bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-LB80 Human Thyroid Cancer Cells Are Highly Sensitive to CDK7 and 9 Inhibition
Authors: Rajan Neel , Bautista Luis , Adik Amy , Ringel Matthew David
Published: May 2020

Cancer cells display lineage and cancer-specific transcriptional control of expression of oncogenic driver genes, particularly those regulated through super-enhancers. Compounds that target CDK7 and 9, key regulators of RNA polymerase II (RNAPII)-mediated gene transcription, selectively reduce transcription of “superenhanced” oncogenes and are in clinical trials. We previously identified that medullary cancer cell lines are highly sensitive to CDK7 inhibition and that the RET-gene is super-enhanced. In the present study, we sought to determine sensitivities of a panel of follicular cell-derived thyroid cancer cell lines to the CDK7 inhibitor, THZ1 and CDK9 inhibitor, AZD4573. We selected 8 independently confirmed thyroid cancer cell lines (TPC1, FTC133, BCPAP, SW1376; K1, THJ16, C643, and 8505C) from a variety of histological subtypes with different drive mutations and performed WST assays with increasing concentration of THZ1 or AZD4573 to determine IC50 for each cell line. Western blots were performed in parallel for target validation. IC50 values ranged from 5-100 nM for both compounds for all cell lines. All cell lines showed inhibition of CDK 7 phosphorylation (Ser 5) of RNAPII with retained CDK7 levels with THZ1 and loss of CDK9 RNAPII phosphorylation (Ser 2) with both compounds. However, treatment with either agent unexpectedly caused a reduction of total RNAPII protein levels. qRT-PCR did not reveal reduced mRNA levels in TPC1 cells with THZ1 treatment while, Bortezomib (proteasome inhibitor) co-treatment with THZ1 rescued RNAPII protein. These results are consistent with THZ1-induced proteasome degradation of RNAPII. BRAF protein levels also decreased in the hemizygous BRAF V600E-mutated cell line (8505C) but not the BRAF WT cell line (TPC1). qRT-PCR of both cell lines treated THZ-1 showed stable BRAF gene expression; further mechanistic studies are ongoing. In summary, human thyroid cancer cell lines are sensitive to inhibition of CDK7 and CDK9 likely through several mechanisms not all directly attributable to RNAPII inhibition.
SUN-930 A Case of Acromegaly Secondary to Ectopic Growth Hormone-Releasing Hormone (GHRH) Secretion from a Bronchial Neuroendocrine Tumour
Authors: Bahrami Jasmine , Mete Ozgur , Prebtani Ally
Published: May 2020

A Case of Acromegaly Secondary to Ectopic Growth Hormone-Releasing Hormone (GHRH) Secretion from a Bronchial Neuroendocrine Tumour

Background

Acromegaly due to ectopic GHRH secretion is a rare disorder and only accounts for less than 1% of all cases of acromegaly.

Case

We present the case of a 42-year old female with acromegaly from a bronchial neuroendocrine tumour (NET) secreting GHRH. The patient presented with gradual onset of dyspnea and wheezing. Subsequent imaging (chest X-ray, CT chest) revealed a large left-sided thoracic mass. Bronchoscopy was performed and a biopsy was taken from the mass. Initial histological examination reported small cell lung carcinoma (SCLC). Therefore, she underwent chemoradiotherapy. The patient was concurrently experiencing increased digital girth, weight gain, and enlarged tongue and was therefore referred to our endocrinology clinic for evaluation of acromegaly. Investigations revealed normal ACTH, markedly elevated IGF-1 (1031 μg/L, normal 63–215 μg/L), and non-suppressed GH levels following a 75g oral glucose tolerance test. The remainder of the pituitary panel, including TSH, prolactin, FSH, LH were all normal. An MRI sella showed a completely normal pituitary and pineal gland with no evidence of brain metastasis. She thus met clinical and biochemical criteria for acromegaly but a pituitary source could not be identified. Given her history, a paraneoplastic process or ectopic GHRH-producing tumour was suspected. Further workup showed a significantly elevated circulating GHRH levels of 73 pg/mL (normal 5 – 18 pg/mL). Subsequently, a second pathologist with expertise in NETs reviewed the same biopsy specimen. The specimen was found to be a GHRH-producing well differentiated pulmonary NET with a Ki67 index of 1.5%, and thus not a SCLC. Furthermore, a somatostatin receptor scintigraphy study was done which showed evidence of a somatostatin avid receptor rich lesion in the lung, corresponding to the known tumour. Thus, what initially appeared to be a SCLC was subsequently found to be a GHRH-secreting NET, illustrating the challenges of diagnosing these rare tumours. She was treated with intramuscular sandostatin 20mg q28days and then underwent a left pneumonectomy, resulting in biochemical resolution of her acromegaly (IGF-1 219 μg/L). Genetic testing for MEN1 was also completed as there is an association between ectopic GHRH NETs and MEN-1; however, genetic testing revealed no pathogenic variants and exon deletions or duplications suggestive of MEN-1.

Learning points

Diagnosis of acromegaly due to ectopic GHRH secretion requires high clinical suspicion by the treating clinicians (e.g., endocrinologist, oncologist) as well as review of histology by expert pathologists. Our case highlights that ectopic GHRH secretion is a rare but important cause of acromegaly, which should always be suspected when a clear pituitary cause is not identified.
SAT-339 Calcium Level in a Patient with Rhabdomyolysis. A Tale of Two Phases
Authors: Samargandy Shaza Ahmed
Published: May 2020

Background: Calcium kinetics can be challenging during the different phases of rhabdomyolysis1. We herein report a case of sever hypercalcemia refractory to hemodialysis following a period of hypocalcaemia that developed in a patient with rhabdomyolysis.

