bluuebunny/crossref_metadata_2025 huggingface dataset:
FRI212 Adrenalitis Caused By Proteus Mirabilis In An Immunocompetent Patient
Authors: Abdelkarim Jumana Omar , Tarabichi Ula , Jakoby Michael
Published: October 2023

Disclosure: J.O. Abdelkarim: None. U. Tarabichi: None. M. Jakoby: None.

Infectious adrenalitis with Mycobacterium tuberculosis remains the leading cause of primary adrenal insufficiency in developing countries, but the incidence of adrenalitis from infection with other bacterial species is quite low. We present a patient with radiographic evidence of adrenalitis during an infection with Proteus mirabilis that resolved after antimicrobial treatment.An 86-year-old male with an indwelling Foley catheter presented to the hospital for evaluation of abdominal pain and distension. The patient was afebrile and normotensive. Examination was notable for a distended bladder and obstructed urinary catheter. Computed tomography (CT) revealed a dense right lower lobe infiltrate and bilaterally enlarged, hypointense adrenal glands with irregular margins. Radiographic findings were new compared to a CT scan obtained approximately 10 weeks before admission to hospital. Turbid and malodorous urine was drained after replacement of the patient’s urinary catheter, and urine culture grew > 105 CFU/mL Proteus mirabilis. Antibiotics were dosed before blood cultures were drawn, and no organisms were grown from blood cultures. Since there was no clinical or biochemical evidence (e.g. hyponatremia or hyperkalemia) of primary adrenal insufficiency, an ACTH stimulation test was deferred. The patient responded well to replacement of his urinary catheter and antibiotics and was discharged to his extended care facility three days later. A CT scan obtained 10 days after treatment showed resolution of the changes to the patient’s adrenal glands observed on admission imaging.The radiographic changes are most plausibly due to P. mirabilis bacteremia and adrenalitis. The patient had urine culture confirmed infection with P. mirabilis and radiographic evidence of disseminated infection in the right lung and adrenal glands. Adrenal enlargement is well described in cases of acute M. tuberculosis adrenalitis, and radiographic changes of adrenalitis resolved after successful treatment of the patient’s infection. P. mirabilis has been documented as an etiology of Waterhouse-Friderichsen syndrome and cultured from an adrenal abscess. Blood cultures in this case were almost certainly negative due to timing relative to initial antibiotic doses. Injury to the adrenals in bacterial adrenalitis is thought to occur due to multiple mechanisms including direct infection of the glands, endotoxemia, vasculitis, and disseminated intravascular coagulation (DIC). Hemorrhage appears to occur in about 60% of cases. Elevated ACTH level is postulated as a factor predisposing to adrenal hemorrhage, and this prompted deferral of stimulation testing to evaluate adrenal function since there was no clinical evidence of primary adrenal insufficiency. Early management of the patient’s infection likely prevented the occurrence of adrenal insufficiency and deterioration of his clinical status.

Presentation: Friday, June 16, 2023
SAT406 Evaluation Of The Emotional And Cognitive Effects Of Hormone Therapy In Transgender Men And Women
Authors: Yaish Iris , Keltch Gali , Greenman Yona , Tordjman Karen Michele
Published: October 2023

Disclosure: I. Yaish: None. G. Keltch: None. Y. Greenman: None. K.M. Tordjman: None.

Background:- Sex hormones have far-reaching effects on the brain, both emotionally and cognitively.

- Varying levels of sex hormones are associated with altered emotional states and cognitive abilities.

-No longitudinal study has assessed the impact of cross-sex hormone on these issues in young transgender people.

Aim:•To prospectively evaluate the effect of gender-affirming hormonal therapy (GAHT) on cognition and emotional state in transgender men and women initiating therapy

Subjects and Methods:- Transgender men (TM) aged 24.6±7.8 y (18-37), and 11 transgender women (TW) 27.3±9.4 (19-46).- Mood questionnaires (PHQ9 and GAD-7), and cognitive tests (short-term logical memory test, sub-tests of knowledge, forward and backward digit recall, number-coding and random learning from WAIS-III, a verbal fluency test and CTMT test) were administered prior to GAHT, and 3-6 months into treatment.

- Scores were calculated for emotional stress, memory, attention, and executive functions.

- Wilcoxon tests for paired samples assessed the impact of GAHT on these variables.

Results

- In TM, GAHT significantly improved executive functions but had no effect on memory, attention, and emotional stress.

- In TW, GAHT significantly improved memory but had no effect on attention, executive functions, and emotional stress.

- Despite a trend for improved emotional stress with GAHT in both groups, over this short study period, this was not significant.

Conclusions:- - In keeping with the literature, this short preliminary study showed that estrogen contributes to memory, and testosterone to executive functions.-- This is the first time this has been shown in transgender individuals.

-The lack of effect on emotional stress is probably due to the small sample size and short duration, larger studies should elucidate this point.

Presentation: Saturday, June 17, 2023
SAT413 Feminising Gender Affirming Hormone Therapy Prolongs QTc Interval
Authors: Angus Lachlan , Lin Tina , Leemaqz Shalem , Grossmann Mathis , Zajac Jeffrey D , Cheung Ada S
Published: October 2023

Disclosure: L. Angus: Speaker; Self; Kirin Brewery. T. Lin: None. S. Leemaqz: None. M. Grossmann: None. J.D. Zajac: None. A.S. Cheung: None.

