bluuebunny/crossref_metadata_2025_split huggingface dataset:
7277 Diabetic Ketoacidosis as the First Manifestation of Ectopic Cushing’s Syndrome
Authors: Saudade Medeiros Regina , Pereira Bernardo , Pataco Andreia , Senra Catarina , João Ponte Maria , Anselmo João , Sousa Isabel 
Published: October 2024

Abstract
Disclosure: R.S. Medeiros: None.
Introduction: Ectopic Cushing’s Syndrome (ECS) represents 10-20% of all ACTH-dependent CS, and the majority of cases arise from lung carcinoids. These indolent lesions usually evolve clinically over 6-24 months, whereas carcinomas are associated with faster onset of ECS. Diabetic Ketoacidosis (DKA) as a presenting manifestation of Cushing’s Syndrome (CS) is very rare, with the few cases published to date related to Cushing’s disease. Clinical Case: A 42-year-old woman was admitted in the emergency room with DKA and COVID-19. During stabilization, florid CS was clinically suspected. She reported a 6-month history of secondary amenorrhea, lack of concentration and memory, easy bruising, proximal myopathy with frequent falls evolving to daily life dependency from relatives. She also reported a 2-month diagnosis of dyslipidemia, Diabetes and hypertension, and a diagnosis of atypical pneumonia 6 months ago. Physical exam showed typical cushingoid appearance, especially for marked limb sarcopenia and proximal myopathy. An overnight dexamethasone suppression test (morning cortisol: 25.7 ug/dL), 24h urinary free cortisol (UFC; 1072.5 ug/dL; reference: &lt;176) and serum cortisol at 23h00 (25.5 ug/dL) confirmed CS. ACTH-dependent CS was diagnosed. She had non-suppressible serum cortisol in high dose dexamethasone suppression test, and CRH stimulation test was suggestive of Cushing’s disease only by a 20% rise of cortisol at 30 minutes. Pituitary MRI was normal. Inferior Petrosal Sinus sampling was postponed for several months due to healthcare strikes. The patient started 750 mg of metyrapone in three divided doses but rapidly decreased the dose and stopped it due to clinical resolution of CS, a dramatic improvement of all glucocorticoid-related comorbidities leading to discontinuation of statin, insulin, main oral anti-hyperglycemic and antihypertensive medications, and normal midnight salivary cortisol and 24h UFC. She remained in this eucortisolemic state for 12 months. Thoracic CT scan revealed thymic hyperplasia and a 25x15 mm well-defined nodule in the lingula. A [6][8]Ga-DOTANOC PET/CT showed a single uptake in the same lung region. The patient underwent lingulectomy plus excisional biopsy of interlobar lymph nodes, and pathology revealed a low-grade neuroendocrine tumor (Ki67&lt;2%, &lt;2 mitosis) without involved lymph nodes. The patient is weaning off from physiologic doses of hydrocortisone. Conclusion: DKA can rarely be the presenting manifestation of severe CS, including ECS. Clinicians should suspect on this etiology of DKA based on clinical signs and cumulative morbidity not typical of a young patient. This hint would lead to the expedite implementation of targeted therapies for initial stabilization of the CS patient, and the timely institution of a proper diagnostic approach and definitive treatment of this challenging patients.
Presentation: 6/2/2024
7232 Direct m6A mRNA-Seq in Endocrine- Resistant and Sensitive Breast Cancer Cells
Authors: Petri B J , Valdes B L , Piell K M , Rouchka E C , Klinge C M 
Published: October 2024

Abstract
Disclosure: B.J. Petri: None. B.L. Valdes: None. K.M. Piell: None. E.C. Rouchka: None. C.M. Klinge: None.
