bluuebunny/crossref_metadata_2025_split huggingface dataset:
OR06-02 TBR-760, a Chimeric Somatostatin-Dopamine Compound, Arrests Aggressive Non-Functioning Pituitary Adenoma Growth In Vivo
Authors: Halem Heather A , Hochgeschwender Ute , Thiagalingam Arunthi , Culler Michael D 
Published: May 2020

Abstract
TBR-760 is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R; EC50 0.064nM) and SST type 2 (SSTR2; EC50 1.2nM) receptors. Prior studies have demonstrated that the chimeric DA-SST compounds are more potent and effective than either individual or combinations of individual DA and/or SST analogs in inhibiting secretion from pituitary adenomas. Non-functioning pituitary adenomas (NFPA) express high levels of D2R as well as lower levels of SSTRs, including the type 2 receptor (1), and thus have an appropriate receptor profile to respond to TBR-760. The present study examines the ability of TBR-760 to inhibit tumor growth in a mouse model of aggressive NFPA. Heterozygous and null mutant mice lacking one or both copies, respectively, of the pro-opiomelanocortin (POMC) gene (POMC-KO mice)(2) spontaneously develop aggressive, non-secreting pituitary adenomas (3). The POMC-KO mouse tumors have been shown to express D2R and SSTR2 at a similar level as human NFPAs (4). In addition, merging of microarray data (Affymetrix, U133 plus_2.0 and Mouse Genome 430 2.0 arrays), reveals 154 common gene signatures between human NFPAs and the POMC-KO mouse tumors. In an initial study, heterozygous POMC-KO mice with an established pituitary tumor of approx. 10mm3 (mean volume 8.9±0.3), as determined by MRI, were treated with a range of TBR-760 doses (0.125 to 12.5mg/kg, sc, QD) for 60 days. During that time, tumors in vehicle-treated mice increased in size by 890±0.7%, whereas all doses of TBR-760 tested resulted in a nearly complete inhibition of tumor growth from treatment initiation. We then compared the effect of the TBR-760 chimera with that of its individual SST agonist (SSTA) and DA agonist (DAA) components on tumor growth in the POMC-KO mice. As in the earlier study, TBR-760 treatment (1mg/kg, sc, QD), initiated when the mice had an established tumor of approx. 10mm3, completely arrested tumor growth during the 8 weeks of treatment (final mean tumor volume of 8.5±1.3mm3 vs. 54.61±10.6mm3 in vehicle-treated mice). Treatment with equimolar or 10x-higher doses of the individual SSTA or DAA, either alone or in combination, had no significant effect on tumor growth, except in the lower dose DAA group where a modest suppression of tumor growth was observed. These data demonstrate that only the dual DA-SST chimeric compound, TBR-760, completely arrested tumor growth in the POMC-KO mouse model of NFPA. Further, despite the highly aggressive nature of the POMC-KO tumors, significant tumor shrinkage was observed in 20% of the mice treated with TBR-760. These results support the development of TBR-760 as a medical therapy to prevent or arrest the growth of NFPAs and, potentially, to induce NFPA shrinkage. References: (1) Florio et al., 2008 Endocr Relat Cancer; 15: 583-596. (2) Yaswen et al., 1999 Nat Med; 9:1066-70 (3) Karpac J et al., 2006 Cell Mol Biol; 52: 47-52.
MON-492 Should Isthmic Thyroid Nodule Be Included in ACR TI-RADS Points in Predicting Thyroid Cancer?
Authors: Jasim Sina , Baranski Thomas J , Teefey Sharlene , Middleton William 
Published: May 2020

Abstract
Background: Thyroid nodules are routinely evaluated with ultrasound. Isthmic nodules carry higher risk of malignancy (in press). Surgical studies suggest higher risk of metastasis from thyroid cancer located in isthmus region. In this study, we evaluate how adding an extra point for isthmic location to current ACR-TIRADS will affect the sensitivity and specificity to predict thyroid cancer.
Methods: We performed a subanalysis of isthmic nodules contained in a retrospectively created database of 3313 adult patients from six referral centers with confirmed benign or malignant nodules. Sensitivity and specificity were calculated using the current ACR TI-RADS scoring system and compared to a system that would add an extra point based on nodule location in the isthmus.
