A long-term prognosis study of human USP8-mutated ACTH-secreting pituitary neuroendocrine tumours.

OBJECTIVE: Somatic variants in the ubiquitin-specific protease 8 (USP8) gene are the most common genetic cause of Cushing disease. We aimed to explore the relationship between clinical outcomes and USP8 status in a single centre. DESIGN, PATIENTS AND MEASUREMENTS: We investigated the USP8 status in 48 patients with pituitary corticotroph tumours. A median of 62 months of follow-up was conducted after surgery from November 2013 to January 2015. The clinical, biochemical and imaging features were collected and analysed. RESULTS: Seven USP8 variants (p.Ser718Pro, p.Ser719del, p.Pro720Arg, p.Pro720Gln, p.Ser718del, p.Ser718Phe, p.Lys713Arg) were identified in 24 patients (50%). USP8 variants showed a female predominance (100% vs. 75% in wild type [WT], p = .022). Patients with p.Ser719del showed an older age at surgery compared to patients with the p.Pro720Arg variant (47- vs. 24-year-olds, p = .033). Patients with p.Pro720Arg showed a higher rate of macroadenoma compared to patients harbouring the p.Ser718Pro variant (60% vs. 0%, p = .037). No significant differences were observed in serum and urinary cortisol and adrenocorticotropin hormone (ACTH) levels. Immediate surgical remission (79% vs. 75%) and long-term hormone remission (79% vs. 67%) were not significantly different between the two groups. The recurrence rate was 21% (4/19) in patients harbouring USP8 variants and 13% (2/16) in WT patients. Recurrence-free survival presented a tendency to be shorter in USP8-mutated individuals (76.7 vs. 109.2 months, p = .068). CONCLUSIONS: Somatic USP8 variants accounted for 50% of the genetic causes in this cohort with a significant female frequency. A long-term follow-up revealed a tendency toward shorter recurrence-free survival in USP8-mutant patients.

Brachytherapy in craniopharyngiomas: a systematic review and meta-analysis of long-term follow-up.

OBJECTIVE: Brachytherapy has been indicated as an alternative option for treating cystic craniopharyngiomas (CPs). The potential benefits of brachytherapy for CPs have not yet been clarified. The purpose of this work was to conduct a meta-analysis to analyze the long-term efficacy and adverse reactions profile of brachytherapy for CPs. MATERIALS AND METHODS: The relevant databases were searched to collect the clinical trials on brachytherapy in patients with CPs. Included studies were limited to publications in full manuscript form with at least 5-year median follow-up, and adequate reporting of treatment outcomes and adverse reactions data. Stata 12.0 was used for data analysis. RESULTS: According to the inclusion and exclusion criteria, a total of 6 clinical trials involving 266 patients with CPs were included in this meta-analysis. The minimum average follow-up was 5 years. The results of the meta-analysis showed that 1-year, 2-3 years and 5 years progression free survival rates (PFS) are 75% (95%CI: 66-84%), 62% (95%CI: 52-72%) and 57% (95%CI: 22-92%), respectively. At the last follow-up, less than 16% of patients with visual outcomes worser than baseline in all included studies. While, for endocrine outcomes, less than 32% of patients worser than baseline level. CONCLUSION: In general, based on the above results, brachytherapy should be considered as a good choice for the treatment of CP.

Development and evaluation of machine learning models for predicting large-for-gestational-age newborns in women exposed to radiation prior to pregnancy.

INTRODUCTION: The correlation between radiation exposure before pregnancy and abnormal birth weight has been previously proven. However, for large-for-gestational-age (LGA) babies in women exposed to radiation before becoming pregnant, there is no prediction model yet. MATERIAL AND METHODS: The data were collected from the National Free Preconception Health Examination Project in China. A sum of 455 neonates (42 SGA births and 423 non-LGA births) were included. A training set (n = 319) and a test set (n = 136) were created from the dataset at random. To develop prediction models for LGA neonates, conventional logistic regression (LR) method and six machine learning methods were used in this study. Recursive feature elimination approach was performed by choosing 10 features which made a big contribution to the prediction models. And the Shapley Additive Explanation model was applied to interpret the most important characteristics that affected forecast outputs. RESULTS: The random forest (RF) model had the highest average area under the receiver-operating-characteristic curve (AUC) for predicting LGA in the test set (0.843, 95% confidence interval [CI]: 0.714-0.974). Except for the logistic regression model (AUC: 0.603, 95%CI: 0.440-0.767), other models' AUCs displayed well. Thereinto, the RF algorithm's final prediction model using 10 characteristics achieved an average AUC of 0.821 (95% CI: 0.693-0.949). CONCLUSION: The prediction model based on machine learning might be a promising tool for the prenatal prediction of LGA births in women with radiation exposure before pregnancy.

