bluuebunny/crossref_metadata_2025 huggingface dataset:
OR07-06 The Roles of GNAQ and GNA11 in Calcium-Sensing Receptor (CaSR) Signalling
Authors: Gluck Anna K , Stevenson Mark , Falcone Sara , Inoue Asuka , Breitwieser Gerda E , Gorvin Caroline M , Lines Kate E , Thakker Rajesh V
Published: May 2020

The G-protein subunits Gα 11 and Gα q, which share >90% peptide sequence identity and are encoded by the GNA11 and GNAQ genes, respectively, mediate signalling by the calcium-sensing receptor (CaSR), a class C G-protein coupled receptor (GPCR) that regulates extracellular calcium (Ca2+e) homeostasis. Germline Gα 11 inactivating and activating mutations cause familial hypocalciuric hypercalcaemia type-2 (FHH2) and autosomal dominant hypocalcaemia type-2 (ADH2), respectively, but such Gα q mutations have not been reported. We therefore investigated the DiscovEHR cohort database, which has exomes from 51,289 patients with matched phenotyping data, for such GNAQ mutations. The DiscovEHR cohort was examined for rare GNAQ variants, which were transiently expressed in CaSR-expressing HEK293A Gα q/11 knockout cells, and their effects on CaSR-mediated intracellular calcium (Ca2+i) release and MAPK activity, in response to increasing concentrations of extracellular calcium were assessed using a nuclear factor of activated T-cells response element (NFAT-RE) luciferase reporter construct and a serum response element (SRE) luciferase reporter construct, respectively. Responses were compared to those of wild-type (WT), inactivating FHH2-associated GNA11 mutations (Leu135Gln and Phe220Ser), and engineered GNAQ mutations that were equivalent to the FHH2-causing GNA11 mutations. Gα q/11 protein expression was confirmed by Western blot analysis. Six rare missense GNAQ variants (Arg19Trp, Ala110Val, Gln299His, Ala302Ser, Ala331Thr, Val344Ile) were identified in DiscovEHR individuals, all of whom had mean plasma calcium values in the normal range (8.30–10.00 mg/dL). Functional characterisation of all six Gα q variants showed no significant difference to WT Gα q responses, thereby indicating that these variants are unlikely to be disease-causing mutations. In addition, the FHH2-causing GNA11 mutations (Leu135Gln and Phe220Ser) had significantly reduced responses, compared to WT Gα 11; however, this could be compensated by WT Gα q. GNAQ Leu135Gln and Phe220Ser, in contrast to their Gα 11 counterparts, showed no differences in protein expression or signalling responses when compared to WT Gα q. Our study, which provides mechanistic insights into the differences between Gα q and Gα 11, indicates that Gα q, unlike Gα 11, does not play a major role in the pathogenesis of FHH2 or ADH2.
SUN-629 Text for Success in Gestational Diabetes: Development and User Experience Testing of a Text Messaging Program
Authors: Blair Rachel A , Dias Jennifer M , McDonnell Marie E , Seely Ellen W
Published: May 2020

Background: Gestational diabetes mellitus (GDM) affects 5–10% of pregnancies in the United States. Poorly controlled GDM can lead to serious fetal and maternal complications. Women diagnosed with GDM are asked to form many new self-management habits. Studies have shown that text messaging is an effective, easily accessible way to improve management of diabetes outside of pregnancy, but this method has not been studied in GDM.

Objective: Obtain user feedback and iteratively incorporate it into a personalized text messaging program for women with GDM.

Methods: We performed user experience testing of a text messaging program (Txt4GDM), which was created by a multidisciplinary team based on the Health Belief Model. The program includes: 1) reminders to check blood glucoses sent 4 times per day based on self-reported mealtimes, 2) positive feedback for each blood glucose reported by a user (with an algorithm instructing users to contact their care team if too high/low), 3) one educational message and 4) one motivational message per week.

Women with GDM received simulated messages on a study smartphone. Subjects participated in semi-structured interviews about the content and phrasing of text messages. Interview replies were categorized into themes and used to iteratively optimize the program.

Results: 10 women completed user experience testing. All participants thought the program would be useful for women with newly diagnosed GDM and would use it during their first pregnancy with GDM. There were several features of the program that participants particularly liked, which were categorized into two themes: 1) customization of timing of messages and 2) messages including information not adequately covered in routine care (such as healthy snack ideas and exercise).

Several themes emerged from the semi-structured interviews that were used to optimize the program. 1) Further customization of message timing: We added the ability to enter different mealtimes for weekends and weekdays, which was well-received in subsequent iterations. 2) Minimization of jargon: Multiple women did not know what the “M” in GDM stood for, so we removed “GDM” from the messages. 3) Women wanted the messages to be more specifically related to GDM. For example, an educational message said: “Drinking water, instead of soda or juice, is healthy for you.” The phrase “and can help regulate your blood sugar” was added based on participant feedback.

Conclusions: Overall, women with GDM would use the Txt4GDM text messaging program and think it would be helpful for GDM self-management. Based on user feedback, enhanced customization of timing of text message delivery, minimization of jargon, and language specific to GDM in educational messages were added. We are testing the optimized text messaging program in an ongoing usability study.
MON-621 Prescription Analysis Shows High Metformin Use and Acceptance in a Diabetes Specialty Centre in Eastern India
Authors: Mishra Sanat Kumar , Mishra Susant , Sahoo Abhay Kumar , Padhi Rajesh Kumar , Jena Biswaranjan , Jena Apurba Ranjan , Khatua Ranjit Kumar , Pradhan Santosh Kumar , Jena Sanghamitra , Khuntia Monalisa , Mahapatra Hariballav
Published: May 2020

Background and aims: Achieving glycemic goals is crucial in the overall management of diabetes. Selecting the right medication for the individual patient is of paramount importance in the present day’s patient centric glucose control. Metformin is the first line and gold standard antihyperglycemic agent that can be offered to type 2 diabetics. Addition of a second or third agent or insulin should be considered in those whose HbA1c remains high despite the up-regulated metformin dose or those who do not tolerate metformin. We aimed to find the pattern of metformin use in type 2 diabetic subjects in a diabetes specialty centre in coastal Odisha.

