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Objectives: Prolactinoma is a common intracranial tumor with a high incidence and serious harm to human health. At present, there is only one therapeutic drug in China, bromocriptine, and the Chinese herb Prunella vulgaris L. (P. vulgaris)(PV) has shown certain anti-prolactinoma effects in the early stage. We expect to develop a candidate drug against prolactinoma. Materials and Methods: First, the extracts of P. vulgaris L.(PVE)were extracted with water, and the cell proliferation test of rat pituitary tumor cells MMQ was checked by the Cell Counting Kit-8 (CCK-8) assay. Then, core targets and correlative pathways were selected by the "protein–protein interaction" (PPI) network and the "PV–Target–Prolactinoma" network. The core targets and main components simulate the binding by molecular docking. Finally, the PVE and MMQ cells were used to verify the results. Results: Through the CCK-8 assay, the PVE inhibited the proliferation of MMQ cells. From the network pharmacology, the 21 targets, 9 signaling pathways, and 20 gene ontology (GO) projects were attained (p < 0.05). As a result the estrogen receptor α (ESR1), RAC-alpha serine/threonine-protein kinase(AKT1), and mitogen-activated protein kinase 3(MAPK3)were the core targets of protein against prolactinomas, which was in line with western blotting analysis. Conclusion: Our findings demonstrate that the PVE was verified against prolactinomas through the ESR1, MAPK3 targets, and the phosphoinositide 3-kinase/protein kinase B pathway. [ABSTRACT FROM AUTHOR]

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Estrogen receptor (ER) is overexpressed in approximately 2/3 of breast cancer patients' lesions. Noninvasive detection of ER in vivo and dynamic monitoring of ER are crucial for individualized treatment decision-making. 16α-18F-17β-fluoroestradiol (18F-FES) positron emission tomography (PET) has been used in a variety of preclinical and clinical studies to detect ER expression. However, there is still a lack of technical specifications in China. This technical specification was jointly written by domestic experts who had experience of 18F-FES PET imaging and was formed through consultation based on their own experience and research progress in this field both domestically and internationally. This technical specification introduced the synthesis method and quality control requirements of 18F-FES, recommended its clinical application scenarios, and classified them. In addition, experts' suggestions were provided throughout the entire process systemically and detailly, including pre-imaging preparation, imaging process, image analysis (normal biological distribution, determination of ER positive and negative, lesion detection, influencing factors, false negative and false positive, report requirements), and the limitations of this imaging technique were proposed. The future application prospects were also discussed. This specification aimed to promote the standardized application of 18F-FES PET in China, achieve repeatability and comparability, and provide important molecular imaging technical support for accurate diagnosis and treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Apostichopus japonicus is a temperate marine invertebrate and an economically important aquatic echinoderm species in China. As a benthic organism, sea cucumbers feed on small benthic particulate matter and are easily affected by pollutants. Therefore, for conservation purposes, it is important to elucidate the effects of specific pollutants on these animals. Bisphenol A (BPA) has been identified as an endocrine disruptor that functions as an estrogen analog and typically causes reproductive toxicity by interfering with the endocrine system. We identified the G protein-coupled estrogen receptor 1 in A. japonicus and found that both BPA and estradiol could activate the estrogen-receptor-mediated mitogen-activated protein kinase signaling pathway. Using biological approaches, we have confirmed the estrogen-analog bioactivity of BPA on sea cucumbers by direct interaction with the estrogen receptor. We also determined that BPA affects the reproduction of sea cucumbers by metabolic disruption in ovary tissue. The sea cucumber, Apostichopus japonicus, is a marine benthic organism that feeds on small benthic particulate matter and is easily affected by pollutants. Bisphenol A (BPA, 4,4′-isopropylidenediphenol) has been identified as an endocrine disruptor. It is ubiquitously detectable in oceans and affects a variety of marine animals. It functions as an estrogen analog and typically causes reproductive toxicity by interfering with the endocrine system. To comparatively analyze the reproductive effects of estradiol (E2) and BPA on sea cucumbers, we identified a G protein-coupled estrogen receptor 1 (GPER1) in A. japonicus and investigated its effects on reproduction. The results showed that BPA and E2 exposure activated A. japonicus AjGPER1, thereby mediating the mitogen-activated protein kinase signaling pathways. High-level expression of AjGPER1 in the ovarian tissue was confirmed by qPCR. Furthermore, metabolic changes were induced by 100 nM (22.83 μg/L) BPA exposure in the ovarian tissue, leading to a notable increase in the activities of trehalase and phosphofructokinase. Overall, our findings suggest that AjGPER1 is directly activated by BPA and affects sea cucumber reproduction by disrupting ovarian tissue metabolism, suggesting that marine pollutants pose a threat to the conservation of sea cucumber resources. [ABSTRACT FROM AUTHOR]

To compare the efficacies of exemestane and fulvestrant as first-line monotherapies for postmenopausal Chinese women having advanced oestrogen-receptor positive (ER+)/ human epidermal growth factor receptor 2 (HER2)-breast cancer (ER+/HER2- ABC) after a previous treatment for ≥2 years with an adjuvant non-steroidal aromatase inhibitor. In this randomised, open-label, multi-centre, parallel-controlled phase 2 FRIEND study, 145 postmenopausal ER+/HER2- ABC patients were assigned into fulvestrant (500 mg on days 0, 14 and 28, and then at every 28 ± 3 days, n = 77) and exemestane (25 mg/day, n = 67) groups. The primary outcome was progression-free survival (PFS), while the secondary outcomes were disease control rate, objective response rate, time to treatment failure, duration of response and overall survival. Exploratory end-points included gene mutation-related outcomes and safety. Fulvestrant was superior to exemestane regarding median PFS times (8.5 versus 5.6 months, p = 0.014, HR = 0.62, 95% confidence intervals: 0.42–0.91), objective response rates (19.5% versus 6.0%, p = 0.017) and time to treatment failure (8.4 versus 5.5 months, p = 0.008). The incidence of adverse or serious adverse events in the two groups was virtually identical. The most frequent mutations in 129 analysed patients were detected in the o estrogen receptor gene 1 (ESR1) (18/14.0%), PIK3CA (40/31.0%) and TP53 (29/22.5%) genes. Fulvestrant produced significant longer PFS times compared to exemestane but only for patients with an ESR1 -wild type (8.5 versus 5.8 months) (p = 0.035), although there was a similar trend also for the ESR1 mutation without statistical significance. All patients with c-MYC and BRCA2 mutations had longer PFS times in the fulvestrant versus the exemestane group (p = 0.049, p = 0.039). Fulvestrant significantly increased overall PFS for ER+/HER2- ABC patients and was well tolerated. NCT02646735, https://clinicaltrials.gov/ct2/show/NCT02646735. • The novel selective oestrogen receptor down regulator fulvestrant is administered to hormone receptor positive advanced breast cancer patients. • Exemestane, a steroidal aromatase inhibitors , is used to treat early and advanced breast cancer patients. • Fulvestrant was superior to exemestane regarding median progression-free survival times and time to treatment failure. • c-MYC and BRCA2 mutations led to longer progression-free survival times in the fulvestrant group. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to explore a new estrogen receptor (ER) and/or progesterone receptor (PR)+ and human epidermal growth factor receptor 2 (HER2)− breast cancer prognostic model, called the extended Cox prognostic model, for determining the cutoff values for multiple continuous prognostic factors and their interaction via the new model concept and variable selection method. Methods: A total of 335 patients with ER/PR+ and HER2− breast cancer were enrolled for the final analysis. The primary endpoint was breast cancer-specific mortality (BCSM). Prognostic factors (histological grade, histological type, stage, T, N, lymphovascular invasion (LVI), P53, Ki67, ER, PR, and age) were included in this study. The four continuous variables (Ki67, ER, PR, and age) were partitioned into a series of binary variables that were fitted in the multivariate Cox analysis. A smoothly clipped absolute deviation (SCAD) variable selection method was used. Model performance was expressed in discrimination and calibration. Results: We developed an extended Cox model with a time threshold of 164-week (more than 3 years) postoperation and developed a user-friendly nomogram based on our extended Cox model to facilitate clinical application. We found that the cutoff values for PR, Ki67, and age were 20%, 60%, and 41–55 years, respectively. There was an interaction between age and PR for patients aged ≥ 41 years and PR ≥ 20% at 164-week postoperation: the older the patients with ER/PR+, HER2−, and PR ≥ 20% were, the lower the survival and more likely to recur and metastasize exceeding 164 weeks (more than 3 years) after surgery. Conclusions: Our study offers guidance on the prognosis of patients with ER/PR+ and HER2− breast cancer in China. The new concept can inform modeling and the determination of cutoff values of prognostic factors in the future. [ABSTRACT FROM AUTHOR]

