RCHY1 and OPTN are required for melanophagy, selective autophagy of melanosomes.

Melanosomes are specific organelles dedicated to melanin synthesis and accumulation in melanocytes. Autophagy is suggestively involved in melanosome degradation, although the potential underlying molecular mechanisms remain elusive. In selective autophagy, autophagy receptors and E3-ligases are the key factors conferring cargo selectivity. In B16F10 cells, ß-mangostin efficiently induced melanosome degradation without affecting other organelles such as mitochondria, peroxisomes, and the endoplasmic reticulum. Among various autophagy receptors, optineurin (OPTN) contributes TANK-binding kinase 1 (TBK1)-dependently to melanosome degradation and its knockdown inhibited ß-mangostin-mediated melanosome degradation. OPTN translocation to melanosomes was dependent on its ubiquitin-binding domain. Moreover, OPTN-mediated TBK1 activation and subsequent TBK1-mediated S187 OPTN phosphorylation were essential for melanosome degradation. ß-mangostin increased K63-linked melanosome ubiquitination. Finally, the E3-ligase RCHY1 knockdown inhibited the melanosome ubiquitination required for OPTN- and TBK1-phosphorylation as well as melanosome degradation. This study suggests that melanophagy, melanosome-selective autophagy, contributes to melanosome degradation, and OPTN and RCHY1 are an essential autophagy receptor and a E3-ligase, respectively, conferring cargo selectivity in melanophagy.

Effect of weight loss before in vitro fertilization in women with obesity or overweight and infertility: a systematic review and meta-analysis.

The effect of weight loss before in vitro fertilization (IVF) procedures on pregnancy outcomes in women with overweight or obesity and infertility remains controversial. In this systematic review and meta-analysis, we investigated whether weight loss before IVF in these women affected the IVF results and reproductive outcomes. PubMed, Embase, and the Cochrane Library databases were searched from the inception dates until December 2022, using combinations of relevant keywords. Only six randomized controlled trials, including 1627 women with obesity or overweight, were analyzed. The weight change in the intensive care group, compared to the control group who underwent IVF without weight loss was - 4.62 kg (mean difference; 95% confidence interval [CI] - 8.10, - 1.14). Weight loss before IVF did not significantly increase the live birth rate in women with obesity or overweight and infertility (odds ratio, 1.38; 95% CI 0.88, 2.10). The clinical pregnancy, miscarriage, ongoing pregnancy, and ectopic pregnancy rates did not differ between the weight loss and control groups before IVF. This meta-analysis demonstrated that even significant weight loss before IVF in women with obesity or overweight and infertility did not improve the live birth, clinical pregnancy, ongoing pregnancy, or ectopic pregnancy rates. PROSPERO Registration Number: CRD42023455800.

Nano-chemical priming strategy to enhance TGF-ß resistance and anti-tumor activity of natural killer cells.

Immunotherapy based on adoptive transfer of natural killer (NK) cells is a promising strategy for circumventing the limitations of cancer treatments. However, components of the immunosuppressive tumor microenvironment (TME), such as transforming growth factor-beta (TGF-ß), compromise the therapeutic efficacy of NK cells significantly. To address these limitations, we developed a novel method of engineering NK cells for adaptive transfer. The method is based on nanogels that serve two functions: (1) they overcome the TGF-ß-mediated stress environment of the TME, and (2) they enhance the direct anti-tumor activity of NK cells. Previously, we demonstrated that cationic compounds such as 25 K branched polyethylenimine (25 K bPEI) prime NK cells, putting them in a 'ready-to-fight' state. Based on these findings, we designed nanogels that have two primary characteristics: (1) they encapsulate galunisertib (Gal), which is used clinically to inhibit TGF-ß receptor activity, thereby blocking TGF-ß signaling; and (2) they provide cells with a surface coating of 25 K bPEI. When grown in culture medium containing TGF-ß, nanogel-treated NK cells demonstrated greater migration ability, degranulation activity, and cytotoxicity towards cancer cells than untreated NK cells. Additionally, the in vivo efficacy of nanogel-treated NK cells against PC-3 xenografts was significantly greater than that of Chem_NK cells primed by 25 K bPEI alone. These findings suggest that Gal-loaded 25 K bPEI-coated nanogels exert anti-tumor effects via chemical priming, as well suppressing the effects of TGF-ß on NK cells. We also expect 25 K bPEI-based nanogels to have great potential to overcome the suppressive effects of the TME through their NK cell-priming activity and delivery of the desired chemicals.

