tbuckley/cabot-search huggingface dataset:
Abstract 4177: Anticancer agent Aminoflavone restores the expression of tumor suppressor miRNA 26a and inhibits putative stemness biomarker α6-integrin in Tamoxifen resistant cells
Authors: Petreena Campbell, Leah Rowland, Anna Opoku-Agyeman, Nichole Mavingire, Ubaldo Soto, Gayathri Nagaraj, Yonghong Zhang, Sean (Xin) Chen, Charles Wang, Eileen Brantley
Journal: Cancer Research (2017)

Abstract Despite the efficacy of anti-estrogen agent Tamoxifen, commonly used to treat patients with estrogen receptor positive (ER+) tumors, up to 40% of patients experience recurrence. Breast tumor-initiating cells (TICs), or breast cancer stem cells, exhibit Tamoxifen resistance and contribute substantially to recurrence. We recently demonstrated that investigational anticancer agent Aminoflavone (AF) disrupts mammospheres (in vitro clusters of cells enriched with TICs) by thwarting the expression of α6-integrin. In the current study, we found AF potently inhibited Tamoxifen resistant (TamR) cell growth and blocked Tamoxifen-mediated stimulation of TamR cell proliferation using the Alamar Blue assay. qPCR analyses revealed α6-integrin expression was significantly elevated in ER+ breast cancer cell models of acquired and de novo Tamoxifen resistance relative to Tamoxifen sensitive cells. In particular, AF decreased the expression of both A and B variants of α6-integrin, the B variant being essential for TIC function. Western blotting revealed AF reduced total α6-integrin expression in TamR cells. Furthermore, we found that an anti-α6-integrin blocking antibody sensitized TamR cells to the active Tamoxifen metabolite, 4-hydroxy-Tamoxifen, and enhanced the efficacy of AF in these cells. AF also reduced the protein expression of p-Src, a downstream target of α6-integrin that is linked to Tamoxifen resistance and decreased breast cancer survival. In addition, miRNA sequencing of Tamoxifen sensitive and TamR mammospheres revealed differential expression of several miRNAs. Notably, miR-26a expression was down-regulated 2-fold in TamR mammospheres compared to Tamoxifen sensitive mammospheres and AF restored miR-26a expression 5-fold in TamR mammospheres. Using miRNA target prediction algorithms TargetScan and PicTar, we found miR-26a binding sites on the α6-integrin promoter. Taken together, our data suggest that AF re-expresses tumor suppressor miR-26a and inhibits the α6-integrin/Src signaling axis to reduce TIC capacity and counteract Tamoxifen resistance. Citation Format: Petreena Campbell, Leah Rowland, Anna Opoku-Agyeman, Nichole Mavingire, Ubaldo Soto, Gayathri Nagaraj, Yonghong Zhang, Sean (Xin) Chen, Charles Wang, Eileen Brantley. Anticancer agent Aminoflavone restores the expression of tumor suppressor miRNA 26a and inhibits putative stemness biomarker α6-integrin in Tamoxifen resistant cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4177. doi:10.1158/1538-7445.AM2017-4177
Abstract 3545: Glucose-dependent regulation of PXR is modulated by AMPK
Authors: Peter O. Oladimeji
Journal: Cancer Research (2017)

