Screening mammography performance according to breast density: a comparison between radiologists versus standalone intelligence detection.

BACKGROUND: Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screening digital mammography considering breast density, between radiologists and AI standalone detection among Korean women. METHODS: We retrospectively included 89,855 Korean women who underwent their initial screening digital mammography from 2009 to 2020. Breast cancer within 12 months of the screening mammography was the reference standard, according to the National Cancer Registry. Lunit software was used to determine the probability of malignancy scores, with a cutoff of 10% for breast cancer detection. The AI's performance was compared with that of the final Breast Imaging Reporting and Data System category, as recorded by breast radiologists. Breast density was classified into four categories (A-D) based on the radiologist and AI-based assessments. The performance metrics (cancer detection rate [CDR], sensitivity, specificity, positive predictive value [PPV], recall rate, and area under the receiver operating characteristic curve [AUC]) were compared across breast density categories. RESULTS: Mean participant age was 43.5 ± 8.7 years; 143 breast cancer cases were identified within 12 months. The CDRs (1.1/1000 examination) and sensitivity values showed no significant differences between radiologist and AI-based results (69.9% [95% confidence interval [CI], 61.7-77.3] vs. 67.1% [95% CI, 58.8-74.8]). However, the AI algorithm showed better specificity (93.0% [95% CI, 92.9-93.2] vs. 77.6% [95% CI, 61.7-77.9]), PPV (1.5% [95% CI, 1.2-1.9] vs. 0.5% [95% CI, 0.4-0.6]), recall rate (7.1% [95% CI, 6.9-7.2] vs. 22.5% [95% CI, 22.2-22.7]), and AUC values (0.8 [95% CI, 0.76-0.84] vs. 0.74 [95% CI, 0.7-0.78]) (all P < 0.05). Radiologist and AI-based results showed the best performance in the non-dense category; the CDR and sensitivity were higher for radiologists in the heterogeneously dense category (P = 0.059). However, the specificity, PPV, and recall rate consistently favored AI-based results across all categories, including the extremely dense category. CONCLUSIONS: AI-based software showed slightly lower sensitivity, although the difference was not statistically significant. However, it outperformed radiologists in recall rate, specificity, PPV, and AUC, with disparities most prominent in extremely dense breast tissue.

IFI16/Ifi202 released from breast cancer induces secretion of inflammatory cytokines from macrophages and promotes tumor growth.

In tumor microenvironment (TME), macrophages trigger and maintain inflammatory responses that promoting tumor progression. Many cellular proteins are secreted from tumors and modulate their own TME by modulating macrophage phenotypes. Recently, we reported that interferon-γ-inducible protein 16 (IFI16), which was identified as an innate immune DNA sensor recognizing foreign DNA, triggered type Ⅰ interferon responses in breast cancer (BC). However, whether IFI16 was released from BC and affects TME has not been studied. Here, we report that IFI16 and its mouse homolog Ifi202 were released from BC cells, but not from normal epithelial cells. Ifi202 induced secretion of proinflammatory cytokines such as Interleukin (IL)-1ß, IL-6, and Tumor necrosis factor-α from macrophages via binding toll-like receptor 2 and activating downstream signaling pathway. Growth of allografted mouse BC 4T1 lacking Ifi202 was suppressed and accompanied with increased infiltration and cytotoxic activity of CD8+ T lymphocytes. Further, IFI16 was detected in sera of patients with BC. High expression level of IFI16 was associated with poor prognosis in patients with BC. Taken together, our findings suggest a novel role of IFI16/Ifi202 in TME, that elicits tumor promoting inflammation and thereby shaping immunosuppressive TME in BC.

Type I IFN stimulates IFI16-mediated aromatase expression in adipocytes that promotes E2-dependent growth of ER-positive breast cancer.

