1,868 results on '"PIWNICA A"'
Search Results
2. Dimerization of the 4Ig isoform of B7-H3 in tumor cells mediates enhanced proliferation and tumorigenic signaling
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Sutton, Margie N., Glazer, Sarah E., Muzzioli, Riccardo, Yang, Ping, Gammon, Seth T., and Piwnica-Worms, David
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- 2024
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3. Targeting neddylation and sumoylation in chemoresistant triple negative breast cancer
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Reid T. Powell, Amanda L. Rinkenbaugh, Lei Guo, Shirong Cai, Jiansu Shao, Xinhui Zhou, Xiaomei Zhang, Sabrina Jeter-Jones, Chunxiao Fu, Yuan Qi, Faiza Baameur Hancock, Jason B. White, Clifford Stephan, Peter J. Davies, Stacy Moulder, W. Fraser Symmans, Jeffrey T. Chang, and Helen Piwnica-Worms
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Triple negative breast cancer (TNBC) accounts for 15–20% of breast cancer cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is the current standard of care for patients with early-stage TNBC. However, up to 70% of TNBC patients have significant residual disease once NACT is completed, which is associated with a high risk of developing recurrence within two to three years of surgical resection. To identify targetable vulnerabilities in chemoresistant TNBC, we generated longitudinal patient-derived xenograft (PDX) models from TNBC tumors before and after patients received NACT. We then compiled transcriptomes and drug response profiles for all models. Transcriptomic analysis identified the enrichment of aberrant protein homeostasis pathways in models from post-NACT tumors relative to pre-NACT tumors. This observation correlated with increased sensitivity in vitro to inhibitors targeting the proteasome, heat shock proteins, and neddylation pathways. Pevonedistat, a drug annotated as a NEDD8-activating enzyme (NAE) inhibitor, was prioritized for validation in vivo and demonstrated efficacy as a single agent in multiple PDX models of TNBC. Pharmacotranscriptomic analysis identified a pathway-level correlation between pevonedistat activity and post-translational modification (PTM) machinery, particularly involving neddylation and sumoylation targets. Elevated levels of both NEDD8 and SUMO1 were observed in models exhibiting a favorable response to pevonedistat compared to those with a less favorable response in vivo. Moreover, a correlation emerged between the expression of neddylation-regulated pathways and tumor response to pevonedistat, indicating that targeting these PTM pathways may prove effective in combating chemoresistant TNBC.
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- 2024
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4. Dimerization of the 4Ig isoform of B7-H3 in tumor cells mediates enhanced proliferation and tumorigenic signaling
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Margie N. Sutton, Sarah E. Glazer, Riccardo Muzzioli, Ping Yang, Seth T. Gammon, and David Piwnica-Worms
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Biology (General) ,QH301-705.5 - Abstract
Abstract B7-H3 (CD276) has two isoforms (2Ig and 4Ig), no confirmed cognate receptor, and physiological functions that remain elusive. While differentially expressed on many solid tumors correlating with poor survival, mechanisms of how B7-H3 signals in cis (tumor cell) versus in trans (immune cell co-regulator) to elicit pro-tumorigenic phenotypes remain poorly defined. Herein, we characterized a tumorigenic and signaling role for tumor cell-expressed 4Ig-B7-H3, the dominant human isoform, in gynecological cancers that could be abrogated upon CRISPR/Cas9 knockout of B7-H3; tumorigenesis was rescued upon re-expression of 4Ig-B7-H3. Size exclusion chromatography revealed dimerization states for the extracellular domains of both human 4Ig- and murine 2Ig-B7-H3. mEGFP lifetimes of expressed 4Ig-B7-H3-mEGFP fusions determined by FRET-FLIM assays confirmed close-proximity interactions of 4Ig-B7-H3 and identified two distinct homo-FRET lifetime populations, consistent with monomeric and homo-dimer interactions. In live cells, bioluminescence imaging of 4Ig-B7-H3-mediated split luciferase complementation showed dimerization of 4Ig-B7-H3. To separate basal from dimer state activities in the absence of a known receptor, C-terminus (cytosolic) chemically-induced dimerization of 4Ig-B7-H3 increased tumor cell proliferation and cell activation signaling pathways (AKT, Jak/STAT, HIF1α, NF-κβ) significantly above basal expression of 4Ig-B7-H3 alone. These results revealed a new, dimerization-dependent intrinsic tumorigenic signaling role for 4Ig-B7-H3, likely acting in cis, and provide a therapeutically-actionable target for intervention of B7-H3-dependent tumorigenesis.
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- 2024
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5. Predictors of success in establishing orthotopic patient-derived xenograft models of triple negative breast cancer
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Echeverria, Gloria V., Cai, Shirong, Tu, Yizheng, Shao, Jiansu, Powell, Emily, Redwood, Abena B., Jiang, Yan, McCoy, Aaron, Rinkenbaugh, Amanda L., Lau, Rosanna, Trevarton, Alexander J., Fu, Chunxiao, Gould, Rebekah, Ravenberg, Elizabeth E., Huo, Lei, Candelaria, Rosalind, Santiago, Lumarie, Adrada, Beatriz E., Lane, Deanna L., Rauch, Gaiane M., Yang, Wei T., White, Jason B., Chang, Jeffrey T., Moulder, Stacy L., Symmans, W. Fraser, Hilsenbeck, Susan G., and Piwnica-Worms, Helen
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- 2023
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6. TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy
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Gonzalez, Caleb, Williamson, Sarah, Gammon, Seth T., Glazer, Sarah, Rhee, Joon Haeng, and Piwnica-Worms, David
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- 2023
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7. Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders
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Li, Yao-Cheng, Lytle, Nikki K, Gammon, Seth T, Wang, Luke, Hayes, Tikvah K, Sutton, Margie N, Bast, Robert C, Der, Channing J, Piwnica-Worms, David, McCormick, Frank, and Wahl, Geoffrey M
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Cancer ,Aetiology ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Autophagosomes ,Cell Membrane ,Humans ,Lysosomes ,Models ,Molecular ,Protein Interaction Domains and Motifs ,Protein Isoforms ,Signal Transduction ,ras Proteins ,KRAS ,NRAS ,HRAS ,protein-protein interaction ,split-luciferase complementation ,protein–protein interaction - Abstract
HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS-RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome-lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.
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- 2020
8. Predictors of success in establishing orthotopic patient-derived xenograft models of triple negative breast cancer
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Gloria V. Echeverria, Shirong Cai, Yizheng Tu, Jiansu Shao, Emily Powell, Abena B. Redwood, Yan Jiang, Aaron McCoy, Amanda L. Rinkenbaugh, Rosanna Lau, Alexander J. Trevarton, Chunxiao Fu, Rebekah Gould, Elizabeth E. Ravenberg, Lei Huo, Rosalind Candelaria, Lumarie Santiago, Beatriz E. Adrada, Deanna L. Lane, Gaiane M. Rauch, Wei T. Yang, Jason B. White, Jeffrey T. Chang, Stacy L. Moulder, W. Fraser Symmans, Susan G. Hilsenbeck, and Helen Piwnica-Worms
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Patient-derived xenograft (PDX) models of breast cancer are an effective discovery platform and tool for preclinical pharmacologic testing and biomarker identification. We established orthotopic PDX models of triple negative breast cancer (TNBC) from the primary breast tumors of patients prior to and following neoadjuvant chemotherapy (NACT) while they were enrolled in the ARTEMIS trial (NCT02276443). Serial biopsies were obtained from patients prior to treatment (pre-NACT), from poorly responsive disease after four cycles of Adriamycin and cyclophosphamide (AC, mid-NACT), and in cases of AC-resistance, after a 3-month course of different experimental therapies and/or additional chemotherapy (post-NACT). Our study cohort includes a total of 269 fine needle aspirates (FNAs) from 217 women, generating a total of 62 PDX models (overall success-rate = 23%). Success of PDX engraftment was generally higher from those cancers that proved to be treatment-resistant, whether poorly responsive to AC as determined by ultrasound measurements mid-NACT (p = 0.063), RCB II/III status after NACT (p = 0.046), or metastatic relapse within 2 years of surgery (p = 0.008). TNBC molecular subtype determined from gene expression microarrays of pre-NACT tumors revealed no significant association with PDX engraftment rate (p = 0.877). Finally, we developed a statistical model predictive of PDX engraftment using percent Ki67 positive cells in the patient’s diagnostic biopsy, positive lymph node status at diagnosis, and low volumetric reduction of the patient’s tumor following AC treatment. This novel bank of 62 PDX models of TNBC provides a valuable resource for biomarker discovery and preclinical therapeutic trials aimed at improving neoadjuvant response rates for patients with TNBC.