Abstract The sensitivity of patients to drugs depends on the pharmacokinetics of the drugs, but largely on the bioavailability of the drugs in the body. Orally administered drugs must pass through the intestinal wall and the portal circulation to reach the liver; both are sites of first-pass metabolism. Thus, many drugs may be metabolized before optimal plasma concentrations are reached, or before getting to target tissues, resulting in diminished drug efficacy and acquired drug resistance. Among the several drug-metabolizing enzymes (DME) is cytochrome P450 (CYP) enzyme 3A4, the most abundant in the liver, metabolizes approximately 50 percent of marketed drugs and a main target of pregnane X receptor (PXR) In addition, transporters including MDR1 are also regulated by PXR. There is increasing evidence that drug metabolism can be affected by energy metabolism and vice versa. PXR has been implicated to have a complex role in energy homeostasis, and increased drug clearance was observed in untreated diabetic patients. The elimination of any chemotherapeutic agents in humans is markedly dependent on the relative expression and activity of the various DMEs and drug transpoters. The heterotrimeric AMP-activated protein kinase (AMPK) serves as a monitor of cellular energy status in most eukaryotic cell, and is activated under energy stress conditions. Interestingly, AMPK is also regarded as a tumor suppressor in various cancers because of its inhibitory effects on anabolic processes that are important for tumor development. Despite the knowledge of the cross-regulation between drug metabolism and energy metabolism, the molecular pathways of this interaction remain vague. In our study, we exposed HepG2 cells to varying glucose concentrations and observed that PXR is greatly induced in high glucose conditions. This finding is consistent with clinical observation of increased drug clearance in untreated diabetic patients. We demonstrate that AMPK modulates PXR transcriptional activity. As such, the pharmacological manipulations of AMPK activation status show an inverse relationship with PXR activity. Activation of AMPK was shown to decrease PXR activity as observed by decreased CYP3A4 transcription, and consistent with that a potentiation of response to drugs. Interestingly, we observed that PXR is not a direct target of AMPK: it remains to be determined what the intermediary between AMPK and PXR is. Taken together, our studies identify novel links between the energy status of the cell, the activation of AMPK and down regulation of PXR. Citation Format: Peter O. Oladimeji. Glucose-dependent regulation of PXR is modulated by AMPK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3545. doi:10.1158/1538-7445.AM2017-3545
Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains
Authors: Leah Alabanza, Melissa Pegues, Claudia Geldres, Victoria Shi, Jed J.W. Wiltzius, Stuart A. Sievers, Shicheng Yang, James N. Kochenderfer
Journal: Molecular Therapy (2017)

Anti-CD19 chimeric antigen receptor (CAR) T cells have caused remissions of B cell malignancies, but problems including cytokine-mediated toxicity and short persistence of CAR T cells in vivo might limit the effectiveness of anti-CD19 CAR T cells. Anti-CD19 CARs that have been tested clinically had single-chain variable fragments (scFvs) derived from murine antibodies. We have designed and constructed novel anti-CD19 CARs containing a scFv with fully human variable regions. T cells expressing these CARs specifically recognized CD19+ target cells and carried out functions including degranulation, cytokine release, and proliferation. We compared CARs with CD28 costimulatory moieties along with hinge and transmembrane domains from either the human CD28 molecule or the human CD8α molecule. Compared with T cells expressing CARs with CD28 hinge and transmembrane domains, T cells expressing CARs with CD8α hinge and transmembrane domains produced lower levels of cytokines and exhibited lower levels of activation-induced cell death (AICD). Importantly, CARs with hinge and transmembrane regions from either CD8α or CD28 had similar abilities to eliminate established tumors in mice. In anti-CD19 CARs with CD28 costimulatory moieties, lower levels of inflammatory cytokine production and AICD are potential clinical advantages of CD8α hinge and transmembrane domains over CD28 hinge and transmembrane domains.
Abstract 4392: Genetic diagnosis of multiple hepatocellular carcinoma
Authors: Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shingo Tsuji, Genta Nagae, Tadatoshi Takayama, Hiroyuki Aburatani
Journal: Cancer Research (2017)

Abstract Multiple hepatocellular carcinoma (HCC) is categorized into two types; multicentric hepatocarcinogenesis (MC) and intrahepatic metastasis (IM). Although discrimination of the types of multiple HCC is of clinical importance, it is quite difficult to determine it correctly even after histological diagnosis. In order to determine multiple HCC as MC or IM, we compared pairs of multiple HCC samples from 40 patients with multiple HCC and 2 patients with pairs of primary HCC and extrahepatic metastasis such as adrenal grand and lung metastasis with regard to molecular aberrations. Exome sequence showed that more than 70% of somatic mutations were common in the pairs of IM, which were consistent with the result of a pair of primary HCC and extrahepatic metastasis, while no common somatic mutations was detected in genomic-MC (gMC) pairs. Notably, more than 60% of clinically metachronous-MC cases were diagnosed as genomic-IM (gIM) due to the concordance of mutation and shows significantly frequent tumor thrombus, suggesting that gIM pairs developed from the common ancestor. In addition, cell-free DNA was analyzed using exome sequence in five patients with recurrent HCC, and found that somatic mutations of cell free DNA were similar to the primary HCC only in gIM but not in gMC cases. Taken together, comparison of mutations in a pair of HCCs makes it possible to classify multiple HCCs into MC and IM, which is difficult to be correctly determined in clinical practice. Furthermore liquid biopsy for mutation analysis is available to make treatment plans for multiple HCC patients. Citation Format: Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shingo Tsuji, Genta Nagae, Tadatoshi Takayama, Hiroyuki Aburatani. Genetic diagnosis of multiple hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4392. doi:10.1158/1538-7445.AM2017-4392
Abstract 1827: Using <i>Drosophila</i> to study the role of metabolic enzyme mutations in glioblastoma and leukemia
Authors: Julia Fabiano, Gabriela Chiaramida, Mira Magner, Meghan O'Connor, Joseph Stallone, Nicholas DiDuca, Kathryn Neville, Richard Tartarini, Marla Tipping
Journal: Cancer Research (2017)

