bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUN-687 MODY-14: A Rare Cause of Inherited Diabetes
Authors: Epp Riley , Arnaout Amel , Doyle Mary-Anne 
Published: May 2020

Abstract
Case: A 29-year-old physically active, lean man presented with a three-year history of poorly controlled diabetes diagnosed during a flu-like illness and no history diabetic ketoacidosis. Despite treatment with various oral hypoglycemic medications his glycated hemoglobin was consistently above target (never falling below 9.3%) and correlated with home blood glucose readings. His mother had gestational diabetes with all three of her pregnancies. His maternal grandmother was also known to have diabetes. Pancreatic islet antibodies were negative. C-peptide levels were low. Monogenic diabetes (MODY) was suspected. Discussion: Genetic testing revealed a mutation in the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) gene. APPL1 is involved in insulin secretion and insulin signaling via the Akt pathway [1,2,3]. Other mutations of APPL1 causing MODY-14 have been previously described [4]. In our case, the substitution of glutamate for aspartate at the 265 position occurs within the unique fourth alpha helix of the BAR domain of APPL1 [5]. Generally, BAR domains contribute to APPL1 dimerization and plasma membrane association [5]. Substitution of glutamate could disrupt protein folding, impairing dimerization and phosphorylation of Akt, thereby decreased insulin secretion as seen in other mutations of the BAR domain of APPL1 [4]. Although this remains a hypothesis, loss-of-function of APPL1 would explain the lack of insulin secretion without evidence of pancreatic autoimmunity. If the hypothesis is correct, it would be a novel mutation attributable to this MODY subtype. 1. Cheng KKY, Lam KSL, Wu D, et al. APPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice. Proc Natl Acad Sci U S A. 2012;109(23):8919–8924. doi:10.1073/pnas.1202435109 2. Ryu J, Galan AK, Xin X, et al. APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep. 2014;7(4):1227–1238. doi:10.1016/j.celrep.2014.04.006 3. Saito T, Jones CC, Huang S, Czech MP, Pilch PF. The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem. 2007;282(44):32280–32287. doi:10.1074/jbc.M704150200 4. Prudente S, Jungtrakoon P, Marucci A, et al. Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus. Am J Hum Genet. 2015;97(1):177–185. doi:10.1016/j.ajhg.2015.05.011 5. Li J, Mao X, Dong LQ, Liu F, Tong L. Crystal Structures of the BAR-PH and PTB Domains of Human APPL1. Structure. 2007;15(5):525–533. doi:10.1016/j.str.2007.03.011
SUN-213 The Role of Filamin A (FLNA) in the Regulation of Insulin-Like Growth Factor System in Adrenocortical Carcinomas
Authors: Peverelli Erika , Catalano Rosa , Giardino Elena , Treppiedi Donatella , Mangili Federica , Morelli Valentina , Mannelli Massimo , Spada Anna , Arosio Maura , Mantovani Giovanna 
Published: May 2020

Abstract
Adrenocortical carcinomas (ACCs) are rare endocrine tumors with poor prognosis. They overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, with molecular dynamics still poorly identified. Although promising, IGF1R/IR-targeted therapies have demonstrated a limited efficacy in clinical trials in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) was shown to impair IR and IGF1R signalling in melanoma and neural progenitor cells, respectively. The aims of this study were to test in ACC cells: 1) FLNA involvement in regulating IGF1R and IR expression and signalling; 2) FLNA role in modulating responsiveness to IGF1R and IGFR/IR inhibitors; 3) FLNA expression in ACCs and correlation with IGF system. In ACC cells we found by immunoprecipitation that both IGF1R and IR interacted with FLNA in basal condition, with an increased or decreased FLNA recruitment to IGF1R and to IR, respectively, after IGF2 stimulation. Genetic silencing of FLNA in ACC cell lines H295R and SW13 induced a significant increase of IGF1R expression (1.4- and 2.3-fold, respectively) and a reduction of IR (-85.5±9.1%, p&lt;0.001 and -32±19.1%, respectively, p&lt;0.05), with a downstream effect of increased cell proliferation (130±13.4%, p&lt;0.01 in H295R and 144.3±23.3%, p&lt;0.01 in SW13 cells) accompanied by an enhanced ERK phosphorylation. Accordingly, in ACC primary cultured cells FLNA silencing increased IGF1R levels (2.9-fold) and enhanced IGF2 effects on ERK phosphorylation by 2.2-fold. In addition, FLNA knockdown potentiated the antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R specific inhibitor NVP-ADW742 in H295R cells and SW13. This key role of FLNA was even more evident in A7/M2 melanoma cell model, since IGF2 and Linsitinib exerted the expected effects on ERK phosphorylation in M2 cells, lacking FLNA, but not in FLNA-expressing counterpart (A7 cells). Finally, western blot analysis showed significantly lower, although variable, FLNA expression in ACCs (n=10) than in adrenocortical adenomas (ACAs) (n=10) (FLNA/GAPDH ratio 0.37±0.38 and 0.90±0.63, respectively, p&lt;0.05). Interestingly, FLNA/IGF1R ratio inversely correlated with ERK phosphorylation status in ACCs (p&lt;0.05) but not in ACA. In conclusion, we demonstrated that low levels of FLNA enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor possibly influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.
