bluuebunny/crossref_metadata_2025_split huggingface dataset:
THU481 Glucocorticoid Regeneration By Tumor Cells Promotes Growth By Enhancing Regulatory T Cell Immunosuppression
Authors: Taves Matthew D , Otsuka Shizuka , Taylor Michaela A , Donahue Kaitlynn M , Ashwell Jonathan D 
Published: October 2023

Abstract
Disclosure: M.D. Taves: None. S. Otsuka: None. M.A. Taylor: None. K.M. Donahue: None. J.D. Ashwell: None.
Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11β-HSD1 (encoded by Hsd11b1). We found that multiple tumor types express Hsd11b1 and produce active glucocorticoids. Genetic ablation of Hsd11b1 in such cells had no effect on in vitro growth but reduced in vivo tumor progression, which corresponded to increased frequencies of tumor-infiltrating cytotoxic T cells expression activation markers and producing effector cytokines. Tumor-derived glucocorticoids upregulated tumor-infiltrating regulatory T cell (Treg) expression of miRNA-342 and downregulated the mTORC2 component Rictor, enhancing Treg activity. Indeed, cytotoxic T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacological inhibition of 11β-HSD1 reduced tumor growth to the same degree as gene knockout, and rendered immunotherapy-resistant tumors susceptible to immune checkpoint blockade. Given that HSD11B1 is upregulated in many human tumors and that inhibition of 11β-HSD1 is well-tolerated in clinical studies, these data suggest that targeting 11β-HSD1 may be a beneficial adjunct in cancer therapy.
Presentation: Thursday, June 15, 2023
THU484 Distinct Genetic Characteristics In Follicular Thyroid Cancer With Different Metastatic Potentials
Authors: Kwak Soo-jung , Lee Eun Kyung , Song Young Shin , Park Young Joo , Kim Jong-Il 
Published: October 2023

Abstract
Disclosure: S. Kwak: None. E. Lee: None. Y. Park: None.
Although most follicular thyroid cancers (FTCs) show excellent prognosis, more than 5% accompany distant metastasis, often diagnosed unexpectedly in the advanced stage. Genetic or genomic markers have been shown to be useful as a prognostic tool in many cancers, but it is unclear whether genetic markers predicting the metastatic potential of FTCs exist. To investigate, 11 pairs of matched formalin fixed paraffin embedded tissue samples of primary (PTM1) and metastatic tumors (MT) from FTC patients with distant metastasis were analyzed by whole exome sequencing. For validation, 78 unmatched FTC samples including 49 well-differentiated tumors, 15 poorly-differentiated tumors and 14 anaplastic thyroid cancer (ATC) samples were analyzed by targeted sequencing. Among the 11 paired PTM1 and MT tumors, 10 showed concordant driver mutations (NRAS, HRAS, DICER1, EIF1AX), and the TERT promoter mutation was concordantly found in 6 pairs. However, the concordance rate of other somatic mutations in paired samples were found to be only 16.2%. Other mutational characteristics such as mutational signatures and CNVs also differed, suggesting the independent subclonal evolution of the paired MT from the PTM1 after metastasis. Interestingly, the frequency of mutations including driver, TERT promoter, and other mutations was lower in primary tumors without metastases (PTM0). Mutational characteristics of PTM0 also differed from those of PTM1 and MT, suggesting that the mutational or molecular characteristics of PTs at the time of diagnosis may distinguish metastatic potential. In a pooled analysis including published data of follicular patterned tumors, we found that metastatic or aggressive tumors were more likely to have the RAS mutation, which tended to be coupled with TERT, DICER1, EIF1AX, and TP53, gradually from minimally invasive FTC, widely invasive FTC to poorly differentiated thyroid cancer (PDTC) and ATC. Transcriptomic profiles from The Cancer Genome Atlas (TCGA) and our data (SNUH) showed RAS(+)/TERT(+) mutated tumors and RAS(+)/TERT(-) tumors had differences in several intracellular signal pathways. Therefore, when follicular neoplasm is diagnosed, NRAS and HRAS mutation tests followed by TERT promoter mutation tests may help diagnose FTCs with metastatic potential. Other genetic mutations could be candidates for a diagnostic or prognostic marker, and large-scale validation studies are warranted.This study was funded by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning (NRF-2019R1A2C2084332).