Background: Cancer cell–specific variation and circulating tumour DNA (ctDNA) methylation are promising biomarkers for non‐invasive cancer detection and molecular classification. Nevertheless, the applications of ctDNA to the early detection and screening of cancer remain highly challenging due to the scarcity of cancer cell–specific ctDNA, the low signal‐to‐noise ratio of DNA variation, and the lack of non‐locus‐specific DNA methylation technologies. Methods: We enrolled three cohorts of breast cancer (BC) patients from two hospitals in China (BC: n = 123; healthy controls: n = 40). We developed a ctDNA whole‐genome bisulfite sequencing technology employing robust trace ctDNA capture from up to 200 μL plasma, mini‐input (1 ng) library preparation, unbiased genome‐wide coverage and comprehensive computational methods. Results: A diagnostic signature comprising 15 ctDNA methylation markers exhibited high accuracy in the early (area under the curve [AUC] of 0.967) and advanced (AUC of 0.971) BC stages in multicentre patient cohorts. Furthermore, we revealed a ctDNA methylation signature that discriminates estrogen receptor status (Training set: AUC of 0.984 and Test set: AUC of 0.780). Different cancer types, including hepatocellular carcinoma and lung cancer, could also be well distinguished. Conclusions: Our study provides a toolset to generate unbiased whole‐genome ctDNA methylomes with a minimal amount of plasma to develop highly specific and sensitive biomarkers for the early diagnosis and molecular subtyping of cancer. [ABSTRACT FROM AUTHOR]

Hepatoma is one of the most common malignant tumors. The incidence rate is high in developing countries, and China has the most significant number of cases. Dahuang is a classic traditional antitumor drug commonly used in China and has also been applied to treat hepatoma. However, the potential mechanism of Dahuang in treating hepatoma is not clear. Therefore, this study is aimed at elucidating the possible molecular mechanism and key targets of Dahuang using methods of network pharmacology, molecular docking, and survival analysis. Firstly, the active ingredients and key targets of Dahuang were analyzed through public databases, and then the drug-ingredient-target-disease network diagram of Dahuang against hepatoma was constructed. Five main active components and five core targets were determined according to the enrichment degree. Enrichment analysis demonstrated that Dahuang treated hepatoma through the multiple pathways in cancer. Additionally, molecular docking predicted that aloe-emodin and PIK3CG depicted the best binding energy. Survival analysis indicated that a high/ESR1 gene expression had a relatively good prognosis for patients with hepatoma (p < 0.05). In conclusion, the current study results demonstrated that Dahuang could treat hepatoma through a variety of active ingredients, targets, and multiantitumor pathways. Moreover, it effectively improved the prognosis of hepatoma patients. ESR1 is the potential key gene that is beneficial for the survival of hepatoma patients. Also, aloe-emodin and beta-sitosterol are the two main active crucial ingredients for hepatoma treatment. The study also provided some functional bases and references for the development of new drugs, target mining, and experimental animal research of hepatoma in the future. [ABSTRACT FROM AUTHOR]

Purpose: To develop a nomogram model to predict overall survival in HR+/HER2-subtype advanced breast cancer. Methods: A total of 3,577 ABC (advanced breast cancer) patients from 21 hospitals in China were involved in this study from January 2012 to December 2014. From all ABC patients, 1,671 HR+/HER2- ABC patients were extracted and enrolled in our study. A nomogram was built based on univariable and multivariable Cox regression analyses, identifying independent predictors. The discriminatory and predictive capacities of the nomogram were assessed using the ROC (receiver operating characteristic) curve and calibration plots. Results: Univariable and multivariable analysis found that ER (estrogen receptor) status, MFIs (metastatic-free intervals), first-line therapy options, the number of metastatic sites, and whether local therapy for metastatic sites was chosen, were significantly related to overall survival (all P < 0.05). These variables were incorporated into a nomogram to predict the 2-year, 3-year, and 5-year OS (overall survival) of ABC patients. The AUC (the area under the curve) of the nomogram was 0.748 (95% CI (confidence interval):0.693-0.804) for 5-year OS in the training cohort and 0.732 (95% CI: 0.676-0.789) for the validation cohort. The calibration curves revealed good consistency between actual survival and nomogram prediction in the training and validation cohorts. Additionally, the nomogram showed an excellent ability to stratify patients into different risk cohorts. Conclusion: We established a nomogram that provided a more straightforward predictive model for the outcome of HR+/HER2-ABC subtype patients and, to some extent, assisted physicians in making the personalized therapeutic option. [ABSTRACT FROM AUTHOR]

Background: Estrogen receptors (ER) and progesterone receptors (PR) have important prognostic value in endometrial cancer, but there is no recognized positive immunohistochemical threshold for predicting the recurrence of early low-risk endometrial cancer. The purpose of this study was to clarify the optimal positive thresholds of the immunohistochemical parameters the ER and PR in early low-risk endometrial cancer. Methods: A total of 332 patients with stage IA endometrial cancer were enrolled from the First Affiliated Hospital of Chongqing Medical University and People's Hospital of Sha ping ba District in Chongqing between January 2013 and December 2018. First, univariate and multivariate Cox regression analyses were used to analyze the correlation between various clinical factors and the prognosis of early low-risk endometrial cancer. Then, the receiver operating characteristic curve (ROC curve) and Youden index were used to determine the positive thresholds of ER and PR. Results: The positive thresholds of ER and PR for predicting the recurrence of early low-risk endometrial cancer were 12% and 8%, respectively. Multivariate analysis showed that ER (P = 0.004), PR (P = 0.026), and p53 (P = 0.021) were risk factors for the prognosis of patients with early low-risk endometrial cancer. The recurrence-free survival and the overall survival in the low ER group and PR group were much lower than those in the high ER group and PR group (P < 0.001 of all). Conclusions: ER and PR positive thresholds of 12% and 8%, respectively, are the most suitable for predicting the recurrence of early low-risk endometrial cancer. [ABSTRACT FROM AUTHOR]

