bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2992: The landscape of long non-coding RNAs in cancer
Authors: Niknafs Yashar S. , Iyer Matthew K. , Chinnaiyan Arul M. 
Published: August 2015

Abstract
Long non-coding RNAs (lncRNAs) are emerging as important players in cancer. The emergence of high-throughput RNA sequencing (RNA-Seq) technology provides a revolutionary means for systematic discovery of transcribed elements. However, efforts to catalog lncRNAs have thus far failed to appreciate the transcriptional robustness and complexity in the human genome because they were confined to select cell lines or small numbers of mostly normal tissue.
In order to delineate genome-wide lncRNA expression, we curated 7,256 RNA-Seq libraries comprising over 43 terabases of sequence from 25 independent studies including tumors, normal tissues, and cell lines. The data were processed using ab initio transcriptome meta-assembly methodologies to develop a consensus of 91,013 expressed genes. Over 68% (58,648) of genes were classified as lncRNAs, of which 79% (48,952) were previously unannotated. About 1% (597) of the lncRNAs harbor ultraconserved elements and 7% (3,900) overlap disease-associated single nucleotide polymorphisms (SNPs). To prioritize lineage-specific, disease-associated lncRNA expression, we developed a non-parametric method for differential expression testing called Sample Set Enrichment Analysis (SSEA), and nominated 7,942 lineage- or cancer-associated lncRNA genes. In order to interrogate potential functionality for these lncRNAs, gene set enrichment testing was performed on genes correlated with each lncRNA.
By uncovering this expansive landscape of cancer-associated lncRNAs, we provide the scientific community a powerful starting point to begin investigating their biological relevance. We anticipate that the lncRNAs identified by this study, as well as the computational tools developed herein, will provide a foundation for lncRNA genomics, biomarker development, and the delineation of cancer disease mechanisms.
Citation Format: Yashar S. Niknafs, Matthew K. Iyer, Arul M. Chinnaiyan. The landscape of long non-coding RNAs in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2992. doi:10.1158/1538-7445.AM2015-2992
Abstract 2994: Clinical applications of comprehensive genome analysis of papillary renal cell carcinoma, type II
Authors: Kim Ji-Yeon , Lee Se-Hoon , Cha Soojin , Moon Kyung Chul , Kim Jong-Il , Heo Dae Seog 
Published: August 2015

Abstract
Purpose
Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell renal cell carcinoma (NCCRCC). Of PRCC, PRCC,type2(PRCC2) is known to have highly aggressiveness and relative drug resistance. In contrast of clear cell renal cell carcinoma (CCRCC), we poorly understand genetic alterations to drive PRCC2. Moreover, though many tyrosine kinase inhibitors (TKIs) are now available to treat PRCC, the predictive marker of TKIs is not in existence. Therefore, we aimed to analyze genetic alteration of PRCC2.
Patients and Methods
We performed whole-exome sequencing (WES) of DNA from 9 PRCC2 samples and matched normal tissue. In addition, whole-transcriptome sequencing (WTS) was conducted for 7 of these samples. We analyzed somatic mutations, copy number alterations, germ line mutations using WES data, pathway alterations and gene fusions through RNA expression data. We investigated the relationship between clinical prognosis and genetic alterations.
Results
Of nine samples, average non-silent mutation rate is 1.13 mutations per Mb (range, 0.49 to 2.14 mutations per Mbs). Forty-seven somatic mutations including SRRD(four), PKD1L2(three) and MX1(three) are discovered in more than 2 specimens. The genes associated to histone modification and ubiqutination are frequently altered. We found FH somatic mutation, a potent target of VEGFR TKI, in young female PRCC2 patient. Her tumor is extremely shrunk after 6cycles treatment and after that she received pazopanib for 52weeks maintaining effective response.
Conclusion
We suggest the possibility of translational research from sequencing data to real medical treatment of PRCC2. This pivotal study demonstrates that novel somatic FH mutation is the therapeutic target of VEGFR TKI. Therefore, further large scaled comprehensive genetic analysis of PRCC2 is required to propose personalized medicine for conquering papillary renal cell carcinoma, type 2.
Note: This abstract was not presented at the meeting.
Citation Format: Ji-Yeon Kim, Se-Hoon Lee, Soojin Cha, Kyung Chul Moon, Jong-Il Kim, Dae Seog Heo. Clinical applications of comprehensive genome analysis of papillary renal cell carcinoma, type II. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2994. doi:10.1158/1538-7445.AM2015-2994
Abstract 2999: DEC1 and DEC2 crosstalk between circadian rhythm and tumor progression
Authors: Sato Fuyuki , Muragaki Yasuteru 
Published: August 2015