Risk of cardiocerebrovascular diseases is increased in Korean women with polycystic ovary syndrome: a nationwide cohort study.

To investigate the relationship between polycystic ovary syndrome (PCOS) and risk of cardiocerebrovascular disease in Korean women. This longitudinal cohort study using data from the Korean National Health Insurance Service included the women aged 15-44 years diagnosed with PCOS between 2002 and 2019, and the controls were matched 1:3 by age group, income, and region of residence. The endpoint outcomes of this study were the occurrence of ischemic heart disease, cerebrovascular diseases, and combined cardiocerebrovascular diseases in the PCOS and control groups. A stratified Cox proportional hazards regression analysis for matched data was performed to evaluate the relative hazard of events in the PCOS group compared to that in the control group. Among a total of 549,400 participants in the cohort, 137,416 women had a diagnosis of PCOS and 412,118 women did not have it. During a median follow-up of 54 months (interquartile range, 30-78 months), the incidence rates of all cardiovascular, ischemic heart, and cerebrovascular diseases were 6.6, 4.0, and 2.9, respectively, per 1000 person-years for women with PCOS, and 4.8, 2.8, and 2.3, respectively, per 1000 person-years for healthy control women. Women with PCOS had a higher hazard ratio of 1.224 (95% confidence interval, 1.18-1.27) of the composite cardiocerebrovascular diseases than those in the controls after propensity score matching for confounding variables, including body mass index, diabetes mellitus, hypertension, dyslipidemia, physical exercise level, alcohol consumption, current smoking, systolic and diastolic blood pressures, total cholesterol, and triglyceride levels. Hazard ratio for ischemic heart and cerebrovascular diseases was higher in women with PCOS than in the control group (hazard ratio, 1.254; 95% confidence interval, 1.20-1.31 and hazard ratio, 1.201; 95% confidence interval, 1.14-1.27, respectively). PCOS is associated with an increased risk of cardiocerebrovascular diseases in Korean women irrespective of their obesity. Counselling on the management of long-term risk of cardiovascular diseases should be offered to women with PCOS in East Asian countries where PCOS is characterized by a relatively low BMI.

Socioeconomic Factors and Abortive Outcomes of Clinical Pregnancy After Embryo Transfer in the Setting of Universal Health Insurance Coverage of IVF.

BACKGROUND: In vitro fertilization-embryo transfer (IVF-ET), an expensive option for infertile couples, started to be fully covered by the National Health Insurance (NHI) from October 2017 in South Korea. We investigated the association between woman's socioeconomic status (SES) and abortive outcomes in pregnancies after IVF-ET in the setting of universal coverage of the treatment. METHODS: Using the NHI database in South Korea, we conducted a retrospective cohort study of all women who achieved clinical pregnancy after ET between October 2017 and February 2019. A total of 44,038 clinical pregnancy episodes of 29,847 women who underwent ET were analyzed. We used employment status, income in percentiles, and living in the Seoul capital area as indicators of SES. Relative risks (RRs) for abortive pregnancy outcomes were calculated for each socioeconomic stratum, using log-binomial regression models included woman's age, body mass index, fasting blood glucose, fresh ET, month of ET, and history of smoking. RESULTS: While most pregnancy outcomes were live births (n = 30,783, 69.9%), 11,215 (25.5%) cycles ended with abortion or early pregnancy loss, 1,779 (4.0%) cycles were ectopic pregnancy, 45 (0.1%) were coded as molar pregnancy, and 224 (0.5%) were fetal death in utero or stillbirth. The risk of overall abortive outcomes was higher when a woman was unemployed (adjusted RR, 1.08; 95% confidence interval [CI], 1.05-1.11) or living in a non-Seoul capital area (1.11; 95% CI, 1.08-1.14). The association between relative income level and abortive outcomes was close to null. Living outside Seoul capital area was associated with the greater risk of abortive outcomes especially in younger women. CONCLUSION: Unemployment and living in non-capital areas were associated with a higher risk of abortive outcomes among pregnancies after ET, even in the setting of universal coverage of IVF-ET. This suggests potential impact of socioeconomic position on the IVF-ET pregnancy.