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- 2023
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9. TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy
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Caleb Gonzalez, Sarah Williamson, Seth T. Gammon, Sarah Glazer, Joon Haeng Rhee, and David Piwnica-Worms
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Biology (General) ,QH301-705.5 - Abstract
TLR5 agonists in combination with immune checkpoint therapies (ICT) enhance survival in ICT-refractory murine 4T1 mammary carcinoma and B16-F10 melanoma tumors. Low serum levels of G-CSF and CXCL5 correlate with enhanced survival.
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- 2023
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10. Imaging of innate immunity activation in vivo with a redox-tuned PET reporter
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Pisaneschi, Federica, Gammon, Seth T., Paolillo, Vincenzo, Qureshy, Sarah A., and Piwnica-Worms, David
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- 2022
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11. Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers
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Xuan Liu, Zhongqi Ge, Fei Yang, Alejandro Contreras, Sanghoon Lee, Jason B. White, Yiling Lu, Marilyne Labrie, Banu K. Arun, Stacy L. Moulder, Gordon B. Mills, Helen Piwnica-Worms, Jennifer K. Litton, and Jeffrey T. Chang
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Germline mutations in BRCA1 or BRCA2 exist in ~2–7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked for biomarkers that were predictive of response (assessed by residual cancer burden) after 6 months of therapy. We found that all resistant tumors exhibited either the loss of SHLD2, expression of a hypoxia signature, or expression of a stem cell signature. These results indicate that the deep analysis of pre-treatment tumors can identify biomarkers that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for better selection of patients for treatment, as well as a roadmap for the development of novel combination therapies to prevent emergence of resistance.
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- 2022
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12. Author Correction: Glypican-1 identifies cancer exosomes and detects early pancreatic cancer
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Melo, Sonia A., Luecke, Linda B., Kahlert, Christoph, Fernandez, Agustin F., Gammon, Seth T., Kaye, Judith, LeBleu, Valerie S., Mittendorf, Elizabeth A., Weitz, Juergen, Rahbari, Nuh, Reissfelder, Christoph, Pilarsky, Christian, Fraga, Mario F., Piwnica-Worms, David, and Kalluri, Raghu
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- 2022
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13. Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma
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Jing Wang, Wencai Ma, Ping Yang, Tracy W Liu, Seth T Gammon, and David Piwnica-Worms
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background The presence of a highly immunosuppressive tumor microenvironment has limited the success of immune checkpoint therapy (ICT). Immune suppressing myeloid cells with increased production of reactive oxygen species are critical drivers of this immunosuppressive tumor microenvironment. Strategies to limit these immune suppressing myeloid cells are needed to enhance response to ICT.Methods To evaluate the contribution of myeloperoxidase (MPO), a myeloid lineage-restricted enzyme and a major source of reactive oxygen species, to mediating ICT response, we compared treatment outcome and immune composition in wild-type, MPO-deficient (MPO−/−), and MPO inhibitor-treated wild-type mice using established primary melanoma models.Results Tumor growth and survival studies demonstrated that either host deficiency (MPO−/−) or pharmacological inhibition of MPO enhanced ICT response in two preclinical models of established primary melanoma in aged animals. The tumor microenvironment and systemic immune landscape underwent striking changes in infiltration of myeloid cells, T cells, B cells, and dendritic cells in MPO−/− mice; furthermore, a significant increase in myeloid cells was observed in ICT non-responders. The contribution of CD4+ T cells and NK cells during ICT response also changed in MPO−/− mice. Interestingly, MPO enzymatic activity, but not protein, was increased in CD11b+Ly6G+ myeloid cells isolated from marrow, spleen, and peritoneal cavities of mice bearing untreated melanoma, indicating systemic activation of innate immunity. Notably, repurposing MPO-specific inhibitors (verdiperstat, AZD5904) in combination with ICT pointedly enhanced response rates above ICT alone. Indeed, long-term survival was 100% in the YUMM3.3 melanoma model on treatment with verdiperstat plus ICT.Conclusion MPO contributes to ICT resistance in established melanoma. Repurposing MPO-specific inhibitors may provide a promising therapeutic strategy to enhance ICT response.
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- 2023
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14. Metabolic stress induces GD2+ cancer stem cell-like phenotype in triple-negative breast cancer
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Jaggupilli, Appalaraju, Ly, Stanley, Nguyen, Khoa, Anand, Vivek, Yuan, Bin, El-Dana, Fouad, Yan, Yuanqing, Arvanitis, Zoe, Piyarathna, Danthasinghe Waduge Badrajee, Putluri, Nagireddy, Piwnica-Worms, Helen, Manning, Henry Charles, Andreeff, Michael, and Battula, V. Lokesh
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- 2022
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15. Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers
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Liu, Xuan, Ge, Zhongqi, Yang, Fei, Contreras, Alejandro, Lee, Sanghoon, White, Jason B., Lu, Yiling, Labrie, Marilyne, Arun, Banu K., Moulder, Stacy L., Mills, Gordon B., Piwnica-Worms, Helen, Litton, Jennifer K., and Chang, Jeffrey T.
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- 2022
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16. The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
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Abena B. Redwood, Xiaomei Zhang, Sahil B. Seth, Zhongqi Ge, Wendy E. Bindeman, Xinhui Zhou, Vidya C. Sinha, Timothy P. Heffernan, and Helen Piwnica-Worms
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The clinical efficacy of these therapies relies on the ability to ascertain which patient populations are most likely to benefit, so there is intense interest in identifying predictive biomarkers of response. To comprehensively evaluate the components that modulate cancer cell sensitivity to replication stress induced by Chk1i, we performed a synthetic-lethal drop-out screen in a cell line derived from a patient with triple-negative breast cancer (TNBC), using a pooled barcoded shRNA library targeting ~350 genes involved in DNA replication, DNA damage repair, and cycle progression. In addition, we sought to compare the relative requirement of these genes when DNA fidelity is challenged by clinically relevant anticancer breast cancer drugs, including cisplatin and PARP1/2 inhibitors, that have different mechanisms of action. This global comparison is critical for understanding not only which agents should be used together for combinatorial therapies in breast cancer patients, but also the genetic context in which these therapies will be most effective, and when a single-agent therapy will be sufficient to provide maximum therapeutic benefit to the patient. We identified unique potentiators of response to ATRi/Chk1i and describe a new role for components of the cytosolic iron–sulfur assembly (CIA) pathway, MMS19 and CIA2B-FAM96B, in replication stress tolerance of TNBC.
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- 2021
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17. Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
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Vrutant V. Shah, Aundrietta D. Duncan, Shiming Jiang, Sabrina A. Stratton, Kendra L. Allton, Clinton Yam, Abhinav Jain, Patrick M. Krause, Yue Lu, Shirong Cai, Yizheng Tu, Xinhui Zhou, Xiaomei Zhang, Yan Jiang, Christopher L. Carroll, Zhijun Kang, Bin Liu, Jianjun Shen, Mihai Gagea, Sebastian M. Manu, Lei Huo, Michael Gilcrease, Reid T. Powell, Lei Guo, Clifford Stephan, Peter J. Davies, Jan Parker-Thornburg, Guillermina Lozano, Richard R. Behringer, Helen Piwnica-Worms, Jeffrey T. Chang, Stacy L. Moulder, and Michelle Craig Barton
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Science - Abstract
Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.