Results: There were 195 nodules in the isthmus (34 malignant). If a recommendation for FNA was considered a positive test result, the sensitivity and specificity would be 50% (17/34) and 61% (99/161) respectively using current ACR TI-RADS scoring. If an additional point was added the sensitivity and specificity would be 62% (21/34) and 36% (58/161) respectively. Adding the additional point would lead to detection of 4 additional malignant nodules at the cost of biopsying 41 additional benign nodules. If a recommendation for either FNA or follow-up ultrasound for 5 years was considered a positive test result, the sensitivity and specificity would be 82% (28/34) and 35% (56/161) respectively using current ACR TI-RADS scoring. If an additional point was added the sensitivity and specificity would be 94% (32/34) and 15% (24/161) respectively. Adding the additional point would lead to detection of 4 additional malignant nodules at the cost of either biopsying or following 32 additional benign nodules.
Conclusions: Isthmic nodules are more likely to be malignant than nodules in other locations. When using the ACR TI-RADS, adding a point for isthmic nodules improves detection of cancer with a moderate increase in the rate of FNA and follow-up of benign nodules. Given the higher risk of extra thyroidal extension and nodal metastases for isthmic cancers, this tradeoff between sensitivity and specificity may be acceptable and should be considered when dealing with nodules in the isthmus.
Keywords: thyroid nodule, ACR TI-RADS, location, isthmus, thyroid cancer
SAT-026 Association of Inflammatory Markers with Depressive Symptoms Across the Perinatal Period
Authors: Braybrook Emma , English Sarah , Sorinola Olanrewaju , Blacklay Jayne , Forbes-Robertson Sarah , Grammatopoulos Dimitris 
Published: May 2020

Abstract
Perinatal depression (PND) is a mood disorder affecting 10-15% of women during pregnancy and postpartum. Its aetiology is complex with contribution from both genetic background and psychosocial as well as environmental stressors that determine individual responses shaped by chronic and acute disease burden (1). It is thought that the molecular basis of PND involves dysregulation of the HPA axis associated with neurotransmitter and neuroactive steroids imbalance. Inflammation appears to be a contributing mechanism, with increased levels of cytokines exerting adverse effects on serotonin metabolism, neuroplasticity and HPA hyperactivity (2). With only 50% of women detected through current screening strategies, there is an urgent unmet need for the development of biomarker-based strategies to identify women at risk of PND. In this study we used data and blood samples from the prospective Coventry and Warwickshire PND study; we investigated for inflammatory markers associated with depressive symptoms, assessed using the Edinburgh Postnatal Depression Score (EPDS) questionnaire between 24-29 weeks of gestation and again 6-10 weeks postpartum. A cut-off score of 10 categorize ‘high’ or ‘low’ risk for depression. Blood samples collected at 28 weeks of gestation were profiled for either IL-6 and IL-10 levels or a panel of 92 inflammatory markers. Individual inflammatory markers were compared across groups using Welch’s ANOVA. Results suggest that IL-10 levels were significantly correlated with EPDS score, exerting a protective effect (r= -.10), with reduced levels in the highest severity category (EPDS ≥ 15). The IL-6/IL-10 ratio was also associated with a raised EPDS score (r=.10, p=.01), as well as delivery complications (r=.09). The highest IL-6/IL-10 ratio is observed in women who had emergency caesarean section. Bayes’ theorem analysis suggested that IL-6/IL-10 ratio could be used as a negative screen to rule out low risk pregnancies. From the 92 inflammatory markers, 14 analytes were below the limit of detection for more than 50% of samples and so were excluded from further analysis. Upon comparison of groups determined by antenatal and postnatal EPDS scores, 29 markers displayed a significance value of P&lt;0.05. Upon the application of post hoc tests, 8 markers including: STAM-BP, SIRT2, CD40, CASP8 and ADA, all associated with apoptotic processes, remained statistically significant in pregnant women with raised antenatal EPDS scores. This data support an association between inflammatory markers and perinatal depression and adverse pregnancy outcomes. Detailed quantitative analysis of such biomarker signatures at different stages of pregnancy, might lead to early detection of disease and application of targeted treatment. (1) Pariante, C. M. & Lightman, S. L. (2008) Trends Neurosci, 31 (9): 464-468. (2) Raison et al., (2006) Trends Immunol, 27 (1): 24-31.
SAT-190 Are Pet Scans Needed in Evaluating Lipid Rich Adrenal Adenomas?