Materials and methods: This observational study was conducted in a diabetes setup in coastal Odisha in June 2018. After obtaining consent from patients, authors looked into the prescriptions of all type 2 diabetic adults. Subjects who were prescribed metformin (in any dose) were enrolled in the study. Those with established nephropathy, coronary artery disease, stroke or cancers were excluded.

Results:There were 802 footfalls noted during the study period, of which 723 metformin taking participants (298 females, 41.2%) were considered for analysis (79 persons were excluded: not meeting inclusion criteria/ not willing to participate/ history of nephropathy/ CAD/ stroke). Mean age, diabetes duration, FPG, HbA1c, serum creatinine, eGFR of the study population were 51.6±10.6 years, 11.9±11.2 years, 138.7±51.7 mg/dl, 7.8±2.1%, 0.93±0.29 mg/dl and 96.5±11.1ml/min respectively. Patients were prescribed metformin in various doses, i.e., 500mg (42 patients, 5.8%), 850mg (47 patients, 6.5%), 1000mg (396 patients, 54.8%), 1500mg (13 patients, 1.8%), 1700mg (86 patients, 11.9%) and 2000mg (130 patients, 18.0%), and 2500mg (9 patients, 1.2%). Metformin was prescribed as monotherapy (n=34, 4.7%) or along with other OADs (n=589, 81.5%) or in combination with insulin (n=178, 24.6%). Retrospective analysis of the medical records and further questioning revealed that gastric intolerance was the commonest reason for withdrawal of metformin in otherwise eligible subjects.

Conclusion: Metformin was the most commonly prescribed antidiabetic drug and the daily dose of more than 85% of the metformin administered individuals was 1000mg or above.
MON-083 Childhood Diabetic Ketoacidosis (DKA) in New-Onset and Established Patients in Central Illinois: Contributing Factors and Risk Stratification
Authors: Szymczuk Vivian , Dunneback James , Wang Yanzhi , Benavides Valeria C
Published: May 2020

Introduction: DKA is the leading cause of hospitalizations in children with type 1 diabetes mellitus (T1DM). Although most cases are preventable, DKA continues to occur in established patients.

Aim: To identify contributing factors and outcomes of DKA pediatric admissions in a tertiary referral center with a large rural catchment area to assess for actionable items to prevent DKA.

Methods: A retrospective, single-center chart review assessing children ˂19 years old admitted in DKA from October 2014 to May 2018. DKA was defined as a pH of ≤7.3 or bicarbonate of ≤15. Demographic data included gender, age, zip code, insurance type and ethnicity. Admission measures included HbA1c, DKA group (new-onset “NT1” or “ET1” established T1DM diagnosis), DKA severity (severe pH <7.1, CO2 <5mEq/L), contact with clinic, home insulin delivery. Outcomes included length of stay (LOS), total admission costs (TAC) and reimbursements amounts (RA).

Results: 272 patients were included (mean age 11.7 y, range 4.4-16; 60% female, 83% Caucasian, 14% African American). Of these, 33% were NT1 DKA. Compared to NT1 DKA, ET1 DKA patients were older (8.7 vs. 13.1 years, p < 0.001), more likely female (49% vs. 65%, p 0.034) with public insurance (55% vs 63%, p 0.028); 73% didn’t contact the diabetes team prior to admission and 52% used an insulin pump. There were no significant differences in HbA1c or DKA severity.

LOS was similar between NT1 and ET1 DKA (p 0.051). Severe DKA was associated with longer LOS (RR 1.47, p < 0.0001). Public vs. private insurance was associated with 1.28 times longer LOS (p < 0.0001).

While there was no difference in TAC between NT1 and ET1 DKA groups (p 0.877), costs were higher with public vs. private insurance (>$900, p 0.050) and severe DKA (RR 1.92; 95% CI 1.62-2.27; p <0.0001). TAC were different between regions within central Illinois (RR 1.39; 95% CI 1.08-1.80; p 0.002).

Hospital RA was higher for NT1 vs. ET1 group (RR 1.26; 95%CI 1.03-1.54; p 0.0237) and higher DKA severity (RR 1.57; 95% CI 1.26-1.95; p <0.0001); but lower for public vs. private insurance (RR 0.43; 95% CI 0.35-0.52; p <0.0001).

Discussion: Established DKA patients tended to be rural teenage females, poorly controlled and public health insured. Severity of DKA and LOS did not differ between the groups. While TAC were similar among the groups, TAC were higher with public insurance and severe DKA. Lower hospital RA were seen for recurrent cases and public insurance. This study provides valuable information about non-metropolitan at-risk population characteristics to inform targeted preventive interventions. These findings suggest a significant difference in hospitalization RA, providing incentive for health care facilities / providers to invest in early outpatient interventions and QI initiatives.
SUN-371 Hyponatremia Correction Normalizes Bone Mineral Density and Bone Fragility in Rats
Authors: Xu Qin , Pillai Sambhu M , Barsony Julia , Herfat Safa , Verbalis Joseph G
Published: May 2020