Background: In trans people using feminising hormone therapy there is an increased risk of cardiovascular events including conduction disorders. It is known that the QTc interval is longer in cisgender women of reproductive age than cisgender men, attributed to factors including serum sex steroid concentrations. Androgen deprivation therapy in men with prostate cancer is associated with prolongation of the QTc interval, but the effects of feminising hormone therapy in trans women are unclear. Methods: We measured the automated QTc interval from a 12-lead electrocardiogram at baseline and 6 months in trans women newly commencing feminising hormone therapy. Sex steroid concentrations were measured by LCMS. Participants were part of a randomised controlled double-blind trial of spironolactone 100mg daily versus cyproterone acetate 12.5mg daily in transgender women commencing estradiol for feminisation (ANZCTR 12620000339954) and this was a prespecified secondary outcome. Statistical analysis was performed using a linear mixed effects model looking at the effects of treatment over time. Results: Sixty-three participants were randomised and 55 participants completed the trial and were included in analysis (spironolactone group n=27, cyproterone acetate group n=28). Baseline group characteristics were comparable. Overall, the QTc interval increased by 18ms (95% CI 14 - 23 ms; p<0.001) at 6 months compared to baseline, but there was no between group difference (p=0.23). One participant had a QTc interval above 450ms. The mean serum total testosterone concentrations were similar between groups at baseline (spironolactone group 16.9 (13.5 - 20.3) nmol/L vs cyproterone acetate group 18.0 (15.0 - 21.0) nmol/L, p=0.60) but higher in the spironolactone group 4.3 (2.0 - 6.5) nmol/L than the cyproterone acetate group 1.5 (0.0 - 2.9) nmol/L, p<0.05 at 6 months. The mean serum estradiol and serum potassium concentrations were similar between groups at baseline and 6 months. Conclusions: Feminising hormone therapy with estradiol and either spironolactone or cyproterone acetate in trans women is associated with prolongation of the QTc interval over a six-month period. Further research is required to investigate the incidence of cardiac arrhythmia in this population.

Presentation: Saturday, June 17, 2023
OR31-04 Testosterone Therapy On Gender Dysphoria, Depression, And Suicidality In Transgender And Gender Diverse Individuals Seeking Masculinisation: A Randomised Controlled Trial
Authors: Nolan Brendan J , Zwickl Sav , Zajac Jeffrey D , Cheung Ada S
Published: October 2023

Disclosure: B.J. Nolan: None. S. Zwickl: None. J.D. Zajac: None. A.S. Cheung: None.

Background: Testosterone treatment is a necessary component of management for some transgender (trans) and gender diverse individuals. Observational studies have demonstrated improvements in gender dysphoria and depression following commencement of gender-affirming hormone therapy but there is a lack of randomised controlled trial data.

Objectives: To assess the impact of testosterone therapy compared to no treatment on gender dysphoria, depression, and suicidality in trans people seeking masculinisation.

Methods: Three-month open-label randomised controlled trial of 64 trans individuals seeking initiation of testosterone therapy comparing immediate testosterone commencement (intervention group) with no treatment (standard care waiting list of 3 months prior to commencement). This design ensured no individuals would be waiting longer than standard care. Primary outcome was gender dysphoria, as measured by the Gender Preoccupation and Stability Questionnaire (GPSQ). Secondary outcomes included the Patient Health Questionnaire-9 (PHQ-9) to assess depression and the Suicidal Ideation Attributes Scale (SIDAS) to assess suicidality. Questionnaires were undertaken at 0 and 3 months. ANCOVA was used to compare mean differences between groups.

Results: Compared to standard care, the intervention group had a decrease in gender dysphoria [mean difference -7.2 points (95% CI (-8.3, -6.1), p<0.001], a clinically significant decrease in PHQ-9 [mean difference -5.6 points (-6.8, -4.4), p<0.001], and a decrease in SIDAS [mean difference -6.5 points (-8.2, -4.8), p<0.001]. Resolution of suicidality assessed by PHQ-9 item 9 occurred in 11 (52%) individuals with immediate testosterone commencement compared to 1 (5%) in standard care (p=0.002).

Conclusions: This randomised controlled trial supports the use of testosterone therapy to significantly reduce gender dysphoria, depression, and suicidality in trans and gender diverse individuals desiring testosterone therapy.

Presentation: Sunday, June 18, 2023
THU477 Drivers Of Estrogen Induced Invasive Lobular Carcinoma
Authors: Ufondu Chinasa , Clem Larkin , Musick Maggie , Sikora Matthew Joseph , Ostrander Julie Hanson
Published: October 2023

Disclosure: C. Ufondu: None. L. Clem: None. M. Musick: None. M.J. Sikora: None. J.H. Ostrander: None.

Invasive lobular carcinoma (ILC) is an estrogen-receptor (ER)-positive histologic subtype of breast cancer typically treated with anti-estrogens (i.e., tamoxifen and aromatase inhibitors). Anti-estrogen resistance and disease progression occur in about 34% of patients with ILC, but mechanisms of resistance have been underexplored. Additionally, estrogen-only hormone replacement therapy increases the risk of ILC, but not the more common invasive ductal carcinoma (IDC), highlighting a potentially unique role for estrogen in ILC initiation and progression. To identify mediators of estrogen-induced ILC progression we are using the the mouse mammary intraductal (MIND) model, which better recapitulates the progression of ILC and response to estrogen in vivo. MM134, MM330, and SUM44PE ILC cell lines were injected intraductally into the #4 mammary glands of NSG mice. Mice were monitored for up to 20 weeks with or without estrogen supplemented in the drinking water. Our results show that MIND supports an in situ-like to invasive disease progression for ILC cell lines, and that estrogen accelerated tumor growth and invasion in vivo. Current studies are aimed at identifying mediators that drive estrogen-induced tumor growth and invasion in vivo, focusing on E-cadherin (CDH1) loss as the genetic hallmark of ILC occurring in ∼95% of cases. We aim to identify how loss of E-cadherin in normal human mammary epithelial cells (HMECs) may lead to reprogramming of ER and promote the development of ILC. We are developing a CRISPR/Cas9 approach for knocking out CDH1 in HMECs. We will study estrogen response in the CDH1-knockout versus control HMECs in vitro to examine whether loss contributes to ILC-specific estrogen activity. Using the MIND model, we will engraft the control and knockout cells into the ducts of adult female NSG mice and monitor tumor growth through bioluminescence imaging. ER reprogramming will be assessed in the engrafted cells using RNAseq and CUT&RUN (Cleavage Under Target & Release Using Nuclease). We predict that E-cadherin loss will reprogram ER DNA binding, dysregulate transcription factors linked to E-cadherin, such as TCF/LEF, and confirm critical downstream regulators that mediate estrogen-driven tumorigenesis. Understanding the unique contributions of ER in ILC could lead to new therapeutic strategies for the prevention and treatment of ILC.