Authors: Castellanos-Diaz Jessica , Mathews Sherin Elsa , Drane Walter , Staal Stephen , Ghayee Hans Kumar , Kathuria Amita 
Published: May 2020

Abstract
Introduction Adrenal glands are highly vascularized organs and can be the foci of metastatic disease. Incidentally discovered adrenal nodules should be evaluated with CT or MRI imaging and biochemical testing. Metastatic lesions do not have a specific clinical presentation or imaging features but are suspected when there is attenuation greater than 10 HU, presence of calcification, hemorrhage, or abnormal enhancement signals in CT scan or MRI. However, malignant lesions can be present along with benign ones as described here. Clinical Case A 74-year-old female initially presented with uncontrolled hypertension in 2002, at which time she was found to have a left adrenal incidentaloma. MRI/MRA of the abdomen with and without gadolinium contrast showed a 2.5 x 2.6 cm left adrenal nodule, described as a benign lipid rich adrenal adenoma. Biochemical testing revealed no evidence of pheochromocytoma, hyperaldosteronism, or hypercortisolism. Follow-up CT scan in 2003 showed the left adrenal nodule was slightly larger (3.0 x 2.5 cm) but remained lipid rich (&lt;10 HU). There was also a new sub-centimeter nodule in the left medial-posterior limb with similar appearance. In the interim, she was diagnosed with a melanoma on her back in 2003, which was resected without any evidence of invasion. In 2004, abdominal MRI with and without gadolinium contrast showed stable left adrenal nodules. As she continued to have persistent hypertension, uncontrolled with several medications, biochemical work-up for pheochromocytoma, hyperaldosteronism, and hypercortisolism was repeated and was again negative. Surveillance CT imaging in 2005 did not show any changes to her adrenal adenomas. In 2016, she presented to the emergency room with a hemorrhagic cerebrovascular accident. MRI of the brain was consistent with metastatic lesions. CT scan of the chest, abdomen and pelvis showed metastatic lesions in the lungs, liver, bone, and spleen. There was a new 8 mm right adrenal nodule noted with no changes in the left adrenal nodules. Biopsy of a subcutaneous chest wall nodule revealed metastatic melanoma. Thus, she was started on palliative immunotherapy with nivolumab. During her follow-up, she had a series of PET CT scans over a 6 month period, which showed increasing size (up to 4.3 cm) and FDG uptake in the left adrenal nodule. Surprisingly, the left adrenal nodule had a predominantly fatty density (mean of 5 HU) but with an area of hyperdensity which could represent either an adenoma with a coexisting metastatic lesion or angiomyolipoma. Biopsy of the left adrenal nodule revealed a metastatic melanoma. Conclusion This case describes a benign adrenal nodule coexistent with a metastatic lesion. As the patient had metastatic melanoma, a PET-CT was ordered. Melanoma is known to metastasize to the adrenal. This case serves to remind clinicians to perform a careful medical history as management and outcomes can be affected.
SAT-601 Development of a Protocol for Stellate and Celiac Ganglia Dissection for Characterization of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Protein and Receptor Expression in Male and Female Mice Following Cold Acclimation
Authors: Pandher Parleen K , Filatov Ekaterina , Gray Sarah L 
Published: May 2020

Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is being studied to understand the endocrine regulation of energy balance and has been shown to be important in the regulation of the stress response (1,2). Specifically, PACAP has been shown to regulate thermogenesis, an energy burning process regulated by the sympathetic nervous system that contributes to achieving energy homeostasis in response to cold stress and overfeeding. PACAP is expressed in the sympathetic nervous system and is required at the adrenomedullary synapse to maintain epinephrine secretion from the adrenal medulla in response to physiological stress (3). Across the branches of the sympathetic nervous system, PACAP receptor expression is most well characterized in the superior cervical ganglia (SCG) (4). However, a detailed characterization of PACAP and its receptors has not been performed in ganglia whose postganglionic fibres innervate adipose tissues (stellate and celiac ganglia) in response to thermogenic stress. We hypothesized that PACAP is produced by preganglionic neurons innervating the stellate and celiac ganglia, and act on PACAP receptors expressed on the post-ganglionic neurons, and this expression will be upregulated in response to chronic cold stress. Due to their small and amorphous shape, we have developed a protocol to reliably isolate the stellate and celiac ganglia and validate their identity through the presence of tyrosine hydroxylase mRNA, using adrenal and SCG samples as positive controls. PACAP receptor expression (VPAC1, VPAC2, PAC1) was examined in the ganglia utilizing real-time PCR, and PACAP protein was visualized in the ganglia of transgenic mice that express eGFP under the control of the PACAP promoter (PACAP-eGFP mice) (5). This research demonstrates the expression of PACAP receptors in ganglia whose postganglionic fibres innervate adipose tissue, enhancing our understanding of PACAP’s role in the SNS, and its contribution to the regulation of adaptive thermogenesis. References: (1) Gray et al., Pacap: Regulator of the stress response. In: Fink G, ed. Stress: Physiology, biochemistry, and pathology. 2019:279-291. (2) Mustafa, Adv Pharmacol. San Diego, Calif:445-457. (3) Eiden et al., Pflungers Arch. 2018 Jan;470(1):79-88. (4) Braas et al., J Biol Chem. 1999 Sep 24;274(39):27702-27710. (5) Condro et al., J Comp Neurol. 2016 Dec 15; 524(18):3827-3848.
