bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2396: Methylation of subtelomeric repeat D4Z4 in peripheral blood leukocytes is associated with biochemical recurrence in localized prostate cancer patients
Authors: Han Yuyan , Kim Jeri , Wu Xifeng , Gu Jian 
Published: July 2017

Abstract
Background: Global DNA methylation may affect chromosome structure and genomic stability and is involved in carcinogenesis. In this study, we aimed to investigate whether methylation of pericentromeric repeat (NBL2) and subtelomeric repeat (D4Z4) in peripheral blood leukocytes was associated with the aggressiveness of prostate cancer (PCa).
Methods: We measured the methylation status of different CpG sites of NBL2 and D4Z4 in 900 PCa patients via pyrosequencing after bisulfite treatment. We then used multivariate logistic regression to estimate the odds ratio (ORs) and 95% confidence intervals (CIs) for analyzing the association of NBL2 and D4Z4 methylation with the aggressiveness of PCa at diagnosis. We then analyzed the association of CpG sites with the risk of biochemical recurrence (BCR) in patients receiving radical prostatectomy or radiotherapy using a multivariate Cox proportional hazards model adjusting for age, BMI, smoking status, pack year, D’Amico risk groups, and treatments. In addition, we used the Kaplan-Meier survival function and log-rank tests to assess BCR-free survival associated with these markers.
Results: There was no significant differences in the methylation level of NBL2 and D4Z4 between clinically defined aggressive and non-aggressive PCa at diagnosis. However, the methylation of subtelomeric region D4Z4 was associated with BCR, while the methylation of NBL2 was not associated with BCR. In tertile analysis, we found that patients with higher methylation of D4Z4 exhibited an increased risk of BCR in localized patients receiving definitive therapy. Because of the relatively low rate of BCR among patients, we combined the highest and second tertiles to increase statistical power. Patients in the second and third (highest) tertiles had an increased risk of BCR (HR=1.74, 95% CI, 1.14-2.65; p= 0.0096) compared to patients in the lowest tertile after adjustment of age, BMI, smoking status, pack year, D’Amico risk groups, and treatments. We assayed 4 CpG sites in this region. In detailed analysis of each CpG site, the association was mostly attributable to the methylation of the 2nd methylation site of D4Z4 (HR=1.80, 95% CI, 1.19 - 2.72).
Conclusion: These data suggest that methylation in the subtelomeric region D4Z4 may be able to predict worse prognosis of localized PCa patients.
Citation Format: Yuyan Han, Jeri Kim, Xifeng Wu, Jian Gu. Methylation of subtelomeric repeat D4Z4 in peripheral blood leukocytes is associated with biochemical recurrence in localized prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2396. doi:10.1158/1538-7445.AM2017-2396
Abstract 2399: Metabolic and epigenetic targets in multiple myeloma therapy
Authors: Maneix Laure , Shih Fu-Yuan , Iakova Polina , Hsu Joanne I. , Catic Andre 
Published: July 2017

Abstract
The dynamic interaction of transcription factors (TFs) with promoters and enhancers allows cells to continuously adjust gene expression. Whereas the composition and binding of TFs at genomic sites is the focus of a widespread research effort, relatively little is known about how these complexes are being removed. We previously devised a method to detect genomic locations that are associated with nuclear protein turnover mediated by the ubiquitin-proteasome system (UPS).
Multiple myeloma, the second most common hematopoietic malignancy, has become a model disease for drugs that interfere with the UPS through either blocking or facilitating protein elimination. The proteasome inhibitor Velcade, for instance, has become first-line treatment in myeloma. Yet, our knowledge of how myeloma cells are killed by this drug is incomplete. Our research is focused on defining how proteolysis regulates transcriptional dynamics in this disease and how this impacts Velcade sensitivity.
