer (2007) 97, 700-704. doi:10.1038/sj.bjc.6603893 www.bjcancer.com Published online 17 July 2007.

Ovarian cancer incidence and survival in Korea: 1993-2002.

This study examined incidence rates, histologic and stage distribution, and long-term survival rates of patients with ovarian cancer in Korea. A total of 11,404 patients diagnosed with ovarian cancer between 1993 and 2002 were reported to the Korea Central Cancer Registry and the Gynecologic Oncology Committee of Korean Society of Obstetrics and Gynecology. All rates were expressed per 100,000. The age-standardized incidence rates were 3.79 and 4.74 per 100,000 women in 1993 and 2002, respectively. The incidence rates of ovary cancer increased with age in Korea, and over half of the patients were in the stage IA (24.8%) and IIIC (26.8%) in this study. The 5-year relative survival rate was 59.6%. Relative survivals according to the stage of FIGO at 5 years were 91.1%, 75.2%, 46.4%, and 21.2% for stages I, II, III, and IV, respectively. The 5-year relative survivals of germ cell tumors and epithelial ovarian cancer were 89.0% and 58.3%, respectively. Surgical stage and histology were the most important prognostic factors of ovarian cancer. However, the 5-year survival rate of FIGO stage IC was significantly higher than that of stage IB.

Cervical cancer incidence and survival in Korea: 1993-2002.

This study examined the incidence rates, histologic and stage distribution, and long-term survival rates of patients with cervical cancer in Korea. A total of 44,182 patients diagnosed with cervical cancer between 1993 and 2002 were reported to the Korea Central Cancer Registry and the Gynecologic Oncology Committee of Korean Society of Obstetrics and Gynecology. The age-standardized incidence rates were 19.0, 17.8, and 15.1 per 100,000 women in 1993-1995, 1996-1998, and 1999-2002, respectively. The incidence rates of adenocarcinoma (AC) have been in the range between 1.2 in 1993-1995 and 1.4 in 1999-2002, while those of squamous cell carcinoma declined from 15.1 in 1993-1995 to 12.2 in 1999-2002. The 5-year relative survival rate was 79.2%. Relative survival rates, according to stage by the FIGO, at 5 years were 94.2%, 69.7%, 38.9%, and 21.1% for stages I, II, III, and IV respectively. Relative survivals improved between 1993 and 1997, probably due to the introduction of cervical cancer screening and effective treatment. The incidence rates of AC have been constant despite decreased cervical cancer in Korea. Introduction of cervical cancer screening and effective treatment may have contributed to the improved relative survival.

CagA-producing Helicobacter pylori and increased risk of gastric cancer: a nested case-control study in Korea.

In a nested-case control study of 100 cases of gastric cancer and 400 matched controls in relation to virulence factors of Helicobacter pylori in a Korean cohort, CagA seropositivity was significantly associated with a higher risk of gastric cancer among H. pylori-infected subjects (OR=3.57, 95% CI 1.05-12.14).

Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis.

BACKGROUND: The proportion of women infected with human papillomavirus (HPV) varies greatly across populations, as might the distribution of HPV types. We aimed to compare HPV-type distribution in representative samples of women from different world regions. METHODS: Women were randomly selected from the general population of 13 areas from 11 countries (Nigeria, India, Vietnam, Thailand, Korea, Colombia, Argentina, Chile, the Netherlands, Italy, and Spain). A standardised protocol was used for cervical specimen collection. All HPV testing was by GP5+/6+ PCR-based EIA. The proportion of HPV-positive women infected with different HPV types was compared by study area and between pooled regions with age-adjusted odds ratios (ORs) with corresponding 95% floating CIs. FINDINGS: 15 613 women aged 15-74 years without cytological abnormalities were included in a pooled analysis. Age-standardised HPV prevalence varied nearly 20 times between populations, from 1.4% (95% CI 0.5-2.2) in Spain to 25.6% (22.4-28.8) in Nigeria. Although both overall HPV prevalence and HPV16 prevalence were highest in sub-Saharan Africa, HPV-positive women in Europe were significantly more likely to be infected with HPV16 than were those in sub-Saharan Africa (OR 2.64, p=0.0002), and were significantly less likely to be infected with high-risk HPV types other than HPV16 (OR 0.57, p=0.004) and/or low-risk HPV types (OR 0.44. p=0.0002). Women from South America had HPV-type distribution in between those from sub-Saharan Africa and Europe. Heterogeneity between areas of Asia was significant. INTERPRETATION: Heterogeneity in HPV type distribution among women from different populations should be taken into account when developing screening tests for the virus and predicting the effect of vaccines on the incidence of infection.

