tbuckley/cabot-search huggingface dataset:
Abstract 476: MicroRNA mediated regulation of ATF5 contributes to homeostasis and benign to malignant transformation in breast cancer cells
Authors: Kari Ann Gaither, Bhanupriya Madarampalli, David X. Liu
Journal: Cancer Research (2017)

Abstract The transcription factor ATF5 modulates survival, proliferation, differentiation, and homeostasis. In unstressed conditions, ATF5 has a short half-life and is rapidly degraded due to post-translational modifications. Conversely, ATF5 is upregulated in cells under cellular stress. Furthermore, we have found that ATF5 is elevated and is a survival factor in transformed C6 glioma and MCF7 breast cancer compared to non-transformed cells. Regulation of ATF5 expression is not fully understood. We hypothesized that microRNA (miRNA) play a role in regulating the expression of ATF5 at the 3’ UTR and sought to better understand the role of ATF5 in the transformation to a malignant cell phenotype. To date, no studies have examined the regulation of ATF5 by miRNA. MiRNAs are endogenous small non-coding RNAs 20-25 nucleotides in length that contribute to regulation of gene expression at the translational level. We used in silico modeling programs to identify miRNAs predicted to bind to the 3’ UTR of ATF5. We then aimed to identify the presence of specific miRNA and their ability to downregulate ATF5 during cellular stress and other physiological conditions in vitro. Luciferase reporter assays and immunoprecipitations of ATF5 3’ UTR mRNA and cell lysate were performed and microRNA quantity analyzed via qPCR analysis. Subsequently, transfections of precursor microRNA were carried out in human MCF10A breast epithelial, MCF7 mammary epithelial, and breast adenocarcinoma MDA-MB-231 cell lines, and expression levels of ATF5 were measured under varying physiological conditions via Western Blot analysis. In vitro migration and invasion assays were performed and transformation was studied via MCF10A mammary epithelial cells with inducible SRC. We demonstrate that miRNA are bound to the 3’ UTR of ATF5 and that miRNAs 433-3p and 520b help to regulate the expression of ATF5 under varying stress conditions and at steady state in MCF10A, MCF7, and MDA-MB-231 cells. Additionally, preliminary data indicate that ATF5 is upregulated during transformation of MCF10A cells with inducible SRC and is overexpressed in MDA-MB-231 cells as compared to MCF7 and MCF10A cell lines, and suggest that ATF5 may enhance migration and invasion. Further studies are necessary to elucidate the role of ATF5 in transformation, migration, and invasion. Better understanding of the regulation of ATF5 could have implications in a broad range of human malignancies. Citation Format: Kari Ann Gaither, Bhanupriya Madarampalli, David X. Liu. MicroRNA mediated regulation of ATF5 contributes to homeostasis and benign to malignant transformation in breast 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 476. doi:10.1158/1538-7445.AM2017-476
Abstract 1573: Detection of late-arising driver mutations using multi-sample tumor sequencing data
Authors: Karen Gomez, Sayaka Miura, Sudhir Kumar
Journal: Cancer Research (2017)

Abstract Whole-genome sequencing of tumors has identified genetic mutations that drive the origination, growth, and spread of cancer. Most driver mutations detected from sequencing tumors have been categorized as early-occurring and are believed to play a role in initial tumor formation. However, single-region primary tumor samples represent just one snapshot of the continuously changing mutational landscape of a tumor. Drivers of initial tumor formation, occurring early on in tumor development, are present in more tumor cells and are more likely to be identified from a single tumor sample than drivers of later events like metastasis, which are likely to be found in only one or a few tumor samples. We analyzed 101 multi-region and/or multi-tumor sequencing data sets using driver mutation annotation and phylogenetic inference to determine whether driver mutations occur preferentially early on. We found driver mutations frequently arise late in the course of tumor evolution, even when statistically accounting for small amounts of total drivers and many early total mutations. In addition, the timing of driver mutation occurrence varies widely depending on cancer type as well as among different individuals