bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CN08-02: Metabolic adaptations and liabilities of TCA cycle-truncated tumors
Authors: Gottlieb Eyal 
Published: May 2016

Abstract
Last century, Otto Warburg observed that cancer tissues have high rates of glycolysis in the presence of oxygen. This was attributed to defects in mitochondrial respiration, and is now considered a key hallmark of cancer. Nevertheless, convincing evidence that mitochondrial dysfunction causes metabolic switch and tumorigenesis, were scarce. Recently, the identification of mutations in key metabolic enzymes with a causal link to tumorigenesis awakened interest in Warburg's hypothesis. Cancer-associated mutations have been identified in genes coding for tricarboxylic acid (TCA) cycle and closely related enzymes. Succinate dehydrogenase (SDH) is a TCA cycle enzyme and complex II of the mitochondrial respiratory chain. Loss of function in any of the SDH subunits is associated with susceptibility to cancers. Loss of SDH causes succinate accumulation, which activates hypoxia-inducible factors and inhibits α-ketoglutarate-dependent histone and DNA demethylases, establishing pseudohypoxic and hypermethylator phenotypes. However, so far no mechanism enabling survival and proliferation of SDH-defective cells has been provided. We generated genetically modified kidney mouse cells in which Sdhb has been deleted and identified metabolic pathways dispensable in normal, but essential in SDH-null cells. We demonstrated that SDH deficient cells depend on extracellular pyruvate to sustain glycolytic flux and to channel glucose-derived carbons to aspartate biosynthesis through pyruvate carboxylase. Our study provides a new potential therapeutic target for treating SDH defective neoplasms.
Citation Format: Eyal Gottlieb. Metabolic adaptations and liabilities of TCA cycle-truncated tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN08-02.
Abstract LB-A07: Using Impedance-Based Approaches for Measuring Cell-Mediated Cytotoxicity and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Authors: Zhao Leyna , Abassi Yama 
Published: May 2016

Abstract
The most common method for measuring cell mediated cytotoxicity is the release assay based on the loss of target cell membrane integrity. Within up to 4 hours following effector cell addition resulting in target cell lysis, either the radioactive release from target cells pre-labeled with Chromium-51 or Indium-111 is measured, or the release of naturally occurring substances, such as lactate dehydrogenase (LDH), into the culture medium is assayed. Release of these substances thus serves as an indirect measure of the extent of cell damage due to effector cell-mediated target cell lysis. Alternative endpoint methods also include flow cytometry, enzyme-linked immunosorbent assay-based granzyme measurement, and morphometric analyses by microscopy.
Here we describe an impedance-based real-time label-free method that can automated capture the kinetics of the cell mediated or antibody-dependent cell mediated cytolysis (ADCC) of the target cancer cells. To determine if cell-mediated cytotoxicity, and specifically ADCC, can be investigated using an impedance-based xCELLigence system, the response of tumor cells (as target cells) to natural killer (NK) cell activity (as effector cells), in the presence or absence of immunoglobulin G isotype-specific antibody, was measured. Importantly, it is shown that the addition of NK cells in suspension, over a monolayer of adherent tumor cells, does not produce impedance changes, because the NK cells do not come in contact with the electronic sensor. However, the secretion of perforins and granzymes by these non-adherent NK cells does activate caspases inducing tumor cell apoptosis. Dysfunctional and dying tumor cells detach from the sensor electrode, reducing the number of viable and adhering cells on the electrode surface.
Overall, our results show that the impedance-base technology is a label-free alternative to the traditional end-point assays. The automated readouts provide direct, sensitive and specific measurement of target cell changes both short-term (hrs) and long-term (days). It allows the easy quantification of the cell-mediated cytotoxicity and evaluation of the potencies for specific antibodies.
Citation Format: Leyna Zhao, Yama Abassi. Using Impedance-Based Approaches for Measuring Cell-Mediated Cytotoxicity and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A07.
Abstract LB-A10: The carcinogenic role of CYP1B1 in cancer cells related to Wnt/β-catenin signaling and uPAR pathway
Authors: Kwon Yeo-Jung , Shin Sangyun , Ye Dong-Jin , Baek Hyoung-Seok , Chun Young-Jin 
Published: May 2016

