bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2869: A three-protein cytokine signature that correlates with the prognosis of osteosarcoma
Authors: Flores Ricardo J. , Li Yiting , Kelly Aaron , Lau Ching , Man Tsz-Kwon 
Published: May 2015

Abstract
Osteosarcoma (OS) is the most common malignant bone tumor in pediatrics. Despite the use of surgery and chemotherapy, the survival rate of patients who develop a metastatic disease or a poor response towards the chemotherapy remains dismal. Identification of novel biomarkers for early prognostication will facilitate risk-based stratification before the treatment is initiated, so that the high-risk patients can be treated more appropriately to increase their chance of survival. Others and we have previously reported that cytokines and chemokines were implicated in OS. In this study, we employed highly sensitive Luminex beads assays to investigate 90 cytokines/chemokines and receptors on a cohort of 40 OS plasma samples collected at diagnosis from the Texas Children's Hospital. The protein expression data were analysed to identify candidate biomarkers that correlate with the chemotherapy response, initial metastatic status, and overall survival. Then, the candidates were validated in a large set of 250 serum samples obtained from the Children's Oncology Group. Our results show that a three-protein signature consisting of CXCL9, CXCL10 and CXCL11, all ligands of the CXCR3 receptor, is significantly associated with survival. Interestingly, the CXCR3-axis has been previously implicated in an OS mouse model, but its role in human is still not known. Hence, the next step is to validate these prognostic biomarkers in an independent cohort of OS patient samples. In addition, we will test the expression of these molecules and their receptor in tumor samples to identify potential therapeutic targets. In summary, we characterized the expression of circulating cytokines/chemokines in osteosarcoma samples and identified candidate prognostic biomarkers that are linked to the CXCR3-axis. A further study of these molecules may allow us to develop a biomarker approach for early prognostication and a novel therapeutic approach for treating high-risk OS.
Citation Format: Ricardo J. Flores, Yiting Li, Aaron Kelly, Ching Lau, Tsz-Kwon Man. A three-protein cytokine signature that correlates with the prognosis of osteosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2869. doi:10.1158/1538-7445.AM2014-2869
Abstract 2871: Correlation between number and sites of metastases and differential pretreated EBV DNA load profiles and their effects on outcomes in patients with metastatic nasopharyngeal carcinoma
Authors: Wang Hung-Ming , Chang Kai-Ping , Lin Tung-Liang , Huang Shiang-Fu , Tsang Ngan-Ming , Chan Sheng-Chieh , Hsu Cheng-Lung 
Published: May 2015

Abstract
Background: To investigate the relationship between pretreatment plasma EBV DNA copy number and sites and numbers of metastases in patients with nasopharyngeal carcinoma (NPC).
Methods: One hundred and thirty-three patients with metastatic NPC were treated at outpatient department. Their plasma EBV DNA concentrations were determined by real-time quantitative PCR.
Results: The overall patient response rate after 3-6 months of treatment was 48.1%. Pretreatment plasma EBV DNA concentrations were lower in patients with solitary nodule (≤5,000 copies/mL, 18/25 [72%] vs. multiple nodules, 49/128 [45.4%], P=0.025) or pure lung metastases (≤5,000 copies/mL, 19/21 [90.5%] vs. not lung metastases alone 48/112 [42.9%], P&lt;0.001) and higher in patients with liver involvement, alone or combined with other organs (≤5,000 copies/mL, 18/54 [33.3%] vs. non-liver metastases 49/79 [62%], P=0.001); and bone related metastases (≤5,000 copies/mL, 33/83 [39.8%] vs. non-bone metastases 34/50 [68%], P=0.002). Moreover, plasma EBV DNA concentration was correlated with overall survival (OS) (≤5,000 vs. &gt;5,000 copies/mL, median OS, 26 vs. 10 months; HR, 2.852; P&lt;0.001).
Conclusions: Pretreatment plasma EBV DNA copy number correlated with number and sites of metastases and with OS in patients with metastatic NPC.
Citation Format: Hung-Ming Wang, Kai-Ping Chang, Tung-Liang Lin, Shiang-Fu Huang, Ngan-Ming Tsang, Sheng-Chieh Chan, Cheng-Lung Hsu. Correlation between number and sites of metastases and differential pretreated EBV DNA load profiles and their effects on outcomes in patients with metastatic nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2871. doi:10.1158/1538-7445.AM2014-2871
Abstract 2905: The activity of a new class of biologics: trastuzumab conjugates designed to treat brain metastases of HER2+ breast cancers
Authors: Vitalis Timothy , Jefferies Wilfred , Gabathuler Reinhard 
Published: May 2015

