Demo Faculty

162 articles

4 publishers

Join mailing list

Nov 2020 • Blood

Safety and Efficacy of Decitabine Plus Ipilimumab in Relapsed or Refractory MDS/AML in the Post-BMT or Transplant Naïve Settings

Jacqueline S Garcia, Yael Flamand, Benjamin K Tomlinson, Michael Keng, Lourdes M Mendez, Samer Khaled, Asad Bashey, Andrew M Brunner, Alexandra Savell, Donna Neuberg, Ilene Galinsky, Marlise R Luskin, David P Steensma, Martha Wadleigh, Eric S Winer, David E Avigan, Nicole Cullen, Scott Rodig, Livius Penter, R Coleman Lindsley, Stephanie Andrews, Matthew S Davids, Catherine J Wu, Richard M Stone, Daniel J DeAngelo, Robert J Soiffer

Background: CTLA-4 blockade with ipilimumab (IPI) has modest activity in hematologic malignancies relapsed post allogeneic hematopoietic cell transplantation (allo-HCT) (Davids M, NEJM). Adding decitabine (DAC) to IPI may increase efficacy of this approach in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), and we further asked the extent to which alloreactivity contributed to this activity. Here, we present safety (Table 1) and clinical activity (Figure 1) from a phase I, multicenter, investigator-initiated study (CTEP 10026) of DAC plus IPI in pts with R/R MDS/AML with (Arm A) and without (Arm B) prior HCT.Methods: Pts ≥ 18 y with R/R MDS (≥ 5% blasts), R/R AML or untreated secondary AML were eligible. Prior HMA was permitted but trial was later amended to exclude those with disease progression on HMA therapy within 12 weeks of study entry. Pts post allo-HCT (Arm A) were required to …

Show more

Nov 2020 • Blood

Clonally Expanded Bone Marrow T Cells Show Effector Differentiation and Rarely Recognize Disease-Associated Antigens in Multiple Myeloma

Carlotta Welters, Meng-Tung Hsu, Christian Alexander Stein, Livius Penter, María Fernanda Lammoglia Cobo, Kerstin Dietze, Eric Blanc, Dieter Beule, Lars Bullinger, Julian Strobel, Holger Hackstein, Armin Gerbitz, Klaus Dornmair, Thomas Blankenstein, Leo Hansmann

Multiple myeloma is a malignancy of monoclonal plasma cells accumulating in the bone marrow. The critical influence of tumor-infiltrating T cells on disease control and therapeutic responses has been shown in a variety of malignancies, however, the role of multiple myeloma bone marrow-infiltrating T cells is incompletely understood. Although it has been shown that multiple myeloma neo-antigen-specific T cells can be expanded in vitro, little is known about functions and specificities of clonally expanded multiple myeloma-infiltrating bone marrow T cells.Here we asked at the single cell level whether clonally expanded T cells i) were detectable in multiple myeloma bone marrow and peripheral blood, ii) showed characteristic immune phenotypes, and iii) recognized antigens selectively presented on multiple myeloma cells.A total of 6,744 single bone marrow T cells from 13 treatment-naïve patients were index …

Show more

Oct 2020 • Trends in Biochemical Sciences, 2020

Computational Approaches to Modeling Transcription Factor Activity and Gene Regulation.

Clifford A Meyer, X Shirley Liu

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

Show more

Oct 2020 • Journal of Vision

Lags and leads of accommodation: Fact or fiction?

Martin Banks, Vivek Labhishetty, Steven Cholewiak

Conventional wisdom is that accommodation in humans exhibits significant errors. When the stimulus is far, the eye is thought to focus too near (“lead of accommodation”). When the stimulus is near, it focuses too far (“lag”). These errors are as large as 1 diopter, which should produce noticeably blurred imagery. But viewers typically do not experience the blur expected from such leads and lags. We re-examined this phenomenon by measuring accommodation objectively and subjectively. Objective measurements are based on measurements of light reflected off the retina. Subjective measurements are based on the viewer performing a visual task; they are more valid because they involve the whole visual process. We used a custom varifocal display apparatus to present accommodative stimuli to six young adults. On each trial, subjects fixated and focused on a Maltese cross at a distance of 0, 2, 4 or 6D. A …

Show more

Oct 2020 • Journal of Vision

Lags and leads of accommodation: Fact or fiction?