Acquired resistance to endocrine therapies (ET) in patients with estrogen receptor α (ER+) breast tumors results in metastatic spread. RNA modifications including N6-methyladenosine (m6A) play crucial roles in the post-transcriptional regulation of gene expression and have been implicated in cancer progression. We hypothesized that m6A epitranscriptomic alterations are associated with pathways in ET resistance. Direct-RNA sequencing technology (nanopore) was used to detect and map m6A modifications at single-nucleotide resolution to comprehensively profile m6A modifications in ET-resistant LCC9 and ET -sensitive MCF-7 breast cancer cell lines with or without 4-hydroxytamoxifen (4-OHT) treatment. Additionally, MCF-7 cells were treated with the METTL3 inhibitor STM2457 to identify m6A positions and transcripts directly regulated by METTL3 activity. We developed a new statistical method by integrating m6Anet, an existing machine-learning algorithm designed to call m6A modified bases, with a generalized linear model following a binomial distribution analysis to identify significant differential m6A modification ratios (DMR). We identified 61 transcripts with DMR between vehicle-treated LCC9 compared to MCF-7 cells and 323 transcripts with DMRs between 4-OHT-treated LCC9 and MCF-7 cells. Fewer transcripts showed DMR after 4-OHT treatment in MCF-7 (41) versus LCC9 cells (399). Thus, more changes in m6A DMRs were detected in response to 4-OHT in the ET-resistant LCC9 versus ET-sensitive MCF-7 cells with “translation elongation” as the top pathway in enrichment analysis. STM2457 treatment resulted in significant changes to DMRs in MCF-7 cells with or without 4-OHT treatment and altered gene expression patterns associated with “cytosolic ribosome” in enrichment analysis. We identified many genes with multiple m6A modifications, e.g., AMIGO2 with 14 m6A sites at METTL 3 target DRACH motifs in MCF-7 cells, compared to no m6A modification in AMIGO2 in LCC9 cells. Our findings reveal distinct m6A modification patterns in ET-resistant LCC9 breast cancer cells compared to their ET-sensitive parental MCF-7 cells and in response to 4-OHT, suggesting a potential role for epitranscriptomic alterations in the development of ET resistance.
Presentation: 6/3/2024
9218 Highly Multiplexed Mapping of the Ductal Carcinoma In Situ Ecosystem to Predict Disease Outcome
Authors: Wilson Gemma M , Doan Tram B , Guild Barbara J , Pathmanathan Nirmala , Graham J Dinny 
Published: October 2024

Abstract
Disclosure: G.M. Wilson: None. T.B. Doan: None. B.J. Guild: None. N. Pathmanathan: None. J.D. Graham: None.
Mammographic screening programs have resulted in remarkable improvements in breast cancer survival due to early-stage detection. However, this has resulted in a dramatic increase in the detection of non-invasive ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive ductal carcinoma (IDC), which is confined to the ducts and surrounded by a normal myoepithelial cell layer. Many DCIS cases will not progress to IDC within the lifetime of the patient. However, there are limited tools to accurately predict progression, thus virtually all DCIS is surgically removed, and most patients receive adjuvant radiotherapy as it halves recurrence rates. This likely represents overtreatment for a majority of patients. Emerging evidence has revealed that the adjacent microenvironment becomes progressively altered in DCIS and IDC compared to normal tissue, and this is correlated with disease outcome. The objective of this study was to investigate changes to the DCIS microenvironment during disease progression and identify disease states that predict patient outcome. We used immunohistochemistry and imaging mass cytometry with a well-annotated cohort of DCIS, with or without adjacent IDC, to measure a panel of 40 phenotypic and functional markers that allowed us to distinguish the diverse cell populations present in the tissues. We observed striking changes to almost all cell types within the DCIS tissue when comparing pure DCIS cases to DCIS adjacent to IDC. In particular, there were considerable changes to tissue-resident immune populations, with differences observed in the type, location and population size of a variety of immune cell subsets, in IDC-associated DCIS compared with DCIS-only cases. Computational mapping of cell type communities in pure and IDC-adjacent DCIS tissues revealed specific differences that could be used to predict the emergence of invasive disease, informing clinical management of this good prognosis malignancy and potentially avoiding over-treatment.