Case: A 27-year-old male patient was diagnosed with meningoencephalitis complicated with septic shock, continuous seizures, rhabdomyolysis, acute kidney injury and oliguria. His creatinine was 219 μmol/L (53–115), urea was 8 mmol/L (2.5–6.4). Creatine kinase (CK) was significantly high above assay range. Corrected serum calcium was 1.82 mmol/L (2.12- 2.52), phosphate was 0.48 mmol/L (0.81–1.58). He required intermittent sessions of hemodialysis and antibiotics therapy which both have been initiated since the first day of admission. Initially he had hypocalcaemia but as rhabdomyolysis improved, his calcium levels started to rise to reach normal levels by day 13 post admission. By day 16, he started to gradually develop hypercalcemia. Initially, it was 2.73 mmol/L and in another 10 days it was 3.39 mmol/L and reached maximum of 3.90 mmo/L despite the intermittent dialysis sessions. PTH was supressed at 0.62 Pmol/L. Over that time, his renal functions and urine output were gradually improving.

The clinical impression was PTH independent hypercalcemia and the work up for that was initiated. CT chest, abdomen and pelvis did not reveal any suspicious masses, lytic bone lesions, or lymphadenopathies. His acid fast bacilli stain and culture were both negative. His chest imaging did not show any findings to suggest sarcoidosis. TSH was normal and random cortisol was 339.2 nmol/l with albumin 20g/L. HIV serology came back negative.

He received Calcitonin 500 IU BID for three days and Denosumab 120 mg SC in order to control the hypercalcemia along with, cautious intravenous hydration. Within one week after Denosumab therapy, serum corrected calcium decreased to 3.07 mmol/L. After another week, corrected calcium reached 2.53 mmol/L. When his urine output improved further and his calcium levels dropped, hemodialysis was discontinued. His calcium level later normalised to 2.49 mmol/L.

After ruling out the common differential of PTH independent hypercalcemia, and from the diuretic phase the patient went through with concomitant hypercalcemia following hypocalcaemia, it was concluded that the cause of hypercalcemia was rebound hypercalcemia following rhabdomyolysis recovery.

Conclusion: hypercalcemia can complicate the recovery phase of rhabdomyolysis. Careful monitoring of calcium levels and management are warranted.

References:

[1] Mohsin N, Budruddin M, Pakkyara A. Calcium Kinetic in a Patient with Acute Renal Failure due to Rhabdomyolysis: A Case Report and Review of Literature. Oman Medical Journal. 2010;25:324–326.
SAT-012 Screening for Gestational Diabetes Mellitus: Universal or Selective Screening? Screening for Gestational Diabetes Mellitus: Universal or Selective Screening?
Authors: Okunowo Bolanle Olajumoke , Fasanmade Olufemi A , Odeniyi Ifedayo A , Ohwovoriole Augustine E
Published: May 2020

Screening for gestational diabetes mellitus: universal or selective screening?

Introduction:

The presence or absence of risk factors is often employed in screening for Gestational Diabetes Mellitus (GDM). The risk factors for GDM includes previous delivery of macrosomic babies, family history of type 2 diabetes mellitus, previous GDM among others. The impact of selective screening is yet to be fully evaluated in our environment.

Objective

To determine the impact of selective screening on diagnosis of gestational diabetes mellitus

Methods

The study was a prospective open cohort study carried out from 1st March to 30th November 2017 at the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria. Ethical approval was obtained from the Health Research Ethics Committee of Lagos University Teaching Hospital (LUTH) before commencement of the study

All the pregnant women were categorized into either risk group or control group based on the presence or absence of clinical risk factors for GDM. All participant had 75g Oral Glucose Tolerance test (OGTT) done at 24 to 28 weeks gestation and follow up till delivery.

The data obtained were age, risk factors for GDM, fasting plasma glucose, one-hour post glucose load plasma glucose & two-hour post glucose load plasma glucose. The data were presented as mean, standard deviation, percentages & chi square. The p value ≤ 0.05 was considered significant

Results

Ninety pregnant women were screened for GDM. Forty-four women had risk factors for GDM while 46 were non risk group. Their mean age was 32.6± 5 years. The mean age for the risk & non-risk group were similar.

The overall prevalence of GDM using the IADPSG criteria was 23.3%. The percentage of women in the risk group with GDM was 38.6% while those women in the non risk group with GDM was 8.7% which was statistically significant (p value 0.004).

Discussion

The most commonly identified risk factors for GDM in this study were family history of type 2 diabetes mellitus, history of unexplained miscarriage & previous history of delivery of macrosomic babies.

Some women in the non-risk were diagnosed, even though the prevalence was lower than that observed among women with risk factors for GDM. Approximately one in ten women would have been missed if selective screening was employed in this study.

Most of the women in the non-risk group who were diagnosed with GDM were managed with medical nutritional therapy while majority of women in the risk group had insulin therapy.

Conclusion

The findings in our study further supports the idea of universal screening for GDM in order to avoid missed diagnosis.

