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Background: Metastasis is the leading cause of cancer related deaths in breast cancer patients. Lymphovascular invasion represents one of the earliest stages of metastasis wherein the cells are introduced to a very different and distinct microenvironment. Methods: We leveraged spatial techniques developed for limited specimens in archival tissue to study patient matched cross-sectional tumor samples from different stages of breast neoplasia including normal breast, ductal carcinoma in situ (DCIS), primary invasive carcinoma (IBC), lymphovascular invasion (LVI) and regional lymph node metastasis. We selected a set of 21 patients with ER+ breast cancer to generate cross-sectional samples of each of these stages, for a total of 331 samples. The areas of LVI were identified by a combination of H&E review and immunohistochemistry for podoplanin. We performed smart-3SEQ for gene expression profiling and light pass whole genome sequencing for DNA copy number alterations. Results: We profiled the spectrum of neoplasia for transcriptome-wide gene expression. Principal component analysis of all 252 DCIS, LVI, IBC, or metastasis samples using the top 500 genes with the highest variance demonstrated that clustering was roughly based on the diagnostic stage (i.e. DCIS, LVI, IBC, or metastasis). Differential gene expression profiling identified thousands of genes increased or decreased in expression across the transitional stages with the largest change in gene expression being the transition from normal breast to DCIS, dominated by gene expression down regulation. We next performed NMF clustering on 62 samples of LVI from 18 cases and identified two patterns of gene expression which define two subgroups. Gene ontology analysis revealed that one cluster was associated with increased proliferation and metabolism, whereas the second cluster was dominated by an immune response. When we analyzed the immune and proliferative LVI subgroups separately, we found that the immune profiles in the patient matched IBC and LVI samples from the LVI Immune cluster were similar, whereas the immune profiles in the patient matched IBC and LVI samples from the Proliferative cluster were significantly different. At the LVI stage, all immune cell populations estimated by CibersortX were decreased in the Proliferative LVI cluster. These changes were validated using immunofluorescence for proliferation (Ki67), T cells (CD3) and macrophages (CD68) on the same samples. Using the LVI centroids, we built a model that could predict the same clusters in the METABRIC IBC. Kaplan-Meier analysis showed a significant difference between groups, with the Proliferative-like IBC group having a worse prognosis than the Immune-like IBC group. Conclusions: We observed a dichotomy at the LVI stage with a more proliferative cluster that may escape the immune response and an immune cluster which has a microenvironment with a similar pattern to its primary IBC. The recognition of two groups of LVI, differing in immune association and proliferation, raises the possibility that the risk of metastasis could be different in these two groups, leading to different biological pathways of progression. Citation Format: Belén Rivero-Gutiérrez, Diego Mallo, Almudena Espín-Pérez, Sujay Vennam, Chunfang Zhu, Sushama Varma, Greg Scott, Joseph Foley, E Shelley Hwang, Carlo Maley, Robert West. Characterization of the lymphovascular invasion microenvironment reveals immune response dichotomy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD2-09.

Background. DCIS consists of a molecularly heterogeneous group of premalignant lesions, with variable risk of invasive progression. Understanding biomarkers for invasive progression could help individualize treatment recommendations based upon tumor biology. As part of the NCI Human Tumor Atlas Network (HTAN), we conducted comprehensive genomic analyses on two large DCIS case-control cohorts. Methods. We performed smart3-seq and low-pass whole genome sequencing on two independent, retrospective, longitudinally sampled DCIS case-control cohorts. TBCRC 038 was a multicenter cohort diagnosed with DCIS between 1998 and 2016 at one of the Translational Breast Cancer Research sites; the RAHBT (Resource of Archival Human Breast Tissue) cohort included women identified through the St. Louis Breast Tissue Repository, and the Women’s Health Repository diagnosed between 1997 and 2001. We studied the spectrum of molecular changes present and sought genomic predictors of subsequent ipsilateral breast events (iBEs: DCIS recurrence or invasive progression) in both DCIS epithelium and stroma in formalin fixed paraffin embedded tissue. We generated de novo tumor and stroma-centric subtypes for DCIS that represents fundamental transcriptomic organization. Copy number analysis was performed using low-pass DNA sequencing. Non-negative matrix factorization (NMF) was applied to the RNA expression of all coding genes to identify clusters. A negative-binomial regression model was used to identify differentially expressed genes. Results. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up. In TBCRC samples, we identified three clusters via NMF in TBCRC referred to as ER low, quiescent, and ER high. The ER-low cluster had significantly higher levels of ERBB2 and lower levels of ESR1 compared to quiescent and ER-high clusters. Quiescent cluster lesions were less proliferative and less metabolically active than ER high and ER low subtypes. These findings were replicated in the RAHBT cohort. Focusing on the stromal component of DCIS from laser capture microdissection in RAHBT samples, we identified four distinct DCIS-associated stromal clusters. A “normal-like” stromal cluster with ECM organization and PI3K-AKT signaling; a “collagen-rich” stromal cluster; a “desmoplastic” stromal cluster with high fibroblast and total myeloid abundance, mostly associated with macrophages and myeloid dendritic cells (mDC); and an “immune-dense” stromal cluster. Further, we compared differentially expressed genes in patients with or without subsequent iBEs within 5 years of diagnosis. Hypothesizing that the resulting 812 DE genes (DESeq2) represent multiple routes to subsequent iBEs, we leveraged NMF to identify paths to progression. In both TBCRC and RAHBT cohorts, poor outcome groups exhibited increased ER, MYC signaling, and oxidative phosphorylation, supporting that these pathways are important for DCIS recurrence and progression. Conclusion. Comprehensive genomic profiling in two independent DCIS cohorts with longitudinal outcomes shows distinct DCIS stromal expression patterns and immune cell composition. RNA expression profiles reveal underlying tumor biology that is associated with later iBEs in both cohorts. These studies provide new insight into DCIS biology and will guide the design of diagnostic strategies to prevent invasive progression. Citation Format: Siri H Strand, Belén Rivero-Gutiérrez, Kathleen E Houlahan, Jose A Seoane, Lorraine M King, Tyler Risom, Lunden Simpson, Sujay Vennam, Aziz Khan, Timothy Hardman, Bryan E Harmon, Fergus J Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F McAuliffe, Julie Nangia, Joanna Lee, Jennifer Tseng, Anna Maria Storniolo, Alastair Thompson, Gaorav Gupta, Robyn Burns, Deborah J Veis, Katherine DeSchryver, Chunfang Zhu, Magdalena Matusiak, Jason Wang, Shirley X Zhu, Jen Tappenden, Daisy Yi Ding, Dadong Zhang, Jingqin Luo, Shu Jiang, Sushama Varma, Cody Straub, Sucheta Srivastava, Christina Curtis, Rob Tibshirani, Robert Michael Angelo, Allison Hall, Kouros Owzar, Kornelia Polyak, Carlo Maley, Jeffrey R Marks, Graham A Colditz, E Shelley Hwang, Robert B West. The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-07.

The association between serum vitamin A (VA) and non-alcoholic fatty liver disease (NAFLD) has not been adequately studied.

Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)–positive epithelial malignancy with an extensive inflammatory infiltrate. Traditional RNA-sequencing techniques uncovered only microenvironment signatures, while the gene expression of the tumor epithelial compartment has remained a mystery. Here, we use Smart-3SEQ to prepare transcriptome-wide gene expression profiles from microdissected NPC tumors, dysplasia, and normal controls. We describe changes in biological pathways across the normal to tumor spectrum and show that fibroblast growth factor (FGF) ligands are overexpressed in NPC tumors, while negative regulators of FGF signaling, including SPRY1, SPRY2, and LGALS3, are down-regulated early in carcinogenesis. Within the NF-κB signaling pathway, the critical noncanonical transcription factors, RELB and NFKB2, are enriched in the majority of NPC tumors. We confirm the responsiveness of EBV-positive NPC cell lines to targeted inhibition of these pathways, reflecting the heterogeneity in NPC patient tumors. Our data comprehensively describe the gene expression landscape of NPC and unravel the mysteries of receptor tyrosine kinase and NF-κB pathways in NPC.

Small cell lung cancer (SCLC) is a highly lethal form of lung cancer. The high mutation burden in SCLC cells makes it challenging to predict key drivers of SCLC from genome sequencing data, thereby hindering the identification of possible therapeutic targets. Here we develop a quantitative multiplexed approach based on lentiviral barcoding with somatic CRISPR/Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. Lentiviral vector-mediated SCLC initiation was greatly enhanced by naphthalene pre-treatment, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Based on a meta-analysis across multiple human SCLC genomic datasets, we quantified the impact of inactivating 39 genes across many candidate pathways and captured both positive and detrimental effects on SCLC initiation and progression upon gene inactivation. This analysis and subsequent validation in human SCLC cells identified TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This new approach should illuminate novel drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify new therapeutic targets.

SUMMARYDuctal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We identified 812 genes associated with ipsilateral recurrence within 5 years from treatment and developed a classifier that was predictive of DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions were identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.HIGHLIGHTS⍰ Development of a new classifier for DCIS recurrence or progression⍰ Outcome associated pathways identified across multiple data types and compartments⍰ Four stroma-specific signatures identified⍰ CNAs characterize DCIS subgroups associated with high risk invasive cancers

RNA sequencing (RNA-seq) is a sensitive and accurate method for quantifying gene expression. Small samples or those whose RNA is degraded, such as formalin-fixed paraffin-embedded (FFPE) tissue, remain challenging to study with nonspecialized RNA-seq protocols. Here, we present a new method, Smart-3SEQ, that accurately quantifies transcript abundance even with small amounts of total RNA and effectively characterizes small samples extracted by laser-capture microdissection (LCM) from FFPE tissue. We also obtain distinct biological profiles from FFPE single cells, which have been impossible to study with previous RNA-seq protocols, and we use these data to identify possible new macrophage phenotypes associated with the tumor microenvironment. We propose Smart-3SEQ as a highly cost-effective method to enable large gene expression profiling experiments unconstrained by sample size and tissue availability. In particular, Smart-3SEQ's compatibility with FFPE tissue unlocks an enormous number of archived clinical samples; combined with LCM it allows unprecedented studies of small cell populations and single cells isolated by their in situ context.

A series of UV-curable polyurethanes were made by copolymerization of isocyanate monomers with various diols (PLA1000/PEG2000/HPDMS). The structure of the resulting polyurethanes with DA-generated bonds was characterized by Fourier transform infrared spectroscopy (FTIR) and 1H NMR. In addition, the UV-curing behavior was studied by FTIR. Diels-Alder (DA) and retro-Diels-Alder (r-DA) reactions within cured films was monitored by differential scanning calorimeter (DSC) and dynamic mechanical analysis (DMA), which indicated that the cured film exhibited excellent thermal reversibility over at least three cycles. The resulting PU resins show different healing effect and PLAPU exhibited the most rapid thermal healing with the defect (a scratch with a width of 100 μm) completely healed within 100 s at 120 ˚C. Furthermore, PLAPU has high tensile strength (3MPa) and robust hardness (H) at the same time which is an advantageous feature for applications in which extreme softening or reverse gelation of a self-healing coating would be unacceptable.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an ideal therapy for type 2 diabetes and, as of recently, for obesity. In contrast to visceral fat, subcutaneous fat appears to be protective against metabolic diseases. Here, we aimed to explore whether liraglutide, a GLP-1RA, could redistribute body fat via regulating lipid metabolism in different fat depots. After being fed a high-fat diet for 8 weeks, 50 male Wistar and Goto-Kakizaki rats were randomly divided into a normal control group, a diabetic control group, low- and high-dose liraglutide-treated groups and a diet-control group. Different doses of liraglutide (400 μg/kg/day or 1200 μg/kg/day) or an equal volume of normal saline were administered to the rats subcutaneously once a day for 12 weeks. Body composition and body fat deposition were measured by dual-energy X-ray absorptiometry and MRI. Isotope tracers were infused to explore lipid metabolism in different fat depots. Quantitative real-time PCR and Western blot analyses were conducted to evaluate the expression of adipose-related genes. The results showed that liraglutide decreased visceral fat and relatively increased subcutaneous fat. Lipogenesis was reduced in visceral white adipose tissue (WAT) but was elevated in subcutaneous WAT. Lipolysis was also attenuated, and fatty acid oxidation was enhanced. The mRNA expression levels of adipose-related genes in different tissues displayed similar trends after liraglutide treatment. In addition, the expression of browning-related genes was upregulated in subcutaneous WAT. Taken together, the results suggested that liraglutide potentially redistributes body fat and promotes browning remodeling in subcutaneous WAT to improve metabolic disorders.

Ductal carcinomain situ(DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand how the tumor microenvironment (TME) changes with transition to IBC, we used Multiplexed Ion Beam Imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to analyze 140 clinically annotated surgical resections covering the full spectrum of breast cancer progression. We compared normal, DCIS, and IBC tissues using machine learning tools for multiplexed cell segmentation, pixel-based clustering, and object morphometrics. Transition from DCIS to IBC was found to occur along a trajectory marked by coordinated shifts in location and function of myoepithelium, fibroblasts, and infiltrating immune cells in the surrounding stroma. Taken together, this comprehensive study within the HTAN Breast PreCancer Atlas offers insight into the etiologies of DCIS, its transition to IBC, and emphasizes the importance of the TME stroma in promoting these processes.

Ductal carcinoma in situ (DCIS) is the most commonly diagnosed precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes to identify predictors of subsequent ipsilateral breast events. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up from two independent cohorts. We made observations on DNA, RNA, and protein expression, and generated a de novo clustering scheme for DCIS that represents the fundamental transcriptomic organization at this early stage of breast neoplasia. Distinct DCIS stromal expression patterns and immune cell compositions were identified. We also found RNA expression patterns that correlate with later events in both cohorts. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

ObjectiveWe aimed to evaluate the effects of different ethnicities and potential environmental exposure on the prevalence of thyroid autoimmune status and hypothyroid status.DesignThe data were obtained from two cross-sectional studies.Participants2105 participants in Shanghai (Han) and 772 participants in Yunnan Honghe Prefecture (Han, Yi, Miao and Hani), aged 18–75 were enrolled.MethodsParticipants underwent several checkups, including urinary iodine concentration, blood lead (BPb) and blood cadmium (BCd), thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), thyroid stimulating hormone (TSH) as well as thyroid ultrasonography (US). Thyroid autoimmune status was defined as: antithyroid antibody positive (ATA+): TPOAb + or TgAb+; and ATA + and US+: TPOAb + or TgAb + together with characteristic US features.ResultsThe standardised prevalence of thyroid autoimmune positivity in Yunnan were higher than those in Shanghai (TPOAb+: 13.56% vs 8.27%, pConclusionsHigher levels of UI/Cr, BPb and BCd may be associated with thyroid autoimmunity and hypothyroid status.

