bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A2-08: Lymph node metastasis-related genes discovered through patient-derived xenograft models
Authors: Moon Hyeong-Gon , Moon Hyun Hye , Han Wonshik , Noh Dong-Young
Published: November 2015

Background PDX model (Patient-derived xenograft model), one of the several advanced techniques for researching cancer, have appeared to overcome and supplement limitation of cell line based cancer research techniques.

Purpose/ Methods To observe variation of gene level during organ-specific metastasis in breast cancer patients, we made PDX model after transplanting primary tissues from TNBC breast cancer patients to NOG-SCID mouse. Then we performed RNA sequencing and analyzed mRNA expression dataset using both metastatic tissues of axillary lymph node and tissues from xenograft tumor which was grown in mouse fat fad. Using breast cancer cell lines, selected genes from RNA sequencing and mRNA array dataset were examined their expression level by RT-PCR and qRT-PCR techniques. In addition, migration ability was also confirmed by migration assay in each cell line.

Results TMSB4X, ANXA2P2, RPLP1 and IGFBP2 were more expressed in LN metastatic tissues than primary tissues and MGP, PROM1, MIA, KRT17 and KRT15 were downregulated in LN metastatic tissues. As a result of RT-PCR, qRT-PCR and migration assay, we knew that TMSB4X, ANXA2P2 and RPLP1 were mostly expressed in 14 breast cancer cell lines except some cell lines, and MIA was highly expressed in TNBC cell lines except MDA-MB-453. In addition, Hs578T, MDA-MB-231, HCC70, HCC38 and BT20 cell line had much higher migration ability than other cell lines.

Discussion PDX model, generated by tissues from breast cancer patients, represents similar changes of gene expression or mutation as compared with the patients. In addition, PDX model can preserve gene expression patterns and mutation profiles. Therefore, candidate gene screening for lymph node metastasis in PDX model is a meaningful process for applying clinical study. Tumor metastasis ability is usually determined by migration or invasion ability of cancer cells, and specific signaling pathways that related to migration or invasion are also important to tumor metastasis mechanisms.

Citation Format: Hyeong-Gon Moon, Hyun Hye Moon, Wonshik Han, Dong-Young Noh. Lymph node metastasis-related genes discovered through patient-derived xenograft models. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-08.
Abstract A2-12: Opposing roles of the 19S regulatory and 20S core proteasomal subunits in controlling sensitivity to proteasome inhibitors
Authors: Cho Min Y. , Acosta-Alvear Diego , Kampmann Martin , Wild Thomas , Choudhary Chuna Ram , Weissman Jonathan S. , Walter Peter
Published: November 2015

Targeted therapies for cancer are often hindered by the variable genetic makeup within and between tumors. This hurdle makes the identification of therapeutic targets challenging. Genetic susceptibilities found within networks encoded in the genome of a cancer cell can provide such therapeutic opportunities. Essential cellular networks overseeing homeostasis are often rewired in tumors, providing a landscape where synthetic lethal pairs may exist. A prominent example is the susceptibility of multiple myeloma (MM) cells to proteasome inhibitors. Because of their highly secretory nature, the proteasomes of MM cells can be burdened in a load-versus-capacity tug-of-war. This renders MM cells sensitive to proteasome inhibitors. Unfortunately, single agent therapies against the proteasome do not provide a cure, as tumor cells often acquire resistance. Because of this, we sought to understand how MM cancer cells respond and adapt to proteasome inhibition. Utilizing ultra-complex shRNA libraries, we screened several MM cell lines exposed to the proteasome inhibitor bortezomib. In these screens, we identified several genes that either sensitize or protect MM cells towards bortezomib intoxication. Unexpectedly we found that, contrary to knockdown of genes encoding subunits of the 20S core particle of the proteasome, knockdown of genes encoding subunits of the 19S regulatory particle of the proteasome lead to bortezomib desensitization. To understand the nature of this phenotype, we queried proteome changes in bortezomib treated cells where we ablated a single 19S subunit. By performing ubiquitin-remnant profiling and total proteome SILAC experiments, we identified several proteins involved in autophagy and NF-κB signaling as potential mediators of the protective phenotype. We are currently investigating the roles of components of these pathways in tailoring the response towards bortezomib. We surmise that some of these will be amenable for pharmacological targeting in developing novel combination therapies.

Citation Format: Min Y. Cho, Diego Acosta-Alvear, Martin Kampmann, Thomas Wild, Chuna Ram Choudhary, Jonathan S. Weissman, Peter Walter. Opposing roles of the 19S regulatory and 20S core proteasomal subunits in controlling sensitivity to proteasome inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-12.
Abstract A2-21: Cancer malignancy induced by C-terminal truncated HBx in Huh-7 Hepatocellular carcinoma cells
Authors: Gal Myeong-Eun Je , Yi Eui-Yeun , Jung Seung-Youn , Kim Yung-Jin
Published: November 2015

Hepatitis B virus-encoded HBx is well known causative factor for the Hepatocellular carcinoma (HCC). HBx interferes with several signaling pathways that are associated with cell proliferation and apoptosis. HBx c-terminal region has been known to play important roles in HBV associated HCC. HBx C-terminal mutant was known to show increased proliferation and invasiveness. In this study, we investigated a molecular mechanism of cancer malignancy induced by C-terminal truncated HBx. Huh-7 Hepatocellular carcinoma cells stably transfected with C-terminal truncated HBx showed higher migrative and invasive phenotype. In addition, the cells were more resistant to doxorubicin compared to cells transfected with full-length HBx. We also observed a higher efflux activity in the cells transfected with C-terminal truncated HBx due to the increased expression of ABCB1. These results suggest that C-terminal truncated HBx up-regulate ABCB1 expression which results in the enhanced efflux of drug. Therefore cancer cells containing C-terminal truncated HBx acquire drug resistancy, and show more malignant phenotypes.

