bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3843: The potential of heat shock proteins 70/90 as molecular therapeutic targets in breast cancer
Authors: Kim Ho Young , Kim Sanghwa , Kim Lee Su 
Published: August 2018

Abstract
Purpose: Heat shock proteins (hsps) are molecular chaperones that are synthesized by cells in response to various stress conditions. The expression of hsps have been shown to be associated with carcinogenesis and the expression of hsps have been implicated in the biological behavior of tumors. Recently, hsps have emerged as novel molecular targets in anticancer protocols. The objectives of this study were to investigate the significance of hsp 70/90 in breast carcinogenesis and effect of geldanamycin (a blocker of hsp 90) and quercetin (a blocker of hsp 70) on growth inhibition in different breast cancer cell lines. Methods: Breast tissues from 82 patients were obtained between January 2010 and December 2010 at the Division of Breast & Endocrine Surgery, Hallym University Sacred Heart Hospital. Expression of hsp 70/90 was studied by immunohistochemistry (IHC) on tissue sections from 63 breast carcinomas and 19 benign breast tissues. Both cytoplasmic and nuclear expression was measured. Expression of hsp 70/90 was also analyzed by use of a Western blot with the breast cancer cell lines. We next investigated the effects of blockers of hsp 70/90 on cell growth of the human breast cancer cell lines. Results: More prominent hsp 90 expression was observed in malignant tissue than in benign tissue by both cytoplasmic and nuclear IHC staining (p&lt;0.001, p&lt;0.001). Nuclear hsp 90 expression was associated with a positive lymph node status (p=0.003) and the presence of poorly differentiated tumors (p=0.028). Expression of hsp 70 was not different in malignant and benign tissues as determined by both cytoplasmic and nuclear IHC staining. The breast cancer cell lines all expressed hsp 70/90. Geldanamycin markedly inhibited the cell growth of these breast cancer cell lines in a dose dependent manner and induced apoptosis in the cell lines. Quercetin inhibited cell growth of the cell lines less efficiently. Conclusion: The expression of hsp 90 was associated with breast carcinogenesis and the presence of more aggressive tumors. Geldanamycin inhibited cell growth of hsp 90 expressing breast cancer cell lines. We suggest that Hsp 90 may be a possible molecular target against breast cancer.
Citation Format: Ho Young Kim, Sanghwa Kim, Lee Su Kim. The potential of heat shock proteins 70/90 as molecular therapeutic targets in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3843.
Abstract 3847: Inhibition of GCN2 sensitizes ASNS-downregulated cancer cells to asparaginase by disrupting amino acid response
Authors: Nakamura Akito , Nambu Tadahiro , Ebara Shunsuke , Hasegawa Yuka , Toyoshima Kosei , Tsuchiya Yasuko , Tomita Daisuke , Fujimoto Jun , Kurasawa Osamu , Takahara Chisato , Kawamura Ayumi , Nishigaki Ryuichi , Satomi Yoshinori , Hata Akito , Hara Takahito 
Published: August 2018

Abstract
General control nonderepressible 2 (GCN2) plays a major role in cellular response to amino acid limitation. Although maintenance of amino acid homeostasis is critical for tumor growth, little is known concerning the contribution of GCN2 to cancer cell proliferation and its potential as a therapeutic target. In this study, we demonstrate that inhibition of GCN2 with small-molecule compounds sensitizes cancer cells to anti-leukemic agent asparaginase (ASNase). We first tested acute lymphoblastic leukemia (ALL) cells and showed that treatment with GCN2 inhibitors rendered ALL cells sensitive to ASNase by preventing the induction of asparagine synthetase (ASNS). The prevention of ASNS expression suppresses asparagine synthesis and thus inhibits protein translation. In addition, comprehensive gene expression profiling revealed that the combined treatment induced stress-activated MAPK pathway and thereby triggering apoptosis. Using cell-panel analyses, we also identified a clear synergy between GCN2 inhibitors and ASNase in acute myelogenous leukaemia (AML) and pancreatic cancer cells besides ALL. Notably, basal ASNS expression levels were significantly correlated with sensitivity to combinatorial treatment. Furthermore, the combination displayed robust antitumor activity in mouse xenograft models of ALL, AML, and pancreatic cancer. These results demonstrate a novel mechanistic insight into a role of GCN2 in amino acid response and provide a rationale for further investigating GCN2 inhibitors for the treatment of cancer.
Citation Format: Akito Nakamura, Tadahiro Nambu, Shunsuke Ebara, Yuka Hasegawa, Kosei Toyoshima, Yasuko Tsuchiya, Daisuke Tomita, Jun Fujimoto, Osamu Kurasawa, Chisato Takahara, Ayumi Kawamura, Ryuichi Nishigaki, Yoshinori Satomi, Akito Hata, Takahito Hara. Inhibition of GCN2 sensitizes ASNS-downregulated cancer cells to asparaginase by disrupting amino acid response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3847.
Abstract 3849: Identification and optimization of chemical compounds as potent agonists of human STING with anticancer activity in mice
Authors: Wu Jian Hui 
Published: August 2018