SUN-735 Functional Analysis of Testis-Specific Noncoding Genes in Estrogen-Dependent Transcription
Authors: Choudhari Ramesh , Yang Barbara , Ramos Enrique Ivan , Zilaie Mina , Sanchez-Michael Laura A , Gadad Shrikanth S 
Published: May 2020

Abstract
Emerging studies have shown that germ cell (GC)-specific genes play critical roles in several cancers. The expression of these genes is tightly regulated and restricted to testis; however, many of them escape regulation and become aberrantly expressed in tumors. Interestingly, our genomic analysis suggests that several of these genes are long noncoding RNAs (lncRNAs) and are located at regions previously considered to be gene deserts in the human genome. In this regard, we used an integrated genomic approach to identify GC-lncRNA genes that are overexpressed in breast cancer. Further, by incorporating gene expression analysis from RNA-seq data from MCF-7 and T47D breast cancer cells, we generated a comprehensive list of estrogen-regulated GC-lncRNA genes. We hypothesize that GC-lncRNA genes regulate estrogen-dependent signaling in breast cancer. The selected genes: (a) CAERRC (Chromatin Associated Estrogen-Regulated RNA in Cancer, (b) LncRNA568, (c) LncRNA16 are primate-specific, and exclusively expressed in testis. All of them are regulated by estrogen, and their expression predicts poor outcome in ERα+ breast cancer patients. They have now been fully annotated (transcription start and stop site, 5’ cap, polyA tail, and exon/intron structure), and cloned. Further, we have created gene-specific KO MCF-7 cell lines using CRISPR to study their molecular roles. Our data suggest that these genes regulate estrogen-dependent gene expression and tumor growth in breast cancer cells. Genome-wide analysis of ERα binding and gene expression data indicate that they play a critical role in the estrogen-dependent transcription. Collectively, our results suggest that GC-genes, including CAERRC, LncRNA568, and LncRNA16, are excellent targets with prognostic and therapeutic potential in ER+ breast cancers.
SAT-068 Bewilderment! Sex Chromosome Non-Invasive Prenatal Screening (NIPS) Results Differ from Phenotype and Postnatal Karyotype
Authors: Perez-Garcia Eliana Melissa , Shahid Nabiha , Yatsenko Svetlana , Schneck Francis Xavier , Witchel Selma Feldman 
Published: May 2020

Abstract
Background
NIPS uses cell-free DNA in maternal serum to identify fetal aneuploidies including sex chromosome aneuploidies (SCA).1 Despite reports of high sensitivity and specificity, NIPS results, phenotype, and postnatal karyotype may be inconsistent. This situation generates parental anxiety and physician apprehension especially when the apparent genital phenotype differs from the NIPS result. We report four cases involving genotype-phenotype discordance in infants with disorders of sex development (DSD).
Case 1:
Female infant with complex congenital heart disease had inconclusive NIPS results. Postnatal karyotype was 46,XY karyotype (positive for SRY gene). Ultrasound [US] confirmed female internal genitalia. Postnatal karyotype on uncultured peripheral blood cells with FISH showed mosaicism [46,XY (85%)/45,X (15%)].
Case 2: Female infant conceived via IVF had 46,XY karyotype on NIPS. Prenatal and postnatal US showed female internal genitalia. Postnatal results showed 46,XX karyotype and Urine FISH analysis reported XX in all examined cells. Maternal karyotype is 46,XX; maternal FISH results are pending.
