bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypercoagulability in ACTH-Dependent Cushing Syndrome
Authors: Singh Sumal Amit Kartar , Katznelson Laurence 
Published: May 2021

Abstract
Introduction: ACTH-dependent Cushing syndrome (CS) is associated with hypercoagulability; however, the incidence and timing of thrombosis during evaluation and management of CS is unclear.
Objective: To evaluate the incidence and timing of thrombotic events in patients with ACTH-dependent CS following diagnosis and management.
Methods: We performed a retrospective, longitudinal study of patients with ACTH-dependent CS seen at Stanford University Health Care from 1998 to 2020. Thrombotic events — deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral vascular accident (CVA), and myocardial infarction (MI) — were recorded between diagnosis and 12 months following therapeutic intervention.
Results: Of 108 patients with ACTH-dependent CS, 97 (89.8%) were women, and the mean age at diagnosis was 43.0 years (± 15.7 years). Sixty-eight (63%) patients had hypertension, 38 (35.2%) had diabetes mellitus, and 11 (10.2%) were active smokers. Of the 108 subjects, 97 (89.8%) had Cushing Disease (CD) and 11 (10.2%) had ectopic CS. Of the 97 patients with CD, 38 (39.2%) underwent inferior petrosal sinus sampling (IPSS), 59 (60.8%) underwent transsphenoidal surgery (TSS), 19 required repeat TSS (19.6%), and 15 underwent TSS and bilateral adrenalectomy (BAL) (15.4%). Of the 11 patients with ectopic CS, 3 (27.2%) underwent IPSS, 6 (54.5%) underwent BAL, and 1 (9.1%) underwent TSS and BAL.
There were 10 thrombotic events among 7 (7.2%) CD patients, but no thrombotic events among ectopic CS patients. Of the thrombotic events, there were 7 (70%) DVT/PE, 2 (20%) CVA, and 1 (10%) cortical vein thrombosis. Six (60%) occurred within 30 days after TSS (range 3-25 days), 2 (20%) between 31 days and 1 year after TSS (range 59-165 days), 1 (10%) 26 days after IPSS but prior to TSS, and 1 (10%) in a patient who did not undergo IPSS or surgery. No thrombotic events were noted after BAL. Of the 8 postoperative thrombotic events, 5 (62.5%) occurred while patients received supraphysiologic glucocorticoid replacement (defined as &gt;25mg hydrocortisone or equivalent daily) after curative surgery, 1 (12.5%) occurred after a patient was tapered to physiologic glucocorticoid replacement, and 2 (25%) occurred in patients who had persistent disease despite surgery. The degree of hypercortisolism at baseline was not associated with risk of thrombotic events.
Conclusions: In this retrospective study, 6.5% of ACTH-dependent CS patients had a thrombotic event, all in patients with CD. The majority had venous thromboembolism with DVT/PE, and the highest incidence occurred up to 30 days after surgery. The degree of hypercortisolism at baseline did not correlate with subsequent thrombotic events. Therefore, it is important to monitor all patients with ACTH-dependent CS following surgical intervention for venous thromboembolism.