Multiple epidemiologic studies have associated chronic hyponatremia with both osteoporosis and bone fractures. Studies in experimental animals and cultured cells have demonstrated that reducing the extracellular sodium concentration ([Na+]) causes bone loss primarily by increasing osteoclast formation and bone resorbing activity. In osteoclastic cell cultures, reducing [Na+] activated biochemical and functional changes in osteoclast activity, which appear to occur by direct sodium-sensing mechanisms on osteoclasts that are independent from changes in osmolality. Whether the pathological changes in bones induced by hyponatremia can be reversed by correction of hyponatremia has not been studied. The present studies were initiated to address this question. 22-month-old F344BN F1-hybrid rats were made hyponatremic using a desmopressin continuous infusion while fed a liquid diet. After 3 months of chronic sustained hyponatremia, a cohort of the hyponatremic rats were corrected to a normal [Na+] by removal of the desmopressin minipumps and allowed to recover for 2 months. Both bone density measurements by DXA and biomechanical testing were performed on excised bones from normonatremic control rats (NN, [Na+]=145±5.6 mmol/L, n=9), chronically hyponatremic rats (HN, [Na+]=114±4.7 mmol/L, n =9) and hyponatremic corrected rats (HC, [Na+]=139±1.4 mmol/L, n =9). The results confirm that chronic hyponatremia caused significant decreases in bone mineral density (BMD, g/cm2) in the L4 vertebra (NN=0.166±0.003, HN=0.151±0.002, P=0.002) and femur (NN=0.229±0.004, HN=0.213±0.005, P=0.024). Bone fragility as measured by ultimate load to fracture (UL, Newtons) was also increased in the L5 vertebra (NN=369.8±51.1, HN=262.9±29.4, P=0.0001), but only slightly in the femur (NN=295.4±57.5, HN=286.0±35.4, P=0.682). Following correction of hyponatremia, both BMD and UL recovered after 2 months to levels not significantly different than the normonatremic controls: L4 BMD (NN=0.166±0.003, HC=0.167±0.002, NS); femur bone density (NN=0.229±0.004, HC=0.226±0.003, NS); UL in the L5 vertebra (NN=369.8±51.1, HC=384.1±63.5, NS). These results show that bone fragility parameters are adversely affected by chronic hyponatremia in addition to the previously reported decreases in BMD in rats. Consistent with the BMD results, the trabecular bone in the spine was more severely affected than the cortical bone in the femur. Our results show that much of the bone pathology of hyponatremia-induced osteoporosis can be reversed following correction of the hyponatremia without using specific antiresorptive therapy. Our findings therefore raise the possibility that correction of hyponatremia may be effective as a therapy for treatment of hyponatremia-induced osteoporosis in selected patients.
SUN-509 Plasmapheresis Treatment of Thyrotoxicosis in Pregnancy for Preparation of Thyroidectomy
Authors: Horani Mohamad Hosam , Brooks Ryan M , Vazques Bianca , Arashahi Robert , Khan Mustapha
Published: May 2020

Introduction: Thyrotoxicosis in pregnancy presents the challenge of maintaining a normal level of maternal free thyroid hormone, while minimizing adverse drug effects, obstetric complications, and the risk fetal hypothyroidism.

Propylthiouracil is used for treatment in the first trimester with thyroidectomy typically performed in the second trimester if PTU/ MTZ are intolerable or if thyrotoxicosis persists. When thyroidectomy is indicated, thyroid hormone levels must be normalized prior to the operation, as there is risk of thyroid storm that can occur during and up to several hours postoperatively. In such cases, preoperative plasmapheresis may be considered.

Case Presentation: We present a 24 year old G2P0101 Hispanic female who reported to the ED with throat pain, chills, tachycardia, and shortness of breath who was found to have a TSH less than 0.005, free T4 3.15, elevated alkaline phosphatase, and an incidentally discovered early pregnancy approximately 4 - 6 weeks gestation. Medical history includes hyperthyroidism with over ten hospitalizations for thyrotoxicosis within the last three years and preterm delivery during her first pregnancy. A recent thyroid biopsy in 2017 showed a benign multinodular goiter. She had been taking methimazole and current CT of the neck demonstrated marked thyroid goiter with mild tracheal narrowing and mild tonsillitis. She was discharged on propylthiouracil 100 mg TID, metoprolol 25 mg TID, and augmentin 875 mg BID with the goal of decreasing her free T4 and T3 in preparation for thyroidectomy. Four days later, the patient returned to the ED with similar symptoms. Labs revealed TSH 0.001, free T4 3.70, FreeT3 15.1 WBC 3.1, platelets 103, and elevated total bilirubin, transaminases, and alkaline phosphatase. EKG demonstrated sinus tachycardia with minimal diffuse ST depression. Ultrasound showed a 0.34 cm round hypoechoic focus in the endometrial cavity without a fetal pole or cardiac activity. Chest X-ray demonstrated minor bibasilar atelectasis. The patient was admitted and PTU was discontinued due to leukopenia and elevated transaminases. Dexamethasone was started and metoprolol was continued.

Total thyroidectomy was planned for when free T4 less 2.0 The patient received two treatments of plasmapheresis, which decreased free T4 to 2.11 and then to 1.40. The thrombocytopenia and transaminitis resolved

A total thyroidectomy was performed and well tolerated. patient had full term pregnancy, uneventful delivery while on thyroid hormone replacement.

