A multiplexed in vivo approach to identify driver genes in small cell lung cancer.

Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of 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. We found that naphthalene pre-treatment enhances lentiviral vector-mediated SCLC initiation, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Candidate drivers of SCLC identified from a meta-analysis across multiple human SCLC genomic datasets were tested using this approach, which defines both positive and detrimental impacts of inactivating 40 genes across candidate pathways on SCLC development. This analysis and subsequent validation in human SCLC cells establish TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This approach should illuminate drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify therapeutic targets.

Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts.

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts 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 are 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.

The microdissected gene expression landscape of nasopharyngeal cancer reveals vulnerabilities in FGF and noncanonical NF-κB signaling.

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.

Are ethnic differences, urinary iodine status, lead and cadmium exposure associated with thyroid autoimmunity and hypothyroid status? A cross-sectional study.

OBJECTIVE: We aimed to evaluate the effects of different ethnicities and potential environmental exposure on the prevalence of thyroid autoimmune status and hypothyroid status. DESIGN: The data were obtained from two cross-sectional studies. PARTICIPANTS: 2105 participants in Shanghai (Han) and 772 participants in Yunnan Honghe Prefecture (Han, Yi, Miao and Hani), aged 18-75 were enrolled. METHODS: Participants 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. RESULTS: The standardised prevalence of thyroid autoimmune positivity in Yunnan were higher than those in Shanghai (TPOAb+: 13.56% vs 8.27%, p<0.001; TgAb+: 9.28% vs 7.09%, p=0.045; ATA+: 16.96% vs 11.10%, p<0.001; ATA + and US+: 8.96% vs 6.64%, p=0.036). For urinary iodine-to-creatinine ratio (UI/Cr), compared with the level of 100.00-199.99 µg/g, the level of ≥300.00 µg/g had a 1.5-fold risk for ATA + and US+ (OR 1.455, p=0.041). The levels of 200.00-299.99 µg/g and ≥300.00 µg/g were positively associated with hypothyroid status (OR 1.509, p=0.002 and OR 1.338, p=0.043). Compared with the first quartiles, the fourth quartiles of BPb were positively associated with TPOAb+: (OR 1.637, p=0.006), ATA+ (OR 1.435, p=0.025), ATA + and US+ (OR 1.641, p=0.013), hypothyroid status (OR 1.467, p=0.013) and TSH levels (B 0.092, p=0.021). The fourth quartile of BCd was positively associated with the prevalence of ATA+ (OR 1.427, p=0.036). CONCLUSIONS: Higher levels of UI/Cr, BPb and BCd may be associated with thyroid autoimmunity and hypothyroid status.

Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma.

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.

Atlas of clinically distinct cell states and ecosystems across human solid tumors.

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.

Transcriptome and genome evolution during HER2-amplified breast neoplasia.

BACKGROUND: The acquisition of oncogenic drivers is a critical feature of cancer progression. For some carcinomas, it is clear that certain genetic drivers occur early in neoplasia and others late. Why these drivers are selected and how these changes alter the neoplasia's fitness is less understood. METHODS: Here we use spatially oriented genomic approaches to identify transcriptomic and genetic changes at the single-duct level within precursor neoplasia associated with invasive breast cancer. We study HER2 amplification in ductal carcinoma in situ (DCIS) as an event that can be both quantified and spatially located via fluorescence in situ hybridization (FISH) and immunohistochemistry on fixed paraffin-embedded tissue. RESULTS: By combining the HER2-FISH with the laser capture microdissection (LCM) Smart-3SEQ method, we found that HER2 amplification in DCIS alters the transcriptomic profiles and increases diversity of copy number variations (CNVs). Particularly, interferon signaling pathway is activated by HER2 amplification in DCIS, which may provide a prolonged interferon signaling activation in HER2-positive breast cancer. Multiple subclones of HER2-amplified DCIS with distinct CNV profiles are observed, suggesting that multiple events occurred for the acquisition of HER2 amplification. Notably, DCIS acquires key transcriptomic changes and CNV events prior to HER2 amplification, suggesting that pre-amplified DCIS may create a cellular state primed to gain HER2 amplification for growth advantage. CONCLUSION: By using genomic methods that are spatially oriented, this study identifies several features that appear to generate insights into neoplastic progression in precancer lesions at a single-duct level.

Association of Insulin Resistance and ß-cell Function With Bone Turnover Biomarkers in Dysglycemia Patients.

