bluuebunny/crossref_metadata_2025_split huggingface dataset:
MON-174 Circadian Misalignment of the 24-H Profiles of Melatonin and Cortisol in Adrenal Insufficiency
Authors: Darji Monika , Pannain Silvana , Sam Susan , Cauter Eve Van , Hanlon Erin C 
Published: May 2020

Abstract
Patients with adrenal insufficiency (AI), in whom cortisol release is absent, need to be on lifelong replacement therapy. Depending on the modality of glucocorticoid replacement, the resulting 24-h profile of circulating cortisol levels maybe dampened, enhanced, abnormally timed or inconsistent. The 24-h cortisol profile is a major internal synchronizing signal between central and peripheral circadian clocks. Misalignment between central and peripheral clocks has a host of adverse effects, particularly on metabolism and cardiovascular function. Melatonin, normally secreted by the pineal gland exclusively at night and considered a robust marker of central circadian timing, also plays a role as an internal synchronizing signal. Conditions like AI, where the 24-h profile of glucocorticoid levels deviates from normality, could produce misalignment between central and peripheral oscillators.
We examined whether AI patients are at higher risk of disturbances of the circadian system. Participants were 13 AI patients (11 females, 2 men; mean age 45.8 yrs old; mean BMI 25.5) and 13 controls (11 females, 2 males; mean age 48.5 yrs old, mean BMI 26.4) matched for age, sex, and BMI. 10 of the AI patients were on hydrocortisone treatment (total dose range: 20 to 40mg/day, number of doses: 1-5 doses/day) and 3 of the AI patients were on prednisone treatment. Cortisol and melatonin were measured over a 24-h period every 30-60 minutes in all patients and controls.
The 24-h profile of cortisol was quite variable across patients, dependent on replacement therapy. Those on prednisone had very little detectable cortisol with small peaks that occurred around dosing. Those on hydrocortisone, had multiple peaks across the 24-h cycle dependent on medication regime and dosing. As expected, control subjects had a quiescent period of cortisol release from early evening to mid-sleep (18:00 to 02:00) and a mid-sleep rise in serum cortisol that peaks in the morning and subsequently dissipates across the day. In contrast, AI patients have low levels of cortisol across the entire sleep period, with a sharp morning rise, delayed compared to controls. Unexpectedly, we observed a marked difference in the melatonin profile in AI subjects compared to controls. Indeed, a significant daytime phase of elevated melatonin levels was detected in 7 of the 13 AI patients. The nocturnal elevation in the patients was similar to that observed in controls albeit advanced.
In conclusion, the abnormalities of the circadian profile of glucocorticoid levels in AI are associated with an abnormal 24-hr profile of melatonin release, a marker of central circadian function, suggesting that the disruption of the glucocorticoid rhythm may affect central circadian function. It is possible that this circadian dysfunction contributes to the well-known adverse cardio-metabolic outcomes in AI.
SUN-156 Adrenal Cortical Carcinoma in a Male Patient Who Presented with Classic Signs and Symptoms of Cushing’s Syndrome
Authors: Humarang Jeffrey Magnaye 
Published: May 2020

Abstract
Background: Adrenal Cortical Cancer (ACC) is a rare malignancy with an annual incidence of 1-2 per million population. ACC is generally considered a highly malignant tumor and account for 0.05-2% of all cancer.Clinical case: A 32-year old male, newly diagnosed diabetic and hypertensive for 1 month, with a BMI of 37.91 kg/m2, presented with intermittent, vague, non-radiating flank pain. Within a month, patient started to develop weight gain associated with Cushingoid fascies, buffalo hump, elevated blood sugars, hypertension, and eventually developed purple striae in the abdomen associated with easy bruisability. Ultrasound was done which showed bilateral nephrolithiasis. Further work-up with CT-stonogram was done which showed bilateral nephrolithiasis and a 55x37x60mm heterogeneous mass above the left kidney in the area of the left adrenal gland. Further imaging with whole abdominal CT scan was done which revealed stable size of the mass in the region of the left adrenal gland with heterogeneous attenuation and enhancement.Initial hormonal work-ups done showed abnormal 1mg dexamethasone suppression test (874mmol/L N: 172-497mmol/L), but with normal aldosterone (73.22, N: &lt;90pg/ml), renin (8.60pg/mL, N: 5-40pg/mL) and 24-hour urine metanephrines (31 mcg/24 hours N: 115-695mcg/24 hours). Serum K and blood glucose was managed accordingly and patient was cleared to undergo surgery. Patient underwent left unilateral laparoscopic adrenalectomy which revealed a 7cm soft, friable left adrenal mass with minimal hematoma on the antero-inferior portion of the adrenal gland, with active bleeding. Histopathology of the left adrenal mass revealed high-grade adrenal neoplasm, consistent with adrenocortical carcinoma.Postoperatively, patient did not have complications of hypo nor hyperglycemia, hypotension and serum potassium was stable. Hydrocortisone was given postoperatively in tapering doses. Repeat cortisol were done 24 and 48 hours post op which showed normal results (4.02ug/dL and 5.37 ug/dL respectively, N: 5-25 ug/dL). Patient was referred to Oncology service for Chemotherapy and was eventually discharged stable with home medications for his Diabetes mellitus.On follow-up, there was noted improvement on the signs and symptoms of Cushing’s syndrome, with no hypokalemia and better blood glucose control. Conclusion: Majority of adrenal mass are benign but a high index of suspicion for malignancy should always be part of the workup. The acuteness of symptoms and size of mass are important determinants of malignancy. Prior to adrenalectomy, perioperative endocrine therapy is a must. Adrenocortical carcinoma should be managed by a multidisciplinary specialist team including an endocrinologist, oncologist, surgeon, radiologist, and a histopathologist.
MON-372 Treatment-Resistant Vitamin D Deficiency: Is It a Vitamin D Binding Protein Issue?
Authors: Thambuluru Sirisha , Unal Imran , Frank Stuart , Warriner Amy , Ovalle Fernando , Banerjee Ronadip R 
Published: May 2020

Abstract
Introduction
Vitamin D is present in free and bound forms; the bound form is complexed mainly to vitamin D binding protein (DBP). Vitamin D levels are affected by age, pregnancy, liver disease, obesity, and DBP mutations. We report a patient with treatment-resistant vitamin D deficiency suggestive of a DBP with abnormal vitamin D binding.
Clinical Case
A 58-year-old Pakistani male with a history of hypertension, sleep apnea and hypogonadism presented to endocrine clinic with symptoms including fatigue, generalized muscle cramps, and joint pain. Evaluation of common causes of fatigue, such as anemia, thyroid dysfunction and adrenal insufficiency were ruled out with CBC, thyroid hormone levels and ACTH stimulation test results all within normal ranges. A 25-OH vitamin D level was profoundly low (4.2 ng/ml; normal 30-100), and a 1,25-OH vitamin D level was undetectable (&lt;8 pg/ml; normal 18-72), leading to a presumptive diagnosis of severe vitamin D deficiency. However, his calcium, phosphorus, alkaline phosphatase and kidney function were in the normal range. Furthermore, the absence of osteoporosis, fracture history, or kidney stones suggested adequate vitamin D action at target tissues; PTH levels were high-normal to minimally elevated, ranging 70-94 pg/ml (12-88pg/mL). Aggressive supplementation with vitamin D3 at 50,000 IU 3 times a week and 5,000 IU daily failed to normalize 25-OH vitamin D (ranged 4.6-10ng/ml; normal 30-100) and 1,25-OH vitamin D levels remained undetectable. Addition of calcitriol resulted in mild hypercalcemia and was discontinued. Malabsorption did not appear to be a contributing factor, as a negative tTG antibody (with normal IgA) excluded celiac disease. Vitamin D metabolites levels measured with mass spectrometry showed undetectable 25-OH vitamin D levels (D2 &lt;4 ng/ml, D3 &lt;2 ng/ml; total &lt;6ng/ml; normal 20-50) and 1,25-OH vitamin D levels (&lt;8 pg/ml). Urine N-telopeptide, 24-hour urine calcium (177mg; 100-240) and bone-specific alkaline phosphatase were all normal. Repeat testing over more than five years showed similar results. DBP levels of 269 ug/ml [104-477] excluded DBP deficiency.
Clinical Lesson
Vitamin D deficiency is increasingly part of routine testing in internal medicine and endocrinology clinics, as is repletion with high-dose vitamin D. However, in rare cases such as this, relying on 25-OH vitamin D levels can be misleading, and supplementation unnecessary or potentially harmful. Thus, treatment decisions should consider the full clinical context and further evaluation performed when warranted. This patient’s labs are suggestive of an abnormality in the DBP, supporting future examination using molecular testing.