Maternal Polycystic Ovary Syndrome and the Risk of Early Childhood Obesity in Female Offspring: A Nationwide Population-Based Study.

BACKGROUND: To investigate the relationship between polycystic ovary syndrome (PCOS) in Korean women and childhood growth and obesity of their offspring. METHODS: This longitudinal case-control study using the Korean National Health Insurance claims database and the National Health Screening Program for Infants and Children database included women who delivered singletons between January 2007 and December 2008. Offspring's body mass index (BMI) measurements taken between 42 and 80 months of age were compared according to a maternal history of PCOS. RESULTS: Among a total of 131,805 participants, 1,213 women had a history of PCOS and 130,592 women did not. Female offspring aged 66-80 months born to women with PCOS had significantly higher BMI than those born to women without PCOS; there was no significant difference in that of male offspring regardless of maternal PCOS. In the generalized estimating equation and multivariable logistic regression analyses, the female offspring born to women with PCOS had a significantly higher risk of obesity during the age of 42-54 and 66-80 months (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.09-2.21 and OR, 1.5; 95% CI, 1.05-2.15, respectively), than those born to women without PCOS, after adjusting for several confounding factors. CONCLUSION: Maternal PCOS is independently associated with an increased incidence of childhood obesity in female offspring among Korean women. Women with PCOS should consider the risk of early childhood obesity in their daughters, even if they maintain a healthy weight themselves.

Comparison of Surgical Outcomes between Single-Port Laparoscopic Surgery and Da Vinci Single-Port Robotic Surgery.

BACKGROUND: The aim of this study is to compare the surgical outcomes of single-port laparoscopic surgery (SPLS) and single-port robotic surgery (SPRS). METHODS: We retrospectively analyzed patients who underwent a hysterectomy, ovarian cystectomy, or myomectomy with SPLS or SPRS from January 2020 to July 2022. Statistical analyses were performed using the SPSS chi-square test and student's t-test. RESULTS: A total of 566 surgeries including single-port laparoscopic hysterectomy (SPLH; n = 148), single-port robotic hysterectomy (SPRH; n = 35), single-port laparoscopic ovarian cystectomy (SPLC; n = 207), single-port robotic ovarian cystectomy (SPRC; n = 108), single-port laparoscopic myomectomy (SPLM; n = 12), and single-port robotic myomectomy (SPRM; n = 56). The SPRH, SPRC, and SPRM groups had a shorter operation time than the SPLS group, although the results were not statistically significant (SPRH vs. SPLH, p = 0.134; SPRC vs. SPLC, p = 0.098; SPRM vs. SPLM, p = 0.202). Incisional hernia occurred as a postoperative complication in two patients only in the SPLH group. Postoperative Hb changes were lower in the SPRC and SPRM groups than in the SPLC and SPLM groups (SPRC vs. SPLC, p = 0.023; SPRM vs. SPLM, p = 0.010). CONCLUSIONS: Our study demonstrated that the SPRS had comparable surgical outcomes when compared to the SPLS. Therefore, the SPRS should be considered a feasible and safe option for gynecologic patients.

Radioactive Iodine-induced hypothyroidism interferes with the maturation of reproductive organs during puberty in immature female rats.