Abstract
The host STING pathway plays a critical role in innate immune sensing of cancer, that drives type-I interferons (IFNs) production and promotes aggressive antitumor responses. Compound DMXAA is an agonist of mouse STING (mSTING) and demonstrated potent antitumor activities in several tumor models, including melanoma. However, DMXAA cannot activate human STING (hSTING), which provides a possible rationale for its failure in recent clinical trial. In this project, we aim to identify novel chemical compounds as potent STING agonists. By combining structure-based drug design and in vitro assays, we have discovered two initial hits as STING agonists that belong to two different chemical scaffolds. Direct binding of our compounds with hSTING was confirmed by Surface plasmon resonance (SPR) analysis. Chemical optimization of our initial hits has led to compound #150 and #171. We demonstrated that #150 and #171 at 10 uM have substantially activated STING pathway in HEK293 cells that were transiently transfected with plasmid expressing hSTING. Compound #171 at 20 uM potently activated STING signaling in human THP-1 cells that harbor hSTINGHAQ as well as PBMC cells from a panel of human donors. Importantly, with DMXAA as the control, we demonstrated that #171 at 20 mg/kg via i.p. has significant antitumor effect against TRAMP-c1 tumor in C57/BL6 mice.
Citation Format: Jian Hui Wu. Identification and optimization of chemical compounds as potent agonists of human STING with anticancer activity in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3849.
Abstract 3861: 3D ex vivo PDX cell model screening to better predict in vivo outcome
Authors: Xu Xiaoxi , Li Zhongliang , Liu Yan , Meng Fanxiu , Lu Yu , Zhang Songling , Dong Chunlan , Xing Frank , Shi Qian 
Published: August 2018

Abstract
Patient-derived xenograft (PDX) models have been highly demanded in preclinical drug discovery and development due to several advantages over conventional 2D cell culture system: 1) reflection of the heterogeneity, molecular and histopathologic signatures of the original tumor than cell lines or genetically engineered mouse models, and 2) certain degree of correlation of their drug-response profiles with clinical response. Certain limitations of using PDX models, however, do exist, including low throughput in candidate drug screening, lack of dose-response curves, high cost and time-consuming studies, and progressive loss of human-derived stromal elements over passages. To overcome these disadvantages, we sought to develop ex vivo 3D assay format on cells isolated from early passage PDX models, and provide genetic mutation information to better interpret results. Moreover, we attempted to incorporate immunotherapy strategy into the 3D system as well. We have recently built up an ex vivo cell bank containing more than 300 frozen ex vivo tumor cells dissociated from freshly isolated PDX tumor tissues. We have collected five panels of such frozen ex vivo cells, each panel representing more than 50 models in a specific tumor type. SOC compounds corresponding to each unique tumor panel were tested, and will be discussed. Moreover, we have established a 3D immune cell and ex vivo somatic tumor cell co-culture system to evaluate drug efficacy of immune checkpoint inhibitors aPD1, aPDL1 and CTLA4 antibodies either as single agent or in combination with small-molecule inhibitors. The data will be presented. In summary, we have developed a robust and reproducible 3D ex vivo assay platform for medium-throughput compound screening with bioinformatics information for data interpretation.
Citation Format: Xiaoxi Xu, Zhongliang Li, Yan Liu, Fanxiu Meng, Yu Lu, Songling Zhang, Chunlan Dong, Frank Xing, Qian Shi. 3D ex vivo PDX cell model screening to better predict in vivo outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3861.
Abstract 3865: ActivSignal platform technology for direct multiplex analysis of signaling pathway activation profiles
Authors: Alexandrov Ilya , Brandina Irina , Rahimi Nader , Sherman Michael , Yaglom Julia , Meyer Rosana , Ali Marwa , Ersoy Esma 
Published: August 2018