Martin Banks, Vivek Labhishetty, Steven Cholewiak

Conventional wisdom is that accommodation in humans exhibits significant errors. When the stimulus is far, the eye is thought to focus too near (“lead of accommodation”). When the stimulus is near, it focuses too far (“lag”). These errors are as large as 1 diopter, which should produce noticeably blurred imagery. But viewers typically do not experience the blur expected from such leads and lags. We re-examined this phenomenon by measuring accommodation objectively and subjectively. Objective measurements are based on measurements of light reflected off the retina. Subjective measurements are based on the viewer performing a visual task; they are more valid because they involve the whole visual process. We used a custom varifocal display apparatus to present accommodative stimuli to six young adults. On each trial, subjects fixated and focused on a Maltese cross at a distance of 0, 2, 4 or 6D. A …

Show more

Oct 2020 • The EMBO Journal

Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer

Sunny Z Wu, Daniel L Roden, Chenfei Wang, Holly Holliday, Kate Harvey, Aurélie S Cazet, Kendelle J Murphy, Brooke Pereira, Ghamdan Al‐Eryani, Nenad Bartonicek, Rui Hou, James R Torpy, Simon Junankar, Chia‐Ling Chan, Chuan En Lam, Mun N Hui, Laurence Gluch, Jane Beith, Andrew Parker, Elizabeth Robbins, Davendra Segara, Cindy Mak, Caroline Cooper, Sanjay Warrier, Alistair Forrest, Joseph Powell, Sandra O'Toole, Thomas R Cox, Paul Timpson, Elgene Lim, X Shirley Liu, Alexander Swarbrick

The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple‐negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal‐targeted therapies. Single‐cell RNA sequencing of five TNBCs revealed two cancer‐associated fibroblast (CAF) and two perivascular‐like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal‐immune crosstalk acts via a diverse array of immunoregulatory molecules …

Show more

Oct 2020 • ONCOLOGY RESEARCH AND TREATMENT 43 (SUPPL 4), 239-239, 2020

Identification of EBV epitope-specific T cell receptors for adoptive T cell transfer against EBV infection and associated malignancies

Lammoglia MF Cobo, C Welters, C Pircher, R Gary, K Dietze, A Takvorian, L Penter, L Bullinger, K Dornmair, A Moosmann, J Mautner, T Blankenstein, T Kammertoens, A Gerbitz, L Hansmann


Sep 2020 • Nature genetics

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale

Xihao Li, Zilin Li, Hufeng Zhou, Sheila M Gaynor, Yaowu Liu, Han Chen, Ryan Sun, Rounak Dey, Donna K Arnett, Stella Aslibekyan, Christie M Ballantyne, Lawrence F Bielak, John Blangero, Eric Boerwinkle, Donald W Bowden, Jai G Broome, Matthew P Conomos, Adolfo Correa, L Adrienne Cupples, Joanne E Curran, Barry I Freedman, Xiuqing Guo, George Hindy, Marguerite R Irvin, Sharon LR Kardia, Sekar Kathiresan, Alyna T Khan, Charles L Kooperberg, Cathy C Laurie, X Shirley Liu, Michael C Mahaney, Ani W Manichaikul, Lisa W Martin, Rasika A Mathias, Stephen T McGarvey, Braxton D Mitchell, May E Montasser, Jill E Moore, Alanna C Morrison, Jeffrey R O’Connell, Nicholette D Palmer, Akhil Pampana, Juan M Peralta, Patricia A Peyser, Bruce M Psaty, Susan Redline, Kenneth M Rice, Stephen S Rich, Jennifer A Smith, Hemant K Tiwari, Michael Y Tsai, Ramachandran S Vasan, Fei Fei Wang, Daniel E Weeks, Zhiping Weng, James G Wilson, Lisa R Yanek, Benjamin M Neale, Shamil R Sunyaev, Gonçalo R Abecasis, Jerome I Rotter, Cristen J Willer, Gina M Peloso, Pradeep Natarajan, Xihong Lin