Abstract Metabolic reprogramming is a common hallmark shared by nearly all proliferating cancer cells, and thus has emerged as an exciting new direction in cancer research. Many signaling pathways have been implicated in mechanisms leading to the shift of metabolic programs in tumors, but more recently a small number of metabolic enzymes have also been identified in this process. Genes encoding the metabolic enzymes Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) were found to be mutated in up to 70% of low-grade and medium grade gliomas, and in 15-20% of adult acute leukemia samples. These findings were the first to link the IDH gene to tumorigenesis. IDH1 and IDH2 function to irreversibly catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). We are studying how mutations in IDH affect the metabolism and cellular processes of the cell. To this end, we have expressed IDH-R132H in Drosophila glial cells and hemoctyes to learn more about the impact of neomorphic activity of IDH in gliobastoma and chronic myeloid leukemia. We have verified that these cells now produce 2-HG, as is known in human tumors harboring IDH mutations. We have observed different cellular responses to IDH mutations in glia versus hemoctyes and have begun to investigate why this may be. Ultimately, the goal of our research is to elucidate the mechanism(s) that cause IDH to contribute to oncogenic activity in specific tissues, and use this knowledge to design tailored therapeutics. Citation Format: Julia Fabiano, Gabriela Chiaramida, Mira Magner, Meghan O'Connor, Joseph Stallone, Nicholas DiDuca, Kathryn Neville, Richard Tartarini, Marla Tipping. Using Drosophila to study the role of metabolic enzyme mutations in glioblastoma and leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1827. doi:10.1158/1538-7445.AM2017-1827
Abstract 5461: Nuclear localization of the caspase 3 cleaved form of p73 in anoikis
Authors: Samar Alsafadi, Sophie Tourpin, Sophie Salome-Desnoulez, Nadia Bessoltane, Fabrice Andre, Jean Charles Ahomadegbe
Journal: Cancer Research (2017)

Abstract The transcription factor p73 is a homologue of p53 that can be expressed as pro- or anti-apoptotic isoforms. Unlike p53, p73 is rarely mutated or lost in cancers and it is found to replace defective p53 inducing apoptosis. Here, we investigated the p73 involvement in anoikis, a type of apoptosis caused by inadequate cell-matrix interactions. Breast cancer cell lines with different p53 status were treated with doxorubicin or docetaxel and cells detached from the extracellular matrix were analyzed. We demonstrate for the first time that doxorubicin-induced cell detachment is associated with p73 cleavage and caspase activation, independently of the p53 status. However, we did not detect p73 cleavage or caspase activation in detached cells under docetaxel treatment. Overexpressing the apoptotic isoform of p73 led to cell detachment associated with p73 cleavage and caspase activation. Interestingly, p73 cleaved forms localize to the nucleus during the late phase of cell death indicating an increase in the transcriptional activity. Our study suggests that the cleavage of p73 on specific sites may release its pro-apoptotic function and contribute to cell death. Note: This abstract was not presented at the meeting. Citation Format: Samar Alsafadi, Sophie Tourpin, Sophie Salome-Desnoulez, Nadia Bessoltane, Fabrice Andre, Jean Charles Ahomadegbe. Nuclear localization of the caspase 3 cleaved form of p73 in anoikis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5461. doi:10.1158/1538-7445.AM2017-5461
Abstract 1402: NME3 links mitochondrial fusion to DNA repair in nuclear genome
Authors: Zee-Fen Chang
Journal: Cancer Research (2017)