A nested case-control study of the association of Helicobacter pylori infection with gastric adenocarcinoma in Korea.

In a nested case-control study of 86 cases of gastric adenocarcinoma in relation to Helicobacter pylori infection in the Korean Multi-center Cancer Cohort, the H. pylori IgG seropositivity was 83.7% and that of the 344 matched controls was 80.8%, with a matched odds ratio for H. pylori infection of 1.06 (95% CI, 0.80-1.40).

Mutational analysis of OGG1, MYH, MTH1 in FAP, HNPCC and sporadic colorectal cancer patients: R154H OGG1 polymorphism is associated with sporadic colorectal cancer patients.

MYH, OGG1 and MTH1 are members of base excision repair (BER) families, and MYH germline mutations were recently identified in patients with multiple adenomas or familial adenomatous polyposis (FAP). A total of 20 APC-negative Korean FAP patients were analyzed for OGG1, MYH and MTH1 germline mutations. A total of 19 hereditary nonpolyposis colorectal cancer (HNPCC), 86 suspected HNPCC, and 246 sporadic colorectal cancer cases were investigated for OGG1 and MYH mutations. A total of 14 R154H OGG1 polymorphisms were identified in hereditary, sporadic colorectal cancers, and normal controls. For the case-control analysis of OGG1 R154H, a total of 625 hereditary or sporadic colorectal cancer patients and 527 normal controls were screened. R154H was a rare polymorphism associated with sporadic colorectal cancer patents (OR: 3.586, P= 0.053). R154H does not segregate with cancer phenotypes. Upon examining the possibility of recessive inheritance of R154H, we could not identify any complementary mutations in OGG1, MYH or MTH1. Samples with R154H were further screened for mutations of K-ras, beta-catenin, APC, p53, BRAF and the microsatellite instability (MSI) status. Eight somatic mutations were identified in these genes and G:C to T:A transversion mutations were not dominant in samples harboring R154H. This result raises the possibility that OGG1 R154H may function as a low/moderate-penetrance modifier for colorectal cancer development.

Hepatitis B and C virus prevalence in a rural area of South Korea: the role of acupuncture.

A cross-sectional study evaluated the prevalence of and the risk factors for hepatitis C and B viruses among 700 adults above the age of 40 years in a rural area of South Korea. Seropositivity for hepatitis C virus antibody (11.0%, 95% confidence interval: 8.7-13.6) was higher than that for hepatitis B surface antigen (4.4%, 95% confidence interval: 3.0-6.2). Anti-hepatitis C virus seropositivity was associated with a history of repeated acupuncture (odds ratio=2.1, 95% confidence interval: 1.1-4.0), and blood transfusion (odds ratio=5.5, 95% confidence interval: 1.6-19.3) before 1992 when hepatitis C virus screening in blood donors became mandatory. Hepatitis C virus 2a was the most prevalent genotype, followed by 1b. Hepatitis C virus risk attributable to acupuncture was 38% (9% for men and 55% for women). Safer acupuncture practice has become a priority for hepatitis C virus prevention in South Korea.

Geographical Variation of Liver Cancer Mortality in Korea (1992-1998).

PURPOSE: The death rate of liver cancer in Korea has been reported as one of the highest in the world. This study was conducted to investigate geographical variations of liver cancer mortality in Korea in order to obtain insight into possible environmental factors related to liver cancer. MATERIALS AND METHODS: The sex-specific standardized mortality ratios (SMRs) of liver cancer were calculated for 168 basic administrative units in Korea based upon the vital statistics for the seven years 1992 to 1998, as well as the sex- and age-specific population of each area for 1995. The SMRs were classified into six categories and depicted on a map for each sex. RESULTS: The southern provinces showed clearly higher mortality rates as compared to the rest of the country in both males and females. Looking at the maps in detail, there was a geographical variation even within the southern provinces. The areas around large rivers, some costal areas, and costal islands showed a high mortality rate. Even in the middle and northern provinces, the eastern costal areas showed relatively higher mortality rates as compared to inland areas. Conversely, some southern areas known for low levels of pollution showed relatively lower mortality rates. CONCLUSION: This finding suggests a possible relationship between liver cancer and water-related foods from polluted rivers or seas. Further studies should be performed in order to clarify which factors cause this geographical variation.

The cancer-preventive potential of Panax ginseng: a review of human and experimental evidence.

