bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1596: Detection of PD-L1 in cell surface vimentin positive circulating tumor cells is associated with poor survival in cancer patients
Authors: Satelli Arun , Brownlee Zachary , Noh Hyangsoon , Meng Qing H. , Kopetz Scott , Overman Michael , Li Shulin 
Published: August 2015

Abstract
Circulating tumor cells (CTCs) are the cells that detach from the primary tumor of patients and enter in to the blood stream and these can be represented as the seeds of metastasis. Increasing evidence has shown the detection of circulating tumor cells (CTCs) from blood of cancer patients parallels with tumor burden and is associated with poor prognosis. Although CTC counts change indicates a good modality to detect therapeutic response to drug treatments, there is an increasing need of a reliable marker that can be used to predict survival in cancer patients. One of the most prevalent markers detected in cancer patients is the cell surface glycoprotein called PD-L1 (also called B7-H1 and CD274). Aberrant expression of PD-L1 has been reported in several cancer types. Here in this study we tested the hypothesis that detection of PD-L1 in CTCs is associated with poor prognosis. To validate the hypothesis, we isolated cell-surface vimentin (CSV) positive CTCs from colorectal cancer patients using 84-1 method and analyzed for PD-L1 expression. Our results indicated that PD-L1 detection in CTCs was associated with poor overall survival (HR, 2.43; 95% CI, 1.11 to 5.35; p, 0.0264) in colorectal cancer patients undergoing treatment. These findings thus suggest that PD-L1 detection in CSV CTC could serve as a new prognostic tool. We further extend our observations in other types of cancers including breast, prostate and sarcoma.
Citation Format: Arun Satelli, Zachary Brownlee, Hyangsoon Noh, Qing H. Meng, Scott Kopetz, Michael Overman, Shulin Li. Detection of PD-L1 in cell surface vimentin positive circulating tumor cells is associated with poor survival in cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1596. doi:10.1158/1538-7445.AM2015-1596
Abstract 1598: Isolation and characterization of circulating melanoma cells by size filtration and fluorescent in situ hybridization
Authors: Yanagita Masahiko , Luke Jason J. , Paweletz Cloud P. , Ivanova Elena , Kirschmeier Paul T. , Hodi Stephen F. , Jänne Pasi A. 
Published: August 2015

Abstract
Somatic mutations in BRAF are predictive of the clinical efficacy of BRAF and/or MEK inhibitors for advanced melanoma. Resistance to treatment is observed for most patients despite a high response rate to kinase inhibitors. While repeated tumor biopsy is the gold standard for evaluating genetic changes following treatment, this is not generally feasible. The analysis of circulating melanoma cells (CMCs) has the potential to be a non-invasive means of interrogating the biology underlying response and resistance.
Here we report on the isolation, detection, and characterization of CMCs from patients using size filtration followed by immunoflourescence and/or fluorescent in situ hybridization (FISH) analyses. Blood from a cohort of 20 patients with advanced melanoma was collected in an initial proof of concept experiment. CMCs were identified in 14 out of 20 melanoma blood samples (70%) with a range of 2.5-99 CMCs per 3mL of blood by immunofluorescence (IF) using a cocktail of 4 melanoma specific antibodies (HMB45, MART-1, Tyrosinase and MiTF). Cells that appeared tumor like by microscopy, but that did not stain for CD45 or the cocktail of melanoma specific antibodies were also detected. To further characterize these cells, FISH was performed with a set of 4 melanoma-specific probes (RREB1, MYB, Centromere 6, CCND1). In a cohort of 13 patients with melanoma specimens that had paired blood specimens, CMCs were detected in all 13 specimens ranging from 7.2-76 CMCs per 3mL of blood with more identification by FISH in 10 out 13 samples. Additionally, cells that were double negative by IF were observed to be positive by FISH.
CMCs are detectable in the majority of patients with advanced melanoma. Use of IF and FISH can help detect and characterize CMCs. These tools will be useful in characterizing treatment related changes in CMCs.
Citation Format: Masahiko Yanagita, Jason J. Luke, Cloud P. Paweletz, Elena Ivanova, Paul T. Kirschmeier, Stephen F. Hodi, Pasi A. Jänne. Isolation and characterization of circulating melanoma cells by size filtration and fluorescent in situ hybridization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1598. doi:10.1158/1538-7445.AM2015-1598
Abstract 1607: Identification of low number circulating tumor cells (CTCs) for cancer treatment monitoring
Authors: George Thomas J. , Sheng Weian , Varillas Jose I. , Liu Chen , Fan Z. Hugh 
Published: August 2015