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- 2021
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18. Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast
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Vidya C. Sinha, Amanda L. Rinkenbaugh, Mingchu Xu, Xinhui Zhou, Xiaomei Zhang, Sabrina Jeter-Jones, Jiansu Shao, Yuan Qi, John A. Zebala, Dean Y. Maeda, Florencia McAllister, and Helen Piwnica-Worms
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Science - Abstract
The classification of breast lesions as indolent or aggressive to tailor treatment is crucial. Here, the authors use single-cell transcriptomics and multiparametric imaging of a breast cancer mouse model, report distinct tumor-immune features for the two types of lesions, and suggest the role of IL-17 signaling in disease progression.
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- 2021
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19. Hyperpolarized [1- 13 C]pyruvate-to-[1- 13 C]lactate conversion is rate-limited by monocarboxylate transporter-1 in the plasma membrane
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Rao, Yi, Gammon, Seth, Zacharias, Niki M., Liu, Tracy, Salzillo, Travis, Xi, Yuanxin, Wang, Jing, Bhattacharya, Pratip, and Piwnica-Worms, David
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- 2020
20. Streamlining the Quantitative Metrics Workflow at a Comprehensive Cancer Center
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Rao, Sujaya H., Virarkar, Mayur, Yang, Wei Tse, Carter, Brett W., Liu, T. Alex, Piwnica-Worms, David, and Bhosale, Priya R.
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- 2021
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21. Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context
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Samuel A Kerk, Lin Lin, Amy L Myers, Damien J Sutton, Anthony Andren, Peter Sajjakulnukit, Li Zhang, Yaqing Zhang, Jennifer A Jiménez, Barbara S Nelson, Brandon Chen, Anthony Robinson, Galloway Thurston, Samantha B Kemp, Nina G Steele, Megan T Hoffman, Hui-Ju Wen, Daniel Long, Sarah E Ackenhusen, Johanna Ramos, Xiaohua Gao, Zeribe C Nwosu, Stefanie Galban, Christopher J Halbrook, David B Lombard, David R Piwnica-Worms, Haoqiang Ying, Marina Pasca di Magliano, Howard C Crawford, Yatrik M Shah, and Costas A Lyssiotis
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tumor metabolism ,pancreatic cancer ,tumor microenvironment ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the malate-aspartate shuttle, a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the TME.
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- 2022
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22. Effects of forced disruption in Medicaid managed care on children with asthma
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Piwnica-Worms, Katherine, Staiger, Becky, Ross, Joseph S., Rosenthal, Marjorie S., and Ndumele, Chima D.
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Asthma in children -- Care and treatment ,Medicaid -- Usage ,Managed care plans (Medical care) -- Usage ,Business ,Health care industry - Abstract
Objective: To evaluate the effect of a forced disruption to Medicaid managed care plans and provider networks on health utilization and outcomes for children with persistent asthma. Data Sources: Medicaid managed care administrative claims data from 2013 to 2016, obtained from a southeastern state. Study Design: A difference-in-difference analysis compared patients' outpatient, inpatient, and emergency department (ED) utilization and receipt of recommended services before and after implementation of a statewide redistribution of patients among nine managed care plans. Data Collection/Extraction Methods: Enrollment data for children with asthma were linked to the administrative claims. Children were included if they had a diagnosis of persistent asthma in 2013 and if they were enrolled continuously throughout 2014-2016. Principal Findings: Among the 28 537 children with asthma, 26% were forced to switch their managed care plan after the redistribution. Of these, 67% also switched their primary care provider (PCP). Relative to those who remained in their plan, disruption was associated with an additional 2.1 percentage-point decrease in the number of children who had an outpatient visit per quarter [95%CI -2.8, -1.3], from 71% to 66% (compared to plan stayers: 74% to 71%). Among children experiencing a change to their plan, there was overall a decrease in the proportion of children receiving an asthma-specific visit per quarter, but there was less of a decrease in children that also changed their PCP [1.6 percentage points, 95%CI 0.7, 2.5], from 9.7% to 8.3% (compared to those who did not switch their PCP: 12% to 8.6%). Indicators of asthma care quality and emergent care utilization were not significantly different between the two periods. Conclusions: While there was a decrease in the number of outpatient visits associated with forced disruption of Medicaid managed care plans for children with persistent asthma, there were no consistent associations with worse asthma quality performance or higher emergent health care utilization. KEYWORDS asthma, child, disruptions to care continuity, managed care programs, Medicaid, 1 | INTRODUCTION Managed care is the dominant model of financing and delivery for over 70 million Americans who receive health insurance coverage through Medicaid. (1) In 2016, approximately 70% [...]
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- 2021
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23. A comprehensive overview of metaplastic breast cancer: clinical features and molecular aberrations
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Tejaswini P. Reddy, Roberto R. Rosato, Xiaoxian Li, Stacy Moulder, Helen Piwnica-Worms, and Jenny C. Chang
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Metaplastic breast cancer ,PI3K signaling ,NOS signaling ,Epithelial-to-mesenchymal transition ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Metaplastic breast cancer (MpBC) is an exceedingly rare breast cancer variant that is therapeutically challenging and aggressive. MpBC is defined by the histological presence of at least two cellular types, typically epithelial and mesenchymal components. This variant harbors a triple-negative breast cancer (TNBC) phenotype, yet has a worse prognosis and decreased survival compared to TNBC. There are currently no standardized treatment guidelines specifically for MpBC. However, prior studies have found that MpBC typically has molecular alterations in epithelial-to-mesenchymal transition, amplification of epidermal growth factor receptor, PI3K/Akt signaling, nitric oxide signaling, Wnt/β-catenin signaling, altered immune response, and cell cycle dysregulation. Some of these molecular alterations have been studied as therapeutic targets, in both the preclinical and clinical setting. This current review discusses the histological organization and cellular origins of MpBC, molecular alterations, the role of radiation therapy, and current clinical trials for MpBC.
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- 2020
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24. Hypoxia-activated prodrug and anti-angiogenic therapy cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration
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Liu, Arthur, primary, Gammon, Seth T., additional, Pisaneschi, Federica, additional, Boda, Akash, additional, Ager, Casey R., additional, Piwnica-Worms, David, additional, Hong, David S., additional, and Curran, Michael A., additional
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- 2023
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25. The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing
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Xiaohui Hu, Samuel E. Harvey, Rong Zheng, Jingyi Lyu, Caitlin L. Grzeskowiak, Emily Powell, Helen Piwnica-Worms, Kenneth L. Scott, and Chonghui Cheng
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Science - Abstract
Splice isoform switching regulated by the heterogeneous nuclear ribonucleoprotein M (hnRNPM) induces EMT and metastasis. Here, the authors report that AKAP8 is a metastasis suppressor that inhibits the splicing activity of hnRNPM and antagonizes genome-wide EMT-associated alternative splicing to maintain epithelial cell state.
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- 2020
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26. Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast
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Sinha, Vidya C., Rinkenbaugh, Amanda L., Xu, Mingchu, Zhou, Xinhui, Zhang, Xiaomei, Jeter-Jones, Sabrina, Shao, Jiansu, Qi, Yuan, Zebala, John A., Maeda, Dean Y., McAllister, Florencia, and Piwnica-Worms, Helen
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- 2021
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27. The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
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Redwood, Abena B., Zhang, Xiaomei, Seth, Sahil B., Ge, Zhongqi, Bindeman, Wendy E., Zhou, Xinhui, Sinha, Vidya C., Heffernan, Timothy P., and Piwnica-Worms, Helen
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- 2021
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28. Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
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Shah, Vrutant V., Duncan, Aundrietta D., Jiang, Shiming, Stratton, Sabrina A., Allton, Kendra L., Yam, Clinton, Jain, Abhinav, Krause, Patrick M., Lu, Yue, Cai, Shirong, Tu, Yizheng, Zhou, Xinhui, Zhang, Xiaomei, Jiang, Yan, Carroll, Christopher L., Kang, Zhijun, Liu, Bin, Shen, Jianjun, Gagea, Mihai, Manu, Sebastian M., Huo, Lei, Gilcrease, Michael, Powell, Reid T., Guo, Lei, Stephan, Clifford, Davies, Peter J., Parker-Thornburg, Jan, Lozano, Guillermina, Behringer, Richard R., Piwnica-Worms, Helen, Chang, Jeffrey T., Moulder, Stacy L., and Barton, Michelle Craig
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- 2021
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29. HIF2 Regulates Intestinal Wnt5a Expression
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Carolina J. García García, Ariana C. Acevedo Diaz, Neeraj Kumari, Suman Govindaraju, Marimar de la Cruz Bonilla, F. Anthony San Lucas, Nicholas D. Nguyen, Iancarlos Jiménez Sacarello, Helen Piwnica-Worms, Anirban Maitra, and Cullen M. Taniguchi
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radiotherapy ,intestinal stem cells ,GI radiotoxicity ,hypoxia ,HIF2 ,Wnt5a ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.
