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  • The Endocrine Society  (49)
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  • Medicine  (49)
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  • 1
    Online Resource
    Online Resource
    Transcription Factor ASCL1 Acts as a Novel Potential Therapeutic Target for the Treatment of the Cushing’s Disease
    The Endocrine Society ; 2022
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 107, No. 8 ( 2022-07-14), p. 2296-2306
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 107, No. 8 ( 2022-07-14), p. 2296-2306
    Abstract: The pathogenesis of Cushing’s disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. In this multiomics study, we combined RNA sequencing (RNA-seq) with Sanger sequencing to depict transcriptional dysregulation under different gene mutation backgrounds. Furthermore, we evaluated the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a novel therapeutic target for treatment of CD and its possible downstream pathway. Methods RNA-seq was adopted to investigate the gene expression profile of CD, and Sanger sequencing was adopted to detect gene mutations. Bioinformatics analysis was used to depict transcriptional dysregulation under different gene mutation backgrounds. The function of ASCL1 in hormone secretion, cell proliferation, and apoptosis were studied in vitro. The effectiveness of an ASCL1 inhibitor was evaluated in primary CD cells, and the clinical relevance of ASCL1 was examined in 68 patients with CD. RNA-seq in AtT-20 cells on Ascl1 knockdown combined with published chromatin immunoprecipitation sequencing data and dual luciferase assays were used to explore downstream pathways. Results ASCL1 was exclusively overexpressed in USP8-mutant and wild-type tumors. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in AtT-20 cells. An ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. Conclusion Our findings help to clarify the pathogenesis of CD and suggest that ASCL1 is a potential therapeutic target the treatment of CD. Summary The pathogenesis of Cushing’s disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. Moreover, few effective medical therapies are currently available for the treatment of CD. Here, using a multiomics approach, we first report the aberrant overexpression of the transcription factor gene ASCL1 in USP8-mutant and wild-type tumors of CD. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in mouse AtT-20 cells. Notably, an ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. Importantly, ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. Thus, our findings improve understanding of CD pathogenesis and suggest that ASCL1 is a potential therapeutic target the treatment of CD.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgac280
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    Clinical Profiles and Genetic Spectra of 814 Chinese Children With Short Stature
    The Endocrine Society ; 2022
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 107, No. 4 ( 2022-03-24), p. 972-985
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 107, No. 4 ( 2022-03-24), p. 972-985
    Abstract: Data and studies based on exome sequencing for the genetic evaluation of short stature are limited, and more large-scale studies are warranted. Some factors increase the likelihood of a monogenic cause of short stature, including skeletal dysplasia, severe short stature, and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown. Objective We aimed to explore the diagnostic efficiency of the associated risk factors and their exome sequences for screening. Methods We defined and applied factors that increased the likelihood of monogenic causes of short stature in diagnostic genetic tests based on next-generation sequencing (NGS) in 814 patients with short stature and at least 1 other factor. Results Pathogenic/likely pathogenic (P/LP) variants in genes, copy number variations, and chromosomal abnormalities were identified in 361 patients. We found P/LP variants among 111 genes, and RASopathies comprised the most important etiology. Short stature combined with other phenotypes significantly increased the likelihood of a monogenic cause, including skeletal dysplasia, facial dysmorphism, and intellectual disability, compared with simple severe short stature ( & lt;–3 SD scores). We report novel candidate pathogenic genes, KMT2C for unequivocal growth hormone insensitivity and GATA6 for SGA. Conclusion Our study identified the diagnostic characteristics of NGS in short stature with different risk factors. Our study provides novel insights into the current understanding of the etiology of short stature in patients with different phenotypes.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgab863
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
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  • 3
    Online Resource
    Online Resource
    Long-term Pegylated GH for Children With GH Deficiency: A Large, Prospective, Real-world Study
    The Endocrine Society ; 2023
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 108, No. 8 ( 2023-07-14), p. 2078-2086
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 108, No. 8 ( 2023-07-14), p. 2078-2086