with a single cancer subtype. Finally, we identify known cancer genes that are enriched in either early or late driver mutations, reflecting different selective pressures at various stages of cancer development. These results illustrate how drivers of primary tumorigenesis must be distinguished from drivers of treatment resistance, metastasis, or recurrence in order to better understand the genetic changes behind cancer progression. Citation Format: Karen Gomez, Sayaka Miura, Sudhir Kumar. Detection of late-arising driver mutations using multi-sample tumor sequencing data [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 1573. doi:10.1158/1538-7445.AM2017-1573
Abstract 5856: Molecular mechanism underlying breast cancer cell radioresistance: role of radiation-induced NF-KB self-sustenance
Authors: Hui Yu, Natarajan Aravindan, Ji Xu, Mohan Natarajan
Journal: Cancer Research (2017)

Abstract Understanding the mechanism of breast cancer cell radioresistance and the associated selection pressure, tumor recurrence, would help us to develop molecular interventions and achieve disease/progression-free survival in patients with cancer. In the present study, we investigated the molecular mechanisms prompted in breast cancer cells in response to clinical radiation and the associated coordination of intra- and inter-cellular signaling that orchestrate radioresistance and tumor relapse/recurrence. Our findings showed that clinical doses of radiation increase NF-κB transcription and DNA-binding activity. Further, radiation exposure resulted in de novo TNF-α synthesis and secretion. An NF-κB gene manipulation approach revealed that NF-κB triggered NF-κB-mediated TNF-α transcriptional activity. NF-κB DNA binding kinetic analysis demonstrated both sustained and dual phase NF-κB activation with radiation. Radiation prompted NF-κB-dependent synthesis/secretion of TNF-α, a requisite for the second phase of NF-κB activation and maintenance. Radiation-associated NF-κB-dependent secretion of TNF-α from irradiated cells also activated NF-κB in the non-irradiated, non-targeted bystander cells. Together, these findings demonstrated that radiation-triggered NF-κB-dependent TNFα secretion is critical for self-sustenance of NF-κB (through autocrine positive feedback signaling) and for coordinating bystander response (through intercellular signaling: de novo activation of NF-κB in bystander cells) after radiation exposure. Further, the data suggest that this NF-κB→TNF-α→NF-κB feedback-dependent self-sustenance of NF-κB could drive the selection pressure (proliferation, clonal expansion) of surviving breast cancer cells and subsequent tumor relapse/recurrence. Note: This abstract was not presented at the meeting. Citation Format: Hui Yu, Natarajan Aravindan, Ji Xu, Mohan Natarajan. Molecular mechanism underlying breast cancer cell radioresistance: role of radiation-induced NF-KB self-sustenance [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 5856. doi:10.1158/1538-7445.AM2017-5856
Abstract 4312: Targeting FoxM1 in inducing anticancer effects in triple-negative breast cancer cells
Authors: Rong Bu, Abdul K. Siraj, Maqbool Ahmed, Fouad Al-Dayel, Khawla S. Al-Kuraya
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC) is highly aggressive and a major threat to survival due to absence of molecular targets. Invasion, metastasis and chemoresistance are the greatest obstacles to the successful tumor treatment in breast cancer patients. In this study, over-expression of Forkhead box transcription factor M1 (FoxM1) was observed in 79% (770/975) of breast cancers from Saudi Arabia. FoxM1 over-expression was found to be an independent prognostic marker in multivariate analysis in late stage (Stage 3 and 4) breast cancer (p=0.0110). Our in vitro results show that treatment with thiostrepton, a dual FoxM1 and proteasome inhibitor caused cell viability loss and induce apoptosis in a dose dependent manner in triple-negative breast cancer cell lines. Thiostrepton treatment also inhibited colony formation and invasion/migration capabilities of triple-negative breast cancer cells. In vivo, thiostrepton treatment regressed TNBC cells; MDA-MB-231 generated xenografts via down-regulation of FoxM1 and its downstream targets. Altogether, our results suggest that FoxM1 and its associated signaling pathway may be a potential target for therapeutic intervention in the treatment of aggressive breast cancer. Key words: Triple-negative breast cancer, FoxM1, Apoptosis and Invasion Citation Format: Rong Bu, Abdul K. Siraj, Maqbool Ahmed, Fouad Al-Dayel, Khawla S. Al-Kuraya. Targeting FoxM1 in inducing anticancer effects in triple-negative breast 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 4312. doi:10.1158/1538-7445.AM2017-4312
