bluuebunny/crossref_metadata_2025_split huggingface dataset:
8127 HOMA-IR Predicts Muscle Wasting during Androgen Deprivation Therapy
Authors: Caeiro Lucas , Jayne Anderson Lindsey , Liu Haiming , Manuel Garcia Jose 
Published: October 2024

Abstract
Disclosure: L. Caeiro: None. L.J. Anderson: None. H. Liu: None. J.M. Garcia: None.
Androgen deprivation therapy (ADT) is the primary treatment for advanced and metastatic prostate cancer. However, it induces adverse effects like reduced muscle mass and function, increased adiposity, and insulin resistance (IR). While muscle wasting is a known complication of ADT-induced hypogonadism, the extent to which other factors determine the variability in muscle loss remains unknown. In other diseases, IR is associated with muscle wasting, but its role in this setting of ADT has yet to be addressed. We hypothesized that patients with greater IR pre-ADT would display larger decreases of muscle mass and function after six months of ADT. Insulin and glucose (to calculate HOMA-IR), body composition, and physical function were assessed in patients with prostate cancer prior to and after three and six months of ADT. Body composition was assessed by dual x-ray absorptiometry and physical function by VO2 peak and 6-minute walk test (6MWT). Fasting blood samples were obtained to measure insulin and glucose in plasma. Pre-ADT, HOMA-IR was directly correlated with body mass index (BMI) (r=0.65, p&lt;0.001, n=49), fat mass (r=0.55, p&lt;0.001, n=49), and appendicular skeletal muscle index (ASMI) (r=0.33, p=0.021, n=49) and was inversely correlated with VO2 peak (r= -0.39, p=0.007, n=46). After three months, fat mass (p=0.015) and IR (p=0.0014) increased and VO2 peak decreased (p=0.0007), which persisted at the six-month visit. Appendicular lean mass and ASMI decreased after six months (p&lt;0.0001). Pre HOMA-IR was negatively associated with delta BMI (r=-0.49, p&lt;0.001, n=46), delta lean mass (r=-0.58, p&lt;0.001, n=46), delta ASMI (r=-0.52, p&lt;0.001, n=46), and delta 6MWT (r=-0.37, p=0.011, n=45) and positively correlated with delta VO2 peak (r=0.44, p=0.007, n=36). No associations were found with Pre-ADT HOMA-IR and changes in fat mass. In conclusion, those with greater Pre-ADT HOMA-IR lost more muscle mass, body weight, and 6MWT while unexpectedly showing less decrease in VO2 peak. This data suggests that HOMA-IR could potentially serve as a predictor of muscle mass loss in patients undergoing ADT. We propose that the significant decrease in muscle mass seen with ADT can be exacerbated by pre-existing IR.
Presentation: 6/3/2024
8212 Insulin Receptor Signaling and Racial Disparities in Triple Negative Breast Cancer
Authors: Engel A J , Samuel K , Bass I R , Lin S , Antoniou I , Yagnik R , LeRoith D , Bickell N A , Gallagher E J 
Published: October 2024

