Pregnancy complications and endometrial cancer in women with polycystic ovarian syndrome: a Korean National Health Insurance Service study.

OBJECTIVE: Polycystic ovarian syndrome is associated with diverse pregnancy related complications and endometrial cancer. However, research on the relationship between pregnancy complications and endometrial cancer in women with polycystic ovarian syndrome is scarce. We aimed to examine the association between gestational diabetes mellitus, pregnancy induced hypertension, and preterm birth and the risk of endometrial cancer in women with polycystic ovarian syndrome. METHODS: We analyzed data from the National Health Information Database established by the Korean National Health Insurance Service between January 2002 and December 2019. We included women with gestational diabetes mellitus, pregnancy induced hypertension, preterm birth, and endometrial cancer from among the polycystic ovarian syndrome population. All conditions were diagnosed according to the Korean Informative Classification of Diseases, 10th revision codes. Age, area of residence, income, body mass index, waist circumference, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, fasting blood sugar, and creatinine levels were included as covariates in the multiple logistic regression analysis. RESULTS: Of 467 221 women with polycystic ovarian syndrome included, 5099 had endometrial cancer. Age, residence, income, body mass index, waist circumference, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, fasting blood sugar, and creatinine levels differed significantly between the endometrial cancer and non-endometrial cancer groups (p≤0.001-0.032). Among the polycystic ovarian syndrome population, the odds ratios (ORs) of endometrial cancer were 1.50, 1.43, and 1.23 in women with a history of gestational diabetes mellitus, pregnancy induced hypertension, and preterm birth, respectively, compared with those without a history of these conditions (OR 1.50, 95% confidence interval (CI) 1.32 to 1.69, p<0.001; 1.43, 1.04 to 1.97, p=0.027; and 1.23, 1.05 to 1.45, p=0.011, respectively). CONCLUSION: Our results suggest that a history of pregnancy complications (gestational diabetes mellitus, pregnancy induced hypertension, and preterm birth) increases the risk of endometrial cancer in women with polycystic ovarian syndrome.

Correction to: Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress.

The original version of this article contained a mistake. The bands for HA Tag and t-ERK in Figs. 2d, 2h, 3d are incorrect. The author informs that these errors had no influence in the scientific content of the paper. The corrected figures (Figs. 2 and 3) are given below.

Total vaginectomy and radical vulvectomy for extension of extra-mammary Paget's disease.

Extra-mammary Paget's disease of the vulva is a rare non-invasive adenocarcinoma that usually occurs in postmenopausal women. Histologically, it often extends beyond the visible lesion, leading to positive surgical margins and frequent recurrences, but can be managed by simple vulvectomy or wide local excision. Although current evidence supports the use of radical surgery as an alternative to the generally performed wide local excision in the treatment of widely extended extra mammary Paget's disease of the vulva, nonetheless there controversy still exists regarding the extent of an adequate resection margin. Here the authors present a case of successful radical vulvectomy with total vaginectomy without adjuvant treatment on a delayed diagnosis of extra-mammary Paget's disease, extending from the vulva to the apex of vagina.

Cyclophilin A regulates JNK/p38-MAPK signaling through its physical interaction with ASK1.

Cyclophilin A (CypA), a member of the immunophilin family, is predominantly localized in the cytoplasm. The peptidylprolyl isomerase (PPIase) activity of CypA has been demonstrated to be involved in diverse cellular processes, including intracellular protein trafficking, mitochondrial function, pre-mRNA processing, and maintenance of multiprotein complex stability. In this study, we have demonstrated that CypA regulates apoptosis signaling-regulating kinase 1 (ASK1) through its direct binding. ASK1 is a member of MAPK kinase kinase (MAP3K) family, and selectively activates both JNK and p38 MAPK pathways. Here, we also report that CypA negatively regulates phosphorylation of ASK1 at Ser966, and that CypA reduces ASK1 and its downstream kinases of the JNK and p38 signaling. ASK1 is known to induce caspase-3 activation and apoptosis, and CypA inhibited ASK1-mediated apoptosis by decrease in caspase-3 activity under cellular stress conditions. Overall, we conclude that CypA negatively regulates ASK1 functions by its physical interaction with ASK1.

Changes in urine dipstick proteinuria and its relation to the risk of diabetic retinopathy and neuropathy.