SUMMARY Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes., In brief A spatial imaging atlas of patient-matched ductal carcinoma in situ and invasive breast cancer depicts coordinated changes in the tumor microenviroment associated with invasive relapse, suggesting a potential protective role of myoepithelial disruption against invasive progression., Graphical Abstract

Context Previous epidemiological studies had inconsistent results regarding the relationship between blood lead level (BLL) and adiposity. Objective We aimed to investigate the associations of BLL with body mass index (BMI) particularly using Mendelian randomization analyses and examine the interaction between obesity-predisposing genes and BLL on the associations. Design and Setting A total of 3922 participants were enrolled from 16 sites in East China in 2014 from the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (ChiCTR-ECS-14005052, www.chictr.org.cn). We calculated the weighted BMI genetic risk score (GRS) based on 29 variants that were identified and validated in East Asians. BLL was measured by atomic absorption spectrometry. Main Outcome Measure BMI was calculated, and BMI ≥25 kg/m2 was defined as overweight. Results Multivariable logistic regression analysis demonstrated significant associations between BMI with each unit increase in lnBLL (β = 0.24; 95% CI, 0.08 to 0.40; P < 0.001) and each 1-point increase in BMI-GRS (β = 0.08; 95% CI, 0.05 to 0.11; P < 0.001). The causal regression coefficients of genetically determined BMI for lnBLL were −0.003 (95% CI, −0.075 to 0.070), which showed no significance. The GRS modified the association of BLL with BMI and overweight (BMI ≥25 kg/m2; P for interaction = 0.031 and 0.001, respectively). Each unit of lnBLL was associated with 63% higher odds of overweight (OR 1.63; 95% CI, 1.30 to 2.05) in the highest quartile of GRS, but no significant associations were found in the lower three quartiles. Conclusions The associations of BLL with BMI and overweight (BMI ≥25 kg/m2) were significantly modulated by BMI genetic susceptibility.

Background/Aims: To demonstrate the function of uncoupling protein 2 (UCP2) in the regulation of human spermatozoa motility. Methods: Semen samples were collected from donors with either normal spermatozoa motility (normospermia [NS]) or poor spermatozoa motility (asthenospermia [AS]). UCP2 protein in spermatozoawas quantified by Western blotting. The level of mitochondrial reactive oxygen species (mROS) was evaluated by MitoSOX Red. The activity of mitochondrial membrane potential (MMP) in spermatozoa was evaluated by a JC-1 assay and the ATP level was monitored by a luciferin-luciferase assay. Results: UCP2 was expressed in both NS and AS groups, with the former exhibiting a higher level than the latter. Immunofluorescence analysis shows that UCP2 is mainly located at the mid-region of human spermatozoa. The inhibition of UCP2 by a highly selective inhibitor, Genipin, results in not only impaired spermatozoa mobility (P

Background. The relationship between vitamin D and insulin resistance is still controversial. Many factors could influence this relationship. In addition, this relationship in different genders was still unclear. Methods. A total of 6597 subjects, including 2813 males and 3784 females, were analyzed. The serum levels of 25(OH)D, fasting blood glucose (FBG), fasting insulin, HbA1c, and other metabolic parameters were tested. The waist circumference (WC), weight, and height were also measured. Questionnaires regarding smoking and drinking were collected from these subjects. Results. Serum 25(OH)D was categorized into quartiles. Increasing 25(OH)D levels were associated with reduced trend of homeostasis model assessment of insulin resistance (HOMA-IR) in both males and females. Pearson’s correlation indicated 25(OH)D level was inversely associated with the HOMA-IR for male subjects (r=−0.055, P=0.028) but not for female subjects (r=−0.005, P=0.798). Age, triglyceride (TG), and low-density lipoprotein (LDL) were associated with the vitamin D levels in males and females. In regression analysis, serum 25(OH)D concentration was significantly associated with HOMA-IR only in overweight males. Conclusion. We found an inverse association between 25(OH)D and HOMA-IR in Chinese overweight males. Vitamin D supplementation might be beneficial in this population. However, further clinical trials are needed to confirm this association.

Determining how cells vary with their local signaling environment and organize into distinct cellular communities is critical for understanding processes as diverse as development, aging, and cancer. Here we introduce EcoTyper, a machine learning framework for large-scale identification and validation of cell states and multicellular communities from bulk, single-cell, and spatially resolved gene expression data. When applied to 12 major cell lineages across 16 types of human carcinoma, EcoTyper identified 69 transcriptionally defined cell states. Most states were specific to neoplastic tissue, ubiquitous across tumor types, and significantly prognostic. By analyzing cell-state co-occurrence patterns, we discovered ten clinically distinct multicellular communities with unexpectedly strong conservation, including three with myeloid and stromal elements linked to adverse survival, one enriched in normal tissue, and two associated with early cancer development. This study elucidates fundamental units of cellular organization in human carcinoma and provides a framework for large-scale profiling of cellular ecosystems in any tissue.

ObjectiveAlthough many studies worldwide have focused on the relationship between vitamin D and insulin resistance, results remain controversial. Furthermore, concentrations of serum 25-hydroxyvitamin D (25(OH)D) in the Chinese population are unclear. We aimed to investigate vitamin D status and its correlation with insulin resistance among a Chinese adult population.DesignSerum 25(OH)D, fasting blood glucose, fasting insulin, glycated Hb (HbA1c) and other metabolic parameters were assessed. Neck circumference, waist circumference, hip circumference, weight and height were also measured. Lifestyle factors including smoking and drinking status were obtained. Diabetes mellitus was diagnosed by HbA1c according to the 2010 American Diabetes Association criteria.SettingEastern China.SubjectsOf 7200 residents included, 6597 individuals were ultimately analysed.ResultsWe enrolled 2813 males (mean age 52·7 (sd 13·5) years) and 3784 females (52·3 (sd 13·5) years); mean serum 25(OH)D concentration was 43·1 (sd 11·6) and 39·6 (sd 9·8) nmol/l, respectively. Additionally, 83·3 % of participants were 25(OH)D deficient. A significant difference in 25(OH)D was observed between males and females in winter and spring (P<0·001). Furthermore, 25(OH)D concentrations were inversely associated with the homeostasis model assessment of insulin resistance (HOMA-IR) in the overweight and pre-diabetic populations. After adjusting for several variables, 25(OH)D was significantly associated with HOMA-IR in winter. When 25(OH)D values were categorized into quartiles, HOMA-IR was significantly associated with decreasing 25(OH)D.ConclusionsThe majority of the Chinese population was vitamin D deficient and this deficiency was negatively associated with insulin resistance, particularly in the overweight and pre-diabetic populations. Moreover, these associations might be more evident in the winter.