Background: The interrelation between glucose and bone metabolism is complex and has not been fully revealed. This study aimed to investigate the association between insulin resistance, ß-cell function and bone turnover biomarker levels among participants with abnormal glycometabolism. Methods: A total of 5277 subjects were involved through a cross-sectional study (METAL study, http://www.chictr.org.cn, ChiCTR1800017573) in Shanghai, China. Homeostasis model assessment of insulin resistance (HOMA-IR) and ß-cell dysfunction (HOMA-%ß) were applied to elucidate the nexus between ß-C-terminal telopeptide (ß-CTX), intact N-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC). ß-CTX, OC and P1NP were detected by chemiluminescence. Results: HOMA-IR was negatively associated with ß-CTX, P1NP and OC (regression coefficient (ß) -0.044 (-0.053, -0.035), Q4vsQ1; ß -7.340 (-9.130, -5.550), Q4vsQ1 and ß -2.885 (-3.357, -2.412), Q4vsQ1, respectively, all P for trend <0.001). HOMA-%ß was positively associated with ß-CTX, P1NP and OC (ß 0.022 (0.014, 0.031), Q4vsQ1; ß 6.951 (5.300, 8.602), Q4vsQ1 and ß 1.361 (0.921, 1.800), Q4vsQ1, respectively, all P for trend <0.001). Conclusions: Our results support that lower bone turnover biomarker (ß-CTX, P1NP and OC) levels were associated with a combination of higher prevalence of insulin resistance and worse ß-cell function among dysglycemia patients. It is feasible to detect bone turnover in diabetes or hyperglycemia patients to predict the risk of osteoporosis and fracture, relieve patients' pain and reduce the expenses of long-term cure.

Vitamin D is associated with blood lead exposure through bone turnover in type 2 diabetes patients.

BACKGROUND: Bone is thought to be the reservoir of the human lead burden, and vitamin D is associated with bone turnover. We aimed to explore whether exposure to lower 25-hydroxy vitamin D (25(OH)D) levels was associated with higher blood lead levels (BLLs) by increasing the bone turnover rate in individuals with type 2 diabetes. METHODS: A total of 4103 type 2 diabetic men and postmenopausal women in Shanghai, China, were enrolled in 2018. Their 25(OH)D, ß-C-terminal telopeptide (ß-CTX), N-MID osteocalcin and procollagen type 1 N-peptide (P1NP) levels were detected. Their BLLs were determined by atomic absorption spectrometry. Mediation analyses were performed to identify the possible role that bone turnover played in the underlying mechanisms. RESULTS: In both the men and postmenopausal women, all three bone turnover markers were inversely associated with 25(OH)D and positively associated with the BLL (all P < 0.01) after adjusting for age, current smoking habits, metabolic parameters, duration of diabetes, vitamin D intake, and use of anti-osteoporosis medication. In the mediation analyses, none of the direct associations between 25(OH)D and BLL was significant for the three bone turnover markers, but all three bone turnover markers were found to be significant mediators of the indirect associations between 25(OH)D and BLL. CONCLUSION: The association between vitamin D and BLL was fully mediated by bone turnover markers in type 2 diabetic patients (mediation effect). This finding suggested that vitamin D may protect against blood lead exposure from the bone reservoir by decreasing bone turnover in individuals with type 2 diabetes.

Prevalence of hyperuricaemia in an Eastern Chinese population: a cross-sectional study.

OBJECTIVES: In 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. DESIGN: Cross-sectional study. SETTING: Survey of Prevalence in East China of Metabolic Diseases and Risk Factors China study. PARTICIPANTS: In this study, 12 770 residents from 22 sites in Eastern China were recruited. Finally, 9225 subjects were included. MAIN OUTCOME MEASURES: The 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. RESULTS: The 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%, p<0.01). The prevalence of HUA was negatively and positively associated with age in men and women, respectively. Residents with high body mass index levels had a higher prevalence of HUA. In the logistic regression analysis, male sex, urban residency, total cholesterol, triglyceride, overweight, obesity, systolic blood pressure and low economic status were independently correlated with HUA. CONCLUSIONS: The 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 NUMBER: ChiCTR-ECS-14005052.

Photodynamic antitumor activity of Ru(ii) complexes of imidazo-phenanthroline conjugated hydroxybenzoic acid as tumor targeting photosensitizers.