Novel Magnetic-Bead-Assisted Sequential Extraction Method for Liquid Chromatography-Mass Spectrometry (MS)/MS of Components with Diverse Properties: Gastrin Determination as a Case Study.

Sample preparation is the rate-limiting step in liquid chromatography-mass spectrometry (LC-MS)/MS-based clinical analysis when target analytes possess significantly different properties. Repeated solid-phase extraction (SPE) processes are typically required, resulting in low throughput and excessive consumption of labor, materials, and samples. In this study, we developed and validated a feasible and productive method to enrich target analytes with different properties during a single operation, while sufficiently removing matrix interferences to meet LC-MS/MS requirements. Gastrin determination was selected as the subject of this study. An automated magnetic-bead-assisted sequential extraction (MBASE) workflow was developed to simultaneously isolate nonsulfated gastrin-17 (G17ns), sulfated gastrin-17 (G17s), nonsulfated gastrin-34 (G34ns), and sulfated gastrin-34 (G34s) from human serum. It performs two different ion-exchange-based magnetic-bead extraction steps on one sample aliquot to produce one combined extract for LC-MS/MS analysis. When compared with the traditional SPE process, the MBASE workflow saves over 75% time and labor expenses as well as over 90% material cost, while providing even higher extraction efficiency. The MBASE LC-MS/MS method was validated as accurate and robust. Clinical sample test results demonstrated that the conventional chemiluminescence immunoassay method significantly under-estimated total gastrins in human serum, and the MBASE LC-MS/MS method could serve as an ideal tool to provide a comprehensive and accurate gastrin profile.

Mesoporous Nickel Sulfide Microsphere Encapsulated in Nitrogen, Sulfur Dual-Doped Carbon with Large Subsurface Region for Enhanced Sodium Storage.

Nickel sulfides are promising anode candidates in sodium ion batteries (SIBs) due to high capacity and abundant reserves. However, their applications are restricted by poor cycling stability and slow reaction kinetics. Thus, mesoporous nickel sulfide microsphere encapsulated in nitrogen, sulfur dual-doped carbon (MNS@NSC) is prepared. The packaged structure and carbon matrix restrain the volume variation together, the N, S dual-doping improves the electronic conductivity and offers extra active sites for sodium storage. Ex-situ X-ray diffraction  appeals copper collector adsorbs polysulfide to inhibit the polysulfide accumulation and enhance conductivity. Moreover, the large subsurface attributed to C-S-S-C bonding further boosts pseudocapacitive capacity, conducive to charge transfer. As a result, MNS@NSC delivers a high reversible capacity of 640.2 mAh g-1 after 100 cycles at 0.1 A g-1 , an excellent rate capability (569.8 mAh g-1 at 5 A g-1 ), and a remained capacity of 513.8 mAh g-1 after undergoing 10000 circulations at 10 A g-1 . The MNS@NSC|| Na3 V2 (PO4 )3 full cell shows a cycling performance of specific capacity of 230.8 mAh g-1 after 100 cycles at 1 A g-1 . This work puts forward a valid strategy of combing structural design and heteroatom doping to synthesize high-performance nickel sulfide materials in SIBs.

Characteristics and response cutoff of octreotide suppression test in thyrotrophin (TSH)-secreting pituitary adenomas.

