Publications by authors named "Haipeng Xiao"

87 Publications

Association Between Prospective Registration and Quality of Systematic Reviews in Type 2 Diabetes Mellitus: A Meta-epidemiological Study.

Front Med (Lausanne) 2021 28;8:639652. Epub 2021 Jun 28.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

We sought to investigate the methodological and reporting quality of published systematic reviews describing randomized controlled trials in type 2 diabetes mellitus and analyze their association with status of protocol registration. We searched the PubMed database and identified non-Cochrane systematic reviews, with or without meta-analysis, reporting on type 2 diabetes mellitus and published between 2005 and 2018. We then randomly selected 20% of these reviews in each year, and performed methodological and reporting quality assessment using the Assessment of Multiple Systematic Review 2 (AMSTAR-2) checklist and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We also conducted regression analyses to explore the association between characteristics of systematic reviews and AMSTAR-2 or PRISMA scores. A total of 238 systematic reviews, including 33 registered and 205 non-registered articles, met the inclusion criteria and were subsequently reviewed. Analysis indicated an increase in both registered rates and quality of systematic reviews in type 2 diabetes mellitus over the recent years. With regards to methodological and reporting quality, we found higher scores in registered, relative to non-registered reviews (AMSTAR-2 mean score: 18.0 vs. 14.5, = 0.000; PRISMA mean score: 20.4 vs. 17.6, = 0.000). AMSTAR-2 and PRISMA scores were associated with registration status, country of the first author, and statistical results, whereas the proportion of discussing publication bias and reporting funding sources were <40% for both registered and non-registered systematic reviews. Methodological and reporting quality of systematic reviews in type 2 diabetes mellitus indicates an improvement in the recent years. However, the overall quality remains low, necessitating further improvement. Future studies are expected to pay more attention to prospective registration, description of publication bias and reporting of funding sources.
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http://dx.doi.org/10.3389/fmed.2021.639652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273164PMC
June 2021

Improvement of the management of mental well-being and empathy in Chinese medical students: a randomized controlled study.

BMC Med Educ 2021 Jul 10;21(1):378. Epub 2021 Jul 10.

Department of Medical Education, Department of Endocrinology, Zhongshan School of Medicine, the First Affiliated Hospital, Sun Yat-sen University, No.58, Zhongshan Road 2, 510080, Guangzhou, People's Republic of China.

Background: Among Chinese medical students, there is a high prevalence of mental health-related issues and low empathy. Effective strategies to improve this situation are lacking. This study aims to investigate the efficacy of the intervention courses designed to enhance the mental health and empathy of senior Chinese medical students.

Methods: A total of 146 3rd - and 4th -year medical students were randomized to an intervention group (n = 74) and a control group (n = 72). A pilot study including 5 pre-clinical students and 5 interns was first carried out to determine the themes and content of the intervention courses. The designed courses were delivered in the intervention group once a month three times, while the control group had no specific intervention. Five self-assessment questionnaires, including the General Self-Efficacy (GSE) scale, Medical Outcomes Study Short Form 8 (SF-8), Patient Health Questionnaire-9 (PHQ-9), Maslach Burnout Inventory (MBI), and Jefferson Scale of Empathy-Health Care Provider Student version (JSE-HPS), were completed by the students before and one month after the courses to evaluate their levels of self-efficacy (SE), quality of life (QoL), depression, burnout, and empathy, respectively. Qualitative data were collected via e-mail two years after the intervention.

Results: Compared to the control group, the intervention group showed significantly higher scores for empathy (111.0 [IQR 102.0, 118.0] vs. 106.0 [IQR 93.0, 111.5]; P = .01) and QoL (32.0 [IQR 28.0, 35.0] vs. 29.5 [IQR 26.0, 34.0]; P = .04). The rate of depression was significantly lower in the intervention group than in the control group (13.5 % vs. 29.2 %; chi-square test, P = .02). However, no significant differences in self-efficacy (25.6 ± 4.8 vs. 24.3 ± 6.3; P = .16) or burnout (27.0 % vs. 34.7 %; Chi-square test, P = .31) were observed between the two groups.

Conclusions: The intervention courses had a positive impact on mental well-being and empathy in senior Chinese medical students, which might help provide novel information for their incorporation into the medical school curriculum.

Trial Registration: ClinicalTrials.gov Identifier: NCT02645643; Date of registration: 05/01/2016.
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http://dx.doi.org/10.1186/s12909-021-02813-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272356PMC
July 2021

The ETS Inhibitor YK-4-279 Suppresses Thyroid Cancer Progression Independent of Promoter Mutations.

Front Oncol 2021 16;11:649323. Epub 2021 Jun 16.

Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Hotspot mutations in the core promoter region of the () gene have been well established to associate with aggressive clinical characteristics, radioiodine refractory, tumor recurrence, and mortality in thyroid cancer. Several E-twenty-six (ETS) transcription factors were reported to selectively bound to the mutant promoter and activated TERT expression. In this study we aimed to investigate whether promoter mutations confer sensitivity to ETS inhibitor YK-4-279 in thyroid cancer cells and whether this inhibitor could be served as a potential therapeutic agent for thyroid cancer. assays showed that YK-4-279 treatment sharply suppressed cell viability, colony formation, migration, and invasion, as well as induced cell cycle arrest and apoptosis in a panel of thyroid cancer cells. The cell viability after YK-4-279 treatment was similar between cell lines harboring mutant and wild-type promoters. Furthermore, YK-4-279 treatment reduced both luciferase activity and mRNA expression of TERT independent of promoter mutation status. Data from RNA-seq further revealed that YK-4-279 significantly affected biological processes including DNA replication and cell cycle. Reduced DNA helicase activity and decreased expression of several helicase genes were observed after YK-4-279 treatment. Moreover, YK-4-279 significantly inhibited tumor growth and induced apoptosis in a xenograft mice model. Thus, ETS inhibitor YK-4-279 suppressed TERT expression and conferred anti-tumor activity in a promoter mutation-independent manner, and it could be a potential agent for the treatment of advanced thyroid cancers.
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http://dx.doi.org/10.3389/fonc.2021.649323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242932PMC
June 2021

Comparison of Clinical Features between Primary Aldosteronism and Essential Hypertension in Chinese Patients: A Case-Control Study.

Int J Endocrinol 2021 7;2021:6685469. Epub 2021 Jun 7.