Abstract
Trastuzumab, a monoclonal antibody against HER2, is an effective therapy for the treatment of peripheral HER2+ breast cancer. However, a significant number of patients eventually succumb to the disease due to brain metastases. In these patients trastuzumab is no longer effective because the blood brain barrier reduces distribution of trastuzumab to the brain tumor. In this study, we conjugate trastuzumab to melanotransferrin (MTf), a protein of the transferrin family, which has been shown to cross the blood brain barrier, and characterize its anti-tumor activity. We used thiol-malemide linkage to conjugate trastuzumab to MTf and generated a mixture of trastuzumab-MTf species of varying molar ratios. Size exclusion chromatography was used to enriched for the 1:1 heterodimer fraction and this fraction was designated as BT2111. The activity of BT2111 against human HER2+ breast cancer cell lines was tested with a cytotoxicity assay, an antibody dependent cellular cytotoxicity (ADCC) assay, and in a peripheral tumor xenograft model. At equimolar equivalents, BT2111 had greater anti-tumor activity than trastuzumab against HER2+ human breast cancer cell lines (SKBR3 and BT474). Furthermore, significant ADCC activity directed against BT474 cells was observed when cells were treated with BT2111 and incubated with human NK cells. Finally, both BT2111 and trastuzumab completely inhibited the growth of peripheral xenograft tumors (BT474) in athymic mice over the course of the experimental period (5-6 weeks). Conjugation of trastuzumab to MTf does not alter the in vivo anti-tumor activity of trastuzumab, supporting the conclusion that HER2 binding and Fc receptor binding was not significantly affected by conjugation. BT2111 is the first example of a new class of biologics that demonstrates the ability to inhibit the growth of peripheral HER2+ tumors and has the added benefit of penetrating the brain for the treatment of HER2+ brain metastases.
Citation Format: Timothy Vitalis, Wilfred Jefferies, Reinhard Gabathuler. The activity of a new class of biologics: trastuzumab conjugates designed to treat brain metastases of HER2+ breast cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2905. doi:10.1158/1538-7445.AM2014-2905
Abstract 2952: Aberrant accumulation of 2-hydroxyglutarate in human breast cancer with myc activation
Authors: Mishra Prachi 
Published: May 2015

Abstract
Metabolite addiction of tumors may represent an Achilles heel for cancer cells and an opportunity for therapeutic intervention. Recently, using an untargeted discovery approach and validation of key metabolites, we characterized the metabolomic profile of human breast tumors and uncovered intrinsic metabolite signatures in these tumors. Importantly, the oncometabolite, 2-hydroxyglutarate (2HG), accumulated in a subset of tumors and human breast cancer cell lines. 2HG reached millimolar concentrations comparable to those in isocitrate dehydrogenase (IDH)-mutant gliomas, despite the absence of IDH mutations. Instead, we discovered a significant association between increased 2HG levels and MYC pathway activation in breast cancer, which was corroborated in human mammary epithelial and breast cancer cells with inducible MYC overexpression and knockdown. Further analyses showed a global increase of DNA methylation in 2HG-high tumors and identified a poor survival tumor subtype with distinct DNA methylation, high tissue 2HG, and heightened occurrence in African-American patients. Tumors of this subtype had a stem cell-like transcriptional signature with WNT and MYC pathway activation. These tumors over-expressed glutaminase, suggesting a functional relationship between glutamine and 2HG metabolism in breast cancer. Accordingly, 13C-labeled glutamine was metabolized into 2HG in cells with aberrant 2HG accumulation, whereas pharmacologic and siRNA-mediated inhibition of glutaminase markedly reduced 2HG. Our findings highlight 2HG as a candidate breast cancer oncometabolite associated with MYC activation and poor prognosis.
Citation Format: Prachi Mishra. Aberrant accumulation of 2-hydroxyglutarate in human breast cancer with myc activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2952. doi:10.1158/1538-7445.AM2014-2952
Abstract 2955: Trail-R2: A death receptor turns malignant upon nuclear localization
Authors: Kalthoff Holger , Haselmann Verena , Kurz Alexandra , Bertsch Uwe , Huebner Sebastian , Fritsche Hendrik , Hauser Charlotte , Schem Christian , Tower Rob , Heilmann Thorsten , Tiwari Sanjay , Glüer Claus C. , Trauzold Anna 
Published: May 2015

