bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P006: Targeting the zymogen granule protein 16B (ZG16B) to suppress breast cell growth and invasiveness
Authors: Lengyel Máté , Uray Iván P. 
Published: January 2023

Abstract
The induction of tumor suppressing effects by retinoid X receptor-selective agonists in premalignant breast cells may become ineffective in the course of malignant transformation. Therefore, this study aimed to identify pro-tumorigenic factors suppressed in a rexinoid-dependent manner, hypothesizing that such a mechanism may remain active and relevant for cancer interception throughout the various stages of breast cell transformation. To minimize toxicity due to long-term rexinoid treatment in the prevention setting, an additional goal was to identify synergistic growth suppressive combinations of bexarotene (Bex) in normal mammary epithelial cells. The selected combination of Bex and a non-selective beta-adrenergic inhibitor carvedilol (Carv) from an unbiased high throughput screen demonstrated marked cancer preventive activity in a mouse model of Her2-induced ER-negative breast cancer at subtherapeutic doses. To elucidate the molecular underpinnings of this chemopreventive activity, genes selectively suppressed by the drug combination over the individual agents were sought. We determined that the zymogen granule protein 16B (ZG16B), a secreted prognostic marker in breast cancer, was suppressed in normal breast cells by the combination of Bex and Carv. Chromatin immunoprecipitation following Bex+Carv treatment revealed enrichment of the chromatin remodeler protein ARID1A at sites of decreased H3K27 acetylation within the enhancer of the ZG16B gene, resulting in a marked down-regulation of ZG16B. Cell-free supernatant containing overexpressed recombinant ZG16B triggered Erk phosphorylation, increased the proliferation and migration of immortalized HME-hTert cells and induced the expression of extracellular matrix proteins. Furthermore, ZG16B promoted mesenchymal characteristics similar to TGF-b, which was inhibited by an antibody against ZG16B. When administered in tandem, ZG16B neutralized the effects of Bex+Carv. In breast cancer cells, ZG16B stimulated the migration of all tested cell lines, but enhanced proliferation only in ER-positive MCF-7 and T47D cells. Anchorage independent 3D growth of both ER-positive T47D and ER-negative MDA-MB231 cells was stimulated by ZG16B, while Bex+Carv reduced colony formation and suppressed ZG16B levels. Taken together, ZG16B is a potent factor in the growth, mesenchymal transition and invasiveness of breast epithelial cells at all stages of transformation. Our data further suggest that ZG16B may represent a relevant target of the tumor suppressing activity of rexinoids and the combination of Bex+Carv.
Citation Format: Máté Lengyel, Iván P. Uray. Targeting the zymogen granule protein 16B (ZG16B) to suppress breast cell growth and invasiveness. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P006.
Abstract P007: Short-term PI3K inhibition prevents breast cancer in preclinical models
Authors: Ku Amy T. , Young Adelaide , Ibrahim Ahmed A. , Bu Wen , Jiang Weiyu , Lin Meng , Williams Laterrica C. , McCue Bryant , Miles George , Nagi Chandandeep , Behbod Fariba , Li Yi 
Published: January 2023

Abstract
Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of breast precancerous lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.
Citation Format: Amy T. Ku, Adelaide Young, Ahmed A. Ibrahim, Wen Bu, Weiyu Jiang, Meng Lin, Laterrica C. Williams, Bryant McCue, George Miles, Chandandeep Nagi, Fariba Behbod, Yi Li. Short-term PI3K inhibition prevents breast cancer in preclinical models. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P007.
Abstract P016: Endomembranes accumulate unesterified cholesterol in Apc mutant models and humans with CRC as assessed by RNAseq and confocal microscopy
Authors: Munoz-Vega Monica , Erazo-Oliveras Alfredo , Salinas Michael L. , Wang Xiaoli , Goldsby Jennifer S. S , Chapkin Robert S. 
Published: January 2023

