bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interrupted IGF-1 Feedback in GHRH Neurons and Somatotrophs Results in Impaired Weight Gain and Increased Energy Expenditure
Authors: Al-Samerria Sarmed , Aloqaily Bahaa , Negron Ariel , Wondisford Fredric Edward , Radovick Sally 
Published: May 2021

Abstract
Growth hormone (GH) expression and release are thought to be primarily regulated by the counter-regulatory effects of growth hormone-releasing hormone (GHRH) and somatostatin (SST). Several reports generated in our lab and others suggest that there are other factors that regulate GH production, such as insulin-like growth factor 1 (IGF-I). Using GH-Cre recombinase targeting of the somatotroph-specific IGF-1R knockout (SIGFRKO) mouse model, we have previously demonstrated the role of IGF-1 signaling in negative feedback regulation of GH production. This model, however, presented with an incomplete phenotype, suggesting additional regulatory pathways in the hypothalamus. To provide insight into this mechanism, we have developed new transgenic mouse models that maintain the integrity of the hypothalamic-pituitary GH axis, with the single exception of IGF-IR deficiency in both hypothalamic GHRH neurons and somatotroph cells, termed GHRH-somatotroph IGF-1R knockout (G-SIFGRKO). Axiological assessments showed normal linear growth until week 14 of age, both male and female G-SIFGRKO mice presented with a significant reduction in growth velocity compared to control animals. Indirect calorimetry assessment performed at 12–14 weeks of age demonstrated that G-SIFGRKO mice had higher volume O2 consumption and lower volume CO2 production associated with increased energy expenditure than controls. The calculated respiratory exchange ratio was significantly reduced in G-SIFGRKO mice with no changes observed in either ambulatory or total activity. Furthermore, glucose and insulin tolerance tests showed no differences in glucose metabolism between G-SIFGRKO and controls. Collectively, these data provide further confirmation of the combinatorial role of IGF-1 signaling in regulating GH production and, for the first time, highlight a new GHRH-IGF-1R mediated pathway to regulate body growth and energy balance. Targeting this pathway has the potential to lead to a better understanding of the intersection between growth and metabolism and therapeutic approaches for obesity.
Identification of a Long Non-Coding RNA Derived From the Antisense Strand of the Thyroid Hormone Receptor Beta Gene
Authors: Ishii Sumiyasu , Horiguchi Kazuhiko , Amano Izuki , Yamada Masanobu , Koibuchi Noriyuki 
Published: May 2021

Abstract
Background: Long non-coding RNAs (lncRNAs) have various functions. Here, we describe a novel lncRNA which is induced from the antisense strand of the thyroid hormone receptor beta (THRB) gene. Methods: We sequenced RNA from leukocytes and identified a novel lncRNA derived from the antisense strand of the THRB gene. The lncRNA was named THRB antisense RNA 2 (THRB-AS2). Transcriptional regulation by THRB-AS2 was assessed by reporter assays. The putative translation initiation codons of THRB-AS2 were mutated to assess potential THRB-AS2 protein function. Results: THRB-AS2 stimulated the activities of multiple promoters irrespective of thyroid hormone response elements. Thyroid hormone treatment did not affect the function of THRB-AS2. These data suggest that THRB-AS2 is a potential general transcriptional activator and has broad specificity on target genes. Mutations in putative translation initiation codons of THRB-AS2 did not affect function, suggesting that THRB-AS2 acts as an RNA molecule. Conclusions: Although a small number of lncRNAs derived from antisense strand of the THRB gene, such as THRB-AS1, has been already reported, their functions remain largely unknown. To our knowledge, this is the first report of the functions of a lncRNA derived from the antisense strand of the THRB gene.