Abstract
High intracellular expression of death receptor TRAIL-R2 correlates with poor prognosis for different tumor entities and thus suggests tumor-promoting activity of intracellular TRAIL-R2. We demonstrate that TRAIL-R2 interacts with the core Microprocessor components Drosha and DGCR8 and the associated regulatory proteins p68, hnRNPA1, NF45 and NF90 in the nucleus. Knockdown of TRAIL-R2 enhances Drosha-mediated processing of pri-let-7 resulting in increased levels of mature let-7, reduced expression of let-7-targets Lin28B and HMGA2 and inhibition of cell proliferation. In contrast, high abundance of nuclear TRAIL-R2, often detected in pancreatic cancer, correlates with enhanced expression of HMGA2 and dictates worse prognosis. Importantly, knockdown of TRAIL-R2 inhibits pancreatic tumor growth in an orthotopic xenotransplantation mouse model and reduced nuclear levels of TRAIL-R2 accompany differentiation of pancreatic epithelial cells in vitro. In conclusion, we define a novel function of nuclear TRAIL death receptor contributing to malignancy by inhibition of let-7-maturation (Haselmann et al., Gastroenterology epub ahead of print).
In extension to our work on pancreatic cancer we further show nuclear TRAIL-R2 functions to be of relevance in breast cancer bone metastasis. Stably shRNA- transfected clones of MDAMB231 cells revealed metastatic lesions in only 2/12 mice upon TRAIL-R2 knock-down, whereas TRAIL-R1 and control knock-down clones exhibited multiple metastases throughout the groups of 12 mice each. Under in vitro conditions some decreased apoptosis rate was observed in both TRAIL-R knock-down clonal populations compared to the controls upon TRAIL treatment. Preliminary results suggest Mesenchymal-Epithelial-Transition (as indicated by increased E-Cadherin expression in TRAIL-R2 knock-down cells) as a mechanism for reduced metastasis.
In summary, we show nuclear death receptor TRAIL-R2 to significantly contribute to malignant progression in two different pre-clinical tumor models. Thus, targeted intervention to prevent nuclear localization may serve as a novel therapeutic strategy.
Supported by DFG (TR 1063/2-1 and TR 1063/3-1 - SKELMET FOR 1586).
Citation Format: Holger Kalthoff, Verena Haselmann, Alexandra Kurz, Uwe Bertsch, Sebastian Huebner, Hendrik Fritsche, Charlotte Hauser, Christian Schem, Rob Tower, Thorsten Heilmann, Sanjay Tiwari, Claus C. Glüer, Anna Trauzold. Trail-R2: A death receptor turns malignant upon nuclear localization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2955. doi:10.1158/1538-7445.AM2014-2955
Abstract 2960: Identification of Runx3 as a gatekeeper of lung adenocarcinoma
Authors: Lee You-Soub , Jang Ju-Won , Chi Xin-Zi , Ito Yoshiaki , Bae Suk-Chul 
Published: May 2015

