Current Status of Human Papillomavirus Infection and Introduction of Vaccination to the National Immunization Program in Korea: an Overview

Human Papillomavirus (HPV) infection is the most common sexually transmitted infection and is associated with the development of cervical cancer. The purpose of this report is to provide the literature evidences on selecting the HPV vaccine for national immunization program (NIP) in Korea. To complete these tasks, we reviewed domestic and foreign literature on the current status of HPV infection, efficacy and effectiveness of HPV vaccine, safety of vaccine and cost effectiveness analysis of vaccination business. Given that the median age of first sexual intercourse is continuing to fall, this may have serious implications for HPV infection and cervical cancer incidence at the age of 20s. The World Health Organization recommends that the HPV vaccination should be included in the NIP being implemented in each country. Both the bivalent and quadrivalent vaccines have a 90% or greater preventive efficacy on cervical intraepithelial lesion 2-3 and cervical cancer by the HPV 16 or HPV 18. In the future, if HPV vaccination rate as part of NIP increases, it is expected that the incidence of HPV infection, genital warts, and cervical precancerous lesions will be decreased in the vaccination age group. Therefore, in order to increase the HPV vaccination rate at this point in Korea, social consensus and efforts such as the introduction and promotion of HPV vaccine to the NIP according to appropriate cost-effectiveness analysis are required.ope

Prognostic implications of forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) in epithelial ovarian cancer

BACKGROUND: Transcription factors forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) have been reported to play important roles in various cancers. However, their role in epithelial ovarian cancer (EOC) has not been elucidated yet. Therefore, we evaluated the expression and clinical significance of FOXO1 and PAX3 in EOC. METHODS: Immunohistochemical analyses of FOXO1 and PAX3 in 212 EOCs, 57 borderline ovarian tumors, 153 benign epithelial ovarian tumors, and 79 nonadjacent normal epithelial tissues were performed using tissue microarray. Various clinicopathological variables, including the survival of EOC patients, were compared. In addition, the effect of FOXO1 on cell growth was assessed in EOC cell lines. RESULTS: FOXO1 and PAX3 protein expression levels were significantly higher in EOC tissues than in nonadjacent normal epithelial tissues, benign tissues, and borderline tumors (all p < 0.001). In EOC tissues, FOXO1 expression was positively correlated with PAX3 expression (Spearman's rho = 0.118, p = 0.149). Multivariate survival analysis revealed that high FOXO1 expression (hazard ratio = 2.77 [95% CI, 1.48-5.18], p = 0.001) could be an independent prognostic factor for overall survival. Most importantly, high expression of both FOXO1 and PAX3 showed a high hazard ratio (4.60 [95% CI, 2.00-10.55], p < 0.001) for overall survival. Also in vitro results demonstrated that knockdown of FOXO1 was associated with decreased cell viability, migration, and colony formation. CONCLUSIONS: This study revealed that high expression of FOXO1/PAX3 is an indicator of poor prognosis in EOC. Our results suggest the promising potential of FOXO1 and PAX3 as prognostic and therapeutic markers. The possible link between biological functions of FOXO1 and PAX3 in EOC warrants further studies.ope

Recurrent spontaneous hepatic rupture in pregnancy

RATIONALE: Spontaneous and repeated hepatic ruptures caused by hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome are uncommon but life-threatening conditions that rarely occur early in the second trimester of pregnancy. PATIENT CONCERNS: We describe a patient who experienced spontaneous hepatic ruptures in the absence of hypertension during the early second trimesters of both her first and second pregnancies. DIAGNOSES: A 34-year-old multiparous woman without hypertension was admitted at 21 weeks' gestation because of a spontaneous hepatic rupture with hemoperitoneum. Four years previously, the patient had undergone an exploratory laparotomy during her first pregnancy that involved the ligation of bleeders, because a hepatic capsule rupture had caused hemoperitoneum development. INTERVENTIONS: Unlike the first pregnancy, she was managed nonsurgically and conservatively during the second pregnancy, and she underwent frequent laboratory analyses and magnetic resonance imaging follow-up. On day 11 of the patient's hospital admission, we decided to deliver the baby at 23 weeks' gestation, because her condition had deteriorated. OUTCOMES: Non-surgical management improved the patient's outcome, and the baby was born alive, even though the pregnancy was in the early second trimester and the maternal condition was deteriorating rapidly. LESSONS: HELLP syndrome without hypertension and the recurrence of an intrahepatic rupture at an extremely premature gestational age are rare. This patient's findings suggested HELLP syndrome, which was subsequently diagnosed. This patient's clinical course highlights the difficult decisions made by clinicians for mothers and fetuses.ope