Presentation: 6/3/2024
7076 Inhibiting Oxidosqualene Cyclase, an Enzyme in the Cholesterol Biosynthetic Pathway, Suppresses Lung Metastasis of Triple-negative Breast Cancer Cells
Authors: Liang Yayun , Hyder Salman M 
Published: October 2024

Abstract
Disclosure: Y. Liang: None. S.M. Hyder: None.
Triple-negative breast cancers (TNBC) lack ER, PR and Her2neu proteins that are commonly targeted in breast cancer therapies. As a consequence, women who suffer from TNBC have poor prognosis and limited treatment options, and are usually administered toxic, non-specific chemotherapeutic agents. Drug-resistance almost always occurs, leading to tumor metastasis, the main cause of patient death. New non-toxic therapeutic strategies to control metastasis of TNBC are urgently needed. Cholesterol is an essential structural and functional component of cell membranes that is necessary for the growth of both primary tumors and metastatic colonies that reside in distant organs. Therefore, inhibiting cholesterol production is an attractive therapeutic strategy. Treatment with statins, a class of cholesterol biosynthesis inhibitors that target HMGCoA-reductase, is associated with certain undesirable side effects; consequently, we targeted oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway, to disrupt tumor metastasis. Potent small molecule inhibitors of OSC have been identified. RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for treating several forms of primary tumors. We developed a mouse model for studying lung metastasis using a MDA-MB-231 variant (LM2) TNBC cell line obtained from Dr. Massagué (Memorial Sloan-Kettering Cancer Center). These are aggressive cells, and injection of only 2 X 10[5] cells produces detectable lung metastatic colonies in approximately 4-6 weeks. We inoculated female nu/nu mice, 5-6 weeks old, with 2 X 10[5] MDA-MB-231/LM2 cells in 0.1 ml DMEM/F12 medium without serum via tail vein. Five days after tumor cell inoculation animals received 20 mg/kg (n=6), 40 mg/kg (n=7) RO (ip) or vehicle alone (n=7) every other day for two weeks. Animals were then sacrificed, and both lungs harvested and immediately fixed in Bouin’s fixative. Metastatic colonies on the lung surface were identified and counted under a dissecting microscope. Our study showed that RO effectively reduced lung metastasis without affecting animal weight. Compared with 56 + 7 colonies (Mean ± SEM) in controls given vehicle alone, RO significantly reduced lung metastatic colonies to 28 ± 5 in animals exposed to 20 mg/kg and 6 ± 1 in 40 mg/kg treated animals (p&lt;0.05, ANOVA). Reduction in number of colonies in 40 mg/kg group was also significantly different from colonies counted in 20 mg/kg treated animals. Our study is the first to demonstrate that disruption of cholesterol biosynthesis in a model of human TNBC leads to reduced metastasis in lungs. Further studies will determine mechanisms through which RO suppresses TNBC metastasis to the lungs. Supported by Zalk Missouri Professor Endowment Funds.
Presentation: 6/3/2024
5112 Late-Onset And Reversible Adrenal Insufficiency In Survivors Of Coronavirus Disease 2019: Results From A 24-Month Longitudinal Study
Authors: Kumar Sahoo Saroj , Menon Jayakrishnan C , Yadav Subhash B 
Published: October 2024

Abstract
Disclosure: S.K. Sahoo: None. J.C. Menon: None. S.B. Yadav: None.