Keywords: gestational diabetes mellitus, Screening, oral glucose tolerance test
SAT-277 A Fierce Presentation of Cushing Disease
Authors: Al Sabie Farah Laith , Jain Meenu , Aziz Ammara
Published: May 2020

Introduction: Cushing disease refers to the endogenous overproduction of glucocorticoid due to an ACTH-producing pituitary adenoma. It is important to recognize and treat due to the adverse health outcomes associated with it. We describe an unusual case of Cushing disease which presented very rapidly and progressively with extremely high cortisol levels mimicking those seen in ectopic production of ACTH.Case Presentation: A 43 year old Caucasian man, with no past medical history, presented with hypertensive crisis. He was discharged home with anti-hypertensive medications. Over the next 4 months, he gained 20 pounds, mainly around his abdomen, developed fatigue, and blood pressure continued to be high despite six anti-hypertensive medications, developed diabetes and hypokalemia, requiring 120 meq/day of potassium chloride. On exam, he had plethora, central obesity and wide, purple striae over his abdomen. Work-up for secondary causes of hypertension showed normal renal Doppler US, normal aldosterone and renin activity, normal plasma metanephrines, however, his 24 hour urinary free cortisol was dramatically elevated at 4022ug/day with a urine volume of 4 L, 1 mg dexamethasone suppression test showed unsuppressed serum cortisol of 55ug/dl. Morning ACTH of 125 pg/ml with concurrent serum cortisol level of 53.8 mcg/dl, indicated ACTH-dependent hypercortisolism. Inferior petrosal sinus sampling indicated a pituitary source of ACTH. Sellar MRI initially did not show a pituitary adenoma, however, repeat MRI with a 3-Tesla magnet showed a 4 mm pituitary adenoma. He was treated with ketoconazole and was started on atovaquone for PCP prophylaxis while awaiting trans-sphenoidal resection, which he had a month later. Pathology showed a 4 mm adenoma which stained strongly for ACTH. On postoperative day 1, serum cortisol dropped to 2.1 from 52.3 mcg/dl, and patient was discharged on hydrocortisone replacement. Three weeks later, he had lost 12 pounds, hyperglycemia improved with discontinuation of insulin, hypokalemia resolved and hypertension was well controlled on two anti-hypertensives. Discussion: ACTH-dependent Cushing syndrome is either caused by Cushing disease, or from ectopic ACTH production from a tumor. Cushing disease is characterized by a gradual onset and subtle manifestations of hypercortisolism. Acute, severe presentation favors an ectopic ACTH producing tumor, and is associated with much higher cortisol levels. In our patient, clinical data suggested ectopic ACTH production, yet he was found to have Cushing disease, and was treated successfully with trans-sphenoidal resection of the pituitary adenoma. It is imperative to consider all possibilities, and do the full work up so as not to miss an atypical presentation of Cushing disease, and direct treatment accordingly.
MON-439 Graves’ Disease and Papillary Thyroid Cancer: A Rare Clinical Case?
Authors: Volkova Natalia , Davidenko Ilia , Dzherieva Irina , Zibarev Alexander , Ganenko Lilia , Reshetnikov Igor , Sorokina Julia , Brovkina Snezhana
Published: May 2020

Background: Nodules on the background of Graves’ disease are less common among men than among women, but more than one in three patients have carcinoma. Despite the improvement of diagnostic methods, most often thyroid cancer is a random histological finding after thyroidectomy for Graves’ disease. Clinical case: A 55-year women complained of discomfort in the neck, sweating, irritability, palpitation. From anamnesis: in 2012 she was diagnosed with thyrotoxicosis syndrome. For 5 years, the patient was treated with thyrostatics, but when trying to reduce the dose, the syndrome of thyrotoxicosis recurred. In March 2017, the patient’s condition worsened, at the time of treatment she took Thyrosol 30 mg/day. Objectively: hypersthenic body type, BMI 33 kg/m2. Thyroid gland visually was increased in volume, dense with palpation, homogeneous, mobile. Elevated titer of antibodies to the TSH receptor was discovered, according to the ultrasound - increase thyroid gland 30.2 cm3, hyperechogenic formation of the left lobe 10х10х9 mm with hypoechoic rim, clear smooth contours, intranodular blood flow. As a result, the Graves’ disease, goiter grade 2, manifest thyrotoxicosis was verified, surgical treatment was recommended. Thyroidectomy, histological examination was performed: Graves’ disease was confirmed, papillary microcarcinoma with metastasis to 1 regional lymph node was revealed. Diagnosed: papillary thyroid cancer I st (pT1aN1aM0x), 2 clinical group. The patient was prescribed suppressive therapy with L-thyroxine 100 µg/day, against which after 3 months TSH reached the target values (0.2–0.5 Mme/l). Taking into account the histological characteristics of the tumor, the nature and volume of the lesion, age, the patient belongs to the group of intermediate cancer risk of progression of cancer. According to scintigraphy residual functioning thyroid tissue (20x15 mm) was detected. Radioiodine therapy was carried out in a specialized hospital. Suppressive therapy of L-thyroxine 150 µg/day, target values of TSH 0.1 - 0.5 Mme/l was recommended. After 6 months, TSH reached target values, and according to the results of ultrasound of thyroid gland no data for structural relapse was found. Conclusion: Patients with long-existing, often recurrent Graves’ disease and questionable effect of conservative therapy, in the presence of nodular formation should be assigned to the risk group for the presence of thyroid cancer and carefully examined, because the need for further surgery depends on it.
SAT-552 Epigenetic Regulation of 11beta-Hydroxysteroid Dehydrogenase 1 and 2 Gene in Salt-Sensitive Hypertensive Rats
Authors: Takeda Yoshiyu , Takeda Yoshimichi , Karashima Shigehiro , Kometani Mitsuhiro , Hashimoto Atsushi , Aono Daisuke , Higashitani Takuya , Yoneda Takashi , Horike Shinichi
Published: May 2020

ENDO 2020

Epigenetic regulation of 11beta-hydroxysteroid dehydrogenase 1 and 2 gene in salt-sensitive hypertensive rats