Follicle stimulating hormone plays direct roles in a variety of nongonadal tissues and sex hormone binding globulin is becoming the convergence of the crosstalk among metabolic diseases. However, no studies have explored the association between follicle stimulating hormone and sex hormone binding globulin. We aimed to study this association among men and women. SPECT-China is a population-based study conducted since 2014. This study included 4206 men and 2842 postmenopausal women. Collected serum was assayed for gonadotropins, sex hormone binding globulin, sex hormones etc. Regression analyses were performed to assess the relationship between sex hormone binding globulin and follicle stimulating hormone and other variables including metabolic factors, thyroid function and sex hormones. Treatment with follicle stimulating hormone at different concentrations of 0, 5, 50 and 100 IU/L for 24 h was performed in HepG2 cells. In Spearman correlation, sex hormone binding globulin was significantly correlated with FSH, triglycerides, thyroxins, body mass index and blood pressure in men and postmenopausal women (all P

To explore the roles of mitochondrial Uncoupling Protein 2 (UCP2) in cumulus cells (CCs), human CCs were cultured in vitro, and the UCP2 was inhibited by treatment with Genipin, a special UCP inhibitor, or by RNA interference targeting UCP2. No significant differences in adenosine triphosphate levels and the ratio of ADP/ATP were observed after UCP2 inhibition. UCP2 inhibition caused a significant increase in cellular oxidative damage, which was reflected in alterations to several key parameters, including reactive oxygen species (ROS) and lipid peroxidation levels and the ratio of reduced GSH to GSSG. UCP2 blocking resulted in an obvious increase in active Caspase-3, accompanied by the decline of proactive Caspase-3 and a significant increase in the LC3-II/LC3-I ratio, suggesting that UCP2 inhibition triggered cellular apoptosis and autophagy. The mRNA and protein expression of connexin 43 (Cx43), a gap junction channel protein, were significantly reduced after treatment with Genipin or siRNA. The progesterone level in the culture medium was also significantly decreased after UCP2 inhibition. Our data indicated that UCP2 plays highly important roles in mediating ROS production and regulating apoptosis and autophagy, as well as maintaining gap junction integrity and progesterone synthesis, which suggests that UCP2 is involved in the regulation of follicle development and early embryo implantation and implies that it might serve as a potential biomarker for oocyte quality and competency.

BACKGROUND/AIMS: Hashimoto thyroiditis, characterized by positive thyroid peroxidase antibodies (TPOAbs), is caused by the interaction of genetic and environment factors. The aim of this study was to clarify the interaction of gene polymorphisms and iodine intake in the incidence of TPOAb positivity. METHODS: 1,733 subjects were included in this study. Genomic DNA was extracted from peripheral blood white cells. Four SNPs (rs11675434 [TPO], rs3094228 [HCP5], rs9277555 [HLA-DPB1], and rs301799 [RERE]) were selected for genotyping. Weighted TPOAb genetic risk score (GRS) was calculated based on these 4 SNPs. Thyroid hormones and autoimmune antibodies (TPOAb and thyroglobulin antibody) were determined using the electrochemiluminescence immunoassay method. RESULTS: The mean serum thyrotropin level in TPOAb-positive subjects was higher than in TPOAb-negative subjects (p < 0.01). Genotype GG of rs9277555 was associated with an increased risk of TPOAb positivity (OR = 1.64, 5–95% CI 1.09, 2.47, p = 0.02). Genotype TT of rs11675434 showed marginal increased risk of TPOAb positivity (OR = 1.57, 5–95% CI 1.01, 2.43, p = 0.048). Logistic regression analysis showed TPOAb-GRS and rs9277555 were associated with TPOAb positivity (OR = 5.09, 5–95% CI 1.30, 19.91, p = 0.02 and OR = 1.30, 5–95% CI 1.05, 1.61, p = 0.02). Subjects with a high TPOAb-GRS had a 52% increased risk of TPOAb positivity compared to subjects with a low TPOAb-GRS (OR 1.52, 5–95% CI 1.05, 2.21, p = 0.03). CONCLUSION: TPOAb-GRS was associated with an increased risk of TPOAb positivity in a Chinese Han population. This effect might be attribute to rs9277555.

Sapogenin is the main block of

The aim of this study is to evaluate blood cadmium levels (BCLs) in Chinese adults and explore whether blood cadmium is associated with diabetes or obesity. This study included 5544 adults from a cross-sectional SPECT-China study. BCL and blood lead level (BLL) was measured by atomic absorption spectrometry. Fasting plasma glucose (FPG) was used to define prediabetes and diabetes. Overweight and obesity were defined by body mass index (BMI). The associations of BCL with prediabetes, diabetes, overweight, and obesity were analyzed by multinomial logistic regression analyses. Medians (interquartile range) of BCL were 1.97 μg/L (0.60-3.82) in men and 1.59 μg/L (0.54-3.51) in women. Subjects in low-economic-status areas and urban areas had significantly higher BCL. BCL in current smokers was significantly higher than in current non-smokers. In the adjusted model, a mild positive relationship between BCL and FPG was found. Meanwhile, the prevalence of prediabetes was increased according to the increase in BCL tertiles. Surprisingly, BCL had a negative relationship with prevalence of overweight. In conclusion, BCL in Chinese adults was much higher than in other developed countries and was influenced by gender, smoking, and residential area. BCL was positively related to prediabetes while negatively related to overweight.

BACKGROUND AND AIM Obesity and diabetes are related to non-alcoholic fatty liver disease (NAFLD). A reduction in follicle-stimulating hormone (FSH) is associated with obesity and diabetes in postmenopausal women. Thus, we aim to investigate whether FSH is associated with NAFLD in women over 55 who were postmenopausal with a high probability. METHODS Our data were obtained from the 2014 Survey on Prevalence in East China for Metabolic Diseases and Risk Factors. A total of 1635 women at the age of 55-89 years were selected. The degrees of fatty liver were categorized into mild and moderate-severe hepatic steatosis groups by ultrasonography. FSH and other sex hormones were measured by chemiluminescence. RESULTS A total of 366 (22.4%) and 417 (25.5%) women had mild and moderate-severe hepatic steatosis, respectively. FSH was negatively correlated with waist circumference, homeostasis model assessment of insulin resistance (HOMA-IR), and other metabolic factors (all P

Epidemiologic studies have indicated that early life nutrition influences later risk of obesity, type 2 diabetes, and metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is also considered a metabolic disease.The aim was to explore the association between adult NAFLD and fetal or childhood exposure to Great Chinese Famine between 1959 and 1962 during fetal and childhood period.In total, 5306 subjects from the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors study were divided into a fetal-exposed (1959-1962), childhood-exposed (1949-1958), adolescence/young adult-exposed (1921-1948), and nonexposed (1963-1974, reference) group.The degrees of steatosis of NAFLD were determined by ultrasonography.The prevalences of NAFLD in the nonexposed (1963-1974), fetal-exposed, and childhood-exposed participants were 55.9%, 55.8%, and 55.4% in men and 33.0%, 46.3%, and 51.7% in women, respectively. Compared with those nonexposed, fetal- and childhood-exposed women but not men had a significantly higher prevalence of moderate-severe steatosis (P.05). A significant association existed in women between increased alanine aminotransferase and both fetal and childhood exposure to famine, after adjusting for age, rural/urban residence, economic status, body mass index, diabetes, dyslipidemia, and hypertension (both P.05). Famine exposure during the fetal period (odds ratio 1.77, 95% confidence interval 1.22, 2.57) and childhood (odds ratio 1.82, 95% confidence interval 1.35, 2.46) was associated with an increased prevalence of moderate-severe NAFLD in women in the above fully adjusted model.Exposure to the Great Famine in early life had sex-specific association with moderate-severe NAFLD. This indicates that malnutrition in early life may influence the development of adult NAFLD; thus pregnant women and their infants and children may require the highest priority in obtaining nutritional relief.

