bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP509 Proof-of-concept, Multicenter, Open-Label Phase 2a Study of Batoclimab in Active and Moderate-to-Severe Thyroid Eye Disease
Authors: Janes Jonathan , Kahaly George , Liang Su , Tedeschi Philip 
Published: November 2022

Abstract
In thyroid eye disease (TED), immunoglobulin G (IgG) autoantibodies target thyrotropin receptors (TSHR) on the thyroid gland causing Graves’ disease. These TSHR-Ab also bind to the TSHR on orbital fibrocytes, inducing inflammation and hyaluronan production, resulting in extraocular muscle swelling and orbital fat expansion, causing the clinical manifestations of TED. Batoclimab (IMVT-1401) is a selective, fully human monoclonal antibody with high affinity for the IgG binding site on the neonatal Fc receptor (FcRn). Normally, the half-life of IgG is extended by FcRn-mediated recycling from lysosomal degradation. By competitively binding to the IgG binding site on FcRn, batoclimab blocks FcRn-mediated recycling of IgG, resulting in increased elimination and decreased levels of IgG. Batoclimab thus has the potential to provide clinical benefit for TED patients by reducing the level of pathogenic IgG anti-TSHR-Ab.
In this open-label, multicenter, phase 2a study (NCT03922321), subjects with anti-TSHR-Ab positive, moderate-to-severe TED with a clinical activity score (CAS) ≥4 received weekly subcutaneous (SC) injections of batoclimab for six weeks (680 mg for two weeks followed by 340 mg for four weeks). Subjects were monitored for up to an additional 11 weeks. Safety and tolerability were assessed throughout the study. Pharmacodynamic changes in serum IgG and anti-TSHR-Ab were monitored weekly. Clinical efficacy was assessed weekly by response rate for proptosis (≥2 mm reduction in study eye without a deterioration in the other eye). The study eye was defined as the eye with greater proptosis at baseline. CAS response was defined as having a CAS score of 0 or 1.
Seven subjects enrolled and completed this study (baseline mean [SD] age 56.7 [14.9] years, CAS 5.4 [1.1], proptosis 23.1 [3.3] mm). Serum IgG and anti-TSHR-Ab were reduced by a mean (SD) of 64.8% (17.7) and 56.7% (33.6), respectively at Week 6 compared to baseline. Similar reductions were also observed with each IgG subclass. Three of seven subjects were proptosis responders and four subjects were CAS responders. Three of seven subjects were joint responders for both proptosis and CAS. All adverse events (AEs) were mild to moderate in severity and no participant reported serious AEs or discontinuation due to AE. The most common AEs were increased lacrimation, fatigue, and dizziness (n=2 for each).There was a reversible reduction in serum albumin while on treatment which returned to normal levels in all subjects by the end of the study.
In conclusion, batoclimab reduced serum IgG and especially the pathogenic anti-TSHR-Ab with an acceptable tolerability profile. Approximately half of study subjects demonstrated improvement in ophthalmologic assessments with six weeks of treatment. Together, these results support further evaluation of SC batoclimab as a therapeutic option for patients with TED.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP533 Graves’ Ophthalmopathy in the Setting of Primary Hypothyroidism
Authors: Alajmi Sarah , Alshehri Sara , Ekhzaimy Aishah 
Published: November 2022

Abstract

Background
Graves’ ophthalmopathy (GO) is commonly associated with hyperthyroidism secondary to Graves’ disease (GD). Although rare, there have been case reports of it occurring in patients who are hypothyroid with underlying Hashimoto's thyroiditis (HT), as well as in euthyroid patients. It is thought that the mechanism behind developing GO in these patients is due to the presence of stimulating thyrotropin receptor antibodies (TRAB). Below we describe a case of GO developing in a patient who has hypothyroidism secondary to HT.