Endocrinology Department, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Primary aldosteronism (PA) is one of the most common forms of secondary hypertension. Recent studies suggest that, compared with essential hypertension (EH), PA presents more severe disorders of glycolipid metabolism and organ damages. This case-control retrospective study aimed to ascertain clinical features and metabolic parameters between Chinese patients of PA and EH. 174 PA patients and 174 matched EH patients were recruited. Their clinical features, biochemistry parameters, the ventricular septal thickness, and left ventricular mass index (LVMI) were compared. HOMA-% and HOMA-IR were calculated to evaluate glucose metabolism. The results showed that there was no significant difference regarding BMI, waist-to-hip ratio, and blood pressure between the two groups. The blood potassium level was significantly lower in PA patients than those in EH patients. The abnormal glucose tolerance and the incidence of diabetes in the PA group were not significantly different from those in EH group, but the insulin secretion levels at 0 min and 30 min were significantly weaker than those in the EH group, and the HOMA-% was also lower in the PA group than those in the EH group. Left ventricular structural abnormalities in PA patients were more severe than those in EH patients. Subtype analysis indicated that patient with aldosterone-producing adenoma (APA) has more serious hypokalemia and lower levels of HOMA-% and HOMA-IR comparing to those in the idiopathic adrenal hyperplasia (IHA) patient. These findings demonstrated that PA patients showed more impaired insulin secretion function and more severe left ventricular structural damage compared with EH patients.
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http://dx.doi.org/10.1155/2021/6685469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203403PMC
June 2021

Genome-Wide Histone H3K27 Acetylation Profiling Identified Genes Correlated With Prognosis in Papillary Thyroid Carcinoma.

Front Cell Dev Biol 2021 11;9:682561. Epub 2021 Jun 11.

Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Thyroid carcinoma (TC) is the most common endocrine malignancy, and papillary TC (PTC) is the most frequent subtype of TC, accounting for 85-90% of all the cases. Aberrant histone acetylation contributes to carcinogenesis by inducing the dysregulation of certain cancer-related genes. However, the histone acetylation landscape in PTC remains elusive. Here, we interrogated the epigenomes of PTC and benign thyroid nodule (BTN) tissues by applying H3K27ac chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) along with RNA-sequencing. By comparing the epigenomic features between PTC and BTN, we detected changes in H3K27ac levels at active regulatory regions, identified PTC-specific super-enhancer-associated genes involving immune-response and cancer-related pathways, and uncovered several genes that associated with disease-free survival of PTC. In summary, our data provided a genome-wide landscape of histone modification in PTC and demonstrated the role of enhancers in transcriptional regulations associated with prognosis of PTC.
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http://dx.doi.org/10.3389/fcell.2021.682561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226268PMC
June 2021

CCR2-engineered mesenchymal stromal cells accelerate diabetic wound healing by restoring immunological homeostasis.

Biomaterials 2021 Jun 10;275:120963. Epub 2021 Jun 10.

Department of Andrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

Impaired wound healing presents great health risks to patients. While encouraging, the current clinical successes of mesenchymal stromal cell (MSC)-based therapies for tissue repair have been limited. Genetic engineering could endow MSCs with more robust regenerative capacities. Here, we identified that C-C motif chemokine receptor 2 (CCR2) overexpression enhanced the targeted migration and immunoregulatory potential of MSCs in response to C-C motif chemokine ligand 2 (CCL2) in vitro. Intravenously infusion of CCR2-engineered MSCs (MSCs) exhibited improved homing efficiencies to injured sites and lungs of diabetic mice. Accordingly, MSC infusion inhibited monocyte infiltration, reshaped macrophage inflammatory properties, prompted the accumulation of regulatory T cells (Treg cells) in injured sites, and reshaped systemic immune responses via the lung and spleen in mouse diabetic wound models. In summary, CCR2-engineered MSCs restore immunological homeostasis to accelerate diabetic wound healing via their improved homing and immunoregulatory potentials in response to CCL2. Therefore, these findings provide a novel strategy to explore genetically engineered MSCs as tools to facilitate tissue repair in diabetic wounds.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120963DOI Listing
June 2021

Utility of multi-parametric quantitative magnetic resonance imaging of the lacrimal gland for diagnosing and staging Graves' ophthalmopathy.

Eur J Radiol 2021 Aug 8;141:109815. Epub 2021 Jun 8.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong Province, China. Electronic address:

Purpose: To explore radiological changes of the lacrimal gland (LG) in Graves' ophthalmopathy (GO) based on multi-parametric quantitative MRI and its clinical utility in LG diagnosis and activity in GO.

Methods: We enrolled 99 consecutive patients with GO (198 eyes) and 12 Graves' Disease (GD) patients (24 eyes) from July 2018 to June 2020. Clinical, laboratory, and MRI data were collected at the first visit. Based on clinical activity scores, eyes with GO were subdivided into active and inactive groups. T2-relaxation time (T2) and the absolute reduction in T1-relaxation time (ΔT1) were determined. After MRI and processing, we performed descriptive data analysis and group comparisons. Novel logistic regression predictive models were developed for diagnosing and staging GO. Diagnostic performance of MRI parameters and models was assessed by receiver operating characteristic curve analysis.

Results: LG in GO group had significantly higher T2 and ΔT1 values than the GD group [106.25(95.30,120.21) vs. 83.35(78.15,91.45), P<0.001, and 662.62(539.33,810.95) vs. 547.35(458.62,585.57), P = 0.002, respectively]. The GO group had higher T2 of LG indicating higher disease activity [110.93(102.54,127.67) vs. 93.29(87.06,101.96), P < 0.001]. Combining T2 and ΔT1 values of LG, Model I had higher diagnostic value for distinguishing GO from GD (AUC=0.94, 95 %CI: 0.89,0.99, P<0.001). Meanwhile, T2 of LG had higher diagnostic value for grading GO activity (AUC = 0.84, 95 %CI: 0.76,0.92, P<0.001).

Conclusions: Multi-parametric quantitative MRI parameters of the LG in GO were significantly altered. Novel models combining LG T2 and ΔT1 values showed excellent predictive performances in diagnosing GO. Furthermore, T2 of LG showed practical utility for staging GO.
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http://dx.doi.org/10.1016/j.ejrad.2021.109815DOI Listing
August 2021

A deep-learning model to assist thyroid nodule diagnosis and management - Authors' reply.

Lancet Digit Health 2021 Jul 10;3(7):e411-e412. Epub 2021 Jun 10.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Electronic address:

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http://dx.doi.org/10.1016/S2589-7500(21)00107-2DOI Listing
July 2021

Corneal Endothelium: A Promising Quantitative Index for Graves Ophthalmopathy Activity Evaluation.