Recent studies have suggested an association between vitamin D and non-alcoholic fatty liver disease (NAFLD); however, some results are subject to debate. This study was carried out to evaluate the correlation between NAFLD and vitamin D in men and women in East China. The data were obtained from a cross-sectional study that focused on the health and metabolic status of adults in sixteen areas of East China. According to ultrasonic assessments, the patients were divided into normal and NAFLD groups. Demographic characteristics and biochemical measurements were obtained. Binary logistic regression analysis was used to explore the association. In total, 5066 subjects were enrolled, and 2193 (43·3 %) were diagnosed with NAFLD; 84·56 % of the subjects showed vitamin D deficiency. Subjects with high vitamin D levels had a lower prevalence of NAFLD, particularly male subjects. Within the highest quartile of vitamin D levels, the prevalence of NAFLD was 40·8 %, whereas the lowest quartile of vitamin D levels showed a prevalence of 62·2 %, which was unchanged in women across the vitamin D levels. Binary logistic analysis showed that decreased vitamin D levels were associated with an increased risk of NAFLD (OR 1·54; 95 % CI 1·26, 1·88). This study suggests that vitamin D levels are significantly associated with NAFLD and that vitamin D acts as an independent factor for NAFLD prevalence, particularly in males in East China. Vitamin D interventional treatment might be a new target for controlling NAFLD; elucidating the mechanism requires further research.

The aim of this prospective, randomized clinical trial (RCT) was to evaluate whether the supplemental protein concentration in embryo transfer (ET) medium affects the clinical outcomes in IVF-ET. A total of 750 patients undergoing IVF-ET who met the inclusion criteria were randomly divided into three groups, according to the concentration of synthetic serum substitute (SSS) in ET medium as follows: 10% (Group A), 20% (Group B) and 50% (Group C). The patient characteristics and embryology data were all similar among the groups. The rates of implantation, clinical pregnancy and live birth were compared. Clinical pregnancy (44.61%, 48.79% and 45.49%), multiple pregnancy (24.18%, 28.71% and 25.0%), implantation (28.21%, 30.68% and 29.86%) and live birth (41.67%, 43.96% and 41.70%) rates in the three groups (A, B and C, respectively) showed no significant differences. This RCT demonstrates that supplemental protein concentration in the ET medium does not affect the treatment outcomes in IVF-ET. There was no statistical evidence to support the hypothesis that supplemental protein concentration in the ET medium influences treatment outcomes in IVF-ET.

Ductal Carcinoma in Situ (DCIS) is a pre-invasive lesion that accounts for nearly 20% of new breast cancer diagnoses. Of these cases, about half will progress to invasive breast cancer (IBC) within ten years. However, because diagnostic criteria for delineating low risk lesions from those likely to progress to IBC have not been identified, many patients are receiving unnecessary chemotherapy and surgery that can result in therapy-related morbidity and death. With this in mind, we used Multiplexed Ion Beam Imaging by time of flight (MIBI-TOF) and RNA-seq laser-capture microdissection (SMART-3SEQ) to construct a comprehensive spatial atlas describing the structure, function, and cellular composition of DCIS. MIBI-TOF and SMART-3SEQ were used to compare lesions from patients that later developed IBC with those from age- and history matched DCIS controls without recurrence. Using a 37-marker staining panel to interrogate 137 lesions, we identified 30 distinct cell populations of the epithelial, stromal, and immune lineages that were arranged in recurrent cellular microenvironments specific for DCIS or invasive disease. We observe a coordinated shift in the immune and stromal compartments as invasive disease arises, including an expansion of immune cell diversity and transition to reactive stromal phenotypes in synchronous DCIS + IBC, which was distinct from the macrophage-dominant microenvironment of recurrent IBC. Single-cell segmentation using a deep learning model was combined with pixel-level coexpression analysis to determine how thickness, continuity, and phenotype of ductal myoepithelium changes as tumors progress from a pre-invasive state. These data were incorporated into a comprehensive model which was subsequently used to identify a subset of features that correlate with disease-free survival following DCIS tumor resection. Taken together, these features represent important prognostic metrics that can be used to separate pre-invasive from indolent DCIS tumors, and allow for tailored therapy that improves patient outcomes and quality of life in this disease. Citation Format: Tyler Risom, Belen Rivero, Candace Liu, Alex Baranski, Siri Strand, Noah Greenwald, Erin McCaffrey, Sushama Varma, Leeat Keren, Sucheta Srivastava, Chunfang Zhu, Sujay Vennam, Shelley Hwang, Graham Colditz, Sean Bendall, Robert West, Michael Angelo. Mapping the tumor and microenvironmental evolution underlying DCIS progression through multiplexed ion beam imaging [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PR05.

ObjectivesIn the past decade, China has been characterised by large-scale urbanisation as well as rapid economic growth. The aim of this study was to further investigate the prevalence of hyperuricaemia (HUA) in an Eastern Chinese population.DesignCross-sectional study.SettingSurvey of Prevalence in East China of Metabolic Diseases and Risk Factors China study.ParticipantsIn this study, 12 770 residents from 22 sites in Eastern China were recruited. Finally, 9225 subjects were included.Main outcome measuresThe serum levels of uric acid (UA), fasting plasma glucose (FPG), glycated haemoglobin and other metabolic parameters were tested. Waist circumference, weight, height and blood pressure were also measured. Questionnaires regarding smoking, drinking, education were collected from the subjects. HUA was defined as serum UA >420 µmol/L for men and >360 µmol/L for women.ResultsThe prevalence of HUA in this Eastern Chinese population was 11.3% (9.9, 12.7) overall, 20.7% (17.7, 23.7) in men and 5.6% (4.3, 6.7) in women. The prevalence of HUA in urban subjects was higher than that in rural subjects (12.9 vs 10.8%, pConclusionsThe estimated prevalence of HUA in this Eastern Chinese population was 11.3% (9.9, 12.7) overall and 20.7% (17.7, 23.7) and 5.6% (4.3, 6.7) in men and women, respectively. HUA has gradually become an important public health issue in China.Trial registration numberChiCTR-ECS-14005052.

Objective: China is experiencing the world's largest urbanization. There are two primary types of urbanization in China: rural-to-urban migration and in situ urbanization, represented by Zhejiang Shangyu (SY) and Jiangsu Nanjing (NJ), respectively. Our aim is to compare changes in the prevalence of metabolic disease between these two types of urbanization in China.Methods: This is a cross-sectional study derived from the SPECT-China 2014 study. This study includes subjects and metabolic parameters from SY and NJ. Furthermore, biochemical and anthropometric indexes were taken into consideration and compared between the areas of interest.Results: The prevalence rates of diabetes, prediabetes and healthy subjects were 6.5, 17.9, and 75.7% in SY and 16.0, 31.0, and 53.0% in NJ, respectively. Industrial and agricultural jobs accounted for 77.9% and 32.0% of employment in SY and NJ, respectively. Fasting plasma glucose (FPG) was higher in SY than in NJ; however, HbA1c was lower in SY than in NJ. There was a significant difference in nonalcoholic fatty liver disease (NAFLD) and healthy subjects between SY and NJ (P < 0.05). Significant differences were also found with respect to body mass index (BMI), waist circumference (WC) and hip circumference (HC) between these two locations (P < 0.001). Logistic regression analysis revealed that the prevalence of prediabetes, diabetes, overweight, obesity and dyslipidemia was higher in NJ than in SY.Conclusions:In situ urbanization has notably changed occupational distribution. The prevalence rates of diabetes, obesity, and NAFLD were increased in rapidly urbanized areas. Thus, more attention should be paid to rapidly urbanizing areas to reduce the prevalence of metabolic disease.