Prediction of small-for-gestational age by fetal growth rate according to gestational age

BACKGROUND: Small-for-gestational age (SGA) infants should be identified before birth because of an increased risk of adverse perinatal outcomes. The objective of this study was to assess the impact of fetal growth rate by gestational age on the prediction of SGA and to identify the optimal time to initiate intensive fetal monitoring to detect SGA in low-risk women. We also sought to determine which the ultrasonographic parameters that contribute substantially to the birthweight determination. METHODS: This was a retrospective study of 442 healthy pregnant women with singleton pregnancies. There were 328 adequate-for-gestational age (AGA) neonates and 114 SGA infants delivered between 37+0 and 41+6 weeks of gestation. We compared the biparietal diameters (BPD), head circumferences (HC), abdominal circumferences (AC), femur lengths (FL), and estimated fetal weights (EFW) obtained on each ultrasound to determine which of these parameters was the best indicator of SGA. We created receiver operating characteristic curves, calculated the areas under the curves (AUCs), and analyzed the data using multivariable logistic regressions to assess the ultrasound screening performances and identify the best predictive factor. RESULTS: Among the four ultrasonographic parameters, the AC measurement between 24+0~28+6 weeks achieved a sensitivity of 79.5% and a specificity of 71.7%, with an AUC of 0.806 in the prediction of SGA. AC showed consistently higher AUCs above 0.8 with 64~80% sensitivities as gestational age progressed. EFW measurements from 33+0~35+6 gestational weeks achieved a sensitivity of 60.6% and a specificity of 87.6%, with an AUC of 0.826. In a conditional growth model developed from the linear mixed regression, the value differences between AC and EFW in the SGA and AGA groups became even more pronounced after 33+0~35+6 weeks. CONCLUSION: Healthy low-risk women with a low fetal AC after 24 weeks' gestation need to be monitored carefully for fetal growth to identify SGA infants with a risk for adverse perinatal outcomes.ope

Overexpression of glucocorticoid receptor promotes the poor progression and induces cisplatin resistance through p38 MAP kinase in cervical cancer patients

Glucocorticoid receptor (GR) is activated by synthetic glucocorticoid or endogenous cortisol which were released by the physical and psychosocial stress, and recent studies reported that it is involved in tumor initiation and metastasis in various solid cancers. However, role of GR in cervical cancer has not been elucidated yet. Therefore, here we aim to unveil the role of GR in cervical cancer with cervical cancer clinical specimen and cervical cancer cell lines. We found that overexpression of GR was associated with poor prognosis in cervical cancer patients. Also, GR knockdown in cervical cancer cell lines showed diminished proliferation, invasion and EMT properties. Besides, we found that GR was positively associated with FoxP3 expression, and combination of GR and FoxP3 overexpression revealed as more reliable biomarker for poor prognosis and poor response to chemotherapy of cervical cancer patient than GR alone. Moreover, FACS-based Annexin-V/PI double staining and cleavage of poly ADP ribose polymerase (PARP) showed that siGR enhanced cisplatin-induced apoptosis, which was mediated by p38 MAP kinase. Collectively, our findings established that the combination of high GR and FoxP3 was associated with cervical cancer progression and platinum resistance, suggesting a potential predictive biomarker for clinical management in patients with cervical cancer.ope

Prognostic Significance of Transient Receptor Potential Vanilloid Type 1 (TRPV1) and Phosphatase and Tension Homolog (PTEN) in Epithelial Ovarian Cancer

Background: Transient receptor potential vanilloid type 1 (TRPV1) has been studied in human malignancies, but has not been studied in epithelial ovarian cancer (EOC). We, therefore, investigated the significance of TRPV1 and correlation with phosphatase and tension homolog (PTEN) in EOC. Materials and methods: Immunohistochemical analyses for TRPV1 and PTEN were performed using a tissue microarray. Moreover, the role of TRPV1 in cell growth was assessed in a EOC cell line. Results: High TRPV1 expression and the combination of high TRPV1 and low PTEN expression were an independent prognostic factor for overall survival and disease-free survival. In vitro results demonstrated that knockdown of TRPV1 was associated with decreased cell viability and colony formation. Conclusion: There is a strong association between TRPV1 and PTEN and the combination of TRPV1 and PTEN is a strong indicator of prognostic predictor in EOC.ope

