bluuebunny/crossref_metadata_2025_split huggingface dataset:
8581 Unusual Case Of Multifactorial Hyperthyroidism
Authors: Daw Bagar Darin , Meyers Erin , Correia Marcelo 
Published: October 2024

Abstract
Disclosure: D.D. Bagar: None. E. Meyers: None. M. Correia: None.
Background: Nivolumab is an immune checkpoint inhibitor that is used to treat specific types of cancer, including melanoma, by increasing the ability of the immune system to detect cancer through activating cytotoxic T-cells. The side effects of immune checkpoint inhibitors are mainly through the overactivation of the immune system that can affect many organs with autoimmune diseases, including endocrine glands, which could be severe and irreversible, like hypothyroidism or immune thyroiditis. The uniqueness of this case is the presence of multifactorial causes of hyperthyroidism; in addition, it is one of the few cases of immune checkpoint inhibitor induced positive TSI thyroiditis.Clinical Case: An 82-year-old male with a known history of atrial fibrillation on amiodarone presented to his dermatologist with a left forearm lesion. A shave biopsy showed melanoma, and he underwent wide local excision with negative sentinel lymph node biopsy. However, he had significant melanoma in situ present within 5 mm of the margin and was deemed not a candidate for further excision. Tumor board recommended close surveillance. He then received two cycles of pembrolizumab for one year, followed by nivolumab. During his treatment course, he had CT scans with iodinated contrast every 8-12 weeks for the clinical trial. At his clinic visit, routine thyroid function tests were significant for hyperthyroidism with a TSH &lt;0.01 and free T4 of 6.07 (0.8-1.8). He was asymptomatic except for unintentional weight loss. He denied using any biotin supplements. His labs also showed positive thyroid stimulating immunoglobulin (TSI) of 1.10 (&lt;=0.54 IU/L). A thyroid US with doppler showed two nodules less than 1.1 cm and no increased vascularity. Amiodarone was discontinued, and prednisone and methimazole were started. His free T4 has since normalized and both prednisone and methimazole are being tapered down. Conclusion: This case is a multifactorial cause of hyperthyroidism. He had been using amiodarone for atrial fibrillation, had multiple imaging studies with iodinated contrast, and was on immune checkpoint inhibitor therapy with a positive TSI. The uniqueness of this case is not only that combined factors can affect thyroid function but also that he developed a positive TSI, which indicates either Graves’ disease or immune-induced thyroiditis by nivolumab, which has been reported only in a few cases.
Presentation: 6/3/2024
7510 Use Of Tumor Markers And Surgery In The Management Of Medullary Thyroid Cancer During Pregnancy
Authors: Garver Megan , Lisa Vaz Cherie 
Published: October 2024

Abstract
Disclosure: M. Garver: None. C. Vaz: None.
Introduction: Thyroid cancer is the second most diagnosed cancer during pregnancy, predominantly differentiated thyroid malignancies. [1] MTC during pregnancy is rare and challenging to manage due to its aggressive nature. We describe the successful diagnosis and management of MTC during pregnancy. Clinical Case: A 28 yo woman presented with a rapidly growing neck lump for 2 months with an associated unintentional 10lb weight loss and without compressive symptoms. She had no history of childhood radiation exposure or family history of thyroid cancer. Physical exam revealed a hard L lobe thyroid nodule without palpable lymphadenopathy. The patient was 5 weeks pregnant at the time. A neck US revealed a 4.2x2.7x2.0 cm L solid isoechoic thyroid nodule with punctate echogenic foci and microcalcifications. The nodule was classified as TIRADS 4 and ATA high suspicion. FNA noted Bethesda IV with positive IHC stains for chromogranin and calcitonin. Afirma MTC classifier was positive, confirming diagnosis of MTC. At 7 weeks gestation, calcitonin was markedly elevated at 3508 pg/mL (n &lt;5 pg/mL), CEA 29.5 ng/mL (n &lt;2.5 ng/mL) and calcium 10.3mg/dL (8.6-10.2mg/dL). Plasma normetanephrines were elevated to176 pg/mL (n &lt;148 pg/mL) with normal metanephrines 28 pg/mL (n &lt;57 pg/mL) and normal 24-hour urine metanephrines. CT neck revealed 3.2x2.8cm L thyroid nodule without cervical lymphadenopathy. Due to pregnancy status, additional imaging to assess for metastatic disease was deferred until after delivery. Genetic testing did not identify mutations within the thyroid cancer panel including APC, CHEK2, DICER1, MEN1, PRKAR1A, PTEN, RET, SDHB, SDHD, and TP53. The patient underwent total thyroidectomy with neck dissection at 19 weeks gestation without complication. Two weeks postoperative Calcitonin was 2 pg/mL(n &lt;5 pg/mL) and CEA was undetectable. Conclusions: The effect of pregnancy on MTC is not well studied because of low incidence. Guidelines on the timing of surgery for MTC diagnosed during pregnancy are lacking. While evidence confirms that surgery can be safely postponed until after delivery for low risk differentiated thyroid malignancies, there is no consensus on timing of surgery for MTC. Given the aggressive nature of MTC, along with marked elevation of calcitonin and CEA in this case, surgery was performed in the 2nd trimester with excellent outcome. Data is conflicting on accuracy of calcitonin and CEA during pregnancy, with some reports suggesting falsely high levels due to pregnancy. The sharp decline in calcitonin and CEA 2 weeks postoperatively suggested these were truly elevated due to MTC and unaffected by pregnant status. We suggest that calcitonin and CEA be followed similar to non-pregnant cases with MTC. Resources: 1.Khaled, H. M., Lahloubi, N. A., & Rashad, N. (2016). A review on thyroid cancer during pregnancy: Multitasking is required. Journal of Advanced Research, 7(4), 565–570.
Presentation: 6/2/2024
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
8213 A Splicing Modulator Inhibits Proliferation And Steroid Production Of H295R Adrenocortical Cancer Cells
Authors: Tanaka T , Ohe K , Yanase T , Kodama S 
Published: October 2024