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- 2021
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30. 18F-fluorodeoxyglucose positron emission tomography correlates with tumor immunometabolic phenotypes in resected lung cancer
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Mitchell, Kyle G., Amini, Behrang, Wang, Yunfei, Carter, Brett W., Godoy, Myrna C. B., Parra, Edwin R., Behrens, Carmen, Villalobos, Pamela, Reuben, Alexandre, Lee, J. Jack, Weissferdt, Annikka, Moran, Cesar A., Fujimoto, Junya, Sepesi, Boris, Walsh, Garrett L., Vaporciyan, Ara A., Hofstetter, Wayne L., William, Jr., William N., Gibbons, Don L., Wang, Jing, Hwu, Patrick, Swisher, Stephen G., Piwnica-Worms, David, Kadara, Humam, Wistuba, Ignacio I., Heymach, John V., Peng, Weiyi, and Cascone, Tina
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- 2020
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31. Association of Provider Performance with Changes in Insurance Networks
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Piwnica-Worms, Katherine, Wallace, Jacob, Lollo, Anthony, and Ndumele, Chima D.
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- 2020
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32. Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions
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Sengupta, Rajarshi, Barone, Amy, Marasa, Jayne, Taylor, Sara, Jackson, Erin, Warrington, Nicole M, Rao, Shyam, Kim, Albert H, Leonard, Jeffrey R, Piwnica-Worms, David, and Rubin, Joshua B
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Brain Cancer ,Rare Diseases ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research ,Cancer ,Neurosciences ,Brain Disorders ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Brain Neoplasms ,Cell Communication ,Cell Line ,Tumor ,Cells ,Cultured ,Coculture Techniques ,Endothelial Cells ,Female ,Glioblastoma ,Humans ,Mice ,Nude ,Phytotherapy ,Plant Extracts ,Protamines ,Resveratrol ,Small Molecule Libraries ,Spirostans ,Stilbenes ,Survival Analysis ,Tumor Burden ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,GBM ,Iridin ,co-culture ,high throughput screen ,perivascular niche ,Oncology and Carcinogenesis - Abstract
Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function. We screened the Microsource Spectrum Collection library for drugs that specifically blocked PVN function, without any direct effect on GBM cells themselves. Three candidate PVN-disrupting agents, Iridin, Tigogenin and Triacetylresveratrol (TAR), were identified and evaluated in secondary in vitro screens against a panel of primary GBM isolates as well as in two different in vivo intracranial models. Iridin and TAR significantly inhibited intracranial tumor growth and prolonged survival in these mouse models. Together these data identify Iridin and TAR as drugs with novel GBM tissue disrupting effects and validate the importance of preclinical screens designed to address tumor tissue function rather than the mechanisms of autonomous tumor cell growth.
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- 2015
33. Kinetics of Regulated Protein-Protein Interactions Revealed with Firefly Luciferase Complementation Imaging in Cells and Living Animals
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Luker, Kathryn E., Luker, Gary D., Gammon, Seth T., Piwnica-Worms, Helen, Piwnica-Worms, David, and Cantley, Lewis C.
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- 2004
34. Evaluation of 89Zr-Labeled Anti-PD-L1 Monoclonal Antibodies Using DFO and Novel HOPO Analogues as Chelating Agents for Immuno-PET
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Bhasker Radaram, Sarah E. Glazer, Ping Yang, Chia-Wei Li, Mien-Chie Hung, Seth T. Gammon, Mian Alauddin, and David Piwnica-Worms
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General Chemical Engineering ,General Chemistry - Published
- 2023
35. Apoptosis Detection in Retinal Ganglion Cells Using Quantitative Changes in Multichannel Fluorescence Colocalization
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Xudong Qiu, Seth T. Gammon, James R. Johnson, Federica Pisaneschi, Steven W. Millward, Edward M. Barnett, and David Piwnica-Worms
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apoptosis ,retinal ganglion cell ,dual-fluorophore peptide sensor ,fluorescence resonance energy transfer ,NMDA ,anterograde axonal transport ,Biotechnology ,TP248.13-248.65 - Abstract
KcapTR488 is a dual-fluorophore peptide sensor for the real-time reporting of programmed cell death by fluorescence imaging. KcapTR488 contains a nuclear localization sequence (NLS) conjugated with Texas Red, a caspase-cleavable sequence (DEVD), and a C-terminus conjugated to Alexa Fluor 488 (AF488). The synthesis and preliminary evaluation in cellulo of KcapTR488 for monitoring cell death by fluorescence imaging has been previously reported, but its utility in vivo has yet to be tested or validated. Herein, in vitro solution experiments verified the intramolecular fluorescence resonance energy transfer (FRET) between the two fluorophores and enabled a quantitative analysis of enzyme rates and selectivity. The sensor delivery kinetics in live rat models were quantified by ex vivo fluorescence microscopy. Studies in healthy control retinas demonstrated that KcapTR488 concentrated in the nucleus of retinal ganglion cells (RGC), with a strong colocalization of red and green fluorescence signals producing robust FRET signals, indicating an intact reporter. By contrast, using an acute but mild NMDA-induced retinal injury model, dual-color confocal ex vivo microscopy of cleaved KcapTR488 identified sensor activation as early as 2 h after injection. Quantitative changes in fluorescence colocalization were superior to changes in FRET for monitoring injury progression. Longitudinal monitoring revealed that the NLS-Texas Red fragment of the cleaved sensor moved out of the cell body, down the axon, and exited the retina, consistent with anterograde axonal transport. Thus, KcapTR488 may be a powerful tool to study RGC death pathways in live preclinical models of glaucoma.
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- 2022
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36. Whole-genome analysis informs breast cancer response to aromatase inhibition
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Ellis, Matthew J, Ding, Li, Shen, Dong, Luo, Jingqin, Suman, Vera J, Wallis, John W, Van Tine, Brian A, Hoog, Jeremy, Goiffon, Reece J, Goldstein, Theodore C, Ng, Sam, Lin, Li, Crowder, Robert, Snider, Jacqueline, Ballman, Karla, Weber, Jason, Chen, Ken, Koboldt, Daniel C, Kandoth, Cyriac, Schierding, William S, McMichael, Joshua F, Miller, Christopher A, Lu, Charles, Harris, Christopher C, McLellan, Michael D, Wendl, Michael C, DeSchryver, Katherine, Allred, D Craig, Esserman, Laura, Unzeitig, Gary, Margenthaler, Julie, Babiera, GV, Marcom, P Kelly, Guenther, JM, Leitch, Marilyn, Hunt, Kelly, Olson, John, Tao, Yu, Maher, Christopher A, Fulton, Lucinda L, Fulton, Robert S, Harrison, Michelle, Oberkfell, Ben, Du, Feiyu, Demeter, Ryan, Vickery, Tammi L, Elhammali, Adnan, Piwnica-Worms, Helen, McDonald, Sandra, Watson, Mark, Dooling, David J, Ota, David, Chang, Li-Wei, Bose, Ron, Ley, Timothy J, Piwnica-Worms, David, Stuart, Joshua M, Wilson, Richard K, and Mardis, Elaine R
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Breast Cancer ,Human Genome ,Biotechnology ,Anastrozole ,Androstadienes ,Antineoplastic Agents ,Aromatase ,Aromatase Inhibitors ,Breast Neoplasms ,DNA Repair ,Exome ,Exons ,Female ,Genetic Variation ,Genome ,Human ,Humans ,Letrozole ,MAP Kinase Kinase 4 ,MAP Kinase Kinase Kinase 1 ,Mutation ,Nitriles ,Receptors ,Estrogen ,Treatment Outcome ,Triazoles ,General Science & Technology - Abstract
To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.
