430 results on '"Lixia Diao"'
Search Results
2. Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti–PD-1 resistance in non–small cell lung cancer
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Jessica M. Konen, B. Leticia Rodriguez, Haoyi Wu, Jared J. Fradette, Laura Gibson, Lixia Diao, Jing Wang, Stephanie Schmidt, Ignacio I. Wistuba, Jianjun Zhang, and Don L. Gibbons
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Immunology ,Oncology ,Medicine - Abstract
Non–small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti–PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti–PD-1 and queried differential gene expression between these tumors and anti–PD-1–sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and effector tumor-infiltrating CD8+ T cells. Pharmacological inhibition of ATX, or the downstream receptor LPAR5, in combination with anti–PD-1 was sufficient to restore the antitumor immune response and efficaciously control lung tumor growth in multiple KP tumor models. Additionally, ATX was significantly correlated with inflammatory gene signatures, including a CD8+ cytolytic score in multiple lung adenocarcinoma patient data sets, suggesting that an activated tumor-immune microenvironment upregulates ATX and thus provides an opportunity for cotargeting to prevent acquired resistance to anti–PD-1 treatment. These data reveal the ATX/LPA axis as an immunosuppressive pathway that diminishes the immune checkpoint blockade response in lung cancer.
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- 2023
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3. Targeting immunosuppressive Ly6C+ classical monocytes reverses anti-PD-1/CTLA-4 immunotherapy resistance
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B. Leticia Rodriguez, Limo Chen, Yanli Li, Shucheng Miao, David H. Peng, Jared J. Fradette, Lixia Diao, Jessica M. Konen, Frank R. Rojas Alvarez, Luisa M. Solis, Xiaohui Yi, Aparna Padhye, Laura A. Gibson, Joshua K. Ochieng, Xiaofei Zhou, Jing Wang, and Don L. Gibbons
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monocytes ,immunotherapy ,resistance ,myeloid cells ,PD-1/CTLA-4 immunotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionDespite significant clinical advancement with the use of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) there are still a major subset of patients that develop adaptive/acquired resistance. Understanding resistance mechanisms to ICB is critical to developing new therapeutic strategies and improving patient survival. The dynamic nature of the tumor microenvironment and the mutational load driving tumor immunogenicity limit the efficacy to ICB. Recent studies indicate that myeloid cells are drivers of ICB resistance. In this study we sought to understand which immune cells were contributing to resistance and if we could modify them in a way to improve response to ICB therapy.ResultsOur results show that combination anti-PD-1/CTLA-4 produces an initial antitumor effect with evidence of an activated immune response. Upon extended treatment with anti-PD-1/CTLA-4 acquired resistance developed with an increase of the immunosuppressive populations, including T-regulatory cells, neutrophils and monocytes. Addition of anti-Ly6C blocking antibody to anti-PD-1/CTLA-4 was capable of completely reversing treatment resistance and restoring CD8 T cell activity in multiple KP lung cancer models and in the autochthonous lung cancer KrasLSL-G12D/p53fl/fl model. We found that there were higher classical Ly6C+ monocytes in anti-PD-1/CTLA-4 combination resistant tumors. B7 blockade illustrated the importance of dendritic cells for treatment efficacy of anti-Ly6C/PD-1/CTLA-4. We further determined that classical Ly6C+ monocytes in anti-PD-1/CTLA-4 resistant tumors are trafficked into the tumor via IFN-γ and the CCL2-CCR2 axis. Mechanistically we found that classical monocytes from ICB resistant tumors were unable to differentiate into antigen presenting cells and instead differentiated into immunosuppressive M2 macrophages or myeloid-derived suppressor cells (MDSC). Classical Ly6C+ monocytes from ICB resistant tumors had a decrease in both Flt3 and PU.1 expression that prevented differentiation into dendritic cells/macrophages.ConclusionsTherapeutically we found that addition of anti-Ly6C to the combination of anti-PD-1/CTLA-4 was capable of complete tumor eradication. Classical Ly6C+ monocytes differentiate into immunosuppressive cells, while blockade of classical monocytes drives dendritic cell differentiation/maturation to reinvigorate the anti-tumor T cell response. These findings support that immunotherapy resistance is associated with infiltrating monocytes and that controlling the differentiation process of monocytes can enhance the therapeutic potential of ICB.
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- 2023
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4. Anti-tumor activity of cetuximab plus avelumab in non-small cell lung cancer patients involves innate immunity activation: findings from the CAVE-Lung trial
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Carminia Maria Della Corte, Morena Fasano, Vincenza Ciaramella, Flora Cimmino, Robert Cardnell, Carl M. Gay, Kavya Ramkumar, Lixia Diao, Raimondo Di Liello, Giuseppe Viscardi, Vincenzo Famiglietti, Davide Ciardiello, Giulia Martini, Stefania Napolitano, Concetta Tuccillo, Teresa Troiani, Erika Martinelli, Jing Wang, Lauren Byers, Floriana Morgillo, and Fortunato Ciardiello
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Innate immunity ,STING ,NK cells ,Cetuximab ,Avelumab ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti-epidermal growth factor receptor (EGFR) drug, as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. We have reported clinically relevant anti-tumor activity in 6/16 patients. Clinical benefit was accompanied by Natural Killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC). Among the 6 responding patients, 3 had progressed after initial response to a previous treatment with single agent anti-PD-1, nivolumab or pembrolizumab. Methods We report long-term clinical follow-up and additional findings on the anti-tumor activity and on the immune effects of cetuximab plus avelumab treatment for these 3 patients. Results As of November 30, 2021, 2/3 patients were alive. One patient was still on treatment from 34 months, while the other two patients had progression free survival (PFS) of 15 and 19 months, respectively. Analysis of serially collected peripheral blood mononuclear cells (PBMC) revealed long-term activation of NK cell-mediated ADCC. Comprehensive genomic profile analysis found somatic mutations and germline rare variants in DNA damage response (DDR) genes. Furthermore, by transcriptomic analysis of The Cancer Genome Atlas (TCGA) dataset we found that DDR mutant NSCLC displayed high STING pathway gene expression. In NSCLC patient-derived three-dimensional in vitro spheroid cultures, cetuximab plus avelumab treatment induced additive cancer cell growth inhibition as compared to single agent treatment. This effect was partially blocked by treatment with an anti-CD16 mAb, suggesting a direct involvement of NK cell activation. Furthermore, cetuximab plus avelumab treatment induced 10-, 20-, and 20-fold increase, respectively, in the gene expression of CCL5 and CXCL10, two STING downstream effector cytokines, and of interferon β, as compared to untreated control samples. Conclusions DDR mutations may contribute to DDR-induced STING pathway with sustained innate immunity activation following cetuximab plus avelumab combination in previously treated, PD-1 inhibitor responsive NSCLC patients.