SAT-396 A Non-Surgical Animal Model of Hypoparathyroidism for Testing PTH Analogues
Authors: Ramezani-Pour Narjes , Esfahani Sayyed Hamid Zarkesh , Pradhananga Sarbendra , Newell-Price John D C , Ross Richard John M , Wilkinson Ian R 
Published: May 2020

Abstract
BACKGROUND:
In vivo animal models for testing the pharmacokinetics and bioactivity of PTH and its analogues require parathyroidectomy by surgery (1, 2). As the parathyroid glands of rodents are very small the surgery often includes thyroidectomy, making this animal model time-limited, single use, complex, and expensive. We have developed a non-surgical rodent model of hypoparathyroidism using the Type II calcimimetic compound, Cinacalcet-HCl, to suppress PTH and thereby serum calcium levels.
Methods:
Normal male Wistar rats were gavaged with 30 mg/kg Cinacalcet-HCl (or vehicle only). To test the effect of PTH 1–34, animals were dosed immediately after Cinacalcet-HCl gavage with either a single subcutaneous injection of PTH at 20 nmol/kg or given as same dose repeated every hour for 6 hrs or vehicle only. Serum samples were analysed for ionised calcium (iCa) using an EasyLyte, fully automated electrolyte analyser (Medica Corporation) and phosphate using a Phosphorus Detection Assay Kit (Pars Azmun, IRAN) and an Hitachi 917 Clinical Chemistry Analyser.
Results:
Rats gavaged with 30 mg/kg Cinacalcet-HCl produced a significant reduction in iCa levels between 2-24hrs returning to baseline at 48-72hrs post dose with the nadir at 8 hours (ANOVA P &lt; 0.0001). This equated to a 25% reduction in iCa at 8 hrs: mean±SD, iCa 1.19 ± 0.09 mmol/L at predose and 0.891 ± 0.04 mmol/L at 8 hours (t-test P &lt; 0.0001). For phosphate there was an initial lowering within the first 2 hrs in all test groups but then a rise such that phosphate was at higher levels than control from 8–24 hrs (ANOVA, ns), returning to baseline at 48 hrs. PTH at 20 nmol/kg given as a single sc dose abrogated the Cinacalcet-HCl induced fall in iCa for up to 2 hrs (AUC±SD (mmol/L).hr, 0.076 ±0.047 versus 0.168±0.0874, t-test P=0.0289).
Conclusions:
We have shown that the administration of Cinacalcet-HCl provides a robust and reproducible lowering of calcium which is line with current published data (3). These studies demonstrate that the use of Cinacalcet-HCl in normal rats produces a hypocalcemic state that can be abrogated by the addition of PTH. This non-surgical animal model of hypoparathyroidism will be of value in testing the pharmacodynamics of PTH analogues.
References
1. Shimizu M, et al. J Bone Miner Res. 2016;31(7):1405–12.
2. Jung SY, et al. PLoS One. 2016;11(10):e0163911-e.
3. Nemeth EF, et al. 2004;308(2):627–35.
SAT-160 Evaluation of Life Style and Anthropometric Parameters in Patients with Nonfunctional Adrenal Incidentalomas
Authors: Dagdemir Arzu Nevin , Akalin Aysen 
Published: May 2020

Abstract
Introduction
Adrenal lesions that are found incidentally during routine imaging of people who do not have any complaints or physical findings related to adrenal gland are called adrenal incidentaloma (1,2). Incidentalomas appear more frequently with the increasing use of imaging techniques and increasing age. It is unclear why most of these masses emerged. It is controversial whether nonfunctional adrenal incidentalomas (NFAI) increase the risk of cardiovascular disease or metabolic syndrome or are more common in people with these diseases. In this study, we aimed to investigate whether lifestyle and body fat have an impact on the occurrence of NFAI.