Citation Format: Myeong-Eun Je Gal, Eui-Yeun Yi, Seung-Youn Jung, Yung-Jin Kim. Cancer malignancy induced by C-terminal truncated HBx in Huh-7 Hepatocellular carcinoma cells. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-21.
Abstract A2-32: Identification of withaferin A as a novel cancer stem cell inhibitor to overcome drug resistance in non-small cell lung carcinoma
Authors: Cheng Tai-shan , Tsai Yu-Chen , Wu Alexander T. H. , Chang Peter M. H. , Hsu Wei-Hsiang , Lai Jin-Mei , Huang Chi-Ying
Published: November 2015

Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance. In this study, we focus on screening drugs that target CSCs to improve the current treatment outcome and overcome drug resistance in patients with lung cancer. We used publicly available embryonic stem cell and CSC-associated gene signatures to query the Connectivity Map (CMap) for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scores were noted for several phenothiazine-like antipsychotic drugs, including trifluoperazine and perphenazine. The combination of gemcitabine with either trifluoperazine or perphenazine shows synergistic effects in anti-NSCLC cells. By using L1000 and CMap analysis, we identified withaferin A (WA) as a potential drug, which shares similar gene expression patterns to trifluoperazine or perphenazine combine with gemcitabine and to reverse differential gene expression of stem-like cell vs. differential cell. Further experiments demonstrated that WA significantly suppressed cancer stemness associated phenotypes, shown by decreasing side population and tumor spheroid formation. Furthermore, WA was accompanied by down-regulation of JAK2/STAT3 signaling pathway. The combination of WA and cisplatin significantly reduced the number of cancer spheroids and attenuated the proportion of ALDH+ cell population in CL97 lung spheroids, which was resistant to cisplatin treatment alone. In vivo study also demonstrated the anti-tumor effect of WA treatment. In conclusion, WA was identified as a potential anti-cancer stem cell inhibitor, which could also inhibit tumorigenesis and overcome cisplatin resistance in lung cancer.

Citation Format: Tai-shan Cheng, Yu-Chen Tsai, Alexander T. H. Wu, Peter M. H. Chang, Wei-Hsiang Hsu, Jin-Mei Lai, Chi-Ying Huang. Identification of withaferin A as a novel cancer stem cell inhibitor to overcome drug resistance in non-small cell lung carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-32.
Abstract A2-33: Molecular profiling of patient-derived xenograft models across cancers
Authors: Kan Zhengyan , Rosfjord Edward , Hardwick James , Ding Ying , Zheng Xianxian , Fernandez Julio , Shi Stephanie , Ozeck Mark , Wang Hui , Troche Gabriel , Upeslacis Eric , Jackson-Fisher Amy , Ching Keith , Deng Shibing , Tao Xie , Chionis John , Lira Maruja , Li Xiaorong , Tsaparikos Konstantinos , Lappin Patrick , Vizcarra Pamela , Shields David , Lucas Judy , Rejto Paul
Published: November 2015

Patient-Derived Xenograft (PDX) provides important preclinical model for pharmacological testing of oncology drug candidates. Molecular profiling of PDX tumors contributes to many areas of drug discovery from target discovery to development of clinical biomarker hypotheses and clinical trial design. We established a work flow to perform genomic and histopathology analyses of large numbers of PDX tumor models being made available for Pfizer internal research. To date we have generated whole-genome sequencing (WGS), whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-Seq) data on PDX models spanning six cancer types including colon, pancreatic and breast cancers. Bioinformatics pipelines were developed to quantify gene expression and detect genetic alterations including mutation, copy number variations and gene fusions. A controlled evaluation study demonstrated that in silico classification of NGS reads into human/mouse origins is more effective than laboratory-based methods for removing mouse tissue contamination. Comparative analyses of molecular profiles from PDX and primary tumors of the same cancer origins suggest that important patterns of gene expression are retained by PDX models. An integrative genomic classifier was developed using the random forest algorithm, trained on primary tumor data, and shown to identify PDX cancer subtypes with high accuracy.