Conclusion : Preoperative plasmapheresis can be considered for the normalization of free T4 if thionamides fail or cannot be tolerated. This case demonstrates the successful management of thyrotoxicosis with plasmapheresis in the first trimester of pregnancy.to Our knowledge Plasmapheresis was not used before in Pregnancy in preparation for thyroidectomy.
OR30-03 Racial Differences in Technology Use Among Type 1 Diabetes in a Safety-Net Hospital
Authors: Wirunsawanya Kamonkiat , Rizo Ivania , Fantasia Kathryn
Published: May 2020

Objective: There is limited data regarding the use of diabetes technology such as continuous glucose monitor (CGM) and continuous subcutaneous insulin infusion (CSII) among patients with type 1 diabetes (T1D) in a minority serving and safety-net hospital. We examined racial differences in the use of CGM and CSII in this setting.

Methods: A retrospective review of 227 patients ≥ 18 years of age with T1D seen in the Endocrinology clinic at a safety-net hospital from October 2016 and September 2017 was completed. Statistical analysis assessed the likelihood of diabetes technology use among different races.

Results: The mean age was 39, 59% male, mean duration of diabetes was 21 years, 30% overweight, 22% obesity, 80% English speaking, and 50% had government insurance. In terms of the distribution of race/ethnicity, 43% were Caucasian, 25% African American (AA), 15% Hispanic, 15% defined as other, and 2% Asian. Mean HbA1c ± standard deviation (SD) of any technology (either CGM or CSII or both) and non-technology users were 8.27 ± 1.58 and 9.49 ± 2.04, respectively. Patients who had government health insurance were found to have lower odds of using technology (odds ratio [OR], 0.43; 95% confidential interval [CI], 0.25 - 0.74) compared to patients who had private health insurance. Overall, 26% of the patients used CSII with 43% of this population Caucasian, 10.5% AA and 14.2% Hispanic. The overall CGM use was 30% with 47% of users Caucasian, 14% AA and 22% Hispanic. In a multivariable logistic regression model that adjusted for insurance and language, AA or other were found to have statistically significant lower odds of using technology (AA OR 0.25 [95% CI 0.11 - 0.53] and other OR 0.33 [95% CI 0.12 - 0.89]) compared to the Caucasian group.

Conclusion: Our study showed that the use of technology in the Caucasian group was statistically significantly higher than in the non-Caucasian groups except for the Asian group. After adjusting for insurance and language, AA and other demonstrated statistically lower rates of technology use. Racial differences in diabetes technology use were observed in our study as well as the association between technology use and lowered HbA1c. Given diabetes technology is a useful tool in reducing HbA1c and hypoglycemia, the barriers to accessing diabetes technology in non-Caucasian individuals should be addressed to decrease health disparities.
SUN-019 Androgens Modulate Lipid Metabolism and Absorption in Control and Polycystic Ovary-Metabolic Syndrome Conditions
Authors: Vine Donna Faye , Lehner Richard , Watts Russell , Horkey Melanie , Ghosh Mahua , Proctor Spencer
Published: May 2020

Introduction: In polycystic ovary syndrome (PCOS) a high plasma level of androgens has been correlated with an adverse plasma lipid profile. At present we do not know the physiological or mechanistic pathways of how androgens regulate lipid metabolism under control or PCOS conditions. We have shown flutamide, an androgen receptor (AR) inhibitor, reduces the plasma concentration of triglycerides (TG) and apoB-lipoproteins, and intestinal secretion of TG. Aim: The aim of this study was to determine the direct physiological and mechanistic effects of androgens, Testosterone (T) and dihydrotestosterone (DHT), on lipid metabolism using a PCOS-prone rodent model. Methods: Control and PCOS-prone animals were administered vehicle, T or DHT for 7 days. PCOS-prone animals also present with the Metabolic Syndrome (MetS). Following treatment animals underwent a mesenteric lymphatic cannulation procedure to determine effects on intestinal chylomicron (CM-apoB48) and lipid secretion, and absorption using radiolabelled [³H]-cholesterol and [14C]-palmitic acid.

Results: Plasma LDL-C was increased with DHT treatment in control animals, and with both T & DHT treatment in PCOS. Intestinal absorption of TG and cholesterol were increased in T and DHT treated PCOS animals but not control animals. Whereas DHT reduced intestinal CM-apoB48 secretion in both control and PCOS groups. These effects were associated with changes in genes and protein expression in lipogenic (SREBP1a/c&2, SREBP1c, SREBP-2, ACC) and steroidogenic pathways (AR, ER and SRDA51) in the liver and intestine.

Conclusion: These results demonstrate androgens modulate lipid metabolism and absorption. T and DHT differentially affect intestinal chylomicron secretion and lipid absorption in PCOS-MetS and control conditions. In conclusion, these results suggest that androgens may directly cause or exacerbate lipid and lipoprotein metabolism in conditions of hyperandrogenemia and the MetS.
OR18-03 Functional TSH Receptor Antibodies Are a Biomarker for Graves’ Disease - a Prospective Trial
Authors: Kahaly George Jean , Diana Tanja , Kanitz Michael , Olivo Paul D
Published: May 2020

Objective

We aimed to evaluate the clinical utility and predictive value of stimulatory (TSAb) and blocking (TBAb) TSH receptor antibodies in the management of Graves’ disease (GD).

Methods

Hundred well-defined, consecutive, unselected, untreated hyperthyroid patients with GD were enrolled in a prospective two-year trial. Methimazole (MMI) was administered for 24 weeks according to baseline serum concentrations of free T3/free T4. Starting dose was 5–30 mg/day. Through a titration regimen, this dose was respectively tapered or increased at each subsequent study visit as the patient became euthyroid or remained hyperthyroid. Goals of therapy were to maintain normal fT4 and TSH levels. MMI therapy was stopped at week 24. The main outcome measure was clinical response versus non-response to a 24-week MMI treatment defined as biochemical euthyroidism versus persistent hyperthyroidism at week 24 and/or relapse at weeks 36, 48, and 96. TSAb was reported as percentage of specimen-to-reference ratio (cut-off SRR% <140). Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off >40% inhibition).