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- 2022
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5. Geraniin ameliorates streptozotocin-induced diabetic retinopathy in rats via modulating retinal inflammation and oxidative stress
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Zhimin Yu, LingWei, Qing Gao, and Lixia Diao
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Diabetic retinopathy ,Geraniin ,Oxidative stress ,Inflammation ,Streptozotocin ,Chemistry ,QD1-999 - Abstract
Background: Diabetic retinopathy (DR) is the major complication of diabetes, which causes acquired vision loss in the working-age group population. Objective: Here, we planned to address the therapeutic roles of geraniin against the streptozotocin (STZ)-challenged DR in rats Methodology: The DR was induced in the animals by 60 mg/kg of STZ, and then treated with 25 mg/kg of geraniin for 60 days. Later, bodyweight, food consumption, and blood glucose levels were investigated. The levels of antioxidants, MMP-9, MCP-1, and VEGF, and inflammatory cytokine status were measured using marker-specific kits. The morphometric study was conducted to assess the retinal thickness. The pancreatic tissues were analyzed microscopically. Results: Geraniin reduced the blood glucose (270.36 ± 81 mg/dL), hemoglobin, and enhanced bodyweight (261.93 ± 72 g)in the DR rats. The antioxidant levels in the STZ-challenged DR rats were substantially improved by geraniin. Geraniin also decreased inflammatory cytokines, MCP-I, MMP-9, and VEGF levels and enhanced the retinal thickness. A histological study demonstrated that geraniin reduced the pancreatic islet cell damage in STZ-induced DR rats. Conclusion: Our outcomes witnessed that geraniin reduced retinal inflammation and oxidative stress in the STZ-induced DR rats.
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- 2023
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6. The EMT activator ZEB1 accelerates endosomal trafficking to establish a polarity axis in lung adenocarcinoma cells
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Priyam Banerjee, Guan-Yu Xiao, Xiaochao Tan, Veronica J. Zheng, Lei Shi, Maria Neus Bota Rabassedas, Hou-fu Guo, Xin Liu, Jiang Yu, Lixia Diao, Jing Wang, William K. Russell, Jason Roszik, Chad J. Creighton, and Jonathan M. Kurie
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Science - Abstract
The way in which metastatic tumour cells control endocytic vesicular trafficking networks to establish a front-rear polarity axis that facilitates motility remains unclear. Here, the authors show that the EMT activator ZEB1 influences vesicular trafficking dynamics to execute cell polarity change.
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- 2021
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7. Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer
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Ming Chen, Runzhe Chen, Ying Jin, Jun Li, Xin Hu, Jiexin Zhang, Junya Fujimoto, Shawna M. Hubert, Carl M. Gay, Bo Zhu, Yanhua Tian, Nicholas McGranahan, Won-Chul Lee, Julie George, Xiao Hu, Yamei Chen, Meijuan Wu, Carmen Behrens, Chi-Wan Chow, Hoa H. N. Pham, Junya Fukuoka, Jia Wu, Edwin Roger Parra, Latasha D. Little, Curtis Gumbs, Xingzhi Song, Chang-Jiun Wu, Lixia Diao, Qi Wang, Robert Cardnell, Jianhua Zhang, Jing Wang, Xiuning Le, Don L. Gibbons, John V. Heymach, J. Jack Lee, William N. William, Chao Cheng, Bonnie Glisson, Ignacio Wistuba, P. Andrew Futreal, Roman K. Thomas, Alexandre Reuben, Lauren A. Byers, and Jianjun Zhang
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Science - Abstract
Small-cell lung cancer (SCLC) is an aggressive disease with limited therapeutic options. Here the authors perform an immunogenomic analysis of limited-stage SCLC, revealing a homogeneous mutational landscape, but limited T-cell infiltration and a cold and heterogeneous T cell repertoire.
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- 2021
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8. Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer
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Kasey R. Cargill, C. Allison Stewart, Elizabeth M. Park, Kavya Ramkumar, Carl M. Gay, Robert J. Cardnell, Qi Wang, Lixia Diao, Li Shen, You-Hong Fan, Wai Kin Chan, Philip L. Lorenzi, Trudy G. Oliver, Jing Wang, and Lauren A. Byers
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MYC ,Glycolysis ,Metabolism ,Small cell lung cancer ,PFK158 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Introduction The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches. Methods We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3. Results MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression. Conclusions Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.
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- 2021
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9. Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers
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David H. Peng, B. Leticia Rodriguez, Lixia Diao, Pierre-Olivier Gaudreau, Aparna Padhye, Jessica M. Konen, Joshua K. Ochieng, Caleb A. Class, Jared J. Fradette, Laura Gibson, Limo Chen, Jing Wang, Lauren A. Byers, and Don. L. Gibbons
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Science - Abstract
Recent clinical trials combining MEK inhibitors with anti-PD-L1 in solid tumours show moderate responses. Here, the authors demonstrate that the combination of MEK inhibition and PD-L1 blockade in KRAS mutant lung cancer models leads to a transient tumour regressions and resistance due to increased infiltration of Th17 cells and that the triple therapy targeting MEK, PD-L1 and IL-17 produced better in vivo responses.
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- 2021
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10. Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity
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Won-Chul Lee, Alexandre Reuben, Xin Hu, Nicholas McGranahan, Runzhe Chen, Ali Jalali, Marcelo V. Negrao, Shawna M. Hubert, Chad Tang, Chia-Chin Wu, Anthony San Lucas, Whijae Roh, Kenichi Suda, Jihye Kim, Aik-Choon Tan, David H. Peng, Wei Lu, Ximing Tang, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Neda Kalhor, Kazutaka Fukumura, Marcus Coyle, Rebecca Thornton, Curtis Gumbs, Jun Li, Chang-Jiun Wu, Latasha Little, Emily Roarty, Xingzhi Song, J. Jack Lee, Erik P. Sulman, Ganesh Rao, Stephen Swisher, Lixia Diao, Jing Wang, John V. Heymach, Jason T. Huse, Paul Scheet, Ignacio I. Wistuba, Don L. Gibbons, P. Andrew Futreal, Jianhua Zhang, Daniel Gomez, and Jianjun Zhang
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Lung cancer ,Metastasis ,Multiomics ,Immune profiling ,Genomics ,DNA methylation ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. Results We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. Conclusions Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.
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- 2020
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11. Multi-omics prediction of immune-related adverse events during checkpoint immunotherapy
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Ying Jing, Jin Liu, Youqiong Ye, Lei Pan, Hui Deng, Yushu Wang, Yang Yang, Lixia Diao, Steven H. Lin, Gordon B. Mills, Guanglei Zhuang, Xinying Xue, and Leng Han
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Science - Abstract
Immunotherapy, the reactivation of the immune system to recognize cancer cells, can be accompanied by severe adverse effects. Here, the authors use pharmacovigilance and genomic data to be able to predict which patients might be susceptible to such severe events.