    Abstract: The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited. Objective This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes. Design A prospective, observational, posttrial study (NCT03290235). Setting, participants and intervention Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to & lt;0.2 mg/kg/wk (low-dose) PEG-rhGH for 30 months. Main outcomes measures Height SD score (Ht SDS) at 12, 24, and 36 months. Results A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P & lt; 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P & lt; 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred. Conclusions PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgad039
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
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  • 4
    Online Resource
    Online Resource
    Effects of Genetic and Nongenetic Factors on Total and Bioavailable 25(OH)D Responses to Vitamin D Supplementation
    The Endocrine Society ; 2017
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 102, No. 1 ( 2017-01-01), p. 100-110
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 102, No. 1 ( 2017-01-01), p. 100-110
    Abstract: Little is known about how genetic and nongenetic factors modify responses of vitamin D supplementation in nonwhite populations. Objective: To investigate factors modifying 25-hydroxyvitamin D [25(OH)D] and bioavailable 25(OH)D [25(OH)DBio] responses after vitamin D3 supplementation. Design, Setting, Participants, and Intervention: In this 20-week, randomized, double-blinded, placebo-controlled trial, 448 Chinese with vitamin D deficiency received 2000 IU/d vitamin D3 or placebo. Main Outcome Measures: Serum 25(OH)D, vitamin D-binding protein (VDBP), parathyroid hormone (PTH) and calcium were measured, and 25(OH)DBio was calculated based on VDBP levels. Six common polymorphisms in vitamin D metabolism genes were genotyped. Results: Between-arm net changes were +30.6 ± 1.7 nmol/L for 25(OH)D, +2.7 ± 0.2 nmol/L for 25(OH)DBio, and −5.2 ± 1.2 pg/mL for PTH, corresponding to 70% [95% confidence interval (CI), 62.8% to 77.2%] net reversion rate for vitamin D deficiency at week 20 (P & lt; 0.001). Only 25(OH)DBio change was positively associated with calcium change (P & lt; 0.001). Genetic factors (GC-rs4588/GC-rs7041, VDR-rs2228570, and CYP2R1-rs10741657; P ≤ 0.04) showed stronger influences on 25(OH)D or 25(OH)DBio responses than nongenetic factors, including baseline value, body mass index, and sex. An inverse association of PTH-25(OH)D was demonstrated only at 25(OH)D of & lt;50.8 (95% CI, 43.6 to 59.0) nmol/L. Conclusions: Supplemented 2000 IU/d vitamin D3 raised 25(OH)D and 25(OH)DBio but was unable to correct deficiency in 25% of Chinese participants, which might be partially attributed to the effect of genetic modification. More studies are needed to elucidate appropriate vitamin D recommendations for Asians and the potential clinical implications of 25(OH)DBio.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2016-2930
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2017
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  • 5
    Online Resource
    Online Resource
    Identification of MicroRNAs in Human Follicular Fluid: Characterization of MicroRNAs That Govern Steroidogenesis in Vitro and Are Associated With Polycystic Ovary Syndrome in Vivo
    The Endocrine Society ; 2013
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 98, No. 7 ( 2013-07-01), p. 3068-3079
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 98, No. 7 ( 2013-07-01), p. 3068-3079
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2013-1715
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2013
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  • 6
    Online Resource
    Online Resource
    Characterization of novel PHEX variants in X-linked hypophosphatemic rickets and genotype-PHEX activity correlation
    The Endocrine Society ; 2024
    In:  The Journal of Clinical Endocrinology & Metabolism ( 2024-03-05)
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, ( 2024-03-05)
    Abstract: X-linked hypophosphatemia (XLHR) is the most common genetic form of hypophosphatemic rickets (HR), which is caused by phosphate regulating endopeptidase homolog X-linked (PHEX) gene mutation. At present, the genotype-phenotype relationship of XLHR and the pathogenic role of PHEX have not been fully understood. Methods In this study, we summarized clinical features in a new cohort of 49 HR patients and detected 16 novel PHEX and 5 novel non-PHEX variants. Subsequently, we studied the pathogenesis of new variants by protein expression, glycosylation analysis, subcellular localization and endopeptidase activity. Results The results showed that missense variants (Q189H and X750R) slightly reduced protein expression without obviously altering protein length and localization, whereas truncating variants significantly impaired the synthesis of PHEX and produced a shorter immature protein in cells. Interestingly, no evident correlation was observed between mutation types and clinical phenotypes. However, when we analyzed the relationship between PHEX activity and serum phosphorus level, we found that patients with low PHEX activity tended to have severe hypophosphatemia and high rickets severity score (RSS). Following this observation, we established two new knock-in XLHR mouse models with two novel Phex variants (c.T1349C and c.C426G, respectively) using CRISPR/Cas9 technology. Both mouse models demonstrated clinical manifestations of XLHR seen in patients and PhexC426G mice showed more severe phenotype than PhexT1349C mice, which further confirmed the rationality of genotype-PHEX enzymatic activity correlation analysis. Conclusion Therefore, our findings demonstrated that novel PHEX variants could disrupt protein function via affecting protein synthesis, post-translational modification, cellular trafficking and catalytic activity. Our study facilitates a better understanding of XLHR pathogenic mechanism and PHEX activity-phenotype correlation, which is of crucial importance for future diagnosis and treatment of XLHR.