Results

Forty-four patients responded to MMI of whom 43% had Graves’ orbitopathy (GO) while 56 were non-responders (66% with GO, p<0.01). At baseline, undiluted serum TSAb but not thyroid binding inhibiting immunoglobulins (TBII) differentiated between thyroidal GD only versus GD+GO (p<0.001). Further, at baseline responders demonstrated marked differences in diluted TSAb titers compared with non-responders (p<0.001). All patients with a TSAb dilution titer above three did not respond to MMI treatment. In contrast, TBII dilution titers did not differentiate between responders and non-responders to MMI and serum samples became TBII negative already at low dilutions. During treatment, serum TSAb levels decreased markedly in responders (p<0.001) but increased in non-responders (p<0.01). In contrast, TBII strongly decreased in non-responders (p=0.002). All non-responders at week 24 and/or those who relapsed during the 72-week follow-up were TSAb positive at week 24. A shift from TSAb to TBAb was noted in eight patients during treatment and/or follow-up and led to remission.

Conclusions

Serum TSAb levels are a biomarker for and mirror severity of GD. Their increase during MMI treatment is a marker for on-going disease activity. TSAb dilution analysis had additional predictive value.
MON-524 Prospective Evaluation of Patients with Encapsulated Classical Variant of Papillary Thyroid Cancer and Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): Have They A Similar Prognosis?
Authors: Giani Carlotta , Torregrossa Liborio , Ugolini Clara , Ramone Teresa , Romei Cristina , Matrone Antonio , Viola David , Molinaro Eleonora , Materazzi Gabriele , Basolo Fulvio , Elisei Rossella
Published: May 2020

Background: Our previous retrospective study demonstrated that the absence of tumor capsule or, if present, its invasion were independent risk factors for the persistence of the disease (OR 6.75, CI 1.97-23.08 and OR 7.89, CI 1.78-34.94, respectively) in papillary thyroid cancer (PTC). This data was confirmed also analyzing separately the most frequent PTC variants [follicular variant (FVPTC) and classical variant (CVPTC)]. Moreover, we demonstrated that the absence of tumor capsule was significantly more frequent in FVPTC BRAF V600E mutated than FVPTC wild-type for BRAF gene or with rare-BRAF mutations (e.g., BRAF K601E, BRAF V600_K601delinsE). These data confirmed the importance of the integrity of the tumor capsule in FVPTC which led in 2016 to the definition of a new thyroid neoplasm entity named NIFTP. According to these retrospective data, we have assumed that the integrity of the tumor capsule in CVPTC could have a prognostic role similar to that confirmed in the NIFTP group.

Methods: we have prospectively collected data of patients (pts) underwent total thyroidectomy or lobectomy for encapsulated-CVPTC (E-CVPTC) or NIFTP. In both cases the tumor was accurately analyzed by the pathologists according to the criteria used for the NIFTP (in particular with one capsule sample every 1 mm). All pts performed at least one clinical control and neck US within 6 months from surgery.

Results: From January 2018 to June 2019, 144 E-CVPTC and 177 NIFTP were prospectively collected. 83/144 (57.6%) E-CVPTC and 106/177 (59.8%) NIFTP cases were included. The others were excluded due to the presence of other thyroid tumors associated in the same gland. No differences in epidemiological and pathological features were found between E-CVPTC and NIFTP except for the tumor size, significantly bigger in NIFTP than E-CVPTC [22±16mm (2-68) vs 8±11mm (1-80), p<0.00]. A significantly higher rate of NIFTP’ pts underwent lobectomy respect to E-CVPTC pts (34%vs14.5%, p=0.02). After a mean of 9 months of follow-up all pts had an excellent response according to ATA guidelines.

Conclusions: These prospective data demonstrated that NIFTP and E-CVPTC have a similar clinical behavior in a short-term follow-up, thus suggesting that the presence of an intact tumor capsule is predictive of a good outcome. A longer follow up is needed to confirm these initial interesting findings.
SAT-137 The Effect of Hypertriglyceridemia on Triple Negative Breast Cancer Progression
Authors: Scully Tiffany , James Annie , Kang Chifei , Antoniou Irini M , Ettela Abora , Wong Nicholas J , Azeloglu Evren U , Kase Nathan G , Qiu Yunping , Kurland Irwin J , Gallagher Emily Jane
Published: May 2020

