bluuebunny/crossref_metadata_2025_split huggingface dataset:
6401 Exogenous Cushing Syndrome By Over The Counter Substance "AK Forte". Case Report
Authors: Mohamed Eid Mennaallah , Gandhi Shriya 
Published: October 2024

Abstract
Disclosure: M.M. Eid: None. S. Gandhi: None.
Introduction: Cushing syndrome is a condition of hypercortisolism, either due to excess activity of hypothalamic-pituitary-adrenal (HPA) axis or exogenous steroid intake. Case: A 36 year old, female with history of type 2 DM, HTN, HLD and arthritis. She was referred for evaluation of face and neck swelling for 3 months. No known allergy. Irrelevant family history. Daily Medications include Glipizide 2.5mg, Metformin 500mg twice, Lisinopril 2.5mg and Glargine 8 units. She reports weight gain, muscle weakness and fall, easy bruise, irregular menstruation and stretch marks for a year. Denies hirsutism. On exam: normal vital signs, BMI 47.87 with cushingoid features facial plethora, moon face, dorsocervical pad fat, violet abdominal and arm striae, proximal muscle weakness. No thyromegaly. Late night salivary cortisol 0.071ug/dl(N &lt; 0.359),24 hr urine free cortisol &lt; 1ug/dl(N &lt; 45), DHEA-S 6 ug/dl (N 61-337), 17 Hydroxyprogesterone (OH progesterone) &lt; 5ng/dl, 1 mg overnight Dexamethasone suppression test: AM cortisol &lt; 1 ug/dl, ACTH 1.7 pg/ml (N 7.2-63.3). Na 137 mmol/L , K 4.1 mmol/L,TSH 0.51mciu/ml(N 0.3-4), FT4 0.9 ng/dl(N 0.6-1.7), HBA1C 14% (was 5.1% a year ago). CT abdomen pelvis with normal adrenal glands. Endogenous hypercortisolism was excluded with low 24 urinary cortisol, and late-night salivary cortisol and adequate suppression of morning cortisol with dexamethasone. Low DHEA-S and 17 OH progesterone raises the possibility of exogenous hypercortisolism. A Thorough review of medications and substance revealed that she has been taking over the counter (OTC) AK Forte 400mg 2 tablets 2 times/day for 13 months for arthralgia. In April 2023, FDA released a public notification that AK Forte contains unspecified amount of diclofenac, dexamethasone, and methocarbamol not listed on the product label and warned against taking it (2). We recommended discontinuation of OTC substance and kept her on hydrocortisone 20mg morning and 10 mg afternoon to avoid adrenal insufficiency with plan of gradual hydrocortisone tapering till HPA axis recovers. For uncontrolled DM, dulaglutide 0.75mg/week, and premeal insulin were started and glargine dose was increased. Conclusion: We are presenting a case of exogenous Cushing’s syndrome by OTC substance that contains undeclared ingredients. Dexamethasone in AK Forte causes exogenous hypercortisolism and Cushingoid features with HPA axis suppression. We emphasize the importance of thorough medication reconciliation including OTC substances. We encourage reporting adverse events of OTC substances to FDA. Reference: 1-J.Newell-Price,X.Bertagna,A.B.Grossman,andL.K.Nieman, “Cushing’s syndrome,” Te Lancet, vol. 367, no. 9522, pp. 1605-1617, 2006. 2-https://www.fda.gov/drugs/medication-health-fraud/public-notification-ak-forte-contains-hidden-drug-ingredients.
Presentation: 6/2/2024
6636 Primary Hyperaldosteronism Leading to Aldosterone Deficiency
Authors: Haverstick Nathan Grant , Anthony Jeremy Richard 
Published: October 2024