Although type I interferons (IFNs) play multifaceted roles during tumorigenesis and cancer treatment, the interplay between type I IFNs and estrogen signaling in breast cancer (BC) microenvironment is not well understood. Here, we report a novel function of type I IFNs in inducing aromatase expression in adipose tissues surrounding BC, which potentiates the E2-dependent growth of estrogen receptor (ER)-positive BC. First, we found that expression levels of type I IFNs correlate negatively with clinical outcome but positively with tumor grade in patients with ER-positive BC. Levels of type I IFNs were elevated in cocultured media of immune cells and BC cells, which increased aromatase expression and E2 production in Simpson-Golabi-Behmel syndrome preadipocytes. The type I IFN-induced aromatase expression was dependent on IFN-γ-inducible protein 16 (IFI16), which is encoded by an interferon-stimulated gene. At the molecular level, type I IFNs led to recruitment of HIF1α-IFI16-PRMT2 complex to the hypoxia-response element located in the aromatase PI.3/PII promoter. Next, we generated an adipocyte-specific Ifi204, which is a mouse ortholog of human IFI16, knockout mouse (Ifi204-AKO). IFNß induced E2 production in the preadipocytes isolated from the control mice, but such E2 production was far lower in the Ifi204-AKO preadipocytes. Importantly, the growth of orthotopically inoculated E0771 ER-positive mammary tumors was reduced significantly in the Ifi204-AKO mice. Taken together, our findings provide novel insights into the crosstalk between type I IFNs and estrogen signaling in the progression of ER-positive BC.

Metabolically healthy and unhealthy obesity and risk of vasomotor symptoms in premenopausal women: cross-sectional and cohort studies.

OBJECTIVE: To examine the relationship between metabolically healthy and unhealthy obesity phenotypes and risk of vasomotor symptoms (VMS) in premenopausal women. DESIGN: Prospective cohort study. SETTING: Middle-aged women in a cohort based on regular health screening examinations. POPULATION: Premenopausal Korean women aged 42-52 years were recruited and were followed up for a median of 4.2 years. The cross-sectional and cohort studies comprised 4672 women and 2590 women without VMS at baseline, respectively. METHODS: Adiposity measures included body mass index (BMI), waist circumference and percentage body fat. Being metabolically healthy was defined as not having any metabolic syndrome components or a homeostasis model assessment of insulin resistance of 2.5 or more. MAIN OUTCOMES MEASURES: VMS (hot flushes and night sweats) assessed using the questionnaire. RESULTS: All adiposity measures were positively associated with an increased risk of VMS in both cross-sectional and longitudinal studies. The multivariable-adjusted prevalence ratio (95% confidence interval [CI]) for VMS comparing percentage body fat of 35% or more with the reference was 1.47 (95% CI 1.14-1.90) in metabolically healthy women, and the corresponding prevalence ratio was 2.32 (95% CI 1.42-3.78) in metabolically unhealthy women (Pinteraction  = 0.334). The multivariable-adjusted hazard ratio for incident VMS comparing percentage body fat of 35% or more with the reference was 1.34 (95% CI 1.00-1.79) in metabolically healthy women, whereas the corresponding hazard ratio was 3.61 (95% CI 1.81-7.20) in metabolically unhealthy women (Pinteraction  = 0.036). The association between BMI, waist circumference and VMS did not significantly differ by metabolic health status. CONCLUSIONS: Maintaining normal weight and being metabolically healthy may help to prevent VMS in premenopausal women. TWEETABLE ABSTRACT: Avoiding obesity and a metabolically unhealthy status may help reduce vasomotor symptoms in premenopausal women.

Pregnancy loss and Income in the Republic of Korea using National Health Insurance Service Data, 2008-2014.

BACKGROUND: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance. METHOD: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss. RESULT: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011. CONCLUSION: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income.

Mammography-based deep learning model for coronary artery calcification.

AIMS: Mammography, commonly used for breast cancer screening in women, can also predict cardiovascular disease. We developed mammography-based deep learning models for predicting coronary artery calcium (CAC) scores, an established predictor of coronary events. METHODS AND RESULTS: We evaluated a subset of Korean adults who underwent image mammography and CAC computed tomography and randomly selected approximately 80% of the participants as the training dataset, used to develop a convolutional neural network (CNN) to predict detectable CAC. The sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), and overall accuracy of the model's performance were evaluated. The training and validation datasets included 5235 and 1208 women, respectively [mean age, 52.6 (±10.2) years], including non-zero cases (46.8%). The CNN-based deep learning prediction model based on the Resnet18 model showed the best performance. The model was further improved using contrastive learning strategies based on positive and negative samples: sensitivity, 0.764 (95% CI, 0.667-0.830); specificity, 0.652 (95% CI, 0.614-0.710); AUROC, 0.761 (95% CI, 0.742-0.780); and accuracy, 70.8% (95% CI, 68.8-72.4). Moreover, including age and menopausal status in the model further improved its performance (AUROC, 0.776; 95% CI, 0.762-0.790). The Framingham risk score yielded an AUROC of 0.736 (95% CI, 0.712-0.761). CONCLUSION: Mammography-based deep learning models showed promising results for predicting CAC, performing comparably to conventional risk models. This indicates mammography's potential for dual-risk assessment in breast cancer and cardiovascular disease. Further research is necessary to validate these findings in diverse populations, with a particular focus on representation from national breast screening programmes.