Clinical Case
A 53 years-old female non-smoker, known to have primary hypothyroidism (Hashimoto's thyroiditis) diagnosed at the age of 39 years, on levothyroxine 75 mcg/day. Presented to our endocrine clinic complaining of diplopia and periorbital swelling for the past 5 months. The diplopia occurs on left gaze while both eyes are open, it resolves with closure of either eye. No history of ocular surgeries, injections, or trauma. No previous hyperthyroid state or radioactive iodine therapy. On physical examination there was no goiter, bruit, palpable lymphadenopathy, tremor, or pretibial myxedema. Ophthalmic examination showed left sided upper and lower eyelid swelling, limited abduction with diplopia and mild punctate keratopathy. Laboratory investigation revealed TSH 3.6 mIU/L (0.250 - 5), T4 14.6 pmol/L (11.5 - 22.7), positive thyroid peroxidase antibody 173.9 units (&gt; 100 units positive) and positive thyroid stimulating immunoglobulin 500IU/ml (Normal &lt; 140). On ultrasound the thyroid gland was small and heterogeneous. MRI orbits demonstrated bilateral ocular proptosis with intraocular muscles enlargement particularly the medial, inferior, superior rectus as well as the levator palpebrae superioris muscles. Our impression was active moderate-severe isolated GO with aBackground of HT, clinically and biochemically euthyroid on levothyroxine. The patient was referred to an ophthalmologist and was started on a course of high dose oral prednisone tapered over 3 months. She reported a 50% improvement in her symptoms after the first month of therapy. Patient was then started and maintained on selenium 100 mcg oral twice daily with lubricating eyedrops. During her last clinic visit she had stable thyroid eye disease and there was no need for further medical or surgical intervention.

Conclusion
GO can occur in patients with HT due to the development of stimulating TRAB targeting thyrotropin receptors expressed on orbital fibroblasts. The incidence varies between studies from 2-7.5%. Awareness of this clinical presentation is important, as early detection and treatment can prevent visual complications. To date there are no clear guidelines on how to treat GO with underlying HT. Treating our patient with high dose steroids extrapolated from treating GO secondary to GD showed significant improvement in her symptoms.
Presentation: No date and time listed
ODP535 Thyrotoxic Periodic Paralysis (TPP) in A Young African American Male: Post Exercise
Authors: Agu Chinyere , Tan Zimri , Cobbs Ronald 
Published: November 2022

Abstract
Thyrotoxic periodic paralysis (TPP) is a rare fatal disorder with hypokalemia as the hallmark feature associated with thyrotoxicosis. Compared with existing studies that TPP is prevalent among younger men of Asian descent, this study intends to complement this area of study by addressing aspects currently not fully covered involving the existence of TPP among men of African descent. This study documents the case of a 37year old African American Man with no previous history of hyperthyroidism who presented with sudden onset lower extremity paralysis and hypokalemia. It is particularly important to note that while majority of patients with TPP have preexisting hyperthyroidism, our patient presented with no history of overactive thyroid. The finding of this work fills a gap in literature highlighting the importance of separating Familial Hypokalemic periodic paralysis (FPP) and TPP at its earliest detection. We find strong and robust evidence suggesting that patients may be easily termed FPP in view of its similarity to TPP thereby leading to a delay in the diagnosis and treatment. TPP has been linked with genetic mutations in specific ion channels (calcium channels and KIR) and increased Na-K ATPase pump activity. This leads to a massive intracellular shift in potassium causing hypokalemia under the influence of excess thyroid hormone. We find that both TPP and FPP have similar clinical presentations and same precipitants hence the need for a high index of suspicion in patients with hypokalemia and sudden onset paralysis with no history of hyperthyroidism to prevent lethal complications. Our results suggest that prompt correction of hypokalemia and treatment of hyperthyroidism is key in resolving attacks and preventing lethal complications.
Presentation: No date and time listed
ODP650 Impaired Cognition in Patients with Mild Autonomous Cortisol Secretion
Authors: Nathani Rohit , Thangamuthu Karthik , Singh Sumitabh , Zhang Catherine , Suresh Malavika , Ebbehøj Andreas , Bancos Irina 
Published: November 2022

Abstract

Background
Limited data describe cognitive deficits in patients with Cushing syndrome (CS). The impact of mild autonomous cortisol secretion (MACS) on cognition is unknown.

Objective
To determine the impact of MACS on cognitive function.

Methods
Single-center cross-sectional study of adults with MACS and age and sex-matched volunteers. MACS was defined as cortisol &gt;1.8 mcg/dL following the dexamethasone suppression test (DST) in patients with an adrenal incidentaloma and no features of CS. We measured cognitive function through the NIH toolbox cognition battery (7 standardized tests of attention, episodic and working memory, language, executive function, and processing speed). T-scores corrected for age, sex, education, and race were used for analysis. All patients completed the SF-36 questionnaire. The frailty index was calculated as previously reported (Singh S. JCEM 2020).