Abstract
Disclosure: T. Tanaka: None. K. Ohe: None. T. Yanase: None. S. Kodama: None.
Adrenocortical carcinoma (ACC) is a rare cancer, and treatment options are limited. The anti-tumor drug CX-4945 (Silmitasertib) is an inhibitor of Casein kinase 2 (CK2). It also inhibits cdc2-like kinase 2 (CLK2). CLK2 phosphorylates Serine/arginine rich splicing factors (SRSFs)/SR proteins and enhances exonic splicing enhancer (ESE) recognition during the pre-RNA splicing process. Anti-tumor agents targeting RNA splicing have been developed recently, and CLK inhibitors have shown anti-tumor effects against blood cancers. In this study, we analyzed the impact of CX-4945 on NCI-H295R cells. CX-4945 inhibited cell proliferation of H295R (IC50 = 6.4 µM, 72hr), and cortisol and aldosterone secretion in vitro. siRNA-induced CK2 inhibition did not alter H295R proliferation and steroid secretion. CX-4945 (150 mg/kg/day oral, 28 days) significantly reduced tumor weight in mice inoculated with H295R subcutaneously on the back. High-density microarray analysis showed reduced Nuclear receptor 5A1 (NR5A1) expression levels, indicating a possible splicing variant. RT-PCR, using a primer set that amplified the coding region, detected short variants of NR5A that were multiple exon-skipped and were not induced by suppression of CK2. The results of western blotting using an antibody that recognizes phospho-epitope of SRSFs/SR proteins showed that the phosphorylation of SRSF4 was reduced in H295R treated with CX-4945. These results suggest that CX-4945 inhibits CLK2 and decreases phosphorylated SRSF4 and ESE recognition, resulting in NR5A1 multiple exon-skipping. The prognosis of ACC patients with high NR5A1 expression levels is poor, independent of stage. CX-4945 may induce NR5A1 multiple exon-skipping, reduce full-length functional NR5A1, and suppress ACC growth and steroidogenesis, as a possible adjuvant in tackling this devastating cancer.
Presentation: 6/1/2024
8636 Characterization Of The Role Of Neutrophils In Promoting Progression Of Lymphangioleiomyomatosis
Authors: Henson Thomas R , Minor Briaunna , Hammes Stephen R 
Published: October 2024