Adiposity, Body Composition Measures, and Breast Cancer Risk in Korean Premenopausal Women.

Objective: To investigate the association between body composition parameters and breast cancer (BC) risk in premenopausal women. Design, Setting, and Participants: Prospective cohort study using data from the Kangbuk Samsung Cohort Study. Participants were women aged 20 to 54 years who were enrolled from 2011 to 2019 and followed up for BC development until December 31, 2020. Data were analyzed from June to August 2023. Exposures: Trained nurses conducted anthropometric measurements and assessed body composition using segmental bioelectric impedance analysis. The analysis encompassed adiposity measures such as body mass index (BMI), waist circumference, and body composition parameters, including muscle mass, fat mass, ratio of muscle mass to weight, ratio of fat mass to weight, and fat mass index. Main outcomes and measures: Adjusted hazard ratios (aHR) for BC during the follow-up period. Results: Among 125 188 premenopausal women, the mean (SD) age was 34.9 (6.3) years. During a mean (range) follow-up of 6.7 (0.5-9.9) years, 1110 incident BC cases were identified. The mean (SD) BMI and waist circumference were 21.6 (3.1) and 75.3 (8.2) cm, respectively. Higher BMI and waist circumference were associated with decreased risk, with an aHR of 0.89 (95% CI, 0.84-0.95) per SD increase in BMI and 0.92 (95% CI, 0.86-0.98) per SD increase in waist circumference. A higher ratio of fat mass to weight was associated with decreased BC risk (aHR, 0.92; 95% CI, 0.86-0.99 per SD increase), whereas the opposite trend was observed for the ratio of muscle mass to weight, with an aHR of 1.08 (95% CI, 1.02-1.15) per SD increase. The results remained consistent even after additional adjustments for height in the model. The fat mass index was also inversely associated with BC risk, with an HR of 0.90 (95% CI, 0.85-0.97) per SD increase. Conclusions and Relevance: In this cohort study of premenopausal women, a higher level of adiposity, represented by increased BMI, waist circumference, and fat mass, was consistently associated with decreased breast cancer risk. Conversely, muscle mass and its ratio to weight displayed opposite or inconsistent patterns. These findings suggest an inverse association between excess adiposity and the risk of BC in premenopausal women, confirming earlier findings that BMI is an indirect measure of adiposity.

Overactive bladder and cognitive impairment in middle-aged women: A cross-sectional study.

BACKGROUND: Overactive bladder (OAB) is a common condition in middle-aged and older women. It has been reported to be potentially linked to cognitive decline, particularly in older adults. This study investigated the association between OAB symptoms and cognitive impairment in middle-aged women. MATERIALS AND METHODS: This cross-sectional study had a sample of 1652 women (mean age 49.3 ± 2.8 years) who were not taking medication for either urinary tract infection or OAB. OAB symptoms and cognitive function were evaluated by self-administered questionnaires: the Overactive Bladder Symptom Score and the Alzheimer's disease 8. Logistic regression models estimated prevalence ratios (PRs) with 95 % confidence intervals (CI) for cognitive impairment according to the presence/absence of OAB. Mediation analyses assessed the impact of poor sleep quality on this association. RESULTS: Cognitive impairment was more prevalent in women with OAB than in those without OAB (multivariable-adjusted PR: 1.88 [95 % CI: 1.52-2.24]). Women experiencing nocturia (≥twice a night), urinary urgency at least once a week, and urgency urinary incontinence at least once a week had multivariable-adjusted PRs (95 % CI) for cognitive impairment of 2.08 (1.50-2.65), 2.12 (1.66-2.58), and 1.75 (1.17-2.34), respectively. Poor sleep quality mediated 10.81 % [95 % CI: 4.55-19.44 %] of the relationship between OAB and cognitive impairment. CONCLUSIONS: Among middle-aged women not taking OAB medications, OAB symptoms were associated with cognitive impairment, partly because of poor sleep quality. Further research is needed to determine whether early screening of patients with OAB can help identify those susceptible to cognitive impairment associated with OAB medication and if preventive measures should be targeted at this group.