Abstract 4322: Exosomal delivery of stroma-derived miR-145 inhibits pancreatic cancer cell proliferation
Authors: Song Han, Sayali Belsare, DongYu Zhang, Mark Beveridge, Carlos Rinaldi, Jose G. Trevino, Thomas D. Schmittgen, Steven J. Hughes
Journal: Cancer Research (2017)

Abstract We previously reported that within the pancreatic ductal adenocarcinoma (PDAC) microenvironment, miR-145 and miR-199a are exclusively expressed in tumor-associated stroma (TAS) cells, but these miRNAs are present in PDAC cells following co-culture with TAS cells. We hypothesized that miRNAs function as paracrine signals via exosomal exchange between TAS cells and adjacent PDAC cells. Primary cultures of human TAS and PDAC cells were employed. Membrane-bound microparticles were isolated from TAS conditioned, serum-free culture media by sequential ultracentrifugation followed by ultrafiltration. Exosomes and microvesicles were then assayed for particle size distribution using nanoparticle tracking analysis and electronic microscopy. miRNA expression levels were determined using quantitative PCR. miRNA transfection was performed with RNAiMax reagents. Cell viability was measured by Alamar Blue. Statistics were performed using Prism 6 software. Following transfection of human TAS cells with cel-miR-39, a nonhuman miRNA, we demonstrated that miRNA exchanges occurred between TAS cells and neighboring PDAC cells via a process that is not dependent upon cell-cell contact. We next confirmed the presence and enrichment of miR-145-5p in TAS-cell-derived exosomes (8-fold higher concentrations in exosomes than parental cells, p&amp;lt;0.05). Feeding of TAS-derived exosomes or transfection of miR-145-5p mimics into PDAC cells led to dose-dependent decreases in PDAC cell viability (p&amp;lt;0.05). Taken together, our data suggest that stroma derived exosomes deliver miRNAs to adjacent PDAC cells and may function as tumor-suppressing paracrine signals in the case of miR-145. This finding provides a potential explanation for the observation that stroma depletion paradoxically accelerates PDAC progression in murine models. Citation Format: Song Han, Sayali Belsare, DongYu Zhang, Mark Beveridge, Carlos Rinaldi, Jose G. Trevino, Thomas D. Schmittgen, Steven J. Hughes. Exosomal delivery of stroma-derived miR-145 inhibits pancreatic cancer cell proliferation [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 4322. doi:10.1158/1538-7445.AM2017-4322
Abstract 4687: Characterization of the cryoablation-induced immune response in kidney cancer patients
Authors: Taigo Kato, Tomoyuki Iwasaki, Motohide Uemura, Akira Nagahara, Hiroki Higashihara, Keigo Osuga, Yuji Ikeda, Kazuma Kiyotani, Jae-Hyun Park, Norio Nonomura, Yusuke Nakamura
Journal: Cancer Research (2017)

Abstract Cryoablation is one of promising treatment modalities for kidney cancer and expected to induce strong local immune response as well as systemic T cell-mediated immune reaction that may lead to regression of distant metastatic lesions. In this study, we collected tumor tissues from 14 kidney cancer patients, at the time points of pre-cryoablation and 3 months after cryoablation. In addition, blood samples were collected from 8 kidney cancer patients at the same time points. We applied a next generation sequencing approach to characterize T cell receptor beta (TCRB) repertoires using mRNA isolated from tumor tissues and peripheral blood mononuclear cells. To assess clonality of T cells, the diversity index of TCRB was calculated according to complementarity-determining region 3 sequences. Through TCRB repertoire analysis, we demonstrated expansion of certain T cell clones in tumor tissues by cryoablation. In addition, we found that proportions of abundant TCRB clonotypes (≥ 1% frequency among total TCRB reads) were significantly increased in the post-cryoablation tissue samples than those of pre-cryoablation tumor samples, suggesting that cryoablation could induce strong immune reactions in tumors with oligoclonal expansion of anti-tumor T cells. Interestingly, some