CONTEXT: Somatostatin analogs are recommended for preoperative therapy in thyrotrophin secreting pituitary adenomas (TSHomas). Octreotide suppression test (OST) was designed to differentiate TSHomas with resistance to thyroid hormones, while its ability to test the sensitivity of SSA has not been fully studied. OBJECTIVE: To test the sensitivity of SSA in TSHomas with OST. PATIENTS: We collected 48 pathologically confirmed TSHoma patients with complete 72 h' data of OST into analysis. INTERVENTION: Octreotide suppression test. MAIN OUTCOME: Sensitivity timepoint and cutoff of OST. RESULTS: During the entire OST, the TSH descended maximally 89.07% (73.85%, 96.77%), while the FT3 and FT4 declined slowly [43.40% (37.80%, 54.44%) and 26.59% (19.01%, 33.13%), respectively]. The 24th hour was the timepoint wherein the stability occurs for TSH, and the 48th hour for FT3 and FT4 during OST. In the patients who received both short- and long-acting somatostatin analogs (SSA), the 24-h timepoint was the most predictive timepoint for the percentage of TSH decline (Spearman's rank correlation analysis, r = .571, p < .001), while the 72-h timepoint was optimal for predicting the magnitude of TSH decline (Spearman's rank correlation analysis, r = .438, p = .005). In the 24th timepoint, a positive correlation was also observed between TSH suppression rate and the percentage decrease and absolute value decrease of FT3 and FT4. Furthermore, in patients treated with long-acting SSA, the 72-h timepoint was optimal for predicting both the percentage (Spearman's rank correlation analysis, r = .587, p = .01) and magnitude (Spearman's rank correlation analysis, r = .474, p = .047) of TSH decline. The 24th hour was the optimal timepoint with 44.54% (50% of median value of TSH in 72-hOST) decrease of TSH being the observing cutoff. The adverse effect of OST was predominantly occurred in the gastrointestinal system and no severe event occurred during OST. Paradoxical response could occur in OST and it did not influence the effect of SSA as long as sensitivity was confirmed. A high level of hormonal control was achieved in the SSA-sensitive patients. CONCLUSION: OST can be used as an efficient tool to guide the adequate use of SSA.

The clinical and metabolic characteristics of children and adolescents with hypothalamic dysfunction: A single-centre study from China.

OBJECTIVE: Hypothalamic dysfunction is characterized by complex aetiologies, multiple forms of onset and various clinical symptoms. This study aims to explore the clinical and metabolic characteristics of hypothalamic dysfunction in Chinese children and adolescents. DESIGN: This study is a single-centre, retrospective study that covers patients from 1989 to 2019. PATIENTS: We included 40 children and adolescents with hypothalamic dysfunction from our medical centre in Beijing, China. RESULTS: Intracranial tumour (37.5%) was the most common aetiology of children and adolescents with hypothalamic dysfunction, especially germ cell tumours, hypopituitarism (82.5%), weight gain (72.5%) and central diabetes insipidus (70.0%) were the most common symptoms in these patients. Furthermore, serum alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, uric acid, total cholesterol, triglycerides and low-density lipoprotein cholesterol was significantly higher in hypothalamic dysfunction patients than sex- and age-matched controls and sex, age and body mass index (BMI)-matched controls (all p < 0.05). However, albumin and high-density lipoprotein cholesterol were lower (p< 0.05). Moreover, 95% (38/40) of the patients had metabolic diseases. In addition, the incidence of dyslipidaemia and hyperuricemia in children and adolescents with hypothalamic dysfunction was significantly higher than both sex- and age-matched controls and sex-, age- and BMI-matched controls (both p < 0.05) as well. CONCLUSIONS: Intracranial tumour was the most common aetiology in children and adolescents with hypothalamic dysfunction. In addition, these patients presented a worse metabolic profile on average than healthy patients.

Intermolecular Triazene Alkene Cycloaddition via Lewis Base Catalysis: Access to Diverse Trifluoromethylated Pyrazolines.

A novel approach to chemoselective synthesis of biologically important CF3 -subsituted pyrazolines was developed via a Lewis base catalyzed intermolecular triazene cycloaddition reaction of an array of terminal/internal alkenes with CF3 CHN2 . This strategy features a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene, high yields (up to 95 %), wide substrate scope and excellent functional group tolerance (54 examples). Importantly, we preformed scaffold diversification of a panel of known pharmaceuticals, natural products, and bioactive heterocycles to generate the corresponding pyrazoline derivatives with potential broad bioactivities for further development.

Bone Microarchitecture and Volumetric Mineral Density Assessed by HR-pQCT in Patients with 21- and 17α-Hydroxylase Deficiency.