[Objective]11Beta-hydroxysteroid dehydrogenase type1 (11-HSD1) is the modulator of glucocorticoid hormone and type2 (11-HSD2) is the modulator of mineralocorticoid hormone. We investigated the effect of high salt diet on the methylation of both enzyme gene in salt-sensitive hypertensive (SSH) rats [Methods]SSH rats were fed a high (7% NaCl) or normal (0.45%) salt chow for 4 weeks. Body weight, blood pressure, plasma and urinary aldosterone concentration and PRA were measured. DNA was extracted from kidneys and visceral fats. Bisulfite sequencing and Pyrosequencing were done for the analysis of methylation status of 11-HSD1 and 2 gene. [Results] High salt diet significantly decreased methylation ratio of 11-HSD1 gene in the visceral fats of SSH rats compared with controls (p<0.05). The methylation ratio of 11-HSD2 gene in the kidney of SSH rats was not influenced by high salt diet. [Discussion and Conclusion]11-HSD1 overexpression in visceral fats in mice was reported to show SSH. We reported decreased 11-HSD2 activity in the artery in SSH rats. In this study high salt diet affected methylation status of 11-HSD1 in the adipose tissue but not 11-HSD2 gene in the kidney in SSH. Food intake such as salt may influence the epigenesis of 11-HSD and induce hypertension.
MON-348 Surgical Management of Bilateral Hip Fracture in a Patient with Fibrodysplasia Ossificans Progressiva Treated with Palovarotene
Authors: Singh Sukhmani , Kidane Joseph , Wentworth Kelly Lee , Motamedi Daria , Morshed Saam , Hsiao Edward Chiaming
Published: May 2020

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder marked by painful, recurrent flare-ups and progressive heterotopic ossification (HO) in soft tissues. The bone formation can be idiopathic or provoked by trauma, illness, or inflammation. There are limited treatment options, with glucocorticoids and non-steroidal anti-inflammatory agents being used for palliative treatment. Palovarotene (PVO), an investigational retinoic acid receptor gamma agonist, offers a potential avenue to prevent HO development.

Clinical Case: The patient was a 29 year-old male, diagnosed with FOP at age 9, who enrolled in a study evaluating chronic PVO (5mg/day) for the treatment of FOP. Major joints affected at enrollment were his spine, jaw, shoulders, right hip and ankles. One year after starting PVO, he had a fall that resulted in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received flare-dosing PVO at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Post-surgical imaging 12 weeks after the surgery showed new bridging HO at the site of intramedullary rod insertion and around the distal screw.

Nine months after the fracture the patient had a second fall resulting in a right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. PVO was increased similarly to the above flare protocol, but, at the time of fracture occurrence rather than post-surgery. He had no skin or healing complications with either treatment regimen.

After each fracture the patient had prolonged recurrent flare-ups at the injury sites, significantly increasing his number of flare-ups per year. After the fractures there was new Brooker class D HO at the left hip, originating at the insertion of the intramedullary rod, and new class B HO at the right greater trochanter, again near the insertion site of the intramedullary rod compared to his pre-surgery baseline. In contrast, there was no new HO at the right distal intramedullary rod whereas HO occurred around the screw placement site at the left distal rod.

Conclusion: This case suggests that PVO in the dosing regimen received by this patient can be tolerated in an individual with FOP following major surgery. HO still occurred in this patient, particularly along the rod insertion track, suggesting that the PVO regimen may need to be optimized for surgical cases or that poly-trauma events may not be adequately blocked by the dosing regimen received by this patient. However, PVO did not negatively impact fracture healing or osteointegration, and no major skin healing effects were identified. Further investigation is needed to assess whether PVO can lead to a dose-dependent reduction in HO in the setting of trauma and surgery.
SUN-519 Hypokalemic Periodic Paralysis
Authors: Godfrey Sean , Hudspeth Victoria , Amoako Patricia , Drewno Michael
Published: May 2020

Background:Hypokalemic periodic paralysis is a rare disorder associated most often with a genetic defect in electrolyte channels, which can also occur in the setting of thyrotoxicosis. The presenting state in the acquired form has a low potassium, low TSH, high free T4 or high T3. It is more common in men, and in the Asian population with an approximate incidence of 2%. Symptoms can last from hours to days and are often precipitated by stress, exercise, and/or high carbohydrate intake. It is believed that the excess thyroid hormone creates an increased catabolic state which drives potassium inward and hyperpolarizes the muscle membrane to create a paralytic state. Case:A 23 year old African American male presented with chest discomfort and palpitations. TSH was <0.01 μU/mL (normal 0.530 - 6.340) with a free T4 of 3.31 ng/dL (normal 0.60–1.60). EKG showed ventricular conduction delay and he was sent home on propranolol 20mg daily and methimazole 5mg three times daily. He returned 5 days later with worsening palpitations and now new onset weakness. He was found to have a potassium of 1.4 mmol/L (normal 3.5–5.1) and magnesium of 1.2 mg/dL (normal 1.6–2.5). EKG showed normal sinus rhythm at a rate of 97, prolonged QT at 524msec (normal 330–470 msec), with repeat EKG 20 minutes later showing atrial tachycardia with a rate of 114 (normal 60–100). He was not able to move anything beyond his head, other than minor upper extremity hand movements, and could not sit up in bed. His potassium was initially repleted with eight doses of 10mEq KCl given q1h. His paralysis significantly improved within the first 4hrs, and was completely resolved by the next morning. Additional lab workup revealed thyroid stimulating antibody level of 13.00% (normal 0.0–0.55). He was discharged on methimazole 10mg twice daily and propranolol 10mg twice daily with instruction to follow up closely with his primary care physician and endocrinology. Conclusion:This patient presented with acute onset of weakness and palpitations in the setting of hyperthyroidism from Graves’ disease and hypokalemia consistent with thyrotoxic periodic paralysis. The physiology behind the presentation is not clear, but the current hypothesis is that depolarization of the neuromuscular junction leads to a tonic state from hyper-polarization. Thyroid hormone increases the metabolic demand, which along with an increase in sympathetic tone drives the sodium-potassium ATPase activity into overdrive, thus decreasing extracellular potassium. Thyrotoxic periodic paralysis is rare presentation, but should be considered for any patient that presents potassium abnormalities and symptoms of thyrotoxicosis.
MON-718 Abundant Circulation of Functional Short Non-Coding RNAs Expressed from the Intergenic Area in Mouse Serum
Authors: Habib Tanwir , Fadda Abeer , Mackeh Rafah , Marr Alexandra K , Kino Tomoshige
Published: May 2020