Citation Format: Zhengyan Kan, Edward Rosfjord, James Hardwick, Ying Ding, Xianxian Zheng, Julio Fernandez, Stephanie Shi, Mark Ozeck, Hui Wang, Gabriel Troche, Eric Upeslacis, Amy Jackson-Fisher, Keith Ching, Shibing Deng, Xie Tao, John Chionis, Maruja Lira, Xiaorong Li, Konstantinos Tsaparikos, Patrick Lappin, Pamela Vizcarra, David Shields, Judy Lucas, Paul Rejto. Molecular profiling of patient-derived xenograft models across cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-33.
Abstract A2-35: Discovery of differentiation therapeutics using a systems biology approach
Authors: Li Yulin , Seita Jun , Felsher Dean , Dill David
Published: November 2015

Accurately assessing the changes in cellular differentiation status in response to drug treatments or genetic manipulations is crucial for understanding the tumorigenesis process and developing novel therapeutics for human cancer. Here we have developed a novel systems biology approach, called the Lineage Maturation Index (LMI), to define the changes in differentiation state of cancer cells based on their gene expression profiles. We have been focusing on hematopoietic malignancies, but this approach is applicable to many human cancer types. We define the expression profile of N genes within a cell to be a point in an N-dimensional space. A lineage vector is derived from a progenitor cell (such as a hematopoietic stem cell) to a mature cell (such as a granulocyte) based on the expression of these N genes. By projecting the expression profile of an unknown cell onto the lineage vector, an LMI can be computed for the differentiation state of this specific cell. Upon drug treatments or genetic manipulations, a shift in LMI from stem cells towards mature cell types indicates differentiation. We have confirmed that the LMI approach can track the differentiation of normal hematopoietic cells. We have further shown that differentiation is a major consequence of various targeted therapies against leukemia irrespective of the driving oncogenes. Most importantly, we have used this approach to analyze the Connectivity Map HL60 leukemia data set for drugs that can induce leukemia cells to differentiate. In addition to drugs known to have differentiation activities (such as all-trans retinoic acid and etoposide), we discovered that several novel drugs (such as dihydroergotamine, mebendazole, and clonidine) have potent differentiation activities in leukemia cells. Currently, we are expanding our study into multiple types of solid tumors, such as breast, prostate, and colon cancers. Our LMI approach is highly robust in characterizing differentiation of the cancer cells and discovering novel differentiation therapies for human cancer.

Citation Format: Yulin Li, Jun Seita, Dean Felsher, David Dill. Discovery of differentiation therapeutics using a systems biology approach. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-35.
Abstract A2-40: TOMA OS-seq™: A high efficiency targeted resequencing strategy for detecting gene amplifications, rearrangements, indels, and point mutations in tumor DNA isolated from FFPE solid tumors and plasma
Authors: Bouhlal Yosr , McKenzie Alexander , So Austin P.
Published: November 2015

Critical genetic errors, namely specific mutations, are required for the development and maintenance of cancer. Molecular diagnostics that leverage the breadth of next-generation sequencing (NGS) to identify this mutational landscape are therefore becoming an important clinical tool in the precision treatment of cancer. However, widespread adoption of NGS technologies in the clinic is hampered by the complexity of the NGS workflow, and the resulting limits in analytical capabilities due to noise introduced by poor step-wise yields and bias arising from extensive application of PCR.

To address these deficiencies, we introduce TOMA OS-Seq™, a complete targeted resequencing workflow designed specifically for the requirements of the clinical laboratory. Based on oligo-selective sequencing, a panel of 96 genes - each with diagnostic or prognostic value - can be sequenced end-to-end from as little as 1 ng of input material, enabling the analysis of DNA purified from fine-needle aspirates and plasma. Utilizing a minimal number of high efficiency processing steps to create a targeted library, this simple workflow minimizes the requirement for PCR amplification, preserving the quantitative relationship among the loci interrogated in the original sample. TOMA OS-Seq™ is therefore capable of detecting of copy number alterations, in addition to rearrangements/fusions, insertions/deletions, and single nucleotide variants.

Citation Format: Yosr Bouhlal, Alexander McKenzie, Austin P. So. TOMA OS-seq™: A high efficiency targeted resequencing strategy for detecting gene amplifications, rearrangements, indels, and point mutations in tumor DNA isolated from FFPE solid tumors and plasma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-40.
Abstract A2-42: Identifying clinically important somatic mutations through a knowledge-based approach
Authors: Ainscough Benjamin J. , Griffith Malachi , Kunisaki Jason , Coffman Adam , McMichael Joshua F. , Eldred James M. , Walker Jason R. , Fulton Robert S. , Wilson Richard K. , Griffith Obi L. , Mardis Elaine R.
Published: November 2015

Large-scale tumor sequencing projects, like The Cancer Genome Atlas (TCGA), have implicated thousands of somatic mutations in cancer. These initiatives have incentivized many improvements in somatic variant detection. However, we have observed that important pathogenic variants are often missed due to stringent filtering, tumor heterogeneity, tumor contamination of normal, low tumor purity, alignment challenges, and other issues. These idiosyncrasies can impede variant detection algorithms from reliably calling even the most clinically relevant variants. To rescue this missed variation we devised a knowledge based variant identification strategy. We mined the literature and other variant databases for pathogenic variation and assembled them into an integrated Database of Curated Mutations(DoCM - www.docm.info). The DoCM contains 488 variants across 63 genes implicated in 34 cancer types. We developed an algorithm to identify any pathogenic variant signal, for all variants in the DoCM, in aligned sequence data. As a proof of principle, we applied this approach to four cancer types sequenced by TCGA: acute myeloid leukemia (AML), breast cancer, ovarian carcinoma, and uterine corpus endometrial carcinoma. Obvious sequencing and alignment errors, like variants in homopolymer runs, were excluded from subsequent analysis by manual review. Across these four TCGA projects, which includes 1,840 individuals, 1,757 clinically relevant variants were identified, 1,223 of which had not been previously reported in TCGA studies. To validate this approach, custom capture probes were designed for all of the DoCM variants, new libraries constructed and deep sequencing performed on 96 tumor and matched normal samples from the AML and breast cancer TCGA projects. Following this strategy, we were able to confirm the rescue of clinically relevant somatic mutations that were missed in the original TCGA analysis. We propose a knowledge-driven variant detection approach be considered as standard practice to avoid false-negative calls of events likely to be clinically relevant.