Due to disturbances in hormones and long-term glucocorticoid replacement therapy (GRT), congenital adrenocortical hyperplasia (CAH) patients are at risk of impaired bone structure and metabolism. This cross-sectional, case-control study aims to investigate for the first time bone microarchitecture features in 21-hydroxylase deficiency (21OHD; N = 38) and 17α-hydroxylase deficiency (17OHD; N = 16) patients using high-resolution peripheral quantitative computed tomography (HR-pQCT) by matching the same sex and similar age [21OHD vs. control: 29.5 (24.0-34.3) vs. 29.6 (25.9-35.2) years; 17OHD vs. controls: 29.0 (21.5-35.0) vs. 29.7 (24.6-35.3) years] with healthy controls (1:3). All patients underwent HR-pQCT scans of the nondominant radius and tibia, and had received GRT. Compared with corresponding controls, 17OHD cases had higher height (P < 0.001), weight (P = 0.013) and similar body mass index (BMI), while 21OHD had lower height (P < 0.001), similar weight and higher BMI (P < 0.001). 17OHD and 21OHD patients demonstrated various significant bone differences in most HR-pQCT indices, suggesting abnormalities in bone microarchitectures from healthy people. Further correlation analyses revealed that some characteristics, such as height and hormones, may contribute to the bone differences in HR-pQCT indices between two diseases. However, treatment dosage and time were not correlated, indicating that the current glucocorticoid doses may be within safety limits for bone impairment. Overall, our study for the first time revealed changes of bone microarchitecture in CAH patients and their potential relations with clinical characteristics. Further longitudinal researches are required to confirm these findings.

Three-Dimensional Fast Spin Echo Pituitary MRI in Treatment-Naïve Cushing's Disease: Reduced Impact of Reader Experience and Increased Diagnostic Accuracy.

BACKGROUND: In patients with Cushing's disease, the preoperative identification of pituitary adenomas is crucial to treatment. However, increasing diagnostic accuracy remains an unresolved issue. PURPOSE: To evaluate the diagnostic accuracy and the impact of readers' experience regarding high-resolution contrast-enhanced magnetic resonance imaging (hrMRI) for identifying pituitary adenomas in comparison with conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI). STUDY TYPE: Retrospective. POPULATION: Sixty-five patients (median age, 39 years; interquartile range [IQR], 28-53 years; 60% females) with treatment-naïve Cushing's disease. FIELD STRENGTH/SEQUENCE: 3-T, seven fast spin echo sequences. ASSESSMENT: The diagnostic accuracies of identifying pituitary adenomas on cMRI, dMRI, combined cMRI and dMRI (cdMRI), and hrMRI were independently evaluated by six readers with three experience levels (high: >20 years, modest: 10-20 years, low: <10 years; two readers for each experience level). Readers were asked to localize the lesion, and measure its diameter on the sequence where identified. The reference standard was postoperative histopathology. The impact of readers' experience and interobserver agreement were assessed. Image quality was assessed using a 5-point Likert scale, including overall image quality, sharpness, and structural conspicuity. STATISTICAL TESTS: McNemar's test, Cochran's test, Wilcoxon signed-rank test, Mann-Whitney U test, and κ statistics for interobserver agreement. A P-value <0.05 was considered statistically significant. RESULTS: For identifying pituitary adenomas (median diameter, 5 mm; IQR, 4-5 mm), hrMRI had significantly higher sensitivity (87.7%-93.8%) than cMRI, dMRI, and cdMRI (52.3%-75.4%) for readers with different experience levels. The interobserver agreement was moderate (κ = 0.461-0.523). The sensitivity for hrMRI was comparable between readers with different experience levels (P = 0.371). All image quality scores on hrMRI were significantly higher than cMRI and dMRI (5.0 vs. 4.0). DATA CONCLUSION: For identifying pituitary adenomas in patients with treatment-naïve Cushing's disease, hrMRI may show high diagnostic accuracy and seems not to be affected by readers' experience. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

A single-center experience on endoscopic ultrasonography-guided ethanol ablation of insulinomas.