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- 2012
37. Noninvasive Imaging of Protein-Protein Interactions in Living Animals
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Luker, Gary D., Sharma, Vijay, Pica, Christina M., Dahlheimer, Julie L., Li, Wei, Ochesky, Joseph, Ryan, Christine E., Piwnica-Worms, Helen, and Piwnica-Worms, David
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- 2002
38. BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1α activation
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Li, Andrew G., Murphy, Elizabeth C., Culhane, Aedin C., Powell, Emily, Wang, Hua, Bronson, Roderick T., Von, Thanh, Giobbie-Hurder, Anita, Gelman, Rebecca S., Briggs, Kimberly J., Piwnica-Worms, Helen, Zhao, Jean J., Kung, Andrew L., Kaelin, William G., and Livingston, David M.
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- 2018
39. High-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer
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Gloria V. Echeverria, Emily Powell, Sahil Seth, Zhongqi Ge, Alessandro Carugo, Christopher Bristow, Michael Peoples, Frederick Robinson, Huan Qiu, Jiansu Shao, Sabrina L. Jeter-Jones, Xiaomei Zhang, Vandhana Ramamoorthy, Shirong Cai, Wenhui Wu, Giulio Draetta, Stacy L. Moulder, William F. Symmans, Jeffrey T. Chang, Timothy P. Heffernan, and Helen Piwnica-Worms
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Science - Abstract
It is unclear how intra-tumoral heterogeneity contributes to metastasis. Here the authors study the clonal dynamics of triple negative breast cancer metastasis using patient derived xenografts and demonstrate that primary tumor clones harbor properties that support seeding and colonization of multiple organs.
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- 2018
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40. Abstract P4-08-05: NOS inhibition reverses epithelial-to-mesenchymal transition and synergizes with alpelisib in metaplastic breast cancer
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Tejaswini Reddy, Akshjot Puri, Liliana Guzman, Wei Qian, Jianying Zhou, Roberto Rosato, Hong Zhao, Christoforos Thomas, Xiaoxian Li, Bijan Mahboubi, Adrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Camila Ayerbe, Noah Giese, Stacy Moulder, Helen Piwnica-Worms, Funda Meric-Bernstam, and Jenny Chang
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Cancer Research ,Oncology - Abstract
Background: Metaplastic breast cancer (MpBC) is a rare, lethal, and highly chemoresistant breast cancer subtype, with no FDA-approved therapeutic options. Most MpBCs are triple-negative, yet have a worse prognosis than non-metaplastic triple-negative breast cancer (non-MpTNBC). MpBC tumors are enriched for markers of epithelial-to-mesenchymal transition (EMT)/cancer stem cells (CSC), produce high nitric oxide (NO) levels, and have a hyperactive phosphoinositide 3-kinase (PI3K) signaling pathway. Increased PI3K and inducible nitric oxide synthase (iNOS) activity are poor prognostic indicators in MpBC. NO can activate multiple oncogenic pathways spatially and temporally, such as PI3K and transforming growth factor beta (TGFβ), a critical regulator of EMT. Therefore, our study evaluates whether pan-NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) augments the efficacy of alpha isoform-specific PI3K inhibitor alpelisib in MpBC in vitro and in vivo models. Methods: MpBC cell lines (SUM159, BT549, Hs578T, HCC1806) and Patient-Derived Xenograft (PDX) models were used in our studies. Droplet digital polymerase chain reaction (ddPCR) was conducted to evaluate the iNOS-associated mutation (RPL39 A14V) and PIK3CA hotspot mutation rates in PDX models. Cell viability (SRB/Cell Titer-Glo), combination index (CI), immunoblotting, and immunofluorescence of treated MpBC cell lines and tumor tissues were evaluated. Results: Immunostaining analysis revealed that MpBC PDX tumors had elevated co-expression of iNOS and pAkt (60% vs 23%, p=0.0495) relative to non-MpTNBC PDX tumors. MpBC PDX tumors had higher RPL39 A14V (66% vs 4.7%, p< 0.0006) and PIK3CA hotspot mutation rates (50% vs 19.1%, p=0.1247) than non-MpTNBC PDX tumors. Combining L-NMMA with alpelisib was synergistic in MpBC cell lines harboring PIK3CA/PIK3R1 mutations (CI< 1) and antagonistic in PIK3CA-wild type and PTEN-deleted models (CI>1). In vivo evaluation using MpBC PDX tumors found that L-NMMA significantly augmented the efficacy of alpelisib in reducing tumor volume in PIK3CA-mutated MpBC PDX models. Transcriptomic analysis found gene sets associated with EMT reversal, such as the formation of cornified envelope (Padj = 0.0254) and keratinization pathway (Padj = 0.048) were enriched pathways in MpBC PDX tumors that responded to combination therapy. Pharmacological and genomic inhibition of iNOS reversed EMT in MpBC cells, as shown by decreased expression of Zeb1, TGFβ, Snail, Vimentin, and increased expression of E-cadherin and ZO-1 in immunoblotting analysis. MpBC cells with NOS2 knockout acquired an epithelial-like cellular morphology and this reversal of EMT rendered MpBC cells more sensitive to alpelisib and taxane-chemotherapy. MpBC PDX tumors that responded to combination therapy also exhibited a reversal in EMT, with an associated decrease in aldehyde dehydrogenase (ALDH1), a CSC marker. L-NMMA and alpelisib therapy also resulted in the loss of tumor-initiating ability, enhanced chemosensitivity, and improved overall survival in MpBC PDX models. These studies paralleled results from a phase 1b/2 clinical trial with L-NMMA combined with taxane chemotherapy in a cohort of anthracycline-refractory MpBC patients (n=15, NCT02834403). The clinical benefit rate was 40% (6/15), the overall response rate was 20% (3/15), and one patient achieved a pathologic complete response. Relative to baseline tumors, the responder end-of-treatment tumors had undergone reversal of EMT, with enhanced expression of E-cadherin, and decreased expression of iNOS, Zeb1, and ALDH1. Conclusion: Our findings suggest that combining L-NMMA and alpelisib is a novel therapeutic strategy to treat MpBC by reversing EMT and decreasing CSCs, rendering MpBC tumors more chemosensitive. This combination therapy is being tested in a first multicenter phase 2 study targeting this orphan disease. Citation Format: Tejaswini Reddy, Akshjot Puri, Liliana Guzman, Wei Qian, Jianying Zhou, Roberto Rosato, Hong Zhao, Christoforos Thomas, Xiaoxian Li, Bijan Mahboubi, Adrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Camila Ayerbe, Noah Giese, Stacy Moulder, Helen Piwnica-Worms, Funda Meric-Bernstam, Jenny Chang. NOS inhibition reverses epithelial-to-mesenchymal transition and synergizes with alpelisib in metaplastic breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-05.