Abstract
Disclosure: N.G. Haverstick: None. J.R. Anthony: None.
Primary Hyperaldosteronism is a disease process that is often missed, and under checked due to poor screening tools. The disease presents with a common problem, uncontrolled hypertension. It also presents with hypokalemia, fatigue and headaches. It can easily be masked with blood pressure medications, CKD, and pain medications. After treatment there are some rare reports of patients developing hypoaldosteronism. Some risk factors are age &gt;50, duration of hypertension &gt;10 years, pre-existing renal impairment and adrenal adenoma size &gt;2 cm. The patient will present with the opposite: hyperkalemia and hypotension. This is due to the atrophy of the previously healthy gland. Usually this resolves within a year. However in our patient she has continued to require long standing mineralocorticoid replacement therapy. This case highlights the importance of early recognition of hyperaldosteronism. A 63 year-old-female with a medical history of hypertension and diabetes mellitus is being followed for 30+ years of uncontrolled hypertension. Patient has been on multiple agents and blood pressure remained elevated after trying triamterene/hctz, metoprolol, irbesartan, amlodipine. After changing her PCP, there was further investigation into the cause. Leading differentials were Primary Hyperaldosteronism vs Renal Artery Stenosis vs Primary Hypertension. She also had multiple labs with her Potassium below 3 mEq/l. Additional labs were obtained and her Aldosterone level 209 ng/dl and Renin &lt;0.167 ng/mL/hr. The patient was referred to Endocrinology who performed a fludrocortisone suppression test, which did not suppress the levels. A CT scan of the abdomen was performed that showed a 1.3 cm right adrenal mass typical with adrenal adenoma. The patient had an adrenalectomy surgery in February 2022. The patient recovered well, however now developed hypotension off medication, and had consistent hyperkalemia with K &gt; 5.5 mEq/l. The patient had now developed aldosterone deficiency. This was due to the long standing hyperaldosteronism that had caused her left adrenal gland to atrophy after 30 years. The patient was started on Fludrocortisone 0.1 mg daily and a low potassium diet. She has remained off any blood pressure medications since her right adrenalectomy. She has continued to require the mineralocorticoid replacement to date. The diagnostic work-up for primary aldosteronism involves screening, confirmatory testing, and localization studies to distinguish unilateral pathology which may be amenable to adrenalectomy from bilateral adrenal hyperplasia. Through literature review, one theory is that chronic suppression of renin may cause atrophy of the zona glomerulosa cells and hypoaldosteronism. Throughout the case report we emphasize on the importance of early diagnostic screening of secondary hypertension as well as the complications from adrenalectomy.
Presentation: 6/2/2024
7324 Regulation of Super Enhancers by Phosphorylated Progesterone Receptors Drives Breast Cancer Stem Cell Expansion
Authors: Gillis N , Lange C A 
Published: October 2024

Abstract
Disclosure: N. Gillis: None. C.A. Lange: None.
Current treatments for estrogen receptor (ER) positive breast cancer largely target rapidly dividing tumor cells. However, aggressive breast cancers often contain long-lived and weakly proliferative cancer stem cells (CSCs) that readily escape treatments aimed at cycling cells. We previously reported that progesterone receptors (PR) and their target genes aid the growth of these CSCs and help them evade anti-estrogen therapy. As proliferation and stemness are directed by separate signaling pathways that lead to the expression of distinct gene programs, it's crucial to understand how PR facilitates this cellular transformation at the genomic level. Establishing a gene expression program that may limit proliferation but encourages stemness requires coordination between transcription factors and their coregulators to alter the nuclear microenvironment and chromatin landscape.To reveal these mechanisms, we profiled PR and ER genomic binding using CUT&RUN in the T47D luminal breast cancer cell line grown in ultra-low attachment (3D) mammosphere conditions. Our analysis of genomic binding profiles displayed a pattern of PR/ER co-occupancy at distant sites more than 10 kilobases away from the nearest transcriptional start site. We used Rank Ordering of Super Enhancer (ROSE) analysis on these PR/ER binding sites to predict which are likely super enhancer elements capable of coordinating the regulation of multi-gene subsets. We employed a genetic approach to directly test the function of novel enhancer sites linked to PR-target genes by disrupting the PR/ER binding with a dCas9-KRAB construct directed to the predicted enhancer elements. We propose that abnormal growth factor signaling in breast cancer cells permits PR/ER complex formation which promotes expression of genes that induce endocrine resistance and CSC expansion through regulation of super enhancer elements. Further studies to elucidate these mechanisms are ongoing. Understanding the intricacies of PR/ER crosstalk is the crucial next step in developing new therapies that target PR-driven processes in ER+ breast cancers.
Presentation: 6/3/2024
8701 Rsk2 Regulates Estrogen Homeostasis in Metabolism and Fertility
Authors: Wright E B 
Published: October 2024