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- 2020
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12. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion
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David H. Peng, Bertha Leticia Rodriguez, Lixia Diao, Limo Chen, Jing Wang, Lauren A. Byers, Ying Wei, Harold A. Chapman, Mitsuo Yamauchi, Carmen Behrens, Gabriela Raso, Luisa Maren Solis Soto, Edwin Roger Parra Cuentes, Ignacio I. Wistuba, Jonathan M. Kurie, and Don L. Gibbons
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Science - Abstract
Tumor extracellular matrix has been associated with cancer progression, therapy resistance and immune suppression. Here, the authors show that collagen generates resistance to PD-1/PD-L1 immunotherapy by upregulating LAIR1 expression and downstream signaling, leading to increased CD8+ T cell exhaustion.
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- 2020
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13. The genetic and pharmacogenomic landscape of snoRNAs in human cancer
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Yaoming Liu, Hang Ruan, Shengli Li, Youqiong Ye, Wei Hong, Jing Gong, Zhao Zhang, Ying Jing, Xiulan Zhang, Lixia Diao, and Leng Han
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Small nucleolar RNA ,Genetic variants ,Pharmacogenomics ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Emerging evidence has revealed significant roles for small nucleolar RNAs (snoRNAs) in tumorigenesis. However, the genetic and pharmacogenomic landscape of snoRNAs has not been characterized. Using the genotype and snoRNA expression data from The Cancer Genome Atlas, we characterized the effects of genetic variants on snoRNAs across 29 cancer types and further linked related alleles with patient survival as well as genome-wide association study risk loci. Furthermore, we characterized the impact of snoRNA expression on drug response in patients to facilitate the clinical utility of snoRNAs in cancer. We also developed a user-friendly data resource, GPSno ( http://hanlab.uth.edu/GPSno ), with multiple modules for researchers to visualize, browse, and download multi-dimensional data. Our study provides a comprehensive genetic and pharmacogenomic landscape of snoRNAs, which will shed light on future clinical considerations for the development of snoRNA-based targeted therapies.
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- 2020
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14. Sex-associated molecular differences for cancer immunotherapy
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Youqiong Ye, Ying Jing, Liang Li, Gordon B. Mills, Lixia Diao, Hong Liu, and Leng Han
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Science - Abstract
Immunotherapy has tremendous potential to treat many patients with cancer. In this study, the authors investigate the impact of gender on the response to therapy, highlighting the importance to include omics profiling in clinical studies.
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- 2020
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15. Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy
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Hong Liu, Jing Wang, Yuan Liu, Yanyan Lou, Ying Jing, Xiang Chen, Lixia Diao, Douglas B Johnson, Steven H Lin, Leng Han, Xue Chen, Zhao Zhang, Yushu Wang, Kunyan Li, Yaoming Liu, and Yiqing Chen
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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16. Profiling of immune features to predict immunotherapy efficacy
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Youqiong Ye, Yongchang Zhang, Nong Yang, Qian Gao, Xinyu Ding, Xinwei Kuang, Rujuan Bao, Zhao Zhang, Chaoyang Sun, Bingying Zhou, Li Wang, Qingsong Hu, Chunru Lin, Jianjun Gao, Yanyan Lou, Steven H. Lin, Lixia Diao, Hong Liu, Xiang Chen, Gordon B. Mills, and Leng Han
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cancer immunotherapy ,immune checkpoints ,immune cell population ,immune activation score ,noninvasive biomarker ,Science (General) ,Q1-390 - Abstract
Immune checkpoint blockade (ICB) therapies exhibit substantial clinical benefit in different cancers, but relatively low response rates in the majority of patients highlight the need to understand mutual relationships among immune features. Here, we reveal overall positive correlations among immune checkpoints and immune cell populations. Clinically, patients benefiting from ICB exhibited increases for both immune stimulatory and inhibitory features after initiation of therapy, suggesting that the activation of the immune microenvironment might serve as the biomarker to predict immune response. As proof-of-concept, we demonstrated that the immune activation score (ISΔ) based on dynamic alteration of interleukins in patient plasma as early as two cycles (4–6 weeks) after starting immunotherapy can accurately predict immunotherapy efficacy. Our results reveal a systematic landscape of associations among immune features and provide a noninvasive, cost-effective, and time-efficient approach based on dynamic profiling of pre- and on-treatment plasma to predict immunotherapy efficacy.
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- 2022
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17. High OX-40 expression in the tumor immune infiltrate is a favorable prognostic factor of overall survival in non-small cell lung cancer
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Erminia Massarelli, Vincent K. Lam, Edwin R. Parra, Jaime Rodriguez-Canales, Carmen Behrens, Lixia Diao, Jing Wang, Jorge Blando, Lauren A. Byers, Niranjan Yanamandra, Sara Brett, Peter Morley, Padmanee Sharma, James Allison, Ignacio I. Wistuba, and John V. Heymach
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OX-40 ,Lung cancer ,NSCLC ,Immune checkpoint ,immunotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Introduction OX-40 co-stimulatory signaling plays a role in mounting anti-tumor immune responses and clinical trials targeting this pathway are ongoing. However, the association of with OX-40 protein expression with clinical outcomes and pathological features in non-small cell lung cancer (NSCLC) are largely unknown. Methods Surgically-resected stage I-III NSCLC specimens (N = 100) were stained by immunohistochemistry (IHC) for the following immune markers: OX-40, PD-L1, PD-1, CD3, CD4, CD8, CD45RO, CD57, CD68, FOXP3, granzyme B, and ICOS. Immune-related markers mRNA expression were also assessed. We evaluated the association of OX-40 levels with major clinicopathologic variables, including molecular driver mutations. Results OX-40 IHC expression was observed in all tested tumors, predominantly localized in the membrane of the tumor immune infiltrate, and was not associated with a specific clinicopathologic or molecular subtype. High OX-40 expression levels measured by IHC median score were associated with better overall survival (OS) (p = 0.002), independent of CD3/CD8, PD-L1, and ICOS expression. High OX-40 IHC score was associated with increased expression of immune-related genes such as CD3, IFN-gamma, ICOS, CD8, CXCL9, CXCL10, CCL5, granzyme K. Conclusions High OX-40 IHC expression in the tumor immune infiltrate is associated with favorable prognosis and increased levels of immune-related genes including IFN-gamma in patients with surgically resected stage I-III NSCLC. Its prognostic utility is independent of PD-L1 and other common markers of immune activation. High OX-40 expression potentially identifies a unique subgroup of NSCLC that may benefit from co-stimulation with OX-40 agonist antibodies and potentially enhance the efficacy of existing immune checkpoint therapies.
