Demo Faculty

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Dec 2016 • Genome biology

Comprehensive analyses of tumor immunity: implications for cancer immunotherapy

Bo Li, Eric Severson, Jean-Christophe Pignon, Haoquan Zhao, Taiwen Li, Jesse Novak, Peng Jiang, Hui Shen, Jon C Aster, Scott Rodig, Sabina Signoretti, Jun S Liu, X Shirley Liu

Understanding the interactions between tumor and the host immune system is critical to finding prognostic biomarkers, reducing drug resistance, and developing new therapies. Novel computational methods are needed to estimate tumor-infiltrating immune cells and understand tumor–immune interactions in cancers. We analyze tumor-infiltrating immune cells in over 10,000 RNA-seq samples across 23 cancer types from The Cancer Genome Atlas (TCGA). Our computationally inferred immune infiltrates associate much more strongly with patient clinical features, viral infection status, and cancer genetic alterations than other computational approaches. Analysis of cancer/testis antigen expression and CD8 T-cell abundance suggests that MAGEA3 is a potential immune target in melanoma, but not in non-small cell lung cancer, and implicates SPAG5 as an alternative cancer vaccine target in multiple cancers. We find that melanomas expressing high levels of CTLA4 separate into two distinct groups with respect to CD8 T-cell infiltration, which might influence clinical responses to anti-CTLA4 agents. We observe similar dichotomy of TIM3 expression with respect to CD8 T cells in kidney cancer and validate it experimentally. The abundance of immune infiltration, together with our downstream analyses and findings, are accessible through TIMER, a public resource at . We develop a computational approach to study tumor-infiltrating immune cells and their interactions with cancer cells. Our resource of immune-infiltrate levels, clinical associations, as well as predicted therapeutic markers may …

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Oct 2016 • Genome research

Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profiles

Su Wang, Chongzhi Zang, Tengfei Xiao, Jingyu Fan, Shenglin Mei, Qian Qin, Qiu Wu, Xujuan Li, Kexin Xu, Housheng Hansen He, Myles Brown, Clifford A Meyer, X Shirley Liu

Model-based analysis of regulation of gene expression (MARGE) is a framework for interpreting the relationship between the H3K27ac chromatin environment and differentially expressed gene sets. The framework has three main functions: MARGE-potential, MARGE-express, and MARGE-cistrome. MARGE-potential defines a regulatory potential (RP) for each gene as the sum of H3K27ac ChIP-seq signals weighted by a function of genomic distance from the transcription start site. The MARGE framework includes a compendium of RPs derived from 365 human and 267 mouse H3K27ac ChIP-seq data sets. Relative RPs, scaled using this compendium, are superior to superenhancers in predicting BET (bromodomain and extraterminal domain) -inhibitor repressed genes. MARGE-express, which uses logistic regression to retrieve relevant H3K27ac profiles from the compendium to accurately model a query set of …

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Jul 2016 • Scientific reports

NF-E2, FLI1 and RUNX1 collaborate at areas of dynamic chromatin to activate transcription in mature mouse megakaryocytes

Chongzhi Zang, Annouck Luyten, Justina Chen, X Shirley Liu, Ramesh A Shivdasani

Mutations in mouse and human Nfe2, Fli1 and Runx1 cause thrombocytopenia. We applied genome-wide chromatin dynamics and ChIP-seq to determine these transcription factors’(TFs) activities in terminal megakaryocyte (MK) maturation. Enhancers with H3K4me2-marked nucleosome pairs were most enriched for NF-E2, FLI and RUNX sequence motifs, suggesting that this TF triad controls much of the late MK program. ChIP-seq revealed NF-E2 occupancy near previously implicated target genes, whose expression is compromised in Nfe2-null cells and many other genes that become active late in MK differentiation. FLI and RUNX were also the motifs most enriched near NF-E2 binding sites and ChIP-seq implicated FLI1 and RUNX1 in activation of late MK, including NF-E2-dependent, genes. Histones showed limited activation in regions of single TF binding, while enhancers that bind NF-E2 and either RUNX1 …