Citation Format: Benjamin J. Ainscough, Malachi Griffith, Jason Kunisaki, Adam Coffman, Joshua F. McMichael, James M. Eldred, Jason R. Walker, Robert S. Fulton, Richard K. Wilson, Obi L. Griffith, Elaine R. Mardis. Identifying clinically important somatic mutations through a knowledge-based approach. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-42.
Abstract A2-44: Stellaris® RNA fluorescence in situ hybridization (RNA FISH) for the detection of long non coding RNA biomarkers
Authors: Orjalo Arturo V. , Johansson Hans E.
Published: November 2015

Long non-coding RNAs (lncRNAs) play important roles in all the central aspects of the gene expression cascade with wide ranging effects on cell proliferation and differentiation. As such, lncRNAs are highly promising additions to many cancer biomarkers portfolios and enable more precise diagnostic staging. This, in turn, provides a clearer prognosis and treatment options of different cancers. Direct visualization and quantification of lncRNAs in single cells and in tissue are thus emerging as essential tools for both basic and clinical research. Interestingly, studies have demonstrated that transcript levels are more strongly correlated to clinical traits than the corresponding protein levels. Because RNA biomarkers have the potential to contribute to the development of targeted cancer therapies, there is also an obvious need for a robust and dependable methodology to discover and validate these RNAs.

RNA fluorescence in situ hybridization (RNA FISH) provides a powerful means to detect RNA biomarkers in single cells, while still maintaining tissue morphology. Significant advances in RNA FISH technology, such as the hybridization of pools of singly labeled fluorescent 20-mer oligonucleotides to the RNA target, now afford specific and sensitive multiplex detection of RNA to yield information on the RNA's distinct spatial distribution within cells and tissue.

Data is presented on the design of probe sets against multiple disease relevant pre-lncRNAs and against the introns of their precursors, as well as on the simultaneous dual-channel imaging of the pre-lncRNAs and mature lncRNAs. Because the absolute majority of post-transcriptional processing, including splicing of mRNAs and lncRNAs, occurs co-transcriptionally, the location of introns can be used as a proxy nuclear location for the encoding gene. We find mature lncRNAs to locate at or close to the site of transcription, but also well away from it. Next, we present data on emerging non-coding RNA biomarkers in breast and prostate cancer tissue and in cell lines utilizing RNA FISH.

In summary, the results and tools presented here will contribute to advancing the current capabilities of the detection and treatment of specific cancers, as well as in the continued discovery and development of cancer drug candidates.

Citation Format: Arturo V. Orjalo, Jr., Hans E. Johansson. Stellaris® RNA fluorescence in situ hybridization (RNA FISH) for the detection of long non coding RNA biomarkers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-44.
Abstract A2-47: Informatics framework for clustering and deriving gene signatures for prognostic stratification of cancer patients
Authors: Jung Segun , Bi Yingtao , Davuluri Ramana V.
Published: November 2015

Stratification of cancer patients into different molecular groups is essential for developing targeted therapies. High-throughput technologies, such as microarrays and next-generation sequencing, have been extensively used for generating multi-omics data. Indeed, The Cancer Genome Atlas (TCGA) consortium, one of the most comprehensive and popular databases of cancer, has been accumulating large volumes of invaluable data for more than 30 cancer types, offering unprecedented opportunity to attain new insights in cancer biology. Despite the technological advances, analyzing, integrating and translating the gene signatures across different platforms remains a computationally challenging task.

Here, we developed a novel computational framework that integrates genomic and clinical data to stratify cancer patients into different molecular subgroups and predict clinically applicable phenotypes, such as survival. Application of this user-friendly framework derives platform-independent isoform-level gene signatures that can be translated from high-dimensional platforms (e.g., RNA-Seq) to clinically adaptable low-dimensional molecular assays (e.g., RT-PCR) for prognostic stratification. We applied the pipeline on two TCGA lung cancer datasets—Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LUSC). Using independent test data, we achieved about 93% (LUAD) and 98% (LUSC) classification accuracy using less than 70 isoform-level gene signature. The proposed informatics platform is applicable to other cancer types in TCGA data portal.

