bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1810: Three-dimensional microtissues as phenotypic screening model to identify radiation modifiers for breast cancer
Authors: Anastasov Natasa , Höfig Ines , Radulovic Vanja , Richter Sabine , Lichtenberg Jan , Kelm Jens M. , Thirion Christian , Atkinson Michael J. 
Published: August 2015

Abstract
Among breast cancer patients, radiation therapy resistance is a common problem in treatment. Overcoming the mechanisms responsible for this phenotype is an ongoing challenge. Options include repurposing established chemotherapeutics and the discovery of new radiosensitizing compounds. Three-dimensional (3D) microtissue models offer a physiological environment for efficient preclinical drug testing. We have adopted the 3D microtissue technology (Insphero, AG) to generate highly reproducible mammary cancer microtissues in a 96 well format. Two breast cancer cell lines (T47D and MDA-MB-361) were shown to be able to form 3D spheroids and grow in a reproducible manner over time. Validation of the phenotypic screen using breast cancer 3D microtissues was performed by HER2_shRNA knockdown, exposure to ionizing radiation and a panel of selected chemotherapeutic compounds. HER2_shRNA knockdown and irradiation decelerated growth, as proven by measuring the area of the cell spheroids after treatment. Of ten analyzed chemotherapeutics, vinblastine was the most effective compound, with docetaxel and doxorubicine being less effective in combination with radiation. To investigate the response in a model closer to the in vivo situation we investigated the response of heterotypic 3D microtissues containing both fibroblasts and breast cancer cells. Drug treatment of these heterotypic 3D cultures confirmed treatment with radiation plus vinblastine to be additive in causing breast cancer growth inhibition. Additionally a histological method to embed 3D microtissues in paraffin was established. The expression of the proliferation marker Ki67 and the apoptosis marker active Caspase 3 was evaluated in MDA-MB-361 cells after irradiation and concurrent vinblastine treatment. Such combined treatment caused prominent 3D microtissue damage - defined as extensive staining of active Caspase 3 and less Ki67. This suggests that combining vinblastine and radiation may be an effective radiation sensitizing strategy.
Citation Format: Natasa Anastasov, Ines Höfig, Vanja Radulovic, Sabine Richter, Jan Lichtenberg, Jens M. Kelm, Christian Thirion, Michael J. Atkinson. Three-dimensional microtissues as phenotypic screening model to identify radiation modifiers for breast cancer. [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 1810. doi:10.1158/1538-7445.AM2015-1810
Abstract 1811: Correlations of COX2 expressions in circulating tumor cells (CTCs) and response to radiotherapy in head and neck squamous cell carcinoma (HNSCC)
Authors: Wang Feng , Xie Xiaoqi , Wang Zhen , Li Ping 
Published: August 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) frequently involves metastasis at diagnosis. Circulating tumor cells (CTCs), captured as “liquid biopsy”, can provide real-time clinical information on prognosis, therapy choice and drug response and resistance. Cyclooxygenase 2 (COX-2), a key enzyme involved in prostaglandin production, participates in inflammatory and neoplastic processes. It is expressed by various tumours and contributes to carcinogenesis. Previous study showed that expression of COX2 in HNSCC tumor tissue samples is associated with clinical response to radiotherapy. The aim of study is to investigate whether expression of COX2 in CTCs could be used as a predict factor to clinical response to radiotherapy.An multiplex RNA in situ hybridization (RNA-ISH) method, named CanPatrol CTC enrichment technique, was used to isolate and categorize CTCs as epithelial, biophenotypic epithelial/mesenchyma, and mesenchymal phenotypes. A total of 51 pateints with HNSCC were enrolled into this study and assessed for CTC levels. Of these 51 pateints, 13 patients were evaluated for COX2 expression in CTCs before and after radiotherapy. The COX2 expression in one CTC or more was defined as positive presence. Primary end point was the overall objective response rate. At baseline, CTCs, ranging from 1 to 15, were identified from 36(70.59%) patients, and the median and mean values were 2 and 3(±3 SD) respectively. No significant correlations were observed between CTCs amounts and clinicopathological parameters. Thirteen (25.49%) patients had ≥2 CTCs both at the beginning and the end of treatment. COX2 expressions was identified in 6(46.15%) patients, which associated with ascending mesenchymal rate afterwards, and indicate a trend of less response to radiotherapy. Compared to 46.15% (6/13) of COX2-positive patients, disease control characterized as decreased CTCs/ mesenchymal CTCs after systemic radiotherapy was obtained in 53.85% (7/13) of COX2-negative (p&lt; 0.05). In summary, COX2-positive CTCs is a promising predictive factor for response to radiotherapy.