Presentation: Thursday, June 15, 2023
THU478 Unchecked Kinase Activation Underlies Pituitary Adenomas Causing Cushing’s Disease
Authors: Asuzu David , Mullaney Dustin , Li Yan , Mandal Debjani , Tatsi Christina , Nieman Lynnette K , Chittiboina Prashant
Published: October 2023

Disclosure: D. Asuzu: None. D. Mullaney: None. Y. Li: None. D. Mandal: None. C. Tatsi: None. L.K. Nieman: None. P. Chittiboina: None.

Introduction: Common mechanisms underlying canonically mutated (USP8, USP48 and BRAF) and ‘wildtype’ pituitary adenomas causing Cushing’s disease remain unknown. Using syngeneic, pairwise transcriptomic analysis at the single cell/nucleus resolution, we found a ubiquitous and robust overexpression of PPP1R17 in CD adenoma corticotrophs. The role of PPP1R17, an endogenous inhibitor of tumor-suppressor phosphatase PP2A in the embryonic context remains unknown in the pituitary. Here, we elucidated mechanistically, the effect of PPP1R17 on the phopshoproteome of CD adenomas.

Methods: We quantitatively profiled the proteome and phosphoproteome of three pairs of CD adenomas and their syngeneic adjacent normal pituitary glands with TMT labeling and mass spectrometry (LC-MS/MS). We validated the mechanisms with murine corticotroph cells (mCort) overexpressing R17 (mCortR17) or GFP (mCortGFP). Elevated total and phosphprotein expression was assessed using R packages by performing cross sample normalization, noise filtering and differential protein abundance or phosphorylation analyses. Pathway enrichment analysis was performed on the KEGG database using ShinyGo 0.76.2.

Results: We identified 37 proteins differentially phosphorylated in CD adenomas compared to adjacent normal pituitary glands, including the AP2-associated protein kinase 1 (Aak1) and the apoptotic chromatin condensation inducer Acin1. Of these 37 proteins, 30 (81%) were also differentially phosphorylated in mCortR17 versus mCortGFP cells, suggesting that differential phosphorylation in CD is driven by R17 hyperactivity. Of the 35 proteins overabundant in CD adenomas, 15 (43%) overlapped with mCortR17, including the Myc-associated protein (Max) and Presenilin 1 (Psen1). Proteins enriched in both human CD and mCort datasets were involved in NOTCH signaling and neurotransmitter release, while phospho-proteome profiling highlighted R17-mediated perturbation of RNA polymerase II transcription termination and mRNA processing.

Conclusions:We first discovered a heavily dysregulated phosphoproteome in CD adenomas compared to syngeneic normal glands. We found that we could replicate the signature phosphoproteomic profile by overexpressing PPP1R17 in-vitro. These data indicate a central role for phosphatase (PP2A) inhibition in CD adenomas, and suggest potential novel anti-tumor targets for patients with CD.

Presentation: Thursday, June 15, 2023
THU480 Loss Of Selenof And A Western Diet Promote Mammary Tumorigenesis
Authors: Flowers Brenna , Zigrossi Alexandra , Diamond Alan , Kastrati Irida
Published: October 2023

Disclosure: B. Flowers: None. A. Zigrossi: None. A. Diamond: None. I. Kastrati: None.

SELENOF is an understudied selenium-containing protein which has previously been postulated to behave as a tumor suppressor in the breast. Examination of patient databases showed that SELENOF levels were lowest in tumors from patients with aggressive late-stage breast cancers. Whether loss of SELENOF drives breast tumorigenesis remains to be determined. To address this question, we used juvenile female wild type or systemic Selenof knockout mice and exposed them to 7,12-Dimethylbenz[a]anthracene (DMBA), a carcinogen which replicates the multistep process of breast tumorigenesis. Previous reports have shown that loss of Selenof led to glucose and metabolic dysregulation in mice suggesting a link between Selenof and metabolism. Because obesity is a risk factor in breast cancer, we challenged the mice with a western diet, high in fats and in calories, to mimic obesity. We hypothesized that loss of Selenof would promote DMBA-induced tumorigenesis and the western diet would exacerbate it. We found that tumor incidence was in fact highest in the Selenof knockout mice and western diet group. The Selenof knockout mice exhibited higher weights and higher fasting glucose levels consistent with metabolic dysfunction. These findings indicate that lower or loss of SELENOF expression may predispose a subset of women, especially obese ones, to increased risk of breast cancer. The link between SELENOF, obesity, and breast cancer warrants further investigation.

Presentation: Thursday, June 15, 2023
THU488 Genetic Alterations In CREBRF Influence Prostate Cancer Survival And Impact Prostate Tissue Homeostasis In Mice
Authors: Pascal Laura E , Frahm Krystle A , Skalitzky Kegan , DeFranco Donald Benedict , Rigatti Lora , Lu Ray , Liu Teresa
Published: October 2023

Disclosure: L.E. Pascal: None. K.A. Frahm: None. K. Skalitzky: None. D.B. DeFranco: None. L. Rigatti: None. R. Lu: None. T. Liu: None.

