bluuebunny/crossref_metadata_2025_split huggingface dataset:
7404 Evaluation Of Cortisol Reserve And Adrenal Imaging In Patients With Graves’ Disease Before And Six Months After Treatment
Authors: Sharma Pooran , Ahmad Mir Shahnaz , Mohd Patto Shoiab , Hussain Bhat Abid , Dar Basharat , Hayat Bhat mohammad , Ahmad Bhat Khurshid , Singh Madhumita , Agrawal Ruchi 
Published: October 2024

Abstract
Disclosure: P. Sharma: None. S. Mir: None. S. Mohd Patto: None. A.H. Bhat: None. B. Dar: None. M. Bhat: None.
Introduction: There is scarcity of data regarding the effect of thyrotoxicosis on cortisol metabolism and adrenal gland size. An increase in cortisol metabolism can deplete the functional reserve of adrenal cortex and lead to adrenocortical insufficiency even when there is no pre-existing Addison's disease. In developing countries patients with Graves’ disease present in advanced states of thyrotoxicosis. Besides they are also exposed to a variety of environmental stresses such as recurrent febrile illnesses, salt, and water loss due to manual labour in hot and humid climates etc., which can precipitate an adrenal crisis in the presence of compromised adrenal reserve. So present study was undertaken to assess cortisol reserve and adrenal gland size in patients with treatment naive Graves' disease. Objectives- The present study, was undertaken to assess cortisol reserve and adrenal imaging in patients with treatment naive Graves' disease. Specific information in this regard would help alert physicians dealing with clinical thyrotoxicosis in developing countries of tropics to the possibility of co-existing adrenal decompensation and adopt appropriate life saving measures promptly. Material & Methods: We examined 38 treatment-naive Graves' Disease patients at GMC, SSH, Srinagar, Kashmir, INDIA. Basal cortisol and cortisol response to ACTH were measured before and after six months of treatment, alongside adrenal CT imaging. Results: In hyperthyroid state, Graves' patients exhibited significantly lower basal cortisol compared to euthyroid and healthy controls (306 vs. 410 vs. 421 nmol/l, p &lt; 0.05). 23.6% patients had subnormal cortisol response to ACTH(250ug). Those with T3 ≥ 400 ng/dl had lower cortisol response (560±133 nmol/l) and delta cortisol response than T3 &lt; 400 ng/dl (724 ± 294 nmol/l, 213+/-73 vs. 428+/-265 nmol/l). After achieving euthyroid state, cortisol levels improved significantly (410±213 nmol/l vs. 306 ± 103 nmol/l, p &lt; 0.05). Adrenal CT scans in 34 patients was done out of which 19 showed statistically significant increases in gland thickness, width, and AP diameter compared to controls (p &lt; 0.01, p &lt; 0.05. Repeat CT in 26 patients demonstrated resolution of hyperplasia (p &lt; 0.05). Conclusion: Treatment-naive Graves' disease patients have compromised adrenocortical reserve and adrenal gland enlargement. Adrenal changes are reversible after achieving euthyroid state. These findings support steroid supplementation in impending thyrotoxic crisis and highlight a unique feature of reversible adrenal gland enlargement in this context. Keywords: Graves’ Disease, Adrenal hyperplasia, Cortisol reserve.
Presentation: 6/3/2024
12220 Impaired Esrra-mediated Regulation Of Lysosomal Protein Translation And Autophagy In MASH: Restoration And MASH Reversal By Alternate Day Fasting
Authors: Tripathi Madhulika , Gauthier Karine , Sandireddy Reddemma , Park Sung-Hee , Giguere Vincent , Chow Pierce K H , Ghosh Sujoy , McDonnell Donald Patrick , Yen Paul Michael , Singh Brijesh Kumar 
Published: October 2024

Abstract
Disclosure: M. Tripathi: None. K. Gauthier: None. R. Sandireddy: None. S. Park: None. V. Giguere: None. P.K. Chow: None. S. Ghosh: None. D.P. McDonnell: None. P.M. Yen: None. B. Singh: None.