Objective The purpose of this study was to explore the similarities and differences between nonalcoholic fatty liver (FL) disease (NAFLD) and abdominal obesity in their association with insulin resistance and metabolic syndrome (MetS). Methods The Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China) is a population-based survey of Chinese adults. A total of 9,685 participants (median age, 53 years; interquartile range, 44-63) were grouped into four categories by waist circumference (WC) and NAFLD status: NWC/FL(-), NWC/FL(+), HWC/FL(-), and HWC/FL(+) [FL(-), without NAFLD; FL(+), with NAFLD; HWC, higher WC; NWC, normal WC]. Logistic regression models were used to obtain the odds ratios as estimates of the associations between different categories and MetS. Results Male participants with HWC/FL(-) had higher homeostatic model assessment for insulin resistance scores than subjects with NWC/FL(+), but female subjects showed the opposite results. Compared with NWC/FL(+), HWC was associated with an increased likelihood of blood pressure disorder and a decreased likelihood of triglyceride and blood glucose disorders in men, but in women, HWC was associated with only a lower likelihood of triglyceride disorder. Despite these differences, patients with NWC/FL(+) and HWC/FL(-) had almost equally serious degrees of metabolic disorders (MetS z score). Conclusions There are significant differences between sexes regarding the association between NAFLD and abdominal obesity status and MetS components.

The aim of the present study was to investigate the potential mechanism of retinopathy of prematurity (ROP) using an oxygen-induced retinopathy (OIR) mouse model. For experiments, mice were divided into either the OIR group or control group. Fluorescein isothiocyanate-dextran cardiac perfusion and stretched retina preparation were performed. The total retina area, area of instillation, density of microvascular network, area of new blood vessels, vein width and the tortuosity of arteries were measured. Next, mice were randomly assigned into the PBS, soluble TEK receptor tyrosine kinase (sTie2)-fusion protein (Fc), angiopoietin 1 (Ang1), ranibizumab, ranibizumab + sTie2-Fc and ranibizumab + Ang1 treatment groups. Following housing for 5 days, the body weight of each mouse was recorded. Mice in the OIR group presented smaller total retina area and larger area of instillation, larger area of new blood vessels, and higher microvascular network density compared with the control PBS group. Obvious retinal vein dilatation and arterial tortuosity were identified in the OIR group. The amount of endotheliocyte nuclei of new vessels beyond the inner limiting membrane was larger in the OIR group compared with the control group. Furthermore in the next set of experiments, a larger area of instillation, smaller area of new blood vessels and decreased amount of endotheliocyte nuclei of new vessels were observed in the sTie2-Fc group, Ang1 group, ranibizumab group, ranibizumab + sTie2-Fc group and ranibizumab + Ang1 group compared with the PBS group. Specifically, the ranibizumab + sTie2-Fc group and ranibizumab + Ang1 group demonstrated markedly reduced retina instillation area and microvascular network density in the instillation area. Total retina area and body weight following 10 days of the experiment for the ranibizumab group were significantly lower compared with other groups. In conclusion, the combined regulation of the Ang/Tie2 and the vascular endothelial growth factor (VEGF)/VEGF receptor pathways markedly increased the efficacy of treatment with retinal neovascularization (RNV). Regulation of these pathways has a potential for treating RNV, in particular ROP.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are an ideal therapy for type 2 diabetes and recently, for obesity. In contrast to visceral fat, subcutaneous fat accumulation appears to be protective against metabolic syndrome. Here, we reported that liraglutide, a GLP-1RA redistributed visceral and subcutaneous fat via the tissue-specific modulation of lipid metabolism and stimulation of subcutaneous white adipose tissue (WAT) browning. We showed that liraglutide decreased visceral fat and relatively increased subcutaneous fat. Lipogenesis was reduced in visceral WAT but elevated in subcutaneous WAT treated with liraglutide. Lipolysis was also attenuated, and fatty acid oxidation was enhanced. The mRNA expression levels of adipose-related genes displayed similar trends. Liraglutide down-regulated the expression levels of lipogenesis- and lipolysis-related genes but up-regulated the expression levels of β-oxidation-related genes in visceral WAT. In subcutaneous WAT, the expression levels of lipogenesis-related genes were up-regulated in both inguinal and cluneal WAT. However, the lipolysis-related gene expressed higher in inguinal WAT but lower in cluneal WAT, while the β-oxidation-related gene expressed lower in inguinal WAT but higher in cluneal WAT after liraglutide treatment. In addition, the uncoupling protein-1 was up-regulated in subcutaneous WAT. Thus, liraglutide potentially redistributes body fat and promotes browning remodeling in subcutaneous WAT to improve metabolic disorders. Disclosure L. Zhao: None. C. Zhu: None. M. Lu: None. C. Chen: None. Y. Chen: None. N. Wang: None. Y. Lu: None.

Yes-associated protein (Yap) is a core transcriptional coactivator in the downstream Hippo pathway that regulates cell proliferation and tissue growth. However, its role in the regulation of myoblast differentiation remains unclear. Regulation of mitochondrial networks by dynamin-related protein 1 (Drp1) and mitofusion 2 (Mfn2) is crucial for the activation of myoblast differentiation. In the present study, we investigated the interplay between the Hippo/Yap pathway and protein contents of Mfn2 and Drp1 during myoblast differentiation. The Hippo/Yap pathway was inactivated at the early stage of myoblast differentiation due to the decreased ratio of phosphorylated mammalian sterile 20 kinases 1/2 (p-Mst1/2) to Mst1/2, phosphorylated large tumor suppressor 1 (p-Lats1) to Lats1, and phosphorylated Yap (serine 112, p-Yap S112) to Yap, which resulted in the translocation of Yap from cytoplasm to nucleus, increased protein content of Drp1, and mitochondrial fission events. Downregulation of Yap inhibited myoblast differentiation and decreased the content of Drp1, which resulted in elongated mitochondria, fused mitochondrial networks, and collapsed mitochondrial membrane potential. Together, our data indicate that inactivation of the Hippo/Yap pathway could induce mitochondrial fission by promoting Drp1 content at the early stage of myoblast differentiation.

Background/Aims: Increasing evidence suggests an association between thyroid-stimulating hormone (TSH) and estimated glomerular filtration rate (eGFR). We conducted a Mendelian randomization (MR) analysis to examine the causality of the association between TSH and eGFR. Methods: 10,603 participants were recruited from the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China), which was performed in 23 sites in East China during 2014-2016. We constructed weighted genetic risk scores (GRS) for TSH based on three TSH-related single nucleotide polymorphisms. eGFR was calculated using the CKD Epidemiology Collaboration formula. The instrumental variable (IV) was used to explore the causal relationship between TSH and eGFR. Results: Higher measured TSH levels were associated with lower eGFR (B -0.717, 95%CI -0.958, -0.476) after multivariable adjustment. However, by MR analysis, per SD increase in the TSH_GRS was significantly associated with TSH (B 0.155, 95%CI 0.076, 0.235, P< 0.001) but not with eGFR (B -0.127, 95%CI -0.364, 0.110). Using IV estimator, no causal associations were observed for genetically instrumented TSH with eGFR. Conclusion: By a genetic approach that limits residual confounding and reverse causation in observational conventional epidemiological studies, TSH and eGFR are not causally associated, which suggests genetically elevated TSH concentrations may not affect the renal function.

