bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5448: An exosomal biomarker for prostate cancer
Authors: Bhagirath Divya , Yang Thao , Sekhon Kirandeep , Bucay Nathan , Majid Shahana , Hashimoto Yutaka , Kulkarni Priyanka , Dasgupta Pritha , Shiina Marisa , Shahryari Varahram , Imai-Sumida Mitsuho , Yamamura Soichiro , Tabatabai Z Laura , Tanaka Yuichiro , Dahiya Rajvir , Deng Guoren , Saini Sharanjot 
Published: July 2017

Abstract
Prostate tumors are highly heterogeneous and molecular characterization based on biopsy sampling is often challenging. Hence, it is desirable to have an easily accessible, minimally invasive way to determine the molecular imprints of a patient’s tumor. Exosomes in blood are an important source of non-invasive, circulating biomarkers and provide an enriched source of microRNAs. With an objective of identifying microRNA based markers, we developed a comprehensive procedure for exosomal microRNA profiling analyses from sera of prostate cancer patients employing Nanostring nCounter technology. In a pilot study, we profiled exosomal miRNAs from a training cohort of normal individuals, patients with benign prostate hyperplasia (BPH), indolent form of PCa and aggressive metastatic prostate cancer. Exosomes were extracted from serum and the integrity of exosomal preparations was confirmed by nanoparticle tracking analysis and Western blot analyses for exosomal markers CD63, CD9 and TSG101. Levels of two miRNAs were significantly upregulated and several candidate miRNAs were markedly downregulated in metastatic PCa serum samples compared with controls. The candidate microRNAs were further validated in a larger cohort by real time PCR based microRNA assays. Of significance, we validated miR-1246 as an exosomal marker for prostate cancer. miR-1246 levels were specifically altered in prostate cancer patients and not significantly altered in BPH. Our analyses suggest that miR-1246 is a promising diagnostic biomarker for prostate cancer.
Citation Format: Divya Bhagirath, Thao Yang, Kirandeep Sekhon, Nathan Bucay, Shahana Majid, Yutaka Hashimoto, Priyanka Kulkarni, Pritha Dasgupta, Marisa Shiina, Varahram Shahryari, Mitsuho Imai-Sumida, Soichiro Yamamura, Z Laura Tabatabai, Yuichiro Tanaka, Rajvir Dahiya, Guoren Deng, Sharanjot Saini. An exosomal biomarker for prostate cancer [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 5448. doi:10.1158/1538-7445.AM2017-5448
Abstract 5449: Nanoparticle delivery of miRNAs to inhibit GBM stem cells
Authors: Lopez-Bertoni Hernando 
Published: July 2017

Abstract
Cancer cells arise from multiple complementary genomic and epigenomic abnormalities that deregulate pathways that control cell proliferation and tissue homeostasis. Epigenetic modifications, involving deregulation of non-coding RNAs, are emerging as critical determinants of gene expression and essential drivers of neoplastic phenotypes. Our knowledge of how these complex epigenetic mechanisms operate in the context of cancer cell phenotype regulation remains limited. Non-coding RNAs, in particular miRNAs, are emerging as critical epigenetic regulators of cell fate and oncogenesis. MiRNAs act by selectively inhibiting gene expression primarily by targeting mRNA for degradation usually via complementary 3’-UTR seed sequences. Numerous miRNAs have been found to regulate tumorigenesis and cancer cell stemness by virtue of their capacity to target tumor-suppressing or tumor promoting transcripts. We recently showed that the coordinated actions of Oct4 and Sox2 induce a tumor-propagating stem-like state in GBM cells through a mechanism that involves the induction of DNMTs and down-regulation of a network of miRNAs through promoter DNA methylation. Two of the miRNAs repressed by Oct4/Sox2, miR-148a and miR-296-5p, efficiently inhibit the tumor propagating capacity of GBM stem-like, making them excellent candidates for therapeutic intervention.
Options for treating high-grade brain tumors remain limited. Recent developments in nanomedicine provide new and exciting opportunities to treat and manage brain tumors. Cationic polymers are a class of biomaterials with great promise for targeted molecular therapeutics. We combined this cutting-edge technology with our newly discovered stem cell inhibiting miRNAs to develop nano/miR conjugates to treat gliomas. We show these nano/miR conjugates distribute throughout an established tumor in vivo, and more importantly, delivering these tumor-suppressing miRNAs using PBAE polymers inhibits the growth of established GBM tumor in mouse models. Our findings demonstrate that identifying and validating stem cell-inhibitory in combination with current advances in nanomedicine will undoubtedly impact the development of novel therapies for targeting the CSC population and treating GBM.
Citation Format: Hernando Lopez-Bertoni. Nanoparticle delivery of miRNAs to inhibit GBM stem cells [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 5449. doi:10.1158/1538-7445.AM2017-5449
Abstract 5453: Dysregulation of miRNAs in esophageal cancer: function and clinical implication
Authors: Sharma Rinu 
Published: July 2017