Early-onset vasomotor symptoms and development of depressive symptoms among premenopausal women.

BACKGROUND: We investigated the association between vasomotor symptoms (VMSs) and the onset of depressive symptoms among premenopausal women. METHODS: This cross-sectional study included 4376 premenopausal women aged 42-52 years, and the cohort study included 2832 women without clinically relevant depressive symptoms at baseline. VMSs included the symptoms of hot flashes and night sweats. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale; a score of ≥16 was considered to define clinically relevant depressive symptoms. RESULTS: Premenopausal Women with VMSs at baseline exhibited a higher prevalence of depressive symptoms compared with women without VMSs at baseline (multivariable-adjusted prevalence ratio 1.76, 95 % confidence interval [CI] 1.47-2.11). Among the 2832 women followed up (median, 6.1 years), 406 developed clinically relevant depressive symptoms. Women with versus without VMSs had a significantly higher risk of developing clinically relevant depressive symptoms (multivariable-adjusted hazard ratio, 1.72; 95 % CI 1.39-2.14). VMS severity exhibited a dose-response relationship with depressive symptoms (P for trend <0.05). LIMITATIONS: Self-reported questionnaires were only used to obtain VMSs and depressive symptoms, which could have led to misclassification. We also could not directly measure sex hormone levels. CONCLUSIONS: Even in the premenopausal stage, women who experience hot flashes or night sweats have an increased risk of present and developed clinically relevant depressive symptoms. It is important to conduct mental health screenings and provide appropriate support to middle-aged women who experience early-onset VMSs.

Long working hours and increased risks of lean non-alcoholic fatty liver disease among Korean men and women.

Despite the increasing prevalence of lean nonalcoholic fatty liver disease (NAFLD), its risk factors are not well established. We examined the association between long working hours and incident NAFLD in lean Korean workers with emphasis on sex-based effect modification. This cohort study involved 46,113 non-overweight (BMI < 23 kg/m2) and NAFLD-free Korean workers (mean age, 35.5 years). Working hours were categorized into 35-40 (reference), 41-52, and ≥ 53 h. The presence of fatty liver and its severity were determined using ultrasonography and NAFLD fibrosis score (NFS), respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using parametric proportional hazards models. Incident cases of 5901 lean NAFLD developed over a median follow-up of 3.8 years. The incidence of lean NAFLD increased with increasing working hours with a stronger association in men than in women (P for interaction < 0.001). For men, multivariable-adjusted HRs (95% CIs) for lean NAFLD in time-dependent models comparing working hours of 41-52 and ≥ 53 h compared to the reference category were 1.17 (1.07-1.28) and 1.25 (1.12-1.39), respectively. The excess relative risk of developing lean NAFLD with intermediate/high NFS was observed in working hours of 41-52 and ≥ 53 h with a corresponding HR of 1.66 (1.13-2.43) and 1.54 (0.94-2.51), respectively. Conversely, no significant associations were found between working hours and incidence of lean NAFLD in women. In conclusion, long working hours were significantly associated with an increased incidence of lean NAFLD and its severe form in men but not in women.

NR1D1 Stimulates Antitumor Immune Responses in Breast Cancer by Activating cGAS-STING Signaling.