Abstract
The carcinogenic role of CYP1B1 in cancer cells related to Wnt/β-catenin signaling and uPAR pathway
Yeo-Jung Kwon*, Sangyun Shin, Dong-Jin Ye, Hyoung-Seok Baek, and Young-Jin Chun
Department of Pharmaceutical Biochemistry, College of Pharmacy, Chung-Ang University, Seoul, Korea
Cytochrome P450 1B1 (CYP1B1) belongs to the CYP1 family and shares the feature as an enzyme for oxidative metabolisms. It has been reported that CYP1B1 expression is higher in the tumor tissues than the normal ones, especially in hormone-related cancers such as breast, ovarian, and prostate cancer cells. To explore the role of CYP1B1 on cancer cell proliferation, we studied the effects of CYP1B1 inhibition and activation in MCF-7 and MCF-10A cells. Here, we confirmed that expression of CYP1B1 affects the level of cell proliferation using CCK assay. To elucidate whether the cell proliferation induced by CYP1B1 is related to Wnt/β-catenin signaling, we examined the alteration of β-catenin and expression using western blot, RT-PCR, immunostaining, and qPCR followed by over-expression of CYP1B1 or treatment with DMBA (7,12-dimethylbenz[α]anthracene), a well known CYP1B1 inducer and these studies also performed when CYP1B1 gene was knockdown or cells were treated with TMS (tetramethoxystilbene), a specific CYP1B1 inhibitor. These investigations all showed that CYP1B1 promotes β-catenin expression in mRNA and protein levels and induces β-catenin nuclear localization. To identify the effect of CYP1B1 on Wnt/β-catenin signaling further, the promoter activity of β-catenin/TCF/LEF or expression level of Wnt/β-catenin signaling target genes such as c-myc, cyclin D1 were examined and all factors also showed to be up-regulated by CYP1B1. To elucidate whether CYP1B1 induces cell metastasis, cell migration and invasion assay were conducted and it has been identified that CYP1B1 enhances cell motility by induction of mesenchymal-like cell morphological changes. Moreover, the uPAR-uPA pathway has been identified to be related to the CYP1B1-induced cell metastasis by detection of uPAR-uPA pathway factors using western blot and qPCR in MCF-7 and HeLa cells. Taken together, these data suggest that CYP1B1 promotes cell proliferation and metastasis via inducing Wnt/β-catenin signaling and uPAR pathway.
Citation Format: Yeo-Jung Kwon, Sangyun Shin, Dong-Jin Ye, Hyoung-Seok Baek, Young-Jin Chun. The carcinogenic role of CYP1B1 in cancer cells related to Wnt/β-catenin signaling and uPAR pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A10.
Abstract LB-A17: Hospital volume determines mortality amongst neutropenic cancer patients within the United States
Authors: Lawrence Yaacov Richard , Urban Damian , Sella Tal , Bar Jair , Berger Raanan , Goldstein Jeffrey , Shacham-Shmueli Einat , Symon Zvi , Golan Talia 
Published: May 2016