Citation Format: Segun Jung, Yingtao Bi, Ramana V. Davuluri. Informatics framework for clustering and deriving gene signatures for prognostic stratification of cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-47.
Abstract A2-54: DNA methylation-dependent transcription regulatory networks elucidate dynamics of transcription regulatory circuitry in cancers
Authors: Liu Yu , Liu Yang , Xiao Zhengtao , Yang Xuerui
Published: November 2015

Context-dependent DNA methylation plays a critical role in regulating gene transcription, thereby serving as an important epigenetic marker or regulator in many biological activities such as pluripotency, development, and complex diseases such as cancer. However, previously in most of the de novo reconstructions of cancer type-specific transcription regulatory networks (TRN), DNA methylation has rarely been taken into account as a significant factor in regulating transcription factor activity and controlling gene expression. The present study was set to systematically assess the involvement of DNA methylation in transcription regulatory circuitry in cancer. We took advantages of the multi-dimensional profiling data of DNA methylations and gene expressions in tumor samples of different cancers in The Cancer Genome Atlas (TCGA) consortium, and developed an integrative analysis pipeline based on conditional mutual information theory, to quantify the cooperative regulatory effects of CpG site methylations and transcription factors on gene expressions, in a genome-wide scale. Our analysis showed that DNA methylation and transcription factors indeed control gene expressions often in duet. To map the interplay between these two major defining factors of gene expression, DNA Methylation-dependent Transcription Regulatory Network (MeTRN), the first of its kind, was assembled for each of 19 major cancer types in TCGA. MeTRN provides a comprehensive view specifically on DNA methylation-dependent transcription events in each cancer type, and has been largely validated by public ChIP-seq and DNaseI-seq data. Comparison of these networks across cancer types showed that context-specificity of transcriptional circuits can be largely attributed to the context-dependent nature of DNA methylation patterns. Therefore, by assembling the cooperative effects of transcription factors and DNA methylations on gene transcription, MeTRN recapitulates an epigenetic scheme that implements dynamics of transcription regulatory circuitry across cancers via context-dependent DNA methylation marks. Supported by extensive cross-validations and experimental evidence, this epigenetically marked and dynamic transcription regulatory circuitry serves as a new basis for further mechanistic studies of gene expression dysregulations in cancers.

Citation Format: Yu Liu, Yang Liu, Zhengtao Xiao, Xuerui Yang. DNA methylation-dependent transcription regulatory networks elucidate dynamics of transcription regulatory circuitry in cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-54.
Abstract A2-60: Phospho-proteomic analysis of MEK inhibition in mutant NRAS melanoma
Authors: Vu Ha Linh , Davies Michael A. , Aplin Andrew E.
Published: November 2015

Melanoma is a devastating form of skin cancer with limited therapeutic options. Fifteen to twenty percent of melanoma patients have an activating mutation in NRAS, a small GTPase. NRAS has several downstream effectors, the most well-characterized is RAF leading to activation of MEK/ERK. While there are no FDA-approved targeted therapies for melanoma patients with a primary mutation in NRAS, one form of targeted therapy that has been explored is MEK inhibition. Phase I to III studies of MEK inhibitors in mutant NRAS melanomas have shown disappointing clinical efficacy, the reasons for which are unclear. In 3D systems that mimic the dermal microenvironment, we found a heterogeneous response in our panel of mutant NRAS melanoma cells to the allosteric MEK inhibitor, trametinib. To explore the underlying basis of this heterogeneity, we utilized a high-throughput reverse-phase protein array (RPPA) platform to identify compensatory signaling alterations. The RPPA analysis of phospho-proteomic changes in NRAS mutant melanoma in response to trametinib indicated a compensatory increase in AKT signaling. Interestingly, we detected a decrease in mitogen inducible gene 6 (MIG6), a negative regulator of ERBB receptors. The overexpression of MIG6 led to a negative regulation of EGFR (ERBB1) and ERBB2, and subsequent decrease in AKT activation. Conversely, the depletion of MIG6 increased EGFR and ERBB2 signaling. Either depletion of MIG6 or addition of EGF increased migration of NRAS mutant cells treated with trametinib, an invasive phenotype that may mitigate the negative effects of trametinib on cell growth. Our results indicate a potential role for the combined inhibition of EGF/ERBB receptors and MEK in NRAS mutant melanoma patients.

Citation Format: Ha Linh Vu, Michael A. Davies, Andrew E. Aplin. Phospho-proteomic analysis of MEK inhibition in mutant NRAS melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-60.
Abstract PR14: Nucleation of transcriptional super-enhancers at tumor oncogenes
Authors: Abraham Brian J. , Kwiatkowski Nicholas , Weintraub Abraham S. , Hnisz Denes , Hannett Nancy , Young Richard A.
Published: November 2015

Transcriptional super-enhancers drive expression of oncogenes in many cancers and are being targeted with novel transcriptional and epigenetic therapeutics (1,2,3,4). Super-enhancers are acquired in cancers through multiple mechanisms, including DNA translocation of an extant super-enhancer and focal amplification. We recently discovered a novel mechanism by which super-enhancers are nucleated in T cell acute lymphoblastic leukemias (T-ALLs) (5). In this case, a small, monoallelic insertion creates a DNA binding site for a master transcription factor protein, which binds and recruits additional factors to nucleate the super-enhancer, which in turn drives high levels of the TAL1 transcription factor. We describe here a method for unbiased identification of similar genomic insertions that nucleate potentially oncogenic regulatory elements in cancers. This approach uses data from genome-wide ChIP-Seq studies that map locations of enhancer-binding proteins to identify sequences missing from reference genomes. We have found many additional genomic insertions in many additional cancers. I will describe new insights into the regulation of cancer that occur due to nucleation of novel regulatory elements.