Citation Format: Feng Wang, Xiaoqi Xie, Zhen Wang, Ping Li. Correlations of COX2 expressions in circulating tumor cells (CTCs) and response to radiotherapy in head and neck squamous cell carcinoma (HNSCC). [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 1811. doi:10.1158/1538-7445.AM2015-1811
Abstract 1814: Effective auger electron radioimmunotherapy using modified anti-HER2 antibody with nuclear localizing signal
Authors: Li Huizi , Hasegawa Sumitaka , Kamada Tadashi , Saga Tsuneo 
Published: August 2015

Abstract
Objective: Radioimmunotherapy has an advantage in treating tumors scattered in the body. Auger electrons have high cell killing effect because of its high LET, and the short range can prevent damages to normal tissue. However, to achieve higher therapeutic effect, it is desirable to deliver Auger electrons into nucleus and locate close to DNA. The use of nuclear localizing signal (NLS) has been proposed to transport Auger electron emitters into nucleus. To evaluate the cytotoxicity of nuclear localized Auger electron emitter, we performed in-vitro assay using 111In-labeled anti-HER2 antibody attached with NLS peptides to human breast cancer cell lines overexpressing HER2.
Material and methods: Trastuzumab, a monoclonal antibody to HER2, was conjugated with CHX-A”-DTPA (DTPA) and derivatized with sulfosuccinimdyl-4-(N-maleimidomethyl) cyclohexane-1carboxylate (sulfo-SMCC) for reaction with synthetic 13-mer NLS peptides (CGYGPKKKRKVGG). 111In was labeled with either trastuzumab-DTPA or NLS-trastuzumab-DTPA, NLS-trastuzumab-DTPA-S carried approximately 4 NLS peptides per antibody and NLS-trastuzumab-DTPA-L carried 10. The radiochemical labeling of 111In-NLS-trastuzumab and 111In-trastuzumab was determined by HPLC. Human mammary epithelial cells HMEpC and two types of human breast cancer cells with low and high HER2 expression, MCF-7 and SKBR3, respectively, were employed for in-vitro study. Nuclear accumulation of 111In was measured in SKBR3 cells by subcellular fraction. Cell viability was evaluated with dye-based cell viability assays in all cell lines. DNA damages were examined with γ-H2AX immunohistochemistry in SKBR3 cells.
Results: Nuclear uptake of 111In was 1.3-1.5-fold higher in SKBR3 cells treated with 111In-NLS-trastuzumab than 111In-trastuzumab and increased depending on the number of NLS peptides. Cell viability was significantly reduced with 111In-NLS-trastuzumab comparing 111In-trastuzumab in SKBR3 cells. Both of 111In-NLS-trastuzumab had little or no cytotoxicity on MCF-7 cells and HMEpC cells. SKBR3 cells treated with 111In-NLS-trastuzumab-L showed more γ-H2AX foci than 111In-trastuzumab.
Conclusions: The cytotoxicity of 111In-NLS-trastuzumab was higher than that of 111In-trastuzumab by inducing more DNA damages in HER2-overexpressing human breast cancer cells. These data demonstrate that delivery of 111In into cell nucleus by anti-HER2 antibody harboring NLS is an effective strategy for targeted cell killing of the human cancer cells overexpressing HER2.