of these TCRB clonotypes were also increased in peripheral blood, indicating that certain numbers of T cell clones may also circulate systemically and then attack tumor cells in distant regions. We also measured mRNA expression levels of immune-related genes in the tissue samples of pre- and post- cryoablation and found significantly elevated expression levels of CD8, CD4, Granzyme A, and CD11c along with high CD8/FOXP3 ratio in the post-cryoablation tissue samples. Furthermore, immunohistochemical analysis confirmed infiltration of a large number of CD11c-positive cells, probably representing macrophages and dendritic cells into the post-cryoablation tissues. Collectively, our findings revealed that cryoablation could induce both local and systemic immune responses associated with CD11c-positive cells infiltration and oligoclonal expansion of anti-tumor T cells. For the translation into clinics, unique TCR sequences identified in post-cryoablation tissues in individual patients can be applied to personalized TCR-engineered T cell therapy. Citation Format: Taigo Kato, Tomoyuki Iwasaki, Motohide Uemura, Akira Nagahara, Hiroki Higashihara, Keigo Osuga, Yuji Ikeda, Kazuma Kiyotani, Jae-Hyun Park, Norio Nonomura, Yusuke Nakamura. Characterization of the cryoablation-induced immune response in kidney 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 4687. doi:10.1158/1538-7445.AM2017-4687
Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and Patients with Chronic Obstructive Pulmonary Disease
Authors: Koralia E. Paschalaki, Anna Zampetaki, Jonathan R. Baker, Mark A. Birrell, Richard D. Starke, Maria G. Belvisi, Louise E. Donnelly, Manuel Mayr, Anna M. Randi, Peter J. Barnes
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Atrial Cardiomyopathy
Authors: Jean-Baptiste Guichard, Stanley Nattel
Journal: Journal of the American College of Cardiology (2017)

The term atrial cardiomyopathy, which has been used sporadically in the medical literature, was recently the subject of a detailed Consensus Document prepared by representatives of the European Heart Rhythm Association, Heart Rhythm Society, Asia-Pacific Heart Rhythm Society, and Sociedad Latinoamericana de Estimulación Cardiaca y Electrofisiología. They discussed aspects of the definition, histopathology, atrial-specific physiology, atrial pathology, impact on arrhythmia occurrence, imaging, mapping, and ablation. Here, the authors consider critically the added clinical value of this concept and its meaningfulness. They review evidence implicating atrial cardiomyopathy as an independent contributor to the risk of stroke associated with atrial fibrillation and as a determinant of arrhythmia progression. The issue of classification is considered and the authors discuss how atrial cardiomyopathic properties might guide stroke prevention, rhythm maintenance, and rate control in atrial fibrillation. Carefully designed clinical trials are needed to evaluate these potential applications, and will ultimately define the value of this terminology.
Abstract 809: A novel woodchuck model of hepatic artery infusion (HAI) with FACT complex targeted drug CBL0137
Authors: Minhyung Kim, Leslie I. Curtin, Colin A. Powers, Sandra Sexton, Katerina V. Gurova, Andrei V. Gudkov, Renuka V. Iyer
Journal: Cancer Research (2017)

Abstract Background: The liver has unique anatomy in that most blood flow to normal hepatocytes is derived from the portal venous system, while liver tumors obtain their nutrient blood supply exclusively from the hepatic artery. Hepatic artery infusion (HAI) concentrates chemotherapy agents delivering them directly to the tumor bed with the first-pass effect. Although, HAI chemotherapy as a regional therapy has been used clinically for decades in the treatment of both primary and metastatic cancers of the liver, significant toxicity remains a concern, and clinical results have been mixed. The purpose of this study was to establish preclinical HAI model in a woodchuck and administer the FACT (facilitates chromatin transcription) complex targeted drug CBL0137. Material and methods: Woodchuck hepatitis virus infected Eastern Woodchucks (Marmota monax) were used for the study. Hepatocellular carcinoma (HCC) developed spontaneously about 18 months after birth. The size of HCC was monitored with ultrasound every 2 weeks, and 4 woodchucks bearing over 2 cm tumors were used for the experimental group. Prophylactic cholecystectomy was performed first, and then a 2Fr. (ID=0.012”, OD=0.025”) vascular access port (VAP) was implanted in the gastroduodenal artery (GDA) after collateral vessel ligations. HAI was performed at room temperature via a VAP using 15mg/kg of CBL0137 at a volume of 3 mL/kg for 30 minutes, and tumor responses were investigated with MRI on day 0 (the surgery day of HAI port) and day 7 after HAI. Results: Anatomy variations existed in the size and location of the supraduodenal artery or pancreatico-duodenal artery. 