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Jul 2016 • Nature genetics

Landscape of tumor-infiltrating T cell repertoire of human cancers

Bo Li, Taiwen Li, Jean-Christophe Pignon, Binbin Wang, Jinzeng Wang, Sachet A Shukla, Ruoxu Dou, Qianming Chen, F Stephen Hodi, Toni K Choueiri, Catherine Wu, Nir Hacohen, Sabina Signoretti, Jun S Liu, X Shirley Liu

We developed a computational method to infer the complementarity-determining region 3 (CDR3) sequences of tumor-infiltrating T cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600,000 CDR3 sequences, including 15% that were full length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage, for infiltrating T cells in many tumors, except in brain and kidney cancers, resembled those for peripheral blood cells from healthy donors. We observed a strong association between T cell diversity and tumor mutation load, and we predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers. Finally, we identified three potential immunogenic somatic mutations on the basis of their co-occurrence with CDR3 sequences. One of them, a PRAMEF4 mutation encoding p. Phe300Val, was predicted to result in peptide …

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Jun 2016 • Nature medicine

Chromatin immunoprecipitation from fixed clinical tissues reveals tumor-specific enhancer profiles

Paloma Cejas, Lewyn Li, Nicholas K O'Neill, Melissa Duarte, Prakash Rao, Michaela Bowden, Chensheng W Zhou, Marta Mendiola, Emilio Burgos, Jaime Feliu, Juan Moreno-Rubio, Héctor Guadalajara, Víctor Moreno, Damián García-Olmo, Joaquim Bellmunt, Stephanie Mullane, Michelle Hirsch, Christopher J Sweeney, Andrea Richardson, X Shirley Liu, Myles Brown, Ramesh A Shivdasani, Henry W Long

Extensive cross-linking introduced during routine tissue fixation of clinical pathology specimens severely hampers chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) analysis from archived tissue samples. This limits the ability to study the epigenomes of valuable, clinically annotated tissue resources. Here we describe fixed-tissue chromatin immunoprecipitation sequencing (FiT-seq), a method that enables reliable extraction of soluble chromatin from formalin-fixed paraffin-embedded (FFPE) tissue samples for accurate detection of histone marks. We demonstrate that FiT-seq data from FFPE specimens are concordant with ChIP-seq data from fresh-frozen samples of the same tumors. By using multiple histone marks, we generate chromatin-state maps and identify cis-regulatory elements in clinical samples from various tumor types that can readily allow us to distinguish between …

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May 2016 • Oncotarget

KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells

Lingzhi Kong, Peng Zhang, Wang Li, Yan Yang, Ye Tian, Xujun Wang, Sujun Chen, Yuxin Yang, Tianhao Huang, Tian Zhao, Liang Tang, Bo Su, Fei Li, X Shirley Liu, Fan Zhang

Epigenetic regulation plays an important role in tumor metastasis. KDM1A is a histone demethylase specific for H3K4me2/me1 demethylation, and has been found to be overexpressed in many cancers, including non-small cell lung cancer (NSCLC). However, the role of KDM1A in lung cancer remains unclear. Here, we show that KDM1A promotes cancer metastasis in NSCLC cells by repressing TIMP3 (tissue inhibitor of metalloproteinase 3) expression. Consistently with this, overexpression of TIMP3 inhibited MMP2 expression and JNK phosphorylation, both of which are known to be important for cell invasion and migration. Importantly, knockdown of TIMP3 in KDM1A-deficient cells rescued the metastatic capability of NSCLC cells. These findings were also confirmed by pharmacological inhibition assays. We further demonstrate that KDM1A removes H3K4me2 at the promoter of TIMP3, thus repressing the …

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Apr 2016 • Nature communications

High-dimensional genomic data bias correction and data integration using MANCIE

Chongzhi Zang, Tao Wang, Ke Deng, Bo Li, Qian Qin, Tengfei Xiao, Shihua Zhang, Clifford A Meyer, Housheng Hansen He, Myles Brown, Jun S Liu, Yang Xie, X Shirley Liu