Abstract
The multiplex IPAD assay technology from ActivSignal monitors activity of 26 major signaling pathways by examining phosphorylation events or expression of more than 60 most relevant human and mouse protein targets. The technology uses antibodies against established and well known targets that reflect activities of canonical pathways. We utilize paired antibodies for each protein target for high specificity, and these pairs are carefully selected and tested. Only if both antibodies in a pair bind to their specific target molecule will the detection take place during the analysis phase - avoiding false hits. The IPAD assay can be used to profile samples made from cell culture, tissues, blood, etc. The IPAD assay requires only minute amounts of sample, which can be easily taken from your precious sample where available amounts may be limited. Applications include:
Direct snapshot of signaling pathway activity rather than downstream effects.
Understanding the physiological effects of a drug.
What pathways are regulated in response to lead candidate drug?
Does the drug of interest cause biologically significant secondary and off target effects?
Evaluation of signaling pathway activities in response to shRNA, CRISPR, hormones, stresses and other treatments.
Elucidating the signaling proteome in a medium-throughput format (96-well format).
Profiling of tissue samples from patients and animals.
Signaling profiling of tumor biopsies.
In one application, our collaborators used the IPAD assay to understand signaling effects of a novel protein, TMIGD1, whose expression is markedly downregulated in renal cancer. The Activsignal platform analysis showed changes in activities of several major pathways, e.g. inhibition of cell cycle and cell proliferation after reintroduction of TMIGD1. In another application of our platform our collaborators studied the mechanism of action of a small molecule inhibitor that targets Hsp70. They used ActivSignal platform technology to profile signaling pathways in response to the inhibitor. They identified several pathways whose activities were affected by the inhibitor. ActivSignal is a breakthrough, low-cost tool for the analysis of signaling pathway activation profiles. It enables researchers to rapidly and efficiently gain insight into function of their favorite drug molecules, genes etc.
Citation Format: Ilya Alexandrov, Irina Brandina, Nader Rahimi, Michael Sherman, Julia Yaglom, Rosana Meyer, Marwa Ali, Esma Ersoy. ActivSignal platform technology for direct multiplex analysis of signaling pathway activation profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3865.
Abstract 3866: A novel assay for rapid identification and isolation of single intact circulating tumor cells
Authors: Huang Lili , Shen Le , Yu Min , Liu Paul 
Published: August 2018

Abstract
We present a magnetic bead assay for rapid identification and isolation of single intact circulating tumor cells (CTCs). Cell viability is essential for cell culture and downstream molecular analysis. Many CTC isolation technologies, including CellSearch, uses fixation and fluorescent imaging for CTC detection that the captured CTCs are no longer viable. This novel assay utilize magnetic sensing for CTC identification, and therefore preserve CTC integrity and viability. The assay is performed on a microelectronic chip which also generates spatially-patterned microscopic magnetic field to sort single CTCs. We evaluated the performance metrics of the assay with EGFP-expression breast cancer patient derived CTC cells mixed with peripheral blood mononuclear cells (PBMCs) in vitro. Cell suspensions were mixed with magnetic microbeads coated with anti-EpCAM antibodies and then isolated with a magnet. Different amount (20, 50, 100, 500) of CTCs from serial dilution were spiked into 5x10^6 human PBMCs labelled with Alexa Flour 488 anti-human CD45 antibodies. After the assay, no PBMCs are visible which shows high purity in recovered CTCs. Recovery rate, defined by the ratio of the mean of the recovered CTC count to the mean of the spiked CTC count, is in the range of 87% to 92% for the various CTC spiked-in amount. In each spiking experiment, triplicate measurement and controls are used. Total assay time is less than 80 minutes. Conclusion: A rapid assay for isolation and detection of CTCs from PBMCs is demonstrated which shows high recovery rate and viability. This novel assay has great potential for single intact rare cell isolation.
Citation Format: Lili Huang, Le Shen, Min Yu, Paul Liu. A novel assay for rapid identification and isolation of single intact circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3866.
Abstract 3869: A nanofiber-based biosensor for ultrasensitive detection of serum CRP in melanoma
Authors: Lin Zuan-Tao , Li Yaxi , Wu Tianfu 
Published: August 2018