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce ‘annotation principal components’, multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples …

Show more

Sep 2020 • Nature Medicine

A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma

Fathima Zumla Cader, Xihao Hu, Walter L Goh, Kirsty Wienand, Jing Ouyang, Elisa Mandato, Robert Redd, Lee N Lawton, Pei-Hsuan Chen, Jason L Weirather, Ron CJ Schackmann, Bo Li, Wenjiang Ma, Philippe Armand, Scott J Rodig, Donna Neuberg, X Shirley Liu, Margaret A Shipp

PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs), which exhibit frequent copy-number gains of CD274 (PD-L1) and PDC1LG2 (PD-L2) on chromosome 9p24. 1. However, in this largely MHC-class-I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined. We utilized the complementary approaches of T cell receptor (TCR) sequencing and cytometry by time-of-flight analysis to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial (NCT02181738). Anti-PD-1 therapy was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton clones during treatment. CD4+, but not CD8+, TCR diversity significantly increased during therapy, most strikingly in patients who had achieved complete responses. Additionally, patients who responded to …

Show more

Sep 2020 • Nature cell biology

Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy

Yang Gao, Naoe Taira Nihira, Xia Bu, Chen Chu, Jinfang Zhang, Aleksandra Kolodziejczyk, Yizeng Fan, Ngai Ting Chan, Leina Ma, Jing Liu, Dong Wang, Xiaoming Dai, Huadong Liu, Masaya Ono, Akira Nakanishi, Hiroyuki Inuzuka, Brian J North, Yu-Han Huang, Samanta Sharma, Yan Geng, Wei Xu, X Shirley Liu, Lei Li, Yoshio Miki, Piotr Sicinski, Gordon J Freeman, Wenyi Wei

Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related …

Show more

Jul 2020 • Nature 583 (7818), 693-698, 2020

Perspectives on ENCODE

Michael P Snyder, Thomas R Gingeras, Jill E Moore, Zhiping Weng, Mark B Gerstein, Bing Ren, Ross C Hardison, John A Stamatoyannopoulos, Brenton R Graveley, Elise A Feingold, Michael J Pazin, Michael Pagan, Daniel A Gilchrist, Benjamin C Hitz, J Michael Cherry, Bradley E Bernstein, Eric M Mendenhall, Daniel R Zerbino, Adam Frankish, Paul Flicek, Richard M Myers

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression 1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

Show more

Jul 2020 • Nature

Expanded encyclopaedias of DNA elements in the human and mouse genomes

Jill E Moore, Michael J Purcaro, Henry E Pratt, Charles B Epstein, Noam Shoresh, Jessika Adrian, Trupti Kawli, Carrie A Davis, Alexander Dobin, Rajinder Kaul, Jessica Halow, Eric L Van Nostrand, Peter Freese, David U Gorkin, Yin Shen, Yupeng He, Mark Mackiewicz, Florencia Pauli-Behn, Brian A Williams, Ali Mortazavi, Cheryl A Keller, Xiao-Ou Zhang, Shaimae I Elhajjajy, Jack Huey, Diane E Dickel, Valentina Snetkova, Xintao Wei, Xiaofeng Wang, Juan Carlos Rivera-Mulia, Joel Rozowsky, Jing Zhang, Surya B Chhetri, Jialing Zhang, Alec Victorsen, Kevin P White, Axel Visel, Gene W Yeo, Christopher B Burge, Eric Lécuyer, David M Gilbert, Job Dekker, John Rinn, Eric M Mendenhall, Joseph R Ecker, Manolis Kellis, Robert J Klein, William S Noble, Anshul Kundaje, Roderic Guigó, Peggy J Farnham, J Michael Cherry, Richard M Myers, Bing Ren, Brenton R Graveley, Mark B Gerstein, Len A Pennacchio, Michael P Snyder, Bradley E Bernstein, Barbara Wold, Ross C Hardison, Thomas R Gingeras, John A Stamatoyannopoulos, Zhiping Weng