Am J Ophthalmol 2021 Jun 6;230:216-223. Epub 2021 Jun 6.

Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address:

Purpose: To investigate the corneal endothelium damage in Graves ophthalmopathy (GO) and its role as a promising quantitative index to evaluate GO activity.

Design: Cross-sectional study.

Methods: This study included 128 eyes of 64 patients with GO. All subjects underwent ophthalmologic examinations, including proptosis, tear break-up time (BUT), corneal fluorescein staining, and Schirmer test. Corneal endothelium was measured by noncontact specular microscope and ocular biometric parameters were measured by IOLMaster 700. Each eye was assigned a specific clinical activity score (CAS), then grouped as active (CAS ≥3 points) or inactive (CAS <3 points). Ocular parameters between the 2 groups were compared using generalized estimating equations accounting for inter-eye correlation, and receiver operating characteristic (ROC) curves were also obtained. Main outcome measures were parameters of corneal endothelium.

Results: Among the included eyes, 81 eyes had inactive GO and 47 eyes had active GO. Corneal endothelial cell morphology was altered in active GO compared with inactive GO. The coefficient variation of cell area (CV) was significantly higher in active GO compared with inactive GO (37.0 [34.4-41.2]% vs 33.9 [30.9-36.8]%, P = .001), and positively correlated with CAS (r = 0.322, P < .001). Moreover, CV showed a diagnostic capacity to differentiate the active eyes from inactive eyes. The area under the ROC curve was 0.705.

Conclusions: Active GO had morphologic changes in corneal endothelium compared with inactive GO. CV is a sensitive indicator to reflect corneal endothelial function, and has the potential to be adopted as a noninvasive, objective, and quantitative index for evaluating the activity status of GO patients.
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http://dx.doi.org/10.1016/j.ajo.2021.05.020DOI Listing
June 2021

Selenite Induces Cell Cycle Arrest and Apoptosis Reactive Oxygen Species-Dependent Inhibition of the AKT/mTOR Pathway in Thyroid Cancer.

Front Oncol 2021 21;11:668424. Epub 2021 May 21.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Thyroid cancer is the most common endocrine malignancy, and its incidence has increased in the past decades. Selenium has been shown to have therapeutic effects against several tumors. However, its role in thyroid cancer and its underlying molecular mechanism remains to be explored. In the present study, we demonstrated that sodium selenite significantly decreased cell viability and induced G0/G1 cell cycle arrest and apoptosis in thyroid cancer cells in a dose-dependent manner. Transcriptomics revealed that sodium selenite induced intracellular reactive oxygen species (ROS) by promoting oxidative phosphorylation. Increased intracellular ROS levels inhibited the AKT/mTOR signaling pathway and upregulated EIF4EBP3. Intracellular ROS inhibition by N-acetylcysteine (NAC) ameliorated the cellular effects of sodium selenite. The findings were reproduced in xenograft thyroid tumor models. Our data demonstrated that sodium selenite exhibits strong anticancer effects against thyroid cancer cells, which involved ROS-mediated inhibition of the AKT/mTOR pathway. This suggests that sodium selenite may serve as a therapeutic option for advanced thyroid cancer.
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http://dx.doi.org/10.3389/fonc.2021.668424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176115PMC
May 2021

A Glycolysis-Related Five-Gene Signature Predicts Biochemical Recurrence-Free Survival in Patients With Prostate Adenocarcinoma.

Front Oncol 2021 19;11:625452. Epub 2021 Apr 19.

Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Prostate cancer (PCa) is one of the most frequently diagnosed cancers in males worldwide. Approximately 25% of all patients experience biochemical recurrence (BCR) after radical prostatectomy (RP) and BCR indicates increased risk for metastasis and castration resistance. PCa patients with highly glycolytic tumors have a worse prognosis. Thus, this study aimed to explore glycolysis-based predictive biomarkers for BCR. Expression data and clinical information of PCa samples were retrieved from three publicly available datasets. One from The Cancer Genome Atlas (TCGA) dataset was used as the training cohort, and two from the Gene Expression Omnibus (GEO) dataset (GSE54460 and GSE70769) were used as validation cohorts. Using the training cohort, univariate Cox regression survival analysis, robust likelihood-based survival model, and stepwise multiply Cox analysis were sequentially applied to explore predictive glycolysis-related candidates. A five-gene risk score was then constructed based on the Cox coefficient as the following: (-0.8367*GYS2) + (0.3448*STMN1) + (0.3595*PPFIA4) + (-0.1940*KDELR3) + (0.4779*ABCB6). Receiver operating characteristic curve (ROC) analysis was used to identify the optimal cut-off point, and patients were divided into low risk and high risk groups. Kaplan-Meier analysis revealed that high risk group had significantly shorter BCR free survival time as compared with that in low risk group in training and validation cohorts. In conclusion, our data support the glycolysis-based five-gene signature as a novel and robust signature for predicting BCR of PCa patients.
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http://dx.doi.org/10.3389/fonc.2021.625452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092437PMC
April 2021

A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1.

BMC Endocr Disord 2021 Apr 21;21(1):76. Epub 2021 Apr 21.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, P. R. China.

Background: Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Mutations in Wolfram syndrome 1 (WFS1) gene may cause dysregulated endoplasmic reticulum (ER)-stress and cell apoptosis, contributing to WS symptoms. The aim of this study was to identify the molecular etiology of a case of WS and to explore the functional consequence of the mutant WFS1 gene in vitro.

Methods: A 27 years-old Chinese man was diagnosed as wolfram syndrome type 1 based on clinical data and laboratory data. DNA sequencing of WFS1 gene and mitochondrial m.3337G > A, m.3243A > G mutations were performed in the patient and his 4 family members. Functional analysis was performed to assessed the in vitro effect of the newly identified mutant. ER stress were evaluated by ER stress response element (ERSE)-luciferase assay. Cell apoptosis were performed by CCK-8, TUNEL staining and flow cytometric analysis.

Results: A novel heterozygous 10-base deletion (c. 2067_2076 del10, p.W690fsX706) was identified in the patient. In vitro studies showed that mutant p.W690fsX706 increased ERSE reporter activity in the presence or absence of thapsigargin instead of wild type WFS1. Knockdown of WFS1 activated the unfolded protein response (UPR) pathway and increased the cell apoptosis, which could not be restored by transfection with WFS1 mutant (p.W690fsX706) comparable to the wild type WFS1.