1 Hnisz, Abraham, Lee, et al., Cell 2013

2 Loven, Hoke, Lin, et al., Cell 2013

3 Kwiatkowski, et al., Nature, 2014

4 Chipumoro, et al., Cell, 2014

5 Mansour et al., Science 2014

Citation Format: Brian J. Abraham, Nicholas Kwiatkowski, Abraham S. Weintraub, Denes Hnisz, Nancy Hannett, Richard A. Young. Nucleation of transcriptional super-enhancers at tumor oncogenes. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR14.
14 Years of Polish Experience in Non-Invasive Prenatal Blood Group Diagnosis
Authors: Orzińska Agnieszka , Guz Katarzyna , Dębska Marzena , Uhrynowska Małgorzata , Celewicz Zbigniew , Wielgoś Mirosław , Brojer Ewa
Published: November 2015

Background: Blood cell antigens may cause maternal alloimmunization leading to fetal/newborn disorders. Non-invasive prenatal diagnostics (NIPD) of the blood group permits the determination of feto-maternal incompatibility. Aim: To evaluate 14 years of blood group NIPD at the Institute of Hematology and Transfusion Medicine (IHTM) in Warsaw. Methods: Plasma DNA from 536 RhD-negative, 24 Rhc-negative, 26 RhE-negative, 43 K-negative, and 42 HPA-1a-negative pregnant women was examined by real-time PCR to detect RHD, RHCE*c, RHCE*E, RHCE*C,KEL*01 and HPA*1A, respectively. We tested for CCR5, SRY or bi-allelic polymorphisms and quantified the total or fetal DNA. Results: The results of fetal antigen status prediction by NIPD in all but one case (false-positive result of KEL*01) were correct taking neonate serology as a reference. It was confirmed that all negative results of NIPD contained fetal DNA except for four cases where there was no difference between the parents' polymorphisms. Conclusions: A fetal genotype compatible with the mother was determined in 25% of all pregnancies tested at the IHTM for the fetal blood group. These cases were not at risk of disease, so it was possible to avoid invasive procedures.
A Report of 134 Newly Diagnosed Multiple Myeloma Patients with Renal Impairment
Authors: Liu Aijun , Yang Guangzhong , Geng Chuanying , Wang Huijuan , Li Lihong , Li Yanchen , Wu Yin , Tian Ying , Leng Yun , Wang Guorong , Gao Wen , Chen Wenming
Published: November 2015

To analyze the effects of bortezomib on the prognosis of the newly diagnosed multiple myeloma patients with renal impairment, we assessed the outcomes of 134 multiple myeloma patients with renal impairment (serum creatinine ≥178 μmol/l) who were treated at Beijing Chaoyang Hospital. The patients were divided into two groups: bortezomib (n = 83) and nonbortezomib (n = 51). The overall response rate of the bortezomib group was higher than that of the nonbortezomib group. There was no significant difference in the time to restore renal function, but the complete renal response ratio was significantly higher in the bortezomib group. The 2-year overall survival (OS) rate of the bortezomib group was significantly greater than the nonbortezomib group, as was the 3-year OS rate. Kaplan-Meier analysis revealed significantly better survival for the bortezomib group. The main side effects in the bortezomib group were thrombocytopenia, peripheral neuropathy, infection, and herpes zoster, and there was a low incidence of grades 3 and 4 adverse events. Our findings indicate that bortezomib-based combination chemotherapy can improve the prognosis of the newly diagnosed multiple myeloma patients with renal impairment and should be considered as a first-line therapy.
Bilateral Through-and-Through Trajectory of a Low-Velocity Transcranial Penetrating Foreign Object in a Twelve-Month-Old
Authors: Heiferman Daniel M. , Hayward Dustin M. , Ashley Jr. William W.
Published: November 2015

A 12-month-old girl sustained a penetrating intracranial trauma of a thin aluminum rod traversing from the left frontal bone and exiting the right occipital bone. The rod entered the left anterior frontal lobe, traveled through the ventricular system, narrowly missed the right posterior cerebral artery by less than 1 mm and exited through the right cerebellum. The rod was surgically extracted, and the child remained neurologically intact. Pre- and postoperative vascular imaging, antibiotics, seizure prophylaxis and surgical planning are paramount to successful care of these delicate cases.
Lowered Levels of Carbonyl Proteins after Vitamin B Supplementation in Patients with Mild Cognitive Impairment and Alzheimer's Disease
Authors: Rommer Paulus S. , Fuchs Dietmar , Leblhuber Friedrich , Schroth Rainer , Greilberger Michaela , Tafeit Erwin , Greilberger Joachim
Published: November 2015