Presentation: Thursday, June 15, 2023
THU498 Establishing The Link Between Glucocorticoid Signaling And The Circadian Regulator DEC1 In Breast Cancer
Authors: Castro Mikaela I , Ybañez Weand S , Bagamasbad Pia D 
Published: October 2023

Abstract
Disclosure: M.I. Castro: None. W.S. Ybañez: None. P.D. Bagamasbad: None.
Epidemiological studies have linked altered circadian rhythms due to irregular shift work, chronic jet lag, and heightened night-time light exposure to increased breast cancer (BCa) pathogenesis. Dysregulated glucocorticoid (GC; CORT) signaling in BCa may further promote chronodisruption by directly regulating the cyclic expression of clock genes found in the breast. The differentiated embryo-chondrocyte expressed gene 1 (DEC1; also known as STRA13/SHARP2/ BHLHB2) is a transcription factor involved in the regulation of circadian rhythmicity and tumor progression of several cancer types including the breast and associated with hormone receptor signaling in BCa. In this study, we explored the involvement of DEC1 in the crosstalk between GC signaling and the circadian axis in BCa. To establish DEC1 expression pattern in BCa tumor samples, we assessed publicly available RNA-seq datasets from the Genotype-Tissue Expression Project and found no significant difference in DEC1 expression in tumors when compared to normal tissue controls. However, when tumor samples were stratified into molecular subtypes based on transcriptomic data from the Cancer Genome Atlas, DEC1 expression was significantly downregulated in triple-negative BCa (TNBC) in comparison to luminal subtypes. This pattern of expression was reflected in the BCa cell lines where we observed higher DEC1 expression in the estrogen receptor-positive MCF7 cells relative to nontumorigenic triple-negative MCF10A cells and the highly aggressive TNBC MDA-MB-231 cell line. To determine if DEC1 is regulated by GCs in the breast, we treated non-tumorigenic breast epithelial MCF10A cells and the TNBC MDA-MB-231 cells with increasing concentrations of CORT and observed that DEC1 mRNA expression decreases in response to increasing concentrations of CORT. Treatment of MCF10A and MDA-MB-231 cells with GC receptor (GR)- specific agonist RU486 abolished the GC-dependent repression of DEC1 expression and this pattern of DEC1 expression persisted even in the presence of the protein synthesis inhibitor cycloheximide, suggesting that DEC1 is a direct transcriptional target of GR in mammary epithelial cells. Through in silico analysis of publicly available ChIP-sequencing datasets from BCa cell lines, we identified multiple CORT-responsive cis-regulatory elements in the DEC1 locus that could mediate the CORT-dependent repression of DEC1 expression. Lentiviral knockdown of DEC1 in three breast epithelial cell lines was generated and will be used in cancer hallmark assays on proliferation, apoptosis, survival, and migration to assess the functional role of DEC1 in BCa. Taken together, our data will contribute to understanding the combined effect of GC signaling and circadian gene regulation towards BCa progression.
Presentation: Thursday, June 15, 2023
THU515 Vitamin D Binding Protein Induces Skeletal Muscle Atrophy And Contributes To Cancer-associated Muscle Wasting
Authors: Raiteri Tommaso , Reano Simone , Scircoli Andrea , Zaggia Ivan , Prodam Flavia , Filigheddu Nicoletta 
Published: October 2023

Abstract
Disclosure: T. Raiteri: None. S. Reano: None. A. Scircoli: None. I. Zaggia: None. F. Prodam: None. N. Filigheddu: None.