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- 2023
41. Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2+ breast cancer stem-like cells
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Debasish Tripathy, Khoa Nguyen, Stanley Ly, Vivek Anand, Fouad El-Dana, Yiming Cai, Shirong Cai, Helen Piwnica-Worms, Aysegul A Sahin, Michael Andreeff, and Venkata Lokesh Battula
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no effective standard therapy. Breast cancer stem-like cells (BCSCs) in primary TNBCs are reported to be responsible for metastatic spread of the disease and resistance to chemotherapy, but no available therapeutic tools target BCSCs. We previously reported that the ganglioside GD2 is highly expressed on BCSCs and that inhibition of its expression hampers TNBC growth. We therefore hypothesized that the anti-GD2 antibody dinutuximab (ch14.18) targets GD2+ BCSCs and inhibits TNBC growth.Method To test our hypothesis, we first determined GD2 expression via immunohistochemistry in frozen primary tumor samples from patients with TNBC (n=89). Then, we examined the effects of dinutuximab on TNBC cell adhesion, migration, and mammosphere formation in vitro and on tumor growth in vivo using TNBC cell-line and patient-derived xenograft (PDX) models.Results We found that GD2 was expressed in around 60% of primary TNBC tumors at variable levels and was associated with worse overall survival of patients with TNBC (p=0.002). GD2 was found to be expressed in tumors and stroma, but normal ducts and lobules in adjacent tissues have shown low or no GD2 staining, indicating that GD2 is potentially a novel biomarker for tumor and its microenvironment. Treatment with dinutuximab significantly decreased adhesion and migration of MDA-MB-231 and SUM159 TNBC cells. Moreover, dinutuximab treatment inhibited mTOR signaling, which has been shown to be regulated by GD2 in BCSCs. Dinutuximab also reduced tumor growth in nude mice bearing TNBC cell-line xenografts. Finally, dinutuximab in combination with activated natural killer cells inhibited tumor growth in a TNBC PDX model and improved overall survival of tumor-bearing mice.Conclusions Dinutuximab successfully eliminated GD2+ cells and reduced tumor growth in both in vivo models. Our data provide proof-of-concept for the criticality of GD2 in BCSCs and demonstrate the potential of dinutuximab as a novel therapeutic approach for TNBC.
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- 2021
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42. Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types
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Caesar-Johnson, Samantha J., Demchok, John A., Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L., Hutter, Carolyn M., Sofia, Heidi J., Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C., Zhang, Jiashan (Julia), Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I., Kim, Jaegil, Lawrence, Michael S., Lin, Pei, Meier, Sam, Noble, Michael S., Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Dhankani, Varsha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Liu, Yuexin, Miller, Michael, Reynolds, Sheila, Shmulevich, Ilya, Thorsson, Vesteinn, Zhang, Wei, Akbani, Rehan, Broom, Bradley M., Hegde, Apurva M., Ju, Zhenlin, Kanchi, Rupa S., Korkut, Anil, Li, Jun, Liang, Han, Ling, Shiyun, Liu, Wenbin, Lu, Yiling, Mills, Gordon B., Ng, Kwok-Shing, Rao, Arvind, Ryan, Michael, Wang, Jing, Weinstein, John N., Zhang, Jiexin, Abeshouse, Adam, Armenia, Joshua, Chakravarty, Debyani, Chatila, Walid K., de Bruijn, Ino, Gao, Jianjiong, Gross, Benjamin E., Heins, Zachary J., Kundra, Ritika, La, Konnor, Ladanyi, Marc, Luna, Augustin, Nissan, Moriah G., Ochoa, Angelica, Phillips, Sarah M., Reznik, Ed, Sanchez-Vega, Francisco, Sander, Chris, Schultz, Nikolaus, Sheridan, Robert, Sumer, S. Onur, Sun, Yichao, Taylor, Barry S., Wang, Jioajiao, Zhang, Hongxin, Anur, Pavana, Peto, Myron, Spellman, Paul, Benz, Christopher, Stuart, Joshua M., Wong, Christopher K., Yau, Christina, Hayes, D. Neil, Parker, Joel S., Wilkerson, Matthew D., Ally, Adrian, Balasundaram, Miruna, Bowlby, Reanne, Brooks, Denise, Carlsen, Rebecca, Chuah, Eric, Dhalla, Noreen, Holt, Robert, Jones, Steven J.M., Kasaian, Katayoon, Lee, Darlene, Ma, Yussanne, Marra, Marco A., Mayo, Michael, Moore, Richard A., Mungall, Andrew J., Mungall, Karen, Robertson, A. Gordon, Sadeghi, Sara, Schein, Jacqueline E., Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Tse, Kane, Wong, Tina, Berger, Ashton C., Beroukhim, Rameen, Cherniack, Andrew D., Cibulskis, Carrie, Gabriel, Stacey B., Gao, Galen F., Ha, Gavin, Meyerson, Matthew, Schumacher, Steven E., Shih, Juliann, Kucherlapati, Melanie H., Kucherlapati, Raju S., Baylin, Stephen, Cope, Leslie, Danilova, Ludmila, Bootwalla, Moiz S., Lai, Phillip H., Maglinte, Dennis T., Van Den Berg, David J., Weisenberger, Daniel J., Auman, J. Todd, Balu, Saianand, Bodenheimer, Tom, Fan, Cheng, Hoadley, Katherine A., Hoyle, Alan P., Jefferys, Stuart R., Jones, Corbin D., Meng, Shaowu, Mieczkowski, Piotr A., Mose, Lisle E., Perou, Amy H., Perou, Charles M., Roach, Jeffrey, Shi, Yan, Simons, Janae V., Skelly, Tara, Soloway, Matthew G., Tan, Donghui, Veluvolu, Umadevi, Fan, Huihui, Hinoue, Toshinori, Laird, Peter W., Shen, Hui, Zhou, Wanding, Bellair, Michelle, Chang, Kyle, Covington, Kyle, Creighton, Chad J., Dinh, Huyen, Doddapaneni, HarshaVardhan, Donehower, Lawrence A., Drummond, Jennifer, Gibbs, Richard A., Glenn, Robert, Hale, Walker, Han, Yi, Hu, Jianhong, Korchina, Viktoriya, Lee, Sandra, Lewis, Lora, Li, Wei, Liu, Xiuping, Morgan, Margaret, Morton, Donna, Muzny, Donna, Santibanez, Jireh, Sheth, Margi, Shinbrot, Eve, Wang, Linghua, Wang, Min, Wheeler, David A., Xi, Liu, Zhao, Fengmei, Hess, Julian, Appelbaum, Elizabeth L., Bailey, Matthew, Cordes, Matthew G., Ding, Li, Fronick, Catrina C., Fulton, Lucinda A., Fulton, Robert S., Kandoth, Cyriac, Mardis, Elaine R., McLellan, Michael D., Miller, Christopher A., Schmidt, Heather K., Wilson, Richard K., Crain, Daniel, Curley, Erin, Gardner, Johanna, Lau, Kevin, Mallery, David, Morris, Scott, Paulauskis, Joseph, Penny, Robert, Shelton, Candace, Shelton, Troy, Sherman, Mark, Thompson, Eric, Yena, Peggy, Bowen, Jay, Gastier-Foster, Julie M., Gerken, Mark, Leraas, Kristen M., Lichtenberg, Tara M., Ramirez, Nilsa C., Wise, Lisa, Zmuda, Erik, Corcoran, Niall, Costello, Tony, Hovens, Christopher, Carvalho, Andre L., de Carvalho, Ana C., Fregnani, José H., Longatto-Filho, Adhemar, Reis, Rui M., Scapulatempo-Neto, Cristovam, Silveira, Henrique C.S., Vidal, Daniel O., Burnette, Andrew, Eschbacher, Jennifer, Hermes, Beth, Noss, Ardene, Singh, Rosy, Anderson, Matthew L., Castro, Patricia