bluuebunny/crossref_metadata_2025_split huggingface dataset:
8805 Nucleostemin is a novel bifunctional transcriptional coregulator of theandrogenreceptorin prostate cancer cells
Authors: Cheung Edwin , Zhang Cuiting 
Published: October 2024

Abstract
Disclosure: E. Cheung: None. C. Zhang: None.
Androgen receptor (AR) is a master transcriptional regulator in prostate cancer, interacting with and recruiting distinct sets of coregulator proteins to mediate the expression of direct target genes. What are the coregulators of AR and how they function in AR transcriptional activity and prostate cancer biology are still unclear. Using chromatin-immunoprecipitation coupled with mass spectrometry, we identified a set of AR interacting proteins that are present in multiple prostate cancer cell lines. We provide biochemical, cell-based, and genomic evidence to show that Nucleostemin, also known as Guanine nucleotide-binding protein-like 3, is a novel AR coregulator. Specifically, we demonstrate Nucleostemin has dual coregulator activities, functioning as both a coactivator and a corepressor of AR-dependent transcription to regulate the expression of genes that are involved for prostate cancer progression and immune response. From cellular and animal studies, we found that inhibiting Nucleostemin sensitizes prostate cancer cells to Enzalutamide. Clinical analyses of Nucleostemin from prostate cancer patient cohorts revealed that it is expressed significantly higher in cancer than normal in tissues. Finally, we found Nucleostemin expression is an excellent predictor of disease-free survival. In conclusion, our work suggests that Nucleostemin is a novel AR coregulator and is a promising diagnostic and therapeutic target for prostate cancer treatment.
Presentation: 6/2/2024
8516 Role of ER, PR, IRS-1 Transcriptional Complexes in Endocrine Resistant Luminal Breast Cancer
Authors: Schmidt S , Lange C A 
Published: October 2024

Abstract
Disclosure: S. Schmidt: None. C.A. Lange: Consulting Fee; Self; Consultant for Astrin.
In the United States, 1 in 8 women will develop invasive BC within their lifetime. For Luminal breast cancer expressing steroid hormone receptors (SRs) for estrogen and progesterone (ER+/PR+), current standard of care targets ER with antagonists, such as tamoxifen, or blocks estrogen synthesis using aromatase inhibitors. Unfortunately, these endocrine therapies ultimately fail in up to 40% of patients with node positive status. Most endocrine resistant breast cancers retain expression of ER and PR, PGR being a key ER target gene. Two common mechanisms of resistance are ESR1 gene mutations, providing ligand-independent activation of ER, high expression of PR, and activation of oncogenic signaling pathways that circumvent therapies. These pathways include mitogen- and stress-induced signaling pathways (MAPKs, CDKs, PI3K/AKT). Notably, PR target genes encode many of the key components of oncogenic signaling pathways, such as ErbB family members and their ligands. Interestingly, PR can act to limit or divert ER-driven proliferation in hormone-sensitive breast cancer models. However, tumor-promoting actions of PR have been identified by the Lange lab and others. Constitutive ER/PR complexes cooperate at cancer-relevant target genes and both progestins and anti-progestins block estrogen-driven proliferation and survival. The Lange lab demonstrated that MAPK-activated phospho-PRs drive tamoxifen resistance and cancer stem cell expansion. Tumor heterogeneity underscores the need to target both hormone sensitive proliferating cells and non-proliferating cancer stem cells to avoid recurrence of newly resistant BC. A cytoplasmic adaptor molecule in the IGF/insulin signaling pathway, insulin receptor substrate-one (IRS-1), has been identified as a new possible target. We previously reported that IRS-1 is a ligand-independent phospho-PR target gene. Once expressed, IRS-1 forms a complex with ER/PR and is required for breast cancer stemness properties. We hypothesize that the transcriptional regulation of target genes by PR/ER/IRS-1 promotes endocrine resistance and supports stemness phenotypes in ER+ breast cancer. Further studies confirmed a close-proximity nuclear interaction between PR and IRS-1 upon estrogen (but not progestin) stimulation in additional models. This interaction was blocked upon IRS-1 inhibition or insulin treatment. Canonical cytoplasmic insulin/IR/IRS-1 signaling may sequester IRS-1 away from nuclear ER/PR complexes. Accordingly, insulin treatment dramatically reprogrammed the estrogen-driven transcriptome. Characterization of the signal-specific roles of cytoplasmic (insulin) or nuclear (estrogen) IRS-1 may reveal how altered SR signaling complexes contribute to endocrine resistance and may lead to new therapeutic targets for improved outcomes for women with endocrine resistant ER+ breast cancer.