Background Chinese population are experiencing remarkably changes of economic and cultural environments. The present study was to examine the prevalence of metabolic syndrome (MetS) by age between genders and to investigate the current characteristics of MetS and its components in China. Methods SPECT-China is a population-based cross-sectional survey on Chinese adults aged ≥18 years in East China. A total of 10,441 Chinese residents participated in anthropometric and laboratory measurements. Of these, 9969 subjects (females, 5868) were eligible for the data analysis reported here. Estimates of the prevalence of MetS and its components were calculated. Presence of MetS was defined based on the IDF/AHA harmonized criteria. MetS z-score was calculated to evaluate the degree of total metabolic disorder. Results The age-standardized prevalence of the metabolic syndrome was 22.0% (21.9% in men and 22.0% in women). Unlike the continuous MetS rise with age in females, the MetS prevalence in males remained stable among 46–55, 56–65 and > 65 yrs. age groups (31.2%, 31.4%, 32.5%, p = 0.538). In the five components of MetS, contrary to the elevated BP and BG disorders, the frequency of TG disorders decreased with age in males (46.6%(46–55 yrs), 37.2% (56–65 yrs), 27.7%(> 65 yrs), p

Table S1. The sociodemographic characteristics by age in both genders (DOCX 22 kb)

Table S2. The clustering of various components by age and gender (DOCX 22 kb)

Aims No study explores the association between follicle-stimulating hormone (FSH) and glucose metabolism in general women. We aim to investigate whether the variation of FSH is associated with prediabetes and diabetes in postmenopausal women. Methods Our data were from survey on prevalence in East China for metabolic diseases and risk factors in 2014. Thousand six hundred and ten postmenopausal women at the age of 55–89 who were not using hormone replacement therapy were selected. Prediabetes and diabetes were defined according to American Diabetes Association 2014 criteria. FSH, luteinizing hormone, total testosterone and estradiol were measured by chemiluminescence. Multinomial logistic analyses were used for the association of FSH with prediabetes and diabetes, and linear regression for the association of FSH with fasting plasma glucose (FPG) and HbA1c. Results Among the participants, 778 (48.3 %) had prediabetes and 121 (7.5 %) had newly diagnosed diabetes. In linear regression, after full adjustment for demographic variables, metabolic factors, E2 and LH, FSH was associated with FPG and HbA1c (P

Few studies have investigated the association between serum uric acid (UA) and cadmium exposure. Our previous study revealed a significantly higher blood cadmium (CdB) level in the Chinese population compared to populations in other countries. To determine whether CdB in Chinese adults is associated with serum UA and hyperuricemia, 2996 participants from the cross-sectional SPECT-China study were recruited. CdB was measured by atomic absorption spectrometry. Hyperuricemia was defined as a serum UA concentration ≥416.4 μmol/L for men and ≥356.9 μmol/L for women. Regression analyses were used to analyze the association of CdB with serum UA and hyperuricemia. We found that the median CdB level was higher in men with hyperuricemia (2.40 μg/L) than in men without hyperuricemia (1.98 μg/L, P 60 mL/min per 1.73 m2. Further, the odds ratio of hyperuricemia increased with increasing CdB quartiles (P for trend

Exposure to lead(Pb) or cadmium(Cd) has been related to decreasing thyroxine in many previous studies. The underlying mechanisms have not been clarified. Heavy metal-induced thyroid autoimmunity in pregnant women has been found, despite having been rarely explored in the general population.We aimed to determine whether the blood levels of lead(BPb) or cadmium(BCd) related to the levels of sera antibodies to thyroid proteins and thyroid dysfunction in the general population.Our study included 5628 Chinese adults and was based on the 2014 SPECT-China study. Thyroid dysfunction and subclinical thyroid dysfunction were defined by total triiodothyronine (TT3), total thyroxine(TT4) and thyroid stimulating hormone (TSH).Thyroid peroxidase antibody (TPOAb), thyroglobulin antibodies (TGAb), TT3, TT4, and TSH were measured by immunochemiluminometric assays. BPb and BCd levels were tested by atomic absorption spectrometry. Linear and logistic regression models were used to analyze the associations.After adjustment for age, body mass index, smoking status (men only) and drinking status, the natural log(ln) BPb was positively related to the lnTPOAb (B = 0.062, P 0.05) and to the lnTSH (B = 0.047, P 0.01) in women. The lnBCd in women was positively related to the lnTGAb (B = 0.046, P 0.05). In the adjusted logistic regression models, the BCd of women was positively related to their hypothyroid status and TGAb tertiles. The ORs of women in the middle and higher TPOAb tertiles were 1.38 (P 0.001) and 1.35 (P 0.001) times greater for every ln-unit increase in BPb, respectively. In men, no continuous correlation was found among variables.In women, BPb and BCd levels were related to higher TSH and hypothyroid status, respectively, suggesting a Pb and Cd induction of sex-biased thyroid autoimmunity.

ZMIZ2, also named ZIMP7, is a protein inhibitor of activated STAT (PIAS)-like protein and a transcriptional coactivator. In this study, we investigated the interaction between ZMIZ2 and β-catenin, a key regulator of the Wnt signaling pathway. We demonstrated that the expression of exogenous ZMIZ2 augments TCF (T cell factor) and β-catenin-mediated transcription. In contrast, shRNA knockdown of ZMIZ2 expression specifically represses the enhancement of TCF/β-catenin-mediated transcription by ZMIZ2. Using Wnt3a-conditioned medium, we demonstrated that ZMIZ2 can enhance Wnt ligand-induced TCF/β-catenin-mediated transcription. We also showed a promotional role of ZMIZ2 in enhancing β-catenin downstream target gene expression in human cells and in Zmiz2 null (Zmiz2(-/-)) mouse embryonic fibroblasts (MEFs). The regulatory role of Zmiz2 in Wnt-induced TCF/β-catenin-mediated transcription can be restored in Zmiz2(-/-) MEFs that were infected with adenoviral expression vectors for Zmiz2. Moreover, enhancement of Zmiz2 on TCF/β-catenin-mediated transcription was further demonstrated in Zmiz2 knockout and Axin2 reporter compound mice. Furthermore, the protein-protein interaction between ZMIZ2 and β-catenin was identified by co-immunoprecipitation and in vitro protein pulldown assays. We also observed recruitment of endogenous ZMIZ2 onto the promoter region of the Axin 2 gene, a β-catenin downstream target promoter, in a Wnt ligand-inducible manner. Finally, a promotional role of ZMIZ2 on cell growth was demonstrated in human cell lines and Zmiz2 knockout MEFs. Our findings demonstrate a novel interaction between ZMIZ2 and β-catenin and elucidate a novel mechanism for PIAS-like proteins in regulating Wnt signaling pathways.