The regulation of global and specific protein synthesis during the progression of metabolic dysfunction-associated steatohepatitis (MASH) is poorly understood. Accordingly, we performed a comprehensive analyses of protein translation by employing label-free quantitative proteomics, puromycin-labeling, and polysome profiling, and found a reduction in protein synthesis during lipotoxic stress in vitro and in liver tissues from MASH mouse models. We also found that expression of estrogen receptor-related receptor-α(ERRa/Esrra) and ribosomal Rplp1 were significantly downregulated at protein levels. Additionally, Esrra recruitment was decreased on the Rplp1 promoter, and led to diminished Rplp1 mRNA and protein expression. Taken together, these events reduced overall translation activity and the specific translation of lysosomal (e.g.,Lamp2, Ctsd) and autophagy (e.g., Sqstm1, Map1lc3b) proteins during MASH. Moreover, Esrra-Rplp1-mediated translation of these lysosomal and autophagy proteins and autophagy was compromised in MASH patients and liver-specific Esrra-deficient mice. Remarkably, alternate day fasting induced hepatic Esrra expression and reactivated Esrra-Rplp1 signaling in mice with MASH, leading to the re-expression of autophagy and lysosomal proteins to restore autophagy and reduce lipotoxicity, inflammation, and fibrosis. Thus, the Esrra-Rplp1-mediated translation of lysosomal and autophagy proteins critical for preventing lipotoxicity, inflammation, and fibrosis was suppressed during MASH. Reactivation of this pathway by intermittent fasting was able to reverse MASH. Our findings showed that Esrra not only regulated the transcription of genes involved in lipid metabolism, but also the specific translation of autophagy and lysosomal proteins via induction of Rplp1; thus, providing a molecular explanation for the beneficial hepatic effects of alternate day fasting in MASH.
Presentation: 6/2/2024
8018 Improving Anti-Breast Cancer Activities by Optimizing Torsion Angle Energies
Authors: Zak D R , Fink E C , Hancock G R , Young K S , Fanning S W 
Published: October 2024

Abstract
Disclosure: D.R. Zak: None. E.C. Fink: None. G.R. Hancock: None. K.S. Young: None. S.W. Fanning: None.
Overexpression of estrogen receptor alpha (ER-alpha) is found in 70% of breast cancer tumors. Normally, ER-alpha remains inactive and sequestered in the cytoplasm until estrogen binds to the ligand-binding domain (LBD) to enable nuclear translocation, coregulator recruitment, and subsequent activation of proliferative ER-alpha-dependent transcriptomic profiles. The majority of breast cancers are treated successfully with ER-targeted endocrine therapies, but hotspot ER-alpha LBD mutants are selected for, namely Y537S and D538G causing therapeutic resistance, relapse, and aggressive metastatic disease. The selective estrogen receptor modulator (SERM) lasofoxifene (laso) and selective estrogen receptor degrader (SERD) elacestrant (RAD1901) are chemically distinctive and show great promise in the ER-alpha mutant setting with potent anti-tumor effects and improved side effect profiles compared to the standard-of-care SERD fulvestrant (ICI). To elucidate the structural-transcriptional relationships of these ligands, we created a laso/RAD1901 chemical hybrid T6I-29 that demonstrated both canonical and unexpected therapeutic mechanisms of action. However, it possesses reduced anti-proliferative potency compared to ICI. We hypothesized that minor chemical changes to T6I-29 could improve potency while maintaining its favorable pharmaceutical profiles. To address this hypothesis, we performed quantum mechanical calculations of a series of T6I-derivatives. The addition of a methyl linker within the scaffold core significantly improved the torsion angle energies of the ligand binding pose. Multiple derivatives were synthesized based on these computations. The new compound T6I-B2 exerted profound anti-proliferative effects on breast cancer cells and adopted a unique ligand binding pose within the LBD. This approach shows that T6I-SERM potency can be improved by optimizing ligand torsion angle energies.
Presentation: 6/3/2024
5119 Structural basis for glucocorticoid receptor multimerization
Authors: Estébanez-Perpiñá E 
Published: October 2024

Abstract
Disclosure: E. Estébanez-Perpiñá: None.