Purpose We studied the temporal course of hypothalamic-pituitary-adrenal (HPA) dysfunction in patients with corona-virus disease (COVID19). Methods Three-hundred and two patients (median age 54 years [interquartile range 42-64], 76% males, 97 with severe/critical illness) were recruited. HPA axis was evaluated by adrenocorticotrophic hormone (ACTH)-stimulation test (APST) at admission in 243, and 12-months after discharge in 90 patients. Those with adrenal insufficiency (AI) at 12-months were further assessed by APST 6-monthly for recovery of hypoadrenalism. Results The median 0-min cortisol, peak cortisol, and ACTH during COVID19 were 295 (IQR 136-461) nmol/L, 846 (719-1088) nmol/L, and 3.9 (0.8-6.9) pmol/L respectively. AI was present in 21 (8.6%) patients. Plasma ACTH was elevated in five patients with AI, while it was low or inappropriately-normal in rest. Additionally, CIRCI was present in 22% (19/87) patients who had severe illness. At 12-months, AI was seen in 13% (12/90) patients and was hypothalamic-pituitary in origin in all. Nine (75%) of these had late-onset AI, who had normal HPA axis during COVID19. AI diagnosed at admission persisted at 12-months in three patients and resolved in six; the remaining 12 patients were lost to follow-up. The presence of AI at 12-months was independent of severity, and steroid use during COVID19. All the patients showed recovery of HPA axis in ensuing 6-12 months. A lower morning cortisol during COVID19 predicted presence of AI at one year. Conclusion AI was common during acute COVID19 and at 12-months of follow-up. AI can be late-onset, developing after recovery from COVID19. The AI was predominantly hypothalamic-pituitary in origin and resolved in the ensuing 6-12 months.
Presentation: 6/1/2024
9260 Insulin Receptor Signaling and Racial Disparities in Triple Negative Breast Cancer
Authors: Joy Engel Alexis , Samuel Krupa , Bass Ilana R , Lin Sylvia , Markella Antoniou Irini , Yagnik Radhi , LeRoith Derek , Bickell Nina A , Jane Gallagher Emily 
Published: October 2024

Abstract
Disclosure: A.J. Engel: None. K. Samuel: None. I.R. Bass: None. S. Lin: None. I. Antoniou: None. R. Yagnik: None. D. LeRoith: None. N.A. Bickell: None. E.J. Gallagher: Consulting Fee; Self; Novartis Pharmaceuticals.
Introduction: Obesity and type 2 diabetes are associated with poor breast cancer (BC) prognosis. These disorders, along with hyperinsulinemia are more common in Black than in White women. Black women also have higher rates of triple negative breast cancer (TNBC), and greater breast cancer mortality than White women. We hypothesized that Black women with TNBC have worse outcomes in part due to tumor promoting effects of hyperinsulinemia via the insulin receptor (IR) signaling pathway. Methods: From our IRB-approved, multi-institutional, cross-sectional, NIH-funded, study of women with newly diagnosed BC, we identified women with TNBC. We performed immunohistochemistry (IHC) analysis of formalin-fixed-paraffin-embedded tumor samples from 45 self-identified Black women and 48 self-identified White women. We quantified the BC expression of IR (n=92), IGF1R (n=92), pERK (n=91), FOXO3a (n=90) for intensity (none=0, weak=1, moderate=2, intense=3). In subsequent analysis, 0 and 1 intensity IHC staining were considered negative, and 2 and 3 were considered positive. Quantification was performed with reviewers blinded to clinical information. Clinical information (age, race, body mass index [BMI], waist circumference, fasting insulin, BC Nottingham Prognostic Index [NPI]) was evaluated after IHC scoring. Statistical proportions were compared using Fishers Exact test, and continuous variables were evaluated using parametric or non-parametric tests, as appropriate. Results: Positive IR staining was seen in 64% of samples (n=59), 74% (n=68) for IGF1R, 68% (n=62) for FOXO3a and 43.3% (n=39) for pERK. Positive IR staining was more prevalent in Black women than White women (P=0.003) but was not significantly associated with age or NPI. IGF1R, FOXO3a, pERK positive staining were not associated with race or NPI. Positive IR staining was also associated with higher BMI, waist circumference, and fasting insulin (P&lt;0.05 for all). Positive IGF1R, FOXO3a, pERK staining were not associated with any of these factors. Conclusions: We found that 64% of TNBCs had positive expression of IR, and IR expression was more prevalent in tumors from Black women and associated with higher insulin levels, suggesting that tumors from Black women may be more sensitive to the tumor promoting effects of systemic hyperinsulinemia.