Universal Multi Gene Panel Testing For Individuals With Pheochromocytomas And Paragangliomas
Authors: Horton Carolyn , Richardson Marcy , Durda Kate , Yussuf Amal , Jackson Michelle , Jasperson Kory , Tian Yuan , LaDuca Holly , Else Tobias 
Published: May 2021

Abstract
Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs) (PPGLs) are a genetically heterogeneous entity, with roughly 25-40% of cases found to harbor a pathogenic or likely pathogenic germline alteration. Existing practice guidelines advocating for the use of a sequential gene testing strategy to identify individuals with hereditary PPGL are driven by the presence of specific clinical features and predate the routine use of multigene panel testing (MGPT). Here we describe results of MGPT for hereditary PPGL in a clinically and ancestrally diverse cohort from a diagnostic laboratory. Methods: Demographic and clinical information of individuals undergoing targeted MGPT for hereditary PPGL were collected from test requisition forms and supporting clinical documents provided by the ordering clinician and retrospectively reviewed. Individuals underwent MGPT of 10-12 genes depending on test order date. From August 2013 through May 2015, 560 individuals had targeted MGPT that included 10 genes (NF1, MAX, SDHA/B/C/D/AF2, RET, TMEM127, and VHL), and from May 2015 through December 2019, 1167 individuals had panel testing of 12 genes due to the addition of MEN1 and FH. Results: Overall, 27.5% of individuals had a pathogenic or likely pathogenic variant (PV), 9.0% had a variant of uncertain significance, and 63.1% had a negative result. Out of all PVs, most were identified in SDHB (40.4%), followed by SDHD (21.1%), SDHA (10.1%), VHL (7.8%), SDHC (6.7%), RET (3.8%), and MAX (3.6%). PVs in FH, MEN1, NF1, SDHAF2, and TMEM127 collectively accounted for 6.5% of PVs. Clinical predictors of a PV included extra-adrenal location, diagnosis before the age of 45 years, multiple tumors, and positive family history (fhx) of PPGL. Affected individuals with a fhx of PPGL were the most likely to have a PV (70.6% of individuals with PCC + fhx; 85.9% of individuals with PGL + fhx). The positive rate in nearly all clinical subgroups even without predictors of a PV remained over 10%, including individuals with a single tumor (PCC = 16.7%; PGL = 46.7%) and those without a fhx (PCC and negative fhx = 15.8%; PGL and negative fhx = 43.7%). Restricting genetic testing of hereditary PPGL to only SDHB/C/D genes misses a third (31.8%) of individuals with PVs. Among individuals with PVs in syndromic genes, over half (41.5%) did not have any additional syndromic features beyond PPGL reported by the ordering clinician. Conclusion: Our data demonstrate a high diagnostic yield in individuals with and without established risk factors, a low inconclusive result rate, numerous individuals with syndromic PVs presenting with isolated PPGL, and a substantial contribution to diagnostic yield from rare genes when included in testing. These findings support updating practice guidelines to incorporate universal testing of all individuals with PPGL and the use of concurrent MGPT as the ideal platform.
Young Adult LEW.1WR1 Rats, a Model of Liver FAT10 Overexpression, Develop Insulin Resistance and Fatty Liver With Age
Authors: Wimalarathne Madushika M , Mercado Luis D , Vidal Quiana C Wilkerson , Wolfsberger James , McConnell Victoria J , Vogler Bernhard , Love-Rutledge Sharifa Tahirah 
Published: May 2021

Abstract
As human lifespan increases, comorbid conditions that impact quality of life have become a serious problem. FAT10 has been identified as a gene that when knocked out, improves age associated metabolic dysfunctions and increased longevity in mice (1). There is increased Fat10 expression in the liver in obesity (2,5). Providing evidence that fat10 expression may be important for triggering the transition to metabolic dysfunction in aging. Adult LEW.1WR1(1WR1) rats have increased body mass without excess abdominal fat mass compared to control rats (3). Yet, it was unclear where the excess mass was stored. We hypothesized that the 1WR1 rat would develop increased liver fat mass as a product of increased insulin resistance in response to increased liver fat10 expression over time. To test this hypothesis, we did insulin tolerance tests(7 weeks & 15 weeks), triglyceride assays, and histological analysis of the liver(23 weeks), in 1WR1 rats(n=7) and Wistar Furth (WF) rats(n=7) on control diets. We analyzed images using histological scoring for nonalcoholic fatty liver disease from the literature (4). We also assessed the slides for Mallory Denk bodies (MBs). The body mass of 1WR1 rats were increased compared to WF rat groups starting from the age of 7 weeks (391.4∓8.572g vs. 271.8∓11.62g; p &lt;0.0006). 1WR1 rats became more insulin resistant with age, the 1WR1 rat group has increased AUC of 7 and 15 week Insulin Tolerance Tests (401.5∓23.54 vs. 245.3∓10.20 7w ITT1; p= 0.0728, 15w ITT2 328.2∓14.86 vs. 217.8∓9.; p &lt;0.0003) compared to WF rats. 1WR1 rats have increased liver mass (11.85g∓0.7699g vs. 7.235g∓0.3864g; p=0.0006) liver triglyceride levels compared to WF rats (192.8∓21.8 mg/mL vs. 130.1∓13.075 mg/mL; p=0.0728). 1WR1 rats have increased steatosis scores(1.857∓0.2608 vs. 1.143∓0.1429;p= 0.0862) yet significantly reduced inflammatory foci level (2∓0.8165 vs. 3∓0;p= 0.007), most 1WR1 hepatocytes are enlarged (ballooned) and contained MBs compared to WF rats suggesting 1WR1 rats have already passed the early inflammation stage. Adult 1WR1 rats developed reduced insulin sensitivity and lipid accumulation in the liver. These data support our hypothesis that 1WR1 rats would develop increased liver fat and impaired insulin resistance in response to aging and show that this process may be inflammation driven.