Obesity is associated with increased cancer risk and cancer-associated mortality1,2. Hypertriglyceridemia (HTG), a component of the metabolic syndrome which frequently co-exists with obesity, has been associated with increased breast cancer risk and mortality in triple negative breast cancer (TNBC)3,4. To determine if HTG is causally related to enhanced TNBC progression in the absence of other obesity-associated characteristics, TNBC growth and metastasis in a mouse model of HTG was examined. Mice overexpressing human apolipoprotein C3 (AC3) were backcrossed onto FVB/N background and crossed with recombination-activating gene 1 (Rag1) knockout mice to generate immunodeficient HTG mice. AC3 mice relative to wild-type (WT) littermates showed a 20-fold higher circulating triglycerides (p < 0.0001) and elevated very low density lipoprotein (VLDL) cholesterol (p = 0.001). No differences in body weight, body composition, blood glucose or plasma insulin levels were observed between the two groups, allowing for investigation on the influence of HTG on TNBC without confounders such as hyperinsulinemia or hyperglycemia. AC3 mice orthotopically implanted with the mouse mammary tumor cell line, Mvt1, showed both increased tumor growth (AC3 vs WT: 1157.0 ± 84.2 vs 707.2 ± 58.6 mm3, p = 0.0009) and lung metastasis (AC3 vs WT: 57.3 ± 3.0 vs 32.9 ± 5.3 mm3, p = 0.001) relative to WT mice. Immunodeficient Rag1/AC3 mice likewise, showed increased tumor growth compared to WT controls when implanted with human TNBC MDA-MB-231 cells (AC3 vs WT: 363.2 ± 113.9 vs 92.95 ± 16.2 mm3, p = 0.038). To investigate how HTG affects tumor lipid metabolism, serum and tumors from both groups were analyzed by liquid chromatography/mass spectrometry. Total alkyl-acyl, di-acyl-phosphatidylcholines and sphingomyelin concentrations were higher in the serum of AC3 mice relative to WT. In contrast, no overall difference in tumor phospholipid or acylcarnitine content was noted between AC3 and WT mice, suggesting no difference in fatty acid oxidation in the setting of HTG. Mvt1 tumors from AC3 and WT mice were analyzed by RNA sequencing. Decreased expression of genes associated with cholesterol synthesis (Fdft1, Pvmk, Acss2) were found in tumors from AC3 mice. Tumors from AC3 mice also showed decreased protein expression of LDLR, which is associated with LDL cholesterol uptake. Overall, these findings suggest that HTG, independently of other obesity-associated characteristics such as hyperinsulinemia and hyperglycemia, leads to changes in intracellular lipid metabolism and promotes TNBC progression.

References: 1Chan, D. S. M. et al. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.25, 1901-1914 (2014). 2Pierobon, M. & Frankenfeld, C. L. Breast Cancer Res. Treat.137, 307-314 (2013). 3Lofterød, T. et al. BMC Cancer18, 654 (2018).4Goodwin, P. J. et al. Nutr. Cancer27, 284-292 (1997).
MON-198 Cosyntropin Stimulation on Adrenal Venous Sampling Obscure Surgically Curable Primary Aldosteronism
Authors: Kobayashi Hiroki , Abe Masanori , Kurihara Isao , Ichijo Takamasa , Takeda Yoshiyu , Yoneda Takashi , Katabami Takuyuki , Wada Norio , Naruse Mitsuhide
Published: May 2020

Context: While it has been shown that ACTH stimulation during adrenal venous sampling (AVS) for primary aldosteronism (PA) leads to correct lateralization, others showed opposite results. Whether to use ACTH stimulation during AVS for the subtype diagnosis of PA remains unsolved. Objectives: Our purpose of this study is to evaluate the clinical implications of ACTH stimulation during AVS in terms of surgical outcomes. Design and settings: Among JRAS cohort, we allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to 3 groups: basal lateralization index (LI)≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n=245); basal LI <2 with ACTH-stimulated LI ≥4 (n=15); basal LI≥2 with ACTH-stimulated LI <4 (U to Bilateral (B) group, n=54). We compared surgical outcomes among the groups. Results: Compared with the U to U group, the U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as a pathological finding. All patients in the U to Bgroup with clinical and biochemical benefits however had adrenal adenoma as a pathological finding and could be well differentiated from those with poor surgical outcome via basal LI, but not ACTH-stimulated LI. A receiver operating characteristic curve analysis demonstrated that the cut-off value of 8.3 showed the specificity of 84% for the prediction of good surgical outcome in U to B group.These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Although, the basal plasma aldosterone concentration (PAC) in the adrenal veins on both dominant and non-dominant sides among patients with better surgical outcome in the U to B group were not significantly different from those in the U to U group, there was a significant difference in the ACTH-stimulated PAC on the dominant side. Conclusions: We demonstrated novel findings showing that patients in the U to B group were shown to be comprised of 2 groups with good and poor surgical outcomes, and basal LI was useful in identifying PA patients with good surgical outcome in U to B group. The low expression level of MC2R receptor on aldosterone-producing adenoma (APA) might be the explanation of the weak response in aldosterone level in a proportion of surgically curable APA cases. These findings point to the important fact that ACTH stimulation on AVS obscure surgically curable cases of PA.
MON-472 A Case of Resistance to Thyroid Hormone with Concurrent Hashimoto’s Thyroiditis and Post-Surgical Hypothyroidism
Authors: Bernthal Julie , Kim Sarah , Grock Shira
Published: May 2020

Introduction: Resistance to thyroid hormone (RTH) is a rare defect that results in impaired sensitivity to thyroid hormone. While most commonly caused by mutations in the thyroid hormone receptor beta (THRβ) gene, in 15% of patients with the RTH phenotype, no mutation is identified.1 This entity is known as non-thyroid hormone receptor RTH (nonTR-RTH). Patients with RTH have an increased risk of autoimmune thyroid disease with a reported odds ratio of 2.36.2 Hashimoto’s thyroiditis or other etiologies of hypothyroidism add a layer of complexity to RTH as such individuals may require high doses of levothyroxine to overcome hormone resistance.