Presentation: 6/2/2024
9304 Integration of Glucocorticoid and Mineralocorticoid Receptor Signaling in Triple-negative Breast Cancer Models
Authors: Harshita Posani Sai , Lange Carol A 
Published: October 2024

Abstract
Disclosure: S. Posani: None. C.A. Lange: None.
Glucocorticoid receptors (GR) sense a convergence of host and cellular stress signaling to orchestrate an array of advanced cancer phenotypes associated with triple-negative breast cancer (TNBC) progression. The Lange lab reported p38 MAP kinase mediated phosphorylation of GR at serine 134 (Ser134) in response to tumor microenvironment-derived cytokines, such as TGF-beta-1. Phospho-Ser134-GR (p-Ser134-GR) upregulated gene sets that promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC models. In addition to acting as ligands for GR, glucocorticoids also bind to and activate another closely related steroid hormone receptor - the mineralocorticoid receptor (MR). The elucidation of functional responses upon activation of MR remains an untapped area in breast cancer research. Our probe into public datasets (METABRIC, and TCGA) demonstrated significantly higher expression of MR transcripts in TNBC relative to luminal breast cancer. High expression of MR predicted worse overall survival in ERα-negative breast cancer patients compared to the low expressing cohort. Silencing of MR was carried out by siRNA-mediated knockdown and treatment with spironolactone, a competitive MR antagonist. Interestingly, MR knockdown significantly reduced the TGF-beta-1 induced migratory capacity of breast cancer cells compared to the wild-type control cells expressing endogenous MR. This biological phenotype of decreased TGF-beta-1 induced migration upon MR knockdown parallels the reduced migration we observed when the p38 MAPK site (Ser134 on GR was mutated to Ala in TNBC models. We therefore hypothesized that MR and GR may cooperate under the influence stress signaling in response to growth factors and cytokines abundantly present in the tumor-microenvironment. Preliminary data suggest that cytoplasmic p-Ser134-GR/MR complexes associate upon TGF-beta-1 treatment, while GR and/or MR ligands stimulate the formation of nuclear GR/MR complexes. We are further investigating cytokine- and stress-signal mediated regulation of GR/MR complexes and their functional role in TNBC biology. The overarching goal of this study is to elucidate if MR is a required GR binding-partner and a potential therapeutic target in GR- and cytokine-driven metastatic TNBC processes.
Presentation: 6/2/2024
7508 Primary Hyperparathyroidism Caused By A CDC73-related Atypical Parathyroid Tumor
Authors: Cardenas Ramiro , Tariq Sarah , Habibi Roshanak , Ebrahimi Neda , Astiazaran-Symonds Esteban 
Published: October 2024

Abstract
Disclosure: R. Cardenas: None. S. Tariq: None. R. Habibi: None. N. Ebrahimi: None. E. Astiazaran-Symonds: None.