OR22-07 Novel Variants in Protein Kinase a Signaling-Related Genes Identified in Obese Children with and Without NAFLD
Authors: Bloyd Michelle , Coon Steven , Iben James , Sinaii Ninet , Faucz Fabio Rueda , Santoro Nicola , Caprio Sonia , Stratakis Constantine A , London Edra 
Published: May 2020

Abstract
Context: Nonalcoholic fatty liver disease (NAFLD) is estimated to affect nearly 10% of Americans age 2-19 and about 38% of those affected are obesei. NAFLD is characterized by triglyceride accumulation in hepatocytes and can progress to nonalcoholic steatohepatitis, end stage liver disease and hepatocellular carcinoma. The underlying causes of NAFLD in youth are unclear although obesity, insulin resistance, type 2 diabetes mellitus and metabolic syndrome are risk factors. Genome-wide association studies and candidate gene studies have found several single nucleotide polymorphisms that affect susceptibility to and progression of NAFLD, but clinical translation for some of these genetics is lackingii.
Study design: Because mouse models of dysregulated PKA signaling demonstrate the centrality of this pathway in hepatic lipid metabolism and glucose homeostasis, we hypothesized that defects in hepatic PKA signaling genes could affect susceptibility to or severity of NAFLD in children. We asked whether identified variants might be associated with differences in clinical markers in a cohort of obese pediatric patients (non-NAFLD, n=295; NAFLD, n=165) followed at Yale Medical School, where clinical data and genomic DNA were collected. Exon sequencing of 54 PKA-related candidate genes included those coding for PKA subunits, PDEs and other proteins integral to the hepatic PKA system. Variants were ranked by allele frequency and potential pathogenicity. Ongoing analyses aim to identify associations between single variants and potential additive effects with clinical parameters (anthropometric, liver function, glucose metabolism, plasma lipids).
Results: Gene variants were identified in ABCA1, ADCY4, ADCY5, AKAP7, CREB3L1, CREB3L4, CREM, CYP27A1, DHCR7, ERN1, GYS2, IL6, IL10RB, MC2R, PDE1B, PDE2A, PDE3B, PDE4A, PDE7B, PDE10A, PDE11A, PPARGC1B, PRKAR2A, and PRKAR1B. Reported variants met criteria of high to moderate impact based on 9 in silico scores that predict pathogenicity. Allele frequency ranged from 2.5 to over 50 times higher in our cohort than the general population. One or more variant was identified in 34.9% of non-NAFLD and 19.4% of NAFLD patients (p=.0004).
Conclusion: We report PKA-related gene variants among a cohort of pediatric obese patients that might serve as useful predictors of risk of NAFLD or obesity. Further analyses will help determine whether any of these variants may play a functional role in NAFLD.
Endnotes
i Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Pediatrics. 2006;118(4):1388.
ii Vespasiani-Gentilucci U, Gallo P, Dell’Unto C et al. World J Gastroenterol. 2018;24(43):4835-4845.
SUN-546 18-Day Lifestyle Program Improves Metabolic Equivalent Measures, BMI, and Exercise Capacity Among Overweight and Obese Adults
Authors: Mpyisi Atieno , Ramirez Francisco , Nedley Neil , Michel Rebecca , Seidel Vinicius 
Published: May 2020

Abstract
Introduction Various kinds of diets, workout programs, exist to lower one’s Body Mass Index (BMI), increase strength, and endurance. Metabolic Equivalent Measures (METS) is often used to measure exercise intensity1. A simple 18-day lifestyle program may be effective in raising METS, lowering BMI, and building endurance among overweight and obese adults. Methods Participants took part in an 18-day residential lifestyle program that encouraged daily outdoor exercise. Those with a BMI greater than 24.9kg/m2 were selected for this study. BMI, METS, and miles walked per day were measured at baseline and 14 days into the program. METS was measured using the Bruce Protocol while participants reported miles walked per day. Participants were given a walking goal of 5 miles per day. Participants ate 2 vegeterian meals a day that were low in sugar and fat but high in fiber. The program also encouraged moderate sunlight exposure, adequate water intake, sleep hygiene, and temperance. The program incorporated spiritual activities such as corporate prayer, spiritual contemplation, and hymn singing. A patient-doctor relationship was established and participants were consistently monitored. Results A total of n=627 participants were used in this study. METS increased from a baseline mean of 7.61 kcal/kg/hour to a final mean of 9.19 kcal/kg/hour. This is an increase of 1.58 kcal/kg/hour, ±1.26, with t(626)=-25.35 and p&lt;0.001. BMI decreased from a baseline mean of 32.49 kg/m2 to a final mean of 31.39 kg/m2. This is a decrease of 1.094 kg/m2, ± 2.22, with t(626)=39.22 and p&lt;0.001. Miles walked per day (MPD) increased from a baseline mean of 0.86 MPD to a final mean of 4.04 MPD. This is an increase of 3.18 MPD, ±2.01, with t(626)=-33.36 and p&lt;0.001. Conclusion The program significantly improved METS, BMI, and physical endurance among the participants. This suggests that simple lifestyle changes are effective even among overweight and obese adults and should be encouraged by health professionals. Longitudinal studies are needed to examine these lifestyle effects outside of this program.