Abstract
Disclosure: A.J. Engel: None. K. Samuel: None. I.R. Bass: None. S. Lin: None. I. Antoniou: None. R. Yagnik: None. D. LeRoith: None. N.A. Bickell: None. E.J. Gallagher: Consulting Fee; Self; Novartis Pharmaceuticals.
Introduction: Obesity and type 2 diabetes are associated with poor breast cancer (BC) prognosis. These disorders, along with hyperinsulinemia are more common in Black than in White women. Black women also have higher rates of triple negative breast cancer (TNBC), and greater breast cancer mortality than White women. We hypothesized that Black women with TNBC have worse outcomes in part due to tumor promoting effects of hyperinsulinemia via the insulin receptor (IR) signaling pathway. Methods: From our IRB-approved, multi-institutional, cross-sectional, NIH-funded, study of women with newly diagnosed BC, we identified women with TNBC. We performed immunohistochemistry (IHC) analysis of formalin-fixed-paraffin-embedded tumor samples from 45 self-identified Black women and 48 self-identified White women. We quantified the BC expression of IR (n=92), IGF1R (n=92), pERK (n=91), FOXO3a (n=90) for intensity (none=0, weak=1, moderate=2, intense=3). In subsequent analysis, 0 and 1 intensity IHC staining were considered negative, and 2 and 3 were considered positive. Quantification was performed with reviewers blinded to clinical information. Clinical information (age, race, body mass index [BMI], waist circumference, fasting insulin, BC Nottingham Prognostic Index [NPI]) was evaluated after IHC scoring. Statistical proportions were compared using Fishers Exact test, and continuous variables were evaluated using parametric or non-parametric tests, as appropriate. Results: Positive IR staining was seen in 64% of samples (n=59), 74% (n=68) for IGF1R, 68% (n=62) for FOXO3a and 43.3% (n=39) for pERK. Positive IR staining was more prevalent in Black women than White women (P=0.003) but was not significantly associated with age or NPI. IGF1R, FOXO3a, pERK positive staining were not associated with race or NPI. Positive IR staining was also associated with higher BMI, waist circumference, and fasting insulin (P&lt;0.05 for all). Positive IGF1R, FOXO3a, pERK staining were not associated with any of these factors. Conclusions: We found that 64% of TNBCs had positive expression of IR, and IR expression was more prevalent in tumors from Black women and associated with higher insulin levels, suggesting that tumors from Black women may be more sensitive to the tumor promoting effects of systemic hyperinsulinemia.
Presentation: 6/2/2024
7948 Integration of Epigenomics and Metabolomics Reveals New Signaling in Aggressive Thyroid Cancer
Authors: Sanghi A , Wu S , Chou T , Orloff L A , Kasowski M , Snyder M 
Published: October 2024

Abstract
Disclosure: A. Sanghi: None. S. Wu: None. T. Chou: None. L.A. Orloff: None. M. Kasowski: None. M. Snyder: None.
Although genetic mutations are causal in human cancers, the contribution of chromatin changes to cancer onset and progression remains less well understood. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in cancer signaling. We applied multi-omics profiling of 36 human thyroid cancer primary tumors, metastases, and patient-matched normal tissue. Over 80% of the tumors harbored BRAFV600E mutations, and the remaining tumors mostly had activating mutations in the MAPK pathway. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify local enhancers that are highly correlated with coordinated RNA and protein expression. The enhancers are predicted to be actively bound by MAPK transcription factor, indicating they are under MAPK control. These cancer-specific enhancers associated with upregulation of lysosomal peptidase expression and dipeptide abundance in tumors. We show that upregulated dipeptides stimulate MAPK activity, and BRAF inhibition results in loss of lysosomal function in mutants. Perturbation of lysosomal peptidases and dipeptide abundance decreases MAPK activity only in mutant cells compared to wildtype. These analyses suggest that BRAF thyroid tumors integrate MAPK-driven epigenetic regulation with lysosomal metabolite signaling in a positive feedback circuit. Using local cancer-specific epigenetic features, we isolated key cancer signaling, making way for potential targets for cancer therapeutics.
Presentation: 6/3/2024
7873 Integration of Glucocorticoid and Mineralocorticoid Receptor Signaling in Triple-negative Breast Cancer Models
Authors: Posani S , Lange C A 
Published: October 2024