The human genome expresses numerous and different forms of non-protein-coding (nc) RNAs from over 80% of its sequence in addition to mRNAs. Although their overall functions and biological importance are still under intensive investigation, they appear to be important for supporting complex human biology. Some of these ncRNAs are recently identified in several human fluids, such as serum, urine and saliva. Here we present a comprehensive analysis on the short RNAs presented in mouse serum by employing three organs, adrenal gland, liver and ovary, as controls. We found that serum has numerous sRNAs. Among them, short ncRNAs (sncRNAs) expressed from the intergenic area (intergenic sncRNAs) dominated the majority (~97%) in serum with their read numbers equivalent to those found in three control organs. In contrast, known sncRNAs, such as ribosomal RNA fragments, transfer RNAs, micro RNAs, piwi-interacting RNAs, small nuclear and small nucleolar RNAs, were very minor components in serum, and were significantly low compared to control organs. Few short RNA fragments derived from mRNAs or long non-coding RNAs were also identified. The principal component analysis for the intergenic sncRNAs found in serum and three control organs revealed that the former was distinct from the latter. Indeed, ~90% of serum intergenic sncRNAs were not identified in each control organ in one-by-one comparisons. Multiple comparison between serum and all three control organs demonstrated a similar tendency: ~75% of the serum intergenic sncRNAs were distinct from the intergenic sncRNAs found in the three control organs, whereas these control organs shared 53% of them. The genomic areas encoding these intergenic sncRNAs tended to distribute around -20 - +20 kbs from the transcription start site of their nearby protein-coding genes. Among four selected serum intergenic sncRNAs, overexpression of the one located closely to the olfactory receptor 1322 gene exerted in a mouse hepatoma cell line the robust transcriptional regulatory activity on ~100 protein-coding genes that were accumulated in several distinct biological pathways. Our results indicate that mouse serum contains biologically active intergenic sncRNAs in addition to other known forms. The results also suggest their potential biological importance and/or usefulness in disease diagnosis and treatment in humans.
MON-327 Soluble Alpha Klotho and IGF-I Before Surgery as Prognostic Factors to Acromegaly Long-term Remission
Authors: de Oliveira Longo Schweizer Junia Ribeiro , Schilbach Katharina , Haenelt Michael , Wang Xiao , Bizzi Mariana Ferreira , Giannetti Alexandre Varella , Schopohl Jochen , Stoermann Sylvère , Rocha Beatriz Santana Soares , Ribeiro-Oliveira Antonio , Bidlingmaier Martin
Published: May 2020

BACKGROUND: Transsphenoidal surgery is the cornerstone of acromegaly treatment. However, cure is obtained in only ~50% of the cases. Until today, no biochemical marker has been identified to preoperatively predict surgical outcome and long-term remission. Recently, soluble alpha klotho (αKL) was proposed as new biomarker for diagnosis and follow-up of acromegaly. Therefore, we aimed to evaluate the potential of pre-surgery αKL concentrations as a prognostic factor to predict remission by surgery alone. Methods: We measured αKL concentrations (IBL-ELISA) and classical biomarkers (IGF-I and GHrandom, both by IDS-iSYS, GHnadir measured by IDS-iSYS (n=13) or DiaSorin-Liaison® (n=7)) in samples from a prospective study in treatment-naïve patients with acromegaly (total n=25). Patients were then followed for at least 6 months after surgery (median (range) 30.1 (6–142) months). Outcome was evaluated and classified as non-remission (NR: IGF-I>1.2xULN (n=2) or continued need for medical treatment with somatostatin analogues (n=10)) or remission (R: improvement on clinical signs and symptoms and IGF-I<1.2xULN without medical treatment, n=13). Results: Before surgery, all patients had elevated IGF-I (>1.2xULN), GHnadir (>0.4 ng/mL) and GHrandom (>1.0 ng/mL). As expected, αKL (pg/mL) was also high (>1.2xULN) in 92% patients. Before surgery, αKL was significantly higher in NR compared to R [6648 (4408–13951) vs. 3389 (2132–6837); p<0.05), as was IGF-I (ng/mL) [NR: 879.7 (771.8–961.5) vs. R: 640.2 (448.6–862.6); p<0.05). There was no difference in GHnadir and GHrandom (ng/mL) [10.42 (6.35–16.40) vs. 5.19 (1.19–10.70) and 12.39 (8.24–24.87) vs. 8.94 (4.24–15.55); p>0.05 for both comparisons). ROC analysis indicated that concentrations of αKL>4470pg/mL (~3.5xULN) (75% specificity, 62% sensitivity, AUC=0.72) and IGF-I>3.8xULN (67% specificity, 85% sensitivity, AUC=0.79) indicate lack of long-term remission. Conclusion: High αKL (>4470pg/mL, ~3.5xULN) and IGF-I (>3.8xULN) concentrations before surgery are significantly associated with persistent disease activity after surgery. However, both biomarkers alone or in combination have insufficient specificity (though acceptable sensitivity) as predictors of surgical outcome.
SAT-573 Eruptive Xanthomas in a Patient with Hypertriglyceredemia and Type 2 Diabetes Mellitus
Authors: Masood Faryal T , Khan Umar
Published: May 2020

BACKGROUND: Eruptive xanthomas are rare, asymptomatic, cutaneous lesions and are markers for serious underlying metabolic disorders that demand an early diagnosis to prevent morbidity and mortality.

