Clinicopathologic significance of mismatch repair protein expression in endometrioid endometrial cancer.

OBJECTIVE: To evaluate the association between mismatch repair (MMR) protein expression and clinico-pathologic outcomes in patients with endometrioid endometrial cancer (EC). MATERIALS AND METHODS: A retrospective review of the clinico-pathologic outcomes was performed on patients who were diagnosed with EC and had results of MMR protein immunohistochemistry. MMR-deficient (MMR-d) was defined as absence of expression in any of the 4 MMR proteins (MLH1, MSH2, MSH6, and PMS2). Demographics, pathologic variables, and survival outcomes were compared according to the MMR status. RESULTS: A total of 193 EC patients with available MMR expression data were included, of whom 163 patients had endometrioid type EC. Overall, 44 patients (27.0%) were classified as MMR-d. Compared with MMR-proficient (MMR-p) group, MMR-d group was associated with more frequent lymphovascular space invasion (LVSI, p = 0.001). MMR-d was also related with higher risk of lymph node (LN) metastasis in endometrioid type EC (p = 0.008), especially para-aortic LN metastasis. During the median follow-up period of 19.1 months (1-44.5), MMR-d group, especially MLH1/PMS2 subgroup, showed a tendency of reduced PFS (p = 0.036 and p = 0.008, respectively). On Cox regression analysis, however, LN metastasis remained as the only independent risk factor for PFS (p = 0.004) in endometrioid EC, and MLH1/PMS2 loss showed a marginally significant association (p = 0.054). CONCLUSION: Our findings of the associations between MMR deficiency and poor prognostic factors, such as LVSI and LN metastasis, may suggest the prognostic value of MMR status in EC and need further prospective validation studies.

Setting the clock of neural progenitor cells during mammalian corticogenesis.

Radial glial cells (RGCs) as primary neural stem cells in the developing mammalian cortex give rise to diverse types of neurons and glial cells according to sophisticated developmental programs with remarkable spatiotemporal precision. Recent studies suggest that regulation of the temporal competence of RGCs is a key mechanism for the highly conserved and predictable development of the cerebral cortex. Various types of epigenetic regulations, such as DNA methylation, histone modifications, and 3D chromatin architecture, play a key role in shaping the gene expression pattern of RGCs. In addition, epitranscriptomic modifications regulate temporal pre-patterning of RGCs by affecting the turnover rate and function of cell-type-specific transcripts. In this review, we summarize epigenetic and epitranscriptomic regulatory mechanisms that control the temporal competence of RGCs during mammalian corticogenesis. Furthermore, we discuss various developmental elements that also dynamically regulate the temporal competence of RGCs, including biochemical reaction speed, local environmental changes, and subcellular organelle remodeling. Finally, we discuss the underlying mechanisms that regulate the interspecies developmental tempo contributing to human-specific features of brain development.

Role of systematic lymphadenectomy in patients with intermediate to high-risk early stage endometrial cancer.

OBJECTIVE: To determine the clinical significance of systematic lymph node dissection (LND) and to better define the relevant extent of LND in intermediate- to high-risk early stage endometrial cancer (EC). METHODS: Patients who received surgery as a primary treatment of histologically confirmed EC and preoperatively considered as uterus-confined early stage disease were included in the study population. The rates of lymph node metastasis (LNM) according to the risk groups and anatomic sites were assessed. Univariate and multivariate analyses were performed to evaluate risk factors for recurrence. RESULTS: A total of 804 patients were included in the study analysis. The rates of LNM were significantly different according to the risk group; 1.2% in low-risk, 20.1% in intermediate-risk, and 30.0% in high-risk group. When assessing the rates of LNM in individual anatomic sites, positive LNs were evenly distributed throughout the pelvic and para-aortic regions. In the intermediate to high-risk EC cases, the rates of para-aortic LNM below and above inferior mesenteric artery (IMA) were 11.1% and 12.5%, respectively. On multivariate analysis, LNM was the only independent risk factor for recurrence in the intermediate to high-risk EC (hazard ratio=2.63, 95% confidence interval=1.01-6.82, p=0.047). CONCLUSION: LNM was frequently observed in intermediate- and high-risk early stage EC and it served as an independent risk factor for recurrence. When considering the similar rates of LNM between below and above IMA, nodal assessment needs to be performed up to the infra-renal level, especially for the staging purpose in high-risk EC.