Citation Format: Huizi Li, Sumitaka Hasegawa, Tadashi Kamada, Tsuneo Saga. Effective auger electron radioimmunotherapy using modified anti-HER2 antibody with nuclear localizing signal. [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 1814. doi:10.1158/1538-7445.AM2015-1814
Abstract 1816: Impact of 5FU and radiation on replication of interferon-expressing adenovirus
Authors: Sell Jordan 
Published: August 2015

Abstract
Pancreatic Cancer is a disease for which there are very limited efficacious treatments, resulting in a 5-year survival rate for affected patients around only 6%. A recombinant oncolytic adenovirus (OAd-IFN) developed by our group to target pancreatic cancer utilizes enhanced oncolysis with an overexpression of the adenoviral death protein, enhanced infectivity with a genetically modified fiber, conditional replication targeted to pancreatic cancer using the Cox-2 promoter, and an expression of human interferonαto enhance the therapeutic effects of chemotherapy and radiation through the antitumor effects of the cytokine. Our previous work analyzing the therapeutic abilities of IFN expressing vectors in human pancreatic cancer xenografts in immonudeficient nude mice and in syngeneic hamster pancreatic cancer nodules in immunocompetent Syrian hamsters, showed a more evident antitumor effect of OAd-IFN in the latter models. This suggests the success of OAd-IFN as an immune system stimulator, making it a promising candidate for combination therapy approaches. The goal of this study is to investigate the possibility for use of OAd-IFN as a therapy for pancreatic cancer in conjunction with 5FU and radiation. Specifically, the adenoviral replicative ability was measured within pancreatic cancer Mia-Paca 2 cells under various conditions of 5FU and radiation exposure. Replication was analyzed by a correlation to the increase in amount of viral DNA extracted from treated cells at two time points post infection. In two preliminary trials, cells were infected with the virus two days prior to receiving 5FU and radiation, and another group of cells was treated with 5FU before viral infection. Based on the initial data collected, radiation seemed to have no effect on viral replication. 5FU treatment prior to viral infection resulted in an increase in replication at low dose, and a decrease in replication with high dose, however, this effect was only seen at the first time point 3 days after infection. Similarly, 5FU treatment post infection showed a minor dose dependent inhibition of viral replication at high doses, with little to no effect observed in the low dose. Combining viral infection with 5FU appears to have an impact on the replication of OAd-IFN in vitro; however, further trials need to be done to explore the effect of various timing among viral infection and therapy treatments as well as different therapy concentrations and viral titers to further analyze the potential combination therapies.
Citation Format: Jordan Sell. Impact of 5FU and radiation on replication of interferon-expressing adenovirus. [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 1816. doi:10.1158/1538-7445.AM2015-1816
Abstract 1836: Triple negative breast cancer: Metabolomics and flux analysis to identify targets for drug development
Authors: Stewart Delisha A. , Winnike Jason , McRitchie Susan , Pathmasiri Wimal , Sumner Susan 
Published: August 2015

Abstract
To date, no targeted therapies are clinically available to treat triple negative breast cancer (TNBC). This highly aggressive form of breast cancer (BCa) derives its name from the absence of estrogen receptor (ER+), progesterone receptor (PR+), and HER2/neu receptor (HER2+). These receptors are expressed in other subtypes of BCa (i.e. Luminal, HER2-enriched) and have been successfully targeted with therapeutics such as Tamoxifen and Herceptin. New therapeutics are needed to improve the prognosis for patients with TNBC. Metabolomics and metabolic flux analysis (MFA) were conducted to reveal differences in TNBC cell lines compared with hormone receptor-positive cell lines (ER+ and +/-HER2+) prior to and following treatment with chemotherapy drugs. Two triple-negative (MDA-MB-231 and MDA-MB-468) and two hormone-responsive (BT474 and MCF-7) cell lines were compared before and after treatment with Taxol®/Paclitaxel. The metabolic profiles were assessed using 1H NMR broad spectrum metabolomics, MFA using [U-13C]-glucose and [U-13C]-glutamine enriched media, and cytokine profiling of the media. Broad spectrum metabolomics analysis demonstrated differences in the metabolic profiles between the TNBC and hormone-responsive cell lines in the absence of treatment, with a higher level of amino acids (e.g. alanine, glutamate, glutamine, glutathione), short chain fatty acids (isobutyrate, β-hydroxybutyrate), and nucleotides and nucleotide sugars (ADP, ATP, UDP-glucose, UDP-glucuronate) in the TNBC cell lines. Further, MFA demonstrated that glucose utilization was greater in the TNBC cells (MDA-MB-468) compared to the hormone-responsive cells (MCF-7). In addition, 13C-labeled glycine and 13C-labeled glutathione were only observed in TNBC cell lines treated in the presence of [U-13C]-glucose. In response to Taxol treatment, more metabolites were altered in the hormone-responsive cell lines compared with the TNBC cells. Profiling of 80 inflammatory cytokines (RayBiotech arrays) also demonstrated different responses in secreted inflammatory signals following treatment. We observed significant upregulation in interleukins-4 and -16 in MDA-MB-468 cells, while there was a downregulation of osteoprotegerin in all four cell lines after treatment with Taxol. This approach holds promise for identifying biomarkers which may be leveraged for development of targeted treatments.