Background Previous studies have suggested that reproductive factors are associated with breast cancer risk. Breast cancer subtypes have distinct natural characteristics and may also have unique risk profiles. The purpose of this study was to determine whether reproductive factors affect the risk of breast cancer by estrogen receptor (ER)/progesterone receptor (PR) and HER2 status. Methods A multicenter, case-control study was conducted. There were 1170 breast cancer patients and 1170 age- and hospital-matched females included in the analysis. Self-reported data were collected about lifestyle behaviors, including reproductive factors. Breast cancer cases were categorized subtypes according to ER, PR, and HER2 expression as HR- positive, HER2-enriched, and triple negative breast cancer (TNBC). Multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results Having ≤1 child increased risk of HR-positive breast cancer (OR 1.882; 95%CI 1.29-2.74), especially in the premenopausal group (OR 2.212; 95%CI 1.23-3.99). Compared with women who first gave birth after age 30 years, earlier age at first birth decreased the risk of HR-positive breast cancer (≤23 years: OR 0.209; 95%CI 0.14-0.30; 24-29 years: OR 0.256; 95%CI 0.18-0.36; P <.001). Compared with those who had an average breastfed/birth period of more than 2 years, those with an average period less than 6 months had an elevated risk of all subtypes (HR positive: OR 2.690; 95%CI 1.71-4.16, P <.001; HER2-enriched: OR 3.779; 95%CI, 1.62-8.79, P =.001; TNBC: OR 2.564; 95%CI 1.11-5.94, P =.022). For postmenopausal patients, shorter period of lifetime menstrual cycles (≤30 years) had an obviously decreased risk in HR-positive cases (OR 0.397; 95%CI 0.22-0.71), while there was no similar appearance in other molecular subtypes. Conclusion The results suggest that reproductive behaviors affect risk of breast cancer differently according to ER/PR and HER2 status. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to identify the clinical characteristics of Chinese patients with ovarian endometrioid carcinoma (EC) and clear cell carcinoma (CCC) and to assess the impact of concurrent endometriosis on this group. Methods: The present study reviewed the medical records of patients who received initial treatment and a postoperative pathological diagnosis of EC or CCC at our center in China between 1998 and 2018. Results: Of 211 patients, 73 had pure EC, and 91 had pure CCC, and the remaining 47 had mixed cancer. The proportion of EC and CCC remained stable over past 21 years. The proportion of EC declined with aging and the age of EC onset to incline to the young. And the age of CCC onset had two peaks, namely, 36 and 77 years. After review by the pathologist, the number of endometriosis cases found in the pathological section of the analysis increased to 114, accounting for 54% of patients. As the stage progressed, the appearance of endometriosis became increasingly scarce in pathological sections(p = 0.001). Compared with CCC, EC had a higher frequency of concurrent endometrial cancer (independent endometrial lesions) and estrogen and progesterone receptor expression(p = 0.000). And more patients were in premenopausal state in EC group(p = 0.040). In the pure group, multivariate analysis showed that correlation existed between relevance to endometriosis and worse outcomes(p = 0.041). In patients with mixed cancer, mixed endometrioid histology was associated with better survival than other subtypes, even with stage III or poorly differentiated tumors(p = 0.001). Conclusions: CCC and EC which are common in ovarian cancer patients who have associated with endometriosis have distinct clinicopathological characteristics. Attention should be paid to ovarian cancer patients with a history of endometriosis and those with concurrent endometriosis in pathological sections. [ABSTRACT FROM AUTHOR]

Purpose. Accumulated evidence suggests that reproductive factors are related to different breast cancer subtypes, but most studies on these relationships are mainly focused on middle-aged and older patients, and it remains unclear how reproductive factors impact different subtypes of breast cancer in young women. Methods. We assessed the relationships between fertility factors and luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative breast cancer (TNBC) subtypes in 3792 patients and 4182 controls aged 20–70 years. Data on the reproductive history of the study participants were acquired through face-to-face interviews and questionnaires. We conducted case-control comparisons among tumor subtypes based on estrogen receptor (ER), progesterone receptor (PR), and HER2 statuses using unconditional polychotomous multivariate logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results. Parity was inversely related to both luminal A and luminal B subtypes in young women and older women (all P trend < 0.05). Later age at first full-term birth was inversely related to the luminal A subtype ( P trend < 0.05) in young women but correlated with an increased risk of the luminal A subtype ( P trend < 0.05) in older women. Parous Chinese women 40 years old or younger who breastfed for 12 months or longer had a lower risk of luminal B and TNBC subtypes than women who never breastfed (OR = 0.55 , 95% CI 0.36-0.84 and OR = 0.52 , 95% CI 0.28-0.99, respectively). Conclusions. Our results implied that parity exerted a strong protective effect against luminal A and luminal B subtype breast cancer in young Chinese women, and long-term breastfeeding obviously decreased the risk of luminal B and TNBC subtypes in this population. [ABSTRACT FROM AUTHOR]

Background: Myoepithelioma-like tumor of the vulvar region (MELTVR) is a recently described mesenchymal neoplasm which typically arising in vulvar regions of adult women. Case presentation: Here we report a case of a 65-year-old woman who presented with a 6-year history of subcutaneous mass in the vulvar region. The mass had recently increased in size continuously. Histologically, the tumor cells had an epithelioid to spindled shape. Epithelioid tumor cells proliferated singly or in a loosely cohesive manner with myxoid areas, while spindled tumor cells grew in diffuse sheets or storiform arrangements mainly in nonmyxoid areas. Immunohistochemically, the tumor cells were positive for vimentin, epithelial membrane antigen, calponin, and were partially mild to moderate positive for estrogen receptor, but completely negative for S100 protein, glial fibrillary acidic protein, CD34, desmin, SMA and cytokeratin. INI1/SMARCB1 expression was deficient. EWSR1 and FUS genes were intact tested by fluorescence in situ hybridization analysis. Based on these findings, we diagnose this case as MELTVR. The patient remained relapse-free after the lesion was widely excised during 8 months follow-up. Conclusions: This disease should be included in the differential diagnostic list of vulvar tumors with epithelioid to spindled morphology. Recognition of its histopathological features and immunohistochemical reactivity will help to understand the tumor better. [ABSTRACT FROM AUTHOR]

Fructus Sophorae (FS), the dry mature fruit of Sophora japonica Leguminosae, is a valuable traditional Chinese medicine resource with flavonoids as the major active ingredients. To identify the plant-derived estrogenlike flavonoids serving as potential osteoporosis chemopreventive agents, we isolated and identified 27 flavonoids compounds, including 17 compounds obtained for the first time from FS. To screen out the flavonoids with estrogen-like biological behavior from the 11 high yield compounds, we set up an in vitro screening system in rat osteoblast MC3T3-E1 cells including MTT assay, alkaline phosphatase staining and Alizarin red S staining assay to examine the effects on cell proliferation, differentiation and mineralization of osteoblast cells respectively. Six flavonoids, including genistein, sophoricoside, sophorabioside, sophoraflavonoloside, nicotiflorin and rutin, significantly increased the cellular activity of MC3T3-E1 cells. Furthermore, blocking the estrogen receptor signaling by tamoxifen compromised the effects above significantly, suggesting the 6 compounds behave as estrogen-like reagents. Moreover, the interaction between the six flavonoids from FS and estrogen receptor was clarified by molecular docking method from Glide XP. Collectively, being used as food and medicine in China, FS is rich in flavonoids with estrogen-like effects, may be used as healthy supplementary in treating postmenopausal women osteoporosis. [ABSTRACT FROM AUTHOR]

Background: A CYP2D6 gene polymorphism is related to the effect of tamoxifen treatment in patient with estrogen-receptor positive (ER) positive breast cancer and CYP2D6*10 T/T can lead to a poor prognosis in Asian patients. Although one-off pharmacogenetic testing may optimize adjuvant endocrine therapy, testing prior to tamoxifen initiation incurs additional costs. Aim: We conducted a study to assess the cost-effectiveness of CYP2D6*10 pharmacogenetic testing to guide the adjuvant endocrine therapy compared with tamoxifen without CYP2D6*10 testing in China. Methods: A semi-Markov model was developed to evaluate costs and health outcomes represented as quality adjusted life year (QALY) gained. Input data were obtained from the public literature. The results were expressed as incremental cost per QALY gained. A one-way deterministic sensitivity analysis explored the impact of uncertainty in the model parameters on results, and probabilistic uncertainty was assessed through a Monte Carlo probabilistic sensitivity analysis. Results: In the base-case analysis, in the CYP2D6*10 testing and alternative adjuvant endocrine therapy group, the incremental total cost was US$17,966.95 and the incremental QALY was 3.582. Thus, the incremental cost-effectiveness ratio was US$5015.693 per QALY gained. Compared with a willingness-to-pay threshold of US$26,508/QALY in China, the CYP2D6*10 testing is the dominant strategy in postmenopausal women with ER-positive breast cancer in China, and the increased cost of genetic testing was completely worthwhile. The sensitivity analyses showed that the model we built was quite stable. Conclusion: From the perspective of the Chinese healthcare system, CYP2D6*10 pharmacogenetic testing was cost effective for postmenopausal women with ER-positive early breast cancer. [ABSTRACT FROM AUTHOR]