BACKGROUND/OBJECTIVES: As the most frequent functional pancreatic neuroendocrine tumor, insulinomas may cause a plethora of symptoms and severe impairment in the living of patients by endogenous hyperinsulinemia and subsequent hypoglycemia. Surgery has been regarded as the first choice although a high risk of complications. Ethanol ablation is a promising non-surgical option that could achieve tumor shrinking in a short-term period. But the impact of symptom control and the long-term efficacy lack sufficient and good-quality evidence. METHODS: A total number of 14 endoscopic ultrasonography-guided ethanol ablations were performed in 9 patients between September 2016 and September 2018 in Peking Union Medical College Hospital. The data were collected and prospectively analyzed. RESULTS: The follow-up duration ranged from 21 to 1567 days in 9 patients, with a median of 994 days. 4 patients were free from relapse during a median follow-up of 1108 days (range: 994-1567 days). In 5 patients who suffered relapses, the median duration with symptom relief after the first ablation was 128 days (range: 13-393 days). If only repeated ablation was taken into consideration, the median duration with symptom relief was 26 days (range: 1-516 days). No complications happened during the procedures. The severe complication rate after the first ablation was 0.0% (0/9), compared to 7.14% (1/14) if each procedure was counted separately. The only severe complication documented was acute pancreatitis which was completely relieved after symptomatic treatment. CONCLUSIONS: For patients who are not suitable for surgical resections, endoscopic ultrasonography-guided ethanol ablation of insulinomas could be an effective and safe alternative to relieve symptoms of hypoglycemia.

Diagnosis and Management of Idiopathic Hypothalamic Dysfunction: A Case Series and Systematic Review.

INTRODUCTION: Idiopathic hypothalamic dysfunction (IHD) is a rare syndrome with heterogeneous clinical symptoms. This study aimed to systematically review the clinical features and potential treatment of IHD based on our case series and literature. METHODS: We analysed six recently diagnosed cases of IHD in Peking Union Medical College Hospital and conducted a systematic review of IHD case studies published before August 25, 2021, using the PubMed/Medline database. All 12 articles that met the definition of IHD and provided individual clinical data were reviewed. RESULTS: Of the 19 cases reviewed (13 from the literature and 6 from our centre), the median age at onset was 6 years. Obesity/weight gain (n = 14, 73.7%) and electrolyte abnormalities (n = 14, 73.7%) were the most common hypothalamic physiological dysfunction, followed by autonomic dysregulation (n = 13, 68.4%) and adipsia (n = 13, 68.4%). The most common initial symptom of young patients was obesity/weight gain, whereas the initial symptoms of the three adult patients were hypothalamic amenorrhoea, delayed sexual development, and polydipsia. 11 (57.9%) patients had obesity, and three of our patients were diagnosed with metabolic syndrome in late adolescence or early adulthood. Three of our cases diagnosed with growth hormone deficiency received growth hormone therapy, which exerted positive effects on growth promotion and weight stabilization. CONCLUSION: Although obesity/weight gain was the most common symptom of IHD, uncommon initial symptoms such as electrolyte abnormalities and sexual disorders also require attention, especially in patients with late childhood- or adult-onset IHD. Consistent monitoring of metabolic profiles is recommended. Positive effects of growth hormone replacement therapy on growth and weight were observed, but more extensive cohort studies are required to confirm its efficacy and safety.

Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs.

INTRODUCTION: Somatotroph pituitary neuroendocrine tumours (PitNETs) are characterized by complex and variable biological behaviours with unpredictable patterns of growth and invasiveness. The molecular mechanisms and reliable predictors of biological markers of invasiveness remain unknown. METHODS: Seventy-two acromegaly patients were consecutively enrolled. Data-independent acquisition-based proteomics and ingenuity pathway analysis were conducted between invasive and noninvasive somatotroph PitNETs. The expression of selected biomarkers was verified in PitNET tissue, and its correlation with various clinical indicators and outcomes of these tumours was assessed. The invasive phenotypes of GH3 cells were validated in vitro. RESULTS: Patients with invasive somatotroph PitNETs were significantly younger at onset and diagnosis, with significantly higher secretion and faster growth and a lower long-term biochemical response rate than patients with noninvasive somatotroph PitNETs. Proteomic data were evaluated in a consecutively collected sample of 19 (10 invasive and 9 noninvasive somatotroph PitNETs) tumours and indicated a distinct proteomic pattern. The enriched and important pathways included IL-4, PDGF, PTEN, VEGF, PI3K/AKT, FAK, and other pathways that were significantly associated with tumour proliferation, migration, and invasion. High cathepsin Z (CTSZ) expression was found in invasive somatotroph PitNETs and significantly positively correlated with parameters of tumour invasion and growth. In Ctsz-overexpressing GH3 cells, cell proliferation, invasion, and migration were consequently increased. CONCLUSION: It is more difficult for patients with invasive somatotroph PitNETs to achieve remission than those with noninvasive somatotroph PitNETs, and proteomic data analysis has revealed the high expression of CTSZ as a contributing factor to invasive transformation and poor prognosis in somatotroph PitNETs for the first time.