Abstract
Introduction:
Hospital Volume is associated with improved outcomes in cancer surgery, and some aspects of cancer care. The influence of hospital volume on outcomes in neutropenic patients is unknown. Neutropenia secondary to bone-marrow suppression is a common, and dangerous complication of cancer treatment. Known factors associated with increased mortality include age, race and co-morbidities. We hypothesized that large-volume hospitals would have reduced mortality rates for neutropenic patients compared with small-volume institutions.
Methods:
We utilized the NIS database of the Healthcare Cost and Utilization Project, focusing on the years 2000-2006. Only inpatient episodes with a diagnosis of both neutropenia and cancer were included in the study. Hospital volume was defined as the number of neutropenic cancer episodes listed for each institution per year. Mortality was defined as death during admission.
Results:
155,512 hospitalizations were included in the study, from 3049 different institutions. Median age was 60 years. The overall inpatient mortality was 7.1%. Mortality increased with patient age, for instance amongst those aged 30-39 years it was 4.3% compared to 10.7% for those aged 70-79 years. The average number of “neutropenic” inpatient episodes in each institution per year ranged from less than one to 225 (median 22.7). The population was split into four equal groups based upon hospital volume. Mortality was 8.5%, 7.7%, 7.0% and 5.2% for each group (from lowest to highest volume), likewise% discharged home was 77.3%, 82.4%, 85.2% and 90.1% (for both p&lt;0.001). In a logistic regression model incorporating age, race and sex, ‘hospital volume’ remained statistically associated with reduced mortality (p&lt;0.001).
Conclusion:
Neutropenic patients hospitalized in large-volume institutions have a substantially lower mortality and a higher likelihood of returning home compared to those hospitalized at low-volume institutions. Our findings have implications for the setting in which phase I/II clinical trials of combination treatments with new biological agents and cytotoxic therapies be performed.
Citation Format: Yaacov Richard Lawrence, Damian Urban, Tal Sella, Jair Bar, Raanan Berger, Jeffrey Goldstein, Einat Shacham-Shmueli, Zvi Symon, Talia Golan. Hospital volume determines mortality amongst neutropenic cancer patients within the United States. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A17.
Abstract LB-A23: Galectin-8 favors growth of endothelial cells and induces production of extracellular matrix by cancer associated fibroblasts
Authors: Gal Peter , Varinska Lenka , Kello Martin , Mojzis Jan , Dvorankova Barbora , Smetana Karel 
Published: May 2016

Abstract
Galectins (Gal) belong to a family of endogenous lectins specifically recognizing sugar motives and playing an important role in the biology of tissue repair and cancer. It has been shown that the tandem-repeat lectin Gal-8 plays an essential role in tumor angiogenesis by improving endothelial cell migration and capillary tube formation. Interestingly by a more prominent way than the proangiogenic growth factor VEGF. Thus, new question arises, i.e. does Gal-8 improves endothelial cell proliferation? To provide answer to that question the MTT and BrDu proliferation assays using HUVEC (human umbilical vein endothelial cells) as a model were used. We found that Gal-8 induces cell proliferation in combination with VEGF, but Gal-8 alone does not exhibit any significant effect. Furthermore, we studied whether human Gal-8 induces production of a bioactive extracellular matrix (ECM) scaffold by cancer associated fibroblasts (CAF). In parallel, the effect of Gal-8 on ECM production by human dermal fibroblasts (HDF) was studied as well. Adding Gal-8 to the culture medium led the CAF to generate a very fine structured 3D meshwork especially rich in fibronectin. Contrary, the ECM production by HDF was not that apparent. Since ECM-cell interactions play an important role in the ability of tumors to spread and form metastasis further research focused on roles of the tandem-repeat-type Gal-8 in other steps of tumorigenesis is warranted by present in vitro study.
This study was supported in part by the Grant Agency of Ministry of Education, Science, Research, and Sport of the Slovak Republic (VEGA-1/0404/15 and VEGA-1/0048/15) and the Agency for Science and Research under the contract no. APVV-0408-12 and APVV-14-0731.
Citation Format: Peter Gal, Lenka Varinska, Martin Kello, Jan Mojzis, Barbora Dvorankova, Karel Smetana Jr.. Galectin-8 favors growth of endothelial cells and induces production of extracellular matrix by cancer associated fibroblasts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A23.
Abstract LB-A24: Molecular alteration of SMAD4 in hindgut-derived colorectal tumors identifies a distinct subset of patients and is associated with worse recurrence-free survival
Authors: Smith Jesse Joshua , Lee Lik Hang , Chen Xi , Wu Chao , Pelossof Raphael , Nash Garrett M. , Temple Larissa R. , Guillem Jose G. , Weiser Martin R. , Paty Philip B. , Shia Jinru , Garcia-Aguilar Julio , Sawyers Charles L. 
Published: May 2016