4/4 success rate of a port implantation was achieved without mortality, but 1/4 animals suffered post-operative bleeding at the port head site, attributed to coagulopathy secondary to hepatic dysfunction. And, 4/4 animals were partially anorexic for up to 7 days post-surgery. Decreased tumor volume and Ktrans (a measure of capillary permeability) were detected 7 days after single HAI with CBL0137. Conclusion: Although the anticancer effect of CBL0137 on HCC was not clear because of a lack of the control group, we successfully implanted a VAP into the GDA of 4 woodchucks bearing unresectable HCC for HAI. The described woodchuck model may serve as a platform for identifying novel drugs and optimal conditions for the treatment of primary and metastatic liver tumors. Citation Format: Minhyung Kim, Leslie I. Curtin, Colin A. Powers, Sandra Sexton, Katerina V. Gurova, Andrei V. Gudkov, Renuka V. Iyer. A novel woodchuck model of hepatic artery infusion (HAI) with FACT complex targeted drug CBL0137 [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 809. doi:10.1158/1538-7445.AM2017-809
Abstract 810: Establishing patient derived preclinical in vitro and in vivo models of pediatric brain cancers
Authors: Sridevi Yadavilli, Madhuri Kambhampati, Jamila Gittens, Eshini Panditharatna, Mojca Stampar, Lindsay B. Kilburn, Suresh Magge, Roger J. Packer, Javad Nazarian
Journal: Cancer Research (2017)

Abstract The recent surge in understanding genomic aberrations of some of the deadliest childhood brain cancers has highlighted the need for robust preclinical models. Such models will allow for robust drug screening and preclinical evaluation of efficacy, toxicity, and tumor penetrance in vivo. Given the rarity and importance of patient derived specimens, handling and processing methods are perhaps the most critical steps for successful establishment of viable and reproducible in vitro and in vivo models. Since specimen source varies (biopsy, autopsy, or cryo-preserved), processing methods should be refined to allow for optimal extraction of maximum numbers of viable cells from each specimen type. We have developed standardized procedures for handling and processing of tissue samples obtained from biopsy, autopsy, or cryo-preserved specimens as well as necropsy tissue obtained from existing xenograft models. Two processing methods for generating viable cell suspensions are described. The first method, which uses collagenase-DNAse mediated digestion of the tissue is efficient with bulky samples and can be used with tissues obtained at autopsy. The second method uses a commercially available enzymatic dissociation kit optimal for small volume samples such as biopsy, cryo-preserved and mouse necropsy specimens. We show that obtaining viable cell suspension from precious tumor tissue by these methods results in successful generation of pre-clinical in vitro and in vivo models of DIPG, pilocytic astrocytoma and medulloblastoma that represent the exact genetic makeup of the original patient tumor. We further demonstrate intracranial injections of these cells into P2 mice for generating orthotopic xenograft models of brainstem or cortical tumors. Our methods and results allow for rapid establishment of preclinical models using rare and valuable childhood brain tumor specimens. These pre-clinical models serve as valuable tools for understanding the molecular mechanisms of the disease, identifying targetable molecules, and screening of novel therapeutics. Citation Format: Sridevi Yadavilli, Madhuri Kambhampati, Jamila Gittens, Eshini Panditharatna, Mojca Stampar, Lindsay B. Kilburn, Suresh Magge, Roger J. Packer, Javad Nazarian. Establishing patient derived preclinical in vitro and in vivo models of pediatric brain cancers [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 810. doi:10.1158/1538-7445.AM2017-810