Animal and human studies suggest that thyroid hormone may have critical roles in the development of the ovary. For example, thyroid deficiency disrupts the ovarian microarchitecture and menstrual cycle in neonate and adult women, respectively. Therefore, it is conceivable that thyroid deficiency might disrupt sexual maturation during the peri-pubertal period. To investigate the impact of radioactive iodine-induced thyroid deficiency on reproductive organs throughout puberty, immature female rats were given water containing radioactive iodine (0.37 MBq/g body weight) twice, on postnatal days 22 and 29. Radioactive iodine-induced hypothyroidism was revealed by low free thyroxin levels. Thyroid deficiency delayed the onset of vaginal opening, reduced ovarian weight and the number of medium-sized follicles and led to elongated uteri. However, there was no effect on the estrous cycle or absolute uterus weight. We conclude that radioactive iodine-induced thyroid deficiency delays sexual maturation and alters normal ovarian growth in peri-pubertal rats.

Effects of time-restricted feeding on letrozole-induced mouse model of polycystic ovary syndrome.

The present study aimed to investigate whether time-restricted feeding (TRF) ameliorates metabolic and reproductive phenotypes in a letrozole-induced mouse model of polycystic ovary syndrome (PCOS). Sixty female C57BL/6 N mice were randomly divided into two groups according to the type of food received: either a chow or a 60% high-fat diet. Those mice were subcutaneously implanted with letrozole or placebo pellets at four weeks of age. Then, letrozole-treated mice were randomly assigned to different feeding regimens: (1) TRF for 4 h (ZT12-ZT16) or (2) ad libitum diet. After 4 weeks of dietary intervention, estrous cycles were determined with daily vaginal smear examination, and serial tail-tip blood sampling was performed at 5-min intervals for 2 h to measure the luteinizing hormone (LH) pulse frequency, amplitude, and mean LH levels in the diestrus cycle stage. Letrozole-treated mice in the ad libitum group demonstrated multiple PCOS-like phenotypes including ovulatory dysfunction, polycystic ovaries, and increased body weight, parametrial fat weight, adipocyte size and inflammation, and higher expression of Cyp17, Cyp19, and Fshr in the ovary, and Kiss1r and Gnrh in the hypothalamus, elevated serum testosterone levels, and more rapid and elevated LH pulsatility, with increased pulse frequency, amplitude, and mean levels in the diestrus stage, compared with the controls. After TRF for 4 weeks, those phenotypes reverted to normal levels in letrozole-treated mice, except the percentage of diestrus cycles indicating the arrest of estrous cycling which did not differ between the TRF and ad libitum groups. Our results demonstrate that TRF has therapeutic effects on the reproductive and metabolic phenotypes of a letrozole-induced mouse model of PCOS.

ERK3 Increases Snail Protein Stability by Inhibiting FBXO11-Mediated Snail Ubiquitination.

Snail is a key regulator of the epithelial-mesenchymal transition (EMT), the key step in the tumorigenesis and metastasis of tumors. Although induction of Snail transcription precedes the induction of EMT, the post-translational regulation of Snail is also important in determining Snail protein levels, stability, and its ability to induce EMT. Several kinases are known to enhance the stability of the Snail protein by preventing its ubiquitination; however, the precise molecular mechanisms by which these kinases prevent Snail ubiquitination remain unclear. Here, we identified ERK3 as a novel kinase that interacts with Snail and enhances its protein stability. Although ERK3 could not directly phosphorylate Snail, Erk3 increased Snail protein stability by inhibiting the binding of FBXO11, an E3 ubiquitin ligase that can induce Snail ubiquitination and degradation, to Snail. Importantly, functional studies and analysis of clinical samples indicated the crucial role of ERK3 in the regulation of Snail protein stability in pancreatic cancer. Therefore, we conclude that ERK3 is a key regulator for enhancing Snail protein stability in pancreatic cancer cells by inhibiting the interaction between Snail and FBXO11.

Risk of Endometrial Polyps, Hyperplasia, Carcinoma, and Uterine Cancer After Tamoxifen Treatment in Premenopausal Women With Breast Cancer.