Abstract
Disclosure: E.B. Wright: None.
Rsk2 is a protein kinase activated downstream of the Ras/Raf/MEK/ERK cascade and has numerous substrates in metabolism, transcription, and translation. However, the role for Rsk2 in regulation of metabolic substrates has only been studied in cancer cell lines. In breast cancer, active nuclear Rsk2 associates with ERα and promotes transformation by activating a transcriptional program critical to the ER+ lineage in the mammary gland[1]. Cancer co-opts programs important in development and homeostasis, and in investigating this possibility we identified that Rsk2 is an important mediator of reproduction2. The link between metabolism and fertility is poorly understood, and Rsk2 may act as a sensor linking metabolism to fertility. To investigate this link, we looked to the liver as a central regulator of metabolism. Hepatic ERα is a transcriptional regulator of metabolic programs, but it is unknown whether Rsk2 regulates hepatic ERα activity. To investigate the role of Rsk2 in regulation of hepatic ERα, livers and mammary epithelial cells were collected from WT or Rsk2-KO female mice in estrus or diestrus, age 14.0 ± 1.8 wk. RNAseq analysis was performed on bulk liver as hepatocytes are ERα+ and comprise 60-70% of the liver cell population. RNAseq on mammary gland was performed on purified ERα+ mammary epithelial cells (MEC), as these cells comprise only 10% of the mammary gland. To evaluate liver response to estrogen, cumulative Z-scores of gene expression were compared to an estrogen signature obtained from the livers of mice treated with oral estradiol3. For the mammary gland, cumulative Z-scores were compared against an estrogen signature obtained from MCF7 treated with estradiol4. Livers from WT mice in estrus had a significantly stronger estrogen signature compared to Rsk2-KO mice in estrus (p = 0.0152, n ≥ 6). In contrast to the liver, Rsk2-KO MEC in estrus had a stronger estrogen response compared to WT (p = 0.028, n =3). Therefore, we have identified differential regulation of estrogen response by Rsk2 in the mammary gland and liver. Rsk2 is a negative regulator of estrogen response in the mammary gland, whereas Rsk2 promotes hepatic estrogen response. These data support our hypothesis that Rsk2 is a physiological regulator of metabolism and fertility by regulating estrogen response. References: (1) Ludwik, K. A., et al. Cancer Res. 2018 (78): 2014-2025. (2) Ludwik, K. A. et al. Cell Reports. 2020 (32): 107931. (3) Palierne, G. et al. Mol Endo. 2016 (30): 709-732. (4) Dutertre, M. et al. Cancer Res. 2010 (70): 3760-3770.
Presentation: 6/3/2024
8060 SIRT4 Plays a Role in Mammary Gland Development
Authors: deSouza B , Huynh F , Anderson K , Batchvarov I , Capel B , Hirschey M 
Published: October 2024

Abstract
Disclosure: B. deSouza: None. F. Huynh: None. K. Anderson: None. I. Batchvarov: None. B. Capel: None. M. Hirschey: None.
Breastfeeding confers a wealth of benefits to both children and mothers. Breastfeeding can be impaired by metabolic diseases such as diabetes and obesity, which are known to interfere with both normal mammary gland development and lactogenesis, although mechanisms remain unclear. Our lab recently discovered a novel connection between metabolic regulation and mammary development in Sirt4 knockout (Sirt4-/-) mice. SIRT4 is an NAD+-dependent mitochondrial enzyme with strong deacylase activity. It is known to regulate several metabolic pathways including those of fatty acids, glutamine, and leucine. Sirt4 knockout mice are resistant to developing high-fat diet-induced obesity but develop early-onset insulin resistance. We observed that Sirt4-/- females are incapable of nursing their offspring due to impaired mammary ductal branching. Transplantation of wild-type mammary epithelia into SIRT4KO mice fails to rescue mammary development; however, mammary epithelia from SIRTKO mice transplanted into wild-type mice develop normally. SIRT4 action is thus required outside the mammary gland, which led us to explore the effect of SIRT4 on steroid hormone signaling. Treatment of pre-pubertal SIRT4KO mice with progesterone and estradiol, but not estradiol alone, rescued mammary ductal branching. Likewise, transplants of wild-type ovaries into SIRT4KO mice partially rescued the ductal branching defect. Given these findings, we hypothesized that SIRT4 expression in the ovary is necessary for sufficient progesterone biosynthesis and subsequent mammary development. In ovaries of adult mice, SIRT4 is most highly expressed in differentiated granulosa cells of the corpus luteum, a temporary endocrine structure responsible for synthesizing peak levels of progesterone during the diestrus phase of the mouse estrous cycle. Future experiments will compare peak circulating progesterone levels in Sirt4-/- vs. wild-type mice. We will characterize progesterone signaling in SIRT4KO mammary glands, including determining the expression of progesterone receptor isoforms. Additionally, we will characterize SIRT4 function in the ovary, including its effects on corpus luteum formation, steroid hormone biosynthesis, and import vs. de novo synthesis of the steroidogenic precursor, cholesterol. This work could offer new insights into the impairment of breastfeeding due to metabolic diseases.
Presentation: 6/3/2024
8711 The Effect of Testosterone Therapy Upon Bone Remodelling in Testosterone Deficient APOE-/- Mice Fed a High Fat Diet
Authors: Williamson A , Bateman L , LeMaitre C , Jones T H , Aberdein N , Kelly D M 
Published: October 2024