(1) Canaan et al.,PNAS. April 2014; 111 (14): 5313-5318.(2)Vidal et al., FASEB.2020, 34: 1-1,(3) Collins et al., J Endocr Soc. 2019;3(1),(4).Kleiner et al., Hepatology, 2005; 41 (6): 1313–1321,(5).Dali-Youcef et al., Hepatol Commun. 2019;3(9):1205-1220.
Growth Hormone Secretion Does Not Increase After Interleukin-2 Administration in Healthy Men
Authors: Roelfsema Ferdinand , Yang Rebecca , Veldhuis Johannes D 
Published: May 2021

Abstract
Context: Interleukin-2 (IL2), a proinflammatory cytokine, is used for treatment of malignancies. Increased cortisol and ACTH were noted, but GH secretion was not investigated in detail. This is the first study in healthy men which uses moderate high IL2 doses as used in cancer treatment. Objective: The goal of this study was to quantify GH secretion after a single sc injection of IL2 in young and older healthy men in relation to dose, age and body composition. Design: This was a placebo-controlled, blinded, prospectively randomized cross-over study in 17 young subjects (mean age 24.1 yr) and 18 older subjects (mean age 63.9 yr). The subjects underwent 24 h of blood sampling at 10-min intervals, starting at 1800 h. At 2000 h IL2 (3 or 6 million units per m2 body surface) or saline was injected sc. Lights were off between 2300 and 0700 h. Outcome Measures: Deconvolution analysis of GH. Abdominal visceral fat (AVF) was calculated from single slice CT. Results: GH secretion (pulsatile and total) was negatively related to AVF (R=0.67, P&lt;0.0001) and to age (R=0.56, P=0.001). These relations were maintained after IL2 administration. GH profiles were pulsatile under both experimental conditions. Since the effect of IL2 might be limited in time, GH deconvolution analyses were performed on the complete 24 h data series, the period with lights off and 6 h after IL2 administration. Total 24 h GH secretion decreased non-significantly from 74.6 ±10.2 to 67.5±7.4 µg/L (P=0.25) and pulsatile secretion from 69.4±9.8 to 62.2±7.4 µg/L (P=0.23). In the GLM procedure the effect of IL2 treatment was borderline significant (P=0.08), no interaction with age (P=0.28), but borderline with IL2 dose (P=0.07), and caused by decreased GH secretion (88 to 67 µg/L) at a low dose IL2. In a sub-analysis of the two age groups no effect on GH secretion in the older group was noted, in contrast to young subjects, especially on low dose IL2 (P=0.07). The analysis was refined further by calculating cumulative pulse masses in 2-h bins. By this approach it could be demonstrated that the cumulative GH pulse mass in older subjects across the 24 h was unchanged, while that in young subjects was temporarily inhibited in the bins between midnight and 0400 h (P=0.019 and 0.038). Conclusion: This study demonstrated that IL2 temporarily diminished GH secretion in young but not elderly volunteers. Pituitary hormone secretion by IL2 has not been studied as extensively as other cytokines, including IL1, IL6 and TNF. IL2 stimulates ACTH and TSH, inhibits LH and has no effect on GH secretion by rat pituitary (PNAS 58:185,1993). In patients with renal cancer IL2 infusion has no effect on GH levels (Anti-Cancer Res 10:753,1990. The present findings extend these observations to a large group of healthy volunteers, in whom we demonstrated previously suppression of the gonadal axis and activation of the HPA-axis (JCEM 101:539,2016, Endocr Connect 9:637,2010).