Ammonia intercalated flower-like MoS2 electrocatalyst film assembled by vertical orientated ultrathin nanosheet on graphite sheethas been successfully synthesized using one-step hydrothermal method. In this strategy, ammonia can effectively insert into the parallel plane of the MoS2 nanosheets, leading to the expansion of lattice and phase transfer from 2H to 1T, generating more active unsaturated sulfur atoms. The flower-like ammoniated MoS2 electrocatalysts with more active sites and large surface area exhibited excellent HER activity with a small Tafel slope and low onset overpotential, resulting a great enhancement in hydrogen evolution. The high efficient activity and recyclable utilization, as well as large-scale, indicate that it is a very promising electrocatalyst to replace Pt in industry application.

Additional file 1: Table S1. The clustering of various components in MetS subjects.

The androgen signaling pathway, mediated through the androgen receptor (AR), is critical in prostate tumorigenesis. However, the precise role of AR in prostate cancer development and progression still remains largely unknown. Specifically, it is unclear whether overexpression of AR is sufficient to induce prostate tumor formation in vivo. Here, we inserted the human AR transgene with a LoxP-stop-loxP (LSL) cassette into the mouse ROSA26 locus, permitting "conditionally" activated AR transgene expression through Cre recombinase-mediated removal of the LSL cassette. By crossing this AR floxed strain with Osr1-Cre (odd skipped related) mice, in which the Osr1 promoter activates at embryonic day 11.5 in urogenital sinus epithelium, we generated a conditional transgenic line, R26hAR(loxP):Osr1-Cre+. Expression of transgenic AR was detected in both prostatic luminal and basal epithelial cells and is resistant to castration. Approximately one-half of the transgenic mice displayed mouse prostatic intraepithelial neoplasia (mPIN) lesions. Intriguingly, four mice (10%) developed prostatic adenocarcinomas, with two demonstrating invasive diseases. Positive immunostaining of transgenic AR protein was observed in the majority of atypical and tumor cells in the mPIN and prostatic adenocarcinomas, providing a link between transgenic AR expression and oncogenic transformation. An increase in Ki67-positive cells appeared in all mPIN and prostatic adenocarcinoma lesions of the mice. Thus, we demonstrated for the first time that conditional activation of transgenic AR expression by Osr1 promoter induces prostate tumor formation in mice. This new AR transgenic mouse line mimics the human disease and can be used for study of prostate tumorigenesis and drug development.

In ovarian stimulation, a 31-year-old woman with polycystic ovary syndrome was at the risk of developing ovarian hyperstimulation syndrome, follicle aspiration was performed, and eight immature oocytes were collected from follicle fluids. After 28 h in vitro culture, six of them reached MII and were vitrified. The patient failed to conceive in her fresh in vitro fertilization cycle and next two replacement cycles. In the third replacement cycle, a successful pregnancy was obtained by vitrified-thawed oocytes. This case demonstrates that follicular aspiration during follicle selection phase has protective effects against developing ovarian hyperstimulation syndrome, and rescued immature oocytes are viable and could produce promising embryos for live birth.

Objective: Nasopharyngeal carcinoma (NPC) is a common Epstein-barr virus-associated epithelial malignancy in several parts of the world including Southeast Asia. While the majority of patients are treated uniformly with a combination of chemo and radiation therapy, 20% of patients experience recurrence, most commonly in the form of distant metastasis. NPC subtypes based on underlying differences in biology are unexplored and are likely responsible for the heterogeneous clinical response. As NPC biopsies are small and have significant stromal infiltrate, obtaining pure epithelial cells for genomic profiling is a challenge. We aim to overcome these limitations to identify biological subtypes and dysregulated molecular pathways in NPC. Methods: We first evaluated 217 whole exomes sequences, including 102 microdissected tumors, from three previous studies for single nucleotide variants and copy number changes, following GATK standards and using next generation sequencing copy number callers. We then applied a novel method for gene expression profiling developed in our lab to a new cohort of EBV-positive primary NPC cases from our institution. We performed laser capture microdissection, separately dissecting tumor, normal and microenvironment for each case. We applied Smart-3SEQ, a novel 3' end RNA-Seq technique which allows for the accurate quantification of transcript abundance in dissected FFPE samples comprising only a few hundred cells. Results: We achieved a per-base concordance of 80.4% between copy number profiles by SNP array and whole exome sequencing. Unsupervised clustering identified three distinct copy-number groups of NPC tumors, with a low copy-number group demonstrating an 18.7% better 5-year disease-specific survival, not attributable to stage. Apart from broad cytogenetic changes, narrow regions of amplifications (e.g. 1q21, 11q13) and deletions (e.g. 9p21, 11q22) were important for defining copy-number subtypes. Preliminary differential gene expression analysis showed that genes involved in cell cycle and cellular differentiation were significantly dysregulated in tumor cells (p < 0.001 and p = 0.03 respectively), while genes involved in cilia assembly and flagella transport were upregulated in normal cells (p < 0.001 for both). Our further analysis includes defining tumor subtypes based on gene expression, identifying key driver pathways, and correlating with EBV-latent gene expression, the immune environment, as well as clinical outcome. Conclusion: NPC tumors are biologically heterogeneous and can be classified based on their mutational and gene expression profiles. This provides an important basis for the consideration of escalation and de-escalation of therapy in selected patient groups. Citation Format: Kai Xun Joshua Tay, Chunfang Zhu, Sujay Vennam, Sushama Varma, Quynh-Thu Le, John Sunwoo, Robert West. Biological subtypes of nasopharyngeal carcinoma by genomic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3411.

The PIAS proteins (protein inhibitor of activated STAT) were originally identified as inhibitors of the JAK-STAT pathway. Subsequently, their roles on transcriptional regulation have been identified in modulation of the androgen receptor (AR) and other nuclear hormone receptor-mediated actions. Zimp7, also named Zmiz2, is a novel PIAS-like protein and functions as a transcriptional co-activator. In this study, we demonstrate an interaction between Zimp7 and PIAS proteins with higher preference for PIAS3. A modified mammalian one-hybrid assay showed that the NH(2)-terminal proline-rich domain of Zimp7 and the region spanning amino acids 321-486 of PIAS3 were the primary interaction segments. The interaction between Zimp7 and PIAS3 proteins was further confirmed by in vitro protein pull-down and co-immunoprecipitation assays with both exogenous and endogenous proteins. Expression of exogenous PIAS3 further enhances Zimp7-mediated augmentation of AR transcription. Knockdown of the endogenous PIAS3 protein using a specific PIAS3 small hairpin RNA reduced the augmentation of Zimp7 on AR-mediated transcription. Co-localization of Zimp7 and PIAS3 proteins was observed in the nuclei of cells by immunostaining. Exogenous PIAS3 expression enhances the stability of the Zimp7 protein. Using chromatin immunoprecipitation assays, we showed that PIAS3 is involved in the AR- and Zimp7-formed protein complex(es) in the AR downstream target promoter to facilitate androgen-induced transcription. Finally, we further demonstrated that loss of Zimp7 significantly impaired PIAS3-mediated enhancement on AR activity in mouse Zimp7 null (zimp7(-/-)) embryonic fibroblasts. Taken together, these results demonstrate a novel interaction between PIAS and PIAS-like proteins and elucidate a novel regulatory mechanism for PIAS proteins in AR-mediated transcription.