Abstract
For most solid tumors, the clinical use of CTCs is limited by current instrument restrictions on detection of infrequent CTCs. Based on the FDA-approved criteria used in current CTC detection instruments, we developed a microfluidic device capable of capturing, enumerating and releasing low numbers of CTCs in the peripheral blood of patients with solid tumors. The device is the size of a microscope slide, consisting of an inlet, an outlet, and eight parallel channels connecting them. Micromixers inside the channels enhance interactions between CTCs and capture agents on the channel surfaces. Epithelial cell-adhesion molecule (EpCAM) antibodies are immobilized onto the surfaces via avidin-biotin chemistry. A blood sample from a cancer patient is introduced through the inlet. Cells captured by anti-EpCAM studded channels are verified as CTCs using triple-color IHC definitions (EpCAM+, cytokeratin+, CD45-, and DAPI+). Using pancreatic cancer as a model for a low frequency CTC condition, device capture efficiency and cell purity was tested under various flow rates (shear stresses) using L3.6pl cells spiked into blood. Capture efficiency was defined as the% of target cells isolated relative to target cells present in a sample, representing device sensitivity. Cell purity was defined as the% of target cells isolated relative to all cells captured (both target and non-target cells), representing device specificity. Capture efficiency (90%) and cell purity (84%) were further optimized by changing the flow rate. A higher flow rate resulted in higher cell purity as non-target bound cells are dislodged by shear forces. This capability of parameter adjustment and performance control is enabled by the microfluidics platform used as opposed to CTC isolation using other commercially approved technologies. The device was then clinically tested in detecting CTCs and monitoring the response to anti-cancer drug treatment in patients with advanced pancreatic cancer. We identified CTCs in 113 out of 115 clinical blood samples (98%). CTC enumeration (CTC number/mL of blood) both correlated with and predated changes in the radiographic tumor size over the treatment period, ranging from 10 to 35 cycles (2 weeks per cycle) of therapy. Microfluidic devices possess the capacity to enumerate infrequent CTCs which also appear to correlate with treatment response.
Note: This abstract was not presented at the meeting.
Citation Format: Thomas J. George, Weian Sheng, Jose I. Varillas, Chen Liu, Z. Hugh Fan. Identification of low number circulating tumor cells (CTCs) for cancer treatment monitoring. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1607. doi:10.1158/1538-7445.AM2015-1607
Abstract 1608: CTC categorization: Subpopulations of CTCs and their potential clinical significance
Authors: Xue Chengsen , Mc Closkey Thomas W. 
Published: August 2015

Abstract
Circulating tumor cells (CTCs) were previously rare events difficult to identify. In clinical practice, CTC enumeration has now been recognized for its prognostic value. Furthermore, as CTC technology has rapidly improved, CTCs are now readily available for further investigation. The tumor cells isolated from CTC instruments may be analyzed for molecular profiles and mutation screening. Here we propose three new subsets of CTCs: elongated CTC (EL-CTC), miniature CTC (Mini-CTC) and cluster CTC (CL-CTC). Elongated CTC have an elongated shape and some of these cells have an enlarged tail composed of the nucleus. The enlarged tail is formed during intravasation because of the less flexible nuclear membrane and these cells represent highly motile tumor cells. The mini-CTCs are much smaller than regular tumor cells and may be dormant and gain the advantage of escaping immune surveillance. The CTC clusters are formed by a group of tumor cells and lymphocytes as well as macrophages. There is strong evidence that these clusters are highly malignant. These three subsets are recognized morphologically and their unique features may directly relate to their functionality and clinical significance. Additional investigation in the area of CTC research, specifically enhanced understanding of CTC subpopulations, may lead to novel therapeutic approaches in oncology.
Citation Format: Chengsen Xue, Thomas W. Mc Closkey. CTC categorization: Subpopulations of CTCs and their potential clinical significance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1608. doi:10.1158/1538-7445.AM2015-1608
Abstract 1622: The AKT inhibitor reverses protein trafficking and inhibits tumor cell motility of p27-mislocalized osteosarcoma cells
Authors: Chen Xiang , Li Yiting , Nakka Manjula , Man Tsz Kwong 
Published: August 2015

