bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3464: Vitamin D supplementation to improve doxorubicin-induced cardiotoxicity in triple negative breast cancers
Authors: Lee Kevin J. , Wright Griffin , Wiggins Leigh Ann , Schuler Michele , Gassman Natalie R. 
Published: September 2020

Abstract
Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), which lacks the molecular targets for hormone or growth factor therapy. Although highly effective as a chemotherapeutic agent, Dox induces severe side effects including cardiotoxicity that can cause patients to stop treatment early and impact the long-term health of patients in remission. Reactive oxygen species (ROS) are the predominant contributing factor to Dox-induced cardiotoxicity. Here, we sought to use the antioxidant vitamin D to provide a cardioprotective environment to prevent or reduce cardiotoxicity in a mouse model of TNBC. Supplementation with vitamin D (10,000 IU/kg) in chow for two weeks significantly increased the active vitamin D metabolite (25(OH)VD3) in plasma from 61.2 ± 4.5 nM (Mean ± SEM) to 85.0 ± 6.3 nM (P &lt; 0.05). Supplemented and normal chow mice were then inoculated with the syngeneic 4T1 mouse model of TNBC, and subjected to 10 mg/kg Dox once per week for two weeks. Cardiotoxicity was monitored through non-invasive echocardiography weekly. After two weeks, mice on standard chow with moderate levels of vitamin D exposed to 10 mg/kg Dox showed clear signs of cardiotoxicity represented by a decrease in cardiac output from 9.7 ± 0.5 mL/min in control mice to 4.8 ± 0.9 mL/min in mice treated with Dox (P &lt; 0.001); a decrease in ejection fraction from 49.2% ± 1.9 in control mice to 35.7% ± 5.9 in Dox mice (P &lt; 0.05); and a decrease in fractional shortening from 24.4% ± 1.2 in control mice to 16.9% ± 3.1 in Dox mice (P &lt; 0.05). Mice treated with Dox also showed detectable levels of cardiac troponin (0.04 ± 0.01 ng/mL) in circulating plasma indicative of cardiac damage, while troponin levels in control mice were undetectable. Vitamin D supplementation during exposure to Dox prevented cardiotoxicity in all parameters tested with levels of cardiac output of 7.4 ± 0.9 mL/min compared to 4.8 ± 0.9 mL/min in Dox mice; ejection fraction of 55.3% ± 3.4 compared to 35.7% ± 5.9 in Dox mice (P &lt; 0.01); and fractional shortening of 28.1% ± 2.1 compared to 16.9% ± 3.1 in Dox mice (P &lt; 0.01). Cardiac troponin levels were also undetectable similar to control mice. Vitamin D supplementation during Dox exposure resulted in cardiac function not significantly different than control, untreated mice. These data support further examination of vitamin D supplementation during chemotherapy to prevent cardiac toxicity and to enhance long-term outcome of TNBC patients.
Citation Format: Kevin J. Lee, Griffin Wright, Leigh Ann Wiggins, Michele Schuler, Natalie R. Gassman. Vitamin D supplementation to improve doxorubicin-induced cardiotoxicity in triple negative breast cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3464.
Abstract 3510: The metabolomic profile of urine from prostate cancer patients using capillary electrophoresis mass spectrometry (CEMS)
Authors: Buko Alexander , Cheng Leo , Gustev Andrew , Feldman Adam 
Published: September 2020

Abstract
Background: Prostate cancer (PCa) pathogenesis is influenced by alterations in cellular metabolism. Metabolomics measures these biochemical changes to create global tissue metabolite profiles. Urinary studies are noninvasive and can potentially identify biomarkers for PCa.
Objective: We used Capillary Electrophoresis Mass Spectrometry (CE-MS) to analyze urine from men undergoing prostate biopsy to investigate their metabolomic profiles.
Methods: We retrospectively analyzed 40 urine samples (20 from bx demonstrating PCa, 20 from benign) that were prospectively collected from men undergoing prostate biopsy. Analysis of charged metabolites done with Agilent CE-MS system (J Proteome Res. 2:488; 2003). Screening of potential biomarkers was performed with statistical protocols and pathway analyses. Metabolites with levels below the detection limit in all samples were excluded. Relative abundances of metabolites were normalized to levels of creatinine. Pathway analysis with MetaboAnalyst (Metabolites 9:57; 2019).