High-dimensional genomic data analysis is challenging due to noises and biases in high-throughput experiments. We present a computational method matrix analysis and normalization by concordant information enhancement (MANCIE) for bias correction and data integration of distinct genomic profiles on the same samples. MANCIE uses a Bayesian-supported principal component analysis-based approach to adjust the data so as to achieve better consistency between sample-wise distances in the different profiles. MANCIE can improve tissue-specific clustering in ENCODE data, prognostic prediction in Molecular Taxonomy of Breast Cancer International Consortium and The Cancer Genome Atlas data, copy number and expression agreement in Cancer Cell Line Encyclopedia data, and has broad applications in cross-platform, high-dimensional data integration.

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Mar 2016 • Cancer cell

Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors

Shom Goel, Qi Wang, April C Watt, Sara M Tolaney, Deborah A Dillon, Wei Li, Susanne Ramm, Adam C Palmer, Haluk Yuzugullu, Vinay Varadan, David Tuck, Lyndsay N Harris, Kwok-Kin Wong, X Shirley Liu, Piotr Sicinski, Eric P Winer, Ian E Krop, Jean J Zhao

Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of …

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Mar 2016 • Biology of Blood and Marrow Transplantation

Allogeneic Stem Cell Transplantation (SCT) in Elderly Patients with AML and ALL: Chance of Cure?

Renate Arnold, Lam Vuong, Christian Jehn, Il-Kang Na, Nils Waldhüter, Livius Penter, Mohammad Ahmed A Shinawi, Wolfgang-Igor Blau, Olaf Penack, Theis Terwey, Philipp Hemmati

Results60/141 patients are alive (43%), 81/141 pts are dead (57%). Causes of death are Non-Relapse mortality (NRM), eg GvHD+/-infection in 34/141 pts (24%) and persistence/relapse of acute leukemia in 47/141 pts (33%). Median f/u of the surviving patients is 24 months (3-104).

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Mar 2016 • Nature communications

Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer

Zhou Du, Tong Sun, Ezgi Hacisuleyman, Teng Fei, Xiaodong Wang, Myles Brown, John L Rinn, Mary Gwo-Shu Lee, Yiwen Chen, Philip W Kantoff, X Shirley Liu

Mounting evidence suggests that long noncoding RNAs (lncRNAs) can function as microRNA sponges and compete for microRNA binding to protein-coding transcripts. However, the prevalence, functional significance and targets of lncRNA-mediated sponge regulation of cancer are mostly unknown. Here we identify a lncRNA-mediated sponge regulatory network that affects the expression of many protein-coding prostate cancer driver genes, by integrating analysis of sequence features and gene expression profiles of both lncRNAs and protein-coding genes in tumours. We confirm the tumour-suppressive function of two lncRNAs (TUG1 and CTB-89H12. 4) and their regulation of PTEN expression in prostate cancer. Surprisingly, one of the two lncRNAs, TUG1, was previously known for its function in polycomb repressive complex 2 (PRC2)-mediated transcriptional regulation, suggesting its sub-cellular localization …

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Feb 2016 • Molecular Cancer Research

Integrative analysis reveals the transcriptional collaboration between EZH2 and E2F1 in the regulation of cancer-related gene expression

Han Xu, Kexin Xu, Housheng H He, Chongzhi Zang, Chen-Hao Chen, Yiwen Chen, Qian Qin, Su Wang, Chenfei Wang, Shengen Hu, Fugen Li, Henry Long, Myles Brown, X Shirley Liu

Overexpression of EZH2 is frequently linked to the advanced and metastatic stage of cancers. The mechanisms of its oncogenic function can be context specific, and may vary depending on the protein complexes that EZH2 interacts with. To identify novel transcriptional collaborators of EZH2 in cancers, a computational approach was developed that integrates protein–DNA binding data, cell perturbation gene expression data, and compendiums of tumor expression profiles. This holistic approach identified E2F1, a known mediator of the Rb tumor suppressor, as a transcriptional collaborator of EZH2 in castration-resistant prostate cancer. Subsequent analysis and experimental validation found EZH2 and E2F1 cobind to a subset of chromatin sites lacking H3K27 trimethylation, and activate genes that are critical for prostate cancer progression. The collaboration of EZH2 and E2F1 in transcriptional regulation is also …