Following proteasome inhibition, we are utilizing next generation sequencing to identify sites of nuclear protein turnover and evaluate epigenetic changes. Our aim is to identify TFs and epigenetic marks that may qualify as more specific targets for treatment compared to blunt proteasome inhibition. Our findings reveal that certain TFs, including metabolic and cell growth regulators, are particularly sensitive to Velcade. Among these transcriptional regulators, the co-repressor NCoR1 plays a key role in controlling cell metabolism by adjusting mitochondrial gene expression. We are currently validating the mechanism of NCoR1 degradation, with a particular emphasis on the new role of its E3-ubiquitin ligase Seven in absentia 2 (Siah2) in mitochondrial regulation, to better understand how this degradation pathway impacts myeloma proliferation and metabolism.
This research project will contribute to our understanding of epigenetic and transcriptional dynamics in multiple myeloma. With the focus on gene programs that are continuously adapting or changing, we seek to unlock new attractive targets for molecular therapy.
Citation Format: Laure Maneix, Fu-Yuan Shih, Polina Iakova, Joanne I. Hsu, Andre Catic. Metabolic and epigenetic targets in multiple myeloma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2399. doi:10.1158/1538-7445.AM2017-2399
Abstract 2407: Inhibition of gene expression during non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is mediated by histone H4 lysine 16 deacetylation
Authors: Dreval Kostiantyn , Conti Aline de , Orisakwe Orish Ebere , Beland Frederick A. , Pogribny Igor P. 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers and the incidence is steadily increasing worldwide. The molecular mechanisms leading to the development of HCC consist of genetic and epigenetic aberrations, including changes in global and gene-specific DNA methylation and altered expression of several classes of non-coding RNAs. While changes in DNA methylation and microRNA expression during the development of HCC are well-studied, the role of aberrant post-translational histone modifications remains unexplored. Using a mouse Stelic Animal Model (STAM) of NASH-associated liver carcinogenesis, we have investigated alterations in hepatic histone modifications at steatotic (6 weeks), fibrotic (12 weeks), and full-fledged HCC (20 weeks) stages of the HCC development. NASH-related liver carcinogenesis was characterized by a progressive decrease in the levels of histone H4 lysine 20 trimethylation (H4K20me3) and histone H4 lysine 16 acetylation (H4K16ac), with the greatest decrease occurring in full-fledged tumors. Mechanistically, the deacetylation of H4K16ac was associated with nuclear protein 1 (Nupr1)-mediated inhibition of histone lysine acetyltransferase KAT8. In addition to a global loss of hepatic H4K16ac, there was a significant decrease of gene-specific H4K16ac, as indicated by a reduced level of H4K16ac in 16 out of 25 critical cancer-related genes. More importantly, the changes in the extent of gene-specific H4K16 deacetylation were positively correlated with the level of gene transcription (r = 0.965, p &lt; 0.01). These results indicate that a reduction of global and gene-specific of H4K16ac is a key pathophysiological mechanism contributing to the development of NAFLD-derived HCC.