Conclusions: CE-MS analysis identified several metabolic pathways that were altered in urine of men with PCa. These metabolites are involved in steroid, aromatic, microorganism and SCFA processes and warrant targeted studies which are underway in our lab. If validated, they have potential to serve as non-invasive biomarkers for PCa diagnosis and therapeutics
Citation Format: Alexander Buko, Leo Cheng, Andrew Gustev, Adam Feldman. The metabolomic profile of urine from prostate cancer patients using capillary electrophoresis mass spectrometry (CEMS) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3510.
Abstract 3533: Germline POLE and POLD1 proofreading domain mutations in endometrial carcinoma from Middle Eastern region
Authors: Siraj Abdul K. , Parvathareddy Sandeep K. , Bu Rong , Iqbal Kaleem , Siraj Sarah , Masoodi Tariq , Ghazwani Laila , Kong Yan , Sabido Maria A. , Albalawy Wafaa , Victoria Ingrid F. , Galvez Mary J. , Al-Kuraya Khawla S. 
Published: September 2020

Abstract
Endometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females. Although most ECs are sporadic, 2%-5% tend to be familial, being associated with Lynch syndrome and Cowden syndrome. In this study, we attempted to uncover the frequency, spectrum and phenotype of germline mutations in the proofreading domain of POLE and POLD1 genes in a large cohort of ECs from Middle Eastern region. We performed Capture sequencing and Sanger sequencing to screen for proofreading domains of POLE and POLD1 genes in 432 EC cases, followed by evaluation of protein expression using immunohistochemistry. Variant interpretation was performed using PolyPhen-2, MutationAssessor, SIFT, CADD and Mutation Taster. In our cohort, four mutations (0.93%) were identified in 432 EC cases, two each in POLE and POLD1 proofreading domains. Furthermore, low expression of POLE and POLD1 was noted in 41.1% (170/1414) and 59.9% (251/419) of cases, respectively. Both the cases harboring POLE mutation showed high nuclear expression of POLE protein, whereas, of the two POLD1 mutant cases, one case showed high expression and another case showed low expression of POLD1 protein. Our study shows that germline mutations in POLE and POLD1 proofreading region are a rare cause of EC in Middle Eastern population. However, it is still feasible to screen multiple cancer related genes in EC patients from Middle Eastern region using multigene panels including POLE and POLD1.
Keywords: POLE; POLD1; Endometrial carcinoma; Proof-reading domain mutations; Germline.
Citation Format: Abdul K. Siraj, Sandeep K. Parvathareddy, Rong Bu, Kaleem Iqbal, Sarah Siraj, Tariq Masoodi, Laila Ghazwani, Yan Kong, Maria A. Sabido, Wafaa Albalawy, Ingrid F. Victoria, Mary J. Galvez, Khawla S. Al-Kuraya. Germline POLE and POLD1 proofreading domain mutations in endometrial carcinoma from Middle Eastern region [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3533.
Abstract 3549: Low frequency of germline mutations in POLE and POLD1 proofreading domains in Middle Eastern colorectal cancers
Authors: Bu Rong , Siraj Abdul K. , Iqbal Kaleem , Parvathareddy Sandeep K. , Masoodi Tariq , Siraj Nabil , Siraj Nabil , Al-Rasheed Maha , Siraj Sarah , Kong Yan , Ahmed Saeeda O. , Al-Obaisi Khadija A.S. , Victoria Ingrid G. , Al-Kuraya Khawla S. 