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www. encodeproject. org), including phase II ENCODE 1 and Roadmap Epigenomics 2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3 …

Show more

Jul 2020 • Nature Communications

An integrative ENCODE resource for cancer genomics

Jing Zhang, Donghoon Lee, Vineet Dhiman, Peng Jiang, Jie Xu, Patrick McGillivray, Hongbo Yang, Jason Liu, William Meyerson, Declan Clarke, Mengting Gu, Shantao Li, Shaoke Lou, Jinrui Xu, Lucas Lochovsky, Matthew Ung, Lijia Ma, Shan Yu, Qin Cao, Arif Harmanci, Koon-Kiu Yan, Anurag Sethi, Gamze Gürsoy, Michael Rutenberg Schoenberg, Joel Rozowsky, Jonathan Warrell, Prashant Emani, Yucheng T Yang, Timur Galeev, Xiangmeng Kong, Shuang Liu, Xiaotong Li, Jayanth Krishnan, Yanlin Feng, Juan Carlos Rivera-Mulia, Jessica Adrian, James R Broach, Michael Bolt, Jennifer Moran, Dominic Fitzgerald, Vishnu Dileep, Tingting Liu, Shenglin Mei, Takayo Sasaki, Claudia Trevilla-Garcia, Su Wang, Yanli Wang, Chongzhi Zang, Daifeng Wang, Robert J Klein, Michael Snyder, David M Gilbert, Kevin Yip, Chao Cheng, Feng Yue, X Shirley Liu, Kevin P White, Mark Gerstein

ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting …

Show more

Jul 2020 • Nucleic acids research

TIMER2. 0 for analysis of tumor-infiltrating immune cells

Taiwen Li, Jingxin Fu, Zexian Zeng, David Cohen, Jing Li, Qianming Chen, Bo Li, X Shirley Liu

Tumor progression and the efficacy of immunotherapy are strongly influenced by the composition and abundance of immune cells in the tumor microenvironment. Due to the limitations of direct measurement methods, computational algorithms are often used to infer immune cell composition from bulk tumor transcriptome profiles. These estimated tumor immune infiltrate populations have been associated with genomic and transcriptomic changes in the tumors, providing insight into tumor–immune interactions. However, such investigations on large-scale public data remain challenging. To lower the barriers for the analysis of complex tumor–immune interactions, we significantly improved our previous web platform TIMER. Instead of just using one algorithm, TIMER2.0 (http://timer.cistrome.org/) provides more robust estimation of immune infiltration levels for The Cancer Genome Atlas (TCGA) or user-provided …

Show more

Jun 2020 • Investigative Ophthalmology & Visual Science

Lags and leads of accommodation are smaller than previously thought

Vivek Labhishetty, Steven A Cholewiak, Martin S Banks

Purpose: Typically, objective measurement of accommodation using autorefractors, photorefractors or aberrometers reveals response lags and leads implying that the eye does not focus precisely at the distance of the object of regard. These errors are thought to be due to the eye’s depth of focus. Because of the depth of focus an out-of-focus image is perceived as acceptably sharp. We examined these response errors by comparing objective and subjective measures of best focus.Methods: Accommodative stimuli were presented to six healthy adults (20-35 years) using a varifocal display system. Changes in accommodation and pupil size were recorded using a wavefront sensor. On each trial, subjects first fixated a Maltese cross at a distance of 0, 2, 4 or 6D and were told to try to maintain image sharpness. After the 3-sec presentation of the cross, we measured visual acuity with a briefly presented tumbling E …