Conclusions: A novel heterozygous mutation of WFS1 detected in the patient resulted in loss-of-function of wolframin, thereby inducing dysregulated ER stress signaling and cell apoptosis. These findings increase the spectrum of WFS1 gene mutations and broaden our insights into the roles of mutant WFS1 in the pathogenesis of WS.
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http://dx.doi.org/10.1186/s12902-021-00748-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059287PMC
April 2021

Glucose-dependent insulinotropic polypeptide modifies adipose plasticity and promotes beige adipogenesis of human omental adipose-derived stem cells.

FASEB J 2021 05;35(5):e21534

Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

The adipocyte precursors (APs) located in white adipose tissue (WAT) are functionally significant in adipose plasticity and browning. Modifying adipogenesis or WAT browning targeted on APs is a promising mechanism for anti-obesity drug. We herein explored the in vitro actions and mechanisms of glucose-dependent insulinotropic polypeptide (GIP), a gut-derived peptide, in human adipose-derived mesenchymal stem cells (hADSCs) isolated from omentum. The hADSCs were cotreated with 100 nM GIP with or without equimolar concentration of GIP3-42 (a GIP receptor antagonist), and subsequently examined in vitro. CCK-8, EdU incorporation, and flow cytometry assays were used to assess cellular proliferation. Annexin V FTIC/PI double stain, TUNEL staining, and Western blot were applied for apoptosis evaluation. Adipogenesis was reflected by Western blot, real-time PCR, Oil Red O staining, mitochondrial staining, and mitochondrial DNA analysis. Results showed that GIP promoted proliferation and inhibited apoptosis of hADSCs via pleiotropic effects. Besides, GIP facilitated de novo beige adipogenesis, by accelerating mitotic clonal expansion (MCE), upregulating core adipogenic regulators (C/EBPα and PPARγ), augmenting beige-related genes (UCP1, PGC1α, and PRDM16), increasing mitochondrial content and improving beige adipocyte functionalities. Above all, our study expands knowledge on the mechanisms of GIP modifying adipogenesis especially in inducing beige adipogenesis, and thus provides a theoretical support for clinical usage of GIP on obesity treatment.
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http://dx.doi.org/10.1096/fj.201903253RDOI Listing
May 2021

Deep learning-based artificial intelligence model to assist thyroid nodule diagnosis and management: a multicentre diagnostic study.

Lancet Digit Health 2021 04;3(4):e250-e259

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address:

Background: Strategies for integrating artificial intelligence (AI) into thyroid nodule management require additional development and testing. We developed a deep-learning AI model (ThyNet) to differentiate between malignant tumours and benign thyroid nodules and aimed to investigate how ThyNet could help radiologists improve diagnostic performance and avoid unnecessary fine needle aspiration.

Methods: ThyNet was developed and trained on 18 049 images of 8339 patients (training set) from two hospitals (the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, and Sun Yat-sen University Cancer Center, Guangzhou, China) and tested on 4305 images of 2775 patients (total test set) from seven hospitals (the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; the Guangzhou Army General Hospital, Guangzhou, China; the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; the First Affiliated Hospital of Sun Yat-sen University; Sun Yat-sen University Cancer Center; and the First Affiliated Hospital of Guangxi Medical University, Nanning, China) in three stages. All nodules in the training and total test set were pathologically confirmed. The diagnostic performance of ThyNet was first compared with 12 radiologists (test set A); a ThyNet-assisted strategy, in which ThyNet assisted diagnoses made by radiologists, was developed to improve diagnostic performance of radiologists using images (test set B); the ThyNet assisted strategy was then tested in a real-world clinical setting (using images and videos; test set C). In a simulated scenario, the number of unnecessary fine needle aspirations avoided by ThyNet-assisted strategy was calculated.

Findings: The area under the receiver operating characteristic curve (AUROC) for accurate diagnosis of ThyNet (0·922 [95% CI 0·910-0·934]) was significantly higher than that of the radiologists (0·839 [0·834-0·844]; p<0·0001). Furthermore, ThyNet-assisted strategy improved the pooled AUROC of the radiologists from 0·837 (0·832-0·842) when diagnosing without ThyNet to 0·875 (0·871-0·880; p<0·0001) with ThyNet for reviewing images, and from 0·862 (0·851-0·872) to 0·873 (0·863-0·883; p<0·0001) in the clinical test, which used images and videos. In the simulated scenario, the number of fine needle aspirations decreased from 61·9% to 35·2% using the ThyNet-assisted strategy, while missed malignancy decreased from 18·9% to 17·0%.

Interpretation: The ThyNet-assisted strategy can significantly improve the diagnostic performance of radiologists and help reduce unnecessary fine needle aspirations for thyroid nodules.

Funding: National Natural Science Foundation of China and Guangzhou Science and Technology Project.
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http://dx.doi.org/10.1016/S2589-7500(21)00041-8DOI Listing
April 2021

SLC6A15 acts as a tumor suppressor to inhibit migration and invasion in human papillary thyroid cancer.

J Cell Biochem 2021 Aug 10;122(8):814-826. Epub 2021 Mar 10.

Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

Solute Carrier Family 6 Member 15 (SLC6A15), a sodium-dependent neutral amino acid transporter, has been found with dysregulated expression in several kinds of cancers. However, the expression pattern and the biological functions of SLC6A15 in papillary thyroid cancer (PTC) remain unknown. In this study, we found that SLC6A15 was downregulated in PTC, which was related to N classification. Ectopic overexpression of SLC6A15 impaired migratory and invasive abilities of PTC cell in vitro. In addition, we identified intercellular adhesion molecule-1, a vital oncogene in thyroid cancer progression, was involved in the effects of SLC6A15 on PTC cell. These results indicate that SLC6A15 acts as a tumor suppressor and might be a potential therapeutic target in the treatment of PTC.
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http://dx.doi.org/10.1002/jcb.29914DOI Listing
August 2021

Single-cell transcriptomic landscape reveals the differences in cell differentiation and immune microenvironment of papillary thyroid carcinoma between genders.

Cell Biosci 2021 Feb 15;11(1):39. Epub 2021 Feb 15.

Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Guangdong, 510080, Guangzhou, China.

Background: Papillary thyroid carcinoma (PTC) is the main pathological type of thyroid carcinoma (TC). Gender is a prominent background parameter for patients with PTC. Here, we aimed to delineate the differences in cell clusters and immune microenvironment in relation to gender in PTC.