D., Ittmann, Michael, Huntsman, David, Kohl, Bernard, Le, Xuan, Thorp, Richard, Andry, Chris, Duffy, Elizabeth R., Lyadov, Vladimir, Paklina, Oxana, Setdikova, Galiya, Shabunin, Alexey, Tavobilov, Mikhail, McPherson, Christopher, Warnick, Ronald, Berkowitz, Ross, Cramer, Daniel, Feltmate, Colleen, Horowitz, Neil, Kibel, Adam, Muto, Michael, Raut, Chandrajit P., Malykh, Andrei, Barnholtz-Sloan, Jill S., Barrett, Wendi, Devine, Karen, Fulop, Jordonna, Ostrom, Quinn T., Shimmel, Kristen, Wolinsky, Yingli, Sloan, Andrew E., De Rose, Agostino, Giuliante, Felice, Goodman, Marc, Karlan, Beth Y., Hagedorn, Curt H., Eckman, John, Harr, Jodi, Myers, Jerome, Tucker, Kelinda, Zach, Leigh Anne, Deyarmin, Brenda, Hu, Hai, Kvecher, Leonid, Larson, Caroline, Mural, Richard J., Somiari, Stella, Vicha, Ales, Zelinka, Tomas, Bennett, Joseph, Iacocca, Mary, Rabeno, Brenda, Swanson, Patricia, Latour, Mathieu, Lacombe, Louis, Têtu, Bernard, Bergeron, Alain, McGraw, Mary, Staugaitis, Susan M., Chabot, John, Hibshoosh, Hanina, Sepulveda, Antonia, Su, Tao, Wang, Timothy, Potapova, Olga, Voronina, Olga, Desjardins, Laurence, Mariani, Odette, Roman-Roman, Sergio, Sastre, Xavier, Stern, Marc-Henri, Cheng, Feixiong, Signoretti, Sabina, Berchuck, Andrew, Bigner, Darell, Lipp, Eric, Marks, Jeffrey, McCall, Shannon, McLendon, Roger, Secord, Angeles, Sharp, Alexis, Behera, Madhusmita, Brat, Daniel J., Chen, Amy, Delman, Keith, Force, Seth, Khuri, Fadlo, Magliocca, Kelly, Maithel, Shishir, Olson, Jeffrey J., Owonikoko, Taofeek, Pickens, Alan, Ramalingam, Suresh, Shin, Dong M., Sica, Gabriel, Van Meir, Erwin G., Zhang, Hongzheng, Eijckenboom, Wil, Gillis, Ad, Korpershoek, Esther, Looijenga, Leendert, Oosterhuis, Wolter, Stoop, Hans, van Kessel, Kim E., Zwarthoff, Ellen C., Calatozzolo, Chiara, Cuppini, Lucia, Cuzzubbo, Stefania, DiMeco, Francesco, Finocchiaro, Gaetano, Mattei, Luca, Perin, Alessandro, Pollo, Bianca, Chen, Chu, Houck, John, Lohavanichbutr, Pawadee, Hartmann, Arndt, Stoehr, Christine, Stoehr, Robert, Taubert, Helge, Wach, Sven, Wullich, Bernd, Kycler, Witold, Murawa, Dawid, Wiznerowicz, Maciej, Chung, Ki, Edenfield, W. Jeffrey, Martin, Julie, Baudin, Eric, Bubley, Glenn, Bueno, Raphael, De Rienzo, Assunta, Richards, William G., Kalkanis, Steven, Mikkelsen, Tom, Noushmehr, Houtan, Scarpace, Lisa, Girard, Nicolas, Aymerich, Marta, Campo, Elias, Giné, Eva, Guillermo, Armando López, Van Bang, Nguyen, Hanh, Phan Thi, Phu, Bui Duc, Tang, Yufang, Colman, Howard, Evason, Kimberley, Dottino, Peter R., Martignetti, John A., Gabra, Hani, Juhl, Hartmut, Akeredolu, Teniola, Stepa, Serghei, Hoon, Dave, Ahn, Keunsoo, Kang, Koo Jeong, Beuschlein, Felix, Breggia, Anne, Birrer, Michael, Bell, Debra, Borad, Mitesh, Bryce, Alan H., Castle, Erik, Chandan, Vishal, Cheville, John, Copland, John A., Farnell, Michael, Flotte, Thomas, Giama, Nasra, Ho, Thai, Kendrick, Michael, Kocher, Jean-Pierre, Kopp, Karla, Moser, Catherine, Nagorney, David, O’Brien, Daniel, O’Neill, Brian Patrick, Patel, Tushar, Petersen, Gloria, Que, Florencia, Rivera, Michael, Roberts, Lewis, Smallridge, Robert, Smyrk, Thomas, Stanton, Melissa, Thompson, R. Houston, Torbenson, Michael, Yang, Ju Dong, Zhang, Lizhi, Brimo, Fadi, Ajani, Jaffer A., Gonzalez, Ana Maria Angulo, Behrens, Carmen, Bondaruk, Jolanta, Broaddus, Russell, Czerniak, Bogdan, Esmaeli, Bita, Fujimoto, Junya, Gershenwald, Jeffrey, Guo, Charles, Lazar, Alexander J., Logothetis, Christopher, Meric-Bernstam, Funda, Moran, Cesar, Ramondetta, Lois, Rice, David, Sood, Anil, Tamboli, Pheroze, Thompson, Timothy, Troncoso, Patricia, Tsao, Anne, Wistuba, Ignacio, Carter, Candace, Haydu, Lauren, Hersey, Peter, Jakrot, Valerie, Kakavand, Hojabr, Kefford, Richard, Lee, Kenneth, Long, Georgina, Mann, Graham, Quinn, Michael, Saw, Robyn, Scolyer, Richard, Shannon, Kerwin, Spillane, Andrew, Stretch, Jonathan, Synott, Maria, Thompson, John, Wilmott, James, Al-Ahmadie, Hikmat, Chan, Timothy A., Ghossein, Ronald, Gopalan, Anuradha, Levine, Douglas A., Reuter, Victor, Singer, Samuel, Singh, Bhuvanesh, Tien, Nguyen Viet, Broudy, Thomas, Mirsaidi, Cyrus, Nair, Praveen, Drwiega, Paul, Miller, Judy, Smith, Jennifer, Zaren, Howard, Park, Joong-Won, Hung, Nguyen Phi, Kebebew, Electron, Linehan, W. Marston, Metwalli, Adam R., Pacak, Karel, Pinto, Peter A., Schiffman, Mark, Schmidt, Laura S., Vocke, Cathy D., Wentzensen, Nicolas, Worrell, Robert, Yang, Hannah, Moncrieff, Marc, Goparaju, Chandra, Melamed, Jonathan, Pass, Harvey, Botnariuc, Natalia, Caraman, Irina, Cernat, Mircea, Chemencedji, Inga, Clipca, Adrian, Doruc, Serghei, Gorincioi, Ghenadie, Mura, Sergiu, Pirtac, Maria, Stancul, Irina, Tcaciuc, Diana, Albert, Monique, Alexopoulou, Iakovina, Arnaout, Angel, Bartlett, John, Engel, Jay, Gilbert, Sebastien, Parfitt, Jeremy, Sekhon, Harman, Thomas, George, Rassl, Doris M., Rintoul, Robert C., Bifulco, Carlo, Tamakawa, Raina, Urba, Walter, Hayward, Nicholas, Timmers, Henri, Antenucci, Anna, Facciolo, Francesco, Grazi, Gianluca, Marino, Mirella, Merola, Roberta, de Krijger, Ronald, Gimenez-Roqueplo, Anne-Paule, Piché, Alain, Chevalier, Simone, McKercher, Ginette, Birsoy, Kivanc, Barnett, Gene, Brewer, Cathy, Farver, Carol, Naska, Theresa, Pennell, Nathan A., Raymond, Daniel, Schilero, Cathy, Smolenski, Kathy, Williams, Felicia, Morrison, Carl, Borgia, Jeffrey A., Liptay, Michael J., Pool, Mark, Seder, Christopher W., Junker, Kerstin, Omberg, Larsson, Dinkin, Mikhail, Manikhas, George, Alvaro, Domenico, Bragazzi, Maria Consiglia, Cardinale, Vincenzo, Carpino, Guido, Gaudio, Eugenio, Chesla, David, Cottingham, Sandra, Dubina, Michael, Moiseenko, Fedor, Dhanasekaran, Renumathy, Becker, Karl-Friedrich, Janssen, Klaus-Peter, Slotta-Huspenina, Julia, Abdel-Rahman, Mohamed H., Aziz, Dina, Bell, Sue, Cebulla, Colleen M., Davis, Amy, Duell, Rebecca, Elder, J. Bradley, Hilty, Joe, Kumar, Bahavna, Lang, James, Lehman, Norman L., Mandt, Randy, Nguyen, Phuong, Pilarski, Robert, Rai, Karan, Schoenfield, Lynn, Senecal, Kelly, Wakely, Paul, Hansen, Paul, Lechan, Ronald, Powers, James, Tischler, Arthur, Grizzle, William E., Sexton, Katherine C., Kastl, Alison, Henderson, Joel, Porten, Sima, Waldmann, Jens, Fassnacht, Martin, Asa, Sylvia L., Schadendorf, Dirk, Couce, Marta, Graefen, Markus, Huland, Hartwig, Sauter, Guido, Schlomm, Thorsten, Simon, Ronald, Tennstedt, Pierre, Olabode, Oluwole, Nelson, Mark, Bathe, Oliver, Carroll, Peter R., Chan, June M., Disaia, Philip, Glenn, Pat, Kelley, Robin K., Landen, Charles N., Phillips, Joanna, Prados, Michael, Simko, Jeffry, Smith-McCune, Karen, VandenBerg, Scott, Roggin, Kevin, Fehrenbach, Ashley, Kendler, Ady, Sifri, Suzanne, Steele, Ruth, Jimeno, Antonio, Carey, Francis, Forgie, Ian, Mannelli, Massimo, Carney, Michael, Hernandez, Brenda, Campos, Benito, Herold-Mende, Christel, Jungk, Christin, Unterberg, Andreas, von