OBJECTIVE: We have reviewed the potential cancer-preventive and other relevant properties of Panax ginseng C. A. Meyer, which has been traditionally used as a natural tonic in Oriental countries. DATA IDENTIFICATION AND STUDY SELECTION: Publications on Panax ginseng and its relation to cancer were obtained from the Medline database (1983-1998) and by checking reference lists to find earlier reports. The reports cover experimental models and human studies on cancer-preventive activity, carcinogenicity and other beneficial or adverse effects. In addition, possible mechanisms of chemoprevention by ginseng were considered. RESULTS: Published results from a cohort and two case-control studies in Korea suggest that the intake of ginseng may reduce the risk of several types of cancer. When ginseng was tested in animal models, a reduction in cancer incidence and multiplicity at various sites was noted. Panax ginseng and its chemical constituents have been tested for their inhibiting effect on putative carcinogenesis mechanisms (e.g., cell proliferation and apoptosis, immunosurveillance, angiogenesis); in most experiments inhibitory effects were found. CONCLUSION: While Panax ginseng C. A. Meyer has shown cancer-preventive effects both in experimental models and in epidemiological studies, the evidence is currently not conclusive as to its cancer-preventive activity in humans. The available evidence warrants further research into the possible role of ginseng in the prevention of human cancer and carcinogenesis.

Female sex hormones and body mass in adolescent and postmenopausal Korean women.

A cross-sectional study was conducted to evaluate the relationship between body mass and serum level of female sex hormones among 153 adolescent girls, and 153 postmenopausal women in Korea. Information on lifestyles, and both menstrual and reproductive factors was collected by personal interview. Serum total estradiol (E2), progesterone (Pg), and sex hormone binding globulin (SHBG) concentrations were measured by radioimmunoassay. Multiple linear regression analysis was used to determine whether the hormonal levels would be affected by the obesity indices. Body weight and body mass index (BMI) were inversely related to SHBG level in both premenopausal (p<0.005) and postmenopausal women (p<0.005) after adjusting for age. E2 levels during any phase in premenopausal girls were not related to BMI, whereas heavier girls had significantly higher levels of late luteal-phase Pg (p<0.05). Taller postmenopausal women had lower E2 levels (p<0.05). Results on the association between SHBG and BMI are consistent with previous results in Caucasian women, and might suggest the potential role of bioavailable estradiol in breast carcinogenesis in pre- and post-menopausal women. The finding that progesterone might be related to body mass in premenopausal women should be pursued in further studies.

Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a case-control study in Pusan, Korea.

BACKGROUND: Liver cancer mortality in Korea is the highest in the world. Hepatitis B and C viruses (HBV, HCV) are known to be the major risk factors of hepatocellular carcinoma (HCC). Cholangiocarcinoma (CLG) accounts for more than 20% of liver cancer in the Pusan area. In Korea, the different roles of known risk factors in the development of HCC or CLG have not been adequately evaluated. METHODS: Case-control studies involved 203 incident HCC cases, 406 controls matched to the HCC cases for age (+/- 4 years) and sex, and 41 CLG cases (the HCC controls were used). They were carried out from August 1990 to August 1993. RESULTS: Relative risk (RR) of HBsAg (87.4; 95% confidence interval [CI]: 22.2-344.3) and RR of anti-HCV positivity (30.3; 95% CI: 6.1-150.6) were significant for the risk of HCC after adjustment for potentially confounding factors. In contrast, RR of Clonorchis sinensis in stool (2.7; 95% CI: 1.1-6.3) and RR of heavy drinking (4.6; 95% CI: 1.4-15.2) were significant for the risk of CLG. Transfusion history, acupuncture history, and cigarette smoking were not associated with the risk of HCC or CLG. CONCLUSIONS: Strong evidence indicated that both HBV and HCV infection were independent risk factors for HCC. In contrast, C. sinensis in stools and heavy drinking were associated with the risk of CLG in Korea.

Health consciousness in relation to education in Korea--focusing on seven preventable health risk factors.

This research was carried out to investigate the relationships of a set of several selected sociodemographic variables with a group of health-related practices with special emphasis on educational attainment. The sample consisted of 5,245 adults aged 20-59 selected through stratified cluster random sampling. Univariate, multiple logistic regression and canonical correlation procedures were employed for analyses. It was found that educational attainment was independently associated with at-risk health behavior; the less educated had less desirable health habits than the more educated. Pattern of at-risk health behavior varied with educational level; the significant health-related practice variables among the seven factors were cigarette smoking, heavy alcohol drinking, physical inactivity, being overweight, and inadequate sleeping. These findings suggested that the less educated should be given higher priority in health education programs for the identified health risk behavior and in the formulation of related health policies.