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Jan 2016 • bioRxiv

Ultrasensitive detection of TCR hypervariable region in solid-tissue RNA-seq data

Bo Li, Taiwen Li, Binbin Wang, Ruoxu Dou, Jean-Chrisophe Pignon, Toni K Choueiri, Sabina Signoretti, Jun S Liu, Xiaole Shirley Liu

Characterization of tissue-infiltrating T cell repertoire is critical to understanding tumor-immune interactions and autoimmune disease etiology. We present TRUST, an open source algorithm for calling the TCR transcript hypervariable CDR3 regions using unselected RNA-seq data profiled from solid tissues. TRUST achieved high sensitivity in CDR3 calling even for samples with low sequencing depth and has demonstrated utilities in its application to large tumor cohorts.

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Jan 2016 • Decision

Agency and rationality: Adopting the intentional stance toward evolved virtual agents.

Peter C Pantelis, Timothy Gerstner, Kevin Sanik, Ari Weinstein, Steven A Cholewiak, Gaurav Kharkwal, Chia-Chien Wu, Jacob Feldman

The interpretation of other agents as intentional actors equipped with mental states has been connected to the attribution of rationality to their behavior. But a workable definition of “rationality” is difficult to formulate in complex situations, where standard normative definitions are difficult to apply. In this study, we explore a notion of rationality based on the idea of evolutionary fitness. We ask whether agents that are more adapted to their environment are, consequently, perceived as more rational and intentional. We created a 2-D virtual environment populated with autonomous virtual agents, each of which behaves according to a built-in program equipped with simulated perception, memory, and decision making. We then introduced a process of simulated evolution that pressured the agents’ programs toward behavior more adapted to the simulated environment. We showed these agents to human subjects in 2 …

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Jan 2016 • Blood

Long-term follow-up of patients with corticosteroid-refractory graft-versus-host disease treated with ruxolitinib

Robert Zeiser, Andreas Burchert, Claudia Lengerke, Mareike Verbeek, Kristina Maas-Bauer, Stephan Metzelder, Silvia Spoerl, Markus Ditschkowski, Matyas Ecsedi, Katja Sockel, Francis Ayuk, Ajib Salem, Flore Sicre de Fontbrune, Il-Kang Na, Penter Livius, Udo Holtick, Dominik Wolf, Esther Schuler, Everett Meyer, Petya Apostolova, Hartmut Bertz, Reinhard Marks, Michael Lübbert, Ralph Wäsch, Christof Scheid, Friedrich Stölzel, Rainer Ordemann, Gesine Bug, Guido Kobbe, Omid Shah, Robert S Negrin, Mats Brune, Alexandros Spyridonidis, Annette Schmitt-Graeff, Walter JFM van der Velden, Gerwin Huls, Stephan Mielke, Goetz Ulrich Grigoleit, Jurgen Kuball, Ryan P Flynn, Gabriele Ihorst, Jing Du, Bruce R Blazar, Renate Arnold, Nicolaus Kröger, Jakob R Passweg, Joerg Halter, Gérard Socié, Dietrich W Beelen, Christian Peschel, Andreas Neubauer, Jürgen Finke, Justus Duyster, Nikolas von Bubnoff

We have previously reported on the efficacy of the JAK1/2 inhibitor ruxolitinib in corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) in 95 patients (pts) (Leukemia 2015;29(10):2062-8). To assess long-term follow-up results, we collected data from the same pts treated in 19 centers in Europe and the US. Pts were classified as SR-aGVHD (n=54, all grade III or IV) or SR-cGvHD (n=41, all moderate or severe). Median numbers of pre-ruxolitinib GVHD treatment lines were 3 (1-7) and 3 (1-10) for SR-aGVHD and SR-cGvHD, respectively. The median follow-up was 19 and 24 months for aGVHD and cGVHD, respectively.The 1-year overall survival (OS) from was 62.4% (CI: 49.4%-75.4%) and 92.7% (CI: 84.7%-100%) for SR-aGVHD and SR-cGvHD, respectively. The estimated median OS (50% death) was 18 months for aGVHD and not reached for cGVHD patients. The median …

