bluuebunny/crossref_metadata_2025_split huggingface dataset:
6564 A Case of Severe Hypercalcemia in Carney's Complex
Authors: Chippior Jessica , Rayan Melanie , Wright Laura , Steven Kirschner Lawrence , Wai Ing Steven 
Published: October 2024

Abstract
Disclosure: J. Chippior: None. M. Rayan: None. L. Wright: None. L.S. Kirschner: Grant Recipient; Self; Medpace, Sparrow, Corcept Therapeutics, Corcept, Spruce, CinCor, Crinetics, Adrenas. S.W. Ing: Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Amgen Inc, Radius Health, Inc, Takeda, Ultragenyx, Amolyt, Bridge Bio.
Carney complex is a rare syndrome with fewer than 750 reported cases, characterized by lentigniosis, myxomas, and the occurrence of both endocrine and non-endocrine tumors. An inactivating mutation PRKAR1A, which encodes for the type 1A regulatory subunit of Protein kinase A, is responsible for over 70% of familial cases and 37% of sporadic cases. A 31-year-old female with a history of Carney complex, Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD), facial lentigines, spinal Schwannomas, and recent ischemic stroke secondary to embolization of a cardiac atrial myxoma, was transferred to our medical center for hyperemesis and severe hypercalcemia. Albumin-corrected serum calcium measured 15.4 mg/dL (8.6-10.5 mg/dL), ionized calcium 7.8 mg/dL (4.6-5.3 mg/dL) associated with suppressed PTH, normal PTH-related protein, and elevated bone turnover markers, C-telopeptide 4,273 pg/ml (150-635) and Procollagen Type 1 N-terminal Propeptide 222 mcg/L (19-83). Evaluation for etiology of hypercalcemia revealed elevated 1,25 dihydroxy vitamin D at 107.0 pg/ml (20-79) and elevated interleukin-6 at 11 pg/ml (&lt;6.4). IL-6 is expressed by cardiac myxomas. Serum angiotensin-converting enzyme level was 50 U/L (16-85) and infectious workup was negative for potential granulomatous causes of elevated calcitriol (including testing for tuberculosis, histoplasma, blastomyces, bartonella, and coccidioides). CT angiogram of the abdomen and pelvis (completed in preparation of atrial myxoma resection) revealed ground-glass opacities in bilateral posterior lung fields and multiple pulmonary nodules, with the largest measuring 8 mm. After treatment with aggressive intravenous fluid resuscitation, intramuscular calcitonin, and intravenous zoledronic acid, corrected calcium normalized to 9.4 mg/dL at discharge. Urinary cortisol was 6.2 mcg per 24-hr (3.5-45), for which she started hydrocortisone 20 mg daily to treat suspected adrenal insufficiency as excess cortisol secretion in PPNAD may be episodic. Thus remission of hypercortisolism may have unmasked an underlying hypercalcemia, and adrenal insufficiency itself may have contributed to this finding. She had excision of left atrial myxoma and has continued to exhibit normal calcium levels on steroid replacement therapy. Repeat chest CT to further characterize these pulmonary findings is planned. This case illustrates a unique constellation of endocrine features associated with severe hypercalcemia in Carney complex.
Presentation: 6/1/2024
7274 Assessing the interactome of hexose-6-phosphate dehydrogenase in breast cancer cells and identifying anterior gradient protein 2 as interacting partner by using a BioID method
Authors: Sakalauskaite Gabriele , Weingartner Michael , Bock Thomas , Birk Julia , Tsachaki Maria , Odermatt Alex 
Published: October 2024