Results
Participants included 50 patients with MACS (median age 61, range 54-68) and 50 volunteers (median age 60 years, range 54-68), with 60% women in both groups. In patients with MACS, median post-DST morning cortisol was 3.6 (range, 2.4-6.2), and median corticotropin was 8.5 (range, 5.9-13) pg/mL (normal 6-60). Patients with MACS had a higher median frailty index (median of 0.26 vs. 0. 05 in volunteers, p&lt;0. 001) and lower quality of life scores on the SF-36 survey (median of 47 vs. 91, p&lt;0. 001). Compared to volunteers, patients with MACS performed worse in the domains of attention and executive function (effective allocation of one's limited capabilities in an abundance of stimuli) (median T-score of 50 vs. 46, p=0. 03), cognitive flexibility (tested as the capacity to plan and monitor goal-directed activities) (median T-score of 61 vs. 55, p=0. 01). The fluid composite score (includes executive function, episodic memory, working memory, and processing speed) was lower in patients with MACS (mean of 53.2 vs. 48.9, p=0. 03). The total composite score was lower in patients with MACS when compared to volunteers (median T score of 50 vs. 54, p=0. 06). The total composite cognitive scores in patients of MACS were associated with the Frailty Index (R2 = 0.13, p = 0. 025) and SF-36 scores (R2 = 0. 08, p = 0. 05), but not post-DST cortisol.

Conclusion
Compared to volunteers, patients with MACS demonstrate cognitive impairment, particularly in the executive domain, which closely mimics changes observed with aging. These deficits do not correlate with the degree of cortisol excess.
Presentation: No date and time listed
OR09-1 Decoding Cancer Immunoediting of Tumor Microenvironment Provides Immunogenomic Marker for Thyroid Cancer Screening
Authors: Ali Sophia , Elsherif Ahmed , Jaume Juan , Kanzy Abed , Khogeer Feras , Madkhali Mohammed , Niaz Azra , Paparodis Rodis , Rafiqi Shafiya , Salim Nancy , Sarwar Haider , Tovar Yara , Zahid Zeeshan , Imam Shahnawaz 
Published: November 2022

Abstract

Thyroid cancer will become 4th most common cancer in women by 2030. Thyroid cancer is the most prevalent endocrine malignancy of women with an age-standardized rate of 10.1/100,000 while in men it is 3.1/100,000.
The microenvironment of thyroid cancer has a high degree of immune invasion, characterized by the presence of T effector (Teff, CD4, and CD8) cells. In our previous study based on 127 human FNA thyroid samples, we reported a dominant T cell species characterized by the deficiency of CD4 and CD8 expression (CD3+CD4-CD8-) Double Negative (DN) T cells, seem to have a regulatory function towards thyroid cancer immune tolerance (1-3).
Here, in another cohort study (46 patients), FNAs of thyroids showed that DN T-cells were significantly more abundant in lymphocytic infiltrates of thyroid cancer patients (post-operatively confirmed diagnosis by an academic pathologist), and if the DN T cell population exceeded our defined threshold (&gt;9.14%), it indicated a high likelihood of cancer presence (96.6% sensitivity, 95% CI, 0.915 to 1.000). Conversely, DN T cells below the threshold (&lt;9.14%) provide 100% specificity in predicting benignity of thyroid nodules. This study identifies DN T cell quantification as an accurate rule-out test. The high specificity of the test is promising since it abolishes false-positive diagnoses and unnecessary surgical procedures. Current molecular diagnostic testing, based on the identification of tumor gene mutations in FNA samples usually reduces the risk of cancer rather than guarantee the absence of cancer which leads to 70% of unnecessary thyroidectomies.
The present study proposes DN T cell quantification as a diagnostic signature for thyroid cancer. Its integration with RNA transcriptomics may provide a simplified technology for thyroid cancer screening and active surveillance.