High ATP6V1B1 expression is associated with poor prognosis and platinum‑based chemotherapy resistance in epithelial ovarian cancer

The vacuolar ATPase H+ transporting V1 subunit B1 (ATP6V1B1) belongs to the family of ATP6Vs, which functions to transport hydrogen ions. The expression of ATP6V1B1 and associated clinicopathological features have been linked to various cancers; however, its role in epithelial ovarian cancer (EOC) has remained to be explored. The present study aimed to unveil the function, molecular mechanisms and clinical significance of ATP6V1B1 in EOC. The mRNA levels of ATP6V1 subunits A, B1 and B2 in EOC tissues were determined using data from the Gene Expression Profiling Interactive Analysis database and RNA sequencing. Protein levels of ATP6V1B1 were evaluated through immunohistochemistry staining of EOC, borderline, benign and normal epithelial tissues. The association between ATP6V1B1 expression and clinicopathological features and prognosis of patients with EOC was analyzed. Furthermore, the biological role of ATP6V1B1 in ovarian cancer cell lines was also assessed. RNA sequencing and public dataset analyses revealed elevated ATP6V1B1 mRNA levels in EOCs. High ATP6V1B1 protein levels were also observed in EOC compared with those of borderline and benign tumors and nonadjacent normal epithelial tissues. High ATP6V1B1 expression was associated with the serous cell type, advanced International Federation of Gynecology and Obstetrics stage, high/advanced tumor grade, elevated serum cancer antigen 125 levels and platinum resistance (P<0.001, P<0.001, P=0.035, P=0.029 and P=0.011, respectively). High expression levels of ATP6V1B1 were also associated with poor overall and disease‑free survival (P<0.001). Knockdown of ATP6V1B1 decreased cancer cell proliferation and colony‑forming abilities (P<0.001) in vitro by inducing cell cycle arrest in G0/G1 phase. Significant upregulation of ATP6V1B1 was observed in EOC and the prognostic significance and association with chemotherapy resistance of ATP6V1B1 in EOC was demonstrated, rendering it an EOC‑related biomarker for prognostic evaluation and chemotherapy resistance, as well as a potential therapeutic target for patients with EOC.ope

Establishment of five immortalized human ovarian surface epithelial cell lines via SV40 T antigen or HPV E6/E7 expression

BACKGROUND: Human ovarian surface epithelial (HOSE) cells are a critical cell source for ovarian cancer research; however, they are difficult to obtain and maintain under standard laboratory conditions in large quantities. The aim of this study was to generate immortalized HOSE (IHOSE) cells with maintained properties to the original cell source, thereby guaranteeing a sufficiently large cell quantity for ovarian cancer research. METHODS: HOSE cells isolated from four non-cancer patients and five IHOSE cell lines were established by induction of HPV-E6/E7 expression or SV40 large T antigen using a lenti-viral system. Each of IHOSE cells was confirmed to be distinct by STR profiling. RNA-sequencing was used to compare gene expression profiles in HOSE, IHOSE and ovarian cancer cells. RESULTS: RNA-sequencing results revealed a stronger linear correlation in gene expression between IHOSE and HOSE cells (R2 = 0.9288) than between IHOSE or HOSE cells and ovarian cancer cells (R2 = 0.8562 and R2 = 0.7982, respectively). The gene expression pattern of 319 differentially expressed genes revealed minimal differences between HOSE and IHOSE cells, while a strong difference between ovarian cancer cells and HOSE or IHOSE cells was observed. Furthermore, the five IHOSE cell lines displayed morphological characteristics typical of epithelial cells but showed a lower level of EpCAM, CD133 and E-cadherin, as cancer stem marker, than ovarian cancer cells. Moreover, unlike cancer cells, IHOSE cells could not form colonies in the anchorage-independent soft agar growth assay. CONCLUSION: These findings demonstrate that five newly established IHOSE cell lines have characteristics of progenitor HOSE cells while exhibiting continuous growth, and thus, should be highly useful as control cells for ovarian cancer research.ope