Radix paeoniae alba (RPA) and Veratrum nigrum (VN) L. belong to the 18 incompatible medicaments and have been prohibited for thousands of years in China. Previous studies focused on the chemical constituents that induced the toxicological response of the two agents, but this study offers preliminary insight into the pharmacodynamics and mechanism on estrogenic activity, which is responsible for their incompatibility. We undertook a characterization of the interaction on estrogenic activity of RPA and VN using in vivo models of immature and ovariectomized (OVX) mice and in vitro studies focused on estrogen receptor (ER) pathway for further mechanism. VN disturbed the estrogenic efficacy of RPA in promoting development of uterus and vagina in immature mice, and reversing the atrophy of reproductive tissues in OVX mice by decreasing the increase of serum estrogen level and upregulation of ER expression in reproductive tissues by treatment with RPA. Besides, VN antagonized the estrogenic efficacy of RPA in stimulating the binding with ERα and ERβ, increasing ERα/β-estrogen response element (ERE) luciferase reporter gene expression and promoting MCF-7 cell viability. This study provided evidence that VN antagonized the estrogenic efficacy of RPA by decreasing the up-regulations of estrogen biosynthesis in circulation and ERs in target tissues caused by RPA, and through ER-ERE-dependent pathway. [ABSTRACT FROM AUTHOR]

This study aimed to assess the exposure level and risk of Di-2-ethylhexyl Phthalate (DEHP) among adults in Jilin Province, China, clarify the impact of DEHP on human thyroid function, and to explore the role of estrogen receptors (ERs)-Notch signaling pathway in the effect of DEHP metabolites on thyroid hormones based on population data and in vitro experiments. 312 adults participated in this study. Urinary DEHP metabolites were determined by high performance liquid chromatography coupled to a tandem mass spectrometer (HPLC-MS/MS). Two pharmacokinetic models were used to evaluate the estimated daily intake (EDI) and hazard quotient (HQ) of the adults. Multiple linear regression and mediating effect models were used to evaluate the target associations. In cell experiments, thyroid follicular epithelial (Nthy-ori3–1) cells were exposed to mono (2-ethylhexyl) phthalate (MEHP) for testing. The inhibitions of ERα and Notch pathway were conducted by siRNA and Notch pathway inhibitor DAPT. The detection rate of five DEHP metabolites was 97.1∼100.0%. The HQ value of 0.3% of adults was higher than 1. The levels of urinary DEHP metabolites were significantly correlated with thyrotropin (TSH), thyrotropin-releasing hormone (TRH), total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3) and free thyroxine (FT4) and gene (estrogen receptor α (ERα), Notch1, Dll4) levels. The ERα-Notch pathway played a mediating role in the association between DEHP metabolite levels and FT4. The cell results showed, the levels of FT3 and FT4 in cell supernatant decreased after MEHP exposure, and the downward trend was reversed after ERα and notch pathways were inhibited, notch pathway genes also decreased after ERα inhibition. Adults in the Jilin Province of China were widely exposed to DEHP. ERs-Notch pathway played an important role in the effect of DEHP metabolites on thyroid hormones. [Display omitted] • Adults were widely exposed to DEHP, and DEHP exposure posed potential health risks to the population. • The DEHP metabolites were negatively correlated with serum FT3, FT4, TT3, TT4, TRH, and positively correlated with key genes of ERα-Notch pathway. • The FT3 and FT4 in the cell supernatant decreased after MEHP exposure, and this downward trend was reversed after the inhibition of ERα and Notch. [ABSTRACT FROM AUTHOR]

Background: Studies suggested that PM2.5 exposure could lead to adverse reproductive effects on male animals. However, the underlying mechanism is still not clear. Besides, animals in the majority of previous studies were exposed to PM2.5 through intratracheal instillation which should be improved. In addition, limited amount of research has been conducted in China where the PM2.5 concentration is higher and the PM2.5 components are different. The aim of this work is to explore the effects of concentrated ambient PM2.5(CAP) on mice sperm quality and testosterone biosynthesis. Methods: A total of 12 male C57BL/6 mice were exposed to filtered air (FA) or CAP for 125 days using the Shanghai Meteorological and Environmental Animal Exposure System. The mice sperm concentration, sperm motility, DNA fragmentation index, high DNA stainability and plasma testosterone were analyzed. Testicular histology and sperm morphology were observed through optical microscope. Testosterone biosynthesis related gene expressions were analyzed using real-time PCR, including cytochrome P450 CHOL side-chain cleavage enzyme (P450scc), steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β HSD), 17β-hydroxysteroid dehydrogenase, cytochrome P450 aromatase (P450arom), estrogen receptor (ER), androgen receptor (AR) and follicle stimulating hormone receptor (FSHR). Results: Exposure to CAP resulted in disturbance of various stages of spermatogenesis and significant higher percentage of abnormal sperm (FA vs. CAP: 24.37% vs. 44.83%) in mice testis. CAP exposure significantly decreased sperm concentration (43.00 × 106 vs. 25.33 × 106) and motility (PR: 63.58% vs. 55.15%; PR + NP: 84.00% vs. 77.08%) in epididymis. Plasma testosterone concentration were significantly declined (0.28 ng/ml vs. 0.69 ng/ml) under CAP exposure. Notably, the levels of testosterone biosynthesis related genes, StAR, P450scc, P450arom, ER and FSHR were significantly decreased with CAP exposure. Conclusion: Concentrated ambient PM2.5 exposure altered mice sperm concentration, motility and morphology, which might be mediated primarily by the decline in testosterone concentration and testosterone biosynthesis process. [ABSTRACT FROM AUTHOR]

The association between dairy intake and breast cancer risk has not been well investigated, especially in the Chinese population. This study aimed to examine the association between the weekly frequency of dairy intake and the risk of breast cancer among women in Northern and Eastern China, and to investigate whether the association varied by hormone receptor status. A total of 1,286 cases of breast cancer and 1,461 controls were enrolled in this study. Dairy intake was obtained using a food-frequency questionnaire (FFQ). Frequency of dairy intake per week was divided into four categories (<1 day/week, 1–2 days/week, 3–4 days/week and 5–7 days/week). Unconditional multivariate logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). Stratified analyses were performed by residence, age, and education level. Separate analyses were also conducted for different estrogen receptor (ER) and progesterone receptor (PR) status. This analysis revealed that weekly frequency of dairy intake was strongly inversely associated with breast cancer risk, with an adjusted OR for intake 5–7 days/week of 0.53 (95% CI=0.39–0.72, P<0.001 for trend). In the stratified analyses, women who consumed dairy 5–7 days/week had a lower risk of breast cancer in urban areas (OR=0.45, 95% CI=0.30–0.66, P<0.001 for trend), in the group 45–59 years old (OR=0.39, 95% CI=0.26–0.60, P<0.001 for trend), and in the group educated to senior high school or above (OR=0.39, 95% CI=0.25–0.59, P<0.001 for trend). There was an inverse association between the weekly frequency of dairy intake and the risk of ER+, PR+, and ER+PR+ breast cancer (all P<0.001 for trend). These results indicated that the weekly frequency of dairy intake was inversely associated with the risk of breast cancer among women in Northern and Eastern China. [ABSTRACT FROM AUTHOR]