Clinical Case: A 27 years old obese female presented with generalized, pruritic eruptions. The eruptions had been present for approximately three weeks. Crops of firm yellow-red circumscribed Papules (diameter 1–3 mm) distributed on the extensor surfaces of both the upper and the lower extremities which were few in numbers to begin with but increased in density subsequently spreading to involve her back, abdomen, knees, and posterior thighs. The patient besides being obese had no other significant past medical or family history. Labs: FBS:258 mg/dl (80-100mg/dl), HbA1c:11.7%(<5.6%), Total lipids: 3680 mg/dl (400–1000 mg/dl), Total Cholesterol: 857 mg/dl (120–200 mg/dl), Triglycerides: 5428 mg/dl (70–150 mg/dl), HDL:15mg/dl (45–64 mg/dl), LDL: 371 mg/l(<130 mg/dl),VLDL: 402 mg/dl (<30 md/dl). Results of kidney, liver and thyroid function tests were normal, as well as amylase and lipase. X-ray chest and abdominal ultrasound were unremarkable. Biopsy of the papules was not carried out due to non-affordability on the part of the patient. The patient was managed by an interdisciplinary approach for diabetes mellitus type 2 and hyperlipidaemia. Treatment was started with oral hypoglycaemic along with lipid lowering agents and the required lifestyle modifications including weight control, adopting a low-fat diet, and regular exercise were advised. The papules resolved within six weeks of the treatment and lab reports indicated improvement in her glycemic control and hypertriglyceridemia. It was clinically diagnosed as Eruptive Xanthomas of secondary hypertriglyceridemia due to diabetes mellitus.

CONCLUSION:

Recognizing eruptive xanthomas and being aware of its association with hypertriglyceridemia and diabetes mellitus can help to decrease any lag between a patient being seen by a physician and treatment for a serious medical conditions such as coronary artery disease and pancreatitis.

REFRENCES: Digby M; Belli R; McGraw T; Lee A (2011). “Eruptive xanthomas as a cutaneous manifestation of hypertriglyceridemia: a case report”. J Clin Aesthet Dermatol. 4: 44–6. PMC 3030216Freely accessible. PMID 21278899.
SUN-237 Sex Differences in the Effect of Osteocalcin and Exercise on Memory and Cognition
Authors: Winberg Jordan , Rentz Jesse , Darwish Lina , Swardfager Walter , Mitchell Jane
Published: May 2020

Osteocalcin is a protein produced in the osteoblasts of bone and found both in the bone matrix and in circulation1. Mouse studies have demonstrated that osteocalcin administration improves type II diabetes through increased insulin release and sensitivity2. Further, osteocalcin can cross the blood-brain barrier and has been shown to restore memory and cognition in mice3. To date, experiments testing the effects of osteocalcin in mice have almost exclusively been conducted in only one sex and could not account for sex as a biological variable. We hypothesized that osteocalcin and exercise would improve behavioral outcomes and aimed to record any difference in response between sexes. In this study, we compare the effects of daily osteocalcin treatment, with or without daily treadmill exercise, in male and female mice (C57BL/6) on a high-fat diet induced model of type II diabetes. Mice were fed high-fat diet for eight weeks, followed by eight weeks of daily osteocalcin injections and/or treadmill exercise. During the final two weeks of treatment behavioural testing for depressive-like behaviour, anxiety-like behaviour, problem-solving, and memory was completed, and the results obtained in male and female mice were compared. The high-fat diet increased depressive-like behaviour and impaired problem solving in both sexes. Significant interactions between sex and exercise and sex and diet were observed. High-fat diet increased anxiety-like behaviour in females, but not males, while exercise increased anxiety-like behaviour in males. Both treatments improved behavioural outcomes, though no difference could be attributed to the combination of treatments. Exercise and osteocalcin decreased depressive-like behaviour in both sexes. Osteocalcin improved problem solving in both sexes, but exercise only improved problem solving in females. The effects of osteocalcin were similar in both male and female mice, however exercise improved problem-solving only in female mice. This suggests that both sexes benefit from osteocalcin treatment and exercise may be more beneficial in females. The results indicate that osteocalcin and exercise have similar but not identical effects on behaviour that may be reflected in overlapping mechanisms of action. References: (1) Lee et al., Cell. 2007; 130(3): 456-469. (2) Ferron et al., Bone. 2012; 50(2): 568–575. (3) Khrimian et al., J Exp Med. 2017; 214(10): 2859-2873.
SUN-359 Antenatal Oral Iron Supplementation, FGF23 and Bone Metabolism in Kenyan Women and Their Offspring: A Randomised Controlled Trial
Authors: Braithwaite Vickie S , Demir Ayse Y , Mwangi Martin N , Jones Kerry S , Prentice Ann , Prentice Andrew M , Andang’o Pauline E A , Verhoef Hans
Published: May 2020

Objectives: FGF23 decreases reabsorption and increases phosphate excretion in the kidney and regulates vitamin D metabolism. Maternal iron deficiency may be implicated in the pathogenesis of hypophosphataemia-driven rickets in offspring through perturbed FGF23 expression. We aimed to determine the effect of antenatal oral iron supplementation on maternal and neonatal markers of bone mineral regulation.