Abstract ENDO-2024 - BostonStructural basis for glucocorticoid receptor multimerization Andrea Alegre-Martí[1]*, Alba Jimenez-Panizo2*, Agustina Lafuente3, Montserrat Abella[1], Thomas A Johnson2, Paloma Pérez4, Juan Fernández-Recio5, Diego M. Presman3, Gordon L. Hager2, Pablo Fuentes-Prior[1], Eva Estébanez-Perpiñá[1] [1]Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain.2National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA.3IFIBYNE, UBA-CONICET, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, C1428EGA, Argentina.4Instituto de Biomedicina de Valencia (IBV)-CSIC, 46010, Valencia, Spain.5Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC - Universidad de La Rioja - Gobierno de La Rioja, 26007 Logroño, Spain. Abstract: The glucocorticoid receptor (GR) is a ubiquitously e2xpressed ligand-regulated transcription factor essential for life and one of the most targeted proteins in drug discovery due to its powerful anti-inflammatory actions. The functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity in cells, remains disputed. Here we present a new crystal structure of agonist-bound ancient GR-LBD in a large cell, along with a thorough analysis of previous structural work. The building block of the current structure is a homodimer we previously identified in GR-LBD crystals and its biological relevance has been verified by studying a battery of GR point mutants including crosslinking assays in solution and quantitative fluorescence microscopy in live cells. Several mutually exclusive multimeric assemblies of this dimer in the crystal highlight the versatility of GR-LBD for self-association and reveal implications for the conformation of the active full-length receptor. Our results underscore the relevance of non-canonical dimerization modes for GR-LBD, especially of contacts made by key residues such as Tyr545, Pro637 and Asp641. Of note, a non-conservative mutation of the latter, p.Asp641Val, causes Chrousos syndrome in humans. Understanding relevant quaternary assemblies of the GR is pivotal not only to understand and predict the therapeutic outcome of major blockbuster drugs but also to lessen their deleterious side effects and open new avenues for drug design.
Presentation: 6/3/2024
7881 Using Selective Estrogen Receptor Modulators to Reveal Therapeutic Vulnerabilities in ESR1 Mutant Breast Cancer
Authors: Fanning S W 
Published: October 2024

Abstract
Disclosure: S.W. Fanning: Grant Recipient; Self; Olema Oncology.
Hotspot activating somatic mutations to ESR1, the gene for estrogen receptor alpha (ER), enable hormone therapy resistance and drive breast cancer metastasis. The Y537S missense mutation within the ER ligand binding domain is the most activating, therapy resistant, and increases metastatic potential. Next generation antiestrogens including lasofoxifene (laso) and elacestrant (RAD1901) show improved progression-free survival over fulvestrant (fulv), but further progress is needed to achieve durable response. To fully address Y537S ESR1, it is critically important to understand how the mutation boosts metastasis. We have developed a small molecule antiestrogen, T6I-29, that uniquely impacts transcriptional pathways related to cell-cell adhesions and morphology. Two allele-specific phenotypes identified by the Oesterreich Laboratory enhance the metastasis of Y537S ESR1 breast cancer cells. T6I-29-specific pathway effects were driven by a significant downregulation of dickkopf-1 (DKK1), which was also observed but to a lesser extent with fulv, laso, and RAD1901. DKK1 is an immunosuppressive, tumor-secreted glycoprotein and its overexpression correlates with poor outcomes in multiple cancers. However, DKK1 acts as a tumor-suppressor in colorectal cancer, which does not rely on ER. Our preliminary studies suggest that DKK1 plays a role in ER+ breast cancer progression. We measured significantly elevated DKK1 protein levels in the blood plasma of 108 diverse ER+ breast cancer patients compared to 100 matched healthy female donors and levels increase coincident with tumor stage. Unfortunately, we lack ESR1 mutation status and other critical details to make further insights on these patients. DKK1 gene expression and protein secretion is stimulated in WT cells by the pathogenic hormone 17β-estradiol (E2), while it is constitutively expressed in Y537S ESR1 cells. DKK1 is characterized as a WNT antagonist but can also induce PI3K/Akt signaling. Interestingly, DKK1 is elevated and ERα responsive in WT not mutant PI3KCA cell lines. DKK1 knockdown also reduced proliferation of Y537S ESR1 breast cancer cells where elevated DKK1 was observed.
Presentation: 6/3/2024
6850 A Case of Anaplastic Thyroid Carcinoma With a Complete Metabolic Response to Pembrolizumab
Authors: Tirthani Ekta , Kung Jacqueline Tam 
Published: October 2024

Abstract
Disclosure: E. Tirthani: None. J.T. Kung: None.