BACKGROUND: Proteinuria is considered as a predictor for cardiovascular complications in diabetes mellitus (DM). However, no study has examined the association between changes in proteinuria and the risk of diabetic microvascular complications. METHODS: Study participants were 71,825 DM patients who received urine dipstick test for proteinuria both in 2003-2004 and 2006-2007. They were categorized into four groups according to changes in proteinuria over 3 years (negative: negative → negative, resolved: proteinuria ≥ 1+ → negative, incident: negative → proteinuria ≥ 1+, persistent: proteinuria ≥ 1+ → proteinuria ≥ 1+). Cox-proportional hazard model was used in assessing the adjusted hazard ratios (HR) and 95% confidence interval (CI) for incidence of retinopathy, and neuropathy (adjusted HR [95% CI]). RESULT: In all of DM patients, risk for comprehensive incidence of retinopathy and neuropathy increased in all types of proteinuria changes. In type 1 DM, HR for retinopathy and neuropathy generally increased in order of negative (reference), resolved (2.175 [1.150-4.114] and 1.335 [0.909-1.961]), incident (2.088 [1.185-3.680] and 1.753 [1.275-2.409]), and persistent proteinuria (1.314 [0.418-4.134] and 2.098 [1.274-3.455]). This pattern of relationship was similarly observed in type 2 DM for retinopathy and neuropathy: negative (reference), resolved (1.490 [1.082-2.051] and 1.164 [0.988-1.371]), incident (1.570 [1.161-2.123] and 1.291 [1.112-1.500]), and persistent proteinuria (2.309 [1.407-3.788] and 1.272 [0.945-1.712]). CONCLUSION: Risk for diabetic retinopathy and neuropathy generally increased in order of negative, resolved, incident, and persistent proteinuria. Once manifested proteinuria was associated with the increased risk of diabetic retinopathy and neuropathy even after remission of proteinuria.

Association of decreased estimated glomerular filtration rate with lung cancer risk in the Korean population.

OBJECTIVES: Inconsistent results are available regarding the association between low estimated glomerular filtration rate (eGFR) and lung cancer risk. We aimed to explore the risk of lung cancer according to eGFR category in the Korean population. METHODS: We included 358,293 adults who underwent health checkups between 2009 and 2010, utilizing data from the National Health Insurance Service-National Sample Cohort. Participants were categorized into 3 groups based on their baseline eGFR, as determined using the Chronic Kidney Disease Epidemiology Collaboration equation: group 1 (eGFR ≥90 mL/min/1.73 m2), group 2 (eGFR ≥60 to <90 mL/min/1.73 m2), and group 3 (eGFR <60 mL/min/1.73 m2). Incidences of lung cancer were identified using the corresponding codes from the International Classification of Diseases, 10th revision. Multivariate Cox proportional hazard models were employed to calculate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer incidence up to 2019. RESULTS: In multivariate analysis, group 2 exhibited a 26% higher risk of developing lung cancer than group 1 (HR, 1.26; 95% CI, 1.19 to 1.35). Furthermore, group 3 demonstrated a 72% elevated risk of lung cancer relative to group 1 (HR, 1.72; 95% CI, 1.58 to 1.89). Among participants with dipstick proteinuria of 2+ or greater, group 3 faced a significantly higher risk of lung cancer than group 1 (HR, 2.93; 95% CI, 1.37 to 6.24). CONCLUSIONS: Low eGFR was significantly associated with increased lung cancer risk within the Korean population. A particularly robust association was observed in individuals with severe proteinuria, emphasizing the need for further investigation.

Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress.

Cyclophilin, a cytosolic receptor for the immunosuppressive drug cyclosporin A, plays a role in diverse pathophysiologies along with its receptor, CD147. Although the interaction between cyclophilin A and CD147 is well established in inflammatory disease, that of cyclophilin B (CypB) with CD147 has not been fully explored, especially in cancer cell biology, and the exact molecular mechanism underlying such an association is poorly understood. In this study, we first identified high expression levels of CypB in 54 % of hepatocellular carcinoma patient tissues but in only 12.5 % of normal liver tissues. Then, we demonstrated that CypB overexpression protects human hepatoma cells against oxidative stress through its binding to CD147; this protective effect depends on the peptidyl prolyl isomerase activity of CypB. siRNA-mediated knockdown of CypB expression rendered hepatoma cells more vulnerable to ROS-mediated apoptosis. Furthermore, we also determined that a direct interaction between secreted CypB and CD147 regulates the extracellular signal-regulated kinase intracellular signaling pathway and is indispensible for the protective functions of CypB. For the first time, we demonstrated that CypB has an essential function in protecting hepatoma cells against oxidative stress through binding to CD147 and regulating the ERK pathway.

A randomized, multi-center, clinical trial to assess the efficacy and safety of alginate carboxymethylcellulose hyaluronic acid compared to carboxymethylcellulose hyaluronic acid to prevent postoperative intrauterine adhesion.