Abstract
Circadian rhythms are tightly regulated by clock genes. It has been reported that clock genes plays important roles in biological function of normal cells. However, it is not well understood the function of clock genes in tumor cells. We showed that basic helix-loop-helix (bHLH) transcription factors, differentiated embryonic chondrocyte gene 1 (DEC1/BHLHE40/Sharp2/Stra13) and DEC2 (BHLHE41/Sharp1), are clock genes and play important roles in circadian rhythm, cell proliferation, apoptosis, hypoxia response, various stresses and epithelial-to-mesenchymal transition (EMT) in tumor cells. Various stresses, such as exposure to transforming growth factor-beta (TGF-β), hypoxia, cytokines, serum-free, and anti-tumor drugs affect DEC expression. The increased or decreased DEC expression by such stresses is involved in tumor progression. The evidence that DEC2 has circadian expression in implanted mouse sarcoma cells and negatively regulates VEGF expression under hypoxia. DEC1 has pro-apoptotic effects in human breast cancer cells, whereas DEC2 has anti-apoptotic effects. DEC1 induced EMT by TGF-β in human pancreatic cancer cells, whereas DEC2 suppressed EMT. Immunohistochemical analysis showed that DEC1 is highly expressed in tumor cells and the expression is involved in malignancy. On the other hand, DEC2 is little expressed in tumor cells compared with adjacent non-tumor cells. These findings suggest that DEC1 and DEC2 have different roles in tumor progression under circadian rhythm. DEC2 regulates the circadian rhythm and VEGF expression by negative feed-back system, and DEC1 and DEC2 regulates EMT by positive and negative feed-back system in tumor cells. So, DEC acts as “accelerator” and “brake” in tumor progression. In this study, we show current progress of the DEC genes in tumor progression.
Citation Format: Fuyuki Sato, Yasuteru Muragaki. DEC1 and DEC2 crosstalk between circadian rhythm and tumor progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2999. doi:10.1158/1538-7445.AM2015-2999
Abstract 300: increasing radiation dose enhances immunotherapy efficacy and together prolongs tumor dormancy in a subgroup of mice treated for advanced intracerebral melanoma
Authors: Smilowitz Henry M. , Micca Peggy , Sasso Daniel , Wu Qian , Dyment Nathanial , Kuo Lynn 
Published: August 2015

Abstract
Previously we developed a clinically relevant therapy model for advanced intracerebral B16 melanomas in syngeneic mice combining radiation and immunotherapies. Here seven days after B16F10Luc2 melanoma cells were implanted intracerebrally (D7), syngeneic mice with bioluminescent tumors that had formed (1E105 to 7E106 photons/minute (&gt;1E106, large (L); &lt;1E106, small (S)) were segregated into L/S-balanced subgroups. Then, mice received either radiation therapy alone (RT) or radiation therapy plus immunotherapy (RT plus IT). Radiation dose was varied (15, 18.75 or 22.5 Gray (Gy), given on D8), while immunotherapy was provided similarly to all mice. The data support the hypothesis that increasing radiation dose increases the efficacy of immunotherapy in a subgroup of mice. The tumors that were greatly delayed in beginning their progressive growth were bioluminescent in vivo–some for many months, indicating prolonged tumor “dormancy,” in some cases presaging long-term cures. Mice bearing such tumors far more likely had received radiation plus immunotherapy than radiation alone. Radiotherapy is a very important adjunct to immunotherapy; the greater the tumor debulking by radiation therapy, the greater should be the benefit to tumor immunotherapy.
Citation Format: Henry M. Smilowitz, Peggy Micca, Daniel Sasso, Qian Wu, Nathanial Dyment, Lynn Kuo. increasing radiation dose enhances immunotherapy efficacy and together prolongs tumor dormancy in a subgroup of mice treated for advanced intracerebral melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 300. doi:10.1158/1538-7445.AM2015-300
Abstract 3004: Contextual RNAi screen identifies ACLY and ACC1 as mediators of hypoxia-induced apoptosis through metabolic and transcriptional mechanisms
Authors: Keenan Melissa M. , Liu Beiyu , Tang Xiaohu , Wu Jianli , Cyr Derek , Stevens Robert D. , Ilkayeva Olga , Lucas Joseph , Muoio Deborah M. , Kim So Young , Chi Jen-Tsan 
Published: August 2015