Abstract
Disclosure: S. Posani: None. C.A. Lange: None.
Glucocorticoid receptors (GR) sense a convergence of host and cellular stress signaling to orchestrate an array of advanced cancer phenotypes associated with triple-negative breast cancer (TNBC) progression. The Lange lab reported p38 MAP kinase mediated phosphorylation of GR at serine 134 (Ser134) in response to tumor microenvironment-derived cytokines, such as TGF-beta-1. Phospho-Ser134-GR (p-Ser134-GR) upregulated gene sets that promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC models. In addition to acting as ligands for GR, glucocorticoids also bind to and activate another closely related steroid hormone receptor - the mineralocorticoid receptor (MR). The elucidation of functional responses upon activation of MR remains an untapped area in breast cancer research. Our probe into public datasets (METABRIC, and TCGA) demonstrated significantly higher expression of MR transcripts in TNBC relative to luminal breast cancer. High expression of MR predicted worse overall survival in ERα-negative breast cancer patients compared to the low expressing cohort. Silencing of MR was carried out by siRNA-mediated knockdown and treatment with spironolactone, a competitive MR antagonist. Interestingly, MR knockdown significantly reduced the TGF-beta-1 induced migratory capacity of breast cancer cells compared to the wild-type control cells expressing endogenous MR. This biological phenotype of decreased TGF-beta-1 induced migration upon MR knockdown parallels the reduced migration we observed when the p38 MAPK site (Ser134 on GR was mutated to Ala in TNBC models. We therefore hypothesized that MR and GR may cooperate under the influence stress signaling in response to growth factors and cytokines abundantly present in the tumor-microenvironment. Preliminary data suggest that cytoplasmic p-Ser134-GR/MR complexes associate upon TGF-beta-1 treatment, while GR and/or MR ligands stimulate the formation of nuclear GR/MR complexes. We are further investigating cytokine- and stress-signal mediated regulation of GR/MR complexes and their functional role in TNBC biology. The overarching goal of this study is to elucidate if MR is a required GR binding-partner and a potential therapeutic target in GR- and cytokine-driven metastatic TNBC processes.
Presentation: 6/2/2024
9316 Modulation Of Intracellular Lipid Access By ATGL Determines Ferroptosis Sensitivity In Castration-resistant Prostate Cancer
Authors: Cao P , Awad D , Han J , Frigo D E 
Published: October 2024

Abstract
Disclosure: P. Cao: None. D. Awad: None. J. Han: None. D.E. Frigo: Grant Recipient; Self; GTx, Inc.. Other; Self; Familial relationship with Biocity Biopharmaceuticals, Hummingbird Bioscience, Bellicum Pharmaceuticals, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals and Barricade Therapeutics.
Ferroptosis induction has recently been recognized as a novel therapeutic approach to alter the outcomes of drug-resistant cancer. Ferroptosis is cell death that is caused by the intracellular accumulation of toxic lipid hydroperoxides. Due to their elevated metabolism, castration-resistant prostate cancer (CRPCs) are highly prone to ferroptosis; yet, many of them manage to avert this cellular fate. We have identified a key enzyme involved in lipid metabolism, adipose triglyceride lipase (ATGL), that engenders CRPCs with the ability to resist ferroptosis. Our data has shown that ATGL deletion by CRISPR-Cas9 knockout method sensitized human CRPC cell lines such as C4-2, C4-2BLT, and PC3 cells to the ferroptosis inducer RSL3. In all cases, RSL3-mediated cell death could be blocked by the antioxidant Ferrostatin-1, confirming ferroptosis as the mechanism of cell death. Knocking out ATGL also augmented the ferroptosis inducer-mediated increase in lipid peroxides as indicated by the increased ratio of oxidized to non-oxidized C11-BODIPY 581/591. With regards to the mechanism for the sensitivity of ATGL KO to ferroptosis induction, previous research has established that the enzyme long-chain acyl-CoA synthetase 4 (ACSL4) is universally essential to facilitate ferroptosis. More specifically, ATGL(PNPLA2) was found to inversely correlate with ACSL4 in the Taylor et al., the TCGA PanCancer Atlas, and Metastatic Prostate Adenocarcinoma (SU2C/PCF Dream Team) datasets in both primary and metastatic tumors. qPCR and western blot analysis of ACSL4 levels further showed that ACSL4 expression is closely tied to the lipase activity of ATGL. Addition of arachidonic acid significantly induced ferroptosis when combined with RSL3 in a dose-dependent manner only in ATGL KO cells. This indicates that PUFAs can render ATGL KO cells even more sensitive to RSL3-induced ferroptosis while cells with functional ATGL remain highly resistant, further reinforcing that ATGL is an essential safeguard of CRPC against ferroptosis. ATGL KO cells also demonstrated sensitivity to the antiandrogen Enzalutamide. The combination of Enzalutamide and RSL3 substantially decreased cell viability in ATGL KO cells as compared to control cells, indicating a strong synergy effect particularly seen in ATGL KO cells. In summary, this work demonstrates that ATGL is an important and novel regulator of ferroptosis in CRPC and supports the use of ferroptosis inducer as a new therapeutic approach in CRPC.
Presentation: 6/2/2024
7906 Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough in Targeting CYP17A1 for Castration Resistant Prostate Cancer Therapy
Authors: Yakubu Jibira 
Published: October 2024