Deimling, Andreas, Bossler, Aaron, Galbraith, Joseph, Jacobus, Laura, Knudson, Michael, Knutson, Tina, Ma, Deqin, Milhem, Mohammed, Sigmund, Rita, Godwin, Andrew K., Madan, Rashna, Rosenthal, Howard G., Adebamowo, Clement, Adebamowo, Sally N., Boussioutas, Alex, Beer, David, Giordano, Thomas, Mes-Masson, Anne-Marie, Saad, Fred, Bocklage, Therese, Landrum, Lisa, Mannel, Robert, Moore, Kathleen, Moxley, Katherine, Postier, Russel, Walker, Joan, Zuna, Rosemary, Feldman, Michael, Valdivieso, Federico, Dhir, Rajiv, Luketich, James, Pinero, Edna M. Mora, Quintero-Aguilo, Mario, Carlotti, Carlos Gilberto, Jr., Dos Santos, Jose Sebastião, Kemp, Rafael, Sankarankuty, Ajith, Tirapelli, Daniela, Catto, James, Agnew, Kathy, Swisher, Elizabeth, Creaney, Jenette, Robinson, Bruce, Shelley, Carl Simon, Godwin, Eryn M., Kendall, Sara, Shipman, Cassaundra, Bradford, Carol, Carey, Thomas, Haddad, Andrea, Moyer, Jeffey, Peterson, Lisa, Prince, Mark, Rozek, Laura, Wolf, Gregory, Bowman, Rayleen, Fong, Kwun M., Yang, Ian, Korst, Robert, Rathmell, W. Kimryn, Fantacone-Campbell, J. Leigh, Hooke, Jeffrey A., Kovatich, Albert J., Shriver, Craig D., DiPersio, John, Drake, Bettina, Govindan, Ramaswamy, Heath, Sharon, Ley, Timothy, Van Tine, Brian, Westervelt, Peter, Rubin, Mark A., Lee, Jung Il, Aredes, Natália D., Mariamidze, Armaz, Ge, Zhongqi, Leighton, Jake S., Wang, Yumeng, Peng, Xinxin, Chen, Zhongyuan, Chen, Hu, Sun, Yutong, Yao, Fan, Zhang, Huiwen, Liu, Jianfang, Piwnica-Worms, Helen, and Ma, Li
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- 2018
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43. Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy
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Zhao, Jun, Wang, Huamin, Hsiao, Cheng-Hui, Chow, Diana S.-L., Koay, Eugene J., Kang, Yaan, Wen, Xiaoxia, Huang, Qian, Ma, Ying, Bankson, James A., Ullrich, Stephen E., Overwijk, Willem, Maitra, Anirban, Piwnica-Worms, David, Fleming, Jason B., and Li, Chun
- Published
- 2018
- Full Text
- View/download PDF
44. Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival
- Author
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Tinkum, Kelsey L., Stemler, Kristina M., White, Lynn S., Loza, Andrew J., Jeter-Jones, Sabrina, Michalski, Basia M., Kuzmicki, Catherine, Pless, Robert, Stappenbeck, Thaddeus S., Piwnica-Worms, David, and Piwnica-Worms, Helen
- Published
- 2015
45. A comprehensive overview of metaplastic breast cancer: clinical features and molecular aberrations
- Author
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Reddy, Tejaswini P., Rosato, Roberto R., Li, Xiaoxian, Moulder, Stacy, Piwnica-Worms, Helen, and Chang, Jenny C.
- Published
- 2020
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46. Spatial and Temporal Confined Photothermolysis of Cancer Cells Mediated by Hollow Gold Nanospheres Targeted to Epidermal Growth Factor Receptors
- Author
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Geng Ku, Qian Huang, Xiaoxia Wen, John Ye, David Piwnica-Worms, and Chun Li
- Subjects
Chemistry ,QD1-999 - Published
- 2018
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47. Human cord blood progenitors with high aldehyde dehydrogenase activity improve vascular density in a model of acute myocardial infarction
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Sondergaard, Claus S, Hess, David A, Maxwell, Dustin J, Weinheimer, Carla, Rosová, Ivana, Creer, Michael H, Piwnica-Worms, David, Kovacs, Attila, Pedersen, Lene, and Nolta, Jan A
- Abstract
Abstract Human stem cells from adult sources have been shown to contribute to the regeneration of muscle, liver, heart, and vasculature. The mechanisms by which this is accomplished are, however, still not well understood. We tested the engraftment and regenerative potential of human umbilical cord blood-derived ALDHhiLin-, and ALDHloLin- cells following transplantation to NOD/SCID or NOD/SCID β2m null mice with experimentally induced acute myocardial infarction. We used combined nanoparticle labeling and whole organ fluorescent imaging to detect human cells in multiple organs 48 hours post transplantation. Engraftment and regenerative effects of cell treatment were assessed four weeks post transplantation. We found that ALDHhiLin- stem cells specifically located to the site of injury 48 hours post transplantation and engrafted the infarcted heart at higher frequencies than ALDHloLin- committed progenitor cells four weeks post transplantation. We found no donor derived cardiomyocytes and few endothelial cells of donor origin. Cell treatment was not associated with any detectable functional improvement at the four week endpoint. There was, however, a significant increase in vascular density in the central infarct zone of ALDHhiLin- cell-treated mice, as compared to PBS and ALDHloLin- cell-treated mice. Conclusions Our data indicate that adult human stem cells do not become a significant part of the regenerating tissue, but rapidly home to and persist only temporarily at the site of hypoxic injury to exert trophic effects on tissue repair thereby enhancing vascular recovery.
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- 2010
48. Imaging Reversal of Multidrug Resistance in Living Mice with Bioluminescence: MDR1 P-Glycoprotein Transports Coelenterazine
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Pichler, Andrea, Prior, Julie L., Piwnica-Worms, David, and Chance, Britton
- Published
- 2004
49. Gender Differences in a Mouse Model of Hepatocellular Carcinoma Revealed Using Multi-Modal Imaging
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Engel, Brian J., primary, Paolillo, Vincenzo, additional, Uddin, Md. Nasir, additional, Gonzales, Kristyn A., additional, McGinnis, Kathryn M., additional, Sutton, Margie N., additional, Patnana, Madhavi, additional, Grindel, Brian J., additional, Gores, Gregory J., additional, Piwnica-Worms, David, additional, Beretta, Laura, additional, Pisaneschi, Federica, additional, Gammon, Seth T., additional, and Millward, Steven W., additional
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- 2023
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50. Evaluation of 89Zr-Labeled Anti-PD-L1 Monoclonal Antibodies Using DFO and Novel HOPO Analogues as Chelating Agents for Immuno-PET
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Radaram, Bhasker, primary, Glazer, Sarah E., additional, Yang, Ping, additional, Li, Chia-Wei, additional, Hung, Mien-Chie, additional, Gammon, Seth T., additional, Alauddin, Mian, additional, and Piwnica-Worms, David, additional
- Published
- 2023
- Full Text
- View/download PDF
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