tbuckley/cabot-search huggingface dataset:
Abstract 467: Analysis of human hypoxia related miRNAs in MDM2 transfected prostate cancer cells
Authors: Saad Ebrahim Alobid, Thiagarajan Venkatesan, Ali Alaseem, Khalid Alhazzani, Appu Rathinavelu
Journal: Cancer Research (2017)

Abstract Recent studies have shown the crucial role of miRNAs in regulating cancer initiation, progression and metastatic process via influencing gene expression patterns. However, the distinct mechanism by which miRNA regulates tumorigenesis remains as an area requiring detailed research investigations. In our earlier studies, we have demonstrated a positive correlation between MDM2 expression and hypoxia inducible factor -1alpha (HIF-1α) levels in both normoxic and hypoxic conditions using prostate cancer cell lines. Subsequently, we postulated that the upregulation of HIF-1α is most likely regulated by MDM2 in cancers cells that are positive for this gene expression. Hence, to confirm our hypothesis, we utilized miScript miRNA PCR Array analysis (Qiagen, USA) and compared the gene expression profile of the hypoxia signaling pathway in LNCaP (prostate cancer cells) and LNCaP-MST (MDM2 transfected prostate cancer cells) under normoxic conditions. This study was expected to outline how MDM2 impacts the differential expression of miRNAs and leading to enhancement of tumor angiogenesis via increase in HIF-1α or other genes of the hypoxia signaling pathway. Our preliminary data indicate that hsamiR99a5p, hsamiR125b5p, hsamiR1385p, hsamiR199b5p and hsalet7c5p are significantly upregulated in LNCaP-MST cells compared to LNCaP. In addition, some of the miRNAs such as hsalet7d5p, hsalet7e5p, hsalet7f5p, hsalet7g5p and hsalet7i5p are significantly downregulated in the same cells. Among the upregulated miRNAs, hsamiR125b5p emerged as an important gene that is known to downregulate the protein levels of hypoxia inducible factor 1alpha inhibitor (HIF1AN or FIH), which can normally inhibit the transcriptional activity of HIF-1α in both normoxic and hypoxic conditions. Therefore, overexpression of hsamiR125b5p seems to be associated with the increase in HIF-1α level. From the aforementioned findings, it is confirmed that the MDM2 overexpression is impacting miRNA levels such as hsamiR125b5p that are involved in hypoxia related signaling pathway. Thus, our results offer a convincing evidence that MDM2 can promote angiogenesis and increase metastatic potential of cancers through altering the miRNA expression levels. (The financial support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida is gratefully acknowledged). Citation Format: Saad Ebrahim Alobid, Thiagarajan Venkatesan, Ali Alaseem, Khalid Alhazzani, Appu Rathinavelu. Analysis of human hypoxia related miRNAs in MDM2 transfected prostate cancer 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 467. doi:10.1158/1538-7445.AM2017-467
Abstract LB-177: Chemopreventive effect of aged citrus peel (Chenpi) extracts against tumor initiator acetaminophen-induced hepatotoxicity through regulating Nrf2 pathway
Authors: Zi-Han Lin, Wan-Tzu Luo, Yen-Fan Chan, Zheng-Yuan Su
Journal: Cancer Research (2017)

Abstract The liver is a critical organ responsible for the major detoxification and metabolism in the human body. Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but it has been demonstrated to be a cancer-initiating agent to induce liver cancer. Aged Citrus peel (Chenpi, CP) is a Chinese herb with hepatoprotective potential to be usually used as foods in Taiwan. Three extracts of CP were prepared in this study, including water extract (CP-WE), ethanol extract (CP-EE), and water extraction residue ethanol extract (CP-WREE). Among these extracts, we found CP-WREE (100 μg/mL) can effectively enhance the Nrf2-ARE pathway in HepG2-C8 cell line which is stably transfected ARE-luciferase construct. CP-WREE (50 μg/mL) also exhibit a significant protective effect on the mouse AML12 hepatocytes from APAP-induced damage. We further find that CP-WREE enhances the activity of some glutathione-related enzymes and inhibits lipid peroxidation in AML12 cells. Furthermore, CP-WREE can also increase the expressions of Nrf2 and Nrf2 downstream enzymes while the expressions of some epigenetic modifying enzymes are regulated. Therefore, CP-WREE may have beneficial effects to protect liver carcinogenesis caused by APAP-induced damage through the regulation of Nrf2/antioxidant pathway as well as epigenetic modification. Citation Format: Zi-Han Lin, Wan-Tzu Luo, Yen-Fan Chan, Zheng-Yuan Su. Chemopreventive effect of aged citrus peel (Chenpi) extracts against tumor initiator acetaminophen-induced hepatotoxicity through regulating Nrf2 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 LB-177. doi:10.1158/1538-7445.AM2017-LB-177