Abstract
Disclosure: G. Sakalauskaite: None. M. Weingartner: None. T. Bock: None. J. Birk: None. M. Tsachaki: None. A. Odermatt: None.
Hexose-6-phosphate dehydrogenase (H6PD) catalyzes the first two steps of the pentose-phosphate pathway in the endoplasmic reticulum (ER). It is so far the only enzyme shown to generate NADPH in the ER. H6PD is involved in physiological processes such as glucose and steroid metabolism, redox regulation, and response to ER-stress. So far, only one H6PD interacting partner, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), has been reported. This enzyme uses NADPH for its well-reported role in glucocorticoid activation. However, H6PD has 11β-HSD1-independent functions, such as the recently described modulation of breast cancer cell properties. Here, we adapted the BioID approach to identify novel H6PD interacting partners in the ER. First, we generated a triple negative breast cancer cell line MDA-MB 231 stably expressing a H6PD-biotin ligase fusion protein. Then, we validated the method to confirm the known interaction between H6PD and 11β-HSD1. Next, we analyzed enriched biotinylated proteins by mass spectrometry and further assessed potential candidates by co-immunoprecipitation and functional assays. The resulting interactome revealed a potential hit cluster of protein disulfide isomerase (PDI) family members, different ER-resident chaperones and luminal calcium binding proteins. Due to its association with breast cancer, we further examined the PDI Anterior gradient protein 2 (AGR2) as H6PD interacting partner. Physical interaction between AGR2 and H6PD was confirmed by co-immunoprecipitation assay in MCF7 cells. Downregulation of AGR2 by siRNA resulted in elevated H6PD protein levels but decreased activity. Furthermore, increased H6PD activity was observed when this protein was co-expressed with AGR2 in HEK-293 cells. In conclusion, the results validated the use of the BioID approach to identify protein interactions within the ER and they revealed that AGR2 physically interacts with H6PD, thereby controlling its expression and enzyme activity.
Presentation: 6/3/2024
12347 Cholesterol Biosynthesis Inhibitor Ro 48-8071 Suppresses Growth Of Triple-negative Breast Cancer Cells By Inducing Apoptosis And Suppressing Angiogenesis
Authors: Liang Y , Hyder S 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. Women who suffer from TNBC have limited treatment options and are administered toxic chemotherapeutic agents. They have poor prognosis due to the emergence of drug-resistant cells that lead to tumor metastasis. New non-toxic therapeutic strategies to control TNBC progression, and prevent metastasis are urgently needed. Cholesterol is an essential structural and functional component of cell membranes necessary for tumor growth and progression. Therefore, inhibiting cholesterol production is an attractive therapeutic strategy since tumor cells grow rapidly, and need a greater supply of cholesterol. We targeted oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway, to disrupt tumor growth. 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 but its effect on TNBC is not known. Pharmacological doses of RO potently reduced the viability of both MDA-MB-231 and BT20 TNBC cells in a dose dependent manner (1-50 μM). IC50 values for loss of cell viability was approximately 10 μM for both cell lines following 48 h exposure to RO. Doses close to the IC50 for OSC (1-10 nM) also reduced cell viability following exposure of TNBC cells to RO for a week. Importantly, RO had no effect on the viability of normal human mammary cells. FACS analysis revealed that RO dose-dependently induced apoptosis of TNBC cell lines in vitro. In vivo, administration of 5-10 mg/kg RO to mice with BT-20 TNBC cell-derived xenografts (100 mm[3]) inhibited tumor growth with no apparent toxicity. Immunohistochemical analysis of tumor tissues at the end of treatment showed that RO increased TUNEL expression, suggesting that the in vivo effects of RO were also exerted through mechanisms affecting apoptosis. Furthermore, IHC of tumor sections showed that RO also reduced levels of the angiogenic markers VEGF and CD-31 (blood vessels) in vivo, indicating that suppression of angiogenesis is also part of the mechanism through which RO exerts its anti-tumor effects. We conclude that RO is a potent inhibitor of TNBC and that its anti-tumor effects involve mechanisms that induce apoptosis and suppress angiogenesis.
Presentation: 6/2/2024
7111 Intrapericardial Paraganglioma, An Exceedingly Rare Finding
Authors: Habibi Roshanak , Pendergrass Merri , Neda Ebrahimi , Cardenas Lara Ramiro 
Published: October 2024

Abstract
Disclosure: R. Habibi: None. M. Pendergrass: None. E. Neda: None. R. Cardenas Lara: None.
Introduction: Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes are rare tumors occasionally resulting from germline pathogenic variant in succinate dehydrogenase subunit B and D (SDHB and SDHD) genes. Hereditary forms are usually present in the posterior mediastinum. Few cases of PGL/PCC syndromes are reported in intrapericardial space. Below, we report on such a patient, illustrating the importance of genetic testing and whole-body imaging surveillance in patients with tumors suggestive of paragangliomas. Presentation: We present a case of a 25-year-old female with an intracardiac mass suspicious for intrapericardial paraganglioma. She was initially diagnosed with a large jugular when she presented to the emergency department with nausea, vomiting, headaches, with recent diagnosis of cranial nerve VI palsy and vertigo. MRI brain with and without contrast showed a hypervascular glomus jugular tumor in the right skull base with extension into the carotid space of the neck, with leftward effacement of the posterior oropharynx and flow into the right sigmoid and transverse sinus during the arterial phase, suggestive of a paraganglioma. The paraganglioma was deemed non secretory with unremarkable initial endocrine work up. Her 24 hours urine 3-methoxythyramine and dopamine levels were elevated as expected with paraganglioma. She was referred to a geneticist and diagnosed with hereditary PGL/PCC syndrome. This was secondary to a germline pathogenic variant in SDHB gene (deletion exon 8). Cardiac MRI revealed an intensely enhancing intrapericardial lesion along the anterior/superior aspect of the left atrium. Imaging features were suggestive of an intrapericardial paraganglioma, given the genetic analysis and concurrent imaging findings of neck glomus tumor. She also had abdominal and pelvic CT scan with IV contrast which did not reveal any mass. Cardiothoracic surgeon decided on non-surgical intervention. The neurosurgery team recommended surgery since surgery in the jugular foramen seemed morbid with probable multiple cranial nerve injuries. The patient eventually received courses of radiation treatment to the glomus paraganglioma of the brain which improved the size of tumor. Discussion: Paragangliomas are chromaffin tumors that arise from either sympathetic or parasympathetic ganglia. The literature reveals about 2 % or less of paragangliomas affect the chest. Most of these tumors will be found in the posterior mediastinum. The very small proportion of them found in the heart are commonly seen arising from the roof of the left atrium in addition to affecting cardiac structures. Due to a high level of vascularization and the inherent risk of hemorrhage, tissue biopsy is not typically advised. In nonfunctional paragangliomas, surgery is often the ultimate treatment.
Presentation: 6/2/2024
8072 Crosstalk between E-cadherin loss and Estrogen receptor drives tumorigenesis in Invasive Lobular Carcinoma
Authors: Ufondu Chinasa A , Musick Maggie , Joseph Sikora Matthew , Hanson Ostrander Julie 
Published: October 2024