Abstract
Disclosure: J. Yakubu: None.
Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough in Targeting CYP17A1 for Castration Resistant Prostate Cancer Therapy. Jibira Yakubu a,b,c, Oya Taritd, Evangelos Natsaridisd, Amit V. Pandey a,ba Translational Hormone Research Program, Department of Biomedical Research, Faculty of Medicine, b Paediatric Endocrinology, Diabetology and Metabolism, University Children’s Hospital, Inselspital, Bern, c Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. d Biointerfaces, Institute of Chemistry and Bioanalytics, University of Life Sciences FHNW, Muttenz, Switzerland. Abstract: Androgens play a pivotal role in prostate cell survival and are implicated in both early-stage and advanced, castration-resistant prostate cancer (CRPC). In CRPC patients on CYP17A1 inhibitors, the development of drug resistance and hypertensive crisis through the inhibition of CYP21A2 and or its substrate are a recognized challenge. Given its crucial role in androgen production, CYP17A1 has become a major target for cancer therapies. In this study, we employed a mini-evaporation technique to nanoencapsulate curcumin, exploring its impact on CYP17A1 activity in human adrenal NCI-H295R cells. We performed steroid profiling with LC-MS, as well as gene and protein expression studies. Initial results demonstrated that curcumin nanoparticles exhibited superior efficacy in reducing CYP17A1 activity compared to known drug Abiraterone acetate. Curcumin and piperine combined in nano-capsules greatly increased the inhibitory effects on CYP17A1 activity. Furthermore, ongoing studies include western blot investigation of the drug's interaction with the CYP17A1 protein and cell cycle effects. We confirmed the efficacy of our nano formulation by testing its impact on the growth of androgen-sensitive prostate cancer cell lines. Notably, nanoencapsulation improved curcumin's inhibitory effects on DHEA production via CYP17A1. Surprisingly, the curcumin-piperine nano-capsules enhanced these effects while having no effect on CYP21A2, offering a promising option for prostate cancer treatment. Our study reveals the promise of nanoencapsulated curcumin-piperine as a game-changing method for targeting CYP17A1 for improved prostate cancer therapy. The synergistic benefits observed in our study open new avenues for addressing the difficulties associated with androgen deprivation therapy. Funding: Cancer Research Switzerland grant number: KFS 5557-02-2022
Presentation: 6/3/2024
8393 Low Polygenic Risk Score For Autoimmune Addison’s Disease Identifies Misdiagnosed Cases of Monogenic Primary Adrenal Insufficiency
Authors: Aranda Guillen Maribel , Botusan Ileana , Fernando Venuja , Christine Røyrvik Ellen , Bøe Wolff Anette Susanne , Johansson Stefan , Sverre Husebye Eystein , Bensing Sophie , Kampe Olle , Eriksson Daniel 
Published: October 2024

Abstract
Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None.
Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling.
Presentation: 6/2/2024
6477 Surprise Finding for a Thyroid Nodule: Metastatic Renal Cell Carcinoma
Authors: Xu Adele , Hsu Emory 
Published: October 2024