Presentation: 6/3/2024
7587 The Estrogen Receptors and ARE/Nrf2 are Involved in Protecting Human Dermal Fibroblasts from Damage Caused by Mitochondrial Disfunction
Authors: Darawshe A , Trachtenberg A , Sharoni Y 
Published: October 2024

Abstract
Disclosure: A. Darawshe: None. A. Trachtenberg: None. Y. Sharoni: None.
Skin ageing is influenced by several factors including environmental exposure and hormonal changes. Reactive oxygen species (ROS), which mediate many of the effects of these factors, can be formed by extrinsic factors, such as sun exposure, or can result from mitochondrial dysfunction as occurs during ageing. Several studies have shown the protective role of estrogens on skin health. The aim of the current study was to examine the damage to dermal fibroblasts by mitochondrially generated ROS, and to study the mechanism of the protective effects of estradiol. Rotenone, a complex I inhibitor, was used to cause mitochondrial dysfunction in human dermal fibroblasts and its effects on mitochondrial and cytosolic ROS levels, mitochondrial respiration, cell death, apoptosis, matrix metalloproteinase-1 (MMP1) and pro-collagen secretion were determined as markers of skin damage. Rotenone caused substantial reduction of respiration, followed by increased mitochondrial and cytosolic ROS which resulted in apoptotic cell death, increased MMP1 secretion and decreased collagen secretion. Pretreatment with estradiol recovered more than 50% of the respiratory activity, reduced mitochondrial and cytosolic ROS levels and MMP1 secretion and increased cell number and collagen secretion. These effects can be partially explained by a cooperative effect of estradiol and rotenone on Antioxidant Response Element (ARE/Nrf2) transcriptional activity, which leads to upregulation of antioxidant proteins such as NQO1 and Trxr1. To determine if estrogen receptors (ER) are involved in the protective effects, we used the ER inhibitor, Fulvestrant. This inhibitor, which completely inhibited ER Response Element reporter activity, partially prevented the protective effects of estradiol. The protective effects of estradiol were Similarly reduced by ML385 and Ochratoxin A, that are inhibitors of the ARE/Nrf2 transcription system. Incubating the cells with Fulvestrant and Ochratoxin A, which inhibit both pathways, completely blocked the protective effect of estradiol. These results suggest that the estrogen receptors and the ARE/Nrf2 signaling pathways are involved in the protective effects of estradiol against the damage caused by rotenone-induced mitochondria generated oxidative stress.
Presentation: 6/3/2024
8242 A Case of Ayme Gripp Syndrome
Authors: Jaisinghani P , Pappas J 
Published: October 2024

Abstract
Disclosure: P. Jaisinghani: Consulting Fee; Self; Novo Nordisk. J. Pappas: None.
We present a 35 year old female with cataracts, generalized seizures and oligodontia, referred to us for hair loss and elevated TSH. For over 10 years, patient had a diffuse hair loss which progressed to a focal patch of hair loss in the setting of prior use of keppra and seborrheic dermatitis. Patient has regular menses, and no symptoms of hyper/hypothyroidism or family history of thyroid disease. Patient established care with dermatology and scalp biopsy noted early androgenetic alopecia. Physical exam was notable for short stature, height 4'11, 98 lbs, BMI 19.8 kg/m², progeric appearance, facial hyperpigmented spot, hair thinning, palpable thyroid R&gt;L. Laboratory evaluation included TSH 6.150 (0.450 - 4.500 uIU/mL), DHEAS 263 (84.8 - 378.0 ug/dL), total testosterone 15 (10 - 55 ng/dL), FSH 6.6 (Follicular phase 3.5 - 12.5 mIU/mL), LH 7.6 (Follicular phase 2.4 - 12.5 mIU/mL), estradiol 83 (Follicular phase 12.5 - 166.0 pg/mL). Thyroid US demonstrated smaller than average size left lobe measuring 2.93 cm x 0.84 cm x 1.36cm vs right lobe measured 4.34 cm x 0.90 cm x 1.62. Labs noted TSH 5.690 (0.450 - 4.500 uIU/mL), establishing subclinical hypothyroidism and negative thyroid antibodies. Clinical genetics evaluation included trio exome sequencing which revealed a de novo pathogenic variant p.(Ser54Leu) (TCG&gt;TTG): c.161 C&gt;T in exon 1 of the MAF gene (NM_005360.4) which establishes the diagnosis of a Ayme- Gripp syndrome (AGS). AGS is characterized by a triad of cataract, sensorineural hearing loss, and characteristic facial features in combination with neurodevelopmental abnormalities. 21 affected individuals from 19 families have been reported with AGS. Clinical features in our case characteristic of AGS included short stature, brachycephaly, midface hypoplasia, long philtrum and premature hair loss. Hypothyroidism was identified in childhood in 3/15 identified individuals who responded to thyroid hormone replacement therapy. For this patient, we will monitor thyroid function tests every 3-6 months and monitor for symptoms of hypothyroidism. Patient has been referred to cardiology and nephrology, and will continue to follow with genetics and dermatology. Our case further establishes the association of hypothyroidism with AGS. Our case demonstrates the value of expanding the differential of endocrinopathies to rare genetic conditions which are currently identifiable by clinically available genomic tests.