Abstract
Disclosure: C.A. Ufondu: None. M. Musick: None. M.J. Sikora: None. J.H. Ostrander: None.
Estrogen receptor (ER) expression and E-cadherin (CDH1) loss are the two major molecular hallmarks of invasive lobular carcinoma (ILC) of the breast; however, it is unclear how ER signaling and E-cadherin loss crosstalk during ILC tumor formation. Furthermore, the risk of ILC is increased by estrogen-only hormone replacement treatment, but not that of the more frequent invasive ductal carcinoma (IDC), suggesting that ER may have a unique role in the initiation and progression of ILC. We hypothesize that E-cadherin loss accelerates estrogen-driven tumorigenesis by reprogramming ER DNA binding through the dysregulation of pathways and transcription factors linked to E-cadherin. To test the effect of E-cadherin loss during estrogen driven tumorigenesis, we established a CRISPR/Cas9 approach for knocking out CDH1 in primary human mammary epithelial cells (HMECs). Since primary HMECs did not show robust ER expression, we also re-expressed ER using lentiviral transduction of ESR1 into HMECs. We performed RNAseq from two independent CDH1 targeting gRNAs vs non-targeting gRNA (NTG) control (-/+ ER). Importantly, when comparing the two independent CDH1 gRNAs to NTG there were 2882 shared genes (1436 upregulated only, 1407 downregulated only) that were differentially regulated. Analysis of these shared genes showed the enrichment of estrogen response, PI3K signaling and cell cycle pathways in the CDH1 knockout cells vs control. We also observed the repression of epithelial mesenchymal transition, hypoxia-related genes and p53 in the CDH1 knockout samples vs control. Overall, analysis of the RNAseq data suggests that the loss of E-cadherin in HMECS impacts proliferation and EMT, which will be explored in future studies. In addition, we hope to identify mediators that drive estrogen-induced tumorigenesis using the mouse mammary intraductal (MIND) model, which better recapitulates the progression of ILC and response to estrogen in vivo. We injected control and CDH1 knockout cells into the mammary glands of adult female NSG mice, with estrogen supplemented in their drinking water, and assessed for engraftment using bioluminescence imaging (BLI). BLI suggests enhanced engraftment of CDH1 knockout cells compared to CDH1 wild-type HMECs and a survival advantage for HMECs expressing ESR1. Importantly, analysis of mammary glands two-month post-MIND injections showed engraftment of human cells positive for cytokeratin-5 and lamin a/c. Ongoing studies aim to assess the estrogen response in the CDH1-knockout versus control HMECs in vitro and in vivo to determine whether loss of E-cadherin contributes to ILC-specific ER activity. Understanding the unique interactions between E-cadherin loss and ER in ILC could lead to novel therapeutic approaches for the prevention and treatment of ILC.
Presentation: 6/2/2024
7401 Development and Evaluation of Ruthenium-based Photoactivated Chemotherapeutic Agents
Authors: Wilson Auden , Cejudo Briseily , Enkhbold Khuslen , Chung Yuna , Chiaino Samantha , Norris Michael R , Pollock Julie 
Published: October 2024