Citation Format: Kostiantyn Dreval, Aline de Conti, Orish Ebere Orisakwe, Frederick A. Beland, Igor P. Pogribny. Inhibition of gene expression during non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is mediated by histone H4 lysine 16 deacetylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2407. doi:10.1158/1538-7445.AM2017-2407
Abstract 242: The anti-tumor effect and the impact on gut microbiota of gypenosides Rd and Rb3 in ApcMin/+ mice
Authors: Hsiao W.L. Wendy , Huang Guoxin , Khan Imran , Chen Lei , Li Xiaoang 
Published: July 2017

Abstract
Gut commensal microbiota (GM) is closely associated with health and diseases, including cancer. In our previous studies, we have demonstrated that Gynostemma pentaphyllum saponins (GpS) exert anticancer effects in both athymic and ApcMin/+ mice. Our recent study also showed that GpS exhibited prebiotic effect by up regulating the beneficial bacteria and improving the epithelial microenvironment of the gut. Gypenoside IV (Rb3) and gypenoside VII (Rd) are the two constituents of GpS. The Rd exhibits stronger anticancer effect than Rb3 in an in vitro cell model system established in our lab. Our aim is to confirm the antitumor effect of these two compounds, as well as their impact on GM in the ApcMin/+ mouse model. In the study, single daily dose of Rb3 or Rd at 20mg/kg, and solvent control were orally fed to the mice for 8 weeks, started at 6 weeks of age before the appearance of spontaneous intestinal polyps. The fecal microbiome was analyzed by enterobacterial repetitive intergenic consensus (ERIC)-PCR and 16S rRNA gene pyrosequencing technique. We found that Rd was more effective than Rb3 in reducing polyp formation, and improving the intestinal lining by up-regulating anti-inflammatory cytokines IL-4 and IL-10. Rd, not Rb3, might facilitate intestinal tissue repair by enhancing M2 marker while suppressing M1 markers expression. Moreover, Rd treatment greatly enhanced the ratio of Bacteroidetes vs Firmicutes, while profoundly reduced the abundance of cancer-cachexia-associated bacteria, such as Parabacteroides goldsteinii (22.25%), Dysgonomonas wimpennyi (48.54%) and Blautia coccoides (36.77%). These findings suggested that the level of antitumor effect of the gypenoside might be correlated with its ability to modulate the gut microbiota from dysbiosis state to symbiosis.
This study was supported by Macau Science and Technology Development Fund 015/2014/A1.
Citation Format: W.L. Wendy Hsiao, Guoxin Huang, Imran Khan, Lei Chen, Xiaoang Li. The anti-tumor effect and the impact on gut microbiota of gypenosides Rd and Rb3 in ApcMin/+ mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 242. doi:10.1158/1538-7445.AM2017-242
Abstract 2434: LEF1 negatively regulates differentiation of HCC by activation of Notch signaling pathway
Authors: FANG Shuo , LI Lei , LIU MIng , Tsang Janice , GUAN Xinyuan 
Published: July 2017

Abstract
Lymphoid enhancer binding factor-1 (LEF1), an essential regulatory protein, plays a crucial role on self-renewal and differentiation properties of several cancers, contributing to tumor malignancy degree and prognosis. However, its molecular mechanisms to promote tumor differentiation still keep unknown, especially in hepatocellular carcinoma (HCC). In this study, by analyzing the transcriptome datasets and our qPCR result of clinical HCC samples, we found that LEF is frequently overexpressed in HCCs and significantly associated with HCC differentiation (p=0.015). In addition, functional study showed that LEF1 could enhance the cell proliferation, matrigel invasion, transwell migration, as well as self-renewal abilities both in vivo and in vitro experiments. We also demonstrated LEF1 is closely related to Notch intracellular domain (NICD), and revealed several putative sites as the targets for LEF1 activating Notch signaling pathway. LEF1 could induce the Notch signaling via transcriptionally up-regulate Notch expression through direct DNA binding. The expressions of several downstream members in Notch signaling pathway including Notch1 and Notch2 were subsequently increased. Moreover, LEF1 could down-regulate various differentiation markers and over-express tumor stemness related genes. Together, LEF1 is a novel oncogene that show a crucial role in the tumorigenesis and progression of HCC via activating Notch signaling pathway and inhibiting the differentiation and stemness of HCC, resulting in poor pathologic differentiation and leads to high degree of malignant. All the findings suggest a novel treatment possibility and a new target for liver stem cell eradication. LEF1 could be investigated for clinical early diagnosis and prognosis prediction of HCC patients and improving the development of new therapy against HCC.
Note: This abstract was not presented at the meeting.
