Reproducible imaging-based prediction of molecular subtype and risk stratification of gliomas across different experience levels using a structured reporting system.

OBJECTIVES: To determine reproducible MRI parameters predictive of molecular subtype and risk stratification in glioma and develop a structured reporting system. METHODS: All study patients were initially diagnosed with glioma, 141 from the Cancer Genome Atlas and 131 from our tertiary institution, as training and validation sets, respectively. Images were analyzed by three neuroradiologists with 1-7 years of experience. MRI features including contrast enhancement pattern, necrosis, margin, edema, T2/FLAIR mismatch, internal cyst, and cerebral blood volume higher than normal cortex were reported using a structured reporting system. The pathology was stratified into five risk types: (1) oligodendroglioma, isocitrate dehydrogenase [IDH]-mutant, 1p19q co-deleted; (2) diffuse astrocytoma, IDH-mutant, grade II-III; (3) glioblastoma, IDH-mutant, grade IV; (4) diffuse astrocytoma, IDH-wild, grade II-III; and (5) glioblastoma, IDH-wild, grade IV. Significant predictors were selected using multivariate logistic regression, and diagnostic performance was tested using a validation set. RESULTS: Reproducible imaging parameters exhibiting > 50% agreement across readers included the presence of necrosis, T2/FLAIR mismatch, internal cyst, and predominant contrast enhancement. In the validation set, prediction of risk type 5 exhibited the highest diagnostic performance with AUCs of 0.92 (reader 1) and 0.93 (reader 2) with predominant enhancement, followed by risk type 2 with AUCs of 0.95 and 0.95 with T2/FLAIR mismatch sign and no necrosis, and risk type 1 with AUCs of 0.84 and 0.83 with internal cyst or necrosis. Risk types 3 and 4 were difficult to visually predict. CONCLUSIONS: Imaging parameters with high reproducibility enabling prediction of IDH-wild-type glioblastoma, IDH-mutant/1p19q co-deletion oligodendroglioma, and IDH-mutant diffuse astrocytoma were identified. KEY POINTS: • Reproducible MRI parameters for determining molecular subtypes of glioma included the presence of necrosis, T2/FLAIR mismatch, internal cyst, and predominant contrast enhancement. • IDH-wild type glioblastoma, IDH-mutant/1p19q co-deletion oligodendroglioma, and IDH-mutant low-grade astrocytoma were identified using MRI parameters with high inter-reader reproducibility. • Identification of IDH-wild type low-grade glioma and IDH-mutant glioblastoma was difficult by visual analysis.

Estimated Prevalence and Incidence of Uterine Leiomyoma, and Its Treatment Trend in South Korean Women for 12 years: A National Population-Based Study.

Background: Although uterine leiomyoma causes many problems, including infertility, there are few studies that have investigated the epidemiologic characteristics of uterine leiomyoma in South Korea. The aim of this study is to estimate the prevalence and incidence of uterine leiomyoma in South Korea and analyze the treatment trends. Materials and Methods: Women of reproductive age (15-54 years) were selected from the Korean National Health Insurance Service (NHIS) sample cohort dataset, which was collected from 2002 to 2013. Patients with uterine leiomyoma were identified by ICD-10 (International Codes of Disease, 10th Edition) and intervention codes. Prevalence and incidence were calculated from the NHIS cohort dataset and the treatment trends were analyzed for diagnosed patients. Results: The prevalence in overall age groups increased from 0.96% in 2002 to 2.43% in 2013, and the 1-year incidences of all age groups increased. The 26-30 age group showed the highest rate of 1-year incidence increase (2.14-folds, 0.33% in 2003 to 0.70% in 2013). The proportion of myomectomy increased from 22% in 2002 to 49% in 2013, whereas the proportion of hysterectomy decreased from 78% to 45%. Conclusions: The prevalence and incidence of uterine leiomyoma are increasing in South Korea as time progresses, and the rate of incidence increase is higher in younger reproductive women. Overall trends in uterine leiomyoma treatment are shifting to the methods of the saving uterus.

The Estimated Prevalence and Incidence of Endometriosis With the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC): A National Population-Based Study.