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgae120
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2024
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  • 7
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    Online Resource
    Change in Amniotic Fluid Levels of Multiple Anti-Angiogenic Proteins before Development of Preeclampsia and Intrauterine Growth Restriction
    The Endocrine Society ; 2010
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 3 ( 2010-03-01), p. 1431-1441
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 95, No. 3 ( 2010-03-01), p. 1431-1441
    Abstract: Context: The cause of preeclampsia remains unknown. Excessive antiangiogenic proteins have been proposed to play a pathogenic role in preeclampsia. Objective: Our objective was to determine the differences in soluble endoglin (sEndoglin), soluble fms-like tyrosine kinase receptor-1 (sFLT1), leptin, adiponectin, and endothelin 1 concentrations between normal and preeclampsia amniotic fluid (AF). Such results may help us understand the pathophysiology of preeclampsia. Methods: We performed a nested case-control study. Seventy-one women with preeclampsia were matched to 71 normotensive controls. The preeclamptic women were broken into two subgroups according to the association with fetal intrauterine growth restriction (IUGR). AF concentrations of sEndoglin, sFLT1, leptin, adiponectin, and endothelin 1 were measured by ELISA. Receiver-operating characteristics curve analysis was used to compare the discriminative values of these potential biomarkers. Functional network analysis was performed using MetaCore to reveal the common functions of the interacting proteins. Results: Increased AF concentrations of sFLT1, sEndoglin, endothelin 1, and leptin were found in women who later developed preeclampsia. sFLT1, sEndoglin, leptin, and adiponectin were significantly higher in the preeclampsia with IUGR than those without IUGR. Leptin has the largest area under the curve (0.753). Network analysis revealed that elevated amniotic proteins are involved in the inflammatory process of the human placenta. Conclusions: Significant elevation of leptin can be detected in AF 2 months earlier than the appearance of symptoms; thus, it may be used as a predictive marker for preeclampsia. The increase of these antiangiogenic proteins supports the roles of inflammation and oxidative stress in pathogenesis of preeclampsia.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2009-1954
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2010
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  • 8
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    Online Resource
    Genetic Risk, a Healthy Lifestyle, and Type 2 Diabetes: the Dongfeng-Tongji Cohort Study
    The Endocrine Society ; 2020
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 105, No. 4 ( 2020-04-01), p. 1242-1250
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 105, No. 4 ( 2020-04-01), p. 1242-1250
    Abstract: The objective of this study is to examine whether healthy lifestyle could reduce diabetes risk among individuals with different genetic profiles. Design A prospective cohort study with a median follow-up of 4.6 years from the Dongfeng-Tongji cohort was performed. Participants A total of 19 005 individuals without diabetes at baseline participated in the study. Main Variable Measure A healthy lifestyle was determined based on 6 factors: nonsmoker, nondrinker, healthy diet, body mass index of 18.5 to 23.9 kg/m2, waist circumference less than 85 cm for men and less than 80 cm for women, and higher level of physical activity. Associations of combined lifestyle factors and incident diabetes were estimated using Cox proportional hazard regression. A polygenic risk score of 88 single-nucleotide polymorphisms previously associated with diabetes was constructed to test for association with diabetes risk among 7344 individuals, using logistic regression. Results A total of 1555 incident diabetes were ascertained. Per SD increment of simple and weighted genetic risk score was associated with a 1.39- and 1.34-fold higher diabetes risk, respectively. Compared with poor lifestyle, intermediate and ideal lifestyle were reduced to a 23% and 46% risk of incident diabetes, respectively. Association of lifestyle with diabetes risk was independent of genetic risk. Even among individuals with high genetic risk, intermediate and ideal lifestyle were separately associated with a 29% and 49% lower risk of diabetes. Conclusion Genetic and combined lifestyle factors were independently associated with diabetes risk. A healthy lifestyle could lower diabetes risk across different genetic risk categories, emphasizing the benefit of entire populations adhering to a healthy lifestyle.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgz325