Pancreatic Ductal Adenocarcinoma Highly Expresses Activin A: Implications in Adipose Tissue and Cancer Cachexia
Authors: Xu Pauline , You Mikyoung , Luan Yi , Eldani Maya , Chung Soonkyu , Kim So-Youn 
Published: May 2021

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer death in the United States and is projected to become the second leading cause by the year 2030. Prognosis for patients with metastatic disease remains dismal. Cancer cachexia is seen in over 85% of PDAC patients who often have the most severe degrees of cachexia and experience adipose tissue loss prior to skeletal muscle loss early in the disease process. Several factors have been proposed to induce cachectic symptoms in human patients, including inhibin subunit βA, or activin A. Hypothesis: While muscle wasting has been the most frequently studied mechanism in cachexia research, changes in adipose tissue are increasingly understood as important components of body weight loss in cachectic patients. We hypothesized that there is a correlation between the marked increase in activin A production in PDAC patients and the remodeling of adipose tissue and consequent cancer-associated cachectic state. Experimental Design: We measured serum activin A levels of a cohort of PDAC patients and analyzed the expression of activin A in tumor-derived cell lines and biopsies of both humans and mice. We further investigated the effect of activin A on remodeling of adipose tissue secondary to tumor progression in PDAC patients and an orthotopic murine model. Results: We observed that PDAC cell lines express and secrete activin A. We recognized a loss of adipose tissue mass and adipocyte diameter in PDAC patients and our orthotopic PDAC mouse model in relation to increased circulating activin A. We also noted that both exogenous activin A and conditioned medium from pancreatic tumor-derived cell lines dampened adipocyte differentiation and lipid droplet formation via reduction of PPARγ expression in mouse mesenchymal stem cells. These treatment conditions also reduced lipid droplet size without upregulating traditional markers of adipose tissue browning and lipolysis such as UCP-1 and ATGL in mature mouse adipocytes. PPARγ, UCP-1, and ATGL expression are also heavily downregulated in adipose tissue of PDAC patients. Furthermore, our studies revealed that the expression of extracellular matrix proteins such as collagen I and fibronectin is dramatically upregulated in adipose tissue of PDAC patients and our orthotopic PDAC mouse model. Thus, we found that there is a clear correlation between elevated levels of activin A and the progression of cancer-associated cachexia in PDAC. Discussion: Our results reveal an imperative role of activin A in relation to the loss and remodeling of adipose tissue in the progression of cachexia in PDAC patients.
Safety Results From MPOWERED, a Phase 3 Trial of Oral Octreotide Capsules in Adults With Acromegaly
Authors: Freda Pamela , Fleseriu Maria , Dreval Akexander V , Pokramovich Yulia , Bondar Irina , Isaeva Elena , Huang Wenyu , Molitch Mark E , Macut Djuro P , Leonova Nina , Raverot Gerald , Gilgun-Sherki Yossi , Ludlam William H , Patou Gary , Haviv Asi , Gordon Murray B , Biermasz Nienke , Melmed Shlomo , Strasburger Christian J 
Published: May 2021

Abstract
Background: Injectable somatostatin receptor ligands (iSRLs) have been a mainstay in acromegaly treatment. Oral octreotide capsules (OOC; MYCAPSSA®) were recently approved in the United States. Results from the placebo-controlled CHIASMA OPTIMAL and open-label CH-ACM-01 studies showed an OOC safety profile consistent with that of iSRLs with no new or unexpected safety signals. Results of the MPOWERED trial have enabled a comparison of OOC safety and efficacy with iSRLs.
Methods: To enter MPOWERED, patients must have the following: acromegaly diagnosis, biochemical control of acromegaly (insulin-like growth factor I &lt;1.3 × upper limit of normal; mean integrated growth hormone &lt;2.5 ng/mL), and ≥6 months’ iSRLs treatment (octreotide or lanreotide). Eligible patients entered a 26-week Run-in phase to determine the effective OOC dose; responders at week 24 then entered a 36-week randomized controlled treatment (RCT) phase receiving OOC or iSRLs. Safety was monitored as adverse events (AEs) in both arms throughout the trial, including the RCT.