Vitamin D binding protein (VDBP), encoded by the Gc gene, is a multifunctional serum glycoprotein synthesized by hepatocytes, whose primary function is the transport of vitamin D metabolites in the bloodstream. In addition, VDBP enhances the chemotactic activity of neutrophil chemoattractants and takes part in the actin-scavenger system by acting as a monomeric G-actin-binding protein. Several studies have reported a correlation between increased levels of VDBP and various pathologies often associated with muscle wasting, including different types of tumors. Given these findings, we hypothesized that VDBP may play a role in muscle atrophy and cancer-associated muscle wasting and investigated its direct effects on skeletal muscle homeostasis in vitro and in vivo. We showed that, in C2C12 myotubes, VDBP uptake through megalin-mediated endocytosis induced mitochondrial dysfunction and exacerbation of mitophagy that resulted in atrophy. Furthermore, VDBP treatment impaired myoblast differentiation and the formation and stability of acetylcholine receptor (AChR) clusters, an in vitro model of neuromuscular junctions (NMJ). The main molecular mechanism behind the atrophic effect of VDBP is the perturbation of intracellular actin dynamics due to VDBP's ability to bind G-actin. To assess if VDBP has a causative role in muscle homeostasis also in vivo, we experimentally induced the expression of VDBP in Gc knock-out mice (VDBP KO) by adeno-associated virus (AAV)-mediated gene delivery, and we observed that a relatively small amount of circulating VDBP was sufficient to affect muscle performances and reduce muscle mass. Moreover, coherently with the in vitro data, VDBP induced morphological abnormalities in the NMJ. Coherently with the upregulation of VDBP observed in cancer patients, we detected an increase of VDBP in two commonly used models of cancer cachexia, C26 colon carcinoma and Lewis Lung Carcinoma (LLC) tumor-bearing mice. To test the hypothesis that VDBP could play a role in cancer-associated muscle wasting, we induced cancer cachexia in VDBP KO mice by inoculating LLC cells. Tumor-bearing VDBP KO mice preserved their body weight and performances, and the muscle loss and NMJ dismantling were minimal compared to cachectic WT mice. Although the primary function of VDBP is the transport of vitamin D metabolites, we demonstrated that VDBP acts as a hormone per se, having a direct pro-atrophic activity on skeletal muscle. Altogether, our data suggest that VDBP is a new player in the onset of cancer-associated muscle wasting, thus representing a potential therapeutic target to treat cancer cachexia.
Presentation: Thursday, June 15, 2023
THU525 Atypical Presentation Of Parathyroid Carcinoma In The Lungs
Authors: Nicolas Jacinto Jorg Jurgen , Reyes Oscar Paulo , Cating-Cabral Monica , Santiago Rex Michael , Andal Jose Jasper 
Published: October 2023

Abstract
Disclosure: J.N. Jacinto: None. O. Reyes: None. M. Cating-Cabral: None. R. Santiago: None. J. Andal: None.
A 66-year-old female with a history of parathyroid adenoma underwent partial parathyroidectomy and thyroidectomy of the right lobe in 2006. She has the following comorbidities: pre-diabetes, hypertension, multiple liver cysts, medullary nephrocalcinosis and nephrolithiasis, ureterolithiasis and uterine intramural myoma. She also has a strong familial disposition of endocrine tumors. During the last quarter of 2018, parathyroid hormone and calcium levels were elevated and parathyroid imaging revealed an adenoma on the posteromedial aspect of the left thyroid lobe. Removal of the adenoma was offered but insisted on medical treatment. In 2022, she was admitted for subarachnoid hemorrhage due to fall. There was an incidental finding of a lung mass with minimal pleural effusion on the right lung lobe. PET-scan revealed five FDG-avid nodules (SUV up to 9.6) with the largest in the right middle lobe measuring 2 x 2 x 2 cm. Percutaneous needle biopsy was performed which showed a tumor with fairly uniform cells in organoid nests and solid clusters. By immunohistochemistry (IHC), the tumor cells were diffusely and strongly positive for CK and GATA-3; focally positive for chromogranin and synaptophysin; and negative for TTF-1, Pax-8, and S100. This was signed out as an epithelial tumor with neuroendocrine features; the differential diagnosis includes pulmonary neuroendocrine tumor versus metastasis from the prior parathyroid lesion. She subsequently underwent completion thyroidectomy and video-assisted thoracoscopic surgery. The lung wedge resections both showed tumors with similar morphology and IHC staining pattern as the biopsy. Additional stains were also performed to rule out other entities, which were all negative (CK7, CK20, CD56, mammaglobin, GCDFP-15, TTF-1, S100, ER, Pax-8, HSA, and SALL-4). The Ki-67 proliferation index was 17.26%. Because the overall findings were not definitive, comprehensive genomic profiling by next generation sequencing (NGS) was recommended and subsequently performed. NGS showed gene alteration in CDC73, with a variant allele frequency of 50%; this finding has been documented in parathyroid carcinoma. Pre-operative parathyroid hormone levels remained unchanged (408 to 397 pg/ml) despite surgery. Currently, there is no available targeted therapy to address her genomic alteration. Hyperparathyroidism-jaw tumor syndrome was entertained. The multidisciplinary team advised en-bloc resection of the lung tumor and additional gene testing for family members. She opted for palliative care and is on cinacalcet for her hyperparathyroidism.