OR21-03 Determining Novel Therapeutic Targets Using an in Vitro Model of TRb Tumor Suppression in Anaplastic Thyroid Cancer
Authors: Gillis Noelle E , Bolf Eric L , Davidson Cole , Cozzens Lauren , Tomczak Jennifer , Lian Jane B , Frietze Seth , Carr Frances E 
Published: May 2020

Abstract
Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors are characterized by rapid local extension, distant metastasis, and resistance to radioactive iodine therapy and mainstream chemotherapy. There are very limited treatment options for this aggressive form of thyroid cancer, highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. Loss of expression of the thyroid hormone receptor beta (TRβ) via epigenetic silencing is common amongst solid tumors, including ATC. Despite its recognized role as a tumor suppressor, the mechanisms underlying TRβ tumor suppressor activity remain uncharacterized. We previously created a stable ATC cell line with constitutive re-expression of TRβ (SW-TRβ). These stable cells exhibit a slower baseline growth rate than both the corresponding parental cell line (SW1736) and the stable empty vector control cell line (SW-EV). Since the effects of thyroid hormone treatment on the growth of cancer cells remain unclear, we investigated changes in growth rates of these cells in response to hormone treatment (triiodothyronine (T3) 10-8M). While T3 had no effect on SW-EV cells, the addition of hormone significantly slowed the growth of the SW-TRβ cells after two days. With longer exposure to T3 (five days), the SW-TRβ cells exhibited an apoptotic phenotype. We confirmed that the observed cell death was due to induction of apoptosis by assessing caspase 3 cleavage by immunoblot. The parental SW1736 cell line harbors a deleterious p53 truncating mutation, which is maintained in our stable cell lines. Therefore, we hypothesize that this T3-induced apoptosis is occurring through an alternate, p53-independent, signaling pathway. This prompted us to examine RNA-seq data obtained from these cell lines under similar conditions to identify potential regulators of this response. Interestingly, pathway analysis revealed decreased CDK4/6-mediated cell cycle progression and activation of JAK1/STAT1 signaling upon T3 treatment. These are novel mechanisms by which activation of T3-TRβ signaling can slow tumor growth and promote apoptosis in p53-deficient cancer cells. Furthermore, these pathways represent novel therapeutic targets specifically for ATC with potential high impact clinical applications.
SAT-516 A Severe Case of Pembrolizumab-Induced Thyroiditis
Authors: Lane Kyrstin , Kim Sarah , Wei Jeffrey , Darwin Christine Hema 
Published: May 2020

Abstract
Pembrolizumab, a programmed death 1 (PD-1) inhibitor used for advanced malignancies, can be associated with thyroid dysfunction.1-2 Specifically, thyroiditis occurs in nearly 2.3% of individuals.2 The hyperthyroid phase is typically non-severe, requiring only beta blockers. Our case illustrates that conservative therapies may be ineffective in pembrolizumab-induced severe thyroiditis.