Importance: The association of tamoxifen use with the risk of uterine diseases, such as endometrial cancer, in premenopausal women with breast cancer remains controversial. However, many studies have reported an increased risk of uterine disease among postmenopausal tamoxifen users. Objective: To investigate the association of tamoxifen use with the risk of endometrial cancer and other uterine diseases in premenopausal women with breast cancer. Design, Setting, and Participants: A nationwide, population-based, retrospective longitudinal cohort study with an 18-year study period was conducted using data obtained from the Korean National Health Insurance Service. Participants included premenopausal women aged 20 to 50 years with breast cancer diagnoses between January 2003 and December 2018. Data were analyzed from April to December 2021. Exposures: Tamoxifen treatment. Main Outcomes and Measures: The incidence of uterine diseases, including endometrial cancer, hyperplasia, polyps, and other uterine cancers, was identified in the study cohort using insurance claim codes. The incidence of uterine diseases per 1000 person-years was compared between women receiving tamoxifen and those not treated with adjuvant hormone therapy. Multivariable Cox proportional hazard regression analysis was performed to determine the risk of each uterine disease. Results: Among 78 320 female participants with a mean (SD) age of 42.1 (6.1) years, 34 637 (44.2%) were categorized into the tamoxifen group and 43 683 (55.8%) were categorized into the control group. Among tamoxifen users, during the mean (SD) follow-up duration of 6.13 (4.15) years, the incidence of newly diagnosed endometrial polyps was 20.13 cases per 1000 person-years, that of endometrial hyperplasia was 13.49 cases per 1000 person-years, that of endometrial cancer was 2.01 cases per 1000 person-years, and that of other uterine cancers was 0.45 cases per 1000 person-years. The risk of endometrial cancer was higher in the tamoxifen group than in the control group (hazard ratio, 3.77; 95% CI, 3.04-4.66) after adjusting for age, body mass index, history of diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, gonadotropin-releasing hormone agonist treatment, and trastuzumab treatment. Conclusions and Relevance: In this longitudinal cohort study, premenopausal Korean women with breast cancer who received tamoxifen as adjuvant hormone therapy had a significantly increased risk of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers compared with those who were not treated with adjuvant hormone therapy. These findings suggest that clinicians should consider the risk of uterine disease among tamoxifen users, including premenopausal women.

Age at Menopause and Suicidal Ideation in Menopausal Women: A Study of Korea National Health and Nutrition Examination Survey Data.

BACKGROUND: Although menopause is considered a risk factor for depression, no association has been established between the risk of suicidal ideation and age at menopause. This study aimed to evaluate the association between age at menopause and suicidal ideation in middle-aged menopausal Korean women. METHODS: This cross-sectional study used data from the Korea National Health and Nutrition Examination Survey (2013-2018). Women aged 40-65 years were divided into the following three categories: primary ovarian insufficiency (POI), early menopause, and menopause, according to age at natural menopause (< 40, 40-45, and > 45 years, respectively). Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: Among 2,232 menopausal women, 25 (1.1%) experienced POI and 114 (5.1%) experienced early menopause. The PHQ-9 items that pertained to low self-esteem and suicidal ideation scored higher in women with POI than in those who experienced menopause after 45 years of age. The prevalence of suicidal ideation differed significantly according to age at menopause (POI, 30.0%; early menopause, 12.7%; menopause, 8.0%; P = 0.016). Logistic regression analysis revealed that POI was significantly associated with suicidal ideation after the adjustment for age, body mass index, and education, household income, and walking levels (odds ratio, 4.2; 95% confidence interval, 1.0-17.7). CONCLUSION: Korean middle-aged women with POI were more likely to have suicidal ideation than those who experienced menopause at 45 years or above, despite not being diagnosed with major depressive disorder.

Excretory-Secretory Products of Trichomonas vaginalis Cause Apoptosis in Mouse Sperm in Vitro.