Methods: 470 rural Kenyan women with singleton pregnancies and haemoglobin concentrations ≥90g/L were randomly allocated to daily, supervised supplementation iron (60mg as ferrous fumarate) or placebo from 13–23 weeks gestational age until 1 month postpartum. We analysed maternal and neonatal plasma samples collected at birth, with primary outcomes being concentrations of FGF23 in its intact form (I-FGF23, the phosphate- and vitamin D-regulating hormone) and its C-terminal fragment (C-FGF23).

Results: In mothers and neonates, antenatal iron supplementation reduced C-FGF23 concentration by 62.6% (95%CI: -70.3% to -53.0%) and 15.2% (-28.4% to 0.3%), respectively; increased neonatal I-FGF23 concentration by 21.6% (1.2% to 46.1%); increased maternal hepcidin concentration by 136%, (86% to 200%); and decreased maternal 25-hydroxyvitamin D concentrations by 6.1nmol/L (1.2 to 11.0nmol/L). We found no effect on markers of bone turnover in either mothers or neonates. The magnitude of the effect of antenatal iron supplementation on concentrations of C-FGF23, I-FGF23 and phosphate, and on estimated glomerular filtration rate (a measure of kidney glomerular function) depended on maternal iron status at baseline

Conclusions: Antenatal iron supplementation may provide health benefits to pregnant women and their offspring beyond increasing iron status. Whether iron supplementation reduces present and future infant risk of rickets remains unclear.
SAT-259 Acromegaly by Pituitary Adenoma Associated with ACTH-Independent Cushing Syndrome by Adrenal Carcinoma: Case Report
Authors: Minuzzi Ricardo Kunde , Landenberger Giullia Menuci , Pereira Lima Julia Fernanda Semmelmann , Oliveira Miriam da Costa , Leães Rech Carolina Garcia Soares
Published: May 2020

Introduction: The coexistence of acromegaly and Cushing’s syndrome is quite rare. Case reports with this association have been described in the literature, including both ACTH-dependent and ACTH-independent Cushing’s syndrome. In these cases, when considering ACTH-independent hypercortisolism, the main etiology reported is adrenal adenoma. We will describe the case of an acromegalic patient with ACTH-independent cushing syndrome due to adrenal cortical carcinoma.

Clinical Case: A 62-year-old male patient with acromegaly diagnosed by headache investigation. He had a previous medical history of T2DM for 20 years, grade III obesity (BMI 40.3), hypertension, obstructive sleep apnea and depression. Initial investigation showed IGF-1 levels of 818 ng/mL (81–225), GH: 3.39 ng/mL (<0.97), prolactin diluted: 2.578 ng/mL (2.1–17, 7), LH: <0.07 mIU/mL (1.5–9.3), FSH: 0.6 mIU/mL (1.4–18.1), total Testosterone: 51 ng/dL (241- 827) Cortisol at 8 AM: 15 µg/dL, TSH: 1.54 µg/dL (0.55–4.78), free T4: 1.0 ng/dL (0.89–1.76) and brain MRI with a large expansive sella turcica process, invading the right cavernous sinus, with growth to the sphenoid sinus and suprasellar compressing the optic chiasm, suggestive of pituitary macroadenoma. He underwent transsphenoidal resection with histology confirming a prolactin and GH co-secretory pituitary adenoma with Ki-67: 5%. He started treatment with octreotide LAR (30 mg/month) and cabergoline (3.5 mg/week) and underwent 25 radiotherapy sessions. Three years after the diagnosis of acromegaly, the patient underwent CT scan of the abdomen, which identified a 3.8 cm left adrenal nodular lesion that evolved in the 12-month control exam to nodular image with lobulated contours (5.0 x 3.4 cm) and non-contrast phase density > 25 HU. At that time, he had two 24-hour cortisoluria samples: 640.9 and 637 µg/24hs (54–403) and ACTH <5.0 pg/mL (<46).The patient underwent videolaparoscopic adrenalectomy confirming the pathology of the lesion compatible with adrenal cortical carcinoma with invasion of the capsule and peri-adrenal adipose tissue and Ki-67: 20%. Even after primary resection of the adrenal lesion, the patient evolves with local and metastatic progression of the disease, dying a few months later, due to infectious complications of a new surgical approach.

Conclusions: To the best of our knowledge, this is the first case of ACTH-independent Cushing’s syndrome caused by adrenocortical carcinoma in an acromegalic patient.
SAT-677 A Case of Opdivo Induced Type 1 Diabetes
Authors: Lucier Jessica , Tabatabai Laila
Published: May 2020

BACKGROUND: Opdivo, or Nivolumab is an immunotherapy medication that works as a checkpoint inhibitor. It is used in various cancers not amenable to surgery, including lung cancer and metastatic melanoma. Opdivo has proven to be a beneficial treatment, though it is not without complications including thyroid dysfunction, hypophysitis, and autoimmune induced diabetes.

Clinical Case: An 80 year old female with a PMH of type 2 diabetes mellitus, hypertension, hyperlipidemia, and melanoma with metastasis to the bone was evaluated by endocrinology for acute worsening of her type 2 diabetes. The patient had been diagnosed with diabetes 10 years prior. She was well controlled on 22 units of levemir and Janumet. Her baseline HbA1c was 6.7%. She had no known complications from her diabetes. Four months prior to presentation she had been started on monthly Opdivo infusions for her metastatic melanoma, which she was tolerating well.

On presentation to the hospital, she had persistent hyperglycemia in the high 400’s, an elevated anion gap, and an elevated betahydroxybutyrate. She had no signs of acute infection and no significant changes in her diet or activity level. She was started on an insulin drip for diabetic ketoacidosis until her anion gap resolved. At discharge she was continued on 22 units of levemir, a humalog sliding scale, and Janumet. At that time it was unclear what precipitated her acute change in glycemic control.