Potentiating antitumor immunity is a promising therapeutic approach for treating a variety of cancers, including breast cancer. One potential strategy to promote antitumor immunity is targeting DNA damage response. Given that the nuclear receptor NR1D1 (also known as REV-ERBα) inhibits DNA repair in breast cancer cells, we explored the role of NR1D1 in antitumor CD8+ T-cell responses. First, deletion of Nr1d1 in MMTV-PyMT transgenic mice resulted in increased tumor growth and lung metastasis. Orthotopic allograft experiments suggested that loss of Nr1d1 in tumor cells rather than in stromal cells played a prominent role in increasing tumor progression. Comprehensive transcriptome analyses revealed that biological processes including type I IFN signaling and T cell-mediated immune responses were associated with NR1D1. Indeed, the expression of type I IFNs and infiltration of CD8+ T cells and natural killer cells in tumors were suppressed in Nr1d1-/-;MMTV-PyMT mice. Mechanistically, NR1D1 promoted DNA damage-induced accumulation of cytosolic DNA fragments and activated cGAS-STING signaling, which increased the production of type I IFNs and downstream chemokines CCL5 and CXCL10. Pharmacologic activation of NR1D1 by its ligand, SR9009, enhanced type I IFN-mediated antitumor immunity accompanied by the suppression of tumor progression and lung metastasis. Taken together, these findings reveal the critical role of NR1D1 in enhancing antitumor CD8+ T-cell responses, suggesting that NR1D1 may be a good therapeutic target for breast cancer. SIGNIFICANCE: NR1D1 suppresses breast cancer progression and lung metastasis by enhancing antitumor immunity via cGAS-STING pathway activation, which provides potential immunotherapeutic strategies for breast cancer.

Targeting HMG-CoA synthase 2 suppresses tamoxifen-resistant breast cancer growth by augmenting mitochondrial oxidative stress-mediated cell death.

AIMS: In this study, we aimed to investigate previously unrecognized lipid metabolic perturbations in tamoxifen-resistant breast cancer (BC) by conducting comprehensive metabolomics and transcriptomics analysis. We identified the role of 3-hydroxy-3-methylglutary-coenzyme-A-synthase 2 (HMGCS2), a key enzyme responsible for ketogenesis, in tamoxifen-resistant BC growth. MAIN METHODS: Comprehensive metabolomics (CE-TOFMS, LC-TOFMS) and transcriptiomics analysis were performed to characterize metabolic pathways in tamoxifen-resistant BC cells. The upregulation of HMGCS2 were verified thorugh immunohistochemistry (IHC) in clinical samples obtained from patients with recurrent BC. HMGCS2 inhibitor was discovered through surface plasmon resonance analysis, enzyme assay, and additional molecular docking studies. The effect of HMGCS2 suppression on tumor growth was studied thorugh BC xenograft model, and intratumoral lipid metabolites were analyzed via MALDI-TOFMS imaging. KEY FINDINGS: We revealed that the level of HMGCS2 was highly elevated in both tamoxifen-resistant T47D sublines (T47D/TR) and clinical refractory tumor specimens from patients with ER+ breast cancer, who had been treated with adjuvant tamoxifen. Suppression of HMGCS2 in T47D/TR resulted in the accumulation of mitochondrial reactive oxygen species (mtROS) and apoptotic cell death. Further, we identified alphitolic acid, a triterpenoid natural product, as a novel HMGCS2-specific inhibitor that elevated mtROS levels and drastically retarded the growth of T47D/TR in in vitro and in vivo experiments. SIGNIFICANCE: Enhanced ketogenesis with upregulation of HMGCS2 is a potential metabolic vulnerability of tamoxifen-resistant BC that offers a new therapeutic opportunity for treating patients with ER+ BC that are refractory to tamoxifen treatment.

Vasomotor and other menopause symptoms and the prevalence of ideal cardiovascular health metrics among premenopausal stage women.