Materials and Methods
100 patients with NFAI were included in the study. Control group consisted of 50 healthy and similar age groups. Physical activities of these groups (with the International Physical Activity Questionnaire Short Form), smoking were questioned and anthropometric measurements were made (Height, body weight, body mass index (BMI), neck, hip, waist circumference and body fat mass, fat percentage, total body water, fet free mass with bioimpedance method). Laboratory tests were examined from the patient file.
Results
Female dominance was observed in patients with NFAI. BMI, waist circumference, hip circumference, neck circumference, total body fat percentage and mass and smoking were found to be higher in the patient group compared to the healthy group and a statistically significant difference was found. When a subgroup of patients with similar age and BMI among the patients and the control group were constituted (25-29,99 kg / m2) waist circumference and total fat mass were again significantly higher in the patient group compared to controls. In addition, there was a significant positive correlation between mass size and waist circumference, BMI, neck circumference, cortisol after 1 mg dexamethasone suppression test and a significant negative correlation with ACTH.
Conclusion
The data obtained showed that body adiposity and smoking were higher in patients with NFAI. Also, ıt was shown that although the patients were regarded as nonfunctional, suppressibility of the cortisol decreases as the mass size of the incidentaloma increase.
Resources
1. Turkey Endocrinology and Metabolic Diseases Society of Adrenal and Gonadal Working Group. Adrenal and Gonadal Diseases Guide. 2019, pages 77–84.
2. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: adrenal tumors. 2016; 175 (2): G1-G34.
SAT-403 Is Most “Primary” Hyperparathyroidism Both Tertiary and Preventable?
Authors: Innerfield Ronald Jay 
Published: May 2020

Abstract
Primary Hyperparathyroidism has reached epidemic proportions since the advent of mass screening for laboratory parameters including calcium. Secondary Hyperparathyroidism has been considered by some individuals as “Normocalcemic Primary Hyperparathyroidism” (4th International Workshop on The Management of Asymptomatic Primary Hyperparathyroidism, Florence, 2013 Bilzekian et al:-”Normocalcemic PHPT is a clinical presentation of PHPT: management approach is recommended.”)We report a single case of severe secondary hyperparathyroidism (with severe osteomalacia due to ileal resection) as well as 56 subsequent secondary hyperpararthyroid cases treated with 1,25dihydroxy-D3 (calcitriol) which were associated with significant reduction of parathormone levels *and continued normalization of calcium levels* [as well as significant improvement in bone density.] We are instituting a long-term, double-blind, placebo controlled clinical trial - with design presented here - to determine whether or not the incidence of hypercalcemic hyperparathyroidism can be significantly reduced or even obliterated by treatment with calcitriol.
Mrs. K.E.
Date Ca++ PTH Calcitriol
---------- - ------ ----- ---------
1997/05/01 8.5 344.0 0.25 i po qd
1997/05/28 8.5 388.0 0.25 i po qd
1997/07/21 9.3 102.0 0.50 ii po tid
1997/08/21 9.3 167.0 0.50 ii po qid
1997/11/14 10.4 11.4 0.50 ii po qid
1998/01/26 11.2 0 (!) 0.50 i po tid
1998/04/28 9.7 8.6 0.50 i po tid
1998/06/26 9.5 11.4 0.50 i po tid
1999/04/28 9.4 15.2 0.50 i po tid
2000/02/04 8.7 16.0 0.50 i po tid
2000/05/01 9.3 15.1 0.50 i po tid
Baseline Values Statistic: Ca++ /PTH, Total: 910.70 /4170.00, Average: 9.49/73.16, Count: 57/57, Maximum: 11.70/211.00, Minimum: 4.90 /12.00, Variance: 1.38 /923.70, SD: 2.47/59.34
Post-Treatment with Calcitriol Statistic: Ca++ PTH, Total: 910.70/4170.00, Average: 9.49/73.16,Count: 57/57, 11.70/211.00, Minimum: 4.90/12.00, Variance: 1.38 /923.70, SD: 1.18/43.86
99% confidence interval around the 49.9 pg/ml difference was (-75.5 to -24.3 pg/ml)
Proposed Clinical Trial:- Calcitriol to Prevent Hyperparathyroidism (CaPH) Trial
Double-blind, randomized, parallel-controlled clinical trial stratified by history of nephrolithiasis with follow-up for 5-year duration
Calcitriol Rx to keep PTH&lt; 70 vs Ergocalcitriol to keep 25-OH D3 &gt;30
N=100 patients/arm
Visits q90 days
Bone densitometry [including lateral spine] qyear
Telopeptides, Crosslinks, Alkaline Phosphatase, UV/Pcalcium/creatinine,Flat Plates
Exclusion: Pcreatinine&gt;2.0,mg/dl, Ca++&gt;10.0 mg/dl,Familial HPTH
Inclusion: PTH &gt;70 pg/ml
Primary Efficacy Variable: Number of documented cases of Hypercalcemic Hyperparathyroidism
Secondary Variables: Mortality, Kidney stones, Bone density, Fractures
SAT-338 An Unusual Case of Brown Tumor in the Left Femur Associated with Secondary Hyperparathyroidism
Authors: Garg Dave , Rhyu Jane , Bhat Shalini 
Published: May 2020

Abstract
Background: Brown tumor of hyperparathyroidism (BTHPT) are non-neoplastic bony lesions that arise from increased osteoclastic activity in the setting of uncontrolled hyperparathyroidism, (HPT). The prevalence is low, with a frequency of 3% in primary HPT and 2% in secondary HPT. It is rare as earlier detection and treatment of HPT prevents the progression and development of BTHPT. BTHPT is more common when HPT is untreated. BTHPT are benign tumors which usually show high 18Fludeoxyglucose-PET/CT (FDG) uptake. The mechanism of elevated FDG uptake has been suggested to be the presence of giant cells, and intracellular glucose metabolism of the macrophages may also play a role. We describe a case of a patient who presents with FDG uptake-negative BTHPT of the left femur.