Abstract
Purpose: Early detection of melanoma is important to improve survival; however, the technology for accurate early diagnosis is still challenging. This study is to develop a novel polymeric biosensor that could provide superior sensitivity in the detection of potential early biomarkers (e.g., CRP) of melanoma.
Experimental Procedure: Our strategy is to construct a highly specific molecular recognition core and a highly responsive transducer made of conductive polypyrrole (PPy) nanofibers. Briefly, a polymeric matrix was produced by polymerization of acrylamide (AM), methylenebisacrylamide (MBAA), N-Isopropylacrylamide (NIPAAm) and CRP/CRP-aptamer complex first. Next, taking advantage of the porous structure of this NIPAAm-AM-CRP-aptamer/CRP polymeric matrix, we synthesized a polypyrrole-based conductive nanofiber structure using copper phthalocyanine-3,4',4'',4‴-tetrasulfonic acid tetrasodium salt (CuPT) as a dopant counterion in situ to achieve uniformly dispersed nanofibers within the polymeric network of NIPAAm-AM-CRP-aptamer/CRP. After removing CRP recombinant protein, we were able to obtain a robust CuPT-PPy/NIPAAm-AM polymeric sensor for the detection of CRP with high sensitivity and selectivity. Two-step signal amplification cascades were involved in this CRP-specific polymeric sensor: 1) CRP binding-induced polymeric network shrinkage; 2) shrinkage-triggered conductance change of the polymeric network. Therefore, serum CRP levels could be quantitatively analyzed through monitoring the conductance change caused by polymeric network shrinkage upon aptamer-CRP binding.
Results: The limit of detection (LOD) of the polymeric sensor for detection of human recombinant CRP could reach 10^−19 M. The Fourier transform infrared (FT-IR) spectra confirmed the chemical structure of the polymeric network, and the morphology was observed using scanning electron microscopy (SEM) and atomic force microscopy (AFM). The results of FT-IR reveal that CuPT-PPy nanofiber was successfully synthesized in situ. The nanostructure of the nanofibers was clearly observed using SEM and AFM, indicating that the diameter of nanofiber is about 20 nm. This CRP-specific biosensor and a commercial CRP ELISA kit were used to perform side-by-side measurement of serum CRP in melanoma patients.
Conclusion: Our results indicated that this CRP-specific conductive polymeric senor is highly sensitive and selective in accurately discriminating melanoma patients from healthy controls. Such a flexible conductive polymeric biosensor may hold great promise as a point-of-care device in the diagnostics of melanoma or other cancers.
Citation Format: Zuan-Tao Lin, Yaxi Li, Tianfu Wu. A nanofiber-based biosensor for ultrasensitive detection of serum CRP in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3869.
Abstract 3878: Drug-loaded microparticles as a treatment approach for pancreatic cancer
Authors: Munoz-Sagastibelza Maria , Okome Oluwafeyikemi , Sanchez Jenny E. Paredes , Palileo Albert , Burkhart Catherine , Martello-Rooney Laura 
Published: August 2018