Markers of Aggressiveness in Craniopharyngiomas
Authors: Del Can-Sanchez Diego Jesús , Sanchez Diego Jesus Del Can , Martínez-Ortega Antonio Jesús , Flores-Martínez Alvaro , Venegas-Moreno Eva , Dios-Fuentes María Elena , Madrazo-Atutxa Ainara , Valdepeñas Eugenio Cárdenas-Ruiz , Kaen Ariel Matías , Márquez-Rivas Francisco Javier , Roldán-Lora Anastasia Florinda , Fajardo-Picó Elena , Cano-González David , Soto-Moreno Alfonso 
Published: May 2021

Abstract
Craniopharyngiomas (CP) are rare tumors that may be locally aggressive. The presence of functional estrogen receptors (ER) has been reported in CP and might be related to risk of recurrence. Our aim is to ascertain if the expression estrogen and progesterone receptor (PR) might be associated with to recurrence in CP. Material and Methods: Descriptive retrospective observational study of patients with confirmed histology of CP and tissue sample available admitted to Virgen Del Rocio University Hospital (Seville, Spain) from January 1967 to October 2020 were included. Estrogen and progesterone receptor expression was analyzed by Immunohistochemistry. Ki-67 levels were also analyzed. Two CP groups were considereded according to Ki67 levels: Group A (Ki67&lt;10%) and group B (Ki67&gt;10%). As all variables followed a non-parametric distribution, U Mann Whitney, Chi-Square, and Z-test with Benjamini-Hochberg correction were used when needed. Results: Our study population includes 80 patients (46 male and 34 female), with a median age at diagnosis of 34 years [10-50.00]. Twenty-six patients were under 18 years old (children) with a median age of 7 years [4.5-10.00], and 54 were adults (aged 18 and above) with a median age of 45 years [33-58.50]. Our data shows higher recurrence rates when Ki67 levels staining were higher than 10%: 8/14 (57.2%) in comparison with Ki67&lt;10% (6/14, 42.9%, p=0.018). In children we found 6 samples with Ki67&lt;10% and 6 samples with Ki67 &gt;10%; recurrences were observed in 2/6 (33,3%) in the first group and in 6/6 (100%) in the second, respectively (p= 0,199). In adults, we found 9 and 3 patients for high and low Ki67 levels, respectively. Recurrences were observed in 4/9 (44,4%) in the group A and in 2/3 (66,7%) in the group B, respectively (p= 0,28). There were no differences between age groups. In patients with positive ER, we observed an increased rate of recurrence: 12/23 (52.17%) versus 2/13 (15,38%) in patients with negative ER stain but it was no significant. (p=0,21). No association between PR and recurrence was observed. Conclusions: In our series, patients with CP with high Ki67 levels are more likely to recur. No clear association between ER, PR expression and recurrence was observed. These findings support the use of Ki67 as a marker of recurrence in CP. Sources of Research Support: Spanish Ministry of Health, ISCIII co-funded with Fondos FEDER (PI16/00175) and Novartis Oncology Spain.
The Change of Bone Turnover Markers and Bone Remodelling Balance in Acromegaly
Authors: Chen Huan , Zhang Yan , Liu Mengsi , Zhang Ziwei , Feng Wenhuan , Li Ping , Zhu Dalong 
Published: May 2021

Abstract
Objectives: The aim of this study was to evaluate the change of bone metabolism and bone remodelling balance in active and biochemical controlled acromegalic patients. Methods: We recruited 68 consecutive patients diagnosed as acromegaly in Nanjing Drum Tower Hospital. Of those, 39 patients after treatments with complete follow-up data were included. 30 sex-, age- and BMI-matched healthy persons were also included as normal controls. Serum calcium, phosphorus, parathyroid hormone (PTH), 25-hydroxy-vitamin D, bone turnover markers [osteocalcin, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP)], and bone remodelling index were investigated at baseline and after treatment. Univariate and multivariate linear regression analysis was used to determine the independent predictors of bone turnover markers. Results: At baseline, acromegalic patients had higher serum calcium, phosphorus and lower PTH levels than controls (all P &lt; 0.01). Acromegalic patients had higher serum osteocalcin [45.98(31.98, 60.27) vs 15.83(12.74, 19.96) ng/ml, P &lt; 0.01], P1NP [115.50(72.64, 145.90) vs 36.45(30.45, 44.28) ng/ml, P &lt; 0.01] and CTX than controls [1.12(0.79, 1.56) vs 0.37(0.30, 0.50) ng/ml, P &lt; 0.01], and the bone remodelling index of acromegaly patients is significantly increase compared to healthy controls [4.27(1.31, 5.99) vs 0.03(-0.38, 0.63), P &lt; 0.01]. Multivariate linear regression analysis revealed that serum insulin-like growth factor 1 (IGF-1) was an independent predictor for osteocalcin (r = 0.610, P = 0.000), P1NP (r = 0.601, P = 0.000) and CTX (r = 0.596, P = 0.000). After treatment, serum calcium and phosphorus decreased, while PTH increased in acromegalic patients. Serum levels of bone turnover markers osteocalcin, PINP, CTX and bone remodelling index were also significantly decreased after treatment (all P &lt; 0.05). In patients with biochemical control after treatment, bone turnover markers and bone remodelling index almost decreased to normal level (all P &gt; 0.05). Conclusion: Acromegalic patients exhibited PTH-independent calcium-phosphate alterations, enhanced bone turnover state and positive bone remodeling balance. The abnormal bone metabolism is reversible after biochemical control of acromegaly. [Key words]Acromegaly; Bone turnover markers; Bone remodelling index; Growth hormone; Insulin-like growth factor 1
Vitamin D Metabolism Alteration in Acromegaly and Its Impact on Calcium-Phosphorus Metabolism
Authors: Povaliaeva Alexandra , Rozhinskaya Liudmila , Zhukov ScD, Artem , Pigarova Ekaterina A , Dzeranova ScD, Larisa K , Nikankina ScD, Larisa , Malysheva Natalya , Bogdanov Viktor , Ioutsi Vitaliy 
Published: May 2021

Abstract
Objective: to evaluate metabolism of vitamin D and calcium-phosphorus metabolism in patients with an active phase of acromegaly in comparison with healthy individuals. Materials and Methods: The study included 44 patients with an active acromegaly (IGF-1 788 [521; 963] ng/mL), as well as 49 conditionally healthy individuals. There were more men in the Acromegaly group (41% vs. 20%, p &lt;0.05), patients were older (median age 42.7 [35.5; 26.5] vs. 26.3 [25; 33.5] years, p &lt;0.05) and had a higher BMI (28.4 [25.2; 30.2] vs. 22.2 [20.1; 26.1] kg/m2, p &lt;0.05) in a minor way compared with the control group. All participants were tested for vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3) by UPLC-MS/MS, free 25(OH)D and vitamin D-binding protein by ELISA, PTH by electrochemiluminescence immunoassay, as well as routine biochemical parameters of blood serum (calcium, phosphorus, creatinine, albumin, magnesium) and urine (calcium and phosphorus-creatinine ratio in spot urine). Results: In the Acromegaly group, we observed significantly higher levels of serum total calcium (2.46 [2.37; 2.56] vs. 2.38 [2.33; 2.45] mmol/L, p &lt;0.05), albumin-corrected calcium (2.33 [2.28; 2.42] vs. 2.26 [2.21; 2.31] mmol/L, p &lt;0.05) and phosphorus (1.39 [1.25; 1.55] vs. 1.15 [1.06; 1.23] mmol/L, p &lt;0.05) as well as lower levels of serum albumin (45 [44; 47] vs. 46 [45; 48] g/L, p &lt;0.05). The rest of the studied biochemical parameters and PTH levels did not differ significantly between the groups. The IGF-1 level in patients with acromegaly positively correlated with the level of total calcium (r = 0.49, p &lt;0.05), albumin-corrected calcium (r = 0.49, p &lt;0.05) and phosphorus (r = 0.55, p &lt;0.05). The Acromegaly group showed lower levels of 25(OH)D3 (14.8 [11.8; 20.5] vs. 20.5 [14.8; 24.6] ng/mL, p &lt;0.05), 3-epi-25(OH)D3 (1.0 [0.7; 1.4] vs. 1.4 [0.9; 1.8] ng/mL, p &lt;0.05), 24,25(OH)2D3 (0.8 [0.4; 1.2] vs. 1.7 [0.9; 2.6] ng/ml, p &lt;0.05) and free 25(OH)D (4.6 [3.7; 5.6] vs. 5.9 [4.0; 7.5] pg/mL, p &lt;0.05), higher levels of 1,25(OH)2D3 (50 [42; 63] vs. 39 [34; 45] pg/mL, p &lt;0.05), a lower 25(OH)D3/1,25(OH)2D3 ratio (289 [226; 443] vs. 517 [340; 641], p &lt;0.05) and a higher 25(OH)D3/24,25(OH)2D3 ratio (19.3 [15.4; 27.7] vs. 11.9 [9.6; 15.2], p &lt;0.05). Conclusion: Our data suggest that high levels of the active vitamin D metabolite (1,25(OH)2D3) resulting from an increase in 1α-hydroxylase activity may contribute to the elevation of calcium and phosphorus serum levels in patients with acromegaly. Our results also indicate a decrease in 24-hydroxylase activity in patients with acromegaly, which may be due to lower levels of 25(OH)D3 in these patients. The results obtained should be evaluated taking into account the observed differences in age, gender and BMI between groups.