OBJECTIVE: We examined the association between menopause symptoms and the prevalence of ideal cardiovascular health (CVH) metrics among premenopausal women. METHODS: This cross-sectional study comprised 4,611 premenopausal women aged 42 to 52 years. Data for CVH metrics were collected during health screening examinations. Menopause symptoms were measured using the Korean version of the Menopause-Specific Quality of Life questionnaire. For vasomotor, psychosocial, physical, and sexual symptoms, participants were divided into absent or symptomatic groups, further divided into tertiles (range, 0-7; 7 being the most bothersome). Ideal CVH metrics were defined according to the American Heart Association Life Simple 7 metrics, except dietary component. Cardiovascular health metrics were scored from 0 (unhealthy) to 6 (healthy) and classified as poor (0-2), intermediate (3-4), and ideal (5-6). Multinomial logistic regression models were used to estimate the prevalence ratios for intermediate and poor CVH metrics using ideal CVH as the reference. RESULTS: The overall and 4 menopause-specific quality of life domain scores were significantly associated with poorer CVH metrics scores in a dose-response manner ( P < 0.05). After adjusting for age, parity, education level, anti-Mullerian hormone levels, and alcohol intake, women with the most bothersome degree for vasomotor, psychosocial, physical, and sexual symptoms had significantly higher prevalence of poor CVH metrics, with corresponding prevalence ratios (95% confidence interval) of 2.90 (1.95-4.31), 2.07 (1.36-3.15), 3.01 (1.19-7.65), and 1.66 (1.15-2.39), respectively, compared with those without each vasomotor, psychosocial, physical, and sexual symptom. CONCLUSIONS: Premenopausal stage women with either vasomotor or nonvasomotor menopausal symptoms have significantly higher prevalence of poor CVH metrics, compared with those without any menopausal symptoms.

DACH1 regulates cell cycle progression of myeloid cells through the control of cyclin D, Cdk 4/6 and p21Cip1.

The cell-fate determination factor Dachshund, a component of the Retinal Determination Gene Network (RDGN), has a role in breast tumor proliferation through the repression of cyclin D1 and several key regulators of embryonic stem cell function, such as Nanog and Sox2. However, little is known about the role of DACH1 in a myeloid lineage as a cell cycle regulator. Here, we identified the differential expression levels of extensive cell cycle regulators controlled by DACH1 in myeloid progenitor cells. The forced expression of DACH1 induced p27(Kip1) and repressed p21(Cip1), which is a pivotal characteristic of the myeloid progenitor. Furthermore, DACH1 significantly increased the expression of cyclin D1, D3, F, and Cdk 1, 4, and 6 in myeloid progenitor cells. The knockdown of DACH1 blocked the cell cycle progression of HL-60 promyeloblastic cells through the decrease of cyclin D1, D3, F, and Cdk 1, 4, and 6 and increase in p21(Cip1), which in turn decreased the phosphorylation of the Rb protein. The expression of Sox2, Oct4, and Klf4 was significantly up-regulated by the forced expression of DACH1 in mouse myeloid progenitor cells.

Regulation of HOXA9 activity by predominant expression of DACH1 against C/EBPα and GATA-1 in myeloid leukemia with MLL-AF9.

Although MLL-AF9 caused by the chromosomal translocation t(9;11) has a critical role in acute myeloid leukemia, the molecular pathogenesis is poorly understood. Here, we identified that the cell fate determination factor DACH1 is directly up-regulated by MLL-AF9. Recently we showed that the forced expression of DACH1 in myeloid cells induced p27(Kip1) and repressed p21(Cip1), which is a pivotal characteristic of the myeloid progenitor. Consistent with our previous study, ectopic expression of DACH1 contributed to the maintenance of colonogenic activity and blocked the differentiation of myeloid progenitors. Moreover, we here identified an endogenous HOXA9-DACH1 complex mediated by the carboxyl terminus of DACH1 in t(9;11) leukemia cells. qRT-PCR revealed that DACH1 has a stronger transcription-promoting activity with HOXA9 than does PBX2 with HOXA9. Furthermore, C/EBPα and GATA-1 can directly bind to the promoter of DACH1 and act as a transcriptional suppressor. Expression of DACH1 is down-regulated during myeloid differentiation and shows an inverse pattern compared to C/EBPα and GATA-1 expression. However, ectopic expression of C/EBPα and/or GATA-1 could not abrogate the over-expression of DACH1 induced by MLL-AF9. Therefore, we postulate that the inability of C/EBPα and GATA-1 to down-regulate DACH1 expression induced by MLL-AF9 during myeloid differentiation may contribute to t(9;11) leukemogenesis.

The Prevalence of Thyroid Dysfunction in Korean Women Undergoing Routine Health Screening: A Cross-Sectional Study.