Abstract
Pancreatic cancer is the fourth leading cause of cancer death in the United States with only 7% of diagnosed patients surviving 5 years. Most pancreatic cancer patients are not surgical candidates due to advanced stage at diagnosis. Also, current systemic chemotherapies have not been very effective at decreasing tumor burden. Poly(lactic-co-glycolic acid)-based (PLGA) microparticles (MPs) are a promising tool for localized drug delivery within the tumor due to their biocompatibility, flexibility in drug encapsulation and extended drug release. The present study investigated whether gemcitabine-loaded microparticles (GMPs), paclitaxel-loaded microparticles (PMPs) or sequential treatment of both, in comparison with blank (no drug) MPs, systemic treatments and no treatment control, are able to promote cancer cell killing effects and modulate drug resistance in vitro and in vivo. We previously showed in vitro studies with PANC-1 cells and we were able to complete the MPs studies with a second human pancreatic cancer cell line, MIAPaCa-2. In both cases, we tested the effect of single and combination treatments on two well-known resistance markers for gemcitabine, ribonucleotide reductase catalytic subunit M1 and cytidine deaminase, as well as on the promotion of cell death measuring cleaved caspase-3 (CC3). When treated with GMPs alone, both markers went up suggesting an increase in resistance against gemcitabine. Interestingly, both cell lines treated with PMPs alone showed an increase in CC3 expression and a significant decrease in the expression of both markers. Subsequently, we tested the in vivo efficacy of MPs by direct injection into established subcutaneous MIAPaCa-2 tumors in nude mice. Following four weeks of treatment, the tumors were excised, biopsied for protein analysis and frozen in OCT to allow visualization of fluorescent MPs and detect apoptosis by immunofluorescence. We also want to evaluate reactive oxygen species production; where we expect to see an increase in the MPs treated groups. This analysis is in progress. In conclusion, we observed a decrease in cell viability and drug resistance proteins in vitro using the drug-loaded microparticles in two grade 3 (or high grade) pancreatic cancer cell lines. The described drug delivery method has the potential to be a more efficient treatment modality than systemic gemcitabine and paclitaxel against early stage and locally advanced pancreatic cancer.
Citation Format: Maria Munoz-Sagastibelza, Oluwafeyikemi Okome, Jenny E. Paredes Sanchez, Albert Palileo, Catherine Burkhart, Laura Martello-Rooney. Drug-loaded microparticles as a treatment approach for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3878.
Abstract 3879: Enhancement of tumor penetration by drug-loaded nanoparticles: An innovative targeted strategy for neuroblastoma
Authors: Ponzoni Mirco , Brignole Chiara , Emionite Laura , Bruno Silvia , Guarnieri Daniela , Sitia Leopoldo , Bauckneht Matteo , Buschiazzo Ambra , Rossi Andrea , Paolo Daniela Di , Perri Patrizia , Curnis Flavio , Gori Alessandro , Sementa Angela Rita , Cilli Michele , Pompa Pier Paolo , Sambuceti Gianmario , Corti Angelo , Pastorino Fabio 
Published: August 2018

Abstract
Background: Anti-cancer drugs-loaded targeted nanocarriers can reduce side-effects and improve therapeutic efficacy in preclinical studies. However, poorly perfused and dysfunctional tumour vessels limit the transport of the payload into the parenchyma of solid tumours. The use of tumour-penetrating nanocarriers might enhance tumour penetration and anti-tumour effects.
Methods: A consensus motif, mediator of tissue penetration (TP) was added to a previously characterized neuroblastoma (NB)-targeting peptide (pep). In vitro NB cell association and internalization of TP-pep, either free or coupled to Stealth Liposomes (SL), were tested by FACS and confocal microscopy. In vitro cytotoxic potential of a novel doxorubicin (DXR)-loaded liposomal (TP-pep-SL[DXR]) was evaluated by MTS assay. Three mouse xenograft models mimicking the growth and spread of NB in humans (injection routes: subcutaneous; adrenal gland; tail vein) were enrolled to examine in vivo penetration, vascular permeability, tumour glucose consumption and sensitivity in response to TP-pep-SL[DXR].
Results: Compared to pep, TP-pep increases its cellular association in vitro on cell lines and cells derived from NB patients. When coupled to SL, TP-pep enhances liposomes penetration and cytotoxic effects in vitro and increases binding and penetration in a mouse model of NB. Moreover, in vivo accumulation of Evans Blue dye within the tumour mass reveals that TP-pep-SL[DXR] increases the tumour vascular permeability into NB tumour mass, but not in non-tumour tissues. Compared to pep-targeted liposomes, TP-pep-SL[DXR] leads to an increased anti-NB effect towards all the animal models tested.
Conclusion: Our findings demonstrate that the enhancement of tumour penetration by drug-loaded nanoparticles might represent an innovative targeted strategy for NB.
Citation Format: Mirco Ponzoni, Chiara Brignole, Laura Emionite, Silvia Bruno, Daniela Guarnieri, Leopoldo Sitia, Matteo Bauckneht, Ambra Buschiazzo, Andrea Rossi, Daniela Di Paolo, Patrizia Perri, Flavio Curnis, Alessandro Gori, Angela Rita Sementa, Michele Cilli, Pier Paolo Pompa, Gianmario Sambuceti, Angelo Corti, Fabio Pastorino. Enhancement of tumor penetration by drug-loaded nanoparticles: An innovative targeted strategy for neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3879.