Presentation: Thursday, June 15, 2023
THU530 What Works For Ferret, Works For Man
Authors: Bhatt Plukshi J , Bendaram Snigdha Reddy , Kantorovich Vitaly 
Published: October 2023

Abstract
Disclosure: P.J. Bhatt: None. S. Bendaram: None. V. Kantorovich: None.
Insulinomas are rare pancreatic neuroendocrine tumors with an incidence of 4 cases per million per year and present with hypoglycemic symptoms due to uncontrolled and excessive insulin secretion by the tumor. Although most commonly benign and treated with surgery, 5-10% are malignant, inoperable and are managed medically with somatostatin analogs, chemotherapy, mTOR inhibitors and diazoxide. A 28 year old male with a history of metastatic insulinoma with progressive disease and refractory hypoglycemia presented with lethargy, diaphoresis, and blood glucose (BG) level of 32mg/dL [65-99].  He was previously admitted for severe hypoglycemia and was treated with FOLFOX, LUTATHERA, Octreotide, TPN, steroids and diazoxide suspension. Sugars were monitored via continuous glucose monitor (CGM) and insulin and C-peptide levels were closely monitored outpatient. Treatment was effective and medications were tapered off so that he no longer needed a CGM and was only on FOLFOX and octreotide prior to presentation. On admission, insulin level was 172 uIU/mL [&lt;17], peaking at 312 uIU/mL and BG dropping to 22mg/dL. He was placed on a dextrose 10% infusion, TPN, diazoxide suspension, and CGM. This admission, however, his insulin levels were much higher requiring higher doses of diazoxide, but he was unable to tolerate the diazoxide solution due to extreme nausea and projectile vomiting, resigning him to a long-term stay in the ICU. Due to a lack of availability of other oral formulations in the US, compounding pharmacies were contacted and pharmaceutical grade diazoxide powder was compounded into 100mg capsules by an outside pharmacy. Dose was adjusted while monitoring BG and insulin levels. Prior to discharge, insulin level was 77.7 uIU/mL and BG levels had normalized. He was sent home on diazoxide 200mg twice a day, TPN, and CGM. FOLFOX was resumed. Outpatient follow up revealed euglycemia and suppressed insulin level of 12.3 uIU/mL [&lt;17], allowing for further tapering of diazoxide dose and discontinuation of TPN. Diazoxide is known to be a safe and effective treatment for hypoglycemia in humans and ferrets alike. It inhibits insulin secretion in pancreatic B cells and increases hepatic glucose production. Side effects of nausea and vomiting can be a barrier to compliance, as seen in our patient. Currently, only oral solutions of diazoxide have been approved for human consumption whereas ferrets, commonly afflicted with insulinomas, are treated with oral pills. Changing the oral formulation to pill form allowed for better compliance, easy dose adjustments using insulin as a marker for response, and symptom resolution due to adequate suppression of insulin levels. Most importantly, it allowed for our patient to transfer out of the ICU and be discharged home with improved quality of life, a feat that was impossible without this change in formulation.
Presentation: Thursday, June 15, 2023
THU541 Impact Of Gender On Treatment Decisions And Outcome In Patients With Neuroendocrine Neoplasms
Authors: Beck Julia , Siebenhüner Alexander , Wild Damian , Christ Emanuel R , Refardt Julie 
Published: October 2023

Abstract
Disclosure: J. Beck: None. A. Siebenhüner: None. D. Wild: None. E.R. Christ: None. J. Refardt: None.