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- 2019
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18. Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS-mutant lung cancer
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Aparna Padhye, Jessica M. Konen, B. Leticia Rodriguez, Jared J. Fradette, Joshua K. Ochieng, Lixia Diao, Jing Wang, Wei Lu, Luisa S. Solis, Harsh Batra, Maria G. Raso, Michael D. Peoples, Rosalba Minelli, Alessandro Carugo, Christopher A. Bristow, and Don L. Gibbons
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Oncology ,Medicine - Abstract
Lack of sustained response to therapeutic agents in patients with KRAS-mutant lung cancer poses a major challenge and arises partly due to intratumor heterogeneity that defines phenotypically distinct tumor subpopulations. To attain better therapeutic outcomes, it is important to understand the differential therapeutic sensitivities of tumor cell subsets. Epithelial-mesenchymal transition is a biological phenomenon that can alter the state of cells along a phenotypic spectrum and cause transcriptional rewiring to produce distinct tumor cell subpopulations. We utilized functional shRNA screens, in in vitro and in vivo models, to identify and validate an increased dependence of mesenchymal tumor cells on cyclin-dependent kinase 4 (CDK4) for survival, as well as a mechanism of resistance to MEK inhibitors. High zinc finger E-box binding homeobox 1 levels in mesenchymal tumor cells repressed p21, leading to perturbed CDK4 pathway activity. Increased dependence on CDK4 rendered mesenchymal cancer cells particularly vulnerable to selective CDK4 inhibitors. Coadministration of CDK4 and MEK inhibitors in heterogeneous tumors effectively targeted different tumor subpopulations, subverting the resistance to either single-agent treatment.
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- 2021
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19. Single-cell reconstruction of differentiation trajectory reveals a critical role of ETS1 in human cardiac lineage commitment
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Hang Ruan, Yingnan Liao, Zongna Ren, Lin Mao, Fang Yao, Peng Yu, Youqiong Ye, Zhao Zhang, Shengli Li, Hanshi Xu, Jiewei Liu, Lixia Diao, Bingying Zhou, Leng Han, and Li Wang
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Cardiac lineage commitment ,Human pluripotent stem cells ,Single-cell RNA sequencing ,Cell-cell crosstalk ,ETS1 ,Transcription regulation ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Cardiac differentiation from human pluripotent stem cells provides a unique opportunity to study human heart development in vitro and offers a potential cell source for cardiac regeneration. Compared to the large body of studies investigating cardiac maturation and cardiomyocyte subtype-specific induction, molecular events underlying cardiac lineage commitment from pluripotent stem cells at early stage remain poorly characterized. Results In order to uncover key molecular events and regulators controlling cardiac lineage commitment from a pluripotent state during differentiation, we performed single-cell RNA-Seq sequencing and obtained high-quality data for 6879 cells collected from 6 stages during cardiac differentiation from human embryonic stem cells and identified multiple cell subpopulations with distinct molecular features. Through constructing developmental trajectory of cardiac differentiation and putative ligand-receptor interactions, we revealed crosstalk between cardiac progenitor cells and endoderm cells, which could potentially provide a cellular microenvironment supporting cardiac lineage commitment at day 5. In addition, computational analyses of single-cell RNA-Seq data unveiled ETS1 (ETS Proto-Oncogene 1) activation as an important downstream event induced by crosstalk between cardiac progenitor cells and endoderm cells. Consistent with the findings from single-cell analysis, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) against ETS1 revealed genomic occupancy of ETS1 at cardiac structural genes at day 9 and day 14, whereas ETS1 depletion dramatically compromised cardiac differentiation. Conclusion Together, our study not only characterized the molecular features of different cell types and identified ETS1 as a crucial factor induced by cell-cell crosstalk contributing to cardiac lineage commitment from a pluripotent state, but may also have important implications for understanding human heart development at early embryonic stage, as well as directed manipulation of cardiac differentiation in regenerative medicine.
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- 2019
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20. Transcriptional landscape and clinical utility of enhancer RNAs for eRNA-targeted therapy in cancer
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Zhao Zhang, Joo-Hyung Lee, Hang Ruan, Youqiong Ye, Joanna Krakowiak, Qingsong Hu, Yu Xiang, Jing Gong, Bingying Zhou, Li Wang, Chunru Lin, Lixia Diao, Gordon B. Mills, Wenbo Li, and Leng Han
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Science - Abstract
Enhancer RNA (eRNA) is a type of noncoding RNA transcribed from enhancer regions. Here, the authors investigate the transcriptional landscape of eRNA in cancer, incorporating pharmacogenomic data to identify potential target genes and therapeutic targets.
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- 2019
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21. Comprehensive characterization of circular RNAs in ~ 1000 human cancer cell lines
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Hang Ruan, Yu Xiang, Junsuk Ko, Shengli Li, Ying Jing, Xiaoyu Zhu, Youqiong Ye, Zhao Zhang, Tingting Mills, Jing Feng, Chun-Jie Liu, Ji Jing, Jin Cao, Bingying Zhou, Li Wang, Yubin Zhou, Chunru Lin, An-Yuan Guo, Xi Chen, Lixia Diao, Wenbo Li, Zhiao Chen, Xianghuo He, Gordon B. Mills, Michael R. Blackburn, and Leng Han
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Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Human cancer cell lines are fundamental models for cancer research and therapeutic strategy development. However, there is no characterization of circular RNAs (circRNAs) in a large number of cancer cell lines. Methods Here, we apply four circRNA identification algorithms to heuristically characterize the expression landscape of circRNAs across ~ 1000 human cancer cell lines from CCLE polyA-enriched RNA-seq data. By using integrative analysis and experimental approaches, we explore the expression landscape, biogenesis, functional consequences, and drug response of circRNAs across different cancer lineages. Results We revealed highly lineage-specific expression patterns of circRNAs, suggesting that circRNAs may be powerful diagnostic and/or prognostic markers in cancer treatment. We also identified key genes involved in circRNA biogenesis and confirmed that TGF-β signaling may promote biogenesis of circRNAs. Strikingly, we showed that clinically actionable genes are more likely to generate circRNAs, potentially due to the enrichment of RNA-binding protein (RBP) binding sites. Among these, circMYC can promote cell proliferation. We observed strong association between the expression of circRNAs and the response to drugs, especially those targeting chromatin histone acetylation. Finally, we developed a user-friendly data portal, CircRNAs in cancer cell lines (CircRiC, https://hanlab.uth.edu/cRic), to benefit the biomedical research community. Conclusions Our study provides the characterization of circRNAs in cancer cell lines and explored the potential mechanism of circRNA biogenesis as well as its therapeutic implications. We also provide a data portal to facilitate the related biomedical researches.
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- 2019
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22. 852 Differential expression of surface protein-encoding genes highlights therapeutic vulnerabilities of four SCLC subtypes
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Jing Wang, Qi Wang, John Heymach, Lixia Diao, Robert Cardnell, Lauren Byers, Elizabeth Park, Carl Gay, C Allison Stewart, and Kasey Cargill
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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23. Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer
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Mauricio S. Caetano, Maya Hassane, Hieu T. Van, Emmanuel Bugarin, Amber M. Cumpian, Christina L. McDowell, Carolina Gonzalez Cavazos, Huiyuan Zhang, Shanshan Deng, Lixia Diao, Jing Wang, Scott E. Evans, Carmen Behrens, Ignacio I. Wistuba, Susan A. W. Fuqua, Huang Lin, Laura P. Stabile, Stephanie S. Watowich, Humam Kadara, and Seyed Javad Moghaddam
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Science - Abstract
Proinflammatory and immunomodulatory events that drive development of K-ras mutant lung adenocarcinoma (LUAD) are poorly understood. Here they develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout mouse model and show a sex-specific role for epithelial Stat3 signaling in K-ras-mutant LUAD.