Excretory-secretory products (ESP) of T. vaginalis have been shown to inhibit sperm motility, viability, and functional integrity, leading to a decreased fertilization rate in vitro. This study investigated whether T. vaginalis induce apoptosis and ultrastructural changes of sperm using flow cytometry and electron microscopy. Incubation of sperm with T. vaginalis ESP increased phosphatidylserine externalization and DNA fragmentation, and decreased mitochondrial membrane potential. Transmission electron microscopy of sperm incubated with ESP revealed abnormal features such as distorted heads, broken necks, and acrosomes exocytosis. This is the first report that demonstrates a direct impact of T. vaginalis ESP on sperm apoptosis and architecture in vitro.

Effect of a Wireless Vital Sign Monitoring System on the Rapid Response System in the General Ward.

While wireless vital sign monitoring is expected to reduce the vital sign measurement time (thus reducing the nursing workload), its impact on the rapid response system is unclear. This study compared the time from vital sign measurement to recording and rapid response system activation between wireless and conventional vital sign monitoring in the general ward, to investigate the impact of wireless vital sign monitoring system on the rapid response system. The study divided 249 patients (age > 18 years; female: 47, male: 202) admitted to the general ward into non-wireless (n = 101) and wireless (n = 148) groups. Intervals from vital sign measurement to recording and from vital sign measurement to rapid response system activation were recorded. Effects of wireless system implementation for vital sign measurement on the nursing workload were surveyed in 30 nurses. The interval from vital sign measurement to recording was significantly shorter in the wireless group than in the non-wireless group (4.3 ± 2.9 vs. 44.7 ± 14.4 min, P < 0.001). The interval from vital sign measurement to rapid response system activation was also significantly lesser in the wireless group than in the non-wireless group (27.5 ± 12.9 vs. 41.8 ± 19.6 min, P = 0.029). The nursing workload related to vital sign measurement significantly decreased from 3 ± 0.87 to 2.4 ± 9.7 (P = 0.021) with wireless system implementation. Wireless vital sign monitoring significantly reduced the time to rapid response system activation by shortening the time required to measure the vital signs. It also significantly reduced the nursing workload.

Body fat distribution and insulin resistance among Korean middle-aged women: a Korean National Health and Nutrition Examination Survey.

OBJECTIVE: To evaluate menopause-related changes in body fat distribution and their relationship with insulin resistance in middleaged Korean women. METHODS: We analyzed women aged 40-60 years using data from the National Health and Nutrition Examination Survey conducted from 2008 to 2011. Body fat was measured using dual-energy X-ray absorptiometry. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Among 3,468 participants, menopausal women (n=1,489) had a higher body mass index (BMI) and higher trunk, arm, and head fat percentages than premenopausal women (n=1,979). However, no significant difference was found in the leg fat percentage according to menopausal status. Multivariable regression analysis for HOMA-IR showed that trunk fat percentage, BMI, and waist circumference positively correlated with insulin resistance and leg fat percentage negatively correlated after adjusting for several confounding factors, whereas menopausal status was not associated with HOMAIR. CONCLUSION: Middle-aged women not only have different body weights and BMI but also have different body fat distributions according to menopausal status. Each fat percentage change in the trunk and leg is differently associated with metabolic health, particularly insulin resistance. To evaluate the metabolic health of middle-aged women, BMI is generally noted; however, body fat distribution, which can be easily assessed using dual-energy X-ray absorptiometry, should also be considered.

Comparison of one-stage laparoscopic common bile duct exploration plus cholecystectomy and two-stage endoscopic sphincterotomy plus laparoscopic cholecystectomy for concomitant gallbladder and common bile duct stones in patients over 80 years old.