Case 3: NIPS reported 45,X. Prenatal US showed male external genitalia. Postnatal exam showed male phenotype with right gonad in inguinal region. Cord blood karyotype and FISH analyses showed mosaicism [45,X (56%)/46,XY (44%)] with 4 different Y chromosome rearrangements. Urine FISH showed mosaicism [45,X (95%)/46,XY (5%)]. Testosterone and AMH concentrations were normal.
Case 4: NIPS reported 46,XY karyotype. Prenatal US showed normal female genitalia. Postnatal physical exam revealed low set ears; additional studies revealed horseshoe kidney and atrial septal defect. Cord blood showed mosaicism [45,X (90%)/46,XY (10%)].
Conclusion
Discrepancies between NIPS and postnatal karyotype occur more commonly with SCA than for autosomal aneuploidies.2 Such inconsistencies generate anxiety regarding sex of fetus, suggest a DSD diagnosis, and warrant additional prenatal and postnatal investigations. Testing to prevent missed detection of sex chromosome mosaicism is necessary. Early diagnosis of DSDs benefits the infant and the family. In some instances, NIPS expose undiagnosed maternal factors.3 Most importantly, communication involving parents and both prenatal and postnatal health care providers is essential to promote timely holistic health care for the infant and family.
References
1.Palka C et al., Eur J Obstet Gynecol Reprod Biol X. 2019; 3:100050
2.Ramdaney A et al., Prenat Diagn. 2018;38:841
3.Richardson EJ, et al., Prenat Diagn. 2017;37:1298
Footnotes
MON-471 The Broken Heart That Hid Behind the Goiter
Authors: Newman Samantha Kass , Greenberg Pietra Dale , Saul Shira R 
Published: May 2020

Abstract
Most goiters grow slowly over many years and are often asymptomatic. Although substernal goiters are estimated to represent between 5-24% of all mediastinal masses [1], a majority are benign. Symptoms may include neck fullness, nocturnal or positional dyspnea, or dysphagia due to tracheal and/or esophageal compression [2-3]. We present a case of a patient with new onset dyspnea that was initially attributed to a large intrathoracic goiter, but ultimately was found to be due to severe heart failure.
A 72-year-old man with a history of HTN, type 2 diabetes, and moderate aortic regurgitation presented to his primary care physician with exertional dyspnea, dry cough, and bilateral leg edema for 2 months. He was referred to pulmonology and a chest CT showed a large intrathoracic goiter, measuring 8.5 x 4.6 x 5.3 cm, extending from the left limb of the thyroid into the mediastinum with rightward tracheal and leftward aortic arch displacement. The patient had no prior history of thyroid disease, cancer, or neck radiation. He denied neck fullness, dysphagia, positional or nocturnal dyspnea, though his exertional dyspnea was progressive. Labs revealed that the patient was biochemically euthyroid. Due to concern for malignancy, the patient underwent a biopsy via EBUS/bronchoscopy, which was non-diagnostic. The case was ultimately discussed at cardiothoracic tumor board, and it was determined that since the mass had likely been present for several years and with the surgical risks being high, to continue monitoring with serial imaging.
At this point, the patient’s dyspnea and edema continued to worsen, and he was evaluated with an echocardiogram which showed a severe worsening of ejection fraction in just three months, from 53% to 5%, with global hypokinesis. He was started on diuretics and medical therapy with prominent improvement in his dyspnea. His cardiology team felt this acute decompensation was likely due to coronary artery disease and recommended left heart cardiac catheterization, however the patient declined.
Goiters tend to be asymptomatic and grow slowly over time. Given their intra-thoracic location and ability to prominently deviate the mediastinum, it can be tempting to attribute respiratory symptoms to large substernal goiters. However, when a patient develops acute symptoms, one must always rule out alternative diagnoses.
References
1. Priola AM, Priola SM, Cardinale L, Cataldi A, Fava C. The anterior mediastinum: diseases. Radiol Med. 2006;111(3):312
2. Katlic MR. Wang CA, Grillo HC. Substernal goiter. Ann thorac surg. 1985;39(4):391.
3. Benbakh M, Abou-elfadl M, Rouadi S, Abada RL, Roubal M, Mahtar M. Substernal goiter: experience with 50 cases. Euroepean annals of otorhinolaryngology, head and neck diseases. 2016-02-01, volume 133, issue 1, 19-22.