Citation Format: Delisha A. Stewart, Jason Winnike, Susan McRitchie, Wimal Pathmasiri, Susan Sumner. Triple negative breast cancer: Metabolomics and flux analysis to identify targets for drug development. [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 1836. doi:10.1158/1538-7445.AM2015-1836
Abstract 1838: MUC1 serves as metabolic regulator in triple negative breast cancer
Authors: Goode Gennifer D. 
Published: August 2015

Abstract
Breast cancer, the second leading cause of cancer deaths in women, is the most common cancer among North American women, accounting for nearly 1 in 3 cancer cases diagnosed in the U.S. women. Triple negative breast cancer (TNBC) subtype accounts for approximately 15-25% of all breast cancer cases and has an increased incidence of metastasis, high recurrence within 1-3 years and a high mortality rate. Therefore, identifying factors that facilitate tumor growth and metastases have the potential to serve as novel molecular targets for breast cancer therapy. Mucin1 (MUC1), a glycoprotein associated with chemoresistance, is aberrantly overexpressed in TNBC and facilitates growth and metastasis of TNBC cells. This occurrence can be partially attributed to MUC1 interaction with hypoxia-inducible factor alpha (HIF1α), a key regulator of glycolysis. In the present study we examined the effect of MUC1 expression on cancer cell metabolism of TNBC cell lines under normoxic (20% Oxygen) and hypoxic (1% Oxygen) conditions. MUC1 was ectopically overexpressed in the MDA-MB-231 cell line and stably knocked down in the MDA-MB-468 cell line. Results indicate that MUC1 interacts with HIF1α and the interaction is further enhanced under hypoxic conditions. In addition, MUC1 expression enhanced glucose and glutamine uptake, enhanced lactate secretion and altered the expression of several metabolic genes. Furthermore, untargeted global metabolomic profiling identified metabolite alterations in which MUC1 expression modulates cancer cell metabolism to facilitate growth properties of TNBC cells. Thus our results support the notion that MUC1 serves as a metabolic regulator in TNBC, facilitating metabolic reprogramming that influences growth of TNBC.