Methods: We generated 6720, 14,666, and 33,373 single-cell transcriptomes that were pooled from the tissues of four male patients with PTC, seven female patients with PTC, and three patients with nodular goiter, respectively. We performed single-cell RNA-sequencing (scRNA-seq) based on BD Rhapsody and characterized the first single-cell transcriptomic landscape of PTC involving gender. The differential cell clusters and their gene profiles were identified and analyzed via a multi-resolution network in male and female patients. The interactions of fibroblasts and endothelial cells with malignant epithelial cells and the difference in the immune infiltration of B and T lymphocytes according to gender were assessed.

Results: Malignant epithelial cells were divided into two distinct subsets in male and female patients with PTC. Moreover, significant differences involving inferred copy-number variations (CNVs), gene profiles, and cell differentiation were detected between male and female patients. Regarding the interactions of fibroblasts and endothelial cells with malignant epithelial cells, members of the human leukocyte antigen (HLA) family and their receptors were considered as typical in female patients with PTC, while transforming growth factor beta 1 (TGFB1) and its receptors were typical of male patients with PTC. The characteristics of B cells, including cell clusters, cell differentiation, and dominant gene sets, were significantly different between genders.

Conclusions: Our data revealed the detailed differences in cell clusters and immune microenvironment in PTC according to gender at the single-cell level, which provided new insights into the understanding of the impact of gender on PTC.
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http://dx.doi.org/10.1186/s13578-021-00549-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885238PMC
February 2021

Translation and validation of the Chinese version of medical maximizer-minimizer scale: a cross-sectional study.

BMJ Open 2021 01 6;11(1):e042432. Epub 2021 Jan 6.

Department of Geriatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Objective: Medical overutilisation and underutilisation affect optimal healthcare. The Medical Maximizer-Minimizer Scale (MMS) was developed to assess individual medical maximising and minimising tendencies. Despite significant improvement in the healthcare system over the past four decades, no psychometric scales to examine treatment maximising and minimising preferences are available in China. This study aimed to translate the MMS into Chinese and examine its reliability and validity in a Chinese population.

Design: This cross-sectional study was conducted in December 2019 through an online survey panel.

Methods: The MMS was translated into a Chinese version (CN-MMS) using a forward-backward translation procedure. Next, a random online survey of the general population in China was conducted. Exploratory factor analysis (EFA) and confirmatory factor analysis were performed to examine the underlying factor structure of the CN-MMS. The internal consistency reliability of the scale was determined using Cronbach's α coefficient and corrected item-total correlation. A multivariate linear regression analysis was used to examine associations between medical maximising and minimising preferences and demographic variables in the Chinese population.

Results: This study included 984 participants aged 18-80 years. The CN-MMS retained 10 items, and the EFA supported a two-factor structure. The model fit for this two-factor structure of the CN-MMS was acceptable with χ/df=3.7, comparative fit index=0.958, goodness-of-fit index=0.951, Tucker-Lewis Index=0.944 and root mean square error of approximation=0.074. The scale had a Cronbach's α coefficient of 0.864, corrected item-total correlation of 0.451-0.667, and test-retest reliability of 0.815. Significant predictors of CN-MMS total score were nationality and household monthly income.

Conclusions: The CN-MMS showed satisfactory psychometric properties. Therefore, it can be used to investigate the individual medical maximising and minimising tendencies among the general Chinese population.
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http://dx.doi.org/10.1136/bmjopen-2020-042432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789444PMC
January 2021

The Current Landscape of Clinical Studies Focusing on Thyroid Cancer: A Comprehensive Analysis of Study Characteristics and Their Publication Status.

Front Endocrinol (Lausanne) 2020 20;11:575799. Epub 2020 Nov 20.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: A better understanding of the current characteristics of clinical trials on thyroid cancer (TC) is important to improve trial designs and identify neglected areas of research. However, there is a lack of a thorough understanding of the clinical studies on TC. Therefore, this study aimed to present a comprehensive overview of clinical trials on TC based on the ClinicalTrials.gov database and evaluate their publication status.

Methods: We searched for TC-related clinical studies registered in the ClinicalTrials.gov database before December 2018 by using the keyword "thyroid cancer" and assessed the characteristics of the included trials. We searched the publication status of primary completed studies in PubMed and Google Scholar.

Results: A total of 450 studies were identified for analysis, including 333 (74.0%) interventional studies and 117 (26.0%) observational studies. Interventional studies about TC were commonly non-randomized (67.6%), single-arm (55.6%), single-center (76.3%), and early-phase (60.0%) trials. The major category for which studies were performed was for target drug-related therapy (53.6%). In addition, 57.0% of the primary completed interventional studies were published. The published studies were more commonly primary completed studies after 2010 and used randomization and were less commonly designed as single-arm studies and were conducted in the USA/Canada, compared to non-published studies ( < 0.05 for all). The median time from primary completion to publication was 46.5 months, and the time decreased to 36.5 months after 2010. Studies conducted in the USA/Canada [odds ratio (OR) = 9.43, = 0.020] and multi-center studies (OR = 6.55,  = 0.021) significantly increased the potential of publication in high-impact journals.

Conclusions: High-quality, randomized phase 3 trials regarding TC are still insufficient. Therefore, more efforts are needed to improve the treatment of poor prognostic TC and timely publication.
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http://dx.doi.org/10.3389/fendo.2020.575799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714929PMC
June 2021

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors.

Nat Commun 2020 12 9;11(1):6318. Epub 2020 Dec 9.

Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, Massachusetts, 02115, USA.

Primary effusion lymphoma (PEL) has a very poor prognosis. To evaluate the contributions of enhancers/promoters interactions to PEL cell growth and survival, here we produce H3K27ac HiChIP datasets in PEL cells. This allows us to generate the PEL enhancer connectome, which links enhancers and promoters in PEL genome-wide. We identify more than 8000 genomic interactions in each PEL cell line. By incorporating HiChIP data with H3K27ac ChIP-seq data, we identify interactions between enhancers/enhancers, enhancers/promoters, and promoters/promoters. HiChIP further links PEL super-enhancers to PEL dependency factors MYC, IRF4, MCL1, CCND2, MDM2, and CFLAR. CRISPR knock out of MEF2C and IRF4 significantly reduces MYC and IRF4 super-enhancer H3K27ac signal. Knock out also reduces MYC and IRF4 expression. CRISPRi perturbation of these super-enhancers by tethering transcription repressors to enhancers significantly reduces target gene expression and reduces PEL cell growth. These data provide insights into PEL molecular pathogenesis.
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http://dx.doi.org/10.1038/s41467-020-20136-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726151PMC
December 2020

Forty-eight weeks of statin therapy for type 2 diabetes mellitus patients with lower extremity atherosclerotic disease: Comparison of the effects of pitavastatin and atorvastatin on lower femoral total plaque areas.