Abstract
Background: Growing evidence suggests importance of aberrant microRNA (miRNA) expression in development and progression of cancer. Recent studies have demonstrated the potential of miRNA panels as promising diagnostic, prognostic and predictive biomarkers.
Objective: The purpose of the present study was to evaluate the clinical and functional significance of miRNAs in esophageal cancer (EC).
Methods: Herein, we evaluated the diagnostic potential of a five miRNA panel (consisting of miR-21, miR-144, miR-107, miR-93 and miR-342) in EC detection using quantitative real time PCR (qRTPCR). To evaluate the discriminatory power of miRNA panel, receiver operating characteristic curve (ROC) curves were generated for each of the miRNAs followed by risk score analysis. Briefly, linear regression models were fitted using the cancer status and each of the risk score as input. ROC curves were then used to evaluate the diagnostic potential of the panel and to find out the appropriate cut-off point. Sensitivity and specificity of the panel were then determined. Further, pathway enrichment analysis was carried out to find the most significant pathways targeted by these miRNAs. Next, we elucidated the role of miR-144, by silencing it in KYSE-410 cells followed by MTT assay, cell cycle analysis, colony formation assay and scratch assay. Potential targets of miR-144 were predicted by in silico approach followed by in vitro validation by luciferase reporter assay.
Results: The ROC curve analysis indicated that the panel of five miRNAs (AUC=0.851, p&lt;0.001) constitutes a more sensitive and specific diagnostic marker as compared to any of the single miRNAs. Most importantly, panel of circulating miRNAs showed enhanced sensitivity (87.5%) and specificity (90.4%) with an AUC of 0.96 (p&lt;0.001) in discriminating EC patients from normal subjects. Inhibition of miR-144 significantly suppressed the proliferation of ESCC cells by 42.085±1.73% at 72 h post transfection. Moreover, knockdown of miR-144 decreased (p=0.046) the migration potential of KYSE-410 cells as compared to the cells treated with negative control. In silico analysis and further validation by dual-luciferase reporter assay revealed PURA to be a direct downstream target of miR-144.
Conclusion: Herein, we have demonstrated the potential diagnostic implication of five miRNA panel. Further, we have shown that mir-144 acts as an oncogenic miRNA by targeting PURA and promotes EC cell proliferation.
Citation Format: Rinu Sharma. Dysregulation of miRNAs in esophageal cancer: function and clinical implication [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 5453. doi:10.1158/1538-7445.AM2017-5453
Abstract 5454: Serum circulating microRNAs as potential biomarkers for prostate cancer
Authors: Kasomva Khanmi , Savarimuthu Ignacimuthu , Paulraj Gabriel Michael , Sen Arnab , Sailo Stephen , SV Ngachan 
Published: July 2017