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Jan 2016 • Nature

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Shaokun Shu, Charles Y Lin, Housheng Hansen He, Robert M Witwicki, Doris P Tabassum, Justin M Roberts, Michalina Janiszewska, Sung Jin Huh, Yi Liang, Jeremy Ryan, Ernest Doherty, Hisham Mohammed, Hao Guo, Daniel G Stover, Muhammad B Ekram, Guillermo Peluffo, Jonathan Brown, Clive D’Santos, Ian E Krop, Deborah Dillon, Michael McKeown, Christopher Ott, Jun Qi, Min Ni, Prakash K Rao, Melissa Duarte, Shwu-Yuan Wu, Cheng-Ming Chiang, Lars Anders, Richard A Young, Eric P Winer, Antony Letai, William T Barry, Jason S Carroll, Henry W Long, Myles Brown, X Shirley Liu, Clifford A Meyer, James E Bradner, Kornelia Polyak

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy 1, 2, 3. BET bromodomain inhibitors, which have shown efficacy in several models of cancer 4, 5, 6, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs 7, 8, 9. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent …

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2016 • Nature Biotech

Genome-scale deletion screening of human long non-coding RNAs using a paired-gude RNA CRISPR-Cas9 library

S Zhu, W Li, J Liu, CH Chen, Q Liao, P Xu, Xu H, T Xiao, Z Cao, J Peng, P Yuan, M Brown, XS* Liu, W* Wei

CRISPR–Cas9 screens have been widely adopted to analyze coding-gene functions, but high-throughput screening of non-coding elements using this method is more challenging because indels caused by a single cut in non-coding regions are unlikely to produce a functional knockout. A high-throughput method to produce deletions of non-coding DNA is needed. We report a high-throughput genomic deletion strategy to screen for functional long non-coding RNAs (lncRNAs) that is based on a lentiviral paired-guide RNA (pgRNA) library. Applying our screening method, we identified 51 lncRNAs that can positively or negatively regulate human cancer cell growth. We validated 9 of 51 lncRNA hits using CRISPR–Cas9-mediated genomic deletion, functional rescue, CRISPR activation or inhibition and gene-expression profiling. Our high-throughput pgRNA genome deletion method will enable rapid identification of …

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2016 • Nucleic Acids Res

Cistrome data browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse

S Mei, Q Qin, Q Wu, H Sun, R Zheng, C Zang, M Zhu, J Wu, X Shi, L Taing, T Liu, M Brown, CA Meyer, XS Liu

Chromatin immunoprecipitation, DNase I hypersensitivity and transposase-accessibility assays combined with high-throughput sequencing enable the genome-wide study of chromatin dynamics, transcription factor binding and gene regulation. Although rapidly accumulating publicly available ChIP-seq, DNase-seq and ATAC-seq data are a valuable resource for the systematic investigation of gene regulation processes, a lack of standardized curation, quality control and analysis procedures have hindered extensive reuse of these data. To overcome this challenge, we built the Cistrome database, a collection of ChIP-seq and chromatin accessibility data (DNase-seq and ATAC-seq) published before January 1, 2016, including 13 366 human and 9953 mouse samples. All the data have been carefully curated and processed with a streamlined analysis pipeline and evaluated with comprehensive quality control …

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2016 • BMC Bioinformatics

ChiLin: a comprehensive ChIP-seq and DNase-seq quality control and analysis pipeline

Q Qin, S Mei, Q Wu, H Sun, L Li, L Taing, S Chen, F Li, T Liu, C Zang, H Xu, Y Chen, CA Meyer, Y Zhang, M Brown, HW Long, XS Liu