Background: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been reported to disrupt endocrine system and reproduction. However, epidemiological evidence on the association between PFAS and preeclampsia is inconsistent. We aimed to investigate the association between prenatal PFAS exposure and hypertensive disorders of pregnancy (HDP) in humans.Methods: PFAS were measured by liquid chromatography system coupled with tandem mass spectrometry in 687 umbilical cord plasma samples collected between 2011 and 2012 in Shanghai, China. Information on HDP including gestational hypertension and preeclampsia was abstracted from medical records. Multiple logistic regression was used to examine the association of each PFAS with gestational hypertension, preeclampsia, and overall HDP in separate models. Elastic net regression with logit link was used to identify independent associations between exposures and outcomes. Logistic regression was used to obtain the unpenalized estimates of the selected PFAS components for the associations with outcomes, adjusting for age, education level, pre-pregnancy BMI, parity, and mutual adjustment of selected PFAS.Results: The risk of gestational hypertension and preeclampsia was 3.3% and 2.8% in our subjects, respectively. Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluoroundecanoic acid (PFUA) were associated with preeclampsia based on elastic net penalty regression. In the fully adjusted statistical model, women with a higher level of standardized ln-transformed PFBS had an increased odds of preeclampsia [adjusted odds ratio (AOR): 1.81, 95% confidence interval (CI): 1.03-3.17], and overall HDP (AOR: 1.64, 95% CI: 1.09-2.47).Conclusions: Prenatal exposure to PFBS was positively associated with the risk of preeclampsia and overall HDP. [ABSTRACT FROM AUTHOR]

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Although recent studies demonstrated that fulvestrant is superior to anastrozole as first-line treatment for hormone receptor ( HR)-positive advanced breast cancer, the cost-effectiveness of fulvestrant versus anastrozole remained uncertain. Thus, the current study aimed to evaluate the cost-effectiveness of fulvestrant compared with anastrozole in the first-line setting. A Markov model consisting of three health states (stable, progressive and dead) was constructed to simulate a hypothetical cohort of patients with HR-positive advanced breast cancer. Costs were calculated from a Chinese societal perspective. Health outcomes were measured in quality-adjusted life-year ( QALY). The incremental cost-effectiveness ratio ( ICER) was expressed as incremental cost per QALY gained. Model results suggested that fulvestrant provides an additional effectiveness gain of 0.11 QALYs at an incremental cost of $32,654 compared with anastrozole, resulting in an ICER of $296,855/ QALY exceeding the willingness-to-pay threshold of $23,700/ QALY. Hence, fulvestrant is not a cost-effective strategy compared with anastrozole as first-line treatment for HR-positive advanced breast cancer. [ABSTRACT FROM AUTHOR]

Previous studies have investigated the association between dietary inflammatory potential and the development of cancer. For breast cancer the results have been equivocal. The present study aimed to investigate whether higher Dietary Inflammatory IndexTM (DII) scores were associated with increased risk of breast cancer among Chinese women. A total of 867 cases and 824 controls were recruited into the present case–control study from September 2011 to February 2016. DII scores were computed based on baseline dietary intake assessed by a validated 81-item FFQ. The OR and 95 % CI were assessed by multivariable logistic regression after adjusting for various potential confounders. DII scores in this study ranged from −5·87 (most anti-inflammatory score) to +5·71 (most proinflammatory score). A higher DII score was associated with a higher breast cancer risk (adjusted ORquartile 4 v. 1 2·28; 95 % CI 1·71, 3·03; adjusted ORcontinuous 1·40; 95 %CI 1·25, 1·39). In stratified analyses, positive associations also were observed except for underweight women or women with either oestrogen receptor+ or progesterone receptor+ status (but not both). Results from this study indicated that higher DII scores, corresponding to more proinflammatory diets, were positively associated with breast cancer risk among Chinese women. [ABSTRACT FROM PUBLISHER]

Hybrid Broussonetia papyrifera (BP) has been widely planted and commonly used as ruminant forage source after fermentation in China. Very less information is available to know the impact of fermented BP on laying hens, thus, we have investigated effects of dietary supplementation of Lactobacillus plantarum -fermented B. papyrifera (LfBP) on laying performance, egg quality, serum biochemical parameters, lipid metabolism, and follicular development of laying hens. A total of 288 HY-Line Brown hens (age, 23 wk) were randomly assigned into 3 treatment groups: control group (Con, a basal diet), LfBP1 and LfBP5 group (a basal diet supplemented with 1% or 5% LfBP). Each group has 8 replicates of twelve birds each. The results demonstrated that dietary supplementation of LfBP increased average daily feed intake (linear, P < 0.05), feed conversion ratio (linear, P < 0.05), and average egg weight (linear, P < 0.05) during the entire experimental period. In addition, dietary inclusion of LfBP enhanced the egg yolk color (linear, P < 0.01) but decreased the eggshell weight (quadratic, P < 0.05) and eggshell thickness (linear, P < 0.01). In serum, the LfBP supplementation linearly decreased the content of total triglyceride (linear, P < 0.01) but increased the content of high density lipoprotein-cholesterol (linear, P < 0.05). The gene expression related to hepatic lipid metabolism including acetyl-CoA carboxylase, fatty acid synthase, and peroxisome proliferator-activated receptor (PPARα) was down-regulated whereas liver X receptor was up-regulated in LfBP1 group. Moreover, LfBP1 supplementation remarkably reduced the F1 follicle number and ovarian gene expression of reproductive hormone receptors including estrogen receptor, follicle stimulating hormone receptor, luteinizing hormone receptor, progesterone receptor, prolactin receptor, and B cell lymphoma-2. In conclusion, dietary inclusion of LfBP could improve feed intake, egg yolk color, and lipid metabolism, but may cause a decline in eggshell quality with higher inclusion level, herein, 1% is suggested. [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimera (PROTAC) technology, one of the targeted protein degradation technologies, has drawn marked attention from researchers of both academia and industry in recent years. After over two decades of development, the literature on it has proliferated. In order to better grasp the frontiers and hot spots of PROTAC, this bibliometric analysis was carried out. The articles and reviews regarding PROTAC were culled from the Web of Science Core Collection. General information and the trend of publication outputs, countries/regions, authors, journals, influential papers, and keywords in this field were visually analyzed using CtieSpace, VOSviewer, or Excel software. As a result, a total of 808 publications were included. The number of papers regarding PROTAC significantly increased yearly. These papers mainly come from 45 countries/regions led by the USA and China. 3886 authors were identified participating in these studies, among which Craig M. Crews had the most significant number and influential articles. Journal of Medicinal Chemistry and European Journal of Medicinal Chemistry are the two journals with the most papers. After analysis, the most influential papers were identified in the area, including highly cited papers, references with citation burst, and high co-citated papers. The most common keywords including cancer, E3 ligase, drug discovery, epigenetic, resistance, and so on, represent the current and developing areas of study. BRDs, androgen receptor (AR), HDACs, estrogen receptor (ER), EGFR, CDKs, and KRAS are the most common targets. At last, frontiers and challenges of PROTAC were discussed through the bibliometric analysis. This paper will be helpful for better understanding the frontiers and hotspots of PROTAC. [Display omitted] • The first bibliometric analysis of PROTAC. • The literature information of PROTAC was visually analyzed. • Highlight the influential papers. • Highlight the PROTACs for the most common targets. [ABSTRACT FROM AUTHOR]

Risk assessment for molecular toxicity endpoints of environmental matrices may be a pressing issue. Here, we combined chemical analysis with species sensitivity distributions (SSD) and in silico docking for multi-species estrogen receptor mediated-risk assessment in water from Dongjiang River, China. The water contains high levels of phenolic endocrine-disrupting chemicals (PEDCs) and phthalic acid esters (PAEs). The concentration of ∑ 4 PEDCs and ∑ 6 PAEs ranged from 2202 to 3404 ng/L and 834–4368 ng/L, with an average of 3241 and 2215 ng/L, respectively. The SSD approach showed that 4-NP, BPA, E2 of PEDCs, and DBP, DOP, and DEHP could severely threaten the aquatic ecosystems, while most other target compounds posed low-to-medium risks. Moreover, binding affinities from molecular docking among PEDCs, PAEs, and estrogen receptors (ERα, Erβ, and GPER) were applied as toxic equivalency factors. Estrogen receptor-mediated risk suggested that PEDCs were the main contributors, containing 53.37–69.79% of total risk. They potentially pose more severe estrogen-receptor toxicity to zebrafish, turtles, and frogs. ERβ was the major contributor, followed by ERα and GPER. This study is the first attempt to assess the estrogen receptor-mediated risk of river water in multiple aquatic organisms. The in silico simulation approach could complement toxic effect evaluations in molecular endpoints. [Display omitted] • PEDCs as well as DBP, DOP and DEHP posed serious threat to aquatic ecosystems. • PEDCs contribution of 53.37–69.79% of estrogen receptor mediated risk. • Zebrafish, turtle and frog shown serious estrogen receptor mediated risk. • ERβ was major contributor among estrogen receptors, followed by ERα and GPER. • In silico approach could be valuable for risk assessment in molecular endpoints. [ABSTRACT FROM AUTHOR]