High-resolution contrast-enhanced MRI with three-dimensional fast spin echo improved the diagnostic performance for identifying pituitary microadenomas in Cushing's syndrome.

OBJECTIVES: To assess the diagnostic performance of high-resolution contrast-enhanced MRI (hrMRI) with three-dimensional (3D) fast spin echo (FSE) sequence by comparison with conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI) with 2D FSE sequence for identifying pituitary microadenomas. METHODS: This single-institutional retrospective study included 69 consecutive patients with Cushing's syndrome who underwent preoperative pituitary MRI, including cMRI, dMRI, and hrMRI, between January 2016 to December 2020. Reference standards were established by using all available imaging, clinical, surgical, and pathological resources. The diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas was independently evaluated by two experienced neuroradiologists. The area under the receiver operating characteristics curves (AUCs) were compared between protocols for each reader by using the DeLong test to assess the diagnostic performance for identifying pituitary microadenomas. The inter-observer agreement was assessed by using the κ analysis. RESULTS: The diagnostic performance of hrMRI (AUC, 0.95-0.97) was higher than cMRI (AUC, 0.74-0.75; p ≤ .002) and dMRI (AUC, 0.59-0.68; p ≤ .001) for identifying pituitary microadenomas. The sensitivity and specificity of hrMRI were 90-93% and 100%, respectively. There were 78% (18/23) to 82% (14/17) of the patients, who were misdiagnosed on cMRI and dMRI and correctly diagnosed on hrMRI. The inter-observer agreement for identifying pituitary microadenomas was moderate on cMRI (κ = 0.50), moderate on dMRI (κ = 0.57), and almost perfect on hrMRI (κ = 0.91), respectively. CONCLUSIONS: The hrMRI showed higher diagnostic performance than cMRI and dMRI for identifying pituitary microadenomas in patients with Cushing's syndrome. KEY POINTS: • The diagnostic performance of hrMRI was higher than cMRI and dMRI for identifying pituitary microadenomas in Cushing's syndrome. • About 80% of patients, who were misdiagnosed on cMRI and dMRI, were correctly diagnosed on hrMRI. • The inter-observer agreement for identifying pituitary microadenomas was almost perfect on hrMRI.

Long Noncoding RNA TPRG1-AS1 Suppresses Migration of Vascular Smooth Muscle Cells and Attenuates Atherogenesis via Interacting With MYH9 Protein.

BACKGROUND: Migration of human aortic smooth muscle cells (HASMCs) contributes to the pathogenesis of atherosclerosis. This study aims to functionally characterize long noncoding RNA TPRG1-AS1 (tumor protein p63 regulated 1, antisense 1) in HASMCs and reveal the underlying mechanism of TPRG1-AS1 in HASMCs migration, neointima formation, and subsequent atherosclerosis. METHODS: The expression of TPRG1-AS1 in atherosclerotic plaques was verified a series of in silico analysis and quantitative real-time polymerase chain reaction analysis. Northern blot, rapid amplification of cDNA ends and Sanger sequencing were used to determine its full length. In vitro transcription-translation assay was used to investigate the protein-coding capacity of TPRG1-AS1. RNA fluorescent in situ hybridization was used to confirm its subcellular localization. Loss- and gain-of-function studies were used to investigate the function of TPRG1-AS1. Furthermore, the effect of TPRG1-AS1 on the pathological response was evaluated in carotid balloon injury model, wire injury model, and atherosclerosis model, respectively. RESULTS: TPRG1-AS1 was significantly increased in atherosclerotic plaques. TPRG1-AS1 did not encode any proteins and its full length was 1279nt, which was bona fide a long noncoding RNA. TPRG1-AS1 was mainly localized in cytoplasmic and perinuclear regions in HASMCs. TPRG1-AS1 directly interacted with MYH9 (myosin heavy chain 9) protein in HASMCs, promoted MYH9 protein degradation through the proteasome pathway, hindered F-actin stress fiber formation, and finally inhibited HASMCs migration. Vascular smooth muscle cell-specific transgenic overexpression of TPRG1-AS1 significantly reduced neointima formation, and attenuated atherosclerosis in apolipoprotein E knockout (Apoe-/-) mice. CONCLUSIONS: This study demonstrated that TPRG1-AS1 inhibited HASMCs migration through interacting with MYH9 protein and consequently suppressed neointima formation and atherosclerosis.