Two novel Ru(ii) polypyridyl complexes bearing imidazo-phenanthroline conjugated hydroxybenzoic acid groups were designed to enhance the tumor targeting ability as photosensitizers for photodynamic therapy. [Ru(bpy)2(phcpip)] (ClO4)2 (Ru-1) and [Ru(bpy)2(ohcpip)] (ClO4)2 (Ru-2) (bpy = 2,2'-bipyridine; phcpip = 2-(3-carboxyl-4-hydroxyphenyl) imidazo [4,5-f]phenanthroline; ohcpip = 2-(2-hydroxyl-3-carboxyphenyl) imidazo [4,5-f] [1,10] phenanthroline) were synthesized and their photodynamic antitumor activities were investigated. Both complexes displayed high photocytotoxicity toward cancerous cell lines HepG2, A549, MCF-7, and MDA-MB-231, but low photocytotoxicity toward normal cell lines GES-1 and Huvec. They were mainly localized at the nucleus of HepG2 cells after 24 h incubation, arrested the cell cycle at the G2/M phase and induced cancer cell apoptosis through reactive oxygen species (ROS) mediated pathways. Tumor targeting of the complexes is attributed to stronger molecular binding to DNA.

Gene expression profiling of single cells from archival tissue with laser-capture microdissection and Smart-3SEQ.

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.

Effects of Vitamin A on Expressions of Apoptosis Genes Bax and Bcl-2 in Epithelial Cells of Corneal Tissues Induced by Benzalkonium Chloride in Mice with Dry Eye.

BACKGROUND The apoptosis of corneal epithelial cells participates in the pathological processes of dry eye, which is expected to be a treatment target for dry eye. The aim of this study was to investigate the effects of vitamin A (VA) on apoptosis of corneal epithelial cells in a mouse model with dry eye induced by benzalkonium chloride (BAC). MATERIAL AND METHODS We randomly divided 60 male BALB/c mice aged 8-10 weeks into 3 groups: the blank control group, the dry eye + vehicle group, and the dry eye + drug group. On the 7th day after the dry eye model successfully induced, the mouse eyeballs removed, and the mouse corneal tissues were isolated. The expression levels of Bax and Bcl-2 in corneal tissues were detected via reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The apoptotic corneal epithelial cells were quantified using terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining technique. RESULTS VA suppressed the upregulation of the Bax gene at the mRNA and protein levels, and upregulated the expression of the Bcl-2 gene (P<0.05). TUNEL results revealed that the number of apoptotic epithelial cells in the dry eye group was 40 times larger as that in the blank control group. After the intervention of VA at an appropriate concentration, the number of apoptotic corneal epithelial cells was remarkably reduced to about 10 times that in the blank control group (P<0.05). CONCLUSIONS VA can inhibit upregulation of the expressions of Bax and Bcl-2 in the epithelial cells of mice with dry eye induced by BAC, so as to suppress the apoptosis of epithelial cells in mice with dry eye.

Genomic analysis of benign prostatic hyperplasia implicates cellular re-landscaping in disease pathogenesis.

Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms in men. Current treatments target prostate physiology rather than BPH pathophysiology and are only partially effective. Here, we applied next-generation sequencing to gain new insight into BPH. By RNAseq, we uncovered transcriptional heterogeneity among BPH cases, where a 65-gene BPH stromal signature correlated with symptom severity. Stromal signaling molecules BMP5 and CXCL13 were enriched in BPH while estrogen regulated pathways were depleted. Notably, BMP5 addition to cultured prostatic myofibroblasts altered their expression profile towards a BPH profile that included the BPH stromal signature. RNAseq also suggested an altered cellular milieu in BPH, which we verified by immunohistochemistry and single-cell RNAseq. In particular, BPH tissues exhibited enrichment of myofibroblast subsets, whilst depletion of neuroendocrine cells and an estrogen receptor (ESR1)-positive fibroblast cell type residing near epithelium. By whole-exome sequencing, we uncovered somatic single-nucleotide variants (SNVs) in BPH, of uncertain pathogenic significance but indicative of clonal cell expansions. Thus, genomic characterization of BPH has identified a clinically-relevant stromal signature and new candidate disease pathways (including a likely role for BMP5 signaling), and reveals BPH to be not merely a hyperplasia, but rather a fundamental re-landscaping of cell types.

UCP2 Mitigates the Loss of Human Spermatozoa Motility by Promoting mROS Elimination.