Citation Format: Shuo FANG, Lei LI, MIng LIU, Janice Tsang, Xinyuan GUAN. LEF1 negatively regulates differentiation of HCC by activation of Notch signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2434. doi:10.1158/1538-7445.AM2017-2434
Abstract 2439: Establishment of six human colorectal cancer cell lines: identification of genes that have metastatic potential
Authors: Kim Soon-Chan , Hong Chang-Won , Jang Sang-Geun , Jeong Seung-Yong , Park Jae-Gahb , Ku Ja-Lok 
Published: July 2017

Abstract
A number of genes have been studied in accordance with their metastatic potential. Nevertheless, widely used metastatic colorectal cancer cell lines such as SW-620 or IS3 only show the influence of metastatic genes within limited mutational landscape. Here, three pairs of primary CRC (SNU-2335A, SNU-2335D, SNU-2404A, SNU-2404B, SNU-2414A, and SNU-2414B) and corresponding metastasis cell lines were established and analyzed by whole exome sequencing and microarray.
Three pairs of primary CRC (SNU-2335A, SNU-2404A, and SNU-2414A) and corresponding matched metastasis cell lines (SNU-2335D, SNU-2404B, and SNU-2414B) were analyzed for gene expression by microarray and whole exome sequencing. Selected target genes from microarray were analyzed again by real-time PCR in order to confirm the mRNA expression level in the paired CRC cell lines.
The genes selected for examination were calponin 3, acidic (CNN3); sorbin and SH3 domain containing 1(SORBS1); epithelial stromal interaction 1 (EPSTI1); bone marrow stromal cell antigen 2(BST2); kelch-like 5 (KLHL5); trypsinogen C (TRY6); and synaptotagmin-like 5 (SYTL5). We calculated the intersection of all three metastatic CRC cell lines. Five genes (BST2, SORBS1, CNN3, EPSTI1, and KLHL5) were up-regulated in metastatic cell lines compared to primary cell lines. Two genes (TRY6 and SYTL5) were down-regulated in metastatic cell lines compared to primary cell lines. Then, we ranked 15 genes that were up-regulated and 15 genes that were down-regulated in omental metastasis regardless of the 2-folds threshold. Of the 30 genes that were differently expressed, we selected three genes (CNN3, SORBS1, and TRY6) that showed the highest fold changes and are found in 2-fold change analysis.
We identified 7 genes that were differently expressed in metastatic CRC cell lines compared to primary CRC cell lines. These genes may serve as diagnostic markers and therapeutic targets for patients with metastatic CRC.
Note: This abstract was not presented at the meeting.
Citation Format: Soon-Chan Kim, Chang-Won Hong, Sang-Geun Jang, Seung-Yong Jeong, Jae-Gahb Park, Ja-Lok Ku. Establishment of six human colorectal cancer cell lines: identification of genes that have metastatic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2439. doi:10.1158/1538-7445.AM2017-2439
Abstract 244: Eicosapentaenoic acid reduces effects of some adipocyte derived factors on breast cancer cell inflammation and glucose metabolism
Authors: Aljawadi Arwa , Alhaj Sara , Dharamawardhane Suranganie , Scoggin Shane , Gollahon Lauren , Gunaratne Preethi , Moustaid-Moussa Naima 
Published: July 2017

Abstract
Breast cancer is still the leading cause of death in women among all cancer types. Obesity, a chronic low grade inflammatory disease, is a key contributor to the progression of breast cancer especially in women, post-menopause. Given the current understanding of cancer-related inflammation and associated microvesicles in restructuring the microenvironment, we hypothesized that adipocyte-derived cytokines and exosomes negatively impact breast cancer progression. By contrast, eicosapentaenoic acid (EPA), a dietary omega 3 polyunsaturated fatty acid and a well-established anti-inflammatory compound will reduce adipocyte-secreted pro-inflammatory factors, thereby reducing breast cancer progression. To test these hypotheses, we investigated the effects of conditioned media or exosomes from 3T3-L1 adipocytes or human mesenchymal stem cells (HMSC), treated +/- 100uM EPA on MCF7 and MDA-MB231 breast cancer cells for 24 – 72 h. Following treatment, changes in breast cancer cell gene expression were measured using RT-qPCR and glycolytic rate was