Abstract
It is thought that SP-C/CC10 double positive cells, which normally contribute to the renewal of lung epithelial cells, are the origin adenocarcinoma (ADC) of the lung. The present study shows that postnatal disruption of Runx3 in the mouse lung results in dedifferentiation of bronchiolar epithelial cells into SP-C/CC10 double positive cells. The double positive cells differentiate into SP-C single positive cells and adenoma (median survival, longer than 1 year). When Adenovirus-Cre was infected, LSL-K-RasG12D mice induced ADC in prolonged latency (median survival, 220 days) and Runx3f/f/LSL-K-RasG12D mice rapidly induced ADC (median survival, 79 days), indicating a strong tumor suppressor activity of Runx3. When Cre was activated in a limited number of cells through a leaky activation of Cretm/ERT in the absence of tamoxifen, K-RasLSL-G12D/+/Cretm/ERT mice did not induce lung ADC. In contrast, simultaneous inactivation of Runx3 and activation of K-Ras (Runx3f/f/K-RasLSL-G12D/+/Cretm/ERT) induced lung ADC with striking morphological similarities to human lung ADC in all mice (median survival, 48 days after birth). We also found that Runx3 forms a complex with BRD2 (a relative of TAF250) in a K-Ras activity-dependent manner and the complex transiently induces p14ARF and p21. When K-Ras was constitutively activated, the Runx3-BRD2 complex was maintained for long time and the expressions of p14ARF and p21 was continued. Disruption of the Runx3-BRD2 complex abolished expression of these two genes. These results suggest that cells recognize oncogenic K-Ras through a monitoring system composed of Runx3-BRD2 complex and Runx3-inactivation leads to abrogation of the monitoring system as well as dedifferentiation of lung epithelial cells.
Citation Format: You-Soub Lee, Ju-Won Jang, Xin-Zi Chi, Yoshiaki Ito, Suk-Chul Bae. Identification of Runx3 as a gatekeeper of lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2960. doi:10.1158/1538-7445.AM2014-2960
Abstract 2979: Effects of VEGF inhibition on skin ulcer induced by administration of cytotoxic anticancer drugs
Authors: Shimoyama Tatsu , Ogura Kiyoshi , Kanemasa Yuusuke , Yamaguti Shigeo , Sasaki Eisaku , Omuro Yasushi , Sawada Takeshi , Koizumi Fumiaki , Maeda Yoshiharu 
Published: May 2015

Abstract
Introduction: An accidental extravasation of vesicant drugs-containing chemotherapy leads to skin ulcer, necrosis and severe tissue destruction.
The clinical evidences that VEGF inhibition suppresses tumorigenesis via inhibiting angiogenesis and causes delaying wound repair have been accumulated. We observed the cases that simultaneous administration of anti-human VEGF antibody, Bevacizumab, avoided critical skin ulcer which should be caused by extravasation of cytotoxic drug in the colorectal cancer combination chemotherapy. Therefore, we examined effects of VEGF or anti-VEGF-antibody and angiogenesis inhibitor on skin ulcer caused by administration of anticancer drug in a mouse model.
Methods: Experiments were performed in accordance with the United Kingdom Coordinating Committee on Cancer Research Guidelines for the welfare of animals in experimental neoplasia. Subcutaneous injections of doxorubicin (0.2mg/0.2ml of saline) in mice induced dose-dependent ulcerations under general anesthesia. The ulcers reached maximal size at 2-3 weeks following doxorubicin administration and were completely healed by 9 weeks. Effects of co-administration of test drugs on the area of the skin ulcer caused by administration of Adriamycin, were compared with control. Bevacizumab is anti-human VEGF antibody, it has no reactivity with mouse VEGF. An anti-mouse VEGF antibody was used alternatively.
Results: VEGF (5μg) increased the skin ulcer size up to 150%, and the healing time was increased to 11 weeks. Anti-VEGF antibody (50μg) and suramin reduced the maximum ulcer size (50%), and the healing time was reduced to 6 weeks.
Hydrocortisone (100μg) slightly reduced the skin ulcer size and the healing time (8 week).
Conclusion: VEGF aggravated skin ulcer caused by the administration of the Adriamycin. Anti-VEGF antibody and angiogenesis inhibitor, suramin, reduced skin ulcer caused by the administration of the Adriamycin.
Discussion: Inhibition of VEGF signaling and/or anti-angiogenesis were suggested to reduce skin ulcer caused by the Adriamycin. Anti-human VEGF antibody, Bevacizumab was suggested to be an effective antidote for skin ulcer and necrosis by extravasation of anticancer drugs and had potential for clinical use.
Citation Format: Tatsu Shimoyama, Kiyoshi Ogura, Yuusuke Kanemasa, Shigeo Yamaguti, Eisaku Sasaki, Yasushi Omuro, Takeshi Sawada, Fumiaki Koizumi, Yoshiharu Maeda. Effects of VEGF inhibition on skin ulcer induced by administration of cytotoxic anticancer drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2979. doi:10.1158/1538-7445.AM2014-2979
Abstract 2982: Macrophages modulate adaptive resistance to anti-angiogenic therapy
Authors: Dalton Heather J. , Pradeep Sunila , Armaiz-Pena Guillermo N. , Previs Rebecca , Davis Ashley , Rupaimoole Rajesha , Zand Behrouz , Hailemichael Yared , Overwijk Willem W. , Lopez-Berestein Gabriel , Sood Anil K. 
Published: May 2015