Background: Women are more likely to experience thyroid diseases than men. However, thyroid dysfunction risk in women undergoing the menopausal transition remains largely unknown. We explored the prevalence of thyroid dysfunction across menopausal stages. Methods: We conducted a cross-sectional study of 53,230 women aged 40 years or older who underwent health screening between 2014 and 2018. Menopausal stages were categorized into 4 based on the Stages of Reproductive Aging Workshop +10 criteria. A multinomial logistic regression model was used to estimate the prevalence ratios (PRs) with confidence intervals [CIs] for thyroid dysfunction in menopausal stages compared with that in premenopause. Results: The prevalence of overt hypothyroidism was significantly increased during late transition and postmenopause; it remained significant after further adjustments for potential confounders (age, center, year of examination, age at menarche, parity, education level, smoking status, alcohol consumption, physical activity, and body mass index) with corresponding multivariable-adjusted PRs [CI] of 1.61 [1.12-2.30] and 1.66 [1.16-2.37] in the late transition and postmenopausal stages, respectively. A significant increase in the prevalence of subclinical hypothyroidism was also observed in the late transition and postmenopausal stage with multivariable-adjusted PRs [CI] of 1.22 [1.06-1.40] and 1.24 [1.07-1.44], respectively. In contrast, subclinical and overt hyperthyroidism were not significantly associated with menopausal stages. Conclusions: In this study of pre- and perimenopausal Korean women, the prevalence of overt and subclinical hypothyroidism was significantly elevated in the late menopausal transition. Future prospective studies are warranted to investigate the clinical and prognostic significance of thyroid dysfunction in women during menopausal transition.

Depressive symptoms and suicidality by menopausal stages among middle-aged Korean women.

AIMS: There has been increasing evidence of hormonal changes during reproductive events that lead to mood changes. However, studies on the severity of psychological problems according to the menopausal stage are limited. Thus, this study aimed to investigate the association between menopausal stages, depression and suicidality. METHODS: A total of 45 177 women who underwent regular health check-ups between 2015 and 2018 at Kangbuk Samsung Hospital were included. Participants were stratified into four groups (pre-menopause, early transition, late transition and post-menopause) based on the Stages of Reproductive Aging Workshop Criteria. The Center for Epidemiological Studies-Depression scale (CESD) was used to evaluate depressive symptoms, and the degree of depressive symptoms was classified as moderate (CESD score 16-24) or severe (CESD score ⩾ 25). To measure suicide risk, we administered questionnaires related to suicidal ideation. RESULTS: Overall, the prevalence of CESD scores of 16-24 and ⩾ 25 was 7.6 and 2.8%, respectively. Menopausal stages were positively associated with depressive symptoms in a dose-dependent manner. Multivariable-adjusted prevalence ratios (PRs, 95% confidence intervals) for CESD scores of 16-24 comparing the stages of the early menopausal transition (MT), late MT and post-menopause to pre-menopause was 1.28 (1.16-1.42), 1.21 (1.05-1.38) and 1.58 (1.36-1.84), respectively. The multivariable-adjusted PRs for CESD scores ⩾ 25 comparing the stages of the early MT, late MT and post-menopause to pre-menopause were 1.31 (1.11-1.55), 1.39 (1.12-1.72), 1.86 (1.47-2.37), respectively. In addition, the multivariable-adjusted PRs for suicidal ideation comparing the early MT, late MT and post-menopause stages to the pre-menopause stage were 1.24 (1.12-1.38), 1.07 (0.93-1.24) and 1.46 (1.25-1.70) (p for trend <0.001), respectively. CONCLUSIONS: These findings indicate that the prevalence of depressive symptoms and suicidal ideation increases with advancing menopausal stage, even pre-menopause.

High low-density lipoprotein cholesterol level is associated with an increased risk of incident early-onset vasomotor symptoms.