BACKGROUND: The incidence and prevalence of endometriosis remain unclear due to diagnostic difficulties. Especially, there has been little information regarding the population-based epidemiology of endometriosis. The purpose of this study is to estimate the prevalence and incidence of endometriosis in Korea based on the health insurance claims data. METHODS: This study is a retrospective cohort study using the Korean National Health Insurance Service-National Sample Cohort, which correspond to approximately 1 million Korean populations from 2002 to 2013. Patients aged 15-54 years were selected, and the prevalence and incidence of endometriosis were estimated by time and age groups. RESULTS: The age-adjusted prevalence rate of endometriosis also increased from 2.12 per 1,000 persons (95% confidence interval [CI], 2.01-2.24) in 2002 to 3.56 per 1,000 persons (95% CI, 3.40-3.71) in 2013. The average adjusted incidence showed no statistically significant increase. However, the age-specific incidence of the 15-19 and 20-24 years age groups increased significantly from 0.24 and 1.29 per 1,000 persons in 2003 to 2.73 and 2.71 per 1,000 persons in 2013 (R2 = 0.93 and 0.77, P < 0.001), while the incidence rate of the age group 40-44 and 45-49 years decreased from 2.36 and 1.72 per 1,000 persons in 2003 to 0.81 and 0.27 per 1,000 persons in 2013 (R2 = 0.83 and 0.89, P < 0.001). CONCLUSION: The prevalence and incidence of endometriosis in Korean women were lower than that of previous reports in high-risk population studies. Furthermore, we found a significant increase in the diagnosis of endometriosis in younger age groups.

Clinical practice guidelines for radiofrequency ablation of benign thyroid nodules: a systematic review.

PURPOSE: Thermal ablation is a novel treatment alternative for benign thyroid nodules, and one of the most promising thermal ablation techniques is radiofrequency ablation (RFA). Considering the increasing use of thyroid RFA, some scientific societies have proposed clinical practice guidelines. We systemically reviewed and compared these guidelines for thyroid RFA to identify a standard treatment strategy that represents the positions of most societies. METHODS: We searched the MEDLINE and EMBASE databases for studies with human participants that were published in English between January 1, 2000 and August 2, 2019. Studies containing clinical practice guidelines for the RFA of benign thyroid nodules were included. We extracted data regarding indications, pre- and post-procedural evaluations, treatment techniques, and the need to obtain informed consent. RESULTS: Of the 83 studies found, four studies were included, and one study was added after searching the bibliographies of those articles. The five included studies were guidelines developed by the Korean Society of Thyroid Radiology, a group of experts from Italian scientific societies, the Italian Working Group on Minimally Invasive Treatments of the Thyroid, the United Kingdom's National Institute for Health and Clinical Excellence, and a group of four professional Austrian thyroid associations. Indications, pre- and post-procedural evaluations, and techniques were similar across studies; however, differences in each of these categories were found. CONCLUSION: While the reviewed guidelines are similar with regard to major categories, international guidelines for the RFA of benign thyroid nodules should be established in the future.

Antiproliferative Effect of 4-Methylumbelliferone in Epithelial Ovarian Cancer Cells Is Mediated by Disruption of Intracellular Homeostasis and Regulation of PI3K/AKT and MAPK Signaling.

Ovarian cancer has a high mortality rate and high resistance to chemotherapy. Thus, many studies are currently assessing the ability of natural products to induce ovarian cancer cell death. A coumarin derivative, 4-methylumbelliferone (4-MU), has been reported to have anti-cancer effects on various cancers, but its effects on ovarian cancer are not fully understood. In this study, we identified the intracellular mechanism underlying the effects of 4-MU on epithelial ovarian cancer cells. Decreased ovarian cancer cell proliferation and an accumulation of cells in the G2/M phase were observed following 4-MU treatment. Moreover, 4-MU interfered with calcium homeostasis; induced endoplasmic reticulum stress in both cell lines; inhibited AKT and S6 phosphorylation; and increased ERK1/2, P38, and JNK phosphorylation. Furthermore, 4-MU and pharmacological inhibitors showed synergic effects in suppressing cell proliferation. Collectively, our current data indicate that antitumor effects of 4-MU could be appropriate for use as a therapeutic agent against epithelial ovarian cancer cells.

Successfully removed uterine angioleiomyoma by robot-assisted laparoscopic myomectomy.

Angioleiomyoma is a rare type of leiomyoma variant and there are a few cases reported to date. Herein, we present a case of angioleiomyoma in a 36-year-old woman with lower abdominal pain, initially diagnosed by degenerated uterine leiomyoma. The transvaginal ultrasonogram showed an ovoid-shaped heterogeneously hyperechoic lesion in left cornual site of uterus and pelvic magnetic resonance image showed an about 5.1 cm sized heterogenous T2 intermediate high mass with poor enhancement. The patient underwent a robot-assisted laparoscopic myomectomy, and final histopathologic diagnosis revealed uterine angioleiomyoma. This case is the first case of angioleiomyoma resected by robotic surgery. The patient is on follow up for over 1 year and shows no evidence of recurrence until now.

Effects of fermentation on SDS-PAGE patterns, total peptide, isoflavone contents and antioxidant activity of freeze-thawed tofu fermented with Bacillus subtilis.