Published: September 2020

Abstract
Colorectal cancer (CRC) is one of the main causes of cancer related morbidity and mortality. Only ~ 5% of all CRCs occur as a result of mutations in well-defined CRC predisposing genes. The underlying causes in genetically unexplained CRC cases from Middle Eastern region are still unknown. We performed Capture sequencing and Sanger sequencing to screen the proofreading domains of DNA Polymerase Epsilon (POLE) and DNA Polymerase Delta 1 (POLD1) genes to find out the genetic causes in over 1100 CRC cases from Middle Eastern region. In our cohort, five mutations (0.44%) were identified in 1135 CRC cases, four in POLE gene (0.35%, 4/1135) and one (0.1%, 1/1135) in POLD1 gene. These mutations have been infrequently reported in Western populations. Furthermore, low expression of POLE was noted in 38.9% (417/1071) of cases and showed significant association with lymph node involvement (p=0.0184) and grade 3 tumors (p=0.0139). Whereas, low expression of POLD1 was observed in 51.9% (555/1069) of cases and was significantly associated with adenocarcinoma histology (p=0.0164), larger tumor size (T3 and T4 tumors; p=0.0012) and stage III tumors (p=0.0341). Our findings revealed that there was a low frequency of
mutations in POLE and POLD1 proofreading region in CRC cases and established that the mutations in the proofreading domain of these two genes were a rare cause of CRC in Middle Eastern region. It is feasible to screen multiple cancer related genes in CRC patients from Middle Eastern region using multigene panels including POLE and POLD1.
Citation Format: Rong Bu, Abdul K. Siraj, Kaleem Iqbal, Sandeep K. Parvathareddy, Tariq Masoodi, Nabil Siraj, Nabil Siraj, Maha Al-Rasheed, Sarah Siraj, Yan Kong, Saeeda O. Ahmed, Khadija A.S. Al-Obaisi, Ingrid G. Victoria, Khawla S. Al-Kuraya. Low frequency of germline mutations in POLE and POLD1 proofreading domains in Middle Eastern colorectal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3549.
Abstract 3553: Three-dimensional (3D) telomere signatures of sporadic pediatric papillary thyroid carcinoma (PTC)
Authors: Sisdelli Luiza , Cordioli Maria Isabel , Vaisman Fernanda , Monte Osmar , Longui Carlos , Cury Adriano N. , Freitas Monique O. , Rangel-Pozzo Aline , Mai Sabine , Cerutti Janete 
Published: September 2020

Abstract
The incidence of thyroid carcinoma has increased worldwide, including in pediatric patients. Papillary thyroid carcinoma (PTC) is the most common subtype. Previous studies have suggested that clinical presentation and outcome diverge between pediatric and adult PTC and that this difference is likely due to distinct genetic alterations. BRAF V600E point mutation is highly prevalent in adults, while genetic fusions (RET/PTC, AGK-BRAF, ETV6-NTRK3) are the most prevalent events in the pediatric population. As telomere loss or dysfunction results in aneuploidy and chromosomal rearrangements, which can promote carcinogenesis, we investigated the three-dimensional (3D) structure of the telomeres in the nuclei from 21 pediatric patients (≤18 y.o), representing 16 PTC cases (with paired normal and tumor tissues for five of them) and five normal thyroid tissues from patients undergoing thyroidectomy for reasons other than cancer. We performed quantitative fluorescence in situ hybridization (FISH), 3D imaging, and 3D telomere analysis using TeloView® software to examine telomere dysfunction. The parameters examined included total number of signals (numbers of telomeres), total number of telomere aggregates, a/c ratio (indicating the phase of the cell cycle), total intensity (telomere length) and nuclear volume. Thyroid cancer cells showed lower average intensity of signals (p&lt;0.0001) and lower intensity signals (p&lt;0.0001), as well as higher nuclear volume (p&lt;0.0001), compared to normal thyroid cells. In addition, tumour cells showed a higher a/c ratio (p&lt;0.0001), indicating that they are more actively dividing than normal cells, which correlates with the high proliferation rate of cancer cells. We did not observe any alterations related to the total number of telomere signals and total number of aggregates, which suggests no significant aneuploidies occurring with these samples. The 3D nuclear telomere signature was able to detect differences in telomere architecture in tumours, compared to normal. Further analysis is necessary to define whether nuclear telomere architecture and specific genetic alterations observed in pediatric thyroid cancer are associated.