Abstract
To become established as a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. While many stress-signaling mechanisms have been well-studied, much remains unknown about how tumor cells survive these stresses during tumor progression. To identify genes that modulate cellular survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that the genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis through both metabolic and transcriptional mechanisms. First, while depleting α-ketoglutarate in control cells, hypoxia unexpectedly increased levels of α-ketoglutarate in the cells depleted of ACC1 or ACLY. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis in a mitochondria-dependent manner. Second, loss of ACLY or ACC1 reduced protein levels and activity of the oncogenic transcription factor ETV4. Silencing of ETV4 protected cells from hypoxia-induced apoptosis and triggered remarkably similar global transcriptional responses as with silenced ACLY or ACC1. Importantly, within tumor expression datasets, ETV4 transcriptional activity was highly correlated with ACLY or ACC1 gene expression signatures. Therefore, ETV4 acted as a key regulator of the transcriptional output of lipogenic activity via ACLY or ACC1. These results reveal a novel interconnectedness between cellular metabolic and transcriptional responses for life or death decisions under stress. Since lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.
Citation Format: Melissa M. Keenan, Beiyu Liu, Xiaohu Tang, Jianli Wu, Derek Cyr, Robert D. Stevens, Olga Ilkayeva, Joseph Lucas, Deborah M. Muoio, So Young Kim, Jen-Tsan Chi. Contextual RNAi screen identifies ACLY and ACC1 as mediators of hypoxia-induced apoptosis through metabolic and transcriptional mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3004. doi:10.1158/1538-7445.AM2015-3004
Abstract 3005: Investigating the impact of hypoxia-induced changes in splicing on tumor microenvironment
Authors: Brady Lauren , Popov Vladimir , Ivan Mircea , Radovich MIlan , Koumenis Constantinos 
Published: August 2015

Abstract
Hypoxia is a cellular stress that influences both normal and tumor development. For many types of cancer, including head and neck carcinomas, tumor hypoxia shows a strong positive correlation with poor patient outcome. In order to gain a deeper understanding of the biology of the tumor microenvironment, we are investigating how transcription is differentially regulated in hypoxic compared to normoxic regions of tumors. Previously, we reported that the expression of over 500 genes differs between hypoxic and normoxic tumors. However, there has not yet been a global sequencing analysis of tumors to characterize hypoxia-induced differences in transcriptional regulation at base-pair resolution. To achieve this, we developed a method to isolate RNA from hypoxic regions of tumors in vivo and used this method to carry out deep RNA-sequencing of normoxic and hypoxic regions of human head and neck tumors grown in mice. Corresponding in vitro samples from cells cultured in 0.5% oxygen conditions (in which the only stress was hypoxia) were also sequenced. We used these data to examine which genes showed changes in isoform-level expression and to define hypoxia-mediated changes in splicing. The data revealed more than 1,000 hypoxia-responsive mRNA isoforms. Using a combined informatics approach to analyze both differential expression of alternatively spliced exons and entire isoforms, we observed that many hypoxia-induced isoforms showed changes in alternate last exons, retained introns and 3′ untranslated regions compared to the isoforms expressed in normoxic cells. Moreover, we observed global repression of genes involved in RNA processing and splicing, which may represent one mechanism to shift patterns in splicing and lead to expression of stress-induced isoforms. Differentially expressed isoforms include genes that play critical roles in fundamental processes involved in hypoxic adaptation, such as the translation, glycolysis and cell cycle. Therefore, we propose that alternative splicing plays a role in mediating tumor growth and survival in hypoxic conditions by regulating stress-responsive pathways.
Citation Format: Lauren Brady, Vladimir Popov, Mircea Ivan, MIlan Radovich, Constantinos Koumenis. Investigating the impact of hypoxia-induced changes in splicing on tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3005. doi:10.1158/1538-7445.AM2015-3005
Abstract 3007: Intracellular detection of hypoxia in live cells
Authors: Mandavilli Bhaskar S. , O'Grady Michael 
Published: August 2015

Abstract
Hypoxia is an important phenomenon in many physiological processes and involved in many human diseases including cancer. Inflammation can lead to significant hypoxia in tissues. The study of hypoxia has been complicated with the lack of proper instrumentation to induce hypoxia in cells and image cells under hypoxic conditions. Here, we describe a live cell-based method to conveniently measure hypoxia using a new Image-iT® Hypoxia Probe and a specialized microscope incubator which can control oxygen concentrations down to 1%, The Image-iT® Hypoxia Probe is an oxygen sensing fluorescent probe, is quenched with increasing oxygen concentrations, and has excitation and emission peaks of 483 and 616 nm respectively. The probe is sensitive to varying concentrations of oxygen and can detect as low as 1% O2 concentrations in cells. Imaging of cells with the Image-iT® Hypoxia Probe in the incubator prevents re-oxygenation of cells and gives more precise measurement of hypoxia in cells, allowing for reversible and dynamic measurements of hypoxia in cells. Using this system, we measured hypoxia in several cell lines including A549, HeLa and U-2 OS. The Image-iT® Hypoxia Probe is also very good at detecting hypoxia in 3D tumor spheroids generated using different methods. The new hypoxia probe gives good signal to noise with more than 3-fold changes at 5% O2 levels with robust statistics. The Image-iT® Hypoxia Probe provides a good system for precise, robust and reproducible measurements of hypoxia in cells.
Citation Format: Bhaskar S. Mandavilli, Michael O'Grady. Intracellular detection of hypoxia in live cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3007. doi:10.1158/1538-7445.AM2015-3007
Abstract 301: RealTVac, a novel strategy to treat advanced, late-stage tumors with real-time tumor vaccination
Authors: Jachimczak Piotr , Mitsch Andreas , Aigner Achim 
Published: August 2015