Background: The critical role of neuro-inflammation and oxidative stress in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) has become evident. Objective: The aim of this study is to assess the influence of vitamin supplementation on parameters of oxidative stress, inflammation as well as on cognition in patients with AD and mild cognitive impairment. Methods: In our study, patients with cognitive impairment and healthy controls were enrolled. All patients were intended to receive vitamin supplementation (vitamin B1, B6, B12 and folic acid) for 3 months. Mini Mental State Examination (MMSE) and laboratory markers [carbonyl proteins (CPs), malondialdehyde, tryptophan (Trp), kynurenine (Kyn), neopterin, folic acid, vitamin B12 level] were assessed for patients and controls at baseline and after 3 months. After half of the patients had been treated for 3 months, analyses were performed resulting in 3 subgroups: healthy controls without supplementation (15 subjects, 11 females), patients with vitamin supplementation (17 subjects, 10 females) and patients without vitamin supplementation (16 subjects, 9 females; baseline values prior to supplementation). Results: Age was significantly higher for the supplemented group (76.4 ± 6.7 years) compared to vitamin-naïve patients (63.3 ± 13.7 years; p < 0.01). The MMSE score was higher in the supplemented group (23.1 ± 4.8 vs. 20.3 ± 9.5) but did not reach significance. Levels of CPs were significantly higher in the vitamin-naïve patients (p < 0.05). Levels of Kyn and the Kyn/Trp ratio were significantly lower in vitamin-naïve patients compared to the supplemented group (p < 0.05). No significant difference was seen for the other markers. Conclusion: Vitamin supplementation leads to reduced levels of CPs in patients. Pearson's correlation coefficient shows a negative relation (r = -0.69) between CPs and MMSE. Future trials should assess whether CPs might be suitable markers for monitoring of demented patients.
Effects of Evodiamine on the Pharmacokinetics of Dapoxetine and Its Metabolite Desmethyl Dapoxetine in Rats
Authors: Li Rui-fang , Fu Jun-min , Lv Xing-zhi , Zhang Dong-tao , Pan Yong-yang , Rao Da-pang , Yu Kai-yuan
Published: November 2015

The objective of this work was to investigate the effect of orally administered evodiamine on the pharmacokinetics of dapoxetine and its active metabolite desmethyl dapoxetine in rats. Twelve healthy male Sprague-Dawley rats were randomly divided into 2 groups: the control group (received oral 10 mg/kg dapoxetine alone) and the combination group (10 mg/kg dapoxetine orally co-administered with 100 mg/kg evodiamine). The plasma concentration of dapoxetine and desmethyl dapoxetine were estimated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and different pharmacokinetic parameters were calculated using the Drug and Statistics 2.0 software. Compared to the control group, the pharmacokinetic parameter of t1/2, AUC(0-∞) and Tmax of dapoxetine in combination group was significantly increased by 63.3% (p < 0.01), 44.8% (p < 0.01) and 50.4% (p < 0.01), respectively. Moreover, evodiamine had significantly decreased the pharmacokinetic parameter of t1/2 and AUC(0-∞) of desmethyl dapoxetine. This study demonstrated that evodiamine inhibits the metabolism of dapoxetine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing dapoxetine to the patients already taking evodiamine.
High-Risk, Advanced-Stage Hodgkin Lymphoma: The Impact of Combined Escalated BEACOPP and ABVD Treatment in Patients Who Rapidly Achieve Metabolic Complete Remission on Interim FDG-PET/CT Scan
Authors: Kedmi Meirav , Apel Arie , Davidson Tima , Levi Itai , Dann Eldad J. , Polliack Aaron , Ben-Bassat Isaac , Nagler Arnon , Avigdor Abraham
Published: November 2015

The escalated BEACOPP (escBEACOPP) regimen improves the outcome of patients with advanced-stage Hodgkin lymphoma (HL) but is associated with cumbersome toxicity. We analyzed the survival outcome of high-risk, advanced-stage HL patients treated with response-adapted therapy. escBEACOPP was administered for 2 cycles, and after complete remission (CR) or partial remission (PR) was observed on FDG-PET/CT, treatment was de-escalated to 4 cycles of ABVD. Sixty-nine patients were evaluated, of them 45 participated in the multicenter, phase II prospective study between 2001 and 2007. Sixty patients had an international prognostic score ≥3. At a median follow-up of 5.6 years, 4 patients had died, 2 of them due to advanced HL. After the initial 2 cycles of escBEACOPP, 52 (75%) patients were in CR and 17 (25%) had a PR. Progression-free survival and overall survival (OS) were 79 and 93%, respectively. OS was predicted from the results of early-interim FDG-PET/CT: 98% of the patients in CR and 79% of those with a PR (p = 0.015). Hematological toxicity was more frequent during the first 2 cycles of escBEACOPP than in the ABVD phase. In conclusion, this retrospective analysis indicates that combined escBEACOPP-ABVD therapy is well tolerated and efficacious in HL patients who achieve negative early-interim PET results, while a positive PET result partially identified those with a worse prognosis.
How Realism Waltzed Off: Liberalism and Decisionmaking in Kenneth Waltz's Neorealism
Authors: Bessner Daniel , Guilhot Nicolas
Published: November 2015