STUDY OBJECTIVE: To estimate the efficacy of alginate carboxymethylcellulose hyaluronic acid (ACH) gel to prevent intrauterine adhesions after hysteroscopic surgery in comparison with carboxymethylcellulose hyaluronic acid (CH) gel, which is known as an effective adhesion inhibitor. DESIGN: Randomized, multicenter, single-blind, clinical trial (Canadian Task Force classification I). SETTING: Tertiary university hospital. PATIENTS: One hundred eighty-seven patients with a surgically treatable intrauterine lesion (myomas, polyps, septa, intrauterine adhesion, dysfunctional uterine bleeding). INTERVENTIONS: Patients were randomized to 2 groups: hysteroscopic surgery plus intrauterine application of ACH or CH. MEASUREMENTS AND RESULTS: The rate of adhesion formation and the adhesion severity score with type and extent were calculated 4 weeks after surgery. The ACH group had results that were comparable to the CH group in terms of the development of intrauterine adhesions at 4 weeks follow-up. The adhesion severities were not different between the 2 groups. In a subgroup without baseline intrauterine adhesion, the ACH group showed a lower intrauterine adhesion rate than the CH group (p = .016). CONCLUSIONS: ACH had a comparable efficacy to CH in terms of the adhesion rate and severity. In the case of no baseline intrauterine adhesion, intrauterine application of ACH after hysteroscopic surgery had a lower rate of intrauterine adhesion than application of CH.

Unusual primary peritonitis due to Streptococcus pyogenes in a young healthy woman.

We describe the first case of primary peritonitis in Korea of a healthy person due to Streptococcus pyogenes. In the absence of comorbid conditions, such as liver cirrhosis, immunosuppression, or nephrotic syndrome, primary peritonitis is uncommon in a young healthy woman. Abdomen computed tomography revealed ascites in the lower abdomen and peritoneal enhancement suggesting peritonitis. In diagnostic laparoscopy, purulent ascites was found in the pelvic cavity but both ovaries and fallopian tubes were intact. There were no intra-abdominal abnormalities such as bowel perforation, appendicitis, or necrosis. The reports of blood culture, ascites culture, and cervical swab culture confirmed S. pyogenes. After use of antibiotics, the patient was cured and discharged without sequelae.

Metastatic hepatic actinomycosis masquerading as distant metastases of ovarian cancer.

Actinomycosis is a chronic disease characterized by abscess, tissue fibrosis and draining sinuses. Pelvic actinomycosis in women most commonly occurs during ascending infections, which are usually associated with intrauterine devices; however, secondary hepatic actinomycosis, while rare, can also occur. We describe a patient with an unusual case of metastatic hepatic actinomycosis misdiagnosed as distant metastases of ovarian cancer.

Stress-induced activation of ovarian heat shock protein 90 in a rat model of polycystic ovary syndrome.

AIM: Polycystic ovarian syndrome is the most common endocrine disorder affecting infertile women of reproductive age. This study evaluated the activation of heat shock protein 90 (Hsp 90) during the formation of stress-induced polycystic ovaries. MATERIAL & METHODS: Female Sprague-Dawley rats (180-200 g) were subjected to one of two stress-inducing conditions; animals were either treated with adrenocorticotropic hormone daily for 18 days or were exposed to daily cold stress for three weeks. Non-treated rats sampled during proestrus or diestrous served as controls. Blood samples were collected from the left ventricles of anesthetized rats and concentrations of follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone and corticosterone were measured in all rats. The expression of messenger RNA for androgen receptor, estrogen receptor-α and -ß, nerve growth factor receptor, and glucocorticoid receptor, and protein expression for Hsp 90 was also assessed in the rat ovaries. RESULTS: Stress increased glucocorticoid receptor and androgen receptor expression, and decreased estrogen expression. Nerve growth factor receptor expression was greater in treated than diestrous rats and less in treated than proestrous rats. Ovarian Hsp 90 protein expression was increased in rats treated with adrenocorticotropic hormone or cold stress. Serum follicle-stimulating hormone levels were reduced and testosterone and corticosterone levels increased by stress, whilst luteinizing hormone and estradiol levels were similar to levels in diestrous and proestrus control rats respectively. CONCLUSIONS: The results indicate that stress, via the activation of ovarian Hsp 90 and changes in steroid hormone receptor expression and serum reproductive hormone levels, may be involved in the induction of polycystic ovaries in rats.

Up-regulation of inhibitors of DNA binding/differentiation gene during alendronate-induced osteoblast differentiation.