Abstract 5574: Retinoic acid as a therapeutic adjuvant in low-grade gliomas
Authors: Aparna Rao, Xiaoran Zhang, Jason Kim, Alexander Pomerantz, Youngmi Kim, Eric Holland, Nduka Amankulor
Journal: Cancer Research (2017)

Abstract Introduction: Malignant gliomas are incurable brain tumors and the most common primary brain tumors in adults. Mutations in isocitrate dehydrogenase (IDH) are enriched in a subset of malignant low-grade gliomas (MLGGs) that arise as lower grade neoplasms and steadily progress to more aggressive and universally fatal glioblastomas (GBMs) usually within 5-10 years after initial diagnosis. Gliomas with IDH1/2 mutations are characterized by hypermethylation of multiple genes, including immune genes, thereby rendering them highly immune evasive. Retinol binding protein 1 (RBP1) gene, that encodes a protein involved in retinoic acid (RA) generation, is significantly hyper-methylated in IDH mutant cells. Since RA is instrumental in the induction of multiple immune genes including immune-activating ligands such as NKG2D ligands (NKG2D-L), we hypothesized that treatment of IDH mutant cells with RA will increase the expression of NKG2D-L on the tumor cells, leading to increased recognition and lysis by immune cells. In addition, we hypothesized that RBP1 methylation was crucial to development of the IDH mutant immune-evasive phenotype. Methods: Primary glioma cells (IDH WT and mutant) were treated with 1μM RA for 48 hours. The cells were assessed for changes in expression of NKG2D-L and other type-1 immune response genes. Effect of RA treatment on NK killing and immune cell chemotaxis were evaluated. We also assessed the impact of RBP1 knock-down in IDH WT cells. Finally, we evaluated the efficacy of RA as a therapeutic modality for low-grade gliomas in a murine model. Results: RA-treated IDH mutant gliomas had a higher expression of NKG2D-L and a higher sensitivity to killing by NK cells, when compared with untreated IDH mutant cells. RA treatment of IDH mutant cells also induced increased chemotaxis of NKs and CD8+ T cells in a CCL2-dependant manner. In addition, RA demonstrated superior anti-tumor efficacy in vivo, compared with controls. Finally, we demonstrated that RBP1 knock-down in IDH WT cells was sufficient to replicate the immune evasive phenotype observed in IDH mutant cells. Conclusions: RA treatment reverses the immune evasion in IDH mutant cells primarily by inducing the upregulation of NKG2D-L and by mediating increased NK and CD8+ T cell chemotaxis via CCL2 induction. Additionally, we established that RBP1 gene silencing is crucial for the development of the immune evasive IDH mutant phenotype. Note: This abstract was not presented at the meeting. Citation Format: Aparna Rao, Xiaoran Zhang, Jason Kim, Alexander Pomerantz, Youngmi Kim, Eric Holland, Nduka Amankulor. Retinoic acid as a therapeutic adjuvant in low-grade gliomas [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 5574. doi:10.1158/1538-7445.AM2017-5574
Abstract 1898: MEG3 as a competing endogenous RNA binds with miR-27a to promote PHLPP2 protein translation, and consequently impairs bladder cancer invasion
Authors: Chao Huang, Xin Liao, Jingxia Li, Chuanshu Huang
Journal: Cancer Research (2017)

Abstract Muscle invasion and metastasis of bladder cancer dramatically decrease survival rate, compared to 77% of 5 year survival rate of all bladder cancer, metastasis bladder cancer is only 5%. This truth implies that one of the therapeutic kernels of bladder cancer is to decrease, even block, its invasiveness. In the current study, we find that MEG3 is significantly downregulate in human muscle-invasive bladder cancer tissues compared with non-muscle invasive tissues. We also demonstrate the MEG3 strongly inhibits human bladder cancer cell invasiveness by acting as a ceRNA. We find that MEG3 competes with PHLPP2 mRNA for miR-27a binding, which leads to a decreased miR-27a activity, and subsequently reducing the translation inhibition of miR-27a