Citation Format: Luiza Sisdelli, Maria Isabel Cordioli, Fernanda Vaisman, Osmar Monte, Carlos Longui, Adriano N. Cury, Monique O. Freitas, Aline Rangel-Pozzo, Sabine Mai, Janete Cerutti. Three-dimensional (3D) telomere signatures of sporadic pediatric papillary thyroid carcinoma (PTC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3553.
Abstract 3566: Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia
Authors: Yashiro Masakazu , Kasashima Hiroaki , Yamamoto Yurie , Kuroda Kenji , Sera Tomohiro , Sugimoto Atsushi , Kushiyama Shuhei , Togano Shingo , Okuno Tomohisa , Miki Yuichiro , Ohira Masaichi 
Published: September 2020

Abstract
Purpose: Hypoxic environments are randomly scattered throughout carcinomas. Although hypoxia is cytotoxic to both cancer cells and normal cells, some types of cancer cells acquire characteristics that allow them to survive and progress in a hypoxic environment. Hypoxia is considered to be associated with aggressive tumor phenotypes of gastric carcinomas, including the ability to metastasize. Hypoxia is clinically associated with metastasis and poor patient outcome, however the underlying processes remain unclear. It has been reported that lysyl oxidase (LOX) is a hypoxia-responsive factor and is associated with the malignant progression of carcinoma. The aim of this study was to clarify the relationship between the epithelial–mesenchymal transition (EMT) and LOX in gastric cancer cells under hypoxia.
Methods: Two gastric cancer cell lines, OCUM-2MD3 and OCUM-12, were used in an in vitro study. The effect of siLOX on the EMT and motility of gastric cancer cells under hypoxic condition was analyzed by RT-PCR, western blot, wound-healing assay, and invasion assay. Correlations between LOX expression and the clinicopathological features of 544 patients with gastric carcinoma were examined immunohistochemically.
Results: Hypoxic conditions increased the number of polygonal or spindle-shaped cells of EMT in gastric cancer cells. The EMT of cancer cells induced by hypoxia was inhibited by treatment with LOX siRNA. Taken together, the number of migrating and invading gastric cancer cells in hypoxia was significantly decreased by LOX knockdown. LOX siRNA significantly increased the E-cadherin level and decreased the vimentin level of gastric cancer cells. LOX expression was significantly associated with invasion depth, tumor differentiation, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal metastasis. Multivariable analysis revealed that LOX was an independent parameter for overall survival.
Conclusion: HIF-1α might increase the expression of LOX, which affects the EMT of gastric cancer cells in hypoxic conditions via down-regulation of E-cadherin level and up-regulation of vimentin level. LOX expression may be a useful prognostic factor for patients with gastric cancer.
Citation Format: Masakazu Yashiro, Hiroaki Kasashima, Yurie Yamamoto, Kenji Kuroda, Tomohiro Sera, Atsushi Sugimoto, Shuhei Kushiyama, Shingo Togano, Tomohisa Okuno, Yuichiro Miki, Masaichi Ohira. Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3566.
Abstract 358: Cancer cell derived TNF mRNA as a marker of cancer cell budding in colorectal cancer
Authors: Nielsen Boye Schnack , Holmstrom Kim 
Published: September 2020

Abstract
Tumor necrosis factor alpha (TNF) is a potent cytokine reported to have several functions, including stimulation of inflammation, directing cell death and cell proliferation. The cellular origin of TNF has generally believed to be the inflammatory cells especially because macrophages are prone to induction of TNF. Using in situ hybridization (ISH) based on TNF mRNA probes (RNAscope) we recently reported that TNF mRNA is also seen in cytokeratin positive cancer cells (CC) and is associated with morphologic appearance interpreted as CC branching (Møller et al, IJMS 2019, doi: 10.3390/ijms20081907). To determine the fraction of CC-derived TNF mRNA signal at different areas in colon cancers we developed a cell and color segmentation-based image analysis tool to process fluorescence signals in digital slides. The approach allowed quantification of the TNF mRNA-positive CC and TNF mRNA-positive stromal cells in the digital slides previously reported, that were also stained for cytokeratin, microRNA-21 (miR-21) and DAPI nuclear stain. In the two cases with most abundant TNF mRNA ISH signal, both showing moderate-to-high budding index, the fraction of TNF-mRNA positive CC in the outer periphery (approximately 500 µm) was 8% and 20%, respectively. The frequency of the TNF-positive CC increased towards the invasive front from 7% (33/500 CC per 0.25 mm2) to 35% (48/137 CC), and from 8% (127/1536 CC per 0.50 mm2) to 28% (108/389 CC), respectively. The upregulation is in agreement with initial qualitative evaluation. In the same areas, the fraction of TNF mRNA positive stromal cells among all TNF mRNA-positive cells was only 8% in both cases, indicating that the majority of the TNF mRNA originates from CC. The fraction of the TNF mRNA-positive CC that were also miR-21 positive was 85% and 43%, respectively, which was higher than the prevalence of the overall miR-21 positive CC, 55% and 30%, suggesting frequent co-expression with miR-21. In conclusion, we have developed a method to obtain quantitative estimates from digital multiplex-stained slides with RNAscope and LNA fluorescence ISH and immunofluorescence. More samples will need to be processed to better understand the importance of TNF expression in cancer cell invasion.