Background: Risk factors for prostate cancer include age, environmental factors, race and ethnicity. Genetic variants in cyclic-adenosine-monophosphate-response-element-binding protein 3 regulatory factor (CREBRF) gene are frequently observed in Pacific Islanders, a population with elevated prostate cancer incidence. CREBRF has been shown to play a role in other cancers, however its function in prostate homeostasis and tumorigenesis has not been previously explored. Methods: Alterations in CREBRF were identified in prostate cancer patients via in silico analysis of several publicly available datasets through cBioPortal. Male Crebrf knockout mice were generated and examined for prostate defects at 4 months of age. Immunohistochemical staining of murine prostate sections was used to determine the impact of Crebrf knockout on proliferation, apoptosis, inflammation and blood vessel density in the prostate. Serum adipokine levels were measured using a Luminex Multiplex Assay. Results: CREBRF alterations were identified in up to 4.05% of prostate tumors and the mutations identified were categorized as likely damaging. Median survival of patients with CREBRF alterations was 41 months, compared to 131 months for patients without CREBRF alterations. In the murine model, the prostates of Crebrf knockout mice had reduced epithelial proliferation and increased TUNEL+ apoptotic cells. Circulating adipokines PAI-1 and MCP-1 were also altered in Crebrf knockout mice compared to age-matched controls. Conclusions: Prostate cancer patients with CREBRF alterations were associated with decreased overall survival suggesting that CREBRF may play a role in prostate tumorigenesis and progression. The murine knockout model demonstrated that CREBRF could modulate proliferation and apoptosis and macrophage density in the prostate. Serum levels of adipokines PAI-1 and MCP-1 were also altered and could contribute to the phenotypic changes observed in the prostates of Crebrf knockout mice. Future studies focused on populations susceptible to CREBRF mutations and mechanistic studies will be required to fully elucidate the potential role of CREBRF in prostate tumorigenesis.

Presentation: Thursday, June 15, 2023
THU489 The Role Of Noncoding Genes With The Bidirectional Promoter In Triple-negative Breast Cancer
Authors: Yang Barbara , Sedano Melina , Jimenez Maria Vanessa , Ramos Enrique Ivan , Gadad Shrikanth
Published: October 2023

Disclosure: B. Yang: None. M. Sedano: None. M.V. Jimenez: None. E.I. Ramos: None. S. Gadad: None.

Breast cancer is the second leading cause of cancer mortality in women after lung cancer. Breast cancer is grouped into different molecular subtypes; triple-negative breast cancer (TNBC) accounts for 20%. TNBC is a highly aggressive histologic subtype; the lack of unique therapeutic targets makes it harder to treat. Recent studies have implicated genes involved in cancers that are transcribed using a process known as divergent transcription. The expression of these genes is tightly regulated; however, many escape regulation and become aberrantly expressed in tumors. Interestingly, our genomic analysis suggests that several of these genes encode noncoding transcripts. Analysis of transcriptome from different tissue types, including cancer and normal, revealed that many are upregulated in various cancers. Selected divergent transcript, such as lncRNA67, has been completely characterized (transcription start and stop site, 5’ cap, polyA tail, and exon/intron structure) and cloned. In functional assays, overexpression of lncRNA67 regulates gene expression, cell proliferation, and tumor growth. Our molecular analyses indicate that lncRNA67 plays a vital role in triple-negative breast cancer biology. Collectively, our results suggest that divergent transcripts are an integral component of cancer biology and present a new repertoire of diagnostic and potential therapeutic targets.

Presentation: Thursday, June 15, 2023
THU502 CYR61, A Member Of The CCN Protein Family, Regulates IGF1 In Metastatic Prostate Cancer
Authors: Ortiz Hernandez Greisha L , Walker Mya , Woods-Burnham Leanne , Kittles Rick A , Casiano Carlos A , Neuhausen Susan L
Published: October 2023

Disclosure: G.L. Ortiz Hernandez: None. M. Walker: None. L. Woods-Burnham: None. R.A. Kittles: None. C.A. Casiano: None. S.L. Neuhausen: None.

The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. Interestingly, CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-1 (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. We hypothesize that the interaction of CYR61 and IGF1 contributes to aggressive tumor properties (e.g., proliferation, tumorsphere formation) in PCa. Using immunoblotting, we demonstrated that CYR61 is upregulated in the androgen receptor-negative and glucocorticoid receptor-positive (AR-/GR+) metastatic cell line, PC3, and downregulated in the docetaxel-resistant cell line PC3-DR. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silenced. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not alter the MAPK pathway. We also initiated studies to determine the co-localization of CYR61 and IGF1 using immunofluorescence microscopy (IF). Based on the initial IF observations, we will proceed to examine if their interaction is primarily intra- or extra-cellular and whether interactions differ based on AR signaling. Using both PC3 and MDA-PCa-2b, which is AR+/GR+, we will co-immunoprecipitate CYR61 with IGF1 to assess intracellular interactions and use the AVidity-based EXtracellular Interaction Screen (AVEXIS) system for extracellular interactions. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Therefore, our goal is to establish the contribution of CYR61-IGF1 protein-protein interaction to PCa cell proliferation and tumor aggressiveness.

Presentation: Thursday, June 15, 2023
THU507 Tumor Activin A Mediates Cachexia Primarily Through White Adipose Tissue Hydrolysis In Pancreatic Ductal Adenocarcinoma
Authors: Yu Seok-Yeong , Luan Yi , Dong Rosemary , Abazarikia Amirhossein , Kim So-Youn
Published: October 2023

Disclosure: S. Yu: None. Y. Luan: None. R. Dong: None. A. Abazarikia: None. S. Kim: None.