Show more

Apr 2020 • The Journal of Clinical Investigation 130 (4), 1595-1607, 2020

Personal tumor antigens in blood malignancies: genomics-directed identification and targeting

Livius Penter, Catherine J Wu

Hematological malignancies have long been at the forefront of the development of novel immune-based treatment strategies. The earliest successful efforts originated from the extensive body of work in the field of allogeneic hematopoietic stem cell transplantation. These efforts laid the foundation for the recent exciting era of cancer immunotherapy, which includes immune checkpoint blockade, personal neoantigen vaccines, and adoptive T cell transfer. At the heart of the specificity of these novel strategies is the recognition of target antigens presented by malignant cells to T cells. Here, we review the advances in systematic identification of minor histocompatibility antigens and neoantigens arising from personal somatic alterations or recurrent driver mutations. These exciting efforts pave the path for the implementation of personalized combinatorial cancer therapy.

Show more

Feb 2020 • Adaptive Optics and Wavefront Control for Biological Systems VI 11248, 1124816, 2020

Creating correct aberrations: why blur isn’t always bad in the eye

Gordon D Love, Martin S Banks, Steven A Cholewiak, Abigail P Finch

In optics in general, a sharp aberration-free image is normally the desired goal, and the whole field of adaptive optics has developed with the aim of producing blur-free images. Likewise, in ophthalmic optics we normally aim for a sharp image on the retina. But even with an emmetropic, or well-corrected eye, chromatic and high order aberrations affect the image. We describe two different areas where it is important to take these effects into account and why creating blur correctly via rendering can be advantageous. Firstly we show how rendering chromatic aberration correctly can drive accommodation in the eye and secondly report on matching defocus-l generated using rendering with conventional optical defocus.

Show more

Jan 2020 • Cancer Research

Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer

Changxin Wan, Matthew P Keany, Han Dong, Linah F Al-Alem, Unnati M Pandya, Suzan Lazo, Karsten Boehnke, Katherine N Lynch, Rui Xu, Dominique T Zarrella, Shengqing Gu, Paloma Cejas, Klothilda Lim, Henry W Long, Kevin M Elias, Neil S Horowitz, Colleen M Feltmate, Michael G Muto, Michael J Worley, Ross S Berkowitz, Ursula A Matulonis, Marisa R Nucci, Christopher P Crum, Bo R Rueda, Myles Brown, Xiaole Shirley Liu, Sarah J Hill

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK …

Show more

Jan 2020 • Clinical Cancer Research

Cross-site concordance evaluation of tumor DNA and RNA sequencing platforms for the CIMAC-CIDC network

Zexian Zeng, Jingxin Fu, Carrie Cibulskis, Aashna Jhaveri, Curtis Gumbs, Biswajit Das, Beatriz Sanchez-Espiridion, Sylvie Janssens, Len Taing, Jin Wang, James Lindsay, Tomas Vilimas, Jianhua Zhang, Collin Tokheim, Avinash Das Sahu, Peng Jiang, Chunhua Yan, Dzifa Y Duose, Ethan Cerami, Li Chen, David Cohen, Qing-Rong Chen, Rebecca A Enos, Xin Huang, J Jack Lee, Yang Liu, Donna S Neuberg, Cu Nguyen, Candace Patterson, Sachet A Shukla, Ming Tang, Junko Tsuji, Mohamed Uduman, Xiaoman Wang, Jason L Weirather, Jijun Yu, Joyce Yu, Jianjun Zhang, Jiexin Zhang, Daoud Meerzaman, Magdalena Thurin, P Andrew Futreal, Chris Karlovich, Stacey B Gabriel, Ignacio I Wistuba, Xiaole Shirley Liu, Catherine Wu