Abstract
Novel anti-cancer immune therapeutic strategies, like various new antibody formats and/or tumor vaccines, show promising results in patients. However, due to the “immune-escape phenomenon” driven by tumor-secreted Transforming Growth Factor-beta (TGF-beta), the host immune system of cancer bearing patients frequently fails to control tumor re-growth.
The RealTVac® approach aims at avoiding this “immune-escape phenomenon” by intratumoral inhibition of active TGF-beta isotypes while simultanously and synergistically inducing an efficient immune response by a highly potent combination of immune stimulating factors.
The synergistic effects of the proposed combination of a TGF-beta inhibitor with immunostimulating cytokines upon human immune cell activation are demonstrated in in-vitro experiments. Both, immune cell proliferation and tumor cell cytotoxicity were significantly enhanced. Initial experiments in a syngenic B16 melanoma xenograft model in immunocompetent mice indicate that the RealTVac® therapy of established subcutaneous B16 tumor xenografts reduced local tumor growth compared to untreated controls.
To summarize, the goal of the local application of RealTVac® is to allow the host immune system to scan in real-time all Tumor Associated Antigens (TAAs) being currently expressed by those tumor cells that are exposed to sufficient TGF-beta inhibition. The repetitive administration of the RealTVac® approach is furthermore expected to provide a continuous update of the immune response, reflecting the changing pattern of TAAs related to the dynamic intratumoral heterogeneity in malignant tumors.
Citation Format: Piotr Jachimczak, Andreas Mitsch, Achim Aigner. RealTVac, a novel strategy to treat advanced, late-stage tumors with real-time tumor vaccination. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 301. doi:10.1158/1538-7445.AM2015-301
Abstract 3011: Two-sided story of DNA repair proteins MRE11 and RAD51 in breast cancer
Authors: Yuan Shyng-Shiou F. , Hung Amos , Hou Ming-Feng 
Published: August 2015

Abstract
Background
DNA repair proteins are required for the maintenance of genome integrity in normal cells. However previous studies also showed that altered expression of MRE11 and RAD51, proteins crucial for DNA double-strand break repair, DNA replication, and telomere maintenance, are associated with cancer outcomes. In this study, we investigated the role of MRE11 and RAD51 in breast cancer in both clinical and in vitro settings.
Methods
The expression of MRE11 and RAD51 in breast tumor tissues were determined by immunohistochemistry, and associations with clinicopathological characteristics and overall survival were assessed using Cox proportional hazards regression models and Kaplan-Meier survival curves. The effect of altered expression of MRE11 and RAD51 on cell proliferation, invasion, and treatment resistance was assessed in vitro using breast cancer cell lines, with the underlying mechanisms explored. The effect of MRE11 and RAD51 overexpression on tumor growth was assessed in an orthotopic xenograft model. All statistical tests were two-sided.
Results
High MRE11 expression was statistically significantly associated with malignant cancer behaviors including increased tumor size and lymph node metastasis as well as resistance to radiotherapy and chemotherapy. MRE11 overexpression in breast cancer cell lines promoted cell proliferation through STAT3, cell cycle entry, invasion and migration, and radioresistance via enhanced DNA repair activity, and also inhibited apoptosis; knockdown of MRE11 had the opposite effect. In xenograft tumor-bearing mice, tumor growth was increased in MRE11-overexpressing group.
RAD51 was expressed both in the cytoplasm and nucleus of all the breast cancer and non-cancerous cell lines. Expression levels of cytoplasmic RAD51 were positively correlated with cancer stage, tumor size, lymph node metastasis in breast cancer patients. High expression of cytoplasmic RAD51 predicted a poor patient survival as well as resistance to radiotherapy and chemotherapy.
Conclusion
High MRE11 and RAD51 expression was associated with a more malignant behavior in breast cancer. MRE11 and RAD51 may serve as potential targets for therapeutic intervention against breast cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Shyng-Shiou F. Yuan, Amos Hung, Ming-Feng Hou. Two-sided story of DNA repair proteins MRE11 and RAD51 in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3011. doi:10.1158/1538-7445.AM2015-3011