Pancreatic ductal adenocarcinoma (PDAC) commonly harbors mutations in KRAS and TP53 genes and its overall 5-year survival rate is only 10% in the US. Among risk factors associated with the dismal PDAC prognosis, cachexia accounts for about 30% of PDAC-related death and is present in nearly 80% of PDAC patients. Significant adipose tissue loss followed by skeletal muscle loss characterizes PDAC-related cachexia in humans and mice. Accumulated evidence indicates that activin A, a homodimer of inhibin βA that is encoded by the INHBA gene, is a recognized key cachexia mediator as supported by mitigation of weight loss by activin A antagonists in PDAC-bearing mice. However, much remains unclear regarding the primary source cells of activin A and the mechanisms by which activin A mediates cachexia in PDAC. To address the unknowns, we employed CRISPR/Cas9 system for Inhba gene knock-down (KD) in mouse KPC (KrasG12D and Trp53R172H) PDAC cells and generated orthotopic mice using Inhba KD or control KPC cells. Sham group which received the same operation except for cell injection was included. Body weight was measured on a daily basis, and blood and white adipose tissues (WATs) and skeletal muscle tissues were harvested on post-surgery day 12. We found that, when compared to the Sham group, injection of control KPC cells significantly elevated serum activin A levels up to 6 ng/mL and temporally decreased the average body weight in the orthotopic mice (Ctrl group), whereas Inhba gene KD significantly reduced serum activin A levels by ∼ 2 ng/mL and prevented weight loss in the orthotopic mice (KD group). When compared to the Sham and KD groups, notable reductions in organ weights of epididymal, mesenteric or subcutaneous WATs were found in the Ctrl group, however, weights for gastrocnemius and plantaris or soleus muscle tissues were statistically similar between the Ctrl and KD groups at post-surgery day 12. Correspondingly, the average serum free fatty acids levels were higher in the Ctrl group than the KD group. Histological observations support that dramatic adipocyte size reductions in WATs were prevented by serum activin A suppression. Immunofluorescence analysis showed that WATs from the Ctrl group had considerably higher protein expression of hormone-sensitive or adipose triglyceride lipase than the KD and Sham groups. Furthermore, phosphorylation of SMAD3 and phosphorylated PKA substrate which regulate adipocyte lipolysis were intensely stained in WATs from the Ctrl group when compared to the KD and Sham groups. Collectively, our findings identify PDAC cancer cells as the major source of activin A in PDAC and suggest systemic activin A as a potential mediator of PDAC-related adipose tissue loss. The current findings warrant further investigation to address clinical relevance.

Presentation: Thursday, June 15, 2023
THU511 Somatostatin Analogs Or Active Surveillance In Sporadic And MEN1 Associated Non-functioning Pancreatic Neuroendocrine Tumors
Authors: Raia Salvatore , Chiloiro Sabrina , Maratta Maria Grazia , Maiorano Brigida , Rossi Ernesto , Brizi Maria Gabriella , Rufini Vittoria , De Marinis Laura , Rindi Guido , Schinzari Giovanni , Pontecorvi Alfredo , Tortora Giampaolo , Bianchi Antonio
Published: October 2023

Disclosure: S. Raia: None. S. Chiloiro: None. M. Maratta: None. B. Maiorano: None. E. Rossi: None. M. Brizi: None. V. Rufini: None. L. De Marinis: None. G. Rindi: None. G. Schinzari: None. A. Pontecorvi: None. G. Tortora: None. A. Bianchi: None.

Introduction: Non-functioning (NF), sporadic and MEN1 associated, G1-G2 pancreatic neuroendocrine tumors (PanNETs) usually display an indolent course. Surgery is the first-choice treatment for localized tumors >2 cm. Unresectable or metastatic PanNETs expressing somatostatin receptors (SSTRs) are treated with somatostatin analogs (SSAs). The standard treatment for patients with PanNETs ≤2cm is active surveillance (AS). Yet no evidence of the value of SSA treatment exist in such patient population. Aim(s): To assess the clinical value of SSAs in patients with PanNETs ≤2cm. Material and methods: Data from patients (pts) NF, G1-G2 PanNETs≤2cm were retrospectively collected. Median progression-free survival (mPFS) and response rate (RR) were analyzed in SSA group and AS group. Results: From June 2007 to June 2022, data from 46 pts were considered: 29 pts, who declined an AS program but had not indication for surgery, entered in the SSA group (21 sporadic and 8 MEN1 associatd PanNET) and 17 in the AS group. At a median follow-up of 64.8 months for sporadic and of 63.9 for MEN1 associated PanNET, no disease progression (PD) was reported in the SSA group, without differences between sporadic and MEN1 associated PanNET. While the PD rate was 23.5 % in the AS group, with a mPFS of 36.2 months. Conclusion: SSAs therapy showed significant antiproliferative activity in patients with both sporadic and MEN1 associated NF, G1-G2 PanNETs ≤2cm. SSAs treatment delay tumor progression and distant spread in small lesions that sometimes may reveal an unpredictable aggressiveness.

Presentation: Thursday, June 15, 2023
FRI219 Pheochromocytoma Presenting As A Case Of Worsening Diabetes Mellitus
Authors: Eapen Jane , Singer Elizabeth Sedlis , Lu Tiffany Xin , Shapiro Joshua Nathan
Published: October 2023

Disclosure: J. Eapen: None. E. Sedlis Singer: None. T.X. Lu: None. J.N. Shapiro: None.