Abstract
MicroRNAs (miRNAs) are small non-coding RNA, whose differential expression has been involved in the development and progression of cancers, including prostate cancer (PCa). In recent studies circulating miRNAs have been demonstrated to have the potential as non-invasive biomarkers in various types of cancer. The aim of this study was to investigate the serum circulating miRNA-103 could be used in diagnosis of prostate cancer in North-Eastern India patient population. To evaluate this study blood samples were collected from prostate cancer patients and healthy controls following ethical approval and informed consent. The samples were reverse transcribed using stem loop primers and expression levels of miRNA-103 were determined using real time PCR. Differential expressions of miRNA-103 for each case were used to compare PCa serum with healthy serum samples. Serum circulating miR-103 levels was significantly down-regulated in the PCa patients comparison with healthy control. The serum circulating miRNA-103 could be potential for the diagnosis of PCa in North-Eastern India Population.
Citation Format: Khanmi Kasomva, Ignacimuthu Savarimuthu, Gabriel Michael Paulraj, Arnab Sen, Stephen Sailo, Ngachan SV. Serum circulating microRNAs as potential biomarkers for prostate cancer [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 5454. doi:10.1158/1538-7445.AM2017-5454
Abstract 5455: Novel miRNA-based therapeutic approach to selectively target mutant p53 in cancer
Authors: Lulla Amriti R. , Einarson Margret B. , Zhou Yan , Dicker David T. , El-Deiry Wafik S. 
Published: July 2017

Abstract
Tumor suppressor p53, guardian of the genome, is frequently mutated or functionally dysregulated in more than 50% of human tumors. p53 mutation is a later event in tumorigenesis and a number of p53 mutants have “Gain of Function” (GOF) properties that have been shown to promote invasive and more aggressive phenotypes in cancer cells. Mutant p53 has been an attractive and promising therapeutic target for advanced stages of tumors. Yet, mutant p53 has proved to be one of the most undruggable targets. Thus, there is continued interest in understanding the GOF properties of mutant p53 and in designing novel strategies to target mutant p53 and/or key GOF pathways. Mature MicroRNAs (miRNAs) are ~22 nt endogenous, non-coding RNA sequences that bind to 3’UTR of their target genes and inhibit their translation. miRNA mimics are emerging therapeutics and attractive tools for mapping pathway networks. We developed a novel functional high throughput screening (HTS) assay to identify miRNAs that selectively target mutant p53-expressing cell lines. The HTS was performed in isogenic TP53+/+ (wild-type), TP53-/- (null) and TP53 R175H (mutant) HCT-116 colorectal cancer cell lines. Cell viability was used as the HTS read-out of our functional screen. Of 2754 miRNA mimics screened, we identified 56 miRNAs that selectively target TP53 R175H (mutant) cells. Our ongoing work is directed to further validating and identifying which of these miRNA mimics selectively induce apoptosis in mutant p53-expressing cells. We are also using reporter-based assays to identify a fraction of the 56 miRNAs that can bind to the p53 3’UTR. Our long-term goal is to selectively target mutant p53-expressing cells using miRNA mimics as single agents or in combination with FDA-approved or experimental therapeutics. Our strategy is may provide a unique opportunity for development of targeted therapy for TP53 mutant tumors.
Citation Format: Amriti R. Lulla, Margret B. Einarson, Yan Zhou, David T. Dicker, Wafik S. El-Deiry. Novel miRNA-based therapeutic approach to selectively target mutant p53 in cancer [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 5455. doi:10.1158/1538-7445.AM2017-5455
Abstract 5457: OGT restrains the NRF2 antioxidant pathway via O-GlcNAcylation of KEAP1
Authors: Chen Po-Han , Smith Timothy J. , Wu Jianli , Boyce Michael , Chi Jen-Tsan Ashley 
Published: July 2017