Clinical Case: A 36-year-old male was referred for abnormal thyroid function tests. He denied symptoms of thyroid dysfunction. Physical examination was notable for a goiter. Weight was 83 kg. Initial labs revealed TSH 6.8 mcIU/mL (0.3-4.7 mcIU/mL), free T4 2.0 ng/dL (0.8-1.7 ng/dL), free T3 491 pg/dL (222-383 pg/dL), and thyroid peroxidase antibody >600 IU/mL (≤20 IU/mL). Additional work-up demonstrated elevated free T4 by equilibrium dialysis 2.5ng/dL (0.9-2.2 ng/dL) and elevated TSH with HAMA treatment 5.96 mIU/L (0.40-4.50 mIU/L), thereby ruling out familial dysalbuminemic hyperthyroxinemia and HAMA interference. Alpha-subunit of 0.30 ng/mL (<0.55 ng/mL) and normal pituitary MRI did not support a TSH-secreting adenoma. Quest Diagnostics RTH Gene Sequencing was negative for a mutation in the THRβ gene. The patient was subsequently diagnosed with nonTR-RTH. Thyroid ultrasound showed multiple thyroid nodules, including a 1.8 cm hypoechoic, complex nodule in the left inferior gland and a 1.7 cm isoechoic nodule in the right inferior gland. Fine needle aspiration of the left nodule was suspicious for papillary thyroid carcinoma and the right nodule showed lymphocytic thyroiditis. The patient underwent total thyroidectomy and pathology demonstrated a benign left nodule and an incidental 0.3 cm right papillary thyroid carcinoma. The patient started levothyroxine 150 mcg daily (1.8 mcg/kg) post-operatively with subsequent TSH of 18.1 mcIU/mL. His dose was increased to 200 mcg daily (2.4 mcg/kg) and TSH was still elevated at 11.7 mcIU/mL. His levothyroxine dose was subsequently increased to 250 mcg daily (3 mcg/kg) and TSH is outstanding.

Conclusions: This case highlights the diagnostic challenge in nonTR-RTH. It also demonstrates the complex management of patients with RTH and concurrent hypothyroidism. Such patients need close monitoring and aggressive titration of levothyroxine to achieve desired hormone levels.

1. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013;1830:3987-4003.

2. Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 2010;95:3189-93.
SAT-114 Loss of DHEA-Targeting SULT2b1b Sulfotransferase Exacerbates Aggressive Traits of Prostate Cancer
Authors: Song Chung Seog , Park Sulgi , Jiang Shoulei , Osmulski Pawel , Marck Brett T , Matsumoto Alvin M , Morrissey Colm , Gaczynska Maria E , Mostaghel Elahe A , Chatterjee Bandana
Published: May 2020

The prostate-expressed sulfotransferase SULT2B1b (SULT2B) regulates intracrine androgen homeostasis by mediating 3β-sulfation of DHEA, thus reducing the precursor pool in the androgen biosynthesis pathway. We explored how loss of SULT2B might influence prostate cancer progression. Results show that SULT2B ablation in castration-resistant prostate cancer (CRPC) cells, generated by stable RNA interference or gene knockout, led to robust activation of the ERK1/2 Map kinase survival signal and induction of epithelial to mesenchymal transition (EMT). EMT activation was concluded on the basis of increased levels of vimentin (a mesenchymal protein) and the EMT-activating transcription factors SNAI1 (Snail) and TWIST1, shown by Western blotting, mass spectrometry and single-cell mass cytometry. Loss of SULT2B was associated with enhanced motility and invasive activity of CRPC cells in vitro and their growth escalation in vivo as xenografts. Higher invasion and metastasis potential of SULT2B-ablated CRPC cells was further indicated by results that these cells are less adhesive (i.e. easily detachable) and less stiff (i.e. more pliable) based on atomic force microscopy analysis of individual cells. Notably, AKR1C3, an aldo-keto reductase, which is elevated frequently in advanced prostate cancer, showed marked upregulation in SULT2B-deficient cells. AKR1C3 regulates androgen receptor (AR) signaling by promoting androgen biosynthesis and functioning as an AR-selective coactivator. While levels of AR and DHT did not change, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several fold higher in SULT2B-silenced cells. The DHT-metabolizing AKR1C2 aldo-keto reductase was also upregulated, which likely accounts for a steady-state androgen level despite elevated AKR1C3 expression. Phosphorylation of ERK decreased in AKR1C3-silenced cells, signifying a causal link between AKR1C3 upregulation and ERK1/2 activation. SULT2B was undetectable immunohistochemically in tissue microarrays of clinical CRPC metastases, while SULT2B-negative samples showed AKR1C3-positive immunostaining. Primary prostate cancer exhibited variable, Gleason score independent SULT2B levels -- varying from strong positive to significantly reduced or undetectable. The reciprocal expression pattern for SULT2B and AKR1C3 in clinical CRPC suggests that AKR1C3 upregulation, ERK1/2 activation and increased aggressive traits of SULT2B-ablated cells, observed in vitro in cell models, may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for delaying disease progression in SULT2B-deficient prostate cancer.Funding Support: 1I01BX000280, VA (BC); W81XWH-14-1-0606, DOD (BC); IK6 BX004207, VA (BC); P50 CA97186, NIH & W81XWH-12-1-0208, DOD (EAM)
SUN-681 Does Short Term Intensive Insulin Therapy in Newly Diagnosed Type 2 Diabetes Mellitus Delay Eventual Insulin Dependence
Authors: Patil Madhuri , Gunasekaran Uma
Published: May 2020

In patients with type 2 diabetes mellitus (T2DM), dysfunction of β-cells starts years before the diagnosis of T2DM and rapidly worsens after overt hyperglycemia. Use of short-term intensive insulin therapy (STIIT) at the time of diagnosis of overt hyperglycemia has shown clinical recovery of β-cells for up to 2 years. A systematic literature review of studies looking for the effect of STIIT, used within two years of diagnosis of T2DM, on the duration from relapse of hyperglycemia to eventual insulin dependence is presented in this abstract.

The key phrases ‘type 2 diabetes mellitus’, ‘short-term insulin therapy’, ‘β-cell failure’, and ‘permanent insulin dependence’ were used to search English literature. For simplicity the duration of diabetes in these studies was divided into three periods: Period 1- Diagnosis of T2DM to initiation of STIIT, Period 2- End of STIIT until relapse of hyperglycemia i.e. total glycemic remission period, and Period 3- Relapse of hyperglycemia to permanent dependence on insulin therapy. Studies were excluded if all of their participants had diagnosis of T2DM for more than 2 years at the time of inclusion, i.e., if period 1 was more than 2 years.