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Friday, November 6.
Citation Format: Jesse Joshua Smith, Lik Hang Lee, Xi Chen, Chao Wu, Raphael Pelossof, Garrett M. Nash, Larissa R. Temple, Jose G. Guillem, Martin R. Weiser, Philip B. Paty, Jinru Shia, Julio Garcia-Aguilar, Charles L. Sawyers. Molecular alteration of SMAD4 in hindgut-derived colorectal tumors identifies a distinct subset of patients and is associated with worse recurrence-free survival. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A24.
Abstract LB-B09: Somatic mutation detection via sequencing using circulating tumor cell samples from patients with renal cell and prostate cancer
Authors: Amato Robert J. , Brobey Reynolds , Dehghani Mehdi , Rosenblatt Kevin , Souza Glauco , Tseng Hubert , Jensen Jeff , Ionescu-Zanetti Cristian 
Published: May 2016

Abstract
Introduction: Tumor genotyping using fluid samples such as blood can potentially allow tracking of dynamic changes in mutational profiles over time and allow better access than biopsies. We present a method to detect somatic mutations from a blood draw, where circulating tumor cell (CTC) enrichment above 10% of total cell numbers allows the use of standard gene panels typically used to analyze tissue-based biopsies.
Methods: Clinical samples were obtained from 9 prostate cancer (PC) patients and 6 renal cell cancer (RCC) patients, followed by CTC enrichment using the IsoFluxTM System. Cells were lysed and DNA amplified by whole genome amplification (WGA) using the NGS Kit (Fluxion Biosciences) and quantified via qPCR. CTCs defined as CK+, CD45- nucleated cells (DAPI+) for cell enumeration. Analytical samples were prepare by spiking tumor derived cell lines into whole blood and parallel analysis. Next-generation sequencing was performed using 3 targeted cancer panels on the Ion torrentTM PGM platform: the Ion ampliseqTM cancer hot spot panel (50 genes; 6 PC samples), Oncomine (143 genes; 3 PC samples), and a 29-gene panel of actionable mutations in RCC (6 samples). Data was analyzed using a customized variant calling/filtering pipeline. Variant filtering and functional interpretation was performed using VarSeqTM. All data was analyzed in a blinded manner.
Results: Our method was able to isolate CTCs from all patient samples. WGA DNA concentrations were at a range of 25-164 ng/μL (median, 69) in PC and 29-180 ng/μL (median, 69) in RCC. CTC purity after the first enrichment step was in 2.9-33.7% (median, 10.5%) of PC samples and 1.9-33% (median, 14.5%) of RCC; final CTC purity is estimated at 5-40%. We found 1 variant/sample using hotpot, 12/sample using Oncomine, and 3/sample using the RCC panel.
Conclusions: Our assay consistently detected somatic variants from blood draw using standard gene panels in both PC and RCC. Obtaining repeat tumor biopsies from patients during treatment and/or at time of progression is both challenging and impractical from a clinical perspective. Our assay provides molecular characterization using standard blood draws and will be prospectively validated in clinical trials.
Citation Format: Robert J. Amato, Reynolds Brobey, Mehdi Dehghani, Kevin Rosenblatt, Glauco Souza, Hubert Tseng, Jeff Jensen, Cristian Ionescu-Zanetti. Somatic mutation detection via sequencing using circulating tumor cell samples from patients with renal cell and prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B09.
Abstract LB-B15: A novel PI3K gamma isoform selective small molecule kinase inhibitor demonstrates single agent anti-tumor activity and enhanced combination activity with checkpoint blockade in syngeneic mouse models of cancer
Authors: Saha Saurabh , Zhang Linping , Hoock Thomas , Aronov Alex , Mahajan Sudipta , Boyd Michael , Come Jon , Damagnez Veronique , Dworakowski Wojciech , Khare-Pandit Suvarna , LeTiran Arnaud , Moody Cameron , O'Dowd Harwin , Prezioso Joseph , Roday Setu , Zhang Xiaoyan M. 
Published: May 2016