Safety of pregnancy in acromegaly patients and maternal and infant outcomes after pregnancy: single-center experience from China and review of the literature.

BACKGROUND: Pregnancy in acromegaly is uncommon and still in debate for fear of tumor progression or potential threat to both mother and fetus's health. Besides, the data for pregnancy complications in uncontrolled acromegaly is limited. Thus, the objective of this study was to summarize pregnancy safety and disease courses after pregnancy in acromegalic patients and review their clinical characteristics based on disease activity in the literature. METHODS: An evaluation of eight acromegalic women from Peking Union Medical College Hospital (PUMCH) with 11 pregnancies was conducted. We also summarized a literature review of 82 disease-active pregnancies and 63 disease-controlled pregnancies with acromegaly. A second analysis was conducted to compare pregnancy courses and outcomes in different disease activities. RESULTS: Before pregnancy, all patients had macroadenomas and underwent pituitary surgery. Pregnancy occurred at a median of 6 years (4-10) after the diagnosis of acromegaly. Assisted reproductive therapy was needed in 42.9% of participants. No cases had a premature birth or congenital malformations. Biochemical control was achieved in 50% of females before pregnancy and 75% at the last follow-up after delivery. Data analysis showed no differences in the prevalence of gestational diabetes mellitus (GDM) or pregnancy-induced hypertension (PIH) between acromegaly-active or acromegaly-controlled groups. The GDM prevalence in patients diagnosed during pregnancy (33.3%) was higher than that in patients diagnosed before pregnancy (4.8%) (p = 0.001). CONCLUSION: Pregnancy without biochemical control in acromegaly and receiving medical treatment during pregnancy are not rare and generally safe for the fetus. There could be a higher prevalence of PIH in acromegalic pregnancies. The treatment of acromegaly and related complications can be managed with regular follow-up after pregnancy.

Clinical characteristics and therapeutic outcomes of acromegalic patients with giant growth hormone-secreting pituitary adenomas: a single-center study of 67 cases.

PURPOSE: Acromegalic patients with giant growth hormone-secreting pituitary adenomas (GHPAs) (≥ 40 mm) are relatively rare, and their clinical characteristics and treatment outcome data are limited. This study aims to analyze the clinical practice experience of giant GHPAs. METHODS: Sixty-seven acromegalic patients with giant GHPAs and 67 patients with macro GHPAs (10-39 mm), matched for age and gender from the same hospital during the same period, were retrospectively recruited. The clinical characteristics, treatment, and outcomes were analyzed. RESULTS: Enlargement of the extremities and facial features were the most common symptoms in most patients (92.5%). Compared with the macroadenoma group, more frequent visual impairment (86.6% vs. 25.4%, P < 0.001) and gonadal axis dysfunction (49.3% vs. 34.3%, P = 0.008), higher preoperative fasting GH, nadir GH after OGTT and IGF-1 levels, and a higher proportion of extrasellar tumor invasion were seen in the giant adenoma group. As the adenoma size increases, the total resection rate decreases, and postoperative complications and multimodal treatment strategies increase significantly. Fasting and nadir GH levels remained higher at 1 week postoperatively, and there were more surgical complications and cases of anterior hypopituitarism in the giant group. After a median follow-up of 36 months, 12 patients (36.4%) in the giant GHPA group and 17 (36.2%) in the macro GHPA group achieved biochemical remission. Other factors such as age of onset, age of diagnosis, delayed diagnosis time, metabolic complications, p53 positive rate, and Ki-67 index showed no significant difference between the two groups. CONCLUSIONS: With aggressive multimodal therapy, the biochemical remission rate of acromegalic patients with giant GHPAs is comparable to that of patients with macro adenoma. However, postoperative complications and hypopituitarism need to be closely monitored.