Pituitary Somatotroph Adenoma Cell-Derived Exosomes: Characterization of Novel Non-Hormonal Functions
Authors: Zhou Cuiqi , Shen Stephen , Moran Rosemary , Melmed Shlomo 
Published: May 2021

Abstract
Exosomes, small extracellular vesicles carrying lipids, proteins, DNA and RNA, enable intercellular communication. Pituitary-derived exosomes have not been well validated, and as no human pituitary cell lines are available, we characterized exosomes derived from rat somatotroph tumor cells (GH1 and GH3). Rat FR and H9C2 cells were used as non-pituitary controls. Exosomes were isolated from serum-free culture supernatants by combining ultrafiltration and ultracentrifugation to eliminate hormone contamination. Derived exosomes were analyzed by NanoSight to visualize, size, and count particles. Exosomal proteins were extracted and exosome markers including TSG101, ALIX, CD63, HSP70, HSP90 detected by Western Blot. The exosome inhibitor GW4869 (10 µM, 30 h) reduced exosome release (up to 81%), whereas treating cells with hydrocortisone (0.1 µM, 72 h) increased exosome production (up to 42%) in GH1 and GH3 cells. Exosomal shuttle RNA characterized by RNA-Seq showed distinct pituitary vs non-pituitary exosome RNA profiles. Selected miRNAs assessed in exosomes and corresponding cells by qRT-PCR validated exosomal RNA-seq and suggested that miRNA signatures in exosomes and in respective cells of origin were concordant. Next, we explored downstream signaling of GH1-derived exosomes (GH1-exo) in vitro and in vivo and studied biological actions in normal hepatocytes and in malignant cells. As evidenced by mRNA-seq, GH1-exo distinctly altered signaling pathways in rat primary hepatocytes, vs pathways elicited by GH or PRL (0.5 µg/mL, 24 h). GH1-exo, FR-exo or vehicle were intravenously injected to 4-week-old female Wistar rats twice weekly for 4 weeks (5*109 exo/200 g, n=3), and livers dissected for mRNA-seq. Among GH1-exo specifically regulated genes, EIF2AK/ATF4, involved in cAMP responses and amino acid biosynthesis, were attenuated. In hepatocytes, GH1-exo suppressed up to 65% of nascent protein synthesis and reduced forskolin (10 µM)-stimulated cAMP activity by 19%, while GH (0.01-1 µg/mL) did not affect this pathway. Notably, GH1-exo also attenuated malignant cell motility. Both GH1-exo incubation or GH1 cell co-culture (48 h) suppressed migration, invasion and wound healing of HCT116 cancer cells by up to 70%. In contrast, treatment with rGH (0.5 µg/mL) increased HCT116 motility. Intravenous administration of GH1-exo (1010 exo/mouse, twice a week for 5 weeks) decreased metastatic tumor volume by 40% in nude mice harboring splenic HCT116 implants (5*105 cells/mouse, n=10), and especially abrogated hepatic metastases. mRNA-seq of GH1-exo treated HCT116 cells vs controls indicated dysregulated p53 and MAPK pathways, which may partially explain mechanisms underlying motility attenuation. The results elucidate novel biological actions of somatotroph adenoma cell-derived exosomes and suggest exosomes as non-hormonal messengers produced by pituitary tumors.
FGF-2-Dependent Signaling Activated in Aged Human Skeletal Muscle Promotes Intramuscular Adipogenesis
Authors: Mathes Sebastian , Fahrner Alexandra , Ghoshdastider Umesh , Rüdiger Hannes A , Leunig Michael , Wolfrum Christian , Krützfeldt Jan 
Published: May 2021

Abstract
Background: A unique feature of muscle during aging, obesity and type 2 diabetes is the appearance of adipose tissue between skeletal muscle fibers, the intramuscular adipose tissue (IMAT). IMAT is generally associated with systemic insulin resistance, decreased muscle strength and, in older adults, impaired mobility. A large body of work over the last years have addressed the origin of IMAT. Skeletal muscle contains preadipocyte progenitors termed fibro/adipogenic progenitors (FAPs) that normally do not form adipocytes, but proliferate during muscle injury to support the commitment of myogenic progenitor cells during muscle repair. However, under the conditions outlined above, FAPs differentiate to adipocytes and give rise to IMAT. The molecular cues that trigger this pathogenesis are unknown and strategies that can modulate the fate of FAPs and their propensity to differentiate to adipocytes in disease states are urgently needed. Methods: We have used molecular cloning and genome editing techniques together with a variety of biochemical, molecular, genomic, transcriptomic and proteomic analyses in pre-adipocyte and muscle cell lines, primary cells isolated from human and mouse skeletal muscle, human skeletal muscle biopsies, and animal models. Results: Using multiple screening assays upstream and downstream of a master regulator of myogenesis, microRNA (miR)-29a, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. We identified FGF-2 as an upstream regulator that increases miR-29a promoter activity and gene expression via MEK1/2/MAPK signaling and consequently decreases the conserved miR-29a target SPARC. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. CRISPR/Cas9-mediated genomic deletions of miR-29a recognition elements located in the Sparc 3′UTR of muscle cells and AAV-mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of FAPs in vitro and IMAT formation in vivo. Skeletal muscle from human donors aged &gt; 75 years versus &lt; 55 years showed activation of FGF-2-dependent signaling and increased IMAT. Conclusion: FGF-2 not only stimulates muscle growth, but also promotes intramuscular adipogenesis via targeting the fate of FAPs. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a novel pathway, which has the potential to provide innovative diagnostic and therapeutic approaches to combat fat accumulation in aged human skeletal muscle.