References
1. Imam S, Paparodis R, Sharma D, et al. 2014 Lymphocytic profiling in thyroid cancer provides clues for failure of tumor immunity. EndocrRelat Cancer 21. 2. Imam S, Dar P, Paparodis R, et al. 2019 Nature of coexisting thyroid autoimmune disease determines success or failure of tumor immunity in thyroid cancer. J Immunother Cancer 7. 3. Imam S, Jaume J C 2021 Stratifying risk of malignancy in indeterminate thyroid nodules and immuno-genomic markers for early detection of thyroid cancer. International Application No. PCT/US2021/012057, Publication Number WO/2021/138661
Presentation: Saturday, June 11, 2022 11:30 a.m. - 11:45 a.m.
OR11-1 Thyroglobulin Structural Requirements in Protein Trafficking for Thyroid Hormonogenesis
Authors: Arvan Peter , Clarke Oliver , Kim Kookjoo , Citterio Cintia 
Published: November 2022

Abstract
In vertebrates, thyroglobulin (Tg) is secreted into the lumen of thyroid follicles to enable its iodination for the synthesis of thyroid hormone — defective Tg secretion causes hypothyroidism. A defining step in Tg secretion is export from the endoplasmic reticulum (ER), but Tg structural features needed to meet ER quality control requirements remain poorly defined. Tg primary structure is composed of Regions I, II, III, and ChEL, each engaged in intradomain disuflide bonding. Two major surprises that have recently emerged from the visualization of bovine Tg 3D-structure by cryoEM include the first identified long-range disulfide bond (C408-C608), which appears to tether a boundary separating two halves of region I, as well as the apparent absence of an evolutionarily conserved disulfide bond between C2444 and C2455 in the ChEL domain, which is known to support folding stability of region I. To understand the cell biological importance of these findings, we employed site-directed mutagenesis to determine the impact of these structural features in protein export of recombinant Tg expressed in cultured cells.
To our surprise, we found that mutation of either a single Cys residue or both cysteines that contribute to the C408-C608 disulfide bridge had no discernible impact on the efficiency of Tg export. These data strongly suggest that the proximity of the two-halves of region I in the final Tg structure may be achieved by protein folding of individual repeating units of region I that must take place independently of (and thus presumably prior to) the formation of this interesting long-range disulfide bond.
As ChEL supports Tg region I folding stability, we turned attention to the apparent absence of the C-2444-C2455 disulfide, which is one of the three disulfide bonds that had been thought to exist in every member of the large Cholinesterase-Like gene superfamily. Reported detection of this disulfide within human Tg, but lack of detection in bovine Tg, means either that this bond is 'structurally optional', or that this surface disulfide bond might have been broken by radiolysis under the X-ray beam used for cryoEM. Unequivocally, we found that mutagenesis of either C2444, C2455, or both, blocks Tg secretion and causes a pattern of intracellular misfolding consistent with incomplete Tg compaction indicative of lack of maturation of region I. Moreover, we found that disruption of these same residues causes misfolding and blocks secretion of an expressed isolated secretory ChEL domain, or acetylcholinesterase itself.
Loss of the C2444-C2455 disulfide bridge behaves similarly to the defective folding observed in the mutant Tg encoded within cog/cog mice and rdw/rdw rats, whereas no pathogenic mutations have been reported affecting the long-range disulfide in Tg region I. Together, these results highlight the importance of ChEL domain structure in the maturation and secretion of Tg.
Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.
OR11-2 RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies
Authors: Dresner-Pollak Rivka , Fridlender Zvi G , Gurt Irina , Kaisar-Iluz Naomi , Lishinsky Natan , Pollack Rena , Shaul Merav E , Stokar Joshua 
Published: November 2022