Abstract
Disclosure: A. Wilson: None. B. Cejudo: None. K. Enkhbold: None. Y. Chung: None. S. Chiaino: None. M.R. Norris: None. J. Pollock: None.
Photoactivated Chemotherapy (PACT) represents an opportunity to limit the off-target toxicity inherent to traditional chemotherapies. Selective activation of toxic effects would allow effective chemical treatment of solid tumors without the normally associated side effects. Expanding on previous work in our lab (1), we have evaluated the potential of ruthenium-based compounds as PACT agents by testing light activation, cell viability in breast cancer and lung cancer cells, biocompatibility, and DNA interactions. We have observed that active ruthenium-complexes with increased lipophilicity tend to be more toxic to the cancer cells. In addition, we have ligated known anticancer compounds (2) to our ruthenium cages, evaluated the capacity to mask the general cytotoxic effects, and examined the release of a fully active drug after light exposure. We can successfully release the active drugs with light, but when using light at 450 nm it takes about six hours of direct exposure in a cuvette to see successful conversion. We are currently systematically exploring different wavelengths of light to reduce activation time and increase potential clinical utility (3). Once optimal wavelengths are determined, cancer cell viability experiments will be performed in the absence and presence of light in order to evaluate the therapeutic window for these ruthenium-complexes. References: (1) Paul, L. et. al. J. Inorg. Biochem.2022, 235: 111930. (2) Peerzada, M. N. et. al. Eur. J. Med. Chem.2018, 155: 13-23. (3) Dunkel, P. & Ilaš, J. T. Cancers2021, 13: 40-42.
Presentation: 6/2/2024
5110 Development of Exosome-mediated Suicide Gene Therapy for Enhanced Cancer Treatment
Authors: Ku Joy , Flojo Renech , Zhang Pengyan , Lu Biao 
Published: October 2024

Abstract
Disclosure: J. Ku: None. R. Flojo: None. P. Zhang: None. B. Lu: None.
Existing suicide gene therapy strategies are designed to express prodrug-converting enzymes in the cytosol of cancer cells, limiting their therapeutic reach to gene-transfected cells and their immediate neighbors through bystander effects (1). This study proposes a novel approach to enhance cancer treatment by redirecting prodrug-converting enzymes into extracellular vesicles, also known as exosomes, potentially enabling metastatic cancer cells to receive therapeutic drugs through cancer-homing mechanisms (2, 3). To achieve this, we aimed to develop an exosome-based suicide gene therapy strategy employing human herpes simplex virus-thymidine kinase (HSV-TK) and cytosine deaminase-uracil phosphoribosyl transferase (CD-UPRT) enzymes. We designed and constructed two lentiviral vectors expressing chimeric fusion proteins, incorporating exosome-targeting motifs, green fluorescent protein, Gaussia luciferase, and HSV-TK/CD-UPRT. We demonstrated that both chimeric fusion proteins were properly shunted into the exosome pathways by transfection of cultured 293T and HepG2 cells, followed by real-time monitoring and confocal imaging. This was further corroborated by colocalizing these fusion proteins with well-established exosome markers, such as CD9, CD63, CD81, and XPACK. Furthermore, the isolation and characterization of secreted exosomes confirmed the successful loading of engineered enzymes onto exosomes, which were subsequently released into the conditioned media of both cell models. Importantly, initial experiments involving transfection and prodrug treatment showed that HepG2 cells were significantly inhibited (up to 84%) in a dose- and time-dependent manner when treated with the prodrug Ganciclovir in the HSV-TK model. Our study demonstrates the potential adaptation of prodrug therapy to an exosome-based platform, opening the door to a novel nano-treatment approach for cancer. Reference: (1) Thoidingjam et al., Translational Medicine communications. 2023. 8:11. (2) Lu et al., Advanced Drug Delivery Reviews. 2022. 114465. (3) Zhang et al., Signal Trnsductio and Targeted Therapy. 2023. 8:124.
Presentation: 6/2/2024
9308 GPNMB Promotes Tumor Growth and is a Biomarker for Lymphangioleiomyomatosis (LAM)
Authors: Gibbons Erin , Taya Manisha , Wu Huixing , Lopa Samia , Moss Joel , Henske Elizabeth P , McCormack Francis X , Hammes Stephen R 
Published: October 2024

Abstract
Disclosure: E. Gibbons: None. M. Taya: None. H. Wu: None. S. Lopa: None. J. Moss: None. E.P. Henske: None. F.X. McCormack: None. S.R. Hammes: None.
Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB regulates TSC2-null tumor cell invasion as well as TSC2-null xenograft tumor growth, and that GPNMB expression is dependent on mTORC1 signaling. Further, we show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by ADAM10 and 17 proteases, and we identify the protease target sequence on GPNMB. In fact, mutating this cleavage sequence so that the GPNMB ectodomain can no longer be shed results in cessation of TSC2-null tumor growth. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.
Presentation: 6/3/2024
8770 Highly Multiplexed Mapping of the Ductal Carcinoma In Situ Ecosystem to Predict Disease Outcome
Authors: Wilson G M , Doan T B , Guild B J , Pathmanathan N , Graham J D 
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