Abstract
Disclosure: A. Williamson: None. L. Bateman: None. C. LeMaitre: None. T.H. Jones: None. N. Aberdein: None. D.M. Kelly: None.
Introduction: Low testosterone can lead to bone loss in males, but the mechanisms are not fully characterised. This study investigates the effects of testosterone depletion, and subsequent testosterone treatment on parameters of bone remodeling in a murine model of cardiometabolic disease. Methods: At 8 weeks of age, high-fat diet-fed ApoE-/- mice were randomised into three groups: sham surgery + placebo treatment (control, n=9), orchidectomy + placebo treatment (n =8), and orchidectomy + testosterone treatment (n=10). 25 week old mice were sacrificed and tissues collected for analysis. Left tibiae were decalcified, paraffin embedded and sectioned prior to immunostaining of bone turnover markers including receptor activator of nuclear factor κB ligand (RANKL), Osteoprotegerin (OPG), runx2, Alkaline Phosphatase (ALP), adiponectin and marrow lipid content. Right tibiae underwent mechanical 3-point bend testing at 0.05mm/s using a CellScale Univert. Results: µCT demonstrated a significant decrease in trabecular bone volume, number, and bone mineral density (BMD) and increased trabecular thickness in orchidectomised mice compared to controls. These parameters returned to control levels in testosterone treated orchiectomised mice. No significant differences were observed in cortical bone. Lipid deposition within the bone marrow was significantly increased in testosterone deficient mice compared to testosterone replete mice. No significant differences in ALP immunopositivity were detected between groups, and runx2 was significantly decreased in orchiectomised mice treated with testosterone compared to controls. The ratio of RANKL/OPG immunopositivity was significantly increased in testosterone deficient mice compared to testosterone replete mice. 3-point bending demonstrated no significant differences in maximal force between groups despite a downward trend in orchiectomised groups compared to controls. Osteoclast number quantified from TRAP-stained sections was not different between groups. Discussion: Testosterone depletion accelerates trabecular bone loss, mediated by increased osteoclastogenesis via the RANKL/OPG pathway and increased bone marrow adiposity, an effect reversed by testosterone treatment. While this study highlights the benefits of testosterone upon trabecular bone health in male mice these changes may not alter fracture risk as 3-point-bend maximal force was not affected.
Presentation: 6/2/2024
7993 Thienopyrimidine-Based Estrogen Receptor Modulators Adopt Unique Ligand Binding Poses to Elicit Anti-Proliferative Activities in ER+ Breast Cancer Cells
Authors: Fink Emma C , Mateus Sofia Lucia , Meganathan Nandakumar , Sammeta Vamshi K R , Norris John D , McDonnell Donald Patrick , Willson Timothy , Fanning Sean William 
Published: October 2024