Results: In the RCT, incidence of treatment-emergent adverse events (TEAEs) was similar between groups; 39 patients (70.9%) in the OOC group and 26 (70.3%) in the iSRL group had ≥1 TEAE. 19 patients (34.5%) in the OOC and 15 (40.5%) in the iSRL group had treatment-related TEAEs. Occurrence was similar for serious AEs (OOC, 5.5%; iSRL, 8.1%) as well as TEAEs classified as severe (OOC, 9.1%; iSRL, 10.8%). One patient in the OOC group discontinued due to a TEAE. The most common gastrointestinal TEAEs were flatulence (OOC, 25.5%; iSRL, 21.6%), nausea (OOC, 20.0%; iSRL, 8.1%), diarrhea (OOC, 10.9%; iSRL, 13.5%), abdominal pain (OOC, 9.1%; iSRL, 8.1%), and constipation (OOC, 5.5%; iSRL, 13.5%). AEs of interest were infrequent, including cholelithiasis (OOC, n=0; iSRL, n=1 [2.7%]) and secondary hypothyroidism (OOC, n=1 [1.8%]; iSRL, n=0). In the iSRL group, 32.4% of patients reported injection site reactions (ISRs) during the RCT, and 47% of patients reported ISRs as part of the Acromegaly Treatment Satisfaction Questionnaire, a newly validated patient-reported outcome tool.1
Conclusion: Safety results from MPOWERED align with prior trials, showing that the OOC safety profile is consistent with that of iSRLs as well as the acromegaly disease burden. No new or unexpected safety signals were identified during the trial. Safety results were mostly similar between OOC and iSRLs, although patients in the OOC group did not experience any ISRs.
1Fleseriu M, et al. Pituitary. 2020 Aug;23(4):347-358.
Use of Oral Concomitant Medications in Patients With Acromegaly
Authors: Petersenn Stephan , Houchard Aude , Schneider Maria del Pilar , Ribeiro-Oliveira Antonio , Neggers Sebastian Jcmm 
Published: May 2021

Abstract
Background: Acromegaly is a rare condition characterized by excess GH and IGF-I levels.1 Injectable somatostatin analogs (SSAs) are recommended as first-line medical treatment.2 Comorbidities including diabetes, hypertension and hypopituitarism reduce quality of life in patients with acromegaly; 3,4 treatment for these includes oral medications. We assessed the most common oral medications used by patients with acromegaly during treatment with lanreotide autogel 120 mg (LAN).
Methods: This post-hoc analysis reports data from the PRIMARYS5 (NCT00690898) and LEAD6 (NCT00701363) open-label trials in which adult patients with acromegaly received LAN. PRIMARYS patients were SSA/surgery-naïve with uncontrolled acromegaly, LEAD patients were previously treated with octreotide long-acting release with normal age-adjusted IGF-I levels for two consecutive measurements.
Results: PRIMARYS included 90 patients: mean (standard deviation [SD]) age 49.5 (12.4) years; 47.8% male; mean (SD) baseline IGF-I 809.9 (300.0) µg/L, 97.8% had IGF-I &gt;1.3xULN. LEAD included 124 patients: mean (SD) age 55.4 (10.9) years; 37.1% male. Median (range) time since diagnosis was 99.0 (27.0-1,261.0) days (PRIMARYS) and 7.1 (0.5-27.0) years (LEAD). 51.1%, 24.4% and 3.3% of participants in PRIMARYS had a history of cardiovascular disorders (including hypertension), diabetes/glucose intolerance, and hypopituitarism/hypothalamic disorders; the corresponding values in LEAD were 69.4%, 33.9% and 18.5%. 83.3% of participants in PRIMARYS and 86.3% in LEAD used ≥1 concomitant oral medication with LAN. Of these participants, &gt;50% used &gt;3 types (PRIMARYS: 53.3%; LEAD: 61.7%). Out of participants in both studies who used concomitant oral medication with LAN, this was commonly indicated for cardiovascular disorders including: renin-angiotensin agents (PRIMARYS: 33.3%; LEAD: 45.8%); antithrombotic agents (PRIMARYS: 10.7%; LEAD: 19.6%); beta-blocking agents (PRIMARYS: 22.7%; LEAD: 19.6%) and calcium channel blockers (PRIMARYS: 16.0%; LEAD: 22.4%). Diuretics (PRIMARYS: 16.0%; LEAD: 20.6%) and lipid modifying agents (PRIMARYS: 20.0%; LEAD: 39.3%) were also common concomitant oral medications, as were medications used in diabetes (PRIMARYS: 17.3%; LEAD: 20.6%) and for thyroid therapy (PRIMARYS: 28.0%; LEAD: 31.8%).
Conclusions: In this analysis, most patients with acromegaly receiving LAN, regardless of prior therapy, used ≥1 concomitant oral medication. An awareness of the ongoing burden of comorbidities requiring oral medications should help physicians in managing acromegaly.
Funding: This study was sponsored by Ipsen.
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4. Vilar L Pituitary 2017;20:22-32
5. Caron PJ J Clin Endocrinol Metab. 2014;99:1282-90
6. Neggers SJ Eur J Endocrinol. 2015;173:313-23