To develop a new healthy functional tofu product, the pH, total cell number, SDS-PAGE patterns, contents of reducing sugar, peptide, isoflavones, antioxidant activity and digestibility of freeze-thawed tofu, fermented with Bacillus subtilis for various time periods, were investigated. In SDS-PAGE patterns, the band intensities of 7S and 11S globulins were slightly decreased and new protein bands of lower molecular weight appeared by fermentation for 12 h. After 18 h, the bands of 7S globulin and the acidic subunit of 11S globulin had almost entirely disappeared and the basic subunit band of 11S globulin was fainter. An 18 h of fermentation was thought to be the most desirable, because the contents of reducing sugar, total peptide, and isoflavone aglycones (daidzein and genistein), as well as antioxidant activities and digestibility of freeze-thawed tofu were more increased by the fermentation for 18 h.

Analysis of MED12 Mutation in Multiple Uterine Leiomyomas in South Korean patients.

Uterine leiomyomas are one of the most common benign gynecologic tumors, but the exact causes are not completely understood. In 2011, through DNA sequencing, MED12 mutation was discovered in approximately 71% of uterine leiomyomas. Several recent studies confirmed the high frequency of MED12 mutation in uterine leiomyoma. Nevertheless, no study has been done on MED12 mutation in the case of patients with multiple leiomyomas in a patient. The purpose of this study was to investigate the frequency of MED12 mutations in uterine leiomyomas of South Korean patients. In addition, we examined MED12 mutation in multiple leiomyomas in the same patients. Uterine leiomyoma tissues were obtained from symptomatic women who underwent hysterectomy or myomectomy for medically indicated reasons. We collected 60 uterine leiomyomas from 41 women. Tumor size ranged from 1 to 12cm. Patients' ages ranged from 25 to 55 years with an average of 38.4 years. Of the 60 tumors, 40 (66.67%) displayed MED12 mutation. Among the 41 patients, 14 patients had multiple leiomyomas and we analyzed those multiple leiomyomas. Three of them had the same mutations. Five of them, each leiomyoma had a different mutation. Two of them did not have mutation. Four of them had both mutation-positive and mutation-negative leiomyomas. In conclusion, we confirmed the high frequency of the MED12 mutation in uterine leiomyomas of South Korean patients. We also identified various MED12 mutation status in patients with multiple leiomyomas. This suggests that in a given patient, different tumors may have arisen from different cell origins and therefore it is supposed that occurrence of multiple leiomyoma in a single patient may not be caused by intrauterine metastasis or dissemination.

Three cases of complications after high-intensity focused ultrasound treatment in unmarried women.

High-intensity focused ultrasound (HIFU) has been regarded as a non-surgical, minimally invasive therapeutic option for patients who prioritize uterus-conservation. Although many studies have shown that HIFU therapy is a safe and effective treatment of uterine fibroid, not all fibroids are suitable for HIFU due to risks of serious complications. We experienced three cases of complications after the HIFU ablation for huge uterine fibroids, including two cases of rapid myoma enlargement and one case of heavy vaginal bleeding.

EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex.

Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing "methyl degron"; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.

In planta expression screens of Phytophthora infestans RXLR effectors reveal diverse phenotypes, including activation of the Solanum bulbocastanum disease resistance protein Rpi-blb2.

The Irish potato famine pathogen Phytophthora infestans is predicted to secrete hundreds of effector proteins. To address the challenge of assigning biological functions to computationally predicted effector genes, we combined allele mining with high-throughput in planta expression. We developed a library of 62 infection-ready P. infestans RXLR effector clones, obtained using primer pairs corresponding to 32 genes and assigned activities to several of these genes. This approach revealed that 16 of the 62 examined effectors cause phenotypes when expressed inside plant cells. Besides the well-studied AVR3a effector, two additional effectors, PexRD8 and PexRD36(45-1), suppressed the hypersensitive cell death triggered by the elicitin INF1, another secreted protein of P. infestans. One effector, PexRD2, promoted cell death in Nicotiana benthamiana and other solanaceous plants. Finally, two families of effectors induced hypersensitive cell death specifically in the presence of the Solanum bulbocastanum late blight resistance genes Rpi-blb1 and Rpi-blb2, thereby exhibiting the activities expected for Avrblb1 and Avrblb2. The AVRblb2 family was then studied in more detail and found to be highly variable and under diversifying selection in P. infestans. Structure-function experiments indicated that a 34-amino acid region in the C-terminal half of AVRblb2 is sufficient for triggering Rpi-blb2 hypersensitivity and that a single positively selected AVRblb2 residue is critical for recognition by Rpi-blb2.