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- 2018
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24. A Pan-cancer Analysis of the Expression and Clinical Relevance of Small Nucleolar RNAs in Human Cancer
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Jing Gong, Yajuan Li, Chun-jie Liu, Yu Xiang, Chunlai Li, Youqiong Ye, Zhao Zhang, David H. Hawke, Peter K. Park, Lixia Diao, John A. Putkey, Liuqing Yang, An-Yuan Guo, Chunru Lin, and Leng Han
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Biology (General) ,QH301-705.5 - Abstract
Summary: Increasing evidence has demonstrated that small nucleolar RNAs (snoRNAs) play important roles in tumorigenesis. We systematically investigated the expression landscape and clinical relevance of snoRNAs in >10,000 samples across 31 cancer types from The Cancer Genome Atlas. We observed overall elevated expression of snoRNAs and their ribonucleoproteins in multiple cancer types. We showed complex regulation of snoRNA expression by their host genes, copy number variation, and DNA methylation. Unsupervised clustering revealed that the snoRNA expression subtype is highly concordant with other molecular/clinical subtypes. We further identified 46 clinically relevant snoRNAs and experimentally demonstrated functional roles of SNORD46 in promoting cell proliferation, migration, and invasion. We developed a user-friendly data portal, SNORic, to benefit the research community. Our study highlights the significant roles of snoRNAs in the development and implementation of biomarkers or therapeutic targets for cancer and provides a valuable resource for cancer research. : Gong et al. analyze snoRNA expression landscape in >10,000 samples across 31 cancer types and perform integrative analyses. They prioritize 46 significant clinically relevant snoRNAs and characterize the functional roles of SNORD46. The data portal, SNORic, allows exploration of snoRNA expression. Keywords: snoRNA, small nucleolar RNA, pan-cancer, clinical relevance, data portal
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- 2017
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25. Selecting Reliable mRNA Expression Measurements Across Platforms Improves Downstream Analysis
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Pan Tong, Lixia Diao, Li Shen, Lerong Li, John Victor Heymach, Luc Girard, John D. Minna, Kevin R. Coombes, Lauren Averett Byers, and Jing Wang
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2016
26. Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
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Joshua D. Campbell, Christina Yau, Reanne Bowlby, Yuexin Liu, Kevin Brennan, Huihui Fan, Alison M. Taylor, Chen Wang, Vonn Walter, Rehan Akbani, Lauren Averett Byers, Chad J. Creighton, Cristian Coarfa, Juliann Shih, Andrew D. Cherniack, Olivier Gevaert, Marcos Prunello, Hui Shen, Pavana Anur, Jianhong Chen, Hui Cheng, D. Neil Hayes, Susan Bullman, Chandra Sekhar Pedamallu, Akinyemi I. Ojesina, Sara Sadeghi, Karen L. Mungall, A. Gordon Robertson, Christopher Benz, Andre Schultz, Rupa S. Kanchi, Carl M. Gay, Apurva Hegde, Lixia Diao, Jing Wang, Wencai Ma, Pavel Sumazin, Hua-Sheng Chiu, Ting-Wen Chen, Preethi Gunaratne, Larry Donehower, Janet S. Rader, Rosemary Zuna, Hikmat Al-Ahmadie, Alexander J. Lazar, Elsa R. Flores, Kenneth Y. Tsai, Jane H. Zhou, Anil K. Rustgi, Esther Drill, Ronglei Shen, Christopher K. Wong, Joshua M. Stuart, Peter W. Laird, Katherine A. Hoadley, John N. Weinstein, Myron Peto, Curtis R. Pickering, Zhong Chen, Carter Van Waes, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Paul Spellman, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Toshinori Hinoue, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, onathan Stretch, Maria Synott, John Thompson, James Wilmott, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
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Biology (General) ,QH301-705.5 - Abstract
Summary: This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches. : Campbell et al. reveal that squamous cell cancers from different tissue sites may be distinguished from other cancers and subclassified molecularly by recurrent alterations in chromosomes, DNA methylation, messenger and microRNA expression, or by mutations. These affect squamous cell pathways and programs that provide candidates for therapy. Keywords: genomics, transcriptomics, proteomics, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, bladder carcinoma with squamous differentiation, human papillomavirus
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- 2018
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27. Activation of the PI3K/mTOR Pathway following PARP Inhibition in Small Cell Lung Cancer.
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Robert J Cardnell, Ying Feng, Seema Mukherjee, Lixia Diao, Pan Tong, C Allison Stewart, Fatemeh Masrorpour, YouHong Fan, Monique Nilsson, Yuqiao Shen, John V Heymach, Jing Wang, and Lauren A Byers
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Medicine ,Science - Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options. We previously found that PARP is overexpressed in SCLC and that targeting PARP reduces cell line and tumor growth in preclinical models. However, SCLC cell lines with PI3K/mTOR pathway activation were relatively less sensitive to PARP inhibition. In this study, we investigated the proteomic changes in PI3K/mTOR and other pathways that occur following PAPR inhibition and/or knockdown in vitro and in vivo. Using reverse-phase protein array, we found the proteins most significantly upregulated following treatment with the PARP inhibitors olaparib and rucaparib were in the PI3K/mTOR pathway (p-mTOR, p-AKT, and pS6) (p≤0.02). Furthermore, amongst the most significantly down-regulated proteins were LKB1 and its targets AMPK and TSC, which negatively regulate the PI3K pathway (p≤0.042). Following PARP knockdown in cell lines, phosphorylated mTOR, AKT and S6 were elevated and LKB1 signaling was diminished. Global ATP concentrations increased following PARP inhibition (p≤0.02) leading us to hypothesize that the observed increased PI3K/mTOR pathway activation following PARP inhibition results from decreased ATP usage and a subsequent decrease in stress response signaling via LKB1. Based on these results, we then investigated whether co-targeting with a PARP and PI3K inhibitor (BKM-120) would work better than either single agent alone. A majority of SCLC cell lines were sensitive to BKM-120 at clinically achievable doses, and cMYC expression was the strongest biomarker of response. At clinically achievable doses of talazoparib (the most potent PARP inhibitor in SCLC clinical testing) and BKM-120, an additive effect was observed in vitro. When tested in two SCLC animal models, a greater than additive interaction was seen (p≤0.008). The data presented here suggest that combining PARP and PI3K inhibitors enhances the effect of either agent alone in preclinical models of SCLC, warranting further investigation of such combinations in SCLC patients.