Purpose: A lack of progesterone receptor (PgR) expression in oestrogen receptor-positive (ER+) tumours is associated with worse survival. PgR status is usually defined as positive or negative using 1% positive nuclei as a cut-off point. In this study, we aimed to assess the clinicopathologic characteristics of ER+/PgR-/HER2- tumours by comparing them with ER+/PgR+/HER2- tumours using a PgR cut-off point of 20% as a divisive criterion. Methods: We analysed 1,522 patients with primary breast cancer who had undergone surgery at the Cancer Center of Fudan University between 2012 and 2014. Age, grade, tumour size, lymph node status and lymphovascular invasion were assessed. Multinomial logistic regression, linear regression and chi-square test models were applied to assess associations between ER, PR and clinical features. Results: ER+/PgR-/HER2- tumours showed poorer clinicopathologic characteristics relative to ER+/PgR+/HER2- tumours using a PgR threshold of 20% instead of 1%. The clinicopathologic characteristics did not differ between tumours with purely negative PgR expression and tumours with a PgR percentage ranging from 1% to 19%. The prognostic significance of PR expression appeared more pronounced in patients under a high Ki-67 status than those under a low Ki-67 status. Conclusions: Based on these findings, we propose the use of a novel threshold of 20% to define PgR status. Nevertheless, the impact of this new criterion on patient management and clinical treatment requires additional study. [ABSTRACT FROM AUTHOR]

The purpose of this study was to test the hypothesis that genetic variants of estrogen receptor α (ERα) are associated with the outcomes of hepatitis C virus (HCV) infection. We genotyped the seven single nucleotide polymorphisms (SNPs) (rs2077647, rs9340799, rs2234693, rs1801132, rs9322354, rs2228480 and rs3798577) of ERα and conducted a case-control study in a high-risk Chinese population, including 429 HCV spontaneous clearance cases, 880 persistent infection cases and 1,174 uninfected controls. The C allele of rs2234693 was significantly associated with increased susceptibility to HCV infection [dominant model: adjusted odds ratio (OR) = 1.377, 95 % confidence interval (CI) =1.126-1.778], and the risk effect remained significant among the younger (≤55 years) and hemodialysis subjects (all P < 0.007). The other three SNPs variant genotypes also showed significant correlation with elevated risk of HCV infection in different strata (rs2077647 in males; rs9340799 in blood donors; rs1801132 in younger subjects; all P < 0.007). It was also discovered that carriage of rs2228480 A allele was more prone to develop persistent HCV infection (dominant model: adjusted OR = 1.203, 95 % CI = 1.154-1.552), and the risk effect was more evident in females and blood donors (all P < 0.007). Haplotype analyses (rs2077647, rs9340799 and rs2234693) showed that, compared with the most frequent haplotype TAT, CAC played a risk effect in subgroups of younger ( P = 3.24 × 10) and male ( P = 5.51 × 10), whereas CAT expressed a protective effect in females ( P = 2.27 × 10) for HCV infection susceptibility. We first report that these SNPs (rs2077647, rs9340799, rs2234693, rs1801132 and rs2228480) in ERα can influence the outcomes of HCV infection in a high-risk Chinese population. [ABSTRACT FROM AUTHOR]

Two types of biological tests were employed for monitoring the toxicological profile of sediment cores in the Three Gorges Reservoir (TGR), China. In the present study, sediments collected in June 2010 from TGR were analyzed for estrogen receptor (ER)- and aryl hydrocarbon receptor (AhR)-mediated activities. The estrogenic activity was assessed using a rapid yeast estrogen bioassay, based on the expression of a green fluorescent reporter protein. Weak anti-estrogenic activity was detected in sediments from an area close to the dam of the reservoir, and weak estrogenic activities ranging from 0.3 to 1 ng 17β-estradiol (E2) equivalents (EQ) g dry weight sediment (dw) were detected in sediments from the Wanzhou to Guojiaba areas. In the upstream areas Wanzhou and Wushan, sediments demonstrated additive effects in co-administration of 1 nM E2 in the yeast test system, while sediments from the downstream Badong and Guojiaba areas showed estrogenic activities which seemed to be more than additive (synergistic activity). There was an increasing tendency in estrogenic activity from upstream of TGR to downstream, while this tendency terminated and converted into anti-estrogenic activity in the area close to the dam. The AhR activity was detected employing rat hepatoma cell line (H4IIE). EROD activities were found homogenously distributed in sediments in TGR ranging from 200 to 311 pg 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) EQ g dw for total AhR agonists and from 45 to 76 pg TCDD EQ g dw for more persistent AhR agonists. The known AhR agonists polycyclic aromatic hydrocarbon, polychlorinated biphenyl, and PCDD/F only explained up to 8 % of the more persistent AhR agonist activity in the samples, which suggests that unidentified AhR-active compounds represented a great proportion of the TCDD EQ in sediments from TGR. These findings of estrogenic potential and dioxin-like activity in TGR sediments provide possible weight-of-evidence of potential ecotoxicological causes for the declines in fish populations which have been observed during the past decades in TGR. [ABSTRACT FROM AUTHOR]

Abstract: Second-grade surface water and ground water are considered as the commonly used cleanest water in the Yangtze River Delta, which supplies centralized drinking water and contains rare species. However, some synthetic chemicals with estrogenic disrupting activities are detectable. Estrogenic activities in the second-grade surface water and ground water were surveyed by a green monkey kidney fibroblast (CV-1) cell line based ER reporter gene assay. Qualitative and quantitative analysis were further conducted to identify the responsible compounds. Estrogen receptor (ER) agonist activities were present in 7 out of 16 surface water and all the ground water samples. Huaihe River and Yangtze River posed the highest toxicity potential. The highest equivalent (2.2 ng E2/L) is higher than the predicted no-effect-concentration (PNEC). Bisphenol A (BPA) contributes to greater than 50% of the total derived equivalents in surface water, and the risk potential in this region deserves more attention and further research. [Copyright &y& Elsevier]

Highlights: [•] We study the association between sex-hormone genes and UG responder behavior. [•] Significant association is found for androgen receptor gene for males in China. [•] Androgen receptor gene finding not replicated in Israeli sample. [•] Significant association is found for estrogen receptor β gene for females in China. [•] Estrogen receptor β gene finding replicated in Israeli sample. [Copyright &y& Elsevier]