Presentation: 6/1/2024
7165 A Case of Severe Myxedema Coma with Levothyroxine Allergy
Authors: Rothstein Costris A , Yaseen A , Levy S 
Published: October 2024

Abstract
Disclosure: A. Rothstein Costris: None. A. Yaseen: None. S. Levy: None.
Introduction: Myxedema coma is a life threatening condition with a mortality rate of 25-60%. Untreated, it can lead to fatal physiological changes. The treatment is thyroid hormone replacement therapy, alongside supportive care for complications. Clinical Case: A 65-year-old woman, who has been dealing with untreated hypothyroidism since 2012 and reported allergies to various levothyroxine brands, presented with falls, weakness, and exacerbated leg numbness. During the examination, she exhibited periorbital edema, non-pitting edema in the lower extremities, bradycardia, and hypothermia. The blood work revealed an elevation in TSH levels at 301 uIU/L (0.45-5.33 uIU/mL). The patient was administered IV Synthroid (200 mcg), Atropine, and Hydrocortisone due to concerns about myxedema coma. After four hours, the patient experienced angioedema and hypotension, necessitating intubation. This situation was complicated by a pulseless electrical activity (PEA) arrest. Following cardiopulmonary resuscitation and the administration of epinephrine, the patient achieved return of spontaneous circulation. The allergy team assessed the patient for potential anaphylactic shock from IV Synthroid. Subsequently, the patient was initiated onIV Liothyronine and Hydrocortisone, leading to improvement in mental status over a period of a few weeks, and no adverse effects were reported. Thyroid labs improved to TSH of 53 (0.45-5.33 uIU/mL), FT3 of 3.3 (2.5-4.4 pg/mL) and total T3 of 133 (87-178 ng/dl). Upon discharge, the patient was prescribed Liothyronine, with plans to perform a Levothyroxine desensitization test in the outpatient setting. Conclusion: Myxedema coma is an endocrine emergency. Patients usually present with deteriorating mental status, hypothermia, and multiple organ system abnormalities. The diagnosis relies more on the clinical presentation and physical examination than on laboratory results. Thyroid replacement therapy serves as the cornerstone of treatment, with a preference for T4 due to its greater availability and lower likelihood of adverse events compared to Liothyronine, which may increase the risk of mortality at higher doses. Despite associated risks, incorporating low doses of Liothyronine is still considered in treatment plans, driven by concerns about reduced T4 to T3 conversion in myxedema patients. Hypersensitivity reactions to Levothyroxine are uncommon but may manifest as widespread hives, swelling, eczema-like skin rashes, elevated body temperature, and compromised liver function, with only one case reporting an anaphylactic reaction to Levothyroxine. In summary, the potential for experiencing an anaphylactic reaction to Levothyroxine exists, highlighting the need to contemplate alternative treatments, such as Liothyronine. Desensitization methods can be considered once the patient's condition is stable.
Presentation: 6/2/2024
12441 Factors Affecting The Evaluation Of Adrenal Incidentalomas
Authors: Poloju A , Pabich S K , Syed S , Krueger A , Chiu A 
Published: October 2024

Abstract
Disclosure: A. Poloju: None. S.K. Pabich: None. S. Syed: None. A. Krueger: None. A. Chiu: None.