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
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  • 9
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    Online Resource
    Thyroid Function in Causal Relation to MRI Markers of Cerebral Small Vessel Disease: A Mendelian Randomization Analysis
    The Endocrine Society ; 2023
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 108, No. 9 ( 2023-08-18), p. 2290-2298
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 108, No. 9 ( 2023-08-18), p. 2290-2298
    Abstract: Observational studies have provided insufficient information on the association between thyroid function and the risk of cerebral small vessel disease (CSVD); moreover, the causality of this link is still unclear. Objective This study aims to investigate whether genetically predicted variation within thyroid function is causally associated with the risk of CSVD using 2-sample Mendelian randomization (MR) analysis. Methods In this 2-sample MR study with genome-wide association variants, we estimated the causal effects of genetically predicted thyrotropin (thyroid-stimulating hormone, TSH; n = 54 288), free thyroxine (FT4; n = 49 269), hypothyroidism (n = 51 823), and hyperthyroidism (n = 51 823) on 3 neuroimaging markers of CSVD, including white matter hyperintensity (WMH; n = 42 310), mean diffusivity (MD; n = 17 467), and fractional anisotropy (FA, n = 17 663). The primary analysis was conducted by the inverse variance–weighted MR method, followed by sensitivity analyses using MR-PRESSO, MR-Egger, weighted median, and weighted mode methods. Results Genetically increased TSH was associated with increased MD (β = .311, 95% CI 0.0763, 0.548, P = .01). Genetically increased FT4 was associated with increased FA (β = .540, 95% CI 0.222, 0.858, P & lt; .001). Sensitivity analyses using different MR methods showed similar directions but lower precision. No significant associations of hypothyroidism or hyperthyroidism with WMH, MD, or FA were found (all P & gt; .05). Conclusion This study indicated that genetically predicted increased TSH was associated with increased MD, as well as increased FT4 with increased FA, implying the causal effect of thyroid dysfunction on white matter microstructural injury. There were no significant causal relationships of hypothyroidism or hyperthyroidism with CSVD. Further investigations should verify these findings and clarify the underlying pathophysiological mechanisms.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgad114
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
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  • 10
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    Online Resource
    Current Pubertal Development in Chinese Children and the Impact of Overnutrition, Lifestyle, and Perinatal Factors
    The Endocrine Society ; 2023
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 108, No. 9 ( 2023-08-18), p. 2282-2289
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 108, No. 9 ( 2023-08-18), p. 2282-2289
    Abstract: Age of pubertal onset has been decreasing in many countries but there have been no data on pubertal development in Chinese children over the last decade. Objective The primary objective of the study was to evaluate the current status of sexual maturation in Chinese children and adolescents. Secondary objectives were to examine socioeconomic, lifestyle, and auxological associations with pubertal onset. Methods In this national, cross-sectional, community-based health survey, a multistage, stratified cluster random sampling method was used to select a nationally representative sample, consisting of 231 575 children and adolescents (123 232 boys and 108 343 girls) between 2017 and 2019. Growth parameters and pubertal staging were assessed by physical examination. Results Compared to 10 years previously, the median age of Tanner 2 breast development and menarche were similar at 9.65 years and 12.39 years respectively. However, male puberty occurred earlier with a median age of testicular volume ≥4 mL of 10.65 years. Pubertal onset did occur earlier at the extremes, with 3.3% of the girls with breast development at 6.5-6.99 years old, increasing to 5.8% by 7.5-7.99 years old. Early pubertal onset was also noted in boys, with a testicular volume ≥ 4 mL noted in 1.5% at 7.5-7.99 years, increasing to 3.5% at 8.5-8.99 years old. Obesity and overweight increased risk of developing earlier puberty relative to normal weight in both boys and girls. Conclusion Over the past decade, pubertal development is occurring earlier in Chinese children. While the cause is multifactorial, overweight and obesity are associated with earlier puberty onset. The currently used normative pubertal data of precocious puberty may not be applicable to diagnose precocious puberty.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgad102
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2026217-6
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