Abstract In mammals, there are 10 isoforms of NME (NDP Kinase), which catalyze the reversible reaction of NTPs formation from NDP and ATP. By RNA interference, NME3 was found critical for DNA repair. Data from analysis of the steady-state levels of rNTPs and dNTPs suggest that NME3 does not play a critical role in determining the total pools of these nucleotides. However, its mitochondrial localization and catalytic function are necessary for its function in DNA repair. Super-resolution microscopy analysis indicates the localization of NME3 at mitochondrial outer membrane. We further used APEX-mediated biotinylation to identify proteins interacting with NME3. Among them, Mfn1 is validated to associate with mitochondrial NME3 in vitro and in vivo. We provide evidence that NME3 is required for DNA damage-induced mitochondria fusion via GTP-mediated fueling of Mfn1. The lack of this process increased nucleotide oxidation and sustained DNA damage in nuclear genome. These data highlight the function of NME3 in mitochondrial fusion, which is required for the maintenance of genome integrity. Citation Format: Zee-Fen Chang. NME3 links mitochondrial fusion to DNA repair in nuclear genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1402. doi:10.1158/1538-7445.AM2017-1402
Abstract 1492: Chemical approaches to development of mitochondrial-targeted Hsp90 inhibitor in anti-cancer therapeutics: Mechanism and structure change of mitochondrial Hsp90
Authors: Sung Hu, Nam Gu Yoon, Byoung Heon Kang
Journal: Cancer Research (2017)

Abstract Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1), a member of the heat shock protein 90 (Hsp90) which located in mitochondria, is thought to promote tumor cell survival and to reprogram energy metabolism in cancer. Previous studies have demonstrated that the inactivation of TRAP1 selectively induced mitochondrial dysfunction and cell death in cancer cells. Therefore, TRAP1 has been suggested as an emerging target protein for anti-cancer drug development. Isopropyl amine of the Hsp90 inhibitor, PU-H71, was replaced with the mitochondria-targeting moiety, triphenyphosphonium, to produce the mitochondria-accumulating TRAP1 inhibitor, SMTIN-P01. To further optimize SMTIN-P01, we have synthesized several SMTIN-P01 derivatives including TPP-PU-X03 with potent TRAP1 inhibitory activities. TPP-PU-X03 increased TRAP1 ATPase enzyme activity while suppressing chaperone activity, suggesting asymmetric effect on dimeric TRAP1 chaperone functions. Electron microscopic analyses showed TPP-PU-X03 shift TRAP1 conformation from open to close conformation, while other TRAP1 or Hsp90 inhibitors stabilizes open conformation. Importantly, TPP-PU-X03 showed improved mitochondria dysfunction and enhanced cytotoxicity to various cancer cells in vitro and in vivo. Collectively, the structure based optimization of current TRAP1 inhibitors may generate potent anti-cancer drugs with novel mechanisms of action. Citation Format: Sung Hu, Nam Gu Yoon, Byoung Heon Kang. Chemical approaches to development of mitochondrial-targeted Hsp90 inhibitor in anti-cancer therapeutics: Mechanism and structure change of mitochondrial Hsp90 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1492. doi:10.1158/1538-7445.AM2017-1492
Abstract 606: Targeting multiple immune checkpoints and their ligands using a humanized mouse model of ovarian cancer
Authors: Ruea-Yea Huang, Kunle Odunsi
Journal: Cancer Research (2017)

Abstract We have recently reported that multiple immune checkpoints are expressed in the TILs (tumor infiltrating T lymphocytes) and TALs (tumor associated T lymphocytes) from a murine ovarian cancer model and that blockade of one checkpoint pathway induces an upregulation of the other unblocked checkpoints. We hypothesized that resistance to single agent blockade (e.g. anti-PD1) is resulted from the compensatory upregulation of the other pathways (e.g. CTLA4 or LAG-3). To test this hypothesis in human ovarian cancer, we first examined the level of several immune checkpoints and their ligands in TILs or TALs from ovarian cancer patients. In addition to the highly expressed PD-1 and CTLA4, other checkpoint molecules such as TIM3, LAG3, VISTA, and TIGIT are also elevated in TALs as compared with control PBMC. The levels of multiple ligands for the immune receptors in the tumor samples were also analyzed. To translate the results from mice to humans, we developed several aggressive human ovarian cancer cell lines from patient derived xenografts to test the combinatorial checkpoint blockade strategies. Using a humanized mouse model of ovarian cancer we observed that adaptive transfer of autologous T cells in combination with checkpoint blockade of PD1 mildly delays ovarian tumor growth. The effect of blocking PD-1 and CTLA-4 pathways on tumor growth and the upregulation of other checkpoints are currently underway. Citation Format: Ruea-Yea Huang, Kunle Odunsi. Targeting multiple immune checkpoints and their ligands using a humanized mouse model of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 606. doi:10.1158/1538-7445.AM2017-606
Abstract 009: Cardiac Human Mesenchymal Stromal Cells from Patients with Ischemic Heart Disease are Proinflammatory and Impair Recovery after Myocardial Infarction in Rat
Authors: Nili Naftali-Shani, Ayelet Itzhaki-Alfia, Natalie Landa-Rouben, David Kain, Radka Holbova, Natali Molotski, Elad Asher, Avishay Grupper, Eran Millet, Ariel Tessone, Eyal Winkler, Jens Kastrup, Micha S. Feinberg, Yigal Kassif, Leonid Sternik, Jacob Lavee, Ehud Raanani, Jonathan Leor
Journal: Circulation Research (2013)