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<.05) but also an elevated level of mROS (P<.05), suggesting that UCP2 is involved in the maintenance of the spermatozoa mobility, which probably is achieved by promoting mROS elimination. Furthermore, H2O2 treatment of spermatozoa increases the mROS level coupled with the loss of spermatozoa mobility. Unexpectedly, this treatment also has a positive impact on the expression of UCP2 within a certain range of supplemental H2O2, indicating the moderate mROS level possibly serves as a feedback signal to stimulate the expression of UCP2. Finally, the treatment of spermatozoa by an ROS scavenger, N-acetyl-l-cysteine (NAC),decreases the level of mROS and increases the curvilinear velocity (VCL) of spermatozoa, but the UCP2 level is not affected. CONCLUSION: These results suggest an UCP2-mROS-motility regulatory system exists for maintaining spermatozoa mobility in humans. In such a system, UCP2 fulfills its function by promoting mROS elimination, and slightly over-produced mROS in turn serves as a signal to stimulates the expression of UCP2. This regulatory system represents a new potential target for the discovery of novel pharmaceuticals for the treatment of patients with low spermatozoa motility.

LH/FSH Ratio Is Associated With Visceral Adipose Dysfunction in Chinese Women Older Than 55.

No study examined the association of luteinizing hormone to follicular stimulating hormone (LH/FSH) ratio with both visceral obesity outside the context of polycystic ovary syndrome. Thus, we hypothesized that the LH/FSH ratio was associated with visceral adipose accumulation and dysfunction among Chinese women older than 55. From 2014 to 2015, a total of 2,525 women aged 55-89 years were identified from a cross-sectional survey on the prevalence of metabolic diseases and risk factors in East China. Anthropometric indices, biochemical parameters, sex hormones and clinical characteristics were measured. Visceral adipose accumulation and function were identified by visceral adiposity index (VAI), Chinese visceral adiposity index (CVAI) and lipid accumulation product (LAP). Linear regression and logistic regression analyses were conducted to explore the association. A total of 1,462 (57.9%) participants had visceral obesity. In the linear regression, after full adjustment for demographic variables, metabolic factors, total testosterone (T), and estradiol (E2), LH/FSH ratio was positively associated with all indices estimating visceral obesity [B (95% CI): Log VAI 0.060 (0.030-0.090), Log CVAI 0.045 (0.029-0.061), Log LAP 0.103 (0.063-0.142), all P < 0.001]. Logistic regression analyses showed that the risk of visceral obesity increased with increasing LH/FSH ratio after controlling for age and smoking [OR (95% CI): 1.99 (1.52, 2.59), P < 0.001]. After further controlling for metabolic factors, the association was attenuated but remained significant [OR (95% CI): 1.89 (1.42, 2.53), P < 0.001]. The OR of visceral obesity in the fully adjusted model was 1.83 (95% CI 1.37, 2.45) (P < 0.001). Thus, high LH/FSH ratio was significantly associated with visceral adipose over-accumulation and dysfunction in women over 55 years old. This ratio may be an early marker for metabolic disorders in Chinese women older than 55, which warrants further investigation.

Yap regulates mitochondrial structural remodeling during myoblast differentiation.

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.

The Association of Thyroid Nodules with Metabolic Status: A Cross-Sectional SPECT-China Study.

PURPOSE: The aim of this study was to investigate the association of thyroid nodules (TNs) and their ultrasound (US) characteristics related to malignancy with metabolic status. METHODS: The data were obtained from a cross-sectional study (SPECT-China, 2014-2015). The study included 9898 participants older than 18 years. Participants underwent several checkups, which included the measurement of anthropometric parameters, blood pressure, TSH levels, glucose, and lipid profiles. TN and nonalcoholic fatty liver disease (NAFLD) were diagnosed by US. TN US characteristics, including microcalcification and a taller-than-wide shape, were recorded. RESULTS: Participants with TN [TN(+)] had a higher prevalence of metabolic syndrome (Met-S), obesity, central obesity, hyperlipidaemia, diabetes, hypertension, and NAFLD, especially women (all P ≤ 0.001). After full adjustment, logistic regression analysis indicated that metabolic syndrome, obesity, central obesity, and hyperlipidaemia were all independent risk factors for the increased prevalence of TN in both genders (P < 0.05). In terms of TN US imaging characteristics associated with malignancy, being female with obesity, central obesity, and NAFLD had 1.91-fold, 2.09-fold, and 1.75-fold increased risks of developing a taller-than-wide nodule (P = 0.014, 0.004, and 0.027, resp.). CONCLUSIONS: The status of metabolic disorders might be associated with higher risks of TN in both genders. In women, obesity, central obesity, and NAFLD might contribute to the development of a taller-than-wide nodule. The potential role of metabolic status in the pathogenesis of the thyroid nodule and thyroid cancer remains to be elucidated.

Sexual Dimorphism for the Association between Vitamin D and Insulin Resistance in Chinese People.

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.