Purpose: This study was performed to compare the safety and efficacy of one-stage laparoscopic common bile duct exploration (LCBDE) plus laparoscopic cholecystectomy (LC) with those of endoscopic sphincterotomy (EST) plus LC for concomitant gallbladder (GB) and common bile duct (CBD) stones in elderly patients. Methods: This single-center retrospective study reviewed the medical records of patients aged >80 years who were diagnosed with concomitant GB and CBD stones between January 2010 and December 2020. Results: Of the 137 patients included in this study, 46 underwent one-stage LCBDE + LC and 91 underwent two-stage EST + LC. The frequency of previous gastrectomy (23.9% vs. 5.5%, p = 0.002) and multiple stones (76.1% vs. 49.5%, p = 0.003) was higher in the LCBDE + LC group than in the EST + LC group. Further, patients in LCBDE + LC group had larger CBD stones (11.9 mm vs. 6.0 mm, p < 0.001). There were no significant differences in the clearance (91.3% vs. 95.6%, p = 0.311) and recurrence (4.3% vs. 8.8%, p = 0.345) rates between the groups. The incidence of posttreatment overall complications (17.4% vs. 22.0%, p = 0.530) and total hospital stay (12.7 days vs. 11.7 days, p = 0.339) were similar in the two groups. Conclusion: One-stage LCBDE + LC is a safe and effective treatment for concomitant GB and CBD stones, even in elderly patients, and may be considered as the first treatment option in elderly patients with previous gastrectomy, multiple large (≥ 15 mm) CBD stones, or inability to cooperate with endoscopic procedures.

Vasomotor symptoms and carotid artery intima-media thickness among Korean midlife women.

OBJECTIVES: To evaluate the association between vasomotor symptoms (VMS) and carotid intima-media thickness (CIMT) in Korean midlife women. STUDY DESIGN: This cross-sectional study included 918 Korean women aged 45-65 years who attended their routine health checkup at a single institution between 2013 and 2016. MAIN OUTCOME MEASURES: All participants' results on the Menopause Rating Scale were used to assess the VMS. Severe and very severe VMS were combined into severe VMS. CIMT and blood flow velocities were measured on the common carotid arteries using duplex ultrasound. RESULTS: All participants' mean age was 54.73 ± 5.37 years, and 627 (68.3%) were postmenopausal. A total of 401 (43.7%) women reported VMS: 217 (23.6%), mild; 109 (11.9%), moderate; and 75 (8.2%), severe. The mean CIMT was 0.062 ± 0.017 mm and 0.064 ± 0.019 mm in premenopausal and menopausal women, respectively. In the multivariate linear regression analysis, the CIMT of women with moderate VMS was 0.102 mm (95% confidence interval [CI] = 0.002-0.009) more than that of women with no VMA, and the CIMT of women with severe VMS was 0.246 mm (95% CI = 0.012-0.021) more than that of women with no VMS, after adjusting for several confounders, including age, body mass index, and lifestyle factors. Severe VMS were associated with the risk of thickened CIMT (≥0.075 mm) and/or plaques (odds ratio = 2.90, 95% CI = 1.74-4.84) in the logistic regression analysis after adjusting for the same variables. CONCLUSIONS: Moderate and severe VMS are independently associated with increased CIMT in otherwise healthy Korean midlife women. Clinicians managing midlife women with bothersome VMS should consider screening for subclinical cardiovascular diseases.

RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells.

Rho GDP dissociation inhibitor 2 (RhoGDI2), a regulator of Rho family GTPase, has been known to promote tumor growth and malignant progression in gastric cancer. We previously showed that RhoGDI2 positively regulates Rac1 activity and Rac1 activation is critical for RhoGDI2-induced gastric cancer cell invasion. In this study, to identify the precise molecular mechanism by which RhoGDI2 activates Rac1 activity, we performed two-hybrid screenings using yeast and found that RhoGDI2 plays an important role in the interaction between Rac1, Filamin A and Rac1 activation in gastric cancer cells. Moreover, we found that Filamin A is required for Rac1 activation and the invasive ability of gastric cancer cells. Depletion of Filamin A expression markedly reduced Rac1 activity in RhoGDI2-expressing gastric cancer cells. The migration and invasion ability of RhoGDI2-expressing gastric cancer cells also substantially decreased when Filamin A expression was depleted. Furthermore, we found that Trio, a Rac1-specific guanine nucleotide exchange factor (GEF), is critical for Rac1 activation and the invasive ability of gastric cancer cells. Therefore, we conclude that RhoGDI2 increases Rac1 activity by recruiting Rac1 to Filamin A and enhancing the interaction between Rac1 and Trio, which is critical for the invasive ability of gastric cancer cells.