to PHLPP2. The upregulated PHLPP2 decreases the c-Jun phosphorylation at Ser63/73, and in turn inhibits the c-Myc transcription and its mediated invasiveness of the bladder cancer cells. This is the first demonstration that MEG3 inhibits the invasiveness of human bladder cancer cells via negative regulation of c-Myc as a ceRNA. These findings not only provides a novel insight into understanding the mechanisms behind the MEG3 inhibiting the cancer cell invasion, but also reveals a potential targets for invasive bladder cancer prevention and therapy. Citation Format: Chao Huang, Xin Liao, Jingxia Li, Chuanshu Huang. MEG3 as a competing endogenous RNA binds with miR-27a to promote PHLPP2 protein translation, and consequently impairs bladder cancer invasion [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 1898. doi:10.1158/1538-7445.AM2017-1898
Abstract 4206: A high-throughput 3D tumor spheroid screening method for drug discovery using imaging cytometry
Authors: Leo Li-Ying Chan, Scott Cribbes, Sarah Kessel, Scott McMenemy, Jean Qiu
Journal: Cancer Research (2017)

Abstract There have been 1600 FDA approved drugs since their inception in 1938. Currently it costs approximately 883 million dollars to bring a drug candidate to the market, and often times the potential candidate fails at the beginning of the clinical phase. Therefore, it is important to develop drug screening methods that are more clinically relevant or predictable. The current 2D methods for cancer drug discovery have had some difficulty in identifying potential drug candidates that can be used for clinical testing. To overcome this challenge, there has been an increase in research of 3D tissue culture that facilitated the development of new in-vitro tumor model assays. Traditional 3D spheroid analysis method relied heavily on visual observation using standard microscopy, which is time-consuming and has high operator variations. In the recent years, high-throughput image-based cytometers, such as Celigo, have demonstrated the ability to perform bright-field and fluorescence cell-based assays. Celigo imaging cytometer can be employed to rapidly analyze and characterize 3D tumor spheroids, which can be used to generate both quantitative and qualitative results. In this work, we demonstrate a high-throughput 3D tumor spheroid screening method using the Celigo imaging cytometer to screen the effects of 14 drug compounds (NIH/NCAT) on U87MG spheroid size, matrigel invasion, and tumor spheroid viability. First, a dose response experiment is performed to screen the growth inhibitory effects of the drug compounds. In addition to direct spheroid size analysis, dose inhibitory responses of tumor invasion into the matrigel are also examined. Finally, the use of specific fluorescent dyes such as Calcein AM, PI, and Caspase 3/7 were used to screen drug induced cytotoxicity on the tumor spheroids. The results showed that Celigo imaging cytometer can quickly generate accurate growth inhibitory data to identify potential drug candidates. Furthermore, tumor invasion were clearly observed and quantified in the captured images, as well as fluorescent analysis of tumor spheroid viability. By utilizing the 3D spheroid screening method, researchers can rapidly characterize and quantify drug effects on tumor spheroids in a high-throughput format, which can improve the efficiency of identifying more qualified cancer drug candidates. Citation Format: Leo Li-Ying Chan, Scott Cribbes, Sarah Kessel, Scott McMenemy, Jean Qiu. A high-throughput 3D tumor spheroid screening method for drug discovery using imaging cytometry [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 4206. doi:10.1158/1538-7445.AM2017-4206
Abstract 3999: Cross talk between tumor cell derived HMGB1 and adaptive B cells in the tumor microenvironment of esophageal squamous cell carcinoma
Authors: Ngar Woon Kam, Xin-Yuan Guan, Dora Lai-Wan Kwong
Journal: Cancer Research (2017)