Abstract
Background: Increased rates of cholesterol synthesis have been recognized as an important aspect of the metabolism of transformed cells. However, precisely how cholesterol dysmetabolism affects membrane homeostasis is not yet fully understood. Since free cholesterol can be transported from the plasma membrane to other organelles in a dynamic and bidirectional fashion, there is an urgent need to determine to what extent endomembranes are affected by driver oncogene-mediated distortions in cholesterol homeostasis. Aim: Determine if cholesterol is increased in endomembranes, relative to the plasma membrane in Apc mutant cell lines and primary Apc null mouse colonocytes amd CRC samples. Methods: Three mouse epithelial isogenic wild type and mutant Apc colonic cell lines (YAMC (Apc +/+), IMCE (Apc +/-), IMCE βcat (Apc +/- + ΔN89 βcat) were used. In addition, primary colonocytes from Apc wildtype and null mice were examined. mRNA was sequenced using a TruSeq Illumina Stranded mRNA kit. Data analysis was conducted as follows: EdgeR was used to identify differentially expressed genes. Human CRC RNAseq data was obtained from a public reservoir and analyzed. A gene target list (~ 290 genes) related to organelle cholesterol transport was subsequently queried. Membranes from the endoplasmic reticulum (ER), mitochondria and lysosomes were assessed using fluorescent probes: ERTracker, MitoTracker and LysoTracker, respectively. Cells were fixed and stained with Filipin III and imaged using confocal microscopy. Fluorescence colocalization was calculated and statistical analysis was performed using a one-way ANOVA. Results: Apc mutant colonocyte cell lines and Apc null mouse models and human CRC samples exhibited differential expression of cholesterol trafficking genes including Acaa1b, Acaa2, Pcsk9, Stard5. Genes related to mitochondrial cholesterol metabolism, transport, and accumulation, e.g., Tspo, Ppargc1a and Cyp27a, were also found differentially expressed in the three models. Imaging experiments revealed that mitochondrial cholesterol was 17% higher in IMCE and IMCE βcat cell lines. Lysosomal cholesterol was 21% higher in IMCE cells. ER cholesterol levels were unaffected. Conclusions: Our preliminary findings indicate dysregulation of mitochondrial and lysosomal unesterified cholesterol levels in colonocytes expressing mutant APC.
Citation Format: Monica Munoz-Vega, Alfredo Erazo-Oliveras, Michael L. Salinas, Xiaoli Wang, Jennifer S. S Goldsby, Robert S. Chapkin. Endomembranes accumulate unesterified cholesterol in Apc mutant models and humans with CRC as assessed by RNAseq and confocal microscopy. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P016.
Abstract P043: A precision medicine gap: limited recognition of colorectal patients eligible for germline testing in molecular residual disease testing setting
Authors: Schrock-Kelley Suzanne , Souter Vivienne , Hall Michael , Weitzel Jeffrey N. 
Published: January 2023

Abstract
Background: Germline testing for hereditary colorectal cancer (CRC) has traditionally been offered to patients with strong cancer family histories, whose colon tumors revealed mismatch repair deficiency (dMMR), and/or individuals diagnosed with CRC under age 50. Underdiagnosis of hereditary cancer syndromes is often attributed to the complexity or unawareness of family history or phenotypic criteria.1,2 The National Comprehensive Cancer Network (NCCN) guidelines for CRC were recently updated (v. 1.2022) to consider germline multigene panel testing (MGPT) evaluation for all individuals with CRC.3,4 Our goal was to evaluate documentation of MGPT in CRC patients referred for molecular residual disease (MRD) testing. Methods: This retrospective cohort study reviewed clinical data submitted to a commercial laboratory for consecutive CRC patients referred from non-academic medical facilities for MRD testing during a two-month study period. Medical diagnoses, treatment history, family history and germline genetic evaluation status were obtained from the test requisition form and pathology reports. Clinical notes were reviewed in 77/80 cases. Results: Of the 80 patients who met criteria for inclusion, 65/80 (81%) had documented MMR testing of their colorectal tumor. Whereas five had abnormal immunohistochemistry, only two (40%) had documented germline results. 19/80 (24%) met NCCN criteria solely based on a personal CRC diagnosis &lt;50 years, but only 1/19 (5.3%) had documented MGPT. Only 5/80 (6%) of all CRC patients had documented MGPT. Conclusion: Our real-world data from the community oncology precision medicine setting suggests that a majority of CRC patients who received MRD testing and met the prior NCCN criteria for MGPT may not have received evaluation beyond routine MMR status. Process and educational improvements are needed in community health settings to increase access and uptake of germline testing in CRC patients regardless of age at diagnosis or MMR status.
Citation Format: Suzanne Schrock-Kelley, Vivienne Souter, Michael Hall, Jeffrey N. Weitzel. A precision medicine gap: limited recognition of colorectal patients eligible for germline testing in molecular residual disease testing setting. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P043.
Abstract P048: Development of the diagnostic method for pancreatic cancer using novel isolation technology of extracellular vesicles
Authors: Shimizu Yuta , Takahashi Kenji , Asai Fumi , Inuzuka Tatsutoshi 
Published: January 2023