PURPOSE: To investigate the effect of alendronate on the expression of Id genes in osteoblast differentiation. METHODS: C2C12 cells were treated with alendronate for various concentrations and time periods. For evaluation of alendronate-induced osteoblast differentiation in C2C12 cells, alkaline phosphatase (ALP) activity was measured. The expression of osteoblast differentiation markers such as ALP, type-1 collagen (Col 1), and osteocalcin (OCN), and the expression of Id-1 and Id-2 were measured by RT-PCR. In order to understand the mechanism underlying the regulation of Id genes, the promoter region of the Id-1 gene was identified. Database analysis of the promoter region for Id-1 using known consensus sequences identified several putative response elements, including CCAAT/enhancer-binding protein beta (C/EBPß). RESULTS: Alendronate treatment significantly increased not only ALP activity but also the expression of ALP, Col 1, and OCN, Id-1 and Id-2. C/EBPß and alendronate cooperatively increased the promoter activity and expression of Id-1. CONCLUSIONS: These results suggest that C/EBPß-mediated Id-1 transcriptional activation may regulate alendronate-induced osteoblast differentiation of C2C12 cells.

Age-Adjusted Prevalence and Characteristics of Women with Polycystic Ovarian Syndrome in Korea: A Nationwide Population-Based Study (2010-2019).

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age and is associated with an increased risk of obesity, compensatory hyperinsulinemia, dyslipidemia, metabolic syndrome, and endometrial cancer. This study analyzed 544619 women using the Korean Informative Classification of Disease, version 10, codes E28.0-E28.9 in the population-based National Health Information Databases from 2010 to 2019. The age-adjusted incidence and prevalence rates of PCOS over 10 years among Korean women were 2.8% and 4.3%, respectively; and they increased in the late teens, peaked in the 20s, and began to decrease at the age of 30. We also found that the body mass index, levels of fasting blood glucose, and high-density lipoprotein values in the recent two years (2018-2019) were higher in women with PCOS compared to the general population. This is the first study to investigate the prevalence of PCOS in a nationwide population of reproductive-aged Korean women. Further research is needed to examine the short- and long-term health risks and psychological problems associated with PCOS.

Plasma-activated medium inhibits cancer stem cell-like properties and exhibits a synergistic effect in combination with cisplatin in ovarian cancer.

Ovarian cancer stem-like cells (CSCs) have been implicated in tumor recurrence, metastasis, and drug resistance. Accumulating evidence has demonstrated the antitumor effect of plasma-activated medium (PAM) in various carcinomas, including ovarian cancer. Thus, PAM represents a novel onco-therapeutic strategy. However, its impact on ovarian CSCs is unclear. Here, we show that ovarian CSCs resistant to high-dose conventional chemotherapeutic agents used for ovarian cancer treatment exhibited dose-dependent sensitivity to PAM. In addition, PAM treatment reduced the expression of stem cell markers and sphere formation, along with the aldehyde dehydrogenase- or CD133-positive cell population. We further investigated the effect of PAM in combination with other chemotherapeutics on ovarian CSCs in vitro. PAM exhibited synergistic cytotoxicity with cisplatin (CDDP) but not with paclitaxel and doxorubicin. In a peritoneal metastasis xenograft model established via intraperitoneal spheroid injection, PAM intraperitoneal therapy significantly suppressed peritoneal carcinomatosis (tumor size and number), with a more significant decrease observed due to the combined effects of PAM and CDDP with no side effects. Taken together, our results indicate that PAM inhibits ovarian CSC traits and exhibits synergetic cytotoxicity with CDDP, demonstrating PAM as a promising intraparietal chemotherapy for enhancing antitumor efficacy and reducing side effects.

MicroRNA-dependent inhibition of WEE1 controls cancer stem-like characteristics and malignant behavior in ovarian cancer.

Cancer stem-like cells (CSCs) have been suggested to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a strong candidate target for anticancer therapies, its role in ovarian CSCs is yet to be elucidated. Here, we show that WEE1 plays a key role in regulating CSC properties and tumor resistance to carboplatin via a microRNA-dependent mechanism. We found that WEE1 expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE1. The overexpression of miR-424/503 suppressed CSC activity by inhibiting WEE1 expression, but this effect was reversed on the restoration of WEE1 expression. Furthermore, we demonstrated that NANOG modulates the miR-424/503-WEE1 axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/503-WEE1 axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503-mediated WEE1 inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seeding in the intraperitoneal mouse models of ovarian cancer. We identified a novel NANOG-miR-424/503-WEE1 pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.

Proteomic analysis of mesenchymal stem-like cells derived from ovarian teratoma: potential role of glutathione S-transferase M2 in ovarian teratoma.