Transcription factor binding, histone modification, and chromatin accessibility studies are important approaches to understanding the biology of gene regulation. ChIP-seq and DNase-seq have become the standard techniques for studying protein-DNA interactions and chromatin accessibility respectively, and comprehensive quality control (QC) and analysis tools are critical to extracting the most value from these assay types. Although many analysis and QC tools have been reported, few combine ChIP-seq and DNase-seq data analysis and quality control in a unified framework with a comprehensive and unbiased reference of data quality metrics. ChiLin is a computational pipeline that automates the quality control and data analyses of ChIP-seq and DNase-seq data. It is developed using a flexible and modular software framework that can be easily extended and modified. ChiLin is ideal for batch processing of many datasets and is well suited for large collaborative projects involving ChIP-seq and DNase-seq from different designs. ChiLin generates comprehensive quality control reports that include comparisons with historical data derived from over 23,677 public ChIP-seq and DNase-seq samples (11,265 datasets) from eight literature-based classified categories. To the best of our knowledge, this atlas represents the most comprehensive ChIP-seq and DNase-seq related quality metric resource currently available. These historical metrics provide useful heuristic quality references for experiment across all commonly used assay types. Using representative datasets, we demonstrate the versatility of the pipeline by applying it to different assay …

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2016 • Nature

REST and stress resistance in ageing and Alzheimer's disease (vol 507, pg 448, 2014)

T Lu, Liviu Aron, Joseph Zullo, Ying Pan, Haeyoung Kim, YW Chen, Tun-Hsiang Yang, Hyun-Min Kim, Derek Drake, X Shirley Liu, David A Bennett, Monica P Colaiacovo, Bruce A Yankner

화학공학소재연구정보센터 홈 로그인 로그아웃 연락처 사이트맵. 센터: 센터소개; 회원가입/정보수정. 뉴스: 공지사항; 연구동향; 우수연구자소개; 취업정보. 연구정보: 문헌DB; KDB; Compound Search; 전문연구정보; 동영상; 심포지움 자료; 연구성과보고서; 저널정보; 논문 작성법; 참고문헌DB; 분석기기DB; 화학공정DB; PSPDB; 연구자지식지도; 상태도정보. 교육정보: 사이버강의-학부; 사이버강의-대학원; 실무강좌; 강의자료 링크; 교육자료 링크; 사이버실험실; 물성측정실험 매뉴얼. 커뮤니티: 공학포럼; 카페; 신진연구자인터뷰. 리소스: 특허정보; 술어DB; 관련법령; 자격증정보; 성과소개서; 연구보고서. 문헌DB: 학술지 검색; 학술대회 발표논문집; 최신 국내 저널; 최신 리뷰페이퍼. KDB: Periodic Table of Elements; Unit Conversion; Universal Constants; Pure Component Properties; Binary Vapor-Liquid Equil …

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2016 • Nature

Addendum: REST and stress resistance in ageing and Alzheimer's disease

T Lu, L Aron, J Zullo, Y Pan, H Kim, Y Chen, TH Yang, HM Kim, D Drake, XS Liu, DA Bennett, MP Colaiacovo, BA Yankner

Addendum: REST and Stress Resistance in Ageing and Alzheimer's Disease. Nature. 2016 Dec 15;540(7633):470. doi: 10.1038/nature20579. Epub 2016 Nov 16 …

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2016 • Scientific reports

An Integrative Pharmacogenomic Approach Identifies Two-drug Combination Therapies for Personalized Cancer Medicine

Y Liu, T Fei, X Zheng, M Brown, P Zhang, X Shirley Liu, Haiyun Wang

An individual tumor harbors multiple molecular alterations that promote cell proliferation and prevent apoptosis and differentiation. Drugs that target specific molecular alterations have been introduced into personalized cancer medicine, but their effects can be modulated by the activities of other genes or molecules. Previous studies aiming to identify multiple molecular alterations for combination therapies are limited by available data. Given the recent large scale of available pharmacogenomic data, it is possible to systematically identify multiple biomarkers that contribute jointly to drug sensitivity and to identify combination therapies for personalized cancer medicine. In this study, we used pharmacogenomic profiling data provided from two independent cohorts in a systematic in silico investigation of perturbed genes cooperatively associated with drug sensitivity. Our study predicted many pairs of molecular …

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