Abstract
Background: Extracellular vesicles (EVs) are secreted by all cells into extracellular fluids and are found in most body fluids, including blood and urine. EVs contain many bioactive molecules, including proteins, RNA, DNA, and phospholipids. EVs have been reported to be associated with various diseases, including cancer metastasis and progression, suggesting that they play an important role in cell-to-cell communication. EVs are a promising modality for liquid biopsy and their clinical applications are desired, but methods for EVs isolation and quantification are still controversial. Traditionally used methods include ultracentrifugation (UC), polymer-based precipitation, and immunoprecipitation (IP) against surface marker antigens, but they are often inadequate in recovery efficiency and purity and are not standardized. In addition, it is very difficult to separate and recover EVs from body fluids that contain many contaminants. Therefore, we developed the original IP method (EViSTEPTM) in which a chelating agent-based reagent combined with in-house antibodies (CD9 and CD63) separate EVs with high purity and high recovery from body fluids such as serum and plasma for clinical applications. In this study, we evaluated whether EViSTEPTM in combination with expression levels of a newly identified long non-coding RNA (lncRNA), LOC100507412 (HEVEPA), could be used for stratification of pancreatic ductal adenocarcinoma (PDAC). Methods: EVs were isolated from serum of PDAC (22 cases), intraductal papillary mucinous neoplasm (IPMN) (23 cases), and healthy controls (HC) (21 cases) using EViSTEPTM, and HEVEPA expression analysis was performed by digital droplet PCR. Results: In the analysis of HC, IPMN, and PDAC samples, HEVEPA was significantly more highly expressed in PDAC compared to HC and IPMN. In ROC analysis between PDAC versus non-PDAC (IMPN and HC), the AUC of HEVEPA (0.80) was comparable to other tumor makers such as CEA (0.48) and CA19-9 (0.89). Furthermore, the AUC improved to 0.99 when HEVEPA was combined with CA19-9 but was not significantly different from that of CA19-9 alone. Conclusion: EViSTEPTM enables us to analyze HEVEPA in EVs, and the combination of HEVEPA and CA19-9 is expected to improve the diagnostic performance of PDAC. The combination of the EViSTEPTM method of EVs isolation and HEVEPA expression levels was suggested to be useful for the stratification of PDAC.
Citation Format: Yuta Shimizu, Kenji Takahashi, Fumi Asai, Tatsutoshi Inuzuka. Development of the diagnostic method for pancreatic cancer using novel isolation technology of extracellular vesicles. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P048.
Abstract P052: Carbidopa, an activator of aryl hydrocarbon receptor, suppresses IDO1 expression in pancreatic cancer and decreases tumor growth
Authors: Korac Ksenija , Bhutia Yangzom D , Rajasekaran Devaraja 
Published: January 2023

Abstract
IDO1 is an immunomodulatory enzyme responsible for tryptophan catabolism. Its expression in immune cells, especially the DCs, has attracted attention because it leads to tryptophan depletion at the immunological synapse, thereby causing T-cell anergy and immune evasion by the tumor cells. Cancer cells also overexpress IDO1. Immunotherapy targeting IDO1 has been one of the focus areas in cancer biology, but lately studies have identified non-immune related functions of IDO1 leading to a paradigm shift about IDO1 function in the context of tumor cells. In this study, we show that PDAC tissues and PDAC cells overexpress IDO1. The expression level is reciprocally related to overall patient survival. We further show that carbidopa, an FDA-approved drug for Parkinson’s disease as well as an AhR agonist, inhibits IDO1 expression in PDAC cells. Using athymic nude mice, we demonstrate that carbidopa-mediated suppression of IDO1 expression attenuates tumor growth. Mechanistically, we show that AhR is responsible for carbidopa-mediated suppression of IDO1, directly as a transcription factor and indirectly by interfering with the JAK/STAT pathway. Overall, targeting IDO1 not only in immune cells but also in cancer cells could be a beneficial therapeutic strategy for PDAC and potentially for other cancers as well and that carbidopa could be repurposed to treat cancers that overexpress IDO1.
Citation Format: Ksenija Korac, Yangzom D Bhutia, Devaraja Rajasekaran. Carbidopa, an activator of aryl hydrocarbon receptor, suppresses IDO1 expression in pancreatic cancer and decreases tumor growth. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P052.
Abstract P059: A case of stage I esophageal adenocarcinoma diagnosed using a multi-cancer early detection test
Authors: Jr David DeAtkine 
Published: January 2023