Introduction: Adrenal incidentalomas are increasingly being detected, owing to the increasing number of high-resolution radiologic studies performed. While most of the nodules are non-functional, 10-15% are hormonally active and hence merit workup. We assessed the rates of, and factors associated with appropriate workup of these nodules. Methods: A retrospective analysis of CT chest and abdominal scans between Jan 1, 2021, and June 1, 2022, in adults ≥18 years at a single tertiary care center was performed. Reports were screened with key phrases to identify adrenal nodules. A chart review was conducted to confirm the reported nodule, obtain demographic data, obtain data on co-morbid conditions, and evaluate for biochemical and radiologic workup. Exclusion criteria included: patients deceased at the time of our review, previously diagnosed nodules, sub-centimeter lesions, and adrenal hemorrhage. Patients were categorized as being from high or low disadvantaged neighborhoods based on their Area Deprivation Index (ADI) score. ADI above the 50th percentile was categorized as more disadvantaged. Charleston Comorbidity Index (CCI), a 10-year survival predictor based on the presence of common diseases was abstracted. Patients with any biochemical workup were compared to patients with no workup. Bivariate analysis was performed using chi-squared and Student’s t-test analysis. A multivariate logistic regression was performed to evaluate factors associated with biochemical workup. Results: A total of 533 records were reviewed. After applying the above exclusion criteria, a total of 245 patients were included in our analysis. Baseline characteristics included: 58.7% female and 41.2% male. 67.3% had hypertension diagnosis, 22% had sleep apnea diagnosis, and 30.6% had diabetes diagnosis. 86% were White, 5.7% Black, 3.2% Hispanic, 3.2% Asian, and 1.6% Other. 71% of the patients had no biochemical workup, 18% had partial workup, and 11% had full workup. Factors associated with having either partial or full workup compared to no workup included female sex (OR 2.33, CI 1.23-4.41), internal medicine/family medicine provider ordering the scan compared to Emergency Department providers (OR 3.84, CI 1.61-9.14), and ADI scores below the 50th percentile (OR 1.98, CI 1.04-3.78). There was no statistically significant difference based on age, race, ethnicity, and CCI. There was no significant difference in the workup for hypercortisolism based on the presence of co-morbid conditions like diabetes, sleep apnea, and overweight/obesity. Conclusions: In our study population, the rates of guideline-based biochemical workup of adrenal incidentalomas were very low at 11%. Factors associated with having at least partial biochemical workup included less socioeconomic disadvantage, female sex, and studies ordered by primary care providers.
Presentation: 6/3/2024
7639 A Rare Cause of Lung Adenocarcinoma with Metastasis to the Thyroid
Authors: Echevarria-Torres Edward , Yap Charmaine G , Izuora Kenneth E 
Published: October 2024

Abstract
Disclosure: E. Echevarria-Torres: None. C.G. Yap: None. K.E. Izuora: None.
A rare cause of lung adenocarcinoma with metastasis to the thyroid. Metastasis to the thyroid gland from non-thyroid malignancies is rare. When metastasis occurs, presenting symptoms are typically nonspecific, representing a diagnostic challenge. With the goal of raising awareness, we present a case of lung adenocarcinoma with metastasis to the thyroid. An 85-year-old man with a history of hypertension, hyperlipidemia and 60 years smoking history presented to the endocrine clinic for evaluation of subclinical hyperthyroidism. On the physical exam, there was fullness in the right thyroid area which on ultrasound showing a large right thyroid nodule occupying the entire lobe. There was also a solid 4.5 cm x 3.4 cm x 4.6 cm nodule in the mid-anterior left thyroid lobe. Fine needle aspiration cytology of right nodule revealed malignant cells and cell block material positive for TTF-1 (Thyroid Transcription Factor 1) concerning for malignancy. The left thyroid nodule cytology was consistent with benign follicular nodule. Chest CT ordered for surgical planning showed right upper lobe pleural-based lung opacity measuring 3.7 cm x 2.9 cm with supra clavicular lymphadenopathy. Biopsy of lung mass and supra clavicular lymph nodes revealed primary lung adenocarcinoma involving the lymph nodes consistent with stage Iva (cT3NxM1b). The patient was referred to oncology for further management. Discussion: Metastatic lesions to the thyroid gland account for less than 1 % of all malignant thyroid tumors with most cases found on autopsy. This is hypothesized to be due to the rich blood supply and high iodine content of the thyroid gland. Thyroid metastasis usually presents several years after initial diagnosis and treatment of non- thyroid malignancy. Patients can present with enlarging thyroid nodules, neck swelling, dysphagia and, in rare instances, upper airway obstruction. We present a rare case of lung cancer with metastasis into the thyroid. The thyroid nodule initially palpated upon physical exam led to eventual thyroid ultrasound and subsequently to his diagnosis of lung adenocarcinoma after findings of lung nodule which was biopsied and showed primary lung adenocarcinoma. TTF-1 was also positive which is typically expressed by lung adenocarcinomas. Treatment for thyroid metastasis is surgery, along with treatment of primary malignancy. The earlier the diagnosis and treatment the more favorable the prognosis. Radiotherapy and chemotherapy are other means to reduce the recurrence. Thyroid hormone replacement will be warranted post operatively for hypothyroidism. We present this uncommon case to raise awareness about the presentation of thyroid metastasis to enhance timely diagnosis and intervention.