Abstract
Osteosarcoma is the most common malignant bone tumor in children. The development of metastasis remains to be the leading cause of death in osteosarcoma. This clinical challenge urges the development of a novel therapeutic strategy to improve the survival of the metastatic patients. mTOR has recently been regarded as a potential target for metastatic osteosarcoma. However, because of its feedback loop in the pathway, it has become clear that inhibition of mTOR alone would not yield effective therapeutics. More importantly, it is still not clear if the mTOR upstream kinases phosphorylate other important molecules that can also promote metastasis. Our lab has recently demonstrated that a vast majority of osteosarcoma cases harbor cytoplasmic mislocalization of p27. p27 is a tumor suppressor gene that regulates normal cell cycle progression when it is localized in the nucleus. We and others have indicated that p27 acquires a new pro-metastatic function in the cytoplasm of osteosarcoma and other tumors. To evaluate if this observation has any therapeutic significance, our lab has created a set of p27 phosphomutants and found that specific phosphorylations (S10 and T198) are important for the pro-metastatic function in the cytoplasm. Furthermore, shRNA-mediated gene silencing experiments showed that knocking down the expression of p27 decreased the motility of metastatic LM7 cells. Since AKT, the upstream kinase of mTOR, has shown to phosphorylate p27, we tested if AKT inhibitors have any effect on the migration/invasion ability of three osteosarcoma cell lines (LM7, MG63 and G292) that harbor the p27 mislocalization. The results showed that both the AKT1/2 inhibitor and the PI3K/mTOR dual inhibitor PP242, but not mTORC1 inhibitor rapamycin, reduced the tumor cell migration/invasion ability. Interestingly, the inhibitors could also reverse the protein trafficking of p27 into the nucleus. These results suggest that the inhibitors may be able to inhibit the pro-metastatic function and restore the cell cycle inhibitory function of p27. Our long-term goal is to develop a precision medicine approach that will ultimately improve the outcome of metastatic osteosarcoma. By targeting the p27 mislocalization, we believe that we will develop a novel and clinically applicable therapeutic strategy that would eradicate metastatic osteosarcoma and improve the outcome of children affected by this tumor.
Citation Format: Xiang Chen, Yiting Li, Manjula Nakka, Tsz Kwong Man. The AKT inhibitor reverses protein trafficking and inhibits tumor cell motility of p27-mislocalized osteosarcoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1622. doi:10.1158/1538-7445.AM2015-1622
Abstract 1640: Exploiting the cytoskeletal filaments of neoplastic cells to potentiate a novel therapeutic approach
Authors: Trendowski Matthew 
Published: August 2015

Abstract
Although cytoskeletal-directed agents have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of neoplastic cells, they are all microtubule-based drugs, and there has yet to be any microfilament- or intermediate filament-directed agents approved for clinical use. There are many inherent differences between the cytoskeletal networks of malignant and normal cells, providing an ideal target to attain preferential damage. Further, numerous microfilament-directed agents, and an intermediate filament-directed agent of particular interest (withaferin A) have demonstrated in vitro and in vivo efficacy, suggesting that cytoskeletal filaments may be exploited to supplement chemotherapeutic approaches currently used in the clinical setting. Therefore, this talk is intended to expose academics and clinicians to the tremendous variety of cytoskeletal filament-directed agents that are currently available for further chemotherapeutic evaluation. The mechanisms by which microfilament directed- and intermediate filament-directed agents damage malignant cells will be discussed in detail in order to establish how the drugs can be used in combination with each other, or with currently approved chemotherapeutic agents to generate a substantial synergistic attack, potentially establishing a new paradigm of chemotherapeutic agents.
Note: This abstract was not presented at the meeting.
Citation Format: Matthew Trendowski. Exploiting the cytoskeletal filaments of neoplastic cells to potentiate a novel therapeutic approach. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1640. doi:10.1158/1538-7445.AM2015-1640
Abstract 1643: Discovery of 1-benzylquinazoline-2,4(1H,3H)-diones as novel and potent PARP inhibitors. SAR of the benzyl group
Authors: Cai Sui Xiong , Xu Qingbing , Wu Lizhen , Yin Feng , Hu Xiuhua , Wang Xiaozhu , Jiang Yangzhen , Bao Qingli , Wang Guoxiang , Zhang Xiuyan , Tian Ye Edward 
Published: August 2015