Partitioning RNAs by length improves transcriptome reconstruction from short-read RNA-seq data.

The accuracy of methods for assembling transcripts from short-read RNA sequencing data is limited by the lack of long-range information. Here we introduce Ladder-seq, an approach that separates transcripts according to their lengths before sequencing and uses the additional information to improve the quantification and assembly of transcripts. Using simulated data, we show that a kallisto algorithm extended to process Ladder-seq data quantifies transcripts of complex genes with substantially higher accuracy than conventional kallisto. For reference-based assembly, a tailored scheme based on the StringTie2 algorithm reconstructs a single transcript with 30.8% higher precision than its conventional counterpart and is more than 30% more sensitive for complex genes. For de novo assembly, a similar scheme based on the Trinity algorithm correctly assembles 78% more transcripts than conventional Trinity while improving precision by 78%. In experimental data, Ladder-seq reveals 40% more genes harboring isoform switches compared to conventional RNA sequencing and unveils widespread changes in isoform usage upon m6A depletion by Mettl14 knockout.

The characterization of exosomes from fibrosarcoma cell and the useful usage of Dynamic Light Scattering (DLS) for their evaluation.

Exosomes are a type of extracellular vesicles containing mRNA, miRNA, and proteins of origin cells, which can control the characteristics of other cells or surroundings. Despite increasing evidence on oncogenic properties of tumor-derived exosomes, fibrosarcoma-derived exosomes remain largely unrevealed. While the proper extraction and characterization of exosomes is critical in exosomes research, there are various limitations in techniques to measure the size and homogeneity of exosomes. Here, we analyzed exosomes from a fibrosarcoma cell line WEHI-164 compared with a breast cancer cell line MDA-MD-231 as a control. Results from dot blot and western blot analysis demonstrated that GM1 ganglioside, and TSG101, HSC70 and GAPDH proteins were contained in exosomes from the WEHI-164 fibrosarcoma cell line. The existence of tetraspanins such as CD81, CD63 and CD9 was confirmed in the exosomes by ExoView analysis. The results obtained from TEM showed their sphere-like shapes of around 50 to 70 nm in radius. Through DLS, we found out that the mean radius of the exosomes derived from WEHI-164 and MDA-MB-231 cell lines was 94.4 nm and 107.8 nm, respectively, with high homogeneity. When comparing the radius measured by TEM with the radius measured by DLS, it was revealed that the difference between the two methods was about 40 nm. This study has significance in characterizing the molecular properties of exosomes from a fibrosarcoma, which has not been researched much before, and in providing clear evidence that DLS can be used as an efficient, convenient and noninvasive technique to simply check the homogeneity and size of exosomes.

A rare case of gastric-type mucinous adenocarcinoma in a woman with Peutz-Jeghers syndrome.

Adenocarcinoma of the cervix is less common than squamous cell carcinoma. Minimal deviation adenocarcinoma (adenoma malignum) is considered an extremely well-differentiated variant of GAS. An association exists between GAS and Peutz-Jeghers syndrome, which is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation and multiple hamartomatous polyps in the gastrointestinal tracts. The incidence of GAS in patients with Peutz-Jeghers syndrome is estimated to be 11-17%. We present a rare case of adenoma malignum, diagnosed using colposcopic biopsy in a woman with Peutz-Jeghers syndrome, which was histopathologically confirmed to be GAS after surgery.

Currarino syndrome in an adult woman.

Currarino syndrome is a hereditary disease characterized by the triad of sacral agenesis, anorectal malformation, and presacral mass. Most patients are diagnosed in childhood, and this condition rarely manifests in adulthood. In women, gynecological malformations associated with Currarino syndrome have been reported, such as bicornuate uterus, rectovaginal fistula, and septate uterus. We present a rare case of a 29-year-old woman with a suspected pelvic mass who was diagnosed with Currarino syndrome.

Human papillomavirus genotype-specific risk in cervical carcinogenesis.