Abstract
O-GlcNAcylation is a reversible post-translational modification that adds an O-linked β-N-acetylglucosamine (O-GlcNAc) moiety onto serine/threonine residues of target proteins. This modification is regulated by only two enzymes: O-GlcNAc transferase (OGT, the writer) and O-GlcNAcase (OGA, the eraser) in mammals. Recent studies have revealed that OGT expression and O-GlcNAc modifications are elevated in several cancers, but specific O-GlcNAc targets are not well defined. We conducted a global transcriptome profiling in MDA-MB-231 breast cancer cells to search for signaling events that respond to O-GlcNAc fluctuation. We found significant up-regulation of genes involved in the NRF2-dependent stress response when OGT activity is inhibited in different tumor types. We also discovered a strong positive correlation of gene signatures between low OGT activity and NRF2 activation in multiple human tumor gene expression datasets. NRF2, the primary regulator of redox balance, is usually activated by oxidative stress and repressed under basal conditions by the KEAP1-CUL3 ubiquitin ligase complex. However, we found that OGT inhibition increases NRF2 protein level through reducing poly-ubiquitination of NRF2 in the absence of oxidative stress. By chemical sugar labeling and mass spectrometry assays, we identified that KEAP1 is directly O-GlcNAcylated by OGT especially within the BTB and Kelch motifs. Of all 11 putative O-GlcNAc sites on KEAP1, we found serine 104 is responsible for regulating NRF2 activity through affecting KEAP1-CUL3 interaction. Interestingly, we found the amount of intracellular glucose co-vary with KEAP1 O-GlcNAcylation and NRF2 protein, suggesting that glucose metabolites may utilize the nutrient sensing O-GlcNAcylation to fine-tune the antioxidant response. We propose that cancer cells could utilize O-GlcNAcylation, specifically on KEAP1, to regulate NRF2-mediated stress responses in response to the dynamics of intracellular glucose level. Since the NRF2 pathway is inappropriately activated in certain tumor types due to dysregulated function of KEAP1, such as non-small cell lung cancer, where it provides stress resistance and a growth advantage. Our study could provide new insight into redox cancer biology and provide novel strategy to modulate NRF2 activity during tumor development.
Citation Format: Po-Han Chen, Timothy J. Smith, Jianli Wu, Michael Boyce, Jen-Tsan Ashley Chi. OGT restrains the NRF2 antioxidant pathway via O-GlcNAcylation of KEAP1 [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 5457. doi:10.1158/1538-7445.AM2017-5457
Abstract 5463: Disulfiram suppresses metastasis via induction of anoikis and calpain activation in triple-negative breast cancer
Authors: Oh Eunhye , Sung Daeil , Cho Youngkwan , Kim Ji Young , Lee Nahyun , Kim Yoon-Jae , Cho Tae-Min , Seo Jae Hong 
Published: July 2017

Abstract
Triple-negative breast cancers (TNBC) exhibit aggressive phenotypes and are associated with poor clinical outcomes due to a lack of effective therapeutic strategies. Disulfiram (DSF) is a clinical therapeutic drug for the treatment of alcoholism, and has also been shown to exhibit antitumor activity in TNBC cells in a copper (Cu)-dependent manner, although how this occurs has not been clearly elucidated. We sought to investigate the mechanisms responsible for DSF/Cu-dependent induction of apoptosis and suppression of lung colonization by TNBC cells. DSF/Cu treatment significantly induced apoptosis, accompanied by an increase in the sub-G1 population, as well as caspase-3 activation. DSF/Cu strongly suppressed cell migration and invasion, while inducing suppression of focal adhesion kinase (FAK) phosphorylation and focal adhesions, concomitant with an observed reorganization of cytoskeletal F-actin and collapse of the plasma membrane. These effects were associated with calpain activation, coinciding with the breakdown of vimentin, FAK and talin, presumably allowing for cell detachment. In a xenograft tumor model, DSF suppressed tumor growth and lung colonization, which was also associated with calpain activation. Taken together, these findings warrant further investigation of disulfiram as a potential treatment for metastatic TNBC.
Citation Format: Eunhye Oh, Daeil Sung, Youngkwan Cho, Ji Young Kim, Nahyun Lee, Yoon-Jae Kim, Tae-Min Cho, Jae Hong Seo. Disulfiram suppresses metastasis via induction of anoikis and calpain activation in triple-negative breast cancer [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 5463. doi:10.1158/1538-7445.AM2017-5463
Abstract 5467: Phosphoproteomic analysis of pyruvate dehydrogenase in response to environmental stress
Authors: O'Neill Wendi , Golias Tereza , Benej Martin , Denko Nicholas 
Published: July 2017