한국 남해안 해양 플라스틱 쓰레기에 서식하는 대형무척추동물의 시공간적 분포

The recruitment of marine organisms by marine plastic debris (MPD) presumably affects the species diversity and community structure of the marine ecosystem, but relevant research is limited. This study analyzed the temporal-spatial distribution characteristics of attached macroinvertebrates on MPD. The Macroinvertebrates attached on MPD were collected once every three months from March to December 2021 in eight regions. MPD materials on aquaculture and fishing gear were most frequently detected during the study; foreign-originating MPD was present in Jeju Island and Shinan. In total, two phyla, 14 orders, 19 families, and 41 species of attached macroinvertebrates were detected during the investigation. Attached macroinvertebrates increased more on MPD from the ocean than on MPD from land, and the number of species that appeared was high on MPDs with soft surfaces such as EPS (Expanded Polystyrene) or rough materials such as ropes. Among the surveyed areas, the number of species was high in Jeju Island and the Shinan. However, there was no difference in the number of observed species according to the collection period. On the entire MPD, the individual numbers of the alien species Mytilus galloprovincialis (blue mussel) was high. Among Chinese-originating MPD, the pelagic species, Lepas (Lepas) anatifera (gooseneck barnacle) was predominant on plastic bottles. These findings suggest that the temporal-spatial distribution of attached macroinvertebrates on MPD may be affected by the duration of exposure to the water layer and the characteristics of the MPD material. In particular, the high appearance of L. anatifera on Chinese-originating MPD suggests that MPD flowing into the ocean serves as a passageway for the inflow of alien species, indicating a need for continuous monitoring.1. Introduction 1 2. Materials and Methods 3 2.1 Study area 3 2.2 Classification of marine plastic debris 5 2.3 Sampling methods 7 3. Results 10 3.1 Marine plastic debris and attached macroinvertebrates 10 3.2 Comparison of marine plastic debris material/area 16 3.3 Comparison of marine plastic debris material/area by period 22 3.4 Comparison of attached macroinvertebrates according to the area of marine plastic debris inflow 26 3.5 Appearance of major species 32 4. Discussion 36 4.1 Marine plastic debris inflow into Korea 36 4.2 Comparison of attached macroinvertebrates according to marine plastic debris material/area 37 4.3 Attached macroinvertebrates dominant species 39 4.4 Attached macroinvertebrates of foreign-originating marine plastic debris 44 4.5 Conclusion 46 References 4 Appendix 52 Abstract (Korean) 54Maste

상피성 난소암에 호르몬 수용체 발현 패턴에 따른 종양침윤 림프구의 임상적 의의 및 상피성 난소암과 재발성 난소암에서 호르몬 수용체 발현 패턴의 변화에 따른 임상적 의의

Hormone receptor expression patterns often correlate with infiltration of specific lymphocytes in tumors. Specifically, the presence of specific tumor infiltrating lymphocytes (TILs) with particular hormone receptor expression is reportedly associated with breast cancer, however, this has not been revealed in epithelial ovarian cancer (EOC). Therefore, we investigated the association between hormone receptor expression and TILs in EOC. Immunohistochemical analysis of estrogen receptor (ER)α, androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), ERβ, CD3+, CD4+, CD8+, FoxP3+, PD-1, and PD-L1 was performed using tissue microarray analysis or whole sections. NanoString analyses compared normal epithelial and EOC tissues, which were clustered based on hormone receptor expression patterns using complementary bioinformatic approaches. ERα, AR, and GR expression increased in EOC, while PR was significantly reduced and ERβ expression showed a reduced trend compared to normal epithelium. Cluster analysis indicated poor disease free survival (DFS) in AR+/GR+/PR+ subgroup (triple dominant group); while Cox proportional-hazards model highlighted the triple dominant group as an independent prognostic factor for DFS. In addition, significant upregulation of FoxP3+ TILs, PD-1, and PD-L1 was observed in the triple dominant group compared to other groups. NanoString analyses further suggested that tumor necrosis factor (TNF) and/or NF-κB signaling pathways were activated with significant upregulation of RELA, MAP3K5, TNFAIP3, BCL2L1, RIPK1, TRAF2, PARP1, and AKT1 in the triple dominant EOC group. The triple dominant subgroup correlates with poor prognosis in EOC. Moreover, the TNF and/or NF-κB signaling pathways may be responsible for hormone-mediated inhibition of the immune microenvironment.open박