Introduction: Pheochromocytoma is often diagnosed incidentally during unrelated abdominal imaging, in patients with a family history of known disease, or in patients presenting with the classic triad of symptoms: episodic headache, sweating, and tachycardia. We describe an atypical case of pheochromocytoma presenting as acute decompensation of DM. Case presentation: A 79 year old female with DM previously well-controlled on glimepiride for 4 years presented with an acute worsening of symptoms notable for abdominal fullness, weakness and weight loss. Laboratory results revealed an increase in HbA1c from 6% to 14% (nl <5.7%) since 3 months prior. Metformin and basal insulin were added to her regimen with a subsequent improvement in HbA1c. An abdominal CT scan was done given the acuity of progression in her DM, which revealed a 5.8cm adrenal mass. The patient denied easy bruising, striae, mood changes, dizziness, or hypertension. Biochemical evaluation demonstrated normal potassium level 3.7 (3.5-5.3 mmol/dL) and aldosterone 8ng/mL (<28), non-suppressed cortisol 7.8mcg/dL after dexamethasone 1mg given the night prior, but Cushing’s Disease was ruled out by normal salivary cortisol 0.08 mcg/dL (nl 0.04-0.56 mcg/dL) and urine free cortisol 22.8 mcg/ 24h (nl 4-50 mcg/24h), and further testing revealed elevated metanephrines and catecholamines during 24 hour urine collection, Epinephrine 129 mcg/24h (nl 2-24 mcg/24h), Metanephrine 7121 mcg/24h (nl 90-315 mcg/24h) and Normetanephrine 2078 mcg/ 24h (nl 122-676 mcg/24h).Repeat CT scan again showed an indeterminate 5.4 x 3.8 x 5.5 cm right adrenal mass, a 6.9mm lipid-rich left adrenal adenoma, and left adrenal gland hyperplasia. Consequently, the patient underwent laparoscopic right adrenalectomy with pathology revealing a diagnosis of pheochromocytoma. Post-op plasma fractionated metanephrines normalized and have remained normal. Immediately post-op, all diabetes medications (including insulin, glimepiride, and metformin) were stopped and she has had resolution of diabetes with HbA1c 6 on no medications when 1-year post-op. Discussion: Excess catecholamines are known to cause disruption of glucose and insulin homeostasis from desensitization of the beta-adrenergic receptor and increased insulin resistance1. Despite this, less than a handful of pheochromocytoma cases have been reported to be presenting as an acute glycemic derangement as in our patient. References: 1. Ronen JA, Gavin M, Ruppert MD, Peiris AN. Glycemic Disturbances in Pheochromocytoma and Paraganglioma. Cureus. 2019 Apr 27;11(4):e4551.doi: 10.7759/cureus.4551. PMID: 31275775; PMCID: PMC6592834.

Presentation: Friday, June 16, 2023
THU516 An Unusual Neck Mass
Authors: Rios Paola , Kalara Niketa , Shyam Tharun , Velez Jaylou , Gomez Carmen , Menendez Silvia Gra
Published: October 2023

Disclosure: P. Rios: None. N. Kalara: None. T. Shyam: None. J. Velez: None. C. Gomez: None. S. Gra Menendez: None.

Background: Parathyroid carcinoma is a rare tumor which presents with a neck mass and hypercalcemia. Non-functional parathyroid tumors account for 10% of all parathyroid carcinomas and are associated with decrease or impaired secretion of PTH, having normal calcium, being difficult to diagnose. We present a case of a patient who presented with a neck mass and normocalcemia, who was diagnosed of non-functional parathyroid tumor, were immunohistochemistry played a useful role in differentiating an unsuspected parathyroid lesion from a thyroid neoplasm. Clinical Case: 49-year-old woman presented with a 6-month history of a firm mass on the left side of her neck that was initially stable but then started to grow and was painful. On examination, she was noted to have a 5 cm firm thyroid mass with bilateral level 2 lymphadenopathy. Patient had a calcium of 9.9 mg/dL (8.6-10.3 mg/dL), normal kidney function and was euthyroid. An ultrasound of the thyroid revealed a left mass near the thyroid lobe, measuring 3.1 x 4 x 2.5 cm. Fine-needle aspiration of the mass revealed a poorly differentiated carcinoma possible originating from the thyroid. The patient underwent total thyroidectomy with central compartment dissection, bilateral neck dissection and radical resection of the tumor. Frozen section revealed malignancy highly concerning for anaplastic thyroid. Immunohistochemistry (IHC) showed that the differentiated component was positive for PTH, chromogranin, PAX8 and GATA-3, while negative for TTF-1, thyroglobulin, BRAF and p53. The higher-grade component was positive for GATA-3, p53, TTF1 (weak focal), PAX-8 (weak focal) and negative for thyroglobulin, chromogranin, PTH and BRAF which was suggestive of parathyroid tissue. The final pathology report was a differentiated parathyroid carcinoma transitioning to a high-grade carcinoma with anaplastic features, 5.6 cm in the largest dimension with invasion to thyroid tissue, skeletal muscle and angiolymphatic invasion. The tumor was a pT3N0Mn/a. Next-Generation Sequencing (NGS) of the tumor showed a high tumor mutational burden as well as high microsatellite instability being beneficial Pembrolizumab for treatment if required. IHC showed PD-L1, were Nivolumab and Pembrolizumab could work in the future if needed. Also, TP53 was detected on the NGS. She completed 32 Gy/16 fractions of adjuvant radiotherapy and continues to be on active surveillance 8 months after diagnosis without evidence of recurrence of the cancer. Conclusion: Non-functional parathyroid carcinoma is a very rare tumor that should be on the differential diagnosis in a patient with normocalcemia and neck mass. Immunohistochemistry would help in the diagnosis between thyroid or parathyroid lesion as described in this case.

Presentation: Thursday, June 15, 2023
THU519 Large Congenital Facial Teratoma: A Case Report
Authors: Solis Pazmiño Andrea Paola , Pazmino-Chavez Camila , Solano Vanessa , Garcia Cristhian
Published: October 2023

Disclosure: A.P. Solis Pazmiño: None. C. Pazmino-Chavez: None. V. Solano: None. C. Garcia: None.