Abstract Esophageal squamous cell carcinoma (ESCC) is the most aggressive type of cancer among gastrointestinal cancers. The lack of effective anti-tumor immunity strategy for ESCC patients imposes urgent demand for new treatment paradigm. Tumor microenvironment (TME) is characterized by diverse cell populations (cancerous, immune cells, and pleiotropic nature of cytokines and inhibitory receptors) whose alternations are closely related with tumor progression. High mobility group box chromosomal protein 1 (HMGB1) has been recognized to be expressed in various tumor cells, and importantly it has also been identified as one of the key factors regulating inflammatory reactions. By comparing differentially expressed genes between ESCC tumors (T) and their corresponding non-tumorous (NT) tissues high-throughput transcriptome sequencing system (RNA-Seq, Illumina HiSeq 2500), we found that the ligands of TIM-3 (an inhibitory receptor), HMGB1 and galectin-9, but not, cell-surface phosphatidylserine, were overexpressed in all ESCC samples when compared to their NT counterparts. We further characterized HMGB1 and galectin-9 gene expression changes in 37 matched primary ESCC T and NT control samples by qRT-PCR. We found that HMGB-1 and galectin-9 mRNA is constitutively expressed in all samples, while ESCC T tissue significantly expressed ~2fold higher of HMGB-1, but not galectin-9, mRNA as compared to paired NT tissue. Histopathological characterization of ESCC tissue by sequential single staining for B-cells (CD20) and plasma cells (CD138), demonstrating that B cell infiltrate was dominated by CD20+ B cells lacking of terminal differentiation into plasma cells. Additionally, CD20+ B cells infiltrates were negative for CD27 (marker for memory B cells) and IgD (marker for naïve B cells). Additionally, we isolated CD20+ B cells from healthy peripheral blood mononuclear cells (PBMC), and stimulated with/without HMGB-1/IgM. Conditional medium (CM) were collected for foci formation and we found that ESCC cell lines KYSE30 and KYSE180 have better capacity for proliferation when culture with activated B cells CM as compared to unstimulated B cells. Collectively, we believe that the suboptimal clinical outcomes relies on CD20+HMGB1 receptor+ B cells that are exposed to high HMGB1 concentrations in the ESCC microenvironment may eventually become pro-tumor B cells subset. Citation Format: Ngar Woon Kam, Xin-Yuan Guan, Dora Lai-Wan Kwong. Cross talk between tumor cell derived HMGB1 and adaptive B cells in the tumor microenvironment of esophageal squamous cell carcinoma [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 3999. doi:10.1158/1538-7445.AM2017-3999
Abstract 3902: Interleukin-6 blockade, a novel cancer stem cell targeted therapy, attenuates lung cancer tissue construction
Authors: Hiroyuki Ogawa, Michiyo Koyanagi-Aoi, Yoshimasa Maniwa, Takashi Aoi
Journal: Cancer Research (2017)

Abstract Background: Lung cancer stem cells are considered to be responsible for lung cancer progression and metastasis. However, little is known about how they actually promote aggressive behaviors of lung cancer. Methods: We transduced OCT3/4, SOX2, and KLF4 (hereafter, OSK) into a KRAS-mutated (G12S) human lung adenocarcinoma cell line (A549) using retrovirus vectors. Dome-shaped colonies appeared in the OSK transduced A549 cells from 10 to 15 days after transduction. The colonies were picked up and sub-cultured. We named them OSK-A549-Colony cells. We evaluated cancer stem cell properties in the OSK-A549-Colony cells in terms of their chemo resistance, and sphere formation ability. We also assessed organoids constructing ability by co-culture with mesenchymal stem cells (MSCs) and human umbilical vein epithelial cells (HUVECs) on low attachment plates. To clarify the molecular mechanisms that determined the properties of the OSK-A549-Colony cells, we performed microarray analysis. We further analyzed the molecular mechanisms of organoids construction by OSK-A549-Colony cells and searched for a method to destroy them. Results: The induced OSK-A549-colony cells were significantly more resistant to cisplatin than the parental A549 cells. Sphere forming ability was enhanced in the OSK-A549-Colony cells. Co-culture with MSCs and HUVECs showed that only the OSK-A549-Colony cells were able to construct consolidated organoids in vitro that mimicked bona-fide human lung cancer tissues. We named them “lung cancer organoids”. We found that interleukin-6 (IL-6), which was the most differentially expressed gene in the OSK-A549-Colony cells by microarray analysis, facilitated the formation of lung cancer organoids via the conversion of MSCs into alpha-smooth muscle actin (αSMA)-positive cells. Surprisingly, the combination of anti-IL-6 antibody and cisplatin could destroy the lung cancer organoids, while cisplatin alone could not. Conclusion: By transducing defined factors, A549 cells acquired lung cancer stem cell like properties. Analysis of chemosensitivity using the lung cancer organoids showed that the combination of IL-6 blockade and cisplatin could be a novel therapy targeting lung cancer stem cells. Citation Format: Hiroyuki Ogawa, Michiyo Koyanagi-Aoi, Yoshimasa Maniwa, Takashi Aoi. Interleukin-6 blockade, a novel cancer stem cell targeted therapy, attenuates lung cancer tissue construction [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 3902. doi:10.1158/1538-7445.AM2017-3902