Background: Anaplastic thyroid carcinoma (ATC) is an aggressive disease with limited therapeutic options and generally poor prognosis. Post-surgery, most patients are treated with a combination of chemotherapy, radiation, and tyrosine kinase inhibitors +/- immune checkpoint inhibitors. We describe a unique case of ATC with a complete metabolic response to pembrolizumab, a selective PD-1 inhibitor, as evidenced by imaging. Clinical Case: A 69-year-old female presented to the clinic for evaluation of a rapidly enlarging neck mass. The initial ultrasound showed a large mixed cystic-solid right thyroid nodule with irregular margins with micro- and macrocalcifications, which was biopsied. Cytology showed discohesive high-grade malignant tumor cells with enlarged nuclei, nuclear hyperchromasia in the background of necrosis, and dense neutrophilic infiltration concerning for ATC. A CT scan of the neck and chest showed a complex cystic thyroid mass with central necrosis and calcification with paratracheal, supraclavicular, and mediastinal lymphadenopathy. MRI of the brain was negative for metastatic disease. The patient underwent a total thyroidectomy with right and left level 6 and 7 neck dissection. Intra-operatively, gross extrathyroidal extension of the tumor was noted to the right carotid, larynx, right recurrent laryngeal nerve, and esophagus, with residual tumor left behind near the larynx. Pathology confirmed stage IVC ATC, positive for PIK3CA, NF1, p53 mutations, and BRAF negative. 90% of tumor cells showed PD-L1 expression on immunohistochemical staining. The post-surgical PET scan showed two discrete, well-defined foci of very intense FDG uptake, corresponding to the right lower cervical and para-esophageal lymph nodes with no evidence of distant metastasis. Systemic chemotherapy with carboplatin and paclitaxel (5 cycles) was initiated with concurrent intensity modulated radiation therapy (total 60 Gy/40 fractions to thyroid bed and bilateral neck). Repeat imaging showed minimal change in the size of the PET-positive lymph nodes. Immunotherapy was initiated and with just 2 cycles of 400 mg IV pembrolizumab, a repeat PET scan was obtained, which showed a complete metabolic response to therapy. Minimal residual FDG activity in the right supraclavicular region was thought to be secondary to posttreatment changes. The patient was able to resume her activities of daily living and had an improvement in appetite. The plan is to continue 400 mg IV pembrolizumab every 6 weeks while cautiously assessing for adverse effects from immunotherapy. Conclusion: It is rare to see a complete metabolic response to therapy with pembrolizumab without concurrent use of tyrosine kinase inhibitors in patients with ATC. A high tumoral PD-L1 expression may be the key to having this kind of dramatic response.
Presentation: 6/3/2024
12396 A Case Of Medullary Thyroid Carcinoma Without Germline RET Mutation
Authors: Rodriguez Isabella Marranzini , Lemelman Michelle , Canham Lorraine 
Published: October 2024

Abstract
Disclosure: I. Marranzini Rodriguez: None. M. Lemelman: None. L. Canham: None.
Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from the parafollicular C cells of the thyroid gland. MTC accounts for approximately 5% of thyroid cancer in children, and the majority of MTC cases are associated with the autosomal dominant tumor predisposition syndrome Multiple Endocrine Neoplasia 2 (MEN2). Sporadic MTC is uncommon in the pediatric population and associated with somatic mutations of RET or RAS (1). Existing management options for metastatic disease have demonstrated some benefit, however, with systemic side effects. Selpercatinib, a highly selective RET kinase inhibitor, is FDA approved for patients &gt;= 12 years of age. Here we present a case of a 10-year-old patient with metastatic MTC with encouraging results. Clinical Case: A previously healthy 10 year 2-month-old male presented with left-sided neck swelling. Imaging showed a 9.7 cm solid mass spanning nearly the entire left neck, occluding the left internal jugular vein, extending to the upper chest, and resulting in high-grade narrowing of the trachea near the thoracic inlet; the mass involved the left thyroid gland and engulfed the left common carotid. His initial lab evaluation showed an elevated TSH of 10.10 mcU/mL (0.6-5.5 mcU/mL) and Free T4 1.22 ng/dL (0.9-1.67 ng/dL). Tumor markers revealed a calcitonin of 32,264 pg/mL (normal range &lt;= 6.0 pg/mL) and carcinoembryonic antigen (CEA) of 200 ng/ml (normal range 0 – 3.4 ng/mL). He underwent biopsy of the mass which showed medullary thyroid carcinoma (MTC) and genetic evaluation of tumoral tissue showed RET c.2753T&gt;C, p.M918T somatic mutation. Evaluation for pheochromocytoma and hyperparathyroidism, given association of MTC with MEN2, was negative. Genetic testing was negative for germline RET mutations. He was started on selpercatinib, 120 mg every 12 hours. Follow up imaging after 2 months of therapy demonstrated a significant decrease in tumor burden. Approximately 5 months after starting he had a decrease in CEA to 14.8 ng/mL and calcitonin to 69 pg/mL, prior to surgery. Given the risk of locoregional recurrence he underwent total thyroidectomy with lateral neck dissection. However, the tumor was noted to be adherent to the trachea, encasing the left recurrent laryngeal nerve, and left carotid artery preventing full resection. He was started on levothyroxine at 62.5 mcg daily on POD#1 and re-started on selpercatinib approximately 2 weeks post-operatively. Conclusion: We present a case of RET-positive metastatic medullary thyroid carcinoma without germline RET mutation successfully treated with selpercatinib. Long-term follow-up for sustained response and tolerability is needed. Reference: 1. Bauer, Andrew J. “Pediatric Thyroid Cancer: Genetics, Therapeutics and Outcome.” Endocrinology and metabolism clinics of North America vol. 49,4 (2020): 589-611. doi:10.1016/j.ecl.2020.08.00
Presentation: 6/2/2024
7067 A Pilot Study on Levothyroxine Administration- Understanding the Effects on Thyroid Hormone Levels and Patient Compliance Without Restrictions on Food or Time
Authors: Patel Riya , Pandya Krutarth Kandarp , Olson Dan 
Published: October 2024

Abstract
Disclosure: R. Patel: None. K. Pandya: None. D. Olson: None.
Background- Hypothyroidism is one of the most common treatable endocrinological disorders that can be managed by replacement therapy. In most cases, compliance is a major hindrance for maintenance medications to express the intended effect. Thus, prescribing medications in a more convenient way would make it easier for the patients to remember and hence amplify compliance. Traditional practice dictates thyroid replacement medication to be administered early in the morning on an empty stomach for optimum absorption. This mandates some patients to set an alarm clock for early morning to take their thyroid medication, which can not just be cumbersome but also increase the chances of having a fall and can alter sleep hygiene as well. We aimed to identify if allowing patients with a more lenient approach in medication timing can help increase compliance while still maintaining thyroid hormone levels with fewer side effects. Methods- As an initial single-arm pilot study, we retrospectively looked at thirteen patients from a single center, for whom patient preference was respected in allowing them to take thyroid replacement in conjunction with any other medication, food, coffee, or any combination of those, as long as it was consistently taken the same way and at the same time each day. In this study, the patient population ranged in age from 44 to 95, with a mean age of 77.38. Most of these patients had follow-ups for over a decade while their TSH levels were observed with minimum follow-up duration being 4 years. Results- On the serial measurement of TSH on this patient cohort, it was discovered that patients were still euthyroid, ranging from 0.36 to 5.28 with a mean of 2.654. This euthyroid state was achieved without requiring any frequent monitoring or extraordinarily high doses of thyroid supplement hormones compared to patients following traditional measures for the same. The highest dose required to achieve Euthyroid status was no more than 125 mcg once/day without any major hormonal fluctuations or adverse events during their treatment course. Thus, indicating that the proposed amendment to thyroid replacement instructions did not negatively impact thyroid function Conclusion- Hence, we propose a more lenient approach to taking Thyroids supplements allowing the patients to take them more conveniently and hence improving the compliance, improving overall outcomes. This can primarily be applied to the elderly population, minimising potential harm, i.e., falls, and other limitations in an attempt to take it consistently. However, this will be further investigated through a clinical trial to gather more comprehensive data on outcomes as well as identify any potential limitations of this concept.
Presentation: 6/2/2024