measured using XFe24 Seahorse extracellular flux analyze. We observed that conditioned medium from HMSC significantly increased the mRNA expression levels of oncogenic genes such as signal transducer and activator of transcription 3 (STAT3), baculoviral IAP repeat-containing protein3 (BIRC3) known as cIAP2, and the lipogenic fatty acids synthase (FASN). In contrast, conditioned media from EPA-treated human adipocytes reduced the expression levels of these genes. Similarly, exosomes isolated from EPA-treated adipocytes showed a significant reduction in mRNA expression levels of STAT3 and cIAP2 in both cancer cell lines. Furthermore, glycolysis was significantly reduced in MCF7 but not MDA-MB231 cells incubated with 3T3-L1 adipocyte-conditioned medium pretreated with EPA for 24 hrs. Taken together, our data suggest that adipocytes play a significant role in promoting breast cancer progression by providing a microenvironment that increases survival and inflammation. EPA is a promising anti-inflammatory nutrient that may help reduce breast cancer cell inflammation and survival, possibly by modulating adipocyte-derived cytokines and exosomes in obesity and thus warrants further investigations.
Citation Format: Arwa Aljawadi, Sara Alhaj, Suranganie Dharamawardhane, Shane Scoggin, Lauren Gollahon, Preethi Gunaratne, Naima Moustaid-Moussa. Eicosapentaenoic acid reduces effects of some adipocyte derived factors on breast cancer cell inflammation and glucose metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 244. doi:10.1158/1538-7445.AM2017-244
Abstract 2442: Simplified sequencing of full-length isoforms in cancer on the PacBio Sequel System
Authors: Ashby Meredith , Hon Ting , Tseng Elizabeth , Vedula Aparna , Clark Tyson A. 
Published: July 2017

Abstract
Tremendous flexibility is maintained in the human proteome via alternative splicing, and cancer genomes often subvert this flexibility to promote survival. Identification and annotation of cancer-specific mRNA isoforms is critical to understanding how mutations in the genome affect the biology of cancer cells. While microarrays and other NGS-based methods have become useful for studying transcriptomes, these technologies yield short, fragmented transcripts that remain a challenge for accurate, complete reconstruction of splice variants. In cancer proteomics studies, the identification of biomarkers from mass spectroscopy data is often limited by incomplete gene isoform expression information to support protein to transcript mapping.
The Iso-Seq™ protocol developed at PacBio offers the only solution for direct sequencing of full-length, single-molecule cDNA sequences needed to discover biomarkers for early detection and cancer stratification, to fully characterize gene fusion events, and to elucidate drug resistance mechanisms. Knowledge of the complete isoform repertoire is also key for accurate quantification of isoform abundance. As most transcripts range from 1 - 10 kb, fully intact RNA molecules can be sequenced using SMRT® Sequencing without requiring fragmentation or post-sequencing assembly. However, some cancer research applications have presented a challenge for the Iso-Seq protocol, due to the combination of limited sample input and the need to deeply sequence heterogenous samples.
Here we report the optimization of the Iso-Seq library preparation protocol for the PacBio Sequel platform and its application to cancer cell lines and tumor samples. We demonstrate how loading enhancements on the higher-throughput Sequel instrument have decreased the need for size fractionation steps, reducing sample input requirements while simultaneously simplifying the sample preparation workflow and increasing the number of full-length transcripts per SMRT Cell. The results highlight the potential for broader application of the Iso-Seq method to more comprehensively characterize alternative splicing in cancer.
Citation Format: Meredith Ashby, Ting Hon, Elizabeth Tseng, Aparna Vedula, Tyson A. Clark. Simplified sequencing of full-length isoforms in cancer on the PacBio Sequel System [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2442. doi:10.1158/1538-7445.AM2017-2442