Abstract
Poly (ADP-ribose) polymerase (PARP) is a key enzyme for DNA repair and PARP-1 inhibitors have been shown to be effective against cancers with DNA repair defects, such as BRCA1 or BRCA2 mutations. Recently, European Medicines Agency (EMA) recommended approval of PARP-1 inhibitor Olaparib (AZD2281) for the treatment of ovarian cancers with BRCA mutations.
In this presentation, we will report our discovery of a series of 1-benzylquinazoline-2,4(1H,3H)-diones (BQD) as novel and potent PARP inhibitors. We will present SAR data for substituents at the 3- and 4-positions of the benzyl group of BQD, and the identification of IMP4297 as a clinical candidate. IMP4297 has advantages in vitro and in vivo over AZD2281. It is not only more potent but also more selective than AZD2281 in cell-based assays, and was 20-fold more efficacious than AZD2281 in a BRCA1 mutated MDA-MB-436 human breast cancer xenograft model. IND enabling studies for IMP4297 is in progress with IND submission planned in 12 months.
Citation Format: Sui Xiong Cai, Qingbing Xu, Lizhen Wu, Feng Yin, Xiuhua Hu, Xiaozhu Wang, Yangzhen Jiang, Qingli Bao, Guoxiang Wang, Xiuyan Zhang, Ye Edward Tian. Discovery of 1-benzylquinazoline-2,4(1H,3H)-diones as novel and potent PARP inhibitors. SAR of the benzyl group. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2015-1643
Abstract 1645: DNA-damaging compound 0404 effectively inhibits hepatocellular carcinoma by upregulation of miR-34a and miR-200c expression
Authors: Xia Caixia , Liu Yanning , Lou Guohua , Xu Xiao , Mao Long , Zheng Min 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the third most common cause of cancer deaths worldwide. DNA-damaging agents have a long history of use in cancer chemotherapy. Unfortunately, chemotherapeutic treatment strategies against HCC are very ineffective. We have screened of a novel DNA-damaging compounds, 0404, by using time-dependent cellular response (TCRP) based on unique TCRP DNA-damage signature. This new compound could induce apoptosis effectively in hepatocellular carcinoma at nM-degree concentration. Since microRNAs (miRNAs) have been show play critical roles in pathogenesis of HCC, the present study was aimed to investigate the role of miRNAs in the anticancer effects of 0404. We found that, HepG2 cells, which retain wild-type p53, were more sensitive to 0404 treatment than Huh7 cells, which with mutant p53. At IC50 and IC99 concentration, 0404 upregulated the expression of miR-34a and miR-200c, two major miRNA regulated by p53, in a dose- and time-dependent manner in HepG2 cells. Western blot analysis further show that up-regulation of miR-34a decreased SIRT1 expression, leading to an increase in acetylated p53 levels and also an increase in p53 targets such as p21 and PUMA. In addition, up-regulation of miR-200c decreased the expression of EMT-inducing transcription factors ZEB1 and ZEB2, which play key role in tumor invasion and metastasis. Furthermore, miR-34a or miR-200c inhibitors impaired the down-regulation of miR-34a or miR-200c target genes, respectively, by 0404 treatment, and partially impaired the tumor suppression effect of 0404. These results suggest that 0404 may be an attractive agent in chemotherapy for HCC, especially in HCC with wt p53, by regulation of miR-34a and miR-200c.
Financial support: This study was supported by the National Natural Science Fund (81272679) and the Major national S&T Projects (2013ZX09041003).
Citation Format: Caixia Xia, Yanning Liu, Guohua Lou, Xiao Xu, Long Mao, Min Zheng. DNA-damaging compound 0404 effectively inhibits hepatocellular carcinoma by upregulation of miR-34a and miR-200c expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1645. doi:10.1158/1538-7445.AM2015-1645
Abstract 1659: The non-cardiotoxic anticancer drug pixantrone targets topoisomerase II
Authors: Hasinoff Brian B. , Wu Xing , Patel Daywin , Yalowich Jack C. 
Published: August 2015