Abstract
Disclosure: E.C. Fink: None. S.L. Mateus: None. N. Meganathan: None. V.K. Sammeta: None. J.D. Norris: None. D.P. McDonnell: None. T. Willson: None. S.W. Fanning: None.
One in eight women will be diagnosed with breast cancer in their lifetimes. Estrogen receptor alpha (ER) drives breast cancer pathology and is expressed in approximately seventy percent of tumors. Hormone therapies are used to treat and prevent the metastasis of ER+ breast cancers and these patients have favorable 5-year survivals. However, most breast cancer patient deaths are ER+. While the next generation of antiestrogens have shown promise in the advanced setting, more work needs to be done to fully address these mortalities. ER is a ligand-dependent master transcriptional regulator, whereby ligand-specific ER conformational ensembles redirect multiple programs to produce oncogenic or therapeutic endpoints. To better understand ER structure-activity relationships, we have developed new antiestrogenic small molecules based on a thienopyrimidine scaffold. Comprehensive structural, ER activity, and cancer endpoint profiling shows that these new molecules adopt a unique ligand binding pose, which perturbs new structural elements within the orthosteric hormone binding pocket. These molecules downregulate ER target genes and halt the proliferation of ER+ breast cancer cells.
Presentation: 6/3/2024
5051 Clinical Correlation between TSH levels and TAU Imaging
Authors: Sunil Surya 
Published: October 2024

Abstract
Disclosure: S. Sunil: None.
Background: Tau-PET Scan measures brain tau deposition. TSH levels related to cognitive impairment. We analyzed the correlation of TSH levels to tau-PET imaging in a memory clinic. Hypothesis: Tau-PET positivity correlates with lower TSH values in the clinic patients. Objectives: To assess the correlation of tau-PET positivity to TSH levels in memory clinic patients. Method: Retrospective observational chart review study of patients attending a memory clinic in Boston, MA, with TSH levels and tau-PET scan included for analysis. No stratification based on initial or final diagnosis, severity of cognitive impairment, or tracer used. Baseline TSH levels and a binary PET scan result were analyzed with covariates age, sex and race. Analysis done on ‘R’ v. 2.4.0. Pearson correlation estimated TSH levels to tau-PET status. Kruskal Wallis/Chi square tests for relationship of age, sex, gender and education with TSH levels and tau-PET status. ROC analyses and sensitivity/specificity were obtained. Results: Tau PET positivity did not correlate significantly with TSH levels (r= 0.0655, 95%CI -0.388 to 0.494, p=0.78). Conclusion: Tau PET does not correlate with TSH levels, possibly due to a ceiling effect in the mild impairment subjects.
Presentation: 6/2/2024
8806 A Case of Autoimmune Thyroid Switching
Authors: Case J , Chemitiganti R V , Suravajjala D 
Published: October 2024

Abstract
Disclosure: J. Case: None. R.V. Chemitiganti: None. D. Suravajjala: None.
Autoimmune thyroid disease comprises both hyper- and hypothyroid states including Graves' disease and Hashimoto's thyroiditis, respectively. The predominant antibody activity, demonstrable by thyrotropin receptor antibody, predicts the clinical presentation and treatment; thyrotropin receptor antibodies may act as a stimulatory or inhibitory stimulus upon the thyroid gland recognized as thyroid stimulating antibody(TSAb) and thyroid blocking antibody(TBAb). Rarely patients may transition from a hyperthyroid to a hypothyroid state and vice versa if the predominant antibody activity shifts which may occur due to a variety of mechanisms and characteristics related to each individual patient and treatment course. A 29 year old female presented to establish care for autoimmune thyroiditis. She was diagnosed with Graves' disease at age 19 when pregnant and treated with propylthiouracil; she switched to methimazole for the next six years when her thyroid function normalized and therapy discontinued. Two years later she became concerned with weight gain and her thyroid function was reevaluated demonstrating hypothyroidism and she was treated with levothyroxine 25mcg daily until presentation. Further labwork revealed undetectable TSI, and TPO antibody elevated at 177 u/mL. She became clinically and biochemically euthyroid on levothyroxine 50mcg daily. Switching between hyper- and hypothyroid states is a rare occurrence among patients with may attributable factors. Both antithyroid drugs including methimazole as well as replacement therapy with levothyroxine may alter the antibody milieu and so the predominant ratio and activity among TSAb and TBAb thereby leading to a shift in clinical presentation and thyroid state. Pregnancy may lead to hemodilution contributing to lessening of autoimmune activity which may return following delivery leading typically to a shift from TSAb to TBAb. Uncontrolled hyper- and hypothyroidism may affect dendritic activity leading to altered presentation and increased immune reactivity. The unlikely occurrence of switching from a hyperthyroid to a hypothyroid state based upon autoimmunity as in this patient was likely affected these factors. Recognition of this potential transition and associated factors would lead to beneficial monitoring and possibly development of assays more attuned to this phenomenon with better capability in maintaining a euthyroid state and potentially predicting a transition.
Presentation: 6/3/2024