Abstract
Disclosure: T.R. Henson: None. B. Minor: None. S.R. Hammes: None.
Lymphangioleiomyomatosis (LAM) is a rare, multisystemic disease that is associated with cystic lung destruction. LAM is caused by small smooth muscle cell-like tumors throughout the lung that contain deleterious mutations in the tuberous sclerosis complex genes TSC1 or TSC2. This attenuates the activity of the mammalian target of rapamycin complex 1 (mTORC1) causing increased proliferation of the smooth muscle cells. LAM is a sexually dimorphic disease that primarily affects genetic females. Clinical observations implicate the role of estrogen in disease progression, as it is exacerbated during pregnancy and by use of exogenous estrogens in birth control. LAM tumor-derived cells lines have shown that direct estrogen stimulation of cell proliferation is modest compared to the dramatic in vivo effects of estradiol (E2) stimulation in a uterine-specific TSC2-null mouse model. Creation of a monoclonal cell line from these mice resulted in the generation of the LTM3 cell line, which also demonstrates low response to direct estrogen stimulation in vitro. This indicates that direct E2 stimulation may act upon other cell types in the tumor microenvironment. Immunophenotyping of uterine-specific TSC2-null mice has shown that the tumor microenvironment is enriched with myeloid cells specifically neutrophils. Functional analysis of neutrophil suppression in vivo has shown a reduction in myometrial growth in the uterine-specific TSC2-null mice, indicating a key role for neutrophil-mediated LAM tumor growth. Altered transcriptional regulation of neutrophils further highlights the importance of neutrophils in LAM progression. Bulk messenger RNA sequencing revealed E2 dependent increase in the neutrophil derived serine protease neutrophil elastase (NE). NE in vitro has been shown to increase migration, invasion, and proliferation of LAM cell lines, while inhibition in vivo has shown a reduction to the myometrial growth. Previously published data by the lab has shown that E2 increases tumor induced expansion of neutrophils in the bone marrow. Isolation and purification of Neutrophils from mouse bone marrow stimulated with tumor conditioned media from the LTM3 cells has shown signs of activation via upregulated gene expression. The focus of the current research has been the characterization of bone marrow derived neutrophils. Currently working with an in vitro system to study the proliferation of LTM3 and the rat leiomyoma (ELT3) cell lines when they are co-cultured with neutrophils. Understanding the mechanism by which neutrophils are activated and interact with LAM cells can give understanding to disease progression may provide insight into future treatment options.
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 mm3) 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
9354 Combination Of Novel Ruthenium-Based Small Molecule Bold-100 And Capecitabine Is Effective In Inhibiting Growth Of Estrogen Receptor Positive Metastatic Breast Cancer
Authors: Scheidemann Erin R , Demas Diane M , Ashai Nadia , Shajahan-Haq Ayesha N 
Published: October 2024

Abstract
Disclosure: E.R. Scheidemann: None. D.M. Demas: None. N. Ashai: None. A.N. Shajahan-Haq: None.
The most common breast cancer subtype in both women and men is estrogen receptor alpha positive (ER+). In the adjuvant setting, ER+ tumors are initially treated with endocrine therapy that includes antiestrogens. Mechanistically, estrogen triggers a mitogenic signaling cascade through the ER, which activates the cyclin D1-cyclin-dependent kinase 4 and 6 (CDK4/6) complex to promote cell growth. ER+ tumors that progress on antiestrogens are subsequently treated with a combination of antiestrogens and CDK4/6 inhibitors (palbociclib, ribociclib or abemaciclib). However, 20% of ER+ tumors never respond to CDK4/6i due to intrinsic resistance and the tumors that initially respond will develop acquired resistance. In the absence of driver mutations, resistant tumors are treated with standard chemotherapies, including capecitabine, which interferes with DNA synthesis. However, treatment with capecitabine show meager success and accompany adverse side effects. BOLD-100 is a ruthenium-based novel small molecule drug that demonstrated antitumor activity as a monotherapy in a phase I clinical trial with a manageable safety profile at the maximum tolerated dose. BOLD-100 has recently been investigated in a multicenter global Phase 1B/2A trial (NCT04421820) of gastrointestinal cancer patients in combination with chemotherapy FOLFOX, which includes fluorouracil, the active form of capecitabine. Previously, we have shown that in breast cancer cells, treatment with BOLD-100 disrupted proteins involved in DNA repair pathway, stimulated reactive oxygen species (ROS) and induced cell death via interrupting autophagy and inducing apoptosis. In this study, we show that combination of BOLD-100 and capecitabine synergistically inhibits growth of breast cancer cells and tumors that are resistant to CDK4/6 inhibitors. Cells treated with combination of capecitabine and BOLD-100 shows increase in apoptosis and DNA damage compared with cells treated with monotherapies or control. Therefore, capecitabine and BOLD-100 is a potential novel combination therapy for breast cancer that has progressed on standard of care treatment.
Presentation: 6/2/2024
5110 Development Of Exosome-Mediated Suicide Gene Therapy For Enhanced Cancer Treatment
Authors: Ku J , Flojo R , Zhang P , Lu B 
Published: October 2024

Abstract
Disclosure: J. Ku: None. R. Flojo: None. P. Zhang: None. B. Lu: None.
Development of Exosome-mediated Suicide Gene Therapy for Enhanced Cancer Treatment Joy Ku#, Renceh Flojo#, Pengyan Zhang, and Biao Lu* Department of Bioengineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA#Authors contributed equally to this work. *Correspondence: blu2@scu.edu 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, CD8[1], 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:[1][1]. (2) Lu et al., Advanced Drug Delivery Reviews. 2022. [1][1]4465. (3) Zhang et al., Signal Trnsductio and Targeted Therapy. 2023. 8:[1]24.
Presentation: 6/2/2024