Background: Craniocervical teratomas are congenital tumors that arise from the endoderm, mesoderm, and ectoderm germ cell layers. In order to have adequate and prompt management for better outcomes, information about its clinical manifestations and prenatal assessment must be widely disseminated because it can cause death in neonatal patients. The purpose of this case report is to deepen understanding of craniocervical teratoma because there is a dearth of information on the subject. Clinical case: A boy infant was brought in with a significant right mass that had existed from birth. He was delivered by cesarean section at the 38th week of gestation by a 26-year-old primiparous female with one living and healthy child. An extended facial appendage measuring 54 x 23 x 49 mm (L x B x W), with a capacity of 32 mL, was seen during prenatal ultrasonography (Figure 1a). On color Doppler imaging, the appendage was shown as a smoothing, hypodense cystic lesion without any vascularity to be concerned about (Figure 1b). The patient underwent an elective cesarean section at term, the pregnancy developed normally overall, and the newborn was delivered in generally healthy condition. The youngster does not experience pain, have trouble opening his lips, have trouble hearing, or have any other neurological deficits, according to the child’s parents. At the time of examination, the mass measured approximately 6.5 cm by 5 cm by 4 cm in the lateral half of the face (Figure 2) and extended superiorly to the right pterygoid region to the sub-maxillary ipsilateral side. Clinical lessons: Although craniocervical teratoma incidence is low, it is important to identify the appendage on neonatal ultrasound to plan correct management ahead of the baby’s delivery. Additionally, using the 3D-printed model makes it easier to organize the surgery and reduces blood loss while debulking.

Presentation: Thursday, June 15, 2023
THU545 Growth Hormone Receptor Antagonist As A Novel Combination Therapy Against Triple Negative Breast Cancer
Authors: Mora-Criollo Patricia , Basu Reetobrata , Kopchick John Joseph
Published: October 2023

Disclosure: P. Mora-Criollo: None. R. Basu: None. J.J. Kopchick: None.

Triple Negative breast (TNBC) cancer is classified based on the absence of ER-, PR-, and HER2- receptors and is associated with high metastatic potential. TNBC accounts for approximately 15-20% of new breast cancer diagnoses and is responsible for most breast cancer-related deaths. First-line treatment of anticancer drugs can be effective in 30-70% of patients with TNBC, but during treatment, more than half of the patients develop resistance and progress into metastatic disease. Previous studies have demonstrated the link between growth hormone receptor (GHR) expression and mammary carcinogenesis and established that GHR signaling promotes breast cancer development and progression. Conversely, inhibition of GHR expression has been shown to arrest tumor initiation and reduce metastasis of mammary carcinoma cells. Here we present the feasibility studies for employing GHR as a target for novel combination therapeutic approaches in TNBC. We performed retrospective analysis of GHR transcript expression and survival in TNBC patients, followed by experimental data in cellular models using combinations of Pegvisomant (an FDA-approved GHR antagonist) with chemotherapeutic agents, as a potential therapeutic option in TNBC. Survival probability plots from the TCGA dataset of 405 TNBC samples showed that patients expressing high levels of the GHR showed a significantly poor survival (27 months, p=0.038) compared to patients expressing low GHRs (40.37 months). Additionally, human breast cancer MDA-MB-453 cells, when treated with human (hGH)(2.5 nM) increased activation of JAK2, STAT5, SRC, ERK1/2, and AKT, associated with cancer progression. Importantly, treatment of the cells with Paclitaxel (1 nM) + (hGH)(2.5 nM) increased ABCG2 expression and the epithelial-to-mesenchymal transition (EMT) makers (SLUG, SNAIL, N-cad) associated with drug resistance and tumor progression. On the contrary, when cells were treated with Pegvisomant (500 nM) in combination with Paclitaxel + GH, a significant decrease in protein and RNA expression of ABCG2 as well as EMT markers was observed. Next, serum collected from GH antagonist (GHA) mice and WT as control, were used to treat PY8119 mouse cells in combination with Paclitaxel (1 nM) + bovine (bGH)(2.5 nM). Downregulation of protein and RNA expression levels of ABCG2 as well EMT makers in GHA serum treatment compared to WT was also found. This preliminary data shows that the GHR antagonist, Pegvisomant, in combination with anticancer drugs, can be effective in attacking drug resistance in TNBC. Key words: Pegvisomant, growth hormone receptor

Presentation: Thursday, June 15, 2023
THU547 Role Of NAD+ Synthesis Pathway In PARP Inhibitor Resistance
Authors: Myong Subin , Challa Sridevi
Published: October 2023

Disclosure: S. Challa: None.

ADP-ribosylation is catalyzed by the poly(ADP-ribose) polymerase (PARP) family of enzymes consisting of 17 members that have distinct structural domains, activities, subcellular localizations, and functions. The catalytic activities of PARP enzymes are intimately tied to the synthesis of NAD+, which is consumed during ADPRylation reactions and, thus, must be regenerated. The intracellular salvage pathway utilizing nicotinamide (NAM) is the primary source of NAD+ in the cell. NAM is converted to nicotinamide mononucleotide (NMN) by NAMPT. Nicotinamide mononucleotide adenylyl transferases (NMNATs) catalyze the final step in the NAD+ salvage pathway, combining NMN and ATP to make NAD+. Three different NMNATs, each with a distinct subcellular localization, control the subcellular levels of NAD+ in each compartment: NMNAT-1 in the nucleus, NMNAT-2 is in the outer membrane of golgi, and NMNAT-3 in the mitochondria. We recently demonstrated that such compartment-specific NAD+ synthesis regulates the levels of ADP-ribosylation. Elevated levels of NMNAT-2, the cytosolic NAD+ synthase, reduces nuclear NAD+ levels and PARP1 activity in adipocytes and ovarian cancer cells.