J Diabetes Investig 2021 Jul 30;12(7):1278-1286. Epub 2020 Dec 30.

Department of Endocrinology and Metabolism, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

Aims/introduction: Type 2 diabetes mellitus is correlated with systemic atherosclerosis. Statin therapies have been proved to reduce low-density lipoprotein cholesterol (LDL-C) level, protecting type 2 diabetes mellitus patients from cardiovascular events. Recently, more interest has been focused on the regression of lower extremity atherosclerotic disease (LEAD) for the potential prevention of amputation. However, the effects of pitavastatin and atorvastatin on LEAD in type 2 diabetes mellitus patients have not been directly compared.

Materials And Methods: This study compared the effects of pitavastatin and atorvastatin on femoral total plaque areas (FTPA), and lipids and glucose metabolism in type 2 diabetes mellitus patients with elevated LDL-C level and LEAD. Type 2 diabetes mellitus patients with LDL-C level >2.6 mmol/L and LEAD were randomly assigned to receive either pitavastatin 2 mg/day or atorvastatin 10 mg/day for 48 weeks. FTPA were measured at baseline and the end of the study. Levels of glucose and lipids profile were measured periodically. The efficacy was evaluated in 63 patients.

Results: The percentage change in FTPA measurements was similar between the pitavastatin group and atorvastatin group (-17.79 ± 21.27% vs -14.34 ± 16.33%), as were the changes in LDL-C (-44.0 ± 18.0% vs -40.3 ± 18.2%) and triglyceride (17.6 ± 20.0% vs 16.2 ± 17.0%). However, the level of high-density lipoprotein cholesterol was significantly higher in the pitavastatin group compared with the atorvastatin group after 48 weeks of treatment (12.9 ± 10.3% vs 7.2 ± 11.7%, P < 0.05). There were no significant differences between groups for the measurements of glucose metabolism.

Conclusion: In type 2 diabetes mellitus patients with elevated LDL-C level and LEAD, 48 weeks of treatment with either pitavastatin or atorvastatin was associated with significant regression of FTPA. Pitavastatin treatment resulted in a significantly higher high-density lipoprotein cholesterol level compared with atorvastatin treatment.
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http://dx.doi.org/10.1111/jdi.13472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264389PMC
July 2021

Genetic alterations in cfDNA of benign and malignant thyroid nodules based on amplicon-based next-generation sequencing.

Ann Transl Med 2020 Oct;8(19):1225

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Circulating cell-free DNA (cfDNA) serves as a biomarker in multiple malignant diseases. However, controversy still surrounds the role of cfDNA detection in the diagnosis and monitoring of papillary thyroid carcinoma (PTC). This study set out to identify the role of cfDNA detection in distinguishing between benign and malignant thyroid nodules.

Methods: Tissue, blood cell, and plasma samples were collected from 10 patients with benign nodules and 10 patients with malignant nodules. The DNA isolated from these samples was subject to PCR-based amplification using primers designed for 50 proto-oncogenes and tumor suppressor genes. PCR products were sequenced using Illumina technology, and the mutations were detected with varScan among sequencing data for each sample and comparative analysis was carried out.

Results: Through amplicon sequencing, we found one non-synonymous somatic mutation in the benign nodules and three in the malignant nodules. Among these four mutations, BRAF mutation was detected in the tissue samples of 8 out of the 10 PTC patients, but it was not detected in the benign nodules. However, no BRAF mutation was detected in cfDNA. Further differential analysis of cfDNA indicated that some genes had more mutations in benign patients than in malignant patients, such as MET and IDH, and some genes had more mutations in malignant patients, such as PIK3CA and EZH2.

Conclusions: We found that BRAF mutation was a credible disease-related mutation in PTC; however, it could not be detected in cfDNA. Moreover, there was a large difference in mutation gene distribution between benign and malignant thyroid nodules.
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http://dx.doi.org/10.21037/atm-20-4544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607131PMC
October 2020

Towards precision medicine in thyroid cancer.

Ann Transl Med 2020 Oct;8(19):1212

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

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http://dx.doi.org/10.21037/atm-20-6450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607071PMC
October 2020

Circ-Tulp4 promotes β-cell adaptation to lipotoxicity by regulating soat1 expression.

J Mol Endocrinol 2020 11;65(4):149-161

Department of Endocrinology and Metabolism, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

This study aimed to identify circular RNAs differentially expressed in the islets of type 2 diabetes (T2DM) models and clarify their roles in the control of β-cell functions. Circular RNAs dysregulated in the islets of diabetic db/db mice were identified by high-throughput RNA sequencing. Then, the expression level of the selected circular RNA circ-Tulp4 was confirmed by real-time PCR in the islets of diabetic models and Min6 cells. MTS, EdU, western blot, flow cytometric analysis, and luciferase assay were performed to investigate the impact of circ-Tulp4 on β-cell functions. This study identified thousands of circular RNAs in mouse pancreatic islets. The circ-Tulp4 level significantly decreased in the diabetic models and altered in the Min6 cells under lipotoxic condition. The modulation of circ-Tulp4 level in Min6 cells regulated cell proliferation. Furthermore, an interaction was demonstrated between circ-Tulp4 and miR-7222-3p, which suppressed the expression of cholesterol esterification-related gene, sterol O-acyltransferase 1 (SOAT1). The accumulation of soat1 activated cyclin D1 expression, thus promoting cell cycle progression. These findings showed that circ-Tulp4 regulated β-cell proliferation via miR-7222-3p/soat1/cyclin D1 signaling. Our research suggested that circ-Tulp4 might be a potential therapeutic intervention for T2DM. Besides, soat1 might be important for β-cell adaptation to lipotoxicity.
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http://dx.doi.org/10.1530/JME-20-0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576671PMC
November 2020

Screening and the epidemic of thyroid cancer in China: An analysis of national representative inpatient and commercial insurance databases.

Int J Cancer 2021 03 28;148(5):1106-1114. Epub 2020 Sep 28.

Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Reasons behind the rapid increase of thyroid cancer (TC) in China are uncertain. We assessed the burden of TC and the role of access to screening and salt iodization. We analyzed two national databases in China: Hospital Quality Monitoring System (HQMS) and China Reinsurance Company (CRC) database. HQMS covered 1037 (44.3%) Class 3 hospitals and 76 263 617 Class 3 hospital inpatients in 2013 to 2017 and CRC covered 93 123 018 clients in 2000 to 2016. The proportion of TC inpatients among inpatients in HQMS and TC incidence in critical illness insurance buyers were used to evaluate the association with screening and iodine status. Between 2013 and 2017, the proportion of TC patients in HQMS with urban employee medical insurance and good access to screening increased sharply while there was little change among those with the other two forms of medical insurance. Across provinces, the proportion of TC inpatients in HQMS was positively correlated with per capita disposable income but not with median urinary iodine. Similar findings were observed in the CRC database. In 2017, approximately 1000 individuals were overdiagnosed with TC daily. We conservatively forecast that 5.1 million healthy individuals would become TC patients unnecessarily between 2019 and 2030. Our findings suggested the epidemic of TC in China was substantially underestimated. It was associated with screening but not with salt iodization.
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http://dx.doi.org/10.1002/ijc.33298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821127PMC
March 2021

Systemic Corticosteroids and Mortality in Severe and Critical COVID-19 Patients in Wuhan, China.

J Clin Endocrinol Metab 2020 12;105(12)

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.

Background: Systemic corticosteroids are now recommended in many treatment guidelines, although supporting evidence is limited to 1 randomized controlled clinical trial (RECOVERY).

Objective: To identify whether corticosteroids were beneficial to COVID-19 patients.

Methods: A total of 1514 severe and 249 critical hospitalized COVID-19 patients from 2 medical centers in Wuhan, China. Multivariable Cox models, Cox model with time-varying exposure and propensity score analysis (inverse-probability-of-treatment-weighting [IPTW] and propensity score matching [PSM]) were used to estimate the association of corticosteroid use with risk of in-hospital mortality in severe and critical cases.

Results: Corticosteroids were administered in 531 (35.1%) severe and 159 (63.9%) critical patients. Compared to the non-corticosteroid group, systemic corticosteroid use was not associated with beneficial effect in reducing in-hospital mortality in either severe cases (HR = 1.77; 95% CI, 1.08-2.89; P = 0.023), or critical cases (HR = 2.07; 95% CI, 1.08-3.98; P = 0.028). Findings were similar in time-varying Cox analysis. For patients with severe COVID-19 at admission, corticosteroid use was not associated with improved or harmful outcome in either PSM or IPTW analysis. For critical COVID-19 patients at admission, results were consistent with multivariable Cox model analysis.

Conclusion: Corticosteroid use was not associated with beneficial effect in reducing in-hospital mortality for severe or critical cases in Wuhan. Absence of the beneficial effect in our study in contrast to that observed in the RECOVERY clinical trial may be due to biases in observational data, in particular prescription by indication bias, differences in clinical characteristics of patients, choice of corticosteroid used, timing of initiation of treatment, and duration of treatment.
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http://dx.doi.org/10.1210/clinem/dgaa627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499588PMC
December 2020

Prior bariatric surgery and perioperative cardiovascular outcomes following noncardiac surgery in patients with type 2 diabetes mellitus: hint from National Inpatient Sample Database.

Cardiovasc Diabetol 2020 07 6;19(1):103. Epub 2020 Jul 6.

Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhong Shan Er Lu, Guangzhou, 510080, China.

Background: Both diabetes and obesity are risk factors for perioperative major adverse events. This study aims to evaluate the association between prior bariatric surgery (prior-BS) and perioperative cardiovascular outcomes following noncardiac surgery in patients with type 2 diabetes mellitus (T2DM).

Methods: We used the National Inpatient Sample Database to identify T2DM patients undergoing major noncardiac surgery from 2006 to 2014. The primary outcome was major perioperative adverse cardiovascular and cerebrovascular events (MACCEs), which include death, acute myocardial infarction and acute ischaemic stroke. In-hospital outcomes between patients with prior BS and morbid obesity were compared using unadjusted logistic, multivariable logistic and propensity score matching analyses.

Results: A weighted of 1,526,820 patients diagnosed with T2DM who underwent noncardiac surgery were included. The rates of both prior BS and morbid obesity significantly increased during the study period (P < 0.0001). Patients with prior BS were younger, were more likely to be female, and had lower rates of cardiovascular risk factors but had higher rates of smoking, alcohol abuse, anaemia, prior venous thromboembolism and prior percutaneous coronary intervention. The incidence of MACCEs was 1.01% and 3.25% in patients with prior BS and morbid obesity, respectively. After multivariable adjustment, we found that prior BS was associated with a reduced risk of MACCEs (odds ratio [OR] = 0.71; 95% confidence interval [CI] 0.62-0.81), death (OR = 0.64, 95% CI 0.52-0.78), acute kidney injury (OR = 0.66, 95% CI 0.62-0.70) and acute respiratory failure (OR: 0.46; 95% CI 0.42-0.50).

Conclusions: Prior bariatric surgery in T2DM patients undergoing noncardiac surgery is associated with a lower risk of MACCEs. Prospective studies are needed to verify the benefits of bariatric surgery in patients undergoing noncardiac surgery.
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http://dx.doi.org/10.1186/s12933-020-01084-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339406PMC
July 2020

Elevation of blood glucose level predicts worse outcomes in hospitalized patients with COVID-19: a retrospective cohort study.

BMJ Open Diabetes Res Care 2020 06;8(1)

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

Introduction: With intense deficiency of medical resources during COVID-19 pandemic, risk stratification is of strategic importance. Blood glucose level is an important risk factor for the prognosis of infection and critically ill patients. We aimed to investigate the prognostic value of blood glucose level in patients with COVID-19.

Research Design And Methods: We collected clinical and survival information of 2041 consecutive hospitalized patients with COVID-19 from two medical centers in Wuhan. Patients without available blood glucose level were excluded. We performed multivariable Cox regression to calculate HRs of blood glucose-associated indexes for the risk of progression to critical cases/mortality among non-critical cases, as well as in-hospital mortality in critical cases. Sensitivity analysis were conducted in patient without diabetes.

Results: Elevation of admission blood glucose level was an independent risk factor for progression to critical cases/death among non-critical cases (HR=1.30, 95% CI 1.03 to 1.63, p=0.026). Elevation of initial blood glucose level of critical diagnosis was an independent risk factor for in-hospital mortality in critical cases (HR=1.84, 95% CI 1.14 to 2.98, p=0.013). Higher median glucose level during hospital stay or after critical diagnosis (≥6.1 mmol/L) was independently associated with increased risks of progression to critical cases/death among non-critical cases, as well as in-hospital mortality in critical cases. Above results were consistent in the sensitivity analysis in patients without diabetes.