Clinical Case: 62-year-old male with end-stage renal disease (ESRD) and secondary HPT presented with severe left hip pain for many months. The patient had poor access to health care and had not received routine medical treatments at an outside facility prior to presentation at our facility. Laboratory studies showed PTH 1942 pg/ml (14–72), Calcium 8.7 ng/dl (8.4–10.2), phosphorus 3.6 mg/dl (2.5–4.9), Vitamin D total 19.7 ng/ml (30–140), Vit D 1,25 9 pg/ml (18–72), and creatinine 7.75 mg/dl (.66-1.28), alkaline phosphatase 57 u/L (33–94). FDG scan revealed several lucencies in the left proximal femur, with no uptake. The patient underwent left total hip arthroplasty due to impending pathological fracture. Surgical pathology revealed fragments of fibrous tissue with fibroblasts, hemosiderin and interstitial hemorrhage, consistent with brown tumor.
Conclusion: We describe a unique case of BTHPT of the left femur which was the unrecognized cause of hip pain. BTHPT occurs late in the setting of HPT and is considered as a sign of poorly controlled disease. This is the first case of BTHPT to our knowledge that is not FDG-avid. This is unusual given the vascularity seen in these tumors and highlights that glucose utilization may not necessarily reflect the degree of osteoclastic activity in these tumors. Medical treatment has been shown to be sufficient in helping resolve these lesions, although the process is usually slow. Conversely, in cases of refractory disease, subtotal parathyroidectomy may be required. Our case describes an FDG-negative BTHPT, and highlights that although rare, this should be considered in the management of patients with ESRD, secondary HPT and hip pain. Patients can present with various imaging characteristics. Despite being rare, this case underscores the importance of recognition of BTHPT, so that intervention may be rendered early.
MON-172 Comparison of a Late-night Salivary Cortisol Immunoassay and a Cortisol and Cortisone LCMS Assay in Patients with Cushing’s Disease
Authors: Kannankeril Joshua , Carroll Ty Brian , Findling James W , Javorsky Bradley Richard , Gunsolus Ian , Phillips Jonathan , Raff Hershel 
Published: May 2020

Abstract
Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA) is established as a reliable screening test and recommended as a first-line test for Cushing’s syndrome.1,2 However, liquid chromatography-tandem mass spectrometry (LCMS), validated to measure salivary cortisol (F) and cortisone (E), has been proposed to be superior diagnostically as well as helpful in detecting saliva contaminated with topical hydrocortisone (i.e. cortisol).3,4 We measured EIA-F, LCMS-F, and LCMS-E in 913 consecutive late-night saliva samples from patients suspected of Cushing’s syndrome. For the current report, we focus only on the patients with Cushing’s disease (CD) who had at least one elevated salivary result using cutoffs established previously [EIA-F ≥3.3 nmol/L, LCMS-F ≥2.8 nmol/L, and LCMS-E ≥8.7 nmol/L].5 We identified 27 patients who had newly diagnosed CD (n-CD) or had persistent/recurrent CD after pituitary surgery (r-CD). Data are shown as mean (SD). There were 19F/8M patients aged 50 (17) y; their BMI was 35 (11) kg/m2. 8 patients had n-CD and 19 had r-CD. In all 27 patients, EIA-F was 9.1 (6.0), LCMS-F was 5.1 (4.0), and LCMS-E was 19.6 (12.3) nmol/L. In n-CD, EIA-F was 14.3 (7.7), LCMS-F was 7.7 (4.6), and LCMS-E was 29.4 (12.8) nmol/L. In r-CD, EIA-F was 6.9 (3.6), LCMS-F was 4.0 (3.2), and LCMS-E was 15.5 (10.0) nmol/L. Mean EIA-F was greater than mean LCMS-F in all patients, and mean LNSC in n-CD patients was greater than mean LNSC in r-CD patients. The LCMS-F/E ratio was &lt;0.8 in all subjects indicating that no saliva samples were contaminated with topical hydrocortisone.3 Furthermore, there was no difference in the