Citation Format: Gennifer D. Goode. MUC1 serves as metabolic regulator in triple negative breast cancer. [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 1838. doi:10.1158/1538-7445.AM2015-1838
Abstract 1839: Development of urinary pseudo-targeted LC-MS based metabolomics method and its application in hepatocellular carcinoma biomarker discovery
Authors: Yao Zhenzhen , Shao Yaping , Xu Guowang 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is one of the pestilent malignancies leading to cancer-related death. Discovering effective biomarkers for HCC diagnosis is an urgent demand. To identify potential metabolites biomarkers, we developed a urinary pseudo-targeted method based on liquid chromatography- triple quadrupole linear ion Q-trap 5500 mass spectrometry (LC-QTRAP- MS). Compared with non-targeted method, the pseudo-targeted method can achieve better data quality which benefits differential metabolites discovery. The established method was applied to cirrhosis (CIR) and HCC investigation. It was found that urinary nucleosides, bile acids, citric acid and several amino acids were significantly changed in liver disease groups compared with the controls, featuring the dysregulation of purine metabolism, energy metabolism and amino metabolism in liver diseases. Furthermore, some metabolites such as cycle cyclic adenosine monophosphate (AMP), glutamine and, short- and medium-chain acylcarnitines were the differential metabolites of HCC and CIR. Based on binary logistic regression, butyrylcarnitine (carnitine C4:0) and hydantoin-5-propionic acid were defined as a combinational marker to distinguish HCC from CIR. The area under curve (AUC) was 0.786 and 0.773 for discovery stage and validation stage samples, respectively. These data show that the established pseudo-targeted method is a complementary one of targeted and non-targeted methods for metabolomics study.
Note: This abstract was not presented at the meeting.
Citation Format: Zhenzhen Yao, Yaping Shao, Guowang Xu. Development of urinary pseudo-targeted LC-MS based metabolomics method and its application in hepatocellular carcinoma biomarker discovery. [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 1839. doi:10.1158/1538-7445.AM2015-1839
Abstract 1856: Preclinical effects of dual AKT/MAPK inhibition in PTEN-deficient prostate cancer
Authors: De Velasco Marco A. , Yamamoto Yutaka , Kura Yurie , Fukushima Emiko , Ando Naomi , Davies Barry , Hatanaka Yuji , Oki Takashi , Shimizu Nobutaka , Nozawa Masahiro , Yoshikawa Kazuhiro , Yoshimura Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2015

Abstract
Targeting signal molecules with single agent monotherapy is met with limited or transient clinical benefits. Therefore, establishing effective rational combinatorial treatment strategies provides a better option for achieving improved clinical outcomes. The AKT/PI3K and MAPK signaling pathways have been identified as key compensatory signal transduction pathways in prostate cancer. We have used genetically engineered mouse models of prostate cancer to show the treatment efficacy of monotherapy with the AKT inhibitor AZD5363 and the MAP/ERK kinase (MEK) inhibitor selumetinib (AZD6244, ARRY142886). We hypothesized that a rational combinatorial approach utilizing both of these inhibitors would improve treatment efficacy compared to single agent monotherapy. To test this hypothesis, we evaluated the treatment effects of AZD5363 and selumetinib in preclinical models of prostate cancer. In vitro experiments were carried out using a panel of human prostate cancer cell lines, and mouse prostate cancer cell lines, derived from PTEN-deficient castration-naïve prostate cancer (CNPC) and castration-resistant prostate cancer (CRPC). Treatments with AZD5363 and selumetinib demonstrated a synergistic combination effect in both human and mouse prostate cancer cell lines. We evaluated the antitumor effects in vivo by comparing the effects of AZD5363 and selumetinib alone or in combination in PTEN-deficient mice. Our studies show that combination therapy of AZD5363/selumetinib was well-tolerated by the mice and demonstrated significantly improved inhibition of tumor growth compared to single agent therapy. In the CNPC model, mice showed 16.7, 10.0 and 24.9% reductions in tumor burden after treatments with AZD5363, selumetinib and AZD5363/selumetinib, respectively (P&lt;0.001). In the CRPC model, mice showed 15.8, 3.8 and 27.0% reductions in tumor burden after treatments with AZD5363, selumetinib and AZD5363/selumetinib, respectively (P&lt;0.001). Target validation studies confirmed the inhibition of downstream targets. Overall, our findings suggest a potential role for targeting the PI3K/AKT and MAPK signaling pathways with AZD5363 and selumetinib for treatment of PTEN-deficient prostate cancer.
Citation Format: Marco A. De Velasco, Yutaka Yamamoto, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry Davies, Yuji Hatanaka, Takashi Oki, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Preclinical effects of dual AKT/MAPK inhibition in PTEN-deficient prostate cancer. [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 1856. doi:10.1158/1538-7445.AM2015-1856