OBJECTIVE: To evaluate the risk of genotype-specific human papillomavirus (HPV) infections for the spectrum of cervical carcinogenesis and the distribution of HPV types according to age and different cervical lesions. METHODS: This study included HPV-positive women who underwent cervical biopsy at the Cheil General Hospital & Women's Healthcare Center between July 1, 2011 and December 31, 2017. HPV genotyping was conducted using a Cheil HPV DNA chip kit. RESULTS: The study sample consisted of 400 normal, 399 cervical intraepithelial neoplasia (CIN) 1, 400 CIN 2, 400 CIN 3, and 389 cervical cancer cases. HPV 16 was the most common type found with a prevalence of 9.5% in normal, 6.8% in CIN 1, 15.0% in CIN 2, 44.5% in CIN 3, and 64.3% in cervical cancer. The most common HPV types were 16, 52, 58, 53, 51, 56, 68, and 18 in all study samples. HPV 16, 31, 33, and 58 were more common in CIN 2/3 and cancer, and HPV 39, 51, 53, 56, 66, and 68 were more common in CIN 1 and normal cases (p<0.001). In CIN 3 and cervical cancer, HPV 16 was the most common type in all age groups. HPV 52 was the most common type in CIN 2 (all age groups) and in CIN 1/normal (age ≤30 years) cases. Among the high-risk HPV types, 16, 31, 33, 52, and 58 showed significant risk for high-grade disease. CONCLUSIONS: HPV 16, 31, 33, 52, and 58 showed the significant risk of high-grade disease for cervical carcinogenesis.

Clinical outcome of high-grade cervical intraepithelial neoplasia during pregnancy: A 10-year experience.

OBJECTIVE: To investigate the clinical outcome of high-grade cervical intraepithelial neoplasia (CIN) diagnosed by colposcopy-directed biopsy during pregnancy and to evaluate the risk factors for persistent disease. STUDY DESIGN: This retrospective study included pregnant women who were diagnosed with CIN2+ by colposcopy-directed biopsy from January 2005 to December 2014. The clinical characteristics, histopathologic results, and human papillomavirus (HPV) test results were reviewed. The final histopathologic result after delivery was compared with the initial diagnosis to determine disease progression, persistence, or regression. RESULTS: During the 10-year period, 215 pregnant women were diagnosed with high-grade CIN (75 CIN2, 140 CIN3) by colposcopy-directed biopsy. The mean age of the patients was 30.4 years. A total of 187 patients (87.0%) had high-risk HPV infections, with 76 (35.3%) infections identified as HPV genotype 16 or 18. Excisional procedures for diagnosis and treatment were not performed during pregnancy. The histopathologic results of 160 patients (normal in 43, CIN1 in 10, CIN2 in 15, CIN3 in 89, and invasive cancer in 3) were evaluated during the postpartum period. Multivariate logistic regression analysis was performed, and postpartum high-risk HPV infection (OR 5.09; 95% CI 2.15-12.05; P < 0.001) was identified as a significant independent predictor of CIN2+ persistence. CONCLUSIONS: Conservative management of CIN2-3 during pregnancy is acceptable. However, persistent high-risk HPV infection is a major risk factor for CIN2+ persistence. Close follow-up with HPV testing, and postpartum colposcopy evaluation are necessary.

Risk factors of persistent HPV infection after treatment for high-grade squamous intraepithelial lesion.

PURPOSE: To evaluate the risk factors associated with persistent high-risk human papillomavirus (HR HPV) infections in patients undergoing cervical excision for treatment of high-grade squamous intraepithelial lesion (HSIL). METHODS: A retrospective cohort study included 160 patients who underwent cervical excision for treatment of HSIL between January 2014 and December 2014. The clinical characteristics, cervical cytology, and HPV test results were reviewed. Persistent HR HPV infections were identified within 6 months after treatment. The effects of various factors such as patient age, menopausal status, parity, HPV type, and histopathological results on persistent HR HPV infections were assessed using univariate and multivariate analyses. RESULTS: The mean age of patients was 38.1 ± 11.5 years (range 18‒86 years). Among them 148 (92.5%) had HR HPV infections, and persistent infections after surgical treatment were detected in 48 (32.4%) patients. Univariate logistic regression analysis showed that older age (> 50 years), short follow-up duration (< 3 months), and menopause were associated with persistent HR HPV infections. Multivariate analysis showed that menopausal status was the only significant independent predictor for HR HPV persistence after treatment (odds ratio, 5.08; 95% confidence interval, 1.93-13.36; P = 0.001). CONCLUSIONS: Persistent HR HPV infections were detected in approximately 30% of patients within 6 months after cervical excision for HSIL. Elderly patients with menopause are at increased risk of HR HPV persistence after treatment for HSIL.