Abstract
Immune checkpoint inhibitors have generated impressive clinical responses, however, a number of patients and cancer types remain resistant to checkpoint blockade. Immunosuppressive cells such as Tregs and MDSCs in the tumor microenvironment are hypothesized to mediate this resistance. The gamma (γ) isoform of PI3K has long been known to modulate myeloid and lymphocyte cell migration and function, including trafficking of monocytic and granulocytic cells into inflamed tissues such as tumors. Here we report the identification and characterization of BVD-723, a PI3Kγ selective small molecule kinase inhibitor which demonstrated single agent and enhanced combination anti-tumor activity[xx]with either an anti-PD-1 or anti-CTLA-4 antibody. In a mouse syngeneic colon cancer model,[xx]BVD-723 in combination with anti-PD-1 or anti-CTLA-4 resulted in complete regression[xx]of tumors in 35% (7/20) and 60% (12/20) of animals treated with each antibody respectively [versus 0% (0/20) and 5% (1/20) with either antibody alone]. Interestingly, the anti-tumor activity was coupled with a decrease in tumor infiltrating Tregs, granulocytic MDSCs, CD4+ T cells and an increase in the CD8+/Treg ratio, suggesting that inhibition of PI3Kγ by BVD-723 promotes immune-reactivation in the tumor microenvironment. Additionally, BVD-723 demonstrated potent synergy with an anti-PD-1 antibody in a syngeneic mouse model of lymphoma. Single agent BVD-723 activity was also observed in syngeneic mouse models of pancreas, colon, lymphoma and bladder cancers. Results from completed safety pharmacology, toxicology and in vivo efficacy studies support clinical evaluation of BVD-723[xx]as a monotherapy or in combination with the checkpoint inhibitors in cancer.[xx]
Citation Format: Saurabh Saha, Linping Zhang, Thomas Hoock, Alex Aronov, Sudipta Mahajan, Michael Boyd, Jon Come, Veronique Damagnez, Wojciech Dworakowski, Suvarna Khare-Pandit, Arnaud LeTiran, Cameron Moody, Harwin O'Dowd, Joseph Prezioso, Setu Roday, Xiaoyan M. Zhang. A novel PI3K gamma isoform selective small molecule kinase inhibitor demonstrates single agent anti-tumor activity and enhanced combination activity with checkpoint blockade in syngeneic mouse models of cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B15.
Abstract LB-B22: CCNY2 promotes lung cancer cell migration and invasion via regulating F-actin expression
Authors: zhao xiaoting , Jiang Mei , Yue wentao 
Published: May 2016

Abstract
Background: Cyclin Y (CCNY) is a novel cyclin and is highly conserved in metazoan species. Cyclin Y mRNA has several transcripts and only ccny1 and ccny2 has been documented. A potential CDK partner of Cyclin Y is PFTAIRE kinase (PFTK1). In hepatocellular carcinoma, cell motility and invasion was enhanced by PFTK1 expression. But the function of CCNY1 and CCNY2 on cell migration and invasiveness has not been reported yet. Methods: Recombined plasmids carrying CCNY1 and CCNY2 were constructed and transfected to H1299 cells to obtain CCNY up-regulation cells. A lentivirus-based RNAi delivery system was used to inhibit CCNY mRNA expression. The role of CCNY in cell motility and invasion was investigated using wound healing and transwell assay. The protein levels in lung cancer cells were determined by western-blot, immunofluorescence technique and high-content cell analysis. Mouse xenograft experiments were carried out to study the metastasis ability of CCNY1 and CCNY2 in vivo. Immunohistochemistry was used to detect the CCNY protein level of lung cancer tissues. Results: cell motility and invasion activity were inhibited and MET (Mesenchymal - Epithelial Transition) was caused by down-regulating of CCNY in 95D and H1299 cells. CCNY2 could enhance cell migration and invasion activity in vivo and vitro. The F-actin level was regulated by CCNY2 expression. In non-small cell lung cancer tissues, CCNY2 was highly expressed and the CCNY2 expression was associated with histological grade. Conclusion: CCNY2 was firstly detected in lung cancer cells and non-small cell lung cancer tissues. Our findings demonstrated CCNY2 not CCNY1 promoted cell motility and invasion by regulating the expression of F-actin and modulating intracellular cytoskeletal components.
Citation Format: xiaoting zhao, Mei Jiang, wentao Yue. CCNY2 promotes lung cancer cell migration and invasion via regulating F-actin expression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B22.