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- 2016
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28. Reproducibility of SELDI Spectra Across Time and Laboratories
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Lixia Diao, Charlotte H. Clarke, Kevin R. Coombes, Stanley R. Hamilton, Jack Roth, Li Mao, Bogdan Czerniak, Keith A. Baggerly, Jeffrey S. Morris, Eric T. Fung, and Robert C. Bast Jr
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2011
29. In Vivo Delivery of miR-34a Sensitizes Lung Tumors to Radiation Through RAD51 Regulation
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Maria Angelica Cortez, David Valdecanas, Sharareh Niknam, Heidi J Peltier, Lixia Diao, Uma Giri, Ritsuko Komaki, George A Calin, Daniel R Gomez, Joe Y Chang, John Victor Heymach, Andreas G Bader, and James William Welsh
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miR-34a ,non-small-cell lung cancer ,RAD51 ,radiation ,Therapeutics. Pharmacology ,RM1-950 - Abstract
MiR-34a, an important tumor-suppressing microRNA, is downregulated in several types of cancer; loss of its expression has been linked with unfavorable clinical outcomes in non-small-cell lung cancer (NSCLC), among others. MiR-34a represses several key oncogenic proteins, and a synthetic mimic of miR-34a is currently being tested in a cancer trial. However, little is known about the potential role of miR-34a in regulating DNA damage response and repair. Here, we demonstrate that miR-34a directly binds to the 3’ untranslated region of RAD51 and regulates homologous recombination, inhibiting double-strand-break repair in NSCLC cells. We further demonstrate the therapeutic potential of miR-34a delivery in combination with radiotherapy in mouse models of lung cancer. Collectively, our results suggest that administration of miR-34a in combination with radiotherapy may represent a novel strategy for treating NSCLC.
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- 2015
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30. Integrated MicroRNA–mRNA Profiling Identifies Oncostatin M as a Marker of Mesenchymal-Like ER-Negative/HER2-Negative Breast Cancer
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Giulia Bottai, Lixia Diao, Keith A. Baggerly, Laura Paladini, Balázs Győrffy, Carlotta Raschioni, Lajos Pusztai, George A. Calin, and Libero Santarpia
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breast cancer ,microRNAs ,molecular subtypes ,immune response ,Oncostatin M ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
MicroRNAs (miRNAs) simultaneously modulate different oncogenic networks, establishing a dynamic system of gene expression and pathway regulation. In this study, we analyzed global miRNA and messenger RNA (mRNA) expression profiles of 17 cell lines representing different molecular breast cancer subtypes. Spearman’s rank correlation test was used to evaluate the correlation between miRNA and mRNA expression. Hierarchical clustering and pathway analysis were also performed. Publicly available gene expression profiles (n = 699) and tumor tissues (n = 80) were analyzed to assess the relevance of key miRNA-regulated pathways in human breast cancer. We identified 39 significantly deregulated miRNAs, and the integration between miRNA and mRNA data revealed the importance of immune-related pathways, particularly the Oncostatin M (OSM) signaling, associated with mesenchymal-like breast cancer cells. OSM levels correlated with genes involved in the inflammatory response, epithelial-to-mesenchymal transition (EMT), and epidermal growth factor (EGF) signaling in human estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Our results suggest that the deregulation of specific miRNAs may cooperatively impair immune and EMT pathways. The identification of the OSM inflammatory pathway as an important mediator of EMT in triple-negative breast cancer (TNBC) may provide a novel potential opportunity to improve therapeutic strategies.
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- 2017
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31. Aberrant expression of proteins involved in signal transduction and DNA repair pathways in lung cancer and their association with clinical parameters.
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Yong He, Zhen Zhou, Wayne L Hofstetter, Yanbin Zhou, Wenxian Hu, Chengcheng Guo, Li Wang, Wei Guo, Apar Pataer, Arlene M Correa, Yiling Lu, Jing Wang, Lixia Diao, Lauren Averett Byers, Ignacio I Wistuba, Jack A Roth, Stephen G Swisher, John V Heymach, and Bingliang Fang
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Medicine ,Science - Abstract
Because cell signaling and cell metabolic pathways are executed through proteins, protein signatures in primary tumors are useful for identifying key nodes in signaling networks whose alteration is associated with malignancy and/or clinical outcomes. This study aimed to determine protein signatures in primary lung cancer tissues.We analyzed 126 proteins and/or protein phosphorylation sites in case-matched normal and tumor samples from 101 lung cancer patients with reverse-phase protein array (RPPA) assay. The results showed that 18 molecules were significantly different (p
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- 2012
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32. The microbial communities in male first catch urine are highly similar to those in paired urethral swab specimens.
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Qunfeng Dong, David E Nelson, Evelyn Toh, Lixia Diao, Xiang Gao, J Dennis Fortenberry, and Barbara Van der Pol
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Medicine ,Science - Abstract
Urine is the CDC-recommended specimen for STI testing. It was unknown if the bacterial communities (microbiomes) in urine reflected those in the distal male urethra. We compared microbiomes of 32 paired urine and urethral swab specimens obtained from adult men attending an STD clinic, by 16S rRNA PCR and deep pyrosequencing. Microbiomes of urine and swabs were remarkably similar, regardless of STI status of the subjects. Thus, urine can be used to characterize urethral microbiomes when swabs are undesirable, such as in population-based studies of the urethral microbiome or where multiple sampling of participants is required.
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- 2011
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33. A two-gene signature, SKI and SLAMF1, predicts time-to-treatment in previously untreated patients with chronic lymphocytic leukemia.
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Carmen D Schweighofer, Kevin R Coombes, Lynn L Barron, Lixia Diao, Rachel J Newman, Alessandra Ferrajoli, Susan O'Brien, William G Wierda, Rajyalakshmi Luthra, L Jeffrey Medeiros, Michael J Keating, and Lynne V Abruzzo
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Medicine ,Science - Abstract
We developed and validated a two-gene signature that predicts prognosis in previously-untreated chronic lymphocytic leukemia (CLL) patients. Using a 65 sample training set, from a cohort of 131 patients, we identified the best clinical models to predict time-to-treatment (TTT) and overall survival (OS). To identify individual genes or combinations in the training set with expression related to prognosis, we cross-validated univariate and multivariate models to predict TTT. We identified four gene sets (5, 6, 12, or 13 genes) to construct multivariate prognostic models. By optimizing each gene set on the training set, we constructed 11 models to predict the time from diagnosis to treatment. Each model also predicted OS and added value to the best clinical models. To determine which contributed the most value when added to clinical variables, we applied the Akaike Information Criterion. Two genes were consistently retained in the models with clinical variables: SKI (v-SKI avian sarcoma viral oncogene homolog) and SLAMF1 (signaling lymphocytic activation molecule family member 1; CD150). We optimized a two-gene model and validated it on an independent test set of 66 samples. This two-gene model predicted prognosis better on the test set than any of the known predictors, including ZAP70 and serum β2-microglobulin.
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- 2011
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34. Characteristic male urine microbiomes associate with asymptomatic sexually transmitted infection.