Purpose: Whole-exome (WES) and RNA sequencing (RNA-seq) are key components of cancer immunogenomic analyses. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the Cancer Immune Monitoring and Analysis Centers (CIMAC) and the Cancer Immunologic Data Commons (CIDC) conducted a systematic harmonization study.Experimental Design: DNA and RNA were centrally extracted from fresh frozen and formalin-fixed paraffin-embedded non–small cell lung carcinoma tumors and distributed to three centers for WES and RNA-seq profiling. In addition, two 10-plex HapMap cell line pools with known mutations were used to evaluate the accuracy of the WES platforms.Results: The WES platforms achieved high precision (> 0.98) and recall (> 0.87) on the HapMap pools when evaluated on loci using > 50× common coverage. Nonsynonymous mutations …

Show more

Jan 2020 • Clinical Cancer Research

Cross-site concordance evaluation of tumor DNA and RNA sequencing platforms for the CIMAC-CIDC network

Zexian Zeng, Jingxin Fu, Carrie Cibulskis, Aashna Jhaveri, Curtis Gumbs, Biswajit Das, Beatriz Sanchez-Espiridion, Sylvie Janssens, Len Taing, Jin Wang, James Lindsay, Tomas Vilimas, Jianhua Zhang, Collin Tokheim, Avinash Das Sahu, Peng Jiang, Chunhua Yan, Dzifa Y Duose, Ethan Cerami, Li Chen, David Cohen, Qing-Rong Chen, Rebecca A Enos, Xin Huang, J Jack Lee, Yang Liu, Donna S Neuberg, Cu Nguyen, Candace Patterson, Sachet A Shukla, Ming Tang, Junko Tsuji, Mohamed Uduman, Xiaoman Wang, Jason L Weirather, Jijun Yu, Joyce Yu, Jianjun Zhang, Jiexin Zhang, Daoud Meerzaman, Magdalena Thurin, P Andrew Futreal, Chris Karlovich, Stacey B Gabriel, Ignacio I Wistuba, Xiaole Shirley Liu, Catherine Wu

Purpose: Whole-exome (WES) and RNA-sequencing (RNA-seq) are key components of cancer immunogenomic analyses. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the Cancer Immune Monitoring and Analysis Centers (CIMACs) and the Cancer Immunologic Data Commons (CIDC) conducted a systematic harmonization study. Experimental Design: DNA and RNA were centrally extracted from fresh frozen (FF) and formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tumors and distributed to three centers for WES and RNA-seq profiling. In addition, two 10-plex HapMap cell-line pools with known mutations were used to evaluate the accuracy of the WES platforms. Results: The WES platforms achieved high precision (> 0.98) and recall (> 0.87) on the HapMap pools when evaluated on loci using > 50X common coverage. Non …

Show more

Jan 2020

In vivo CRISPR Screens Identify E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target

Xiaoqing Wang, Collin Tokheim, Binbin Wang, Shengqing Stan Gu, Qin Tang, Yihao Li, Nicole Traugh, Yi Zhang, Ziyi Li, Boning Zhang, Jingxin Fu, Tengfei Xiao, Wei Li, Clifford A Meyer, Peng Jiang, Jun Chu, Paloma Cejas, Klothilda Lim, Henry Long, Myles Brown, Xiaole Shirley Liu

Despite remarkable clinical efficacies of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits in triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that inhibition of the E3 ubiquitin ligase Cop1 in cancer cells decreases the secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, and shows synergy in anti-tumor immunity with ICB. Transcriptomics, epigenomics, and proteomics analyses revealed Cop1 functions through proteasomal degradation of the C/ebpδ protein. Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. Cop1 inhibition stabilizes C/ebpδ to suppress the expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy by regulating chemokine secretion and macrophage levels in the TNBC tumor microenvironment.

Show more

logo
Articali

Powered by Articali

TermsPrivacy