Introduction: Human mesenchymal stromal cells (hMSCs) from adipose cardiac tissue have attracted considerable interest for cell-based therapies. However, the best source of hMSCs for infarct repair is still unknown. Hypothesis: We aimed to test the hypothesis that, because of their proximity to the heart, hMSCs from the heart and epicardial fat would be better cells for infarct repair. Methods and Results: We isolated and grew hMSCs from patients with ischemic heart disease (IHD) from four different sources: 1) epicardial fat 2) pericardial fat 3) subcutaneous fat and 4) the right atrium. hMSCs from the right atrium and epicardial fat secreted the highest amounts of trophic and inflammatory cytokines, while hMSCs from pericardial and subcutaneous fat secreted the lowest (p&lt;0.05, n=5-6 per source). Subsequently, the greatest angiogenic effect was induced with conditioned medium from atrium and epicardial fat hMSCs, by tube formation assay. To determine the effect of hMSCs in vivo , we allocated rats to hMSC transplantation 7 days after myocardial infarction (MI) (n=8-10 per group). Atrial hMSCs induced the highest number of vessels in the infarct, together with the highest inflammation score and macrophage accumulation 27 days after their injection. However, left ventricular (LV) dysfunction was worst after therapy with atrium and epicardial fat hMSCs, and minimal after subcutaneous fat hMSC therapy. Notably, there was a correlation between levels of tumor necrosis factor-α and hepatocyte growth factor, in vitro , and post-transplantation LV systolic dilatation. These surprising findings were supported by gene expression analysis in hMSCs from different sources of a patient with IHD. We found that the relative expression of inflammation and fibrosis-related genes was considerably higher in hMSCs from the right atrium and epicardial fat than in subcutaneous fat hMSCs. Conclusions: The origin of hMSCs affects their reparative and immunomodulatory properties. Because of their pro-inflammatory properties, hMSCs from the right atrium and epicardial fat of IHD patients could impair heart function after MI. Our findings might be relevant to autologous MSC therapy and pathogenesis and progression of IHD.
Atomic Force Microscopy as a Tool to Assess the Specificity of Targeted Nanoparticles in Biological Models of High Complexity
Authors: Carla P. Gomes, Cátia D. F. Lopes, Michael Leitner, Andreas Ebner, Peter Hinterdorfer, Ana P. Pêgo
Journal: Advanced Healthcare Materials (2017)

Abstract The ability to design nanoparticle delivery systems capable of selectively target their payloads to specific cell populations is still a major caveat in nanomedicine. One of the main hurdles is the fact that each nanoparticle formulation needs to be precisely tuned to match the specificities of the target cell and route of administration. In this work, molecular recognition force spectroscopy (MRFS) is presented as a tool to evaluate the specificity of neuron‐targeted trimethyl chitosan nanoparticles to neuronal cell populations in biological samples of different complexity. The use of atomic force microscopy tips functionalized with targeted or non‐targeted nanoparticles made it possible to assess the specific interaction of each formulation with determined cell surface receptors in a precise fashion. More importantly, the combination of MRFS with fluorescent microscopy allowed to probe the nanoparticles vectoring capacity in models of high complexity, such as primary mixed cultures, as well as specific subcellular regions in histological tissues. Overall, this work contributes for the establishment of MRFS as a powerful alternative technique to animal testing in vector design and opens new avenues for the development of advanced targeted nanomedicines.