Risk factors for cytological progression in HPV 16 infected women with ASC-US or LSIL: The Korean HPV cohort.

OBJECTIVE: This study was to identify the risk factors for cytological progression in women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). METHODS: We analyzed data from women infected with the human papillomavirus (HPV) who participated in the Korean HPV cohort study. The cohort recruited women aged 20-60 years with abnormal cervical cytology (ASC-US or LSIL) from April 2010. All women were followed-up at every 6-month intervals with cervical cytology and HPV DNA testing. RESULTS: Of the 1,158 women included, 654 (56.5%) and 504 (43.5%) women showed ASC-US and LSIL, respectively. At the time of enrollment, 143 women tested positive for HPV 16 (85 single and 58 multiple infections). Cervical cytology performed in the HPV 16-positive women showed progression in 27%, no change in 23%, and regression in 50% of the women at the six-month follow-up. The progression rate associated with HPV 16 infection was higher than that with infection caused by other HPV types (relative risk [RR], 1.75; 95% confidence interval [CI], 1.08-2.84; P=0.028). The cytological progression rate in women with persistent HPV 16 infection was higher than that in women with incidental or cleared infections (P<0.001). Logistic regression analysis showed a significant relationship between cigarette smoking and cytological progression (RR, 4.15; 95% CI, 1.01-17.00). CONCLUSION: The cytological progression rate in HPV 16-positive women with ASC-US or LSIL is higher than that in women infected with other HPV types. Additionally, cigarette smoking may play a role in cytological progression.

Full-color capable light-emitting diodes based on solution-processed quantum dot layer stacking.

To date, most of the studies on quantum dot-light-emitting diodes (QLEDs) have been dedicated to the fabrication of high-efficiency monochromatic devices. However, for the ultimate application of QLEDs to the next-generation display devices, QLEDs should possess a full-color emissivity. In this study, we report the fabrication of all-solution-processed full-color-capable white QLEDs with a standard device architecture, where sequentially stacked blue (B)/green (G)/red (R) quantum dot (QD)-emitting layers (EMLs) are sandwiched by poly(9-vinylcarbazole) as the hole transport layer and ZnO nanoparticles (NPs) as the electron transport layer. To produce interlayer mixing-free, well-defined B/G/R QD layering assemblies via successive spin casting, an ultrathin ZnO NP buffer is inserted between different-colored QD layers. The present full-color-capable white QLED exhibits high device performance with the maximum values of 16 241 cd m-2 for luminance and 6.8% for external quantum efficiency. The promising results indicate that our novel EML design of ZnO NP buffer-mediated QD layer stacking may afford a viable means towards bright, efficient full-color-capable white devices.

Clinical outcomes and risk of recurrence among patients with vaginal intraepithelial neoplasia: a comprehensive analysis of 576 cases.

OBJECTIVE: To evaluate the clinical outcomes of vaginal intraepithelial neoplasia (VAIN) and to assess the risk of recurrence and progression to invasive vaginal carcinoma. METHODS: A retrospective review of the clinicopathologic data and clinical outcomes was performed on patients who were diagnosed with VAIN at a single center between January 2000 and July 2016. Demographics, treatments, and clinical outcomes were abstracted from medical records. RESULTS: A total of 576 patients with VAIN1-3 were included in the study analysis. The distribution of VAIN1-3 was as follows: VAIN1 31.1%, VAIN2 45.3%, and VAIN3/carcinoma in situ (CIS) 23.6%. In VAIN1 patients, observation was performed in 29.1% of the cases and 48.8% obtained regression. In VAIN2+ patients, management included observation (3.5%), topical management (6.5%), laser ablation (75.3%), excision (14.1%), and radiotherapy (0.5%) with the following rates of recurrence/progression: 46.2%, 62.5%, 26.4%, 32.7%, and 0%, respectively. Four patients among VAIN3/CIS patients (3.2%) developed invasive vaginal cancer during the follow-up period with a median time to cancer diagnosis of 21.4 months (range, 5.0-44.8 months). On multivariate analysis, high-risk human papillomavirus (HPV) positivity and treatment method were found to be independent risk factors for recurrence and progression (p=0.003 and p=0.001). CONCLUSION: Patients with VAIN are at high-risk of recurrence, but the risk of progression to vaginal cancer is relatively low. Laser or excision provides higher regression rate than topical agent or observation, and high-risk HPV positivity is a risk factor for recurrence. Whatever the treatment method is used, however, the high rate of recurrence warrants long-term follow-up surveillance.