Abstract: Temporal variations in estradiol-17β (E2) and testosterone (T) levels from initiation to partially spent stages of Fujian oyster, Crassostrea angulata from China were investigated by enzyme-linked immunosorbent assay. E2 concentration varying between 95.97 and 280.98pg/g wet weight in the female gonads was higher than that in the male gonads (P <0.05), while T concentration ranging from 16.06 to 30.09pg/g wet weight in the male gonads was higher than that in the female gonads (P <0.05). Both steroids increased during sexual maturation in females and males respectively, and then decreased markedly after spawning. These findings indicated that the fluctuations in the levels of both steroids were closely related to the reproductive cycle, thus E2 and T could have a role as endogenous modulators in sex determination, development and maturation of C. angulata. In addition, a full-length cDNA (3161bp) encoding a peptide of 744 amino acids of estrogen receptor (ER) from C. angulata was obtained and the similarities of its deduced amino acid sequence to these of other molluscan species were more than 60%. caER mRNA transcript was most abundantly expressed in ovary (P <0.05) and in situ hybridization revealed that the distribution of this gene was expressed exclusively in “auxiliary cells” of ovary. Similar to the variation trends of E2, the expression of caER in the ovary continuously increased from initiation to ripeness stages (P <0.05), and then decreased sharply to the lowest level in the partially spent stage (P <0.05), whereas the caER mRNA transcript of male oyster in the testis maintained a relatively stable low level during the reproductive cycle. These findings suggested that ER may play an important role in the gonad development of oysters. [Copyright &y& Elsevier]

Abstract: The estrogenic activities of source water from Yangtze River, Huaihe River, Taihu Lake and groundwater in Yangtze River Delta in the dry and wet season were determined by use of reporter gene assays based on African green monkey kidney (CV-1) cell lines. Higher estrogenic activities were observed in the dry season, and the estrogenic potentials in water samples from Taihu Lake were greater than other river basins. None of the samples from groundwater showed estrogen receptor (ER) agonist activity. The 17β-Estradiol (E2) equivalents (EEQs) of water samples in the dry season ranged from 9.41×10−1 to 1.20×101 ngE2L−1. In the wet season, EEQs of all the water samples were below the detection limit as 9.00×10−1 ngE2L−1 except for one sample from Huaihe River. The highest contribution of E2 was detected in Yangtze River as 99% of estrogenic activity. Nonylphenol (NP, 100% detection rate) and octylphenol (OP, 100% detection rate) might also be responsible for the estrogenic activities in water sources. Potential health risk induced by the estrogenic chemicals in source water may be posed to the residents through water drinking. [Copyright &y& Elsevier]

Summary: The aim of this study was to determine the clinicopathological impact of PIK3CA mutations and phosphatidylinositol 3′-kinase pathway alterations in endometrial cancers in Chinese women. The PIK3CA mutation status was analyzed by sequencing in 94 tumors. The status of phosphatase and tensin homolog, p-(Ser/Thr)AKT, human epidermal growth factor receptor 2, p53, and estrogen and progesterone receptor was assessed in 102 tumors using immunohistochemistry. Biomarker status was correlated with clinicopathologic variables and with patient survival. We found that 28 mutations occurred in the helical domain encoded by exon 9 of PIK3CA and 16 occurred in the kinase domain (exon 20). Mutations of both exons were more common in low-grade than in high-grade endometrioid carcinomas, and the correlation between exon 9 mutation and lower grade was statistically significant (P = .045). In univariate analysis, phosphatidylinositol 3′-kinase pathway activation (defined as PIK3CA mutation and/or phosphatase and tensin homolog loss) was associated with a favorable prognosis (P = .034) and showed an increased predictive power when combined with expression of p-AKT, the phosphatidylinositol 3′-kinase pathway downstream effector (P = .022). In multivariate analysis, phosphatidylinositol 3′-kinase pathway activation was not an independent predictor of disease-free survival (P = .091). Interestingly, in the estrogen receptor–negative subgroup, the phosphatidylinositol 3′-kinase pathway alteration was significantly related to prolonged patient survival (P = .048), whereas this association was not present in the estrogen receptor–positive subgroup (P > .05). Our findings suggest that phosphatidylinositol 3′-kinase pathway alteration might have a favorable prognostic impact on endometrial cancers in Chinese women. Furthermore, the function of the phosphatidylinositol 3′-kinase pathway might be affected by estrogen receptor status. [Copyright &y& Elsevier]

ABSTRACT The present study intended to develop receptor-mediated luciferase reporter gene assays to evaluate and compare the estrogen receptor (ER), androgen receptor (AR) and thyroid hormone receptor (TR) activities of target chemicals. Di-2-ethylhexyl-phthalate (DEHP), chlorpyrifos (CPF), 2,4-dichlorophenoxyacetic acid (2,4-D) and bisphenol A (BPA) are some of the most common contaminants in drinking water and are frequently detected in China and worldwide. The chemicals were tested at concentrations of 0.1, 1, 10 and 100 times their maximum contaminant level in drinking water. The results showed that BPA possessed various activities on ER, AR and TR. DEHP and CPF could suppress 17 β-estradiol or testosterone activity with different potencies, and DEHP possessed weaker anti-thyroid hormone activity. 2,4-D showed no agonist or antagonist activity against these hormone receptors, but it significantly enhanced the activity of testosterone through AR. Furthermore, the mixture of DEHP and CPF exhibited stronger ER and AR antagonist activities than each single component alone, but their combined effects were less than the expected effects based on the additive model. These results implied that the transcription activation mediated by hormone receptors was the potential endocrine-disrupting mechanism of the test chemicals. Our study also provided useful tools for evaluation of their endocrine disrupting activity. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: To investigate the single nucleotide polymorphism 12 (SNP12) in the estrogen receptor α (ESR1) gene in hypospadiac or cryptorchid patients from Northwestern China. Methods: 103 patients and 40 controls were analyzed for SNP12 to verify whether this genetic variant was associated with hypospadias or cryptorchidism. Results: The frequencies of the A allele and homozygote individuals for the A allele of SNP12 in the hypospadiac group were higher than in the control group, respectively (p = 0.011, p = 0.005). The frequency of the A allele of SNP12 in the cryptorchid group was higher than in the control group (p = 0.038). However, no significant difference was observed between the cryptorchid group and control group of homozygote individuals for the A allele of SNP12 (p = 0.070). Conclusions: Our results suggested that the A allele of SNP12 may increase the risk of hypospadias or cryptorchidism. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Few studies have evaluated the relationship between the consumption of dietary folate and one-carbon metabolism-related nutrients and breast cancer risk defined by oestrogen receptor (ER) and progesterone receptor (PR) status. The objective of the present study was to examine the associations between dietary folate, vitamin B6, vitamin B12, and methionine intake and the risk of breast cancer by ER and PR status among Chinese women in Guangdong. A hospital-based case–control study was conducted from June 2007 to August 2008, with 438 cases and 438 age (5-year interval)- and residence (rural/urban)-matched controls. Dietary intake information was assessed using a validated FFQ administered through a face-to-face interview. Unconditional logistic regression models were used to calculate multivariate-adjusted OR and 95 % CI. A significant inverse association was found between dietary folate and vitamin B6 intake and breast cancer risk. The adjusted OR of the highest v. the lowest quartile were 0·32 (95 % CI 0·21, 0·49; Ptrend < 0·001) for dietary folate and 0·46 (95 % CI 0·30, 0·69; Ptrend < 0·001) for vitamin B6. No associations were observed for vitamin B12 and methionine intake. A significant inverse association between dietary folate intake and breast cancer risk was observed in all subtypes of ER and PR status. These findings suggest that dietary folate and vitamin B6 intakes were inversely associated with breast cancer risk. The inverse association did not differ by ER and/or PR status. [ABSTRACT FROM PUBLISHER]

Background/Objectives:There is few data on the association between dietary fiber intake and estrogen receptor (ER)/progesterone receptor (PR)-defined breast cancer risk. The present study aimed to investigate the associations between total dietary fiber and dietary fiber fractions intake and breast cancer risk by ER and PR status in a hospital-based case-control study among Chinese women.Subjects/Methods:Four hundred and thirty-eight cases with primary breast cancer were consecutively recruited from June 2007 to August 2008 and frequency matched to 438 controls by age (5-year interval) and residence (rural/urban). A validated food frequency questionnaire was used to assess the dietary intake through a face-to-face interview. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence interval (CI) after adjusting for various potential confounders.Results:A statistically significant inverse association was found between total dietary fiber and fiber fractions intake and breast cancer risk. The adjusted ORs (95% CIs) for the highest versus the lowest quartile of intake were 0.31 (0.20-0.47) for total dietary fiber, 0.73 (0.48-1.11) for soy fiber, 0.48 (0.22-0.97) for vegetable fiber and 0.54 (0.31-0.92) for fruit fiber. No association was observed for cereal fiber intake and risk. An inverse association between dietary fiber intake and breast cancer risk was observed in ER+, ER−, PR+, ER+PR+ and ER−PR+ tumors.Conclusions:Our results suggest that consumption of total dietary fiber and fiber from vegetable and fruit was inversely associated with breast cancer risk. These inverse associations were more prominent in some subtypes of ER and PR breast cancers. [ABSTRACT FROM AUTHOR]