Abstract
Introduction: There is no guideline-recommended screening test for esophageal cancer, a cancer that occurs in approximately 1 in 125 men and 1 in 417 women in the US. Risk factors for esophageal adenocarcinoma include gastroesophageal reflux disease, Barrett’s esophagus, obesity, and smoking. A multi-cancer early detection (MCED) test that analyzes methylation patterns of cell-free DNA in the blood using sequencing assays and machine-learning classifiers is available as a complement to existing single-cancer screening tests. The MCED test reports either (1) ‘cancer signal detected’ with 1 or 2 cancer signal origin (CSO) prediction(s) or (2) ‘cancer signal not detected’. A case of esophageal adenocarcinoma is presented here to demonstrate early detection using the MCED test and to review the diagnostic journey following a cancer signal detected (positive) test result. Case Description/Methods: An asymptomatic 63-year-old White male (BMI: 27 kg/m2) with history of peptic ulcer disease was screened using the MCED test. He reported moderate alcohol use (6/week) and no tobacco use. His last colonoscopy was 5 years prior to using the test. Nine days after a blood sample was collected for analysis by the MCED test, a positive test result (CSO prediction=Stomach/Esophagus) was reported and communicated to the patient (Day 1). Computed tomography (CT) of the chest, abdomen, and pelvis with contrast showed no significant findings (Day 13). A submucosal bulge just below the gastroesophageal junction (GEJ) was noted on upper endoscopy. The lesion, and area above the GEJ were extensively biopsied (Day 15). Pathologic evaluation confirmed diagnosis of Clinical Stage I esophageal adenocarcinoma with superficial focally invasive adenocarcinoma arising in a background of intestinal metaplasia with high grade dysplasia (Day 29). The patient underwent total gastrectomy without complications (Day 104). He will undergo appropriate follow-up 6 months post-op. Discussion: The MCED test detected a cancer signal and predicted a gastrointestinal CSO for an asymptomatic individual with Clinical Stage I esophageal cancer. Diagnostic resolution was achieved within 1 month and treatment was provided with curative intent. Given that there is no guideline-recommended screening test available for esophageal cancer, the use of this MCED test detected cancer early, directed diagnostic workup, and potentially improved outcomes for this asymptomatic patient.
Citation Format: David DeAtkine Jr. A case of stage I esophageal adenocarcinoma diagnosed using a multi-cancer early detection test. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P059.
Abstract P067: Evaluating the risk of clinically significant prostate cancer in lesions detected on multiparametric MRI of the prostate
Authors: Molokwu Chidi N. , Gkikas Christos , Lee Nicola , Lesniak-Buzon Joanna , Ali Faisal , Bardgett Harry 
Published: January 2023

Abstract
Introduction: Multiparametric Magnetic Resonance Imaging (mpMRI) is a valuable tool in the prostate cancer diagnostic pathway. mpMRI has a negative predictive value (NPV) of approximately 90% for detecting clinically significant prostate cancer (csPCa), defined as the presence of any Gleason Grade (GG) 4 or 5. Lesions detected on mpMRI are scored using the PIRADS scoring system from 1 to 5. PIRADS-3, 4 and 5 lesions are recommended for biopsy. The use of mpMRI to guide prostate biopsy has been shown to be superior to systematic biopsy alone for detecting early csPCa as small lesions can be identified and accurately targeted. We analysed the outcome of targeted biopsy of prostate lesions detected on mpMRI, and systematic biopsy when no lesions were detected, to determine the risk of csPCa based on mpMRI findings. Methods: Men attending our prostate diagnostic pathway were offered mpMRI before biopsy. The criteria for pre-biopsy mpMRI were any man suitable for radical surgery or radiotherapy, plus one or more of PSA &gt; 3, palpable lesion on digital rectal examination, or family history of PCa in a first degree relative (father or brother). mpMRI was performed with a 1.5-Tesla magnet and included T2, DWI and DCE sequences. Men with PIRADS 3, 4, and 5 lesions were offered targeted biopsy with 2-4 biopsy cores per lesion, and men with no lesion on MRI were offered systematic prostate biopsy with 8-16 biopsy cores. Results: 546 targeted lesions were biopsied in 349 men. 159 lesions were PIRADS-3, 226 were PIRADS-4, and 161 were PIRADS-5. 141 men with negative mpMRI had systematic prostate biopsy. Of the PIRADS-3 lesions, 84% were benign, 5% had GG 3, 11% had GG 4 and none had GG 5. Of the PIRADS-4 lesions, 44% were benign, 12% had GG 3, 42% had GG 4, and 2% had GG 5. Of the PIRADS-5 lesions, 23% were benign, 2% had GG 3, 62% had GG 4, and 13% had GG 5. Of the men with no lesion on mpMRI, 9% had GG 3, 4% had GG 4, and none had GG 5. Conclusion: Most men with negative mpMRI or PIRADS-3 lesions have benign tissue on biopsy or early PCa and are unlikely to have csPCa. A decision for biopsy vs PSA monitoring in these men should weigh the risks and benefits of biopsy and should be a shared decision taking into consideration individual risk factors for PCa, age and co-morbidities.
Citation Format: Chidi N. Molokwu, Christos Gkikas, Nicola Lee, Joanna Lesniak-Buzon, Faisal Ali, Harry Bardgett. Evaluating the risk of clinically significant prostate cancer in lesions detected on multiparametric MRI of the prostate. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P067.