Neorealism is one of the most influential theories of international relations, and its first theorist, Kenneth Waltz, a giant of the discipline. But why did Waltz move from a rather traditional form of classical realist political theory in the 1950s to neorealism in the 1970s? A possible answer is that Waltz's Theory of International Politics was his attempt to reconceive classical realism in a liberal form. Classical realism paid a great deal of attention to decisionmaking and statesmanship, and concomitantly asserted a nostalgic, anti-liberal political ideology. Neorealism, by contrast, dismissed the issue of foreign policymaking and decisionmaking. This shift reflected Waltz's desire to reconcile his acceptance of classical realism's tenets with his political commitment to liberalism. To do so, Waltz incorporated cybernetics and systems theory into Theory of International Politics, which allowed him to develop a theory of international relations no longer burdened with the problem of decisionmaking.
Indignation, Ideologies, and Armed Mobilization: Civil War in Italy, 1943–45
Authors: Costalli Stefano , Ruggeri Andrea
Published: November 2015

Ideas shape human behavior in many circumstances, including those involving political violence. Yet they have usually been underplayed in studies of the causes of armed mobilization. Likewise, emotions have been overlooked in most analyses of intrastate conflict. A mixed-methods analysis of Italian resistance during the Fascist regime and the Nazi occupation (1943–45) provides the opportunity to theorize and analyze empirical evidence on the role of indignation and radical ideologies in the process of armed mobilization. These nonmaterial factors play a crucial role in the chain that leads to armed collective action. Indignation is a push factor that moves individuals away from accepting the status quo. Radical ideologies act as pull factors that provide a new set of strategies against the incumbent. More specifically, detachment caused by an emotional event disconnects the individual from acceptance of the current state of social relations, and individuals move away from the status quo. Ideologies communicated by political entrepreneurs help to rationalize the emotional shift and elaborate alternative worldviews (disenchantment), as well as possibilities for action. Finally, a radical ideological framework emphasizes normative values and the conduct of action through the “anchoring” mechanism, which can be understood as a pull factor attracting individuals to a new status.
‘Human Semen Eucharist’ Among the Manichaeans?
Authors: van Oort Johannes
Published: November 2015

Starting from his De haeresibus 46,9-10, the present article examines Augustine’s contention that, among the Manichaeans, there was a certain ceremony in which human semen (i.e., sperma and menstrual fluid) was collected and consumed during a eucharistic rite. My contextual analysis of the pivotal passage, haer. 46,9-10, is followed by an overview of scholarly opinions on this text. From here I proceed to interpret the incriminated rite in light of the Seduction of the Archons myth and conclude that, according to Augustine, the Manichaeans consider the ‘vital substance’ (or ‘light’ or ‘living soul’) in the life of plants, animals and human beings, to be the very nature of God, which should be released whenever possible. I finish my research by interpreting the Manichaean practice within a wider ‘gnostic’ context, in particular Epiphanius’ report on the ‘Borborites’. My final conclusion is that we should try to understand both Manichaeans (like the ‘Catharists’) and Gnostics (like the ‘Borborites’) according to their own logic: both appear to have considered the life-substance of man, i.e., the semen, as divine, and indeed a part of God.
Heroic Bishops: Hilary of Poitiers’s Exilic Discourse
Authors: Barry Jennifer
Published: November 2015

In this article, I examine the progressive development of Hilary of Poitiers’s exilic discourse in two key texts: To Constantius and Against Constantius. Hilary’s exilic identity is intimately tied to the emperor and spaces of imperial power. In the first text, To Constantius, Constantius ii plays a sympathetic role in Hilary’s explanation of his exile. Hilary envisions himself in the presence of the emperor as he guides him to the truth. In Against Constantius, we find quite a different role relationship: the emperor is the chief antagonist and Hilary the champion of truth. In this second text, Hilary’s exile again confirms his orthodoxy and his overt condemnation of the emperor affirms his episcopal authority. As Hilary imagines it, his posture as an exile is enough to dethrone an emperor.
Tropopause-Penetrating Convection from Three-Dimensional Gridded NEXRAD Data
Authors: Solomon David L. , Bowman Kenneth P. , Homeyer Cameron R.
Published: November 2015

A new method that combines radar reflectivities from individual Next Generation Weather Radars (NEXRAD) into a three-dimensional composite with high horizontal and vertical resolution is used to estimate storm-top altitudes for the continental United States east of the Rocky Mountains. Echo-top altitudes are compared with the altitude of the lapse-rate tropopause calculated from the ERA-Interim reanalysis and radiosondes. To sample the diurnal and annual cycles, tropopause-penetrating convection is analyzed at 3-h intervals throughout 2004. Overshooting convection is most common in the north-central part of the United States (the high plains). There is a pronounced seasonal cycle; the majority of overshooting systems occur during the warm season (March–August). There is also a strong diurnal cycle, with maximum overshooting occurring near 0000 UTC. The overshooting volume decreases rapidly with height above the tropopause. Radiosonde observations are used to evaluate the quality of the reanalysis tropopause altitudes and the dependence of overshooting depth on environmental characteristics. The radar–radiosonde comparison reveals that overshooting is deeper in double-tropopause environments and increases as the stability of the lower stratosphere decreases.