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David E Nelson, Barbara Van Der Pol, Qunfeng Dong, Kashi V Revanna, Baochang Fan, Shraddha Easwaran, Erica Sodergren, George M Weinstock, Lixia Diao, and J Dennis Fortenberry
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Medicine ,Science - Abstract
BackgroundThe microbiome of the male urogenital tract is poorly described but it has been suggested that bacterial colonization of the male urethra might impact risk of sexually transmitted infection (STI). Previous cultivation-dependent studies showed that a variety of non-pathogenic bacteria colonize the urethra but did not thoroughly characterize these microbiomes or establish links between the compositions of urethral microbiomes and STI.Methodology/findingsHere, we used 16S rRNA PCR and sequencing to identify bacteria in urine specimens collected from men who lacked symptoms of urethral inflammation but who differed in status for STI. All of the urine samples contained multiple bacterial genera and many contained taxa that colonize the human vagina. Uncultivated bacteria associated with female genital tract pathology were abundant in specimens from men who had STI.ConclusionsUrine microbiomes from men with STI were dominated by fastidious, anaerobic and uncultivated bacteria. The same taxa were rare in STI negative individuals. Our findings suggest that the composition of male urine microbiomes is related to STI.
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- 2010
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35. Shared Nearest Neighbors Approach and Interactive Browser for Network Analysis of a Comprehensive Non-Small-Cell Lung Cancer Data Set
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Stephanie T, Schmidt, Neal, Akhave, Ryan E, Knightly, Alexandre, Reuben, Natalie, Vokes, Jianhua, Zhang, Jun, Li, Junya, Fujimoto, Lauren A, Byers, Beatriz, Sanchez-Espiridion, Lixia, Diao, Jing, Wang, Lorenzo, Federico, Marie-Andree, Forget, Daniel J, McGrail, Annikka, Weissferdt, Shiaw-Yih, Lin, Younghee, Lee, Erika, Suzuki, Jeffrey J, Kovacs, Carmen, Behrens, Ignacio I, Wistuba, Andrew, Futreal, Ara, Vaporciyan, Boris, Sepesi, John V, Heymach, Chantale, Bernatchez, Cara, Haymaker, Tina, Cascone, Jianjun, Zhang, Christopher A, Bristow, Timothy P, Heffernan, Marcelo V, Negrao, and Don L, Gibbons
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Lung Neoplasms ,Carcinoma, Non-Small-Cell Lung ,Gene Expression Profiling ,Cluster Analysis ,Humans ,General Medicine ,Software - Abstract
PURPOSE Advances in biological measurement technologies are enabling large-scale studies of patient cohorts across multiple omics platforms. Holistic analysis of these data can generate actionable insights for translational research and necessitate new approaches for data integration and mining. METHODS We present a novel approach for integrating data across platforms on the basis of the shared nearest neighbors algorithm and use it to create a network of multiplatform data from the immunogenomic profiling of non–small-cell lung cancer project. RESULTS Benchmarking demonstrates that the shared nearest neighbors-based network approach outperforms a traditional gene-gene network in capturing established interactions while providing new ones on the basis of the interplay between measurements from different platforms. When used to examine patient characteristics of interest, our approach provided signatures associated with and new leads related to recurrence and TP53 oncogenotype. CONCLUSION The network developed offers an unprecedented, holistic view into immunogenomic profiling of non–small-cell lung cancer, which can be explored through the accompanying interactive browser that we built.
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- 2023
36. Thyme-Loaded Nanofibrous Dressing for Skin Wound Healing: A Combination of Chinese Traditional Medicine with Cutting-Edge Technology
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Yang Li, Xin Yan, Lei Zhang, and Lixia Diao
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Biomedical Engineering ,Pharmaceutical Science ,Medicine (miscellaneous) ,General Materials Science ,Bioengineering - Abstract
The skin has vital functions and its defects and damages must be properly treated and healed. Chinese traditional herbal medicine has a long history in skin wound healing, and its merging with novel approaches (nanotechnology) has resulted in more promising results. The current study aimed to combine the biological properties of a long-lasting Chinese traditional herbal medicine (Thyme) with cutting-edge technology (electrospinning) to the fabricated interactive and bioactive wound dressing. The extract of Thyme was obtained and added into the polymeric solution and converted to the nanofibrous wound dressing. The SEM analysis revealed that the fabricated nanofibers were intact without deformity with an acceptable nanometric diameter. The release kinetics evaluation showed that 80±4% of the extract was released from the nanofibers during the first 24 h. Hemolysis lower than 8% for all nanofibers revealed hemocompatibility in the fabricated wound dressings. The in vitro studies confirmed the cytocompatibility of the nanofibers. The applied animal studies exhibited that the Thyme-loaded nanofibrous dressing enhanced the wound-healing process in a dose-dependent manner. These findings demonstrate the combination of Chinese traditional herbal medicine with modern cutting-edge technology, resulting in an interactive nanofibrous mat with promising potential as the wound dressing material.
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- 2022
37. Supplementary Methods, Figures 1 - 5 from Bisphosphorylated PEA-15 Sensitizes Ovarian Cancer Cells to Paclitaxel by Impairing the Microtubule-Destabilizing Effect of SCLIP
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Naoto T. Ueno, Gabriel N. Hortobagyi, Keith A. Baggerly, Lixia Diao, Anna Kazansky, Ahmed A. Ahmed, Chandra Bartholomeusz, and Xuemei Xie
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PDF file - 357K, Supplementary Figure 1. Chemical structure of paclitaxel: (2α,4α,5β,7β,10β,13α)-4,10-bis(acetyloxy)-13-{(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyloxy}-1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate. Supplementary Figure 2. Overexpression of PEA-15 phosphorylated at both Ser104 and Ser116 enhanced the apoptotic effect of paclitaxel in ovarian cancer cells. Supplementary Figure 3. The addition of caspase 8 and 9 inhibitors reduced paclitaxel-induced apoptosis in SKOV3.ip1-AA and SKOV3.ip1-DD cells. Supplementary Figure 4. Quantification of SCLIP mRNA levels in SKOV3.ip1 stable cells. Supplementary Figure 5. SCLIP mediated paclitaxel resistance in ovarian cancer cells.