Ratiometric fluorescent detection of lead ions in aquatic environment and living cells using a fluorescent peptide-based probe.

Ratiometric fluorescent detection using dual emission bands is highly necessary to quantify Pb(II) in aquatic environment and live cells. We synthesized a ratiometric fluorescent peptidyl probe (1) by conjugation of a peptide receptor for Pb(II) with an excimer-forming benzothiazolylcyanovinylene fluorophore. The peptidyl probe dissolved well in aqueous solution and displayed an emission band at 538 nm (λex = 460 nm). Upon addition of Pb(II) (0-20 µM), the emission maximum shifted from 538 nm to 575 nm and the emission intensity ratio (I575 /I538) increased significantly from 0.40 to 2.26. 1 exhibited a selective ratiometric response to Pb(II) over other metal ions. 1 with a low detection limit (1.2 ppb) of Pb(II) detected nanomolar concentrations (0-500 nM) of Pb(II) ions in groundwater and tap water. The cell-permeable probe detected intracellular Pb(II) by ratiometric fluorescent images. The binding mode study using NMR, IR and CD spectroscopy, and TEM revealed that the probe formed a 1:1 complex with Pb(II) and then formed red-emissive nanoparticles and fibrils. The probe exhibited desirable detection properties such as ratiometric detection, high solubility in water, visible light excitation, high selectivity and sensitivity for Pb(II), cell-permeability, and rapid response (< 6 min).

Artificial intelligence approaches to the determinants of women's vaginal dryness using general hospital data.

The aim of this study is to analyse the determinants of women's vaginal dryness using machine learning. Data came from Korea University Anam Hospital in Seoul, Republic of Korea, with 3298 women, aged 40-80 years, who attended their general health check from January 2010 to December 2012. Five machine learning methods were applied and compared for the prediction of vaginal dryness, measured by a Menopause Rating Scale. Random forest variable importance, a performance gap between a complete model and a model excluding a certain variable, was adopted for identifying major determinants of vaginal dryness. In terms of the mean squared error, the random forest (1.0597) was much better than linear regression (17.9043) and artificial neural networks with one, two and three hidden layers (1.7452, 1.7148 and 1.7736, respectively). Based on random forest variable importance, the top-10 determinants of vaginal dryness were menopause age, age, menopause, height, thyroid stimulating hormone, neutrophils, years since menopause, lymphocytes, alkaline phosphatase and blood urea nitrogen. In addition, its top-20 determinants were peak expiratory flow rate, low-density lipoprotein cholesterol, white blood cells, monocytes, cancer antigen 19-9, creatinine, eosinophils, total cholesterol, triglyceride and amylase. Machine learning presents a great decision support system for the prediction of vaginal dryness. For preventing vaginal dryness, preventive measures would be needed regarding early menopause, the thyroid function and systematic inflammation.Impact StatementWhat is already known on this subject? Only a few studies have investigated the risk factors of vaginal dryness in middle-aged women. More research is to be done for finding its various risk factors, identifying its major risk groups and drawing its effective clinical implications.What do the results of this study add? This study is the first machine-learning study to predict women's vaginal dryness and analyse their determinants. The random forest could discuss which factors are more important for the prediction of vaginal dryness. Based on random forest variable importance, menopause age was the most important determinant of vaginal dryness and their association was discovered to be negative in this study. Vaginal dryness was closely associated with the height, rather than the body weight or body mass index. The importance rankings of blood conditions related to systematic inflammation were within the top-20 in this study: neutrophils, lymphocytes, white blood cells, monocytes and eosinophils.What are the implications of these findings for clinical practice and/or further research? Machine learning presents a great decision support system for the prediction of vaginal dryness. For preventing vaginal dryness, preventive measures would be needed regarding early menopause and systematic inflammation.