Abstract
Targeted anti-angiogenic therapies were a highly anticipated addition to cancer treatment, but their clinical use has been tempered by the development of resistance. To understand the role of immune cells in potentially mediating such resistance, we carried out systematic immune cell profiling in a syngeneic ovarian cancer mouse model following treatment with the B20 anti-VEGF antibody. Following injection of luciferase-labeled cancer cells and initiation of treatment, mice (n=8/group) were divided into B20-sensitive and resistant groups based on longitudinal bioluminescence imaging of tumor burden. Immune cell profiling confirmed a dramatic increase in macrophages with emergence of resistance to B20. Using the syngeneic model, resistance to B20 was documented with bioluminescence imaging as an increase in tumor burden in mice with previously stable disease. Zoledronic acid, a macrophage-depleting bisphosphonate, was then added to B20 treatment. Restoration of sensitivity to B20 with the addition of zoledronic acid was demonstrated by a 68% prolongation of survival in this treatment group as compared to those receiving B20 alone (p&lt;0.0001). Zoledronic acid in combination with the VEGF antibody, bevacizumab, significantly reduced both tumor size and nodules when compared to either drug alone in additional orthotopic models of ovarian cancer. CD68 staining confirmed significantly reduced macrophage numbers in tumor samples following treatment with zoledronic acid. In vitro immunofluorescence imaging of macrophages following prolonged exposure to anti-VEGF therapy showed downregulation of VEGF receptors compared to short-term exposure, suggesting a possible mechanism for their persistence in an anti-VEGF resistant microenvironment. Collectively, these data demonstrate a novel role for macrophages in resistance to anti-VEGF therapy and offer a new therapeutic strategy to overcome this problem with important translational implications.
Citation Format: Heather J. Dalton, Sunila Pradeep, Guillermo N. Armaiz-Pena, Rebecca Previs, Ashley Davis, Rajesha Rupaimoole, Behrouz Zand, Yared Hailemichael, Willem W. Overwijk, Gabriel Lopez-Berestein, Anil K. Sood. Macrophages modulate adaptive resistance to anti-angiogenic therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2982. doi:10.1158/1538-7445.AM2014-2982
Abstract 299: Circulating microRNAs in association with colorectal neoplasia
Authors: Adams Scott V. , Newcomb Polly A. , Burnett-Hartman Andrea N. , Upton Melissa P. , Zhu Lee-Ching , Mandelson Margaret , Potter John D. , Makar Karen W. 
Published: May 2015

Abstract
Purpose: MicroRNAs (miRNAs) are non-coding regulatory RNAs that are stable in circulation and implicated in the etiology of many cancers including colorectal cancer (CRC). In this study we investigated whether candidate miRNAs could serve as blood-based biomarkers of colorectal adenoma.
Methods: We conducted a colonoscopy-based case-control study of men and women ages 50-79; this report includes data from 48 polyp-free controls, 43 advanced adenoma, 73 non-advanced adenomas, and 8 CRC cases. We selected 12 miRNA candidates that are highly expressed in adenoma tissue and have low expression in blood cells, in addition to miRNAs previously reported as biomarkers of adenoma. miRNAs were extracted from stored plasma samples, and copy number assessed with qRT-PCR. Odds ratios (ORs) and area-under-the-curve (AUC) from receiver-operator characteristic curves were estimated to quantify the association between plasma copy-number of these candidate miRNAs and each case group.
Results: No miRNA transcripts were associated with risk of adenoma or advanced adenomas, or with an AUC significantly above 0.5 that would indicate usefulness in discriminating either category of adenoma cases from controls. In contrast, statistically significant and strong associations (ORs&gt;5) with CRC were observed for 6 miRNA candidates, with corresponding AUCs significantly greater than 0.5.
Conclusions: Our results suggest that these candidate miRNAs, assayed with qRT-PCR, are unlikely to have clinical utility as blood-based screening biomarkers of adenomas. However, strong associations were observed with CRC. Circulating miRNAs may therefore have promise as potential early detection biomarkers to augment current CRC screening methods, but an optimal screening biomarker would detect pre-malignant colorectal adenomas as well as frank CRC.
Citation Format: Scott V. Adams, Polly A. Newcomb, Andrea N. Burnett-Hartman, Melissa P. Upton, Lee-Ching Zhu, Margaret Mandelson, John D. Potter, Karen W. Makar. Circulating microRNAs in association with colorectal neoplasia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 299. doi:10.1158/1538-7445.AM2014-299