Conclusions: Elevation of blood glucose level predicted worse outcomes in hospitalized patients with COVID-19. Our findings may provide a simple and practical way to risk stratify COVID-19 inpatients for hierarchical management, particularly where medical resources are in severe shortage during the pandemic.
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http://dx.doi.org/10.1136/bmjdrc-2020-001476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298690PMC
June 2020

Circulating Myeloid-derived Suppressor Cells Facilitate Invasion of Thyroid Cancer Cells by Repressing miR-486-3p.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Background: Myeloid-derived suppressor cells (MDSCs) have become increasingly recognized as facilitators of tumor development. However, the role of MDSCs in papillary thyroid carcinoma (PTC) progression has not been clearly explored.

Objective: We aimed to evaluate the levels and function of circulating MDSCs in PTC.

Methods: The proportion of circulating polymorphonuclear (PMN)-MDSCs and mononuclear-MDSCs from patients with PTC or benign thyroid nodules and healthy controls was measured using flow cytometry. For immunosuppressive activity analysis, sorted circulating MDSCs were cocultured with CD3/CD28-costimulated T lymphocytes and the proliferation of T cells was determined. PTC cell lines (TPC-1 and BC-PAP) were cocultured with PMN-MDSCs, and the effects on cell migration, invasion, proliferation, and apoptosis were evaluated. The differential expressed microribonucleic acids (RNAs) and messenger RNAs and their function were also explored in TPC-1 cells cocultured with or without PMN-MDSCs.

Results: PMN-MDSCs were increased in peripheral blood mononuclear cells of patients with PTC. Circulating PMN-MDSCs displayed strong T cell suppressive activity. PTC cells demonstrated enhanced invasive capabilities in vitro and in vivo when cocultured with sorted PMN-MDSCs. PMN-MDSCs decreased expression of miR-486-3p and activated nuclear factor kappa B2 (NF-κB2), a direct target of miR-486-3p. Rescue of miR-486-3p diminished the cell migration and invasion induced by PMN-MDSCs.

Conclusion: Collectively, our work indicates that circulating PMN-MDSCs promote PTC progression. By suppressing miR-486-3p, PMN-MDSCs promote the activity of the NF-κB2 signaling pathway, resulting in accelerated invasion of PTC cells, which may provide new therapeutic strategies for treatment of thyroid cancer.
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http://dx.doi.org/10.1210/clinem/dgaa344DOI Listing
August 2020

LncRNA-Malat1 is Involved in Lipotoxicity-Induced ß-cell Dysfunction and the Therapeutic Effect of Exendin-4 via Ptbp1.

Endocrinology 2020 07;161(7)

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

Increasing evidence indicates that long noncoding RNAs (lncRNAs) have crucial roles in various biological processes. However, the contribution of lncRNAs to β-cell dysfunction and their roles in diabetes therapeutics remain poorly understood. The aim of this study was to identify the lncRNAs dysregulated in diabetic islets and to explore the lncRNAs involved in β-cell function as potential therapeutic targets. By using RNA sequencing and real-time PCR, we identified thousands of lncRNAs in the islets of db/db mice and db/m littermate mice. Among the differentially expressed lncRNAs, lncRNA-Malat1 (metastasis-associated lung adenocarcinoma transcript 1) was reduced in the islets of db/db mice and palmitate-treated MIN6 cells. The results of TUNEL, Western blot and flow cytometric analyses, and GSIS assays revealed that Malat1 knockdown significantly induced β-cell apoptosis and inhibited insulin secretion. Mechanistically, RNA immunoprecipitation showed that Malat1 enhanced polypyrimidine tract-binding protein 1 (Ptbp1) protein stability by direct interaction, thereby adjusting the ratio of pyruvate kinase muscle (PKM) isoforms 1 and 2 (PKM1/PKM2). Moreover, luciferase assay and chromatin immunoprecipitation indicated that Malat1 was transcriptionally activated by pancreatic and duodenal homeobox 1 (Pdx1), through which exendin-4 alleviated lipotoxicity-induced β-cell damage. In summary, our findings suggested the involvement of Malat1 in β-cell dysfunction under diabetic conditions via the Malat1/Ptbp1/PKM2 pathway. In addition, exendin-4 ameliorated β-cell impairment by Pdx1-mediated Malat1 upregulation. Hence, Malat1 may serve as a therapeutic target for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1210/endocr/bqaa065DOI Listing
July 2020

Novel Roles of Chloroquine and Hydroxychloroquine in Graves' Orbitopathy Therapy by Targeting Orbital Fibroblasts.

J Clin Endocrinol Metab 2020 06;105(6)

Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Context: Graves' orbitopathy (GO) causes infiltrative exophthalmos by inducing excessive proliferation, adipogenesis, and glycosaminoglycan production in orbital fibroblasts (OFs). Interference with OF autophagy is a potential therapy for proptosis.

Objectives: Here, we aimed to evaluate the effects of chloroquine (CQ) and hydroxychloroquine (HCQ), the autophagy inhibitors commonly used in clinical practice, on OFs.

Design/setting/participants: OFs isolated from patients with GO (GO-OFs) or control individuals (non-GO-OFs) were cultured in proliferation medium (PM) or subjected to differentiation medium. OFs were treated with CQ or HCQ (0, 0.5, 2, and 10 μM), and subsequently examined in vitro.

Main Outcome Measures: CCK-8, EdU incorporation, and flow cytometry assays were used to assess cellular viability. Adipogenesis was assessed with Western blot analysis, real-time polymerase chain reaction (PCR) , and Oil Red O staining. Hyaluronan production was determined by real-time PCR and enzyme-linked immunosorbent assay. Autophagy flux was detected through red fluorescent protein (RFP)-green fluorescent protein (GFP)-LC3 fluorescence staining and Western blot analyses.

Results: CQ/HCQ halted proliferation and adipogenesis in GO-OFs in a concentration-dependent manner through blockage of autophagy, phenotypes that were not detected in non-GO-OFs. The inhibitory effect of CQ/HCQ on hyaluronan secretion of GO-OFs was also concentration dependent, mediated by downregulation of hyaluronan synthase 2 rather than hyaluronidases. Moreover, CQ (10 μM) induced GO-OF apoptosis without aggravating oxidative stress.

Conclusions: The antimalarials CQ/HCQ affect proliferation, adipogenesis, and hyaluronan generation in GO-OFs by inhibiting autophagy, providing evidence that they can be used to treat GO as autophagy inhibitors.
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http://dx.doi.org/10.1210/clinem/dgaa161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183395PMC
June 2020
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