In the current study, we aim to delineate the role of compartmentalized synthesis of NAD+ in PARP inhibitor resistance in ovarian cancers. To identify these mechanisms, we generated ovarian cancer cells with acquired resistance to Niraparib, an FDA approved PARP inhibitor (NirR). We found that NirR cells have elevated levels of NAD+ biosynthesis. Moreover, treatment of parental cells with NAD+ precursors reduced the sensitivity to Niraparib while inhibition of NAD+ metabolism in NirR cells increased the sensitivity to Niraparib. Interestingly, the resistant cells have comparable levels of PARP1 activation to the parental cells. These data collectively suggests that NAD+ metabolism confers resistance to Niraparib without altering PARP1 activity. In line with this, NirR cells are sensitive to the effects of depletion of the cytosolic NAD+ biosynthesis, suggesting high NAD+ biosynthesis in NirR cells supports processes regulated by the cytosolic NAD+ which may drive the resistance phenotype. There is an urgent need to identify the mechanisms of resistance to PARP inhibitors to increase their clinical efficacy. This study identifies the NAD+ biosynthesis pathway as a key mechanism of PARP inhibitor resistance.

Presentation: Thursday, June 15, 2023
THU549 Targeting The Growth Hormone Receptor Attenuates Tumor Exosome Mediated Propagation Of Chemoresistance In Melanoma
Authors: Kulkarni Prateek , Basu Reetobrata , Bonn Taylor , Kopchick John Joseph
Published: October 2023

Disclosure: P. Kulkarni: None. R. Basu: None. T. Bonn: None. J.J. Kopchick: None.

Elevated ATP-binding cassette (ABC) transporters in tumor cells resulting in decreased intracellular drug accumulation is a major reason for chemotherapy resistance in cancer. Mounting evidence indicates that extracellular vesicles (EVs), particularly exosomes, the smallest subset of EVs, play a crucial role in the spread of drug resistance. We have previously shown that growth hormone (GH) decreases therapeutic efficacy in melanoma via upregulating the levels of ABC transporters, whereas when GHR is knocked down or GH/GHR interaction is inhibited by GHR antagonist, Pegvisomant, these ABC transporters are significantly downregulated. No study has yet directly assessed the effect of GH or GHR antagonism on exosomal cargoes in terms of promoting drug resistance. We observe that human melanoma cells (Malme3M, SK-Mel28, and MDA-MB-435) when treated with GH or doxorubicin alone or in combination increase the exosomal protein levels of multiple multi-drug efflux pumps, namely ABCC1, ABCC2, ABCB1, and ABCG2. On adding Pegvisomant to these treatments, we found a significant decrease in the levels of these exosomal drug efflux pumps induced by both autocrine and endogenously added GH. Furthermore, we assessed the role of GH in exosome-mediated dissemination of chemoresistance from drug-resistant to drug-sensitive cells. When GH and doxorubicin-treated melanoma-derived exosomes were administered to treatment-naïve melanoma cells, a significant increase in drug efflux was observed in the latter, compared to the control. On the other hand, when Pegvisomant co-treated melanoma-derived exosomes were administered to treatment-naïve melanoma cells, the drug efflux was attenuated, indicating chemo-sensitization. Collectively, these observations indicate that Pegvisomant suppresses various exosomal cargoes modulating drug resistance in melanoma.

Acknowledgment: This work was supported in part by the State of Ohio’s Eminent Scholar Program includes a gift from Milton and Lawrence Goll, by the AMVETS, Ohio University’s Student Enhancement Award, and Edison Biotechnology Institute.

Presentation: Thursday, June 15, 2023
THU552 Understanding Radiation Therapy Sensitivity In Invasive Lobular Carcinoma Of The Breast
Authors: Boysen Michael Rhinehart , Sikora Matthew Joseph , Shackleford Madeleine , Sottnik Joseph
Published: October 2023

Disclosure: M.R. Boysen: None. M.J. Sikora: None. M. Shackleford: None. J. Sottnik: None.

Invasive lobular carcinoma of the breast (ILC) affects ∼40,000 US women annually and is a top-ten most common cancer affecting women. Despite most ILC having biomarkers of “low risk” disease (e.g. ∼95% are estrogen receptor α /ER-positive), ILC is associated with poorer long-term outcomes and anti estrogen resistance. ILC are also notoriously non-responsive to chemotherapy, critically limiting treatment options for advanced or metastatic ILC. However, ILC are highly responsive to radiation therapy (XRT), which suppresses ILC recurrence and improves survival. We hypothesize that this sensitivity may be due to a dysfunction in DNA damage repair unique to ILC cells. We examined formation and resolution of DNA damage repair foci (namely RAD51, γH2AX and 53BP1 foci) by immunofluorescence with ILC and IDC cell lines treated with ionizing radiation +/- anti-estrogen therapy as surrogates for the initiation and resolution of DNA repair. We also assessed cell growth via 7-day growth assays with ILC and IDC cell lines treated with ionizing radiation. Imaging with immunofluorescence suggested a deficiency in γH2AX foci formation in ILC cells compared to IDC cells following treatment with XRT, despite robust formation of 53BP1 foci. This suggests that a deficiency in performing DNA damage repair in response to XRT is likely present in ILC cells. Additionally, our growth assays demonstrated an inability in ILC cells to recover from ionizing radiation compared to IDC cells. Taken together, the potential dysfunction in γH2AX foci formation in ILC cells suggests that ILC cells may not form the appropriate DNA repair structures to initiate the DNA damage response, suggesting that a form of DNA repair deficiency underlies radiation sensitivity in ILC cells.

Presentation: Thursday, June 15, 2023