Abstract: Assignment of ecological impacts of contamination to specific classes of contaminants is a prerequisite for risk assessment and remediation. In this study, the combination of polarity-based fractionation, two-hybrid yeast bioassay, and chemical analysis were used to evaluate and identify estrogen receptor agonists (ER-agonists) in sediments from Wenyu River, Beijing, China. By bioassay, organic raw sediment extracts could induce significant estrogenicity and the bioassay-derived 17β-estradiol equivalents (EEQs) of raw extracts (EEQraws) ranged from 0.8 to 19.8 ng/g dry weight. By polarity-based fractionation, the raw extracts were separated into three fractions, i.e. non-polar, moderately polar, and polar fractions, which were subjected to bioassay and chemical analysis. The highest estrogenicity was observed in the polar fraction, which accounted for more than 78% of the total. The medium polar fraction contains PAHs and OCPs, and the estrogenic activities in this fraction contributed 3%–12% of the total in raw extract. An estrogenic activity of non-polarity fraction was negligible in compare to other two fractions. By chemical analysis and toxic equivalent calculation, major part of the estrogenicity in polar fraction could be attributed to six natural/synthetic estrogens (16%–63%), i.e. 17β-estradiol, estrone, estriol, 17α-ethynylestradiol, diethylstilbestrol, and β-estradiol-17-valerate, and to nonylphenols (26%–55%). The proposed approach has been successfully used for characterization of ER-agonists in this case study. [Copyright &y& Elsevier]

The article offers information on a 10-year retrospective clinical epidemiological study of breast cancer in China. It states that a total number of 4,211 breast cancer cases were identified over a period of 10 years, from 1998 to 2008, where 67.6 percent women were of normal body mass index (BMI). It mentions that the higher proportion of estrogen receptor (ER) positive and progesterone receptor (PR) positive breast cancer patients is a challenge for breast cancer management in China.

Background and purpose: Fulvestrant, an oestrogen receptor (ER) antagonist with no known agonist effects, has shown activity in postmenopausal patients with ER-positive advanced breast cancer recurring or progressing following prior endocrine therapy. This double-blind, double-dummy, randomised phase III study (NCT00327769) was designed to compare the efficacy and safety of fulvestrant versus anastrozole in advanced breast cancer of Chinese postmenopausal women whose disease has progressed following prior endocrine treatment. Materials and methods: A total of 234 patients were randomised to fulvestrant 250 mg/month ( n = 121) or 1 mg/day anastrozole ( n = 113), together with matching placebo. The primary endpoint was time to progression (TTP). Secondary endpoints included objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR) and time to treatment failure (TTF). Results: Baseline characteristics were similar, with the possible exception that a higher number of fulvestrant patients had received two prior chemotherapy regimens. Median TTP was 110 days in the fulvestrant group versus 159 days in the anastrozole group (hazard ratio [HR], 1.314; 95% confidence intervals [CI], 0.948, 1.822; P = 0.101). ORR was 10% in the fulvestrant group and 14% in the anastrozole group. Median DoR from randomisation to progression was 436 days versus 432 days for the fulvestrant and anastrozole groups, respectively. CBR for fulvestrant (36.1%) versus anastrozole (48.2%) was not statistically different between the groups. TTF (110 days versus 147 days for the fulvestrant and anastrozole groups, respectively) was not statistically different between the treatments (HR, 1.307; 95% CI, 0.961, 1.778; P = 0.088). Both treatments were well tolerated, with only two patients treated with fulvestrant and four patients treated with anastrozole withdrawn from study treatment due to adverse events. Conclusions: These data demonstrate that fulvestrant 250 mg and anastrozole were similarly effective and well tolerated in the treatment of postmenopausal Chinese women with advanced breast cancer whose disease had progressed or recurred on prior endocrine treatment. [ABSTRACT FROM AUTHOR]

Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case–control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1–2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9–4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4–5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3′ of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3–8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men. [ABSTRACT FROM PUBLISHER]

Estrogen was considered to be an important protective factor for cardiovascular diseases in women. Genetic association studies suggested that variations of ESR1and ESR2 genes might have a potential role in lipid profile. Our study aimed to investigate the association of single-nucleotide polymorphisms (SNPs) of ESR1 and ESR2 with hyperlipidemia in Chinese Han postmenopausal women. A total of 443 postmenopausal women aged between 55 and 71 years were recruited from Shanghai, China for a case–control study (154 women with hyperlipidemia and 289 controls). We measured plasma estradiol concentration, glucose and lipid profile levels, evaluated their lifestyle and sequenced four SNPs, namely PvuII (rs2234693) and XbaI (rs9340799) of ESR1 and 1082A>G (rs1256049) and 1730A>G (rs4986938) of ESR2. PvuII (rs2234693) and XbaI (rs9340799) showed significantly different distributions between cases and controls (P=0.002 and P=0.023, respectively). In addition, haplotypes constructed from PvuII–XbaI were also associated with hyperlipidemia (global P=0.012). Haplotypes T–A (P=0.005, odds ratio (OR) 1.52, 95% confidence interval (95% CI): 1.13–2.05) and C–G (P=0.010, OR 0.62, 95% CI: 0.43–0.89) had susceptible and protective effects, respectively. 1082A>G (rs1256049) and 1730A>G (rs4986938) showed no statistical association with hyperlipidemia. In conclusion, our results suggested that ESR1 might have a potential role in hyperlipidemia risk, independent of age, estradiol level, body mass index and lifestyle in Chinese Han postmenopausal women. [ABSTRACT FROM AUTHOR]

Patents for Chinese herbal medicines can be difficult to obtain. When the active ingredients of an herbal formula are known, danfang (single herb prescriptions) is better protected with quantified composition claims. When the active ingredients are unknown, 'product by processing', 'method of processing', 'method of administration' and 'new use claims' are often powerful tools to distinguish a traditional danfang from 'the prior art'. Additional patents may also be filed continuously in the product development process. Existing patents for fufang (composite prescriptions) are primarily drafted to protect traditional herbal formulations. More efforts are needed to protect various herbal combinations and their multiple applications. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association of estrogen receptor alpha (ER-α) PvuII polymorphisms with the effect of calcium supplementation on bone development in Chinese pubertal girls, and to study the importance of calcium supplementation by maximizing the peak bone mass at their pubertal stage for bone development and osteoporosis prevention and the role of estrogen in regulating bone mass. Methods: Ninety-four pubertal girls were recruited in the study and divided into two groups and three sub-groups according to the ER-α PvuII polymorphisms. One year before and after calcium supplementation, bone mineral density (BMD) was measured by DEXA, while BGP, BAP, TRACP5b, and 25-OH-VitD3, as well as estrogen were detected by ELISA. Analysis of covariance was used to examine the effect of ER-a polymorphisms on bone development. Results: The absolute increase and percentage change of BGP were significantly higher in the supplemented group than in the control group (P<0.05). In the intervened group, The increase and percentage change of the total body and radio distal 1/3 BMD were higher in PP than in PP genotype (P<0.05), and the increase of BAP in Pp was also higher than PP in the same group (P<0.05). Conclusion: PP genotype shows a better response to calcium supplementation than the other PvuII polymorphisms. [Copyright &y& Elsevier]