Delphinidin inhibits BDNF-induced migration and invasion in SKOV3 ovarian cancer cells.

Brain-derived neurotrophic factor (BDNF), the TrkB ligand, is associated with aggressive malignant behavior, including migration and invasion, in tumor cells and a poor prognosis in patients with various types of cancer. Delphinidin is a diphenylpropane-based polyphenolic ring structure-harboring compound, which exhibits a wide range of pharmacological activities, anti-tumor, anti-oxidant, anti-inflammatory, anti-angiogenic and anti-mutagenic activity. However, the possible role of delphinidin in the cancer migration and invasion is unclear. We investigated the suppressive effect of delphinidin on the cancer migration and invasion. Thus, we found that BDNF enhanced cancer migration and invasion in SKOV3 ovarian cancer cell. To exam the inhibitory role of delphinidin in SKOV3 ovarian cancer migration and invasion, we investigated the use of delphinidin as inhibitors of BDNF-induced motility and invasiveness in SKOV3 ovarian cancer cells in vitro. Here, we found that delphinidin prominently inhibited the BDNF-induced increase in cell migration and invasion of SKOV3 ovarian cancer cells. Furthermore, delphinidin remarkably inhibited BDNF-stimulated expression of MMP-2 and MMP-9. Also, delphinidin antagonized the phosphorylation of Akt and nuclear translocation of NF-κB permitted by the BDNF in SKOV3 ovarian cancer cells. Taken together, our findings provide new evidence that delphinidin suppressed the BDNF-induced ovarian cancer migration and invasion through decreasing of Akt activation.

Method to minimize ozone effect on Cy5 fluorescent intensity in DNA microarrays.

Cyanine 5 (Cy5) is an established fluorescent dye in microarray analysis. It is degraded rapidly when exposed to atmospheric ozone during post-hybridization washes, which leads to loss of fluorescent intensity. To minimize this undesirable effect, we coated microarray slides with sodium dodecyl sulfate (SDS) solution at post-hybridization washes. The fluorescent intensities on coated slides were more stable than those on uncoated slide. We also performed the microarrays with SDS solution for a year to check the solution's effectiveness along with seasonal changes of atmospheric ozone level. Consistent results in microarray analysis were obtained using Cy5 dye under atmospheric ozone.

Prognostic assessment of sarcomatous histologic subtypes of ovarian carcinosarcoma.

OBJECTIVE: Ovarian carcinosarcoma is a rare subtype of this disease that has not been thoroughly investigated. The aim of this study was to evaluate the prognostic factors and out comes in patients with ovarian carcinosarcoma. METHODS: All patients with histologically confirmed ovarian carcinosarcoma who were treated at Cheil General Hospital and Women's Healthcare Center between January 2000 and December 2015 were identified and analyzed. Data were extracted from medical records, and statistical analyses were performed to determine correlations between clinicopathological parameters and survival outcomes. RESULTS: Of the 822 patients diagnosed with ovarian cancer over 16 years, 11 (1.3%) had ovarian carcinosarcoma histology. Every patient underwent surgery as the initial treatment followed by intravenous adjuvant chemotherapy. Only 18.1% of cases were early stage (I or II) while 81.8% were advanced stage (III or IV) according to the FIGO (International Federation of Gynecology and Obstetrics) classification. Six cases were of the homologous subtype (54.5%) and five were of the heterologous subtype (45.5%). There was no significant difference in survival according to stage (P=0.24). The heterologous subtype and residual disease were associated with poor disease-free survival (P=0.02 and P=0.04) and overall survival (P=0.02 and P=0.04), On multivariate analysis, the histological subtype was an independent prognostic factor (P=0.02). CONCLUSION: Optimal cytoreduction without gross residual disease and a homologous subtype are favorable prognostic factors in terms of disease relapse and survival.