Abstract
Disclosure: A. Xu: None. E. Hsu: None.
Introduction: A patient with an incidental and asymptomatic thyroid nodule underwent fine needle aspiration biopsy (FNA) after the nodule increased in size. Without a definite pathology after three FNA attempts, thyroidectomy was performed, where pathology found metastatic renal cell carcinoma (RCC). Clinical Case: A 64 year old woman had a past medical history of obesity, type 2 diabetes, RCC (stage I: pT1bN0M0) treated with right radical nephrectomy five years prior and thought to be in remission, remote smoking history smoking, and coronary artery disease with coronary artery bypass graft (CABG) two months prior, on anticoagulation. The patient reported a distant history of right thyroid lobectomy over a decade prior for unclear reasons, but she was adamant that the pathology was benign. Two years prior to presentation, CT chest done for RCC surveillance had detected a left thyroid nodule. Ultrasound at the time revealed a 3.6 x 1.9 x 2.3 cm solid, isoechoic nodule in the upper left lobe, which was not taller than wide, and had smooth margins and no echogenic foci. A repeat ultrasound at the time of presentation showed interval growth of the nodule, now measuring 4.3 x 2.1 x 2.9 cm. FNA was unsatisfactory, yielding predominantly blood. Patient felt well and had no compressive neck symptoms. We opted to wait two months and repeat FNA, which resulted as atypia of undetermined significance - Bethesda category III (AUS). We recommended completion thyroidectomy, but patient preferred to avoid surgery. We decided to wait two months and repeat FNA with molecular testing. This third FNA resulted AUS again; however, due to non-medical reasons, molecular testing was not performed. Another ultrasound showed slight growth of the nodule, 5.1 x 2.9 x 2.0 cm, which appeared hypoechoic now, but was still not taller than wide, with smooth margins and no echogenic foci. Completion thyroidectomy was performed, with pathology showing metastatic clear cell renal cell carcinoma. Immunostains were positive for carbonic anhydrase and renal cell carcinoma marker and negative for TTF-1. Whole-body PET-CT showed no hypermetabolic foci, and a repeat PET-CT one year later still showed no evidence of metastatic disease. Other than a hospitalization for COVID-19, patient is doing well and asymptomatic now over a year after her thyroidectomy. Oncology will continue routine surveillance imaging for her metastatic renal cell carcinoma thought to be in remission. Clinical Lessons: This case of metastatic renal cell carcinoma to the thyroid adds to the small body of literature showing the thyroid as a possible site of RCC metastasis. The long time interval between initial RCC presentation and metastasis to the thyroid makes this diagnosis more difficult; however, clinicians should be aware of the possibility, making thyroidectomy a stronger option in cases where FNA cytology is indeterminate.
Presentation: 6/2/2024
8414 Utilization of Cell Free DNA Integrity Index to Differentiate Benign from Malignant Thyroid Nodules
Authors: Tarafdar S , Dutta S , Mukhopadhyay P , Bhattacharya N P , Ghosh S 
Published: October 2024

Abstract
Disclosure: S. Tarafdar: None. S. Dutta: None. P. Mukhopadhyay: None. N.P. Bhattacharya: None. S. Ghosh: None.
Introduction: Recent advances in molecular genetics have evaluated a potential role for plasma cell-free DNA (cfDNA) integrity index as a non-invasive cancer marker. Data on cfDNA integrity in differentiated thyroid cancer is sparse and needs to be investigated further. Aim of the study: The purpose of this study is to investigate the hypothesis that longer DNA strands in plasma may serve as a marker for thyroid cancer. Methods: Patients presenting with thyroid nodules underwent ultrasonography with Thyroid Image Reporting and Data Systems (TIRADS) scoring and FNAC (Bethesda classification).Patients with Bethesda 3, 4, 5, and 6 had surgery and confirmation by histopathology. Patients with Bethesda 2 presenting with compressive symptoms and cosmetic concerns underwent surgery; the remaining patients were considered benign based on clinical follow-up, USG, and FNAC characteristics. Blood sample collected prior to FNAC was used to extract and quantify cfDNA. To assess the integrity index 180/67, 306/67, and 476/67 for the APP gene, we used a quantitative real-time PCR (qPCR) method based on the quantification of four amplicons of varying lengths (67, 180, 306, and 476 bp, respectively). Because culture cells had extremely intact genomic DNA, the genomic DNA obtained from the MDA-T32 papillary thyroid cancer cell line was utilised as a reference to estimate the relative DNA strand integrity in plasma DNA. To determine the (ΔCt) value for 67,180, 306, and 476 bp, the Ct value of the sample was subtracted from that of the MDA-T32 control. Results: A total of 161 subjects were recruited, of these 92 were benign and 69 had differentiated thyroid cancer(confirmed by histopathology). Using the 180/67 bp integrity index benign thyroid nodule patients had significant lower value (median 0.39, 95% CI: 0.33-0.46) compared to patients with differentiated thyroid cancer (median 0.62, 95% CI: 0.56-0.68). A cfDNA integrity index of 180/67 bp could significantly differentiate between benign and malignant thyroid nodules (P&lt;0.001). However, there was no significant difference between malignant and benign thyroid nodules based on the cell free DNA integrity indexes of 306/67 and 476/67. Conclusions: The cfDNA integrity score of 180/67 exhibits potential as a circulating marker for the detection of thyroid nodules and as a means of monitoring cfDNA fragmentation in patients with thyroid cancer. However, further confirmation through prospective trials is necessary.
Presentation: 6/3/2024