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- 2023
38. Supplementary figure 3 from A Comprehensive Evaluation of Biomarkers Predictive of Response to PI3K Inhibitors and of Resistance Mechanisms in Head and Neck Squamous Cell Carcinoma
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Faye M. Johnson, Bonnie S. Glisson, Jeffrey N. Myers, John V. Heymach, Katherine Stemke-Hale, You-Hong Fan, Lixia Diao, Shaohua Peng, Gordon B. Mills, Patrick Kwok Shing Ng, Lauren A. Byers, and Tuhina Mazumdar
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Supplementary figure 3. Correlation of PI3K mutation, amplification, PI3K score, and mTOR score with sensitivity to GDC0941
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- 2023
39. Supplementary Data from Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado
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John V. Heymach, Varsha Gandhi, John D. Minna, Ferdinandos Skoulidis, Jing Wang, William G. Wierda, Monique Nilsson, Jayanthi Gudikote, Uma Giri, Jie Ding, Lixia Diao, Pan Tong, Youhong Fan, Mary L. Ayres, Ishita Akhter, Xiao Qu, Yu Qian, Chao Yang, Emrullah Yilmaz, Christine M. Stellrecht, and Ana Galan-Cobo
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Supplementary Data from Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado
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- 2023
40. Supplementary Figures 1-7 and Tables 1 and 2 from AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers
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Khandan Keyomarsi, Lauren Averett Byers, Jing Wang, Kelly K. Hunt, John V. Heymach, Steve Warner, Tuyen N. Bui, Jason P.W. Carey, Youhong Fan, Pan Tong, Lixia Diao, Smruthi Vijayaraghavan, and Kavitha Balaji
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Supplementary Fig. 1. AXL is a direct mediator of EMT Supplementary Fig. 2. AXL inhibition causes DNA damage and reduces levels of DNA repair markers. Supplementary Fig. 3. AXL knockdown cause DNA damage and decreases gene expression of DNA repair genes Supplementary Fig. 4. AXL inhibition is synergistic with PARP inhibition. Supplementary Fig. 5. AXL inhibition in combination with PARP inhibition causes increased subG1 and G2/M populations Supplementary Fig. 6. Correlation analysis with AXL expression in patient cohorts. Supplementary Fig. 7. AXL expression corresponds to expression of DNA repair proteins and EMT markers in patient cohorts Supplementary Table 1. Doubling time upon AXL knockdown Supplementary Table 2. DNA repair proteins and EMT markers analyzed by Reverse Phase Protein Assay
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- 2023
41. Supplementary Methods, Table S2 from Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
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John V. Heymach, Ignacio I. Wistuba, Jing Wang, Andrew Futreal, James P. Allison, John D. Minna, Waun K. Hong, Gordon B. Mills, Padmanee Sharma, Jianhua Zhang, Kwok-Kin Wong, Roy S. Herbst, John N. Weinstein, Vincent Miller, Garrett M. Frampton, Murim Choi, Timothy P. Heffernan, Carlo Toniatti, Kevin R. Coombes, Luc Girard, Michael Peyton, Youhong Fan, Chao Yang, Maria A. Cortez, Jayanthi Gudikote, Uma Giri, Jianjun Zhang, Jaime Rodriguez Canales, Edwin R. Parra, Humam Kadara, Carmen Behrens, Julie Izzo, Pan Tong, Vassiliki A. Papadimitrakopoulou, Lixia Diao, Lauren A. Byers, and Ferdinandos Skoulidis
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Supplementary Methods. Supplementary Table 2. Details of the antibody used for TTF1 immunostaining.
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- 2023
42. Data from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
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John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
- Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.Significance: SCLC is a highly lethal cancer with a 5-year survival rate of less than 10%. To date, no molecularly targeted agents have prolonged survival in patients with SCLCs. As a step toward identifying new targets, we systematically profiled SCLCs with a focus on therapeutically relevant signaling pathways. Our data reveal fundamental differences in the patterns of pathway activation in SCLCs and NSCLCs and identify several potential therapeutic targets for SCLCs, including PARP1 and EZH2. On the basis of these results, clinical studies evaluating PARP and EZH2 inhibition, together with chemotherapy or other agents, warrant further investigation. Cancer Discov; 2(9); 798–811. ©2012 AACR.Read the Commentary on this article by Rosell and Wannesson, p. 769.This article is highlighted in the In This Issue feature, p. 753.
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- 2023
43. Table S6 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma
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Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
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Table S6 contains results from the analysis of DNA methylation in SETD2 mutated and BAP1 inactivated samples.
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- 2023
44. Supplementary Materials from Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
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Lauren A. Byers, Don L. Gibbons, John V. Heymach, Julien Sage, Ignacio I. Wistuba, Bonnie S. Glisson, Jing Wang, Yongbin Yang, Youhong Fan, Lerong Li, Lixia Diao, Thuyen Nguyen, Sandra Cristea, Junya Fujimoto, Naoto Morikawa, Carminia M. Della Corte, Limo Chen, B. Leticia Rodriguez, and Triparna Sen
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This file contains supplementary materials and methods; figures and figure legends and Tables.
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- 2023
45. Supplementary Table S1 from CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade
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Don L. Gibbons, F. Xiao-Feng Qin, John V. Heymach, Ignacio I. Wistuba, Stephen E. Ullrich, Jing Wang, Ethan Dmitrovsky, Vassiliki A. Papadimitrakopoulou, Scott E. Woodman, Lauren Averett Byers, Masanori Kawakami, Jaime Rodriguez-Canales, Jingfen Zhu, Caleb A. Class, Youhong Fan, Carl M. Gay, Brett W. Carter, Weiyi Peng, Ferdinandos Skoulidis, Junna Oba, Pan Tong, Jonathon Roybal, Christin Ungewiss, David H. Peng, Jared J. Fradette, Di Peng, Qiang Zhao, Anfei Huang, Philip L. Lorenzi, Lin Tan, Xi Liu, Tina Cascone, Pamela A. Villalobos, Yanli Li, B. Leticia Rodriguez, Xiaohui Yi, Yongbin Yang, Lixia Diao, and Limo Chen
- Abstract
Genes differentially expressed between IgG control and anti-PD-L1 treatment.
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- 2023
46. Supplementary Tables and Methods from A Comprehensive Evaluation of Biomarkers Predictive of Response to PI3K Inhibitors and of Resistance Mechanisms in Head and Neck Squamous Cell Carcinoma
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Faye M. Johnson, Bonnie S. Glisson, Jeffrey N. Myers, John V. Heymach, Katherine Stemke-Hale, You-Hong Fan, Lixia Diao, Shaohua Peng, Gordon B. Mills, Patrick Kwok Shing Ng, Lauren A. Byers, and Tuhina Mazumdar
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Supplementary Tables and Methods
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- 2023
47. Supplementary figure 2 from A Comprehensive Evaluation of Biomarkers Predictive of Response to PI3K Inhibitors and of Resistance Mechanisms in Head and Neck Squamous Cell Carcinoma
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Faye M. Johnson, Bonnie S. Glisson, Jeffrey N. Myers, John V. Heymach, Katherine Stemke-Hale, You-Hong Fan, Lixia Diao, Shaohua Peng, Gordon B. Mills, Patrick Kwok Shing Ng, Lauren A. Byers, and Tuhina Mazumdar
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Supplementary figure 2. Representative FISH data
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- 2023
48. Supplementary Table 6 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
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John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
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PDF file, 35K, IC50 values for AZD2281 and AG01469 after 14d treatment.
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- 2023
49. Supplementary Fig. S2 from AXL Inhibition Induces DNA Damage and Replication Stress in Non–Small Cell Lung Cancer Cells and Promotes Sensitivity to ATR Inhibitors
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Lauren A. Byers, Don L. Gibbons, Carl M. Gay, Jing Wang, John V. Heymach, You-Hong Fan, B. Leticia Rodriguez, David H. Peng, Robert J. Cardnell, Lixia Diao, Li Shen, Qi Wang, Carminia M. Della Corte, Kasey R. Cargill, C. Allison Stewart, and Kavya Ramkumar
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Supplementary Fig. S2: Spectra of EMT score and AXL expression across different tumor types.
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- 2023
50. Supplementary Table 1 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
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John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
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PDF file, 54K, Small cell lung cancer cell lines.
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- 2023
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