Human GPR17 Nonsynonymous Variants Identified in Individuals with Metabolic Diseases Have Distinct Functional Signaling Profiles
Authors: Conley Jason M , Ren Hongxia 
Published: May 2021

Abstract
GPR17 is a G protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Our genetic knockout studies in rodents suggest that GPR17 is a potential therapeutic target for the treatment of metabolic diseases. However, the contributions of GPR17 to human metabolism and metabolic deficits are not well understood. Here, we analyzed the human GPR17 coding sequences of individuals from control and metabolic disease cohorts that were comprised of patients with clinical phenotypes including severe insulin resistance, hypercholesterolemia, and obesity. Across cohorts, 18 nonsynonymous GPR17 variants were identified, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, cellular localization, and downstream functional signaling profiles of nine human GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). We found that the protein expression levels and subcellular localization for each of the nine GPR17 variants were similar to that of the wild type GPR17. As the endogenous GPR17 ligand is still elusive, we used a synthetic GPR17 agonist to quantitatively measure the functional signaling profiles of GPR17 variants. We found some of the variants had distinctly altered signaling profiles. GPR17-G136S lost agonist-mediated cAMP, Ca2+, and beta-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT but had impaired Ca2+ and beta-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca2+ signaling but enhanced agonist-stimulated beta-arrestin recruitment. Also, GPR17-G354V retained cAMP and Ca2+ signaling function but had attenuated beta-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with distinct signaling profiles, including differential signaling perturbations that resulted in receptor signaling bias. These results are expected to contribute to our understanding of the molecular signaling mechanisms underlying GPR17 in metabolic regulation.
12-year Trends in Lipid Levels in Korean Children and Adolescents: A Cross-sectional Study Based on the Korea National Health and Nutrition Examination Survey
Authors: Song Kyungchul , Soyoung Jeon , Lee Hye Sun , Choi Youngha , Oh Jun Suk , Choi Han Saem , Suh Junghwan , Kwon Ahreum , Kim Ho-Seong , Chae Hyun Wook 
Published: May 2021

Abstract
Background: Dyslipidaemia at a young age is one of the risk factors of adulthood cardiovascular disease. However, investigations on the trends in lipid levels among the youth are scarce. Thus, we aimed to analyse the trends in lipid levels in Korean youth from 2007 through 2018. Methods: This cross-sectional study investigated the lipid profiles of 10,734 youths aged 10-18 years using data from the four phases of the Korea National Health and Nutritional Examination Survey: IV (2007-2009), V (2020-2012), VI (2013-2015), and VII (2016-2018). We assessed the age-, sex-, and body mass index (BMI)-adjusted mean levels of lipids at each survey. Findings: The mean levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) levels increased from phase IV to VII. Among boys, the prevalence of subjects with acceptable levels of TC, LDL-C, and non-HDL-C decreased, whereas that of subjects with adverse levels increased from phase VI to VII. In BMI- and sex-specific analysis, adverse trends in TC, LDL-C, and non-HDL were more apparent among boys with normal BMI than among those who were overweight and obese. Among girls, the mean TC, LDL-C, and triglycerides levels increased in subjects with normal BMI and overweight. Interpretation: Our results suggest worsening trends in lipid levels and dyslipidaemia among Korean youth. These adverse trends were seen even in youth with normal BMI. These findings indicate the need for more concern about lipid levels in youth with normal BMI as well as those with overweight and obesity.