Update: Temporary Total Depletion of U.S. Licensed Yellow Fever Vaccine for Civilian Travelers Addressed by Investigational New Drug Use of Imported Stamaril Vaccine
Authors: Mark D. Gershman, Mark J. Sotir
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Sanofi Pasteur, the manufacturer of the only yellow fever vaccine (YF-VAX) licensed in the United States, has announced that their stock of YF-VAX is totally depleted as of July 24, 2017. YF-VAX for civilian use will be unavailable for ordering from Sanofi Pasteur until mid-2018, when their new manufacturing facility is expected to be completed. However, YF-VAX might be available at some clinics for several months, until remaining supplies at those sites are exhausted. In anticipation of this temporary total depletion, in 2016, Sanofi Pasteur submitted an expanded access investigational new drug application to the Food and Drug Administration to allow for importation and use of Stamaril. The Food and Drug Administration accepted Sanofi Pasteur's application in October 2016.
Abstract 723: Improved detection of cancer specific serum exosomal aspartyl (asparaginyl) beta hydroxylase (HAAH)
Authors: Mark A. Semenuk, Anokhi S. Cifuentes, Eleanor R. Ghanbari, Michael S. Lebowitz, Hossein A. Ghanbari
Journal: Cancer Research (2017)

Abstract By means of an ELISA, we have found the pan-cancer biomarker HAAH to be closely associated with serum exosomes primarily in cancers of the breast, lung, colon, and prostate. This new understanding of the HAAH target has led to a dramatically improved serological detection assay, and in turn diagnostic reagent kit. In keeping with the multivalent particulate nature of exosomes, appropriately reformatting the ELISA assay has yielded a simplified so-called simultaneous-homologous format. Currently in this format, a single monoclonal anti-HAAH antibody (FB50) serves both as microplate capture and as a biotinylated detector. All reagents, including peroxidase-streptavidin, are co-incubated in the FB50- coated microplate simultaneously with serum samples, in the absence of intervening sequential steps. This considerably shorter exosome-enabled ELISA format requires half the time and yields generally on average a two-fold or higher increase in detection of HAAH. This format was evaluated with over 100 banked serum samples from several early stage cancers. While increasing the sensitivity for HAAH in cancer samples, the improved detection and performance has not caused any undesirable increases in false positives among more than 30 normal serum samples from healthy subjects. The reagent kit components include recombinant HAAH calibrators, positive /negative controls, vialed detection reagents and a Mylar packaged FB50 pre-coated microplate. The simplified reagent kit format has yielded close inter-operator and day to day trending consistency with a limit of detection (LOD) of 3 ng/mL. Recognizing the exosomal nature of the HAAH target has resulted in some changes in blood sample procurement, sample processing, and sample shipping. Such field testing of the HAAH reagent kit was recently done with serum samples from 48 high risk or mildly symptomatic volunteers with general concerns about cancer. Upon testing these samples 9 had an HAAH level greater than 3.0 ng/ mL (range 4.2 to 116.7) and 39 had less than 3.0 ng/ mL. Based upon the post-analysis diagnostic determination, there were two false negatives and one false positive, hence an overall accuracy of 93.8%. Citation Format: Mark A. Semenuk, Anokhi S. Cifuentes, Eleanor R. Ghanbari, Michael S. Lebowitz, Hossein A. Ghanbari. Improved detection of cancer specific serum exosomal aspartyl (asparaginyl) beta hydroxylase (HAAH) [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 723. doi:10.1158/1538-7445.AM2017-723