LCMS-F/E ratio between n-CD [0.3 (0.1)] and r-CD [0.3 (0.2)] patients. Using previously identified cutoffs, 9 of the 27 CD patients had normal LCMS-F whereas only 1 patient had a normal EIA-F (P=0.011). The EIA-F results of patients with normal LCMS-F were significantly lower than patients with increased LCMS-F demonstrating that LCMS-F was more likely to provide false negative results with milder hypercortisolism. Most of these false-negative LCMS-F results occurred in the r-CD patients (8 out of 19) who had milder hypercortisolism compared to the n-CD patients (P=0.006). No differences in diagnostic performance were found between EIA-F and LCMS-E. In summary, EIA-F appears to be superior to LCMS-F in identifying CD patients with milder hypercortisolism using established diagnostic cutoffs.5 Neither LCMS-E nor F/E ratio improved the diagnostic sensitivity in newly diagnosed CD or persistent/recurrent CD after pituitary surgery. We suggest that late-night salivary cortisol measured by EIA provides the best sensitivity for CD diagnosis.
1J Clin Endocrinol Metab 2008;93:1526–1540.
2Clin Chem 2003;49:203–204.
3Clin Chem 2012;58:947–948.
4J Clin Endocrinol Metab 2010;95:4951–4958.
5J Endocr Soc 2019;3:1631–1640.
SUN-410 Reverse T3 in Patients with Hypothyroidism, Helpful or a Waste of Time?
Authors: Friedman Theodore C , Wilson Julian B 
Published: May 2020

Abstract
BACKGROUND: The normal thyroid secretes T4 (an inactive precursor), T3 (the active hormone) and reverse T3, a biologically inactive form of T3 that may block T3 from binding to the thyroid hormone receptor. As about 15% of patients on L-T4 replacement with a normalized TSH report continued fatigue and other hypothyroid symptoms, efforts are needed to understand this phenomenon. Decades ago, endocrinologists realized that in severe illnesses, rT3 is often high and T3 is often low and termed this “sick euthyroid syndrome”. However, more recently, alternative or functional doctors have argued that high rT3 is detrimental and can block T3 from binding to the thyroid hormone receptor. Without peer-reviewed publications, these functional doctors rely heavily on rT3 levels to treat patients that may have no other laboratory findings of hypothyroidism and often prescribe them L-T3-only preparations to try to lower the rT3.
Hypothesis: Patients on L-T4 alone will more likely have an elevated rT3 compared to patients on desiccated thyroid or L-T4/L-T3 therapy.
Methods rT3 was measured in 98 consecutive patients seen in a tertiary Endocrinology clinic with possible or confirmed hypothyroidism (all with severe fatigue) with many of them were already treated with different thyroid preparations.
Results: The figure shows the 25%-75% quartiles, ranges and ratio of rT3 above the normal range/patients in that category. The cutoff of 24 ng/dL (upper limit of normal for rT3 at either Quest or LabCorp) is indicated by the line. Overall, 18 of the 98 patients had a rT3 above the normal range. Patients on L-T4 alone or desiccated thyroid plus L-T4 had the highest levels of rT3 and the highest % above the cut-off. Three of the patients with a high rT3 were not on any thyroid medicine, and in 2 of them, the rT3 normalized when repeated. The 8 patients with a high rT3 on L-T4 was a relatively high percentage (29%).
Conclusion: Measuring rT3 may be helpful in patients who are already on T4-containing thyroid treatments who still have hypothyroid symptoms. Based on this data, measuring rT3 in most patients who are not taking thyroid medicine is not recommended, as only a very small percentage of them had an elevated rT3. Future studies are needed to determine if high rT3 levels correlate with hypothyroid symptoms and if adding L-T3 or desiccated thyroid to hypothyroid patients on L-T4 normalizes rT3 and improves hypothyroid symptoms.