Abstract
Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, however, are associated with immune-related adverse events (irAEs). Thyroid dysfunction is among the most common irAEs, yet its mechanism has not been fully elucidated. To further explore the molecular mechanism of ICI-induced thyroid dysfunction, we profiled changes in transcription induced by PD-1/PD-L1 antibody treatment in a non-small cell lung cancer murine model using RNA-seq. We used bioinformatic tools to compare transcriptional changes in our model to previously published transcription data sets of drug-induced thyroiditis. C57BL6/129SvJ mice harboring LKR-M (Lung cancer K-ras metastatic tumor) flank tumors were treated with PD-1 antibody, PD-L1 antibody, or vehicle every 3 days over a period of 7 days when mice were sacrificed, and thyroid glands were removed. The tumor volume increased in the control mice (1.38 ± 0.19) and decreased in the anti PD-1 treated (0.64 ± 0.15; P=0.0001) and PD-L1 treated mice (0.74 ± 0.11; P=0.004). RNA-seq was performed in the LKR-M tumor-bearing control mice and in the anti PD-1/PD-L1 treated mice (n=4 per group). A total of 952 differentially expressed genes (DEGs), including 265 upregulated and 688 downregulated, were identified with anti PD-1 treatment (fold-change ≥1.8, FDR ≤0.05). Only 35 genes were differentially expressed with anti PD-L1 treatment, and we therefore chose to focus on the anti PD-1 treated group alone. Using Ingenuity Pathway Analysis (IPA), we determined that of the DEGs in the PD-1 treatment group, 362 were associated with functions of cell death and survival, with a predicated activation of pathways for apoptosis and necrosis (Z=2.89 and 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z=-6.22 and -6.45, respectively). When compared to previously published datasets of interleukin-1β and interferon gamma-treated human thyroid cells, the apoptosis pathways were similarly activated. To our knowledge this is the first study to evaluate transcriptomic changes in thyroid tissue following ICI therapy. Our data suggest that there are unique changes in gene expression in the thyroid associated with anti PD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.
Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.
OR11-5 Outcomes and Predictors of 30-day Readmission for Hyperthyroidism: A Nationwide Study
Authors: Adeoti Oluwatomi , Salim Michael , Kichloo Asim , Shaka Hafeez 
Published: November 2022

Abstract
This retrospective cohort study examines the 30-day readmission rate for patients with hyperthyroidism. Analysis of data from the 2018 Nationwide Readmissions Database exposed factors that affect this rate and described key healthcare quality indices that are associated with these readmissions. Understanding these will help identify areas for improving patient outcomes.
Presentation: Sunday, June 12, 2022 12:00 p.m. - 12:15 p.m.
OR19-4 A Minimal Human Physiologically Based Kinetics Model of Thyroid Hormones and Effects of Endocrine-Disrupting Chemicals
Authors: Zhang Qiang , Bagga Anish 
Published: November 2022

Abstract
Thyroid hormones (THs) thyroxine (T4) and triiodothyronine (T3) are under homeostatic and circadian control by the hypothalamic-pituitary-thyroid axis while their free plasma concentrations are strongly buffered by three TH binding proteins (THBPs): thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB). The THBPs are crucial to the even delivery of THs from the blood to tissues, but their relative contributions and spatial kinetics within tissues are unclear. Many endocrine-disrupting chemicals (EDCs) can interfere with the regulation and actions of THs, some of which are structurally similar to THs with comparable or even higher binding affinities for THBPs. It has been suspected that by disrupting the binding of THs with THBPs, EDCs may alter the plasma TH concentrations and the delivery to tissues. Given that the majority of the binding sites on THBPs are unoccupied—thus available for EDC binding—it is uncertain whether TH homeostasis can be tangibly perturbed by EDC exposure. To answer these questions, we constructed a spatial multi-compartment human physiologically based kinetic (PBK) model of TH production, distribution, and metabolism. The model contains the thyroid, liver, and rest-of-body compartments with explicit descriptions of the reversible binding kinetics between THs and THBPs in the blood. The model was parameterized and validated extensively based on literature data. Here we reported several novel findings: (1) The contribution to TH tissue delivery by each THBP is not spatially constant across a tissue: ALB always contributes more THs to the arterial side of the tissue while TBG contributes more to the venous side. (2) THBPs are essential for a uniform TH tissue delivery but are cross-compensatory in this role. (3) Contrary to the long-held assumption that ALB is the dominant contributor, TBG contributes more of the THs delivered to a tissue overall than ALB and TTR. (4) Bode plot analysis using control theory suggests that a circadian signal driving T4-to-T3 conversion in the extra-thyroidal tissue is crucial to establish the distinct phase and amplitude profiles of circulating T3 and T4 in humans. (5) Displacement of THs from THBPs by high-affinity EDCs has a negligible effect on free plasma THs even under high exposures. (6) Daily exposure to THBP-binding EDCs does not affect the circadian variations in tissue delivery of THs. The PBK model can be further elaborated in the future to make tissue-specific predictions of TH kinetics.
Presentation: Monday, June 13, 2022 11:45 p.m. - 12:00 p.m.