Introduction/Background: Gender differences affect the treatment of several diseases in both male and female patients. However, the influence of gender on treatment decisions and outcome in neuroendocrine neoplasms (NENs) has scarcely been investigated. Aims: Comparison of tumor characteristics, treatment decisions and outcome of patients with NENs, stratified by gender. Material and Methods: Retrospective analysis of the SwissNET cohort involving NENs of gastroenteropancreatic, pulmonal or unknown origin from 07/14 – 09/21. Site of origin, tumor grading, time to first treatment, choice of treatment and overall survival was assessed. Results: 2329 patients were included in the analysis with 54% being male and 46% female patients. No significant difference in site of origin, tumor grading and staging was found between male and female patients. There was also no difference in time of symptoms onset until diagnosis and first treatment intervention. Surgery was performed in 66.3% of male and 71% of the female patients, p=0.016. Meanwhile, male patients received more often PRRT (22% vs 19.3%, p=0.007) and chemotherapy (15.9% vs 12.7%, p=0.032). Despite the similar tumor characteristics, the median overall survival of male patients was significantly lower compared to female patients (Male: 124.8 months, Female: 158.5 months, p&lt;0.001). Interestingly, this difference was most pronounced in patients with lung NENs (Male: 142 months, Female: not reached) and cancer of unknown origin (Male: 18.5 months, Female: 35 months). Conclusions: Male gender seems to be a risk factor for worse outcome, specifically for lung NENs and NENs of unknown origin. The underlying mechanisms of these findings remain to be established.
Presentation: Thursday, June 15, 2023
OR16-02 Histone ADP-Ribosylation Site Mutations As Oncogenic Drivers In Breast And Ovarian Cancers
Authors: Huang Dan , Camacho Cristel V , Nagari Anusha , Lee Kraus W 
Published: October 2023

Abstract
Disclosure: D. Huang: None. C.V. Camacho: None. A. Nagari: None. W.L. Kraus: Other; Self; - Founder and stockholder for Ribon Therapeutics, Inc. - Founder, stockholder, scientific advisory board member, member of the board of directors for ARase Therapeutics, Inc. - Coholder of U.S. Patent.
Recent studies have identified oncohistones, which are encoded by histone genes that harbor missense mutations, as a new class of cancer drivers. We found that many of the oncohistone mutations identified with the highest frequencies in human cancers occur on glutamate (Glu, E) and aspartate (Asp, D) residues, which are potential sites of ADP-ribosylation (ADPRylation). ADPRylation is a post-translational modification, which is catalyzed by the PARP family of ADP-ribosyl transferases and results in the covalent attachment of ADP-ribose on protein substrates. Unlike other well characterized histone modifications, the functions of histone ADPRylation are poorly characterized. Mass spectrometry analyses confirmed that 20 Glu or Asp residues subjected to oncohistone mutation are bona fide sites of ADPRylation by PARP-1. Ectopic expression of each of six different oncohistone mutants from three different core histones (H2B, H3, and H4) altered the proliferation of at least 2 out of 3 cancer cell lines, including MCF-7 and MDA-MB-231 breast cancer cells, as well as OVCAR-3 ovarian cancer cells. We focused on H2B-D51, whose mutation resulted in enhanced cell proliferation in both of the breast cancer cell lines for further characterization of its potential transcription regulatory effects. Proteomic (histone PTMs) and genomic (ATAC-Seq, ChIP-Seq and RNA-Seq) analyses revealed that loss of ADPRylation on H2B-D51 by mutation to alanine (Ala, A) or asparagine (Asn, N) dramatically enhanced p300-mediated acetylation of H2B, altered chromatin accessibility, and changed the pattern of gene expression in MDA-MB-231 cells. To determine the effects of H2B-D51 ADPRylation on cancer cell growth in vivo and their responses to the FDA-approved PARP inhibitor Niraparib, we performed xenograft tumor growth assays in immunocompromised mice using MDA-MB-231 cells ectopically expressing wild-type or D51A mutant histone H2B. Ectopic expression of the H2B-D51A mutant led to a significant increase in tumor growth versus wild-type H2B. Interestingly, these effects were inhibited by treatment with Niraparib, suggesting that the H2B-D51A mutant alone does not confer resistance to PARP inhibitor. Taken together, this study demonstrates that functional sites of Glu/Asp ADPRylation on histones are mutated in cancers, allowing cancer cells to escape the growth-regulating effects of ADPRylation. (This work was supported by grants from the NIH/NIDDK and CPRIT, and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K.)
Presentation: Friday, June 16, 2023