Presentation: 6/1/2024
8176 An Unusual Case of Thyroid Eye Disease (TED) Occurring in Autoimmune Hypothyroidism
Authors: Prasongdee K , Tessier C M 
Published: October 2024

Abstract
Disclosure: K. Prasongdee: None. C.M. Tessier: None.
Background: It is unusual for TED to present in patients with autoimmune thyroid disease who are euthyroid or hypothyroid. Clinician recognition of this rare presentation is important in ensuring proper treatment and improving patient outcomes. Clinical Case:Our patient is a 57-year-old female with a past medical history of COPD, hypothyroidism presenting with several months of blurry vision. She reports double vision when looking down, and eye pain at rest and with eye movement. She was diagnosed with hypothyroidism one year prior to presentation, and her TSH subsequently normalized after titration to levothyroxine of 112 mcg daily. She reported no history of head or neck radiation. No family history of thyroid disease. She smoked for 30 pack years but stopped 2 years prior. Physical exam showed eye lid swelling and redness, pain and diplopia on end-lateral gaze, no chemosis, no conjunctival injection, or inflammation of the caruncle, lids closed completely, proptosis with Hertel ophthalmometer measured 23 mm on the right eye and 22 mm in the left eye (normal range &lt; 18 to 20 mm for Caucasians), thyroid not enlarged with no palpable nodules, no thyroid bruits. The initial Clinical Activity Score (CAS) was 4, which indicated active TED. A thyroid ultrasound showed Inhomogeneous echogenicity with increased vascularity consistent with autoimmune thyroiditis. An MRI of the orbits revealed diffuse extraocular muscle enhancement and enlargement with tendinous insertion sparing, increased T2 hyperintensity findings which favored thyroid eye disease. Further laboratory testing confirmed the presence of multiple thyroid autoantibodies: Thyrotropin binding inhibitory immunoglobulin 2.76 IU/L (normal range &lt; 1.75 IU/L), Thyroid peroxidase antibody 1135 IU/mL (normal range &lt;9 IU/mL), Thyroglobulin antibodies 157 IU/mL (normal range &lt; 116 IU/mL), thyroid-stimulating immunoglobulin 447% (normal range &lt;140 % Baseline). She was referred to ophthalmology for management of TED and was started on teprotumumab. Her CAS improved to 0 and her diplopia resolved. Her proptosis remained stable. This case illustrates an unusual clinical course in a patient who initially presented with autoimmune hypothyroidism, later developed Thyroid Eye Disease. A study by Kahaly GJ et al showed that in Hashimoto’s thyroiditis (HT), thyroid-stimulating autoantibodies are highly correlated with thyroid eye disease (TED) with positive thyroid-stimulating autoantibodies detected in 5.5% of the patients with HT and 68.2% in the patients with HT and TED. Even though it is less common, up to 6% of patients with HT may be affected by TED. Rare presentations such as this case emphasizes the need to be vigilant when evaluating eye symptoms in patients with autoimmune thyroid disease. Teprotumumab that showed improvement in patients with Grave’s and thyroid eye disease, was also successful in treating our patient symptoms.
Presentation: 6/3/2024