Abstract
Pyruvate dehydrogenase is a mitochondrial enzyme that regulates the flux of carbohydrates into oxidative phosphorylation. The activity of PDH is largely regulated by reversible phosphorylation. The pyruvate dehydrogenase kinases add inhibitory phosphorylations to PDH on the E1α subunit at positions 232, 293, and 300. Interestingly, there is a family of 4 related PDHK genes with overlapping affinity for the 3 phosphorylation sites. PDHK1 and PDHK3 have been identified as hypoxia-inducible at the transcriptional level, and PDHK1 has been shown to be important for the growth of model tumors. This work attempts to more carefully define the functions of PDHK1 and 3 using CRISPR technology in colorectal cancer lines in vitro and genetically engineered mice in vivo.
Using antibodies specific for the phosphorylated sites on E1α, we find that PDHK1 is essential for the phosphorylation of the 232 site in response to hypoxia and partially responsible for the hyperphosphorylation of 293 and 300. The level of phosphorylation in response to hypoxia is also sensitive to nutrients in the environment, with high levels of glucose enhancing E1α phosphorylation in hypoxia. Analysis of the number of phosporylations on individual E1α molecules using isoelectric focusing shows a range of events, with some molecules having 2 or 3 phosphorylations, while a large fraction of the E1α remains unphosphorylated in hypoxia. This type of pattern suggests a non-random phosphorylation of the multiple sites.
Analysis of PDH activity supports the in vitro findings that any single phosphorylation event is sufficient to inhibit PDH complex activity. Preliminary mitochondrial oxygen consumption experiments show that colorectal cancer cells are less dependent on PDHK1 for regulating mitochondrial function compared to published data in pancreatic and head and neck cancer. Finally, analysis of PDH phosphorylation in mice supports a role for PDHK1 in the regulation of PDH activity in response to fasting and blood glucose levels.
In conclusion, regulation of PDH in normal and cancerous colonocytes appears to be sensitive to environmental oxygen and nutrients. PDHK1 is the PDHK family member with the greatest influence on the addition of non-random inhibitory phosphorylation events. These in vitro findings will be analyzed with respect to the findings obtained using the new PDHK1 fl/fl villin Cre mouse.
Citation Format: Wendi O'Neill, Tereza Golias, Martin Benej, Nicholas Denko. Phosphoproteomic analysis of pyruvate dehydrogenase in response to environmental stress [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 5467. doi:10.1158/1538-7445.AM2017-5467
Abstract 5469: Low dose ionizing radiation induces persistent activation of NADPH oxidase pathway in mouse colon
Authors: Kumar Santosh , Suman Shubhankar , Moon Bo-Hyun , Fornace Albert J. , Datta Kamal 
Published: July 2017

Abstract
Exposure to ionizing radiation has been linked to persistent oxidative stress. The purpose of the current study was to characterize the role of NADPH oxidase pathway in radiation-induced increased oxidant production in colon epithelial cells. Mice (C57BL/6J; 6-8 weeks, male) were exposed to either sham or 0.5 Gy γ radiation, and NADPH oxidase pathway and oxidative stress markers were assessed in colon samples 60 d after exposure. Radiation exposure led to higher elevation of 4-HNE and 8-oxo-dG staining relative to unirradiated control. We also observed increased staining for the proliferative marker phospho-histone H3 in colon sections of irradiated mice. PCR analysis showed increased expression of two NADPH oxidase isoforms, Nox1 and Nox3, in irradiated samples. Additionally, expression of NoxA1 and Noxo1 along with Hif1α were also increased after radiation. Immunoblot analysis confirmed the PCR results, and ChIP assay revealed greater binding of stress response factor GATA6 and Hif1α to Nox1 and Nox3, and Nox3 promoters respectively after radiation exposure relative to control. Co-immunoprecipitation experiments show enhanced binding of Rac1, an activator of NADPH oxidase, to Nox1 and Nox3. In summary, we demonstrated that exposure to a low dose of γ radiation caused long-term upregulation of NADPH oxidase isoforms as well as its regulators and activators such as NoxA1, Noxo1, Hif1α, TLR4, GATA6, Doux1, and Doux2. When considered along with our results on oxidative stress and proliferative markers, our observations on NADPH oxidase pathway provides new insight into molecular events contributing to radiation-induced persistent oxidative stress and cell proliferation in colon, and have implications for colorectal carcinogenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Santosh Kumar, Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace, Kamal Datta. Low dose ionizing radiation induces persistent activation of NADPH oxidase pathway in mouse colon [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 5469. doi:10.1158/1538-7445.AM2017-5469