We investigated the associations between serum lipid profiles and risk of early-onset vasomotor symptoms (VMSs) in premenopausal women. This cohort study comprised 2,540 premenopausal women aged 42-52 years without VMSs at baseline (median follow-up: 4.4 years). VMSs, including hot flashes and night sweats, were assessed using the Menopause-Specific Quality of Life questionnaire (Korean version). Early-onset VMSs were defined as VMSs that occurred premenopause; moderate/severe VMSs were defined as a score of ≥ 3 points (range: 0 to 6, 6 being most bothersome). Cox proportional hazard regression models were used to estimate hazard ratios with 95% confidence intervals (CI) for the development of VMSs across the lipid levels. Higher low-density lipoprotein (LDL) cholesterol levels were positively associated with increased risk of early-onset VMSs. Compared to the < 100 mg/dL LDL group, the multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for incident VMSs were 1.19 (1.03-1.37) and 1.20 (1.03-1.40) in participants with LDL cholesterol levels of 100-129 mg/dL and ≥ 130 mg/dL, respectively (P for trend = 0.027). The multivariable-adjusted HR for incident moderate/severe VMSs was 1.37 (95% CI: 1.08-1.73) in participants with LDL ≥ 130 mg/dL, compared to those with LDL < 100 mg/dL. Meanwhile, triglycerides and total and high-density lipoprotein cholesterol levels were not significantly associated with early-onset VMSs risk in premenopausal women. Premenopausal women with high serum LDL cholesterol concentrations had a higher risk of incident early-onset VMSs. Further studies should confirm our findings and examine whether LDL-lowering interventions reduce the risk of early-onset VMSs among women during menopause transition.

Alcohol Consumption Patterns and Risk of Early-Onset Vasomotor Symptoms in Premenopausal Women.

The role of alcohol consumption in the risk of vasomotor symptoms (VMS), the most cardinal climacteric symptoms, is not well established. We examined their relationship with early-onset VMS among premenopausal women. Moderately-to-severely bothersome VMS, the primary outcome, was assessed using the Korean version of the Menopause-Specific Quality of Life questionnaire. The alcohol consumption categories included lifetime abstainer, former drinker, or current drinker, categorized as light, moderate, heavy, and very heavy. Compared with the lifetime-abstinence (reference), the multivariable-adjusted odds ratio (95% CIs) for prevalent VMS in alcohol consumption of <10, 10−19, 20−39, and ≥40 g/day were 1.42 (1.02−1.99), 1.99 (1.27−3.12), 2.06 (1.19−3.57), and 3.52 (1.72−7.20), respectively (p trend <0.01). Compared with the lifetime-abstinence, the multivariable-adjusted hazard ratios (95% CIs) for incident bothersome VMS among average alcohol consumption of <10, 10−19, 20−39, and ≥40 g/day were 1.10 (0.85−1.41), 1.03 (0.70−1.51), 1.72 (1.06−2.78), and 2.22 (1.16−4.23), respectively (p trend = 0.02). Increased alcohol consumption positively and consistently showed a relationship with increased risk of both prevalent and incident early-onset VMS. Refraining from alcohol consumption may help prevent bothersome VMS in premenopausal women.

Ideal Cardiovascular Health Metrics and Risk of Incident Early-Onset Vasomotor Symptoms Among Premenopausal Women.

CONTEXT: The relationship of ideal cardiovascular health (CVH) behaviors with preventing early-onset vasomotor symptoms (VMSs) is unknown. OBJECTIVE: We investigated the association between CVH metrics and the development of early-onset VMSs in premenopausal women. METHODS: This cohort study included 2541 premenopausal women aged 42 to 52 years without VMSs at baseline. CVH metrics were defined according to the American Heart Association Life Simple 7 metrics. Owing to limited availability of dietary information, CVH metrics were scored from 0 (unhealthy) to 6 (healthy) and classified into 3 groups: poor (0-2), intermediate (3-4), and ideal (5-6) CVH. VMSs, including hot flashes and night sweats, were assessed using the Menopause-Specific Quality of Life questionnaire. Moderate/severe VMSs was defined as a score of 3 or more points (range, 0 to 6; 6 being most bothersome). RESULTS: During a median follow-up of 4.5 years, 1241 women developed VMSs before menopause. After adjustment for age, parity, education level, and alcohol consumption, the hazard ratio (HR) (95% CI) for developing early-onset VMSs comparing poor CVH group to the ideal group was 1.41 (1.07-1.86). CVH scores were also inversely associated with moderate/severe VMSs in a dose-response manner (P for trend = .004); specifically, multivariable-adjusted HRs comparing intermediate and poor CVH groups to the ideal group were 1.20 (95% CI, 1.02-1.43) and 1.57 (95% CI, 1.08-2.29), respectively. CONCLUSION: Unfavorable CVH metrics were significantly associated with an increased risk of early-onset VMSs and its more severe forms among premenopausal women.