Citation Format: Boye Schnack Nielsen, Kim Holmstrom. Cancer cell derived TNF mRNA as a marker of cancer cell budding in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 358.
Abstract 3632: Genomic profiling in circulating tumor DNA from Chinese advanced gastric adenocarcinomas patients
Authors: ZHANG ZHE , Chen Hui , Zhou Yifan , Zhang Bei , Bai Yuezong , Guo Lieping 
Published: September 2020

Abstract
Background and Objective: Circulating tumor DNA (ctDNA) is considered to be an ideal sample for advanced unresectable cancer patients to perform gene sequencing to guide clinical therapy, which might help to avoid tumor heterogeneous, especially in gastric adenocarcinomas (GACs). However, the ctDNA genomic profiling of Chinese advanced GACs is still missing.
Methods: Blood samples were obtained from 122 advanced GACs patients. Target sequencing were performed on ctDNA using a validated commercial 150-gene-panel NCC-GP150, which includes 100 microsatellite loci. Blood tumor mutation burden (bTMB) and blood microsatellite instability (bMSI) were calculated according to the NGS results. Statistical analysis was performed by the Mann-Whitney U test and Fisher exact test using GraphPad Prism.
Results: In 122 patients, 47 (38.5%) were female and 75 (61.5%) were male, with the median age of 61 (range 24 to 84). A total of 660 somatic variations were identified in 118 genes as indicated by a maximum somatic allele frequency (MSAF) of &gt;0.3%. One hundred and two (83.6%) patients carried at least one somatic variation and 84 (68.9%) patients had at least on pathogenic or likely pathogenic variations. The median pathogenic or likely pathogenic variations was 2.5 per patient in our cohort. The most frequent altered genes were TP53 (36.9%), LRP1B (18%), MYC (14.8%), RBM10 (13.9%), ERBB2 (13.9%), KRAS (12.3%), AR (11.5%) and FAT1 (10.7%). From the perspective of signaling pathway, the variations occurred frequently in RTK-Ras-MAPK pathway (53.3%), cell cycle pathway (52.5%), DNA damage repair (DDR) pathway (22.1%), Wnt pathway (18.9%), PI3K/AKT pathway (16.4%), and TGF-β pathway (2.5%). The median bTMB was 3 (mean 5.27, range 0 to 52); and 8 (7.8%) patients had high bMSI. The bMSI-H patients had significantly higher bTMB than bMSS patients (22 vs 3, p&lt;0.0001) and patients harboring DDR pathway gene variations had significantly higher bTMB than wildtype subgroups (6 vs 3, p=0.0004).
Conclusions: Our study revealed a comprehensive genomic profiling of advanced Chinese GACs patients. And the relationship between the genomic profiling and target-therapy as well as immunotherapy will be studied in an enlarged group of GACs patients.
Citation Format: ZHE ZHANG, Hui Chen, Yifan Zhou, Bei Zhang, Yuezong Bai, Lieping Guo. Genomic profiling in circulating tumor DNA from Chinese advanced gastric adenocarcinomas patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3632.