At her follow up endocrinology appointment several labs were drawn including a c-peptide, though antibodies were not obtained. Her c-peptide was less than 0.1 with a concurrent blood glucose value of 370. It was determined that she had developed autoimmune induced diabetes secondary to Opdivo therapy and would require life long insulin therapy. Her Janumet was discontinued. She was started on a T-slim insulin pump and Dexcom G6 sensor, with improvement in her glucose control. Her Opdivo treatments were discontinued. She has since developed worsening metastasis in her femur and will be started on Yervoy. Yervoy also carries a risk of further endocrine disorders, including increased risk of hypophysitis.

Discussion: Acute changes in glycemic control warrants further investigation to determine the underlying precipitating factor. The most common complications of Opdivo are rashes and fatigue, though endocrinopathies have been noted in several patients. It was crucial in this patient to identify this side effect of Opdivo, as it helped to prevent further episodes of DKA. Careful review of recent medication changes helped identify this uncommon complication of Opdivo and prompted a timely change in her diabetes care regimen.
SAT-541 Difference in Aldosterone Dependency Between Cardiovascular Diseases and Renal Impairments in Patients with Primary Aldosteronism
Authors: Sone Masakatsu , Ohno Youichi , Kawashima Akiyuki , Inagaki Nobuya , Naruse Mitsuhide ,   JPAS/JRAS Study Group
Published: May 2020

BACKGROUND:

There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) and renal impairment in patients with primary aldosteronism (PA); however, their results have left it unclear as to whether they are affected by the plasma aldosterone concentration (PAC) itself.

Method:

This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalences of CVD (stroke, ischemic heart disease, and heart failure) and renal impairment (proteinuria and lowered eGFR) among patients with PA and those with essential hypertension (EHT). We also performed logistic regression analysis to determine which parameters significantly increased the odds ratio for these complications.

Results:

The prevalence of CVD was significantly higher among 2814 patients with PA than among matched patients with EHT. The prevalence of proteinuria was also significantly higher among PA than EHT patients, whereas there was no significant difference in the prevalence of lowered eGFR. Multivariable logistic regression analysis showed that the PAC significantly increases the adjusted odds ratios for proteinuria and lowered eGFR independent of other known risk factors. By contrast, the PAC was not linearly related to the adjusted odds ratio for CVD.

Conclusion:

Plasma aldosterone levels are closely associated with renal impairment in patients with PA. This is contrast to our finding that the PAC was not, itself, linearly associated with CVDs, such as stroke or ischemic heart disease. The mechanism underlying the kidney damage in patients with PA may thus differ from that affecting the cardiovascular system.
SAT-576 Possible Involvement of Thyroid Function in PCSK9 Inhibitor Therapy
Authors: Iwabuchi Masayasu
Published: May 2020

INTRODUCTION

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition is an effective strategy for lowering plasma LDL-cholesterol and enhancing the LDL-cholesterol lowering ability of statins. PCSK9, a serine protease that binds to the LDL receptor promoting its degradation, is an important regulator of LDL metabolism. In addition, LDL-cholesterol is also controlled by TSH and thyroid hormones via PCSK9. TSH has received increasing attention as being closely associated with increased LDL-cholesterol level and higher atherosclerotic risks. In vitro study, the effects of TSH on hepatic PCSK9 expression in HepG2 cells were reported (1). I here report a case of transient hyperthyroidism secondary to PCSK9 inhibitor therapy. This case highlights the involvement of thyroid function in PCSK9 Inhibitor therapy.

CLINICAL CASE

A 65-year-old man had a weight loss of 6 kg (13 lbs.) in 4 months, accompanied with fatigue. He had a past history of myocardial infarction and his LDL was 83 mg/dL by 2.5mg of rosuvastatin and heart rate was controlled by 10mg of carvedilol. Six months ago, he started a PCSK9 Inhibitor therapy with 140mg of evolocumab every 2 weeks for 6 weeks. He had no preceding viral illness and denied anterior neck pain or tenderness. His height was 1.53 m, weight 52.6 kg (115 lbs.), and body mass index (BMI) 22.46 kg/m2. His thyroid was not enlarged and non-tender without clear palpable thyroid nodules or neck lymph nodes. Hyperthyroidism was suspected and confirmed by thyroid function tests: TSH was less than 0.0005 μIU/mL (normal 0.35–4.94), and free T4 1.830 ng/dL (0.70–1.48). Graves’ disease was considered, and thyroid antibody tests performed. Thyroid peroxidase (TPO) antibody titer was less than 9 IU/mL (<9), and TSI 141% (<120%). To confirm the diagnosis of this hyperthyroid patient, Technetium-99m uptake and scan was done which showed uptake of 0.8% (0.5–7%). After careful observation for 2 months with 5mg of carvedilol, he turned asymptomatic and free T4 lowered to 1.480 ng/dL and TSH remained less than 0.0005 μIU/mL.

CLINICAL LESSONS

I here report a case of transient hyperthyroidism secondary to PCSK9 inhibitor therapy. There has been no report of hyperthyroidism induced by PCSK9 inhibitors. Immunological influence of anti-PCSK9 therapy on thyroid is unknown. In this case, the decrease of TSH due to hyperthyroidism was considered to reduce hepatic PCSK9 expression, leading to additive effect to PCSK9 inhibitor. PCSK9 inhibitors may modify the effects of hyperlipidemia treatment by causing changes in thyroid function. When using PCSK9 inhibitors, follow-up of thyroid function should be considered. This case highlights the involvement of thyroid function in PCSK9 inhibitor therapy.

Reference

(1) Gong, Y., Ma, Y., et al. Thyroid stimulating hormone exhibits the impact on LDLR/LDL-c via up-regulating hepatic PCSK9 expression. Metabolism. 2017;76;32–41