Primary mucinous adenocarcinoma of the vulva, intestinal type.

Primary vulva malignancy is a rare gynecologic malignancy. Most of them are squamous cell carcinomas and adenocarcinomas are much less common. Intestinal type is a rare variant of primary adenocarcinoma of the vulva. It histologically resembles mucinous colonic carcinomas. Origin from cloacal remnants has been suggested but remains speculative. A 64-year-old woman was referred to our clinic with a 1-month history of an itching vulva mass. An incisional biopsy was performed at other hospital and disclosed adenocarcinoma of intestinal type. Extensive workups were performed to detect other underlying carcinomas but revealed nothing abnormal. She underwent wide local excision without lymph node dissection for a primary vulva carcinoma. She received no adjuvant therapy and has been free from recurrent disease for 12 months after surgery. The authors report a rare case and review the relevant literature.

Dioscin suppresses TGF-ß1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration and invasion.

Epithelial-to-mesenchymal transition (EMT), an important cellular process, occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Dioscin is a polyphenolic component isolated from Phyllanthus amarus, which exhibits a wide range of pharmacological and physiological activities, such as anti-tumor, anti-inflammatory, anti-obesity, anti-fungal, and anti-viral activities. However, the possible role of dioscin in the EMT is unclear. We investigated the suppressive effect of dioscin on the EMT. Transforming growth factor-beta 1 (TGF-ß1) is known to induce EMT in a number of cancer cell types and promote lung adenocarcinoma migration and invasion. To verify the inhibitory role of dioscin in lung cancer migration and invasion, we investigated the use of dioscin as inhibitors of TGF-ß1-induced EMT in A549 lung cancer cells in vitro. Here, we found that dioscin prominently increased expression of the epithelial marker E-cadherin and expression of the mesenchymal marker N-cadherin and Snail during the TGF-ß1-induced EMT. In addition, dioscin inhibited the TGF-ß1-induced increase in cell migration and invasion of A549 lung cancer cells. Also, dioscin remarkably inhibited TGF-ß1-regulated activation of MMP-2/9, Smad2, and p38. Taken together, our findings provide new evidence that dioscin suppresses lung cancer migration, and invasion in vitro by inhibiting the TGF-ß1-induced EMT.

Synthesis of highly efficient azure-to-blue-emitting Zn-Cu-Ga-S quantum dots.

To realize blue emission-capable non-Cd I-III-VI quantum dots (QDs), we explore the synthesis of ternary Cu-Ga-S (CGS) QDs and subsequent quaternary Zn-Cu-Ga-S (ZCGS) via Zn alloying into a CGS host. The resulting ZCGS/ZnS core/shell QDs possess not only Zn content-dependent tunable emissions in the azure-to-blue range but also exceptional quantum yields of 78-83%.

Polyethylenimine Ethoxylated-Mediated All-Solution-Processed High-Performance Flexible Inverted Quantum Dot-Light-Emitting Device.

We report on an all-solution-processed fabrication of highly efficient green quantum dot-light-emitting diodes (QLEDs) with an inverted architecture, where an interfacial polymeric surface modifier of polyethylenimine ethoxylated (PEIE) is inserted between a quantum dot (QD) emitting layer (EML) and a hole transport layer (HTL), and a MoOx hole injection layer is solution deposited on top of the HTL. Among the inverted QLEDs with varied PEIE thicknesses, the device with an optimal PEIE thickness of 15.5 nm shows record maximum efficiency values of 65.3 cd/A in current efficiency and 15.6% in external quantum efficiency (EQE). All-solution-processed fabrication of inverted QLED is further implemented on a flexible platform by developing a high-performing transparent conducting composite film of ZnO nanoparticles-overcoated on Ag nanowires. The resulting flexible inverted device possesses 35.1 cd/A in current efficiency and 8.4% in EQE, which are also the highest efficiency values ever reported in flexible QLEDs.