Six clinical trials involving STIIT were identified (Period 2). No studies that examined the clinical course of T2DM in their patients beyond the relapse of hyperglycemia (Period 3) were identified.

This literature review identified a lack of data about this important clinical question- do ‘recovered’ β-cells from STIIT exhibit a better response to non-insulin therapies after the end of period 2 and, hence, delay the secondary β-cell failure in period 3? There is a need to conduct studies with longer follow up to characterize the differences in the disease course between patients treated with STIIT and patients treated with non-insulin therapies. This can help us understand scope of STIIT beyond the initial functional remission of β-cells.
SUN-333 Burosumab Improves Bone Density in Patients with X-Linked Hypophosphatemia
Authors: Murari Keerti , Insogna Karl Leonard
Published: May 2020

Background: X-linked hypophosphatemia (XLH) causes rickets in children and osteomalacia in adults due to lifelong renal phosphate wasting that is mediated by high circulating levels of FGF-23. Burosumab, is a recently approved fully human monoclonal antibody that blocks FGF23, thereby correcting the renal phosphate leak, improving mineral metabolism and reducing osteomalacia by 50-75% in adults [1]. Whether this results in measurable changes in skeletal mass and microarchitecture is unclear. Objective: We examined the impact of burosumab on regional bone mineral density (BMD) and trabecular bone scores (TBS) in study subjects involved in two phase III clinical trials of burosumab.

Methods: In these trails subjects received burosumab 1 mg/kg every 4 weeks. Some patients received placebo for the first 6 months of one trial so we considered their month 6 data as their baseline. Most of the patients had been treated at some point in the past with calcitriol and phosphorus. DXA and TBS were obtained at baseline and then after 6, 12 and 18-24 months of drug treatment. Paired t-tests and ANOVA were performed to assess changes in L-spine BMD, Total Hip BMD and TBS.

Results: 25 subjects with XLH (mean age 38.9 years, 56% female) were enrolled in these studies. Paired data were available in 23 subjects at 6 months, 15 subjects at 12 months and 18 subjects at 18-24 months. Compared to baseline, there were significant increases in L-spine BMD at all time points by paired analysis: 6 months (+6.0%, p=<0.0001), 12 months (+6.95%, p=<0.0001), 18-24 months (+6.13%, p=0.0005). Although there was no significant difference in total hip BMD at 6 months when compared to baseline, there were significant increases at 12 months (+6.72%, p=0.0005) and a further increase at 18-24 months (+10.02%, p=0.0029). When all available subjects were analyzed by one-way ANOVA, there was a significant effect of time of treatment on these regional BMD measurements. There was no change in trabecular bone score over the course of treatment.

Conclusion: Treatment with burosumab is associated with a marked improvement in BMD, particularly in the hip. Since the hip is a frequent site of fracture in XLH, the effect of burosumab at this site is of considerable clinical relevance. The lack of an effect on TBS may relate to the fact that this measurement is much less sensitive to therapeutic interventions than BMD assessed by DXA.

References:

[1] JBMR. 2019. https://doi.org/10.1002/jbmr.3843.
SAT-577 Severe Asymptomatic Hypertriglyceridemia
Authors: Rodriguez Daniel , Drame Awa
Published: May 2020

Background

Case reports of patients with severely elevated serum triglyceride levels (>1000 mg/dL) have been documented where Insulin infusions, heparin and plasmapheresis have demonstrated rapid and successful decrease in serum Triglyceride levels. The benefits of one approach versus the other to prevent major complications such as cardiovascular events or acute pancreatitis has not been well investigated. We present the case of a patient with severely elevated serum triglyceride levels without any manifestations.

Case Description

A 53-year-old male presented from his primary care provider’s office due to elevated Triglycerides levels over 6000 as per outpatient lab work. Inpatient labs were unattainable initially due to hemolysis secondary to the severely high lipid content. Patient was admitted to the medical ICU for closer monitoring and initiated on an insulin drip. Two days after insulin initiation patient’s triglyceride levels returned as 2,887 with a total cholesterol count of 848. His insulin drip was continued until his TAG levels were less than 1000. Upon discharge his levels were less than 600.

Discussion

Most patients with hypertriglyceridemia are asymptomatic. However, in patients with levels above 1000 mg/dL, the risk of pancreatitis or cardiovascular event is of concern. Hypertriglyceridemia may account for 1 to 14 percent of cases of acute pancreatitis. Treatment is largely based upon symptoms and complications. In the event of pancreatitis or other cardiovascular complication, plasmapheresis is usually recommended. If asymptomatic, Insulin may be used. Insulin promotes synthesis of lipoprotein lipase which functions to hydrolyze triglycerides, and has been shown to be an effective lowering agent in the treatment of such individuals. Case reports of Heparin being used as a lipid lowering agent have also been documented, but was not used in our particular patient.

Normal triglyceride plasma levels are defined as less than 150 mg/dL. Mild hypertriglyceridemia typically ranges between 150-499 mg/dL, moderate between 500-866 mg/dL, and severe is defined as levels greater than 886 mg/dL. Plasma triglyceride levels above 1000 mg/dL occur in fewer than 1 in 5000 individuals. It is said that patients with TAG levels above 2000 mg/dL almost always have both a secondary and a genetic form of Hypertriglyceridemia. For this reason it is very important to identify these patients as early as possible to treat appropriately. Our patient was a known alcohol abuser, yet without the presence of some polygenic familial disorder, the likelihood of our patient having TAG levels >6000 mg/dL, is very unlikely.