Ovarian teratoma is a dermoid cyst in the ovary that contains mature tissues such as hair, teeth, bone, thyroid, etc. To understand the molecular mechanisms of ovarian teratoma growth, a comparative proteomic analysis was undertaken using mesenchymal stem cell-like cells (MSCLCs) isolated from normal human ovarian or teratoma tissues. Both normal ovarian and teratoma MSCLCs expressed stem cell markers OCT4 and NANOG, and were negatively staining with the senescence-associated (SA) ß-galactosidase. Furthermore, teratoma MSCLCs had higher proliferation and colony formation rates, with more angiogenic property than that of normal MSCLCs. Proteomic study revealed that 17 proteins had the expression changes over eightfold in ovarian teratoma MSCLCs compared with normal control. Interestingly, among them, GSTM2 was strongly expressed in teratoma MSCLCs. Moreover, overexpressed GSTM2 in the teratoma was associated with downregulation of p38 MAPK and activation of AKT and survivin. Taken together, these findings suggest that that ovarian teratoma MSCLCs have a higher potency for proliferation and angiogenesis and GSTM2 appears to be involved in the regulation of other survival genes.

Retroperitoneal Castleman's disease presenting with hydronephrosis indistinguishable from lymphoma.

Castleman's disease is a rare benign lymphoproliferative disease. We describe a patient with an unusual case of retroperitoneal Castleman's disease who initially presented with hydronephrosis. Her disease manifested with a malignant appearance in positron emission tomography/computed tomography and was located in the common and internal iliac area. Retrograde double-J stent insertion failed and nephrostomy was then performed. Complete surgical removal of the disease failed because the disease was severely adherent to the ureter and adjacent iliac vessels. Antegrade double-J stent insertion also failed. The patient eventually underwent laparoscopic ureteroneocystostomy. Retroperitoneal Castleman's disease should be added to the extensive list of differential diagnoses for primary retroperitoneal tumors.

Prospective comparison of biopsy results from curettage and hysteroscopy in postmenopausal uterine bleeding.

AIM: To evaluate the diagnostic accuracy of biopsy by dilatation and curettage in postmenopausal women with abnormal uterine bleeding. MATERIAL AND METHODS: A prospective observational study conducted with 112 consecutive postmenopausal women. Biopsy by dilatation and curettage was immediately followed by hysteroscopic biopsy and the histologic results were compared. RESULTS: By curettage, although performed under anesthesia, 3/3 (100%) cases of endometrial hyperplasia were reported as normal proliferative endometrium. There were two endometrial cancers (1.8%) and one case was missed as normal endometrium by curettage. Among endometrial polyps, only 3/39 (7.7%) cases were diagnosed by curettage. CONCLUSIONS: In postmenopausal women with abnormal uterine bleeding, biopsy by curettage may be not reliable for evaluation of endometrial pathology.

Hydrocinchonine, cinchonine, and quinidine potentiate paclitaxel-induced cytotoxicity and apoptosis via multidrug resistance reversal in MES-SA/DX5 uterine sarcoma cells.

Multidrug resistance (MDR) is one of important issues to cause the chemotherapy failure against cancers including gynecological malignancies. Despite some MDR reversal evidences of natural compounds including quinidine and cinchonine, there are no reports on MDR reversal activity of hydrocinchonine with its analogues quinidine and cinchonine especially in uterine sarcoma cells. Thus, in the current study, we comparatively investigated the potent efficacy of hydrocinchonine and its analogues quinidine and cinchonine as MDR-reversal agents for combined therapy with antitumor agent paclitaxel (TAX). Hydrocinchonine, cinchonine, and quinidine significantly increased the cytotoxicity of TAX in P-glycoprotein (gp)-positive MES-SA/DX5, but not in the P-gp-negative MES-SA cells at nontoxic concentrations by 3-(4,5-dimethylthiazol-2-yl)-2,5--diphenyltetrazolium bromide (MTT) assay. Rhodamine assay also revealed that hydrocinchonine, cinchonine, and quinidine effectively enhanced the accumulation of a P-gp substrate, rhodamine in TAX-treated MES-SA/DX5 cells compared with TAX-treated control. In addition, hydrocinchonine, cinchonine, and quinidine effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-3, and downregulated P-gp expression as well as increased sub-G1 apoptotic portion in TAX-treated MES-SA/DX5 cells. Taken together, hydrocinchonine exerted MDR reversal activity and synergistic apoptotic effect with TAX in MES-SA/DX5 cells almost comparable with quinidine and cinchonine as a potent MDR-reversal and combined therapy agent with TAX.