Abstract
Pixantrone is a new non-cardiotoxic aza-anthracenedione anticancer drug structurally related to anthracyclines and anthracenediones such as doxorubicin and mitoxantrone. Pixantrone is approved in the EU for the treatment of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. This study was undertaken to investigate both the mechanisms of its anticancer activity and its lack of cardiotoxicity. The reduced cardiotoxicity of pixantrone compared to doxorubicin may be due to the fact that it did not bind iron(II) or iron(III). Thus, unlike doxorubicin it would not be able to induce iron-based oxidative stress in the heart. Pixantrone did, however, form a weak complex with Cu(II). Pixantrone was 10-fold less damaging to neonatal rat myocytes than doxorubicin as measured by LDH release. As measured by EPR spectrometry pixantrone generated about two-fold higher levels of its semiquinone free radical than doxorubicin in the hypoxanthine-xanthine oxidase reducing system. Conversely, in intact K562 cells under nitrogen, doxorubicin produced much more semiquinone radical than pixantrone. The reduced myocyte toxicity and semiquinone-forming ability in K562 cells compared to doxorubicin may be due low cell accumulation of dicationic pixantrone. Multidrug resistant Pgp- (ABCB1) overexpressing MDCK/MDR cells were 40-fold cross resistant to pixantrone, compared to parental cells. Pixantrone bound to DNA much more strongly than doxorubicin as determined in a DNA melting point assay. Pixantrone targeted topoisomerase II as evidenced by its ability to inhibit kDNA decatenation, to produce linear double-stranded DNA in a pBR322 DNA cleavage assay, and to form covalent topoisomerase II-DNA complexes in a cellular ICE assay. Pixantrone was 3-fold cross-resistant to K562-derived etoposide-resistant cells. DNA double strand breaks produced by pixantrone assessed in a cellular γH2AX assay were also characteristic of a topoisomerase II-targeted drug. These results support the conclusion that pixantrone displays characteristics that are consistent with targeting topoisomerase II. Support: CIHR; a Canada Research Chair in Drug Development; R01 CA090787.
Citation Format: Brian B. Hasinoff, Xing Wu, Daywin Patel, Jack C. Yalowich. The non-cardiotoxic anticancer drug pixantrone targets topoisomerase II. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1659. doi:10.1158/1538-7445.AM2015-1659
Abstract 167: Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines
Authors: Ho Tsui-Ting , Zhou Nanjiang , Huang Jianguo , Koirala Pratirodh , Xu Min , Fung Roland , Wu Fangting , Mo Yin-Yuan 
Published: August 2015

Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system (CRISPR/Cas) has been recently shown to be a powerful genome-editing tool in a variety of organisms. However, these studies are mainly focused on protein-coding genes. The present study aims to determine whether this technology can be applied to non-coding genes. One of the challenges for knockout of non-coding genes is that a small deletion or insertion generated by the standard CRISPR/Cas system may not necessarily lead to functional loss of a given non-coding gene because of lacking an open reading frame, especially in polyploidy human cell lines. To overcome this challenge, we adopt a selection system that allows for marker genes to integrate into the genome through homologous recombination (HR). Moreover, we construct a dual guide RNA vector that can make two cuts simultaneously at designated sites such that a large fragment can be deleted. With these approaches, we are able to successfully generate knockouts for miR-21, miR-29a, lncRNA-21A, UCA1 and AK023948 in various human cell lines. Finally, we show that the HR-mediated targeting efficiency can be further improved by suppression of the non-homologous end joining pathway. Together, these results demonstrate the feasibility of knockout for non-coding genes by the CRISPR/Cas system in human cell lines.
Citation Format: Tsui-Ting Ho, Nanjiang Zhou, Jianguo Huang, Pratirodh Koirala, Min Xu, Roland Fung, Fangting Wu, Yin-Yuan Mo. Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 167. doi:10.1158/1538-7445.AM2015-167