A 54-year-old woman with metastatic non-small cell lung cancer with normal baseline TSH received pembrolizumab. She was hospitalized nearly 30 days later with nausea, vomiting and tachycardia. Labs showed TSH &lt;0.02 mcIU/mL (normal 0.3-4.7), free T4 &gt;7 ng/dL (normal 0.8-1.7) and free T3 2105 pg/dL (normal 222-383). TSH receptor antibody was undetectable; hyperthyroidism was attributed to pembrolizumab. Metoprolol was initiated. She was re-hospitalized three days later with persistent symptoms and inability to tolerate orals. Labs again showed severe hyperthyroidism and TPO antibody 201 IU/mL (normal ≤ 20). Burch-Wartofsky score was 25. Given her symptom severity, propylthiouracil, hydrocortisone, and propranolol were initiated to reduce peripheral T4 to T3 conversion. A cortisol of 5 mcg/dL (collected 9:47AM) further supported the use of hydrocortisone. Following a normal Cosyntropin stimulation test, hydrocortisone was discontinued. Her symptoms improved but hypothyroidism developed 68 days after pembrolizumab initiation. Propylthiouracil was discontinued; levothyroxine was started. Her TFTs ultimately normalized.
Beta blockers are the mainstay of treatment of the hyperthyroid phase of PD-1 inhibitor-related thyroiditis, though case reports have described use of glucocorticoids, anti-thyroid drugs and iodine.2 -4 In our patient, severe thyrotoxicosis was not responsive to beta blockers. Consideration of additional therapies is reasonable in these cases.
References:
1. Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, Lenihan D, Onofrei C, Shannon V, Sharma R, Silk AW, Skondra D, Suarez-Almazor ME, Wang Y, Wiley K, Kaufman HL, Ernstoff MS; Society for Immunotherapy of Cancer Toxicity Management Working Group. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017 Nov 21;5(1):95.
2. de Filette J, Andreescu CE, Cools F, Bravenboer B, Velkeniers B. A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors. Horm Metab Res. 2019 Mar;51(3):145-156.
3. Tan MH, Iyengar R, Mizokami-Stout K, Yentz S, MacEachern MP, Shen LY, Redman B, Gianchandani R. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clin Diabetes Endocrinol. 2019 Jan 22;5:1.
SUN-718 Reciprocal Regulation of miR-375 and ICER in Pancreatic Beta Cells
Authors: Frias Stephanye , Nielsen Ryan , Perez Isis , Garcia Jesse , Keller David M 
Published: May 2020

Abstract
MicroRNA-375 (miR-375) is overexpressed in people with type 2 diabetes (T2D) and has been linked to decreased insulin secretion and beta cell proliferation. Investigation into the transcription factor inducible cAMP early repressor (ICER) as an intermediate regulator of miR-375 was proposed because both are regulated by the cAMP pathway. This overexpression of miR-375 in T2D led us to hypothesize that beta cells with elevated and reduced levels of miR-375 will result in decreased and increased glucose-stimulated insulin secretion (GSIS), respectively. Results showed that when miR-375 was overexpressed, GSIS decreased by 61% when compared to a control in 25 mM glucose. Results showed that when miR-375 was inhibited, GSIS increased 6% when compared to a control in 25 mM glucose. In human islets, we found that inhibiting miR-375 led to an average 19% increase in GSIS, though due to the variability of human tissue these data were not significant (N=5). To investigate ICER’s binding affinity to the miR-375 promoter, a luciferase reporter assay was conducted. HEK-293 (human embryonic kidney) cells that were transfected with a luciferase reporter plasmid containing a cAMP recognition element (CRE) and a plasmid driving the overexpression of ICER had a 75% decrease when compared to our control (P&lt;0.05). When transiently-expressed ICER was knocked down via siRNA, promoter activity increased by 13.1-fold (P&lt; 0.05). Using a chromatin immunoprecipitation assay we found that an ICER antibody pulled down the rat miR-375 promoter an average of 13-fold compared with a control antibody (N=2). Additionally, because of a sequence alignment showing possible binding of miR-375 to the human ICER transcript we hypothesize that the two are in a negative feedback loop and can regulate each other’s expression. To investigate the double negative feedback loop a plasmid was constructed containing the GFP reporter gene and either the human or rodent ICER 3’UTR predicted miR-375 binding site. The GFP reporter assay was conducted to determine if miR-375 binds to ICER’s microRNA recognition element (MRE) in a species-specific way. In our GFP reporter experiment, data shows there is a 50% reporter gene decrease between our negative control and the human ICER MRE (N=4, P=0.017). Understanding microRNA gene regulation in the pancreas may have important implications for patients with T2D. MiR-375 may have the ability to interact with human ICER in a double negative feedback loop in the cAMP second messenger pathway, which will further clarify cellular mechanisms to potentially improve T2D drugs.