Background: Primary hyperparathyroidism (PHPT) is a common endocrine disease, causes include: parathyroid adenomas (80-85%), parathyroid hyperplasia (10-15%), atypical parathyroid adenomas (APA) (1.2 %) and parathyroid carcinomas (PC) (1%). APA share many anatomic and histopathologic features with PC making the distinction between the two challenging. Although most are sporadic, some APA are caused by germline mutations in the CDC73 gene, which is associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome PC and familial isolated PHPT with APA. Clinical Case: A 42-year-old female presented to the clinic for evaluation of recurrent PHPT. She was diagnosed at age 22 when she experienced fatigue, polydipsia with hypercalcemia (12.9mg/dl). She underwent superior bilateral parathyroidectomy with pathology consistent with parathyroid adenoma. Twenty years later, symptoms recurred and tests showed hypercalcemia (13.0 mg/dl), elevated PTH (252 pg/dl), kidney function preserved (GFR: 82.5 ml/min), normal vitamin D 25 OH (31 ng/dl). Patient denied history of nephrolithiasis or fractures. Family history was positive for kidney stones in father and siblings, also history of a jaw tumor in niece. Sestamibi scan showed a left inferior parathyroid adenoma. Patient underwent resection of the adenoma; pathology revealed a left parathyroid adenoma with atypical parathyroid tumor, &gt;95% cellularity with cytologic features concerning for malignancy, prominent macronucleoli, necrosis, elevated mitotic activity and Ki67 with 15% tumor cells without vascular invasion. Post-op Calcium and PTH normalized (9.6 mg/dl and 10.8 pg/ml, respectively). Genetic testing via multi-gene panel identified a whole gene deletion of CDC73, consistent with hyperparathyroidism-jaw tumor syndrome. Panoramic jaw x-rays did not show jaw tumors. Genetic testing for family members is underway. Conclusion: Although somatic mutations in CDC73 are frequently found in sporadic APA and PC, germline mutations are a rare cause of PHPT associated with these tumors. Histopathological examination is necessary to confirm the diagnosis of APA and to differentiate it from PC, which has a recurrence rate &gt;50%. APA should be treated as a “tumor of uncertain malignant potential” and needs to be carefully and periodically followed up with measurement of Ca, PTH and vitamin D. Confirmation of a CDC73 mutation by genetic testing helped identify the increased risk for other associated tumors in jaw, kidneys and uterus prompting initiation of surveillance with panoramic jaw x-rays with neck shielding, renal US and pelvis US. Genetic testing of family members will allow timely detection and treatment of individuals at risk.
Presentation: 6/3/2024
7323 Prostatic Acid Phosphatase Is Negatively Regulated by Androgens and Persists in Castration-resistant Prostate Cancer
Authors: Kirschenbaum Alexander , Cheung Pamela , Yao Shen , Cheung Pamela 
Published: October 2024

Abstract
Disclosure: A. Kirschenbaum: None. P. Cheung: None. S. Yao: None. P. Cheung: None.
Background: Prostate cancer (PCa) is the most common cancer and second leading cause of cancer death in American men. Most patients with metastatic PCa respond initially to androgen deprivation therapy (ADT) but the majority will progress to lethal, metastatic, castrate-resistant PCa (mCRPC). The identification of markers of mCRPC that are not regulated or negatively regulated by androgens can serve as markers and therapeutic targets in mCRPC. We hypothesized that prostatic acid phosphatase (PAP), a protein phosphatase and 5’ectonucleotidase that is expressed in both the cytoplasm and transmembrane (TM-PAP) of PCa cells, is negatively regulated by androgen signaling and can serve as a therapeutic target. Methods: PAP protein expression was assessed by immunohistochemistry (IHC) in PCa cell line spheroids (VCaP, 22Rv1, LNCaP, C42B) +/- androgen addition as well as in LNCaP s.c. xenografts +/- castration. Protein expression of PAP was assessed with western blotting in PCa cell lines after treatment with androgens (DHT) and anti-androgen (enzalutamide). Results: In spheroids derived from PCa cell lines, there is some IHC expression of PAP with the strongest staining in VCaP and 22Rv1 spheroids. DHT decreased PAP IHC expression in all spheroids. LNCaP and VCaP s.c. xenografts demonstrated that castration decreased tumor growth rates but that in castrate as well as control tumors PAP expression persisted. All forms of PAP including TM-PAP are expressed in VCaP cell line and were negatively regulated by androgen addition. Conclusions: The identification of markers of mCRPC that are not regulated or are negatively regulated by androgen could help identify recalcitrant tumor cells and mount targeted delivery of therapeutic agents. In several androgen sensitive PCa cell lines, DHT addition decreased PAP expression in spheroids. In vivo, PAP expression persists after castration in spite of decreases in tumor growth rates. Finally, DHT decreases and enzalutamide restores PAP expression in vitro. These data demonstrate that PAP is a more progenitor cell marker in PCa that persists after castration and may be targeted in castration-resistant disease.
Presentation: 6/3/2024