Should We Use Prolactin Adjustment in Bilateral Inferior Petrosal Sinus Sampling to Diagnose Cushing Disease? A Joint Meta-Analysis of Head-to-Head Diagnostic Tests Accuracy Studies.

OBJECTIVE: Previous studies have shown inconsistent results regarding the usefulness of prolactin adjustment in bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (CS). This meta-analysis compared the diagnostic accuracy of prolactin adjustment versus no adjustment in BIPSS. METHODS: This study searched the PubMed, Embase, Web of Science, Cochrane library, and WanFang databases for published data as of March 2022 on the use of prolactin adjustment in BIPSS to differentially diagnose ACTH-dependent CS. A Bayesian joint bivariate model was used in the head-to-head comparison of the diagnostic accuracy. RESULTS: This meta-analysis included a total of 10 studies with 300 patients. The combined sensitivity and specificity for BIPSS without prolactin adjustment were 94.47% (95% CI, 88.67%-98.44%) and 91.14% (95% CI, 57.17%-99.80%), respectively. The combined sensitivity and specificity after prolactin adjustment were 99.97% (95% CI, 99.03%-100.00%) and 80.69% (95% CI, 50.27%-97.82%), respectively. After the prolactin adjustment, the sensitivity of BIPSS to diagnose Cushing disease was improved with a statistically significant difference (difference in sensitivity, 5.39%; 95% CI, 1.37%-11.26%), whereas the decrease in specificity was without a statistically significant difference (difference in specificity, -9.20%; 95% CI, -42.02% to 26.61%). CONCLUSION: This meta-analysis indicated that prolactin adjustment in BIPSS might help to recognize Cushing disease among patient with ACTH-dependent CS. However, prolactin adjustment may not help identify ectopic ACTH syndrome in BIPSS.

Safflower yellow and its main component hydroxysafflor yellow A alleviate hyperleptinemia in diet-induced obesity mice through a dual inhibition of the GIP-GIPR signaling axis.

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity-promoting factor. In this study, we systematically investigated the anti-obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet-induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3-L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high-fat-diet-fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet-induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP-GIPR axis.

Effects of online continuing medical education on perspectives of shared decision-making among Chinese endocrinologists.

BACKGROUND: Shared decision-making (SDM) may influence the clinical outcomes of patients with endocrine disorders. There are few studies describing perspectives towards SDM among endocrinologists in China. METHODS: In the first stage, we conducted a national survey using an online questionnaire about SDM among endocrinologists in China. The national survey focused on attitude and propensity, potential barriers, and the effectiveness of SDM implementation strategies. In the second stage, survey participants were further recruited to participate in a prospective cohort study in the online continuing medical education (CME) program of Peking Union Medical College Hospital in Beijing. The Shared Decision-Making Questionnaire (SDM-Q-Doc) was employed to assess the effects of online CME on physicians' perspectives during the process of SDM, which was conducted before and after the CME course was provided. RESULTS: In the national survey, 280 endocrinologists (75.7% female, mean age 38.0 ± 4.5 years, 62.5% with a duration of practice of more than ten years) completed the questionnaire. Participants had a generally positive attitude towards SDM in clinical practice. The main perceived barriers included time consumption, information inequality between doctors and patients, and a lack of technical support and training for SDM. The main uncertainties of implementation steps included inviting patients to participate in SDM (16.3%), assisting in decision-making (15.3%), facilitating deliberation and decision-making (13.7%), and providing information on benefits and risks (12.6%). Of the physicians who participated in the national survey, 84 registered for the eight-day online CME course. The SDM-Q-Doc score increased from 87.3 ± 18.2 at baseline to 93.0 ± 9.3 at the end of the 8-day online CME training (p = 0.003, paired t test). The participants' age, sex, education level, practice duration, the annual number of patients with rare endocrine diseases, and the annual number of patients requiring MDT or CME were not significantly related to increased SDM-Q-Doc scores after online CME (all p > 0.05). CONCLUSIONS: Chinese endocrinologists had a generally positive attitude towards SDM in clinical practice. There were also several uncertainties in the implementation steps of SDM. Regardless of a physician's educational background or prior professional experience, CME may help to improve their perspectives regarding SDM.