bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1220: Investigation of the biological properties of human breast cancer in a nude rat model
Authors: Mokhtari Reza Bayat , Nofiele Joris Tchouala , Islam Syed S. , Yeger Herman , Cheng Hai-Ling Margaret 
Published: May 2015

Abstract
Developing imaging technology for cancer diagnosis and treatment monitoring is best performed on larger pre-clinical animal models recapitulating tumor growth and metastasis more similar to that found in humans. Such models are amenable to morphological and functional imaging techniques at spatial resolutions appropriate for animal imaging and, translatable to human imaging. In comparison to mouse xenografts, rat models offer the advantages of clinical imaging capabilities, development of xenograft and metastatic models, in orthotopic sites. Human breast cancer cell lines MDA-MB-231 and MCF-7 show a variable take rate in mice, ∼ 68% incurring considerable cost and time. Having a more reproducible method is needed for breast cancer studies. Here we present evidence for development of a novel method in the immune-compromised nude rats. Spheroids grown under stem cell conditions were derived from human breast adenocarcinoma estrogen dependent (MCF-7, ZR-75-1) and independent (MDA-MB-231) lines, and xenografted in both subcutaneous and orthotopic (fat pad) sites in the nude rat. To verify that rat tumors could be studied in detail at spatial resolutions achievable on a clinical 3 Tesla scanner, high-resolution magnetic resonance imaging was performed to identify vascular, viable, and necrotic tumor regions. The breast cancer phenotype and was confirmed by immunohistochemistry for ER and HER2. Tumors were characterized with proliferation marker Ki67, vascularization by CD34 and VEGF, and presence of hypoxic regions by HIF1α. Our results indicated that spheroids from all three lines readily generated tumors independent of exogenous estrogen. MRI is an effective and sensitive method for investigating the biological behavior and vascularization of breast cancer. These findings offer a potential novel method for pre-clinical study and investigation of human breast cancer.
Citation Format: Reza Bayat Mokhtari, Joris Tchouala Nofiele, Syed S. Islam, Herman Yeger, Hai-Ling Margaret Cheng. Investigation of the biological properties of human breast cancer in a nude rat model. [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 1220. doi:10.1158/1538-7445.AM2014-1220
Abstract 1221: Establishment and characterization of a chemoresistant glioblastoma cell line from an Iraqi patient
Authors: Al-Shammari Ahmed M. , Al-Juboory Ahmed A. , Al-Mukhtar Asmaa A. , Ali Amal M. , Al-Hili Zaid A. , Yaseen Nahi Y. 
Published: May 2015

Abstract
Glioblastoma multiforme is the most common and aggressive malignant primary brain tumour in humans, and has a very poor prognosis. As it is a well known fact that environmental factors especially radiation exposure is a major risk for glioblastoma multiforme and Iraq had been exposed in a relatively short period to 2 international wars with documented radiation exposure, so this paper might give justification for establishment of a new glioblastoma cell line. This cell line has been established from a cerebral glioblastoma multiforme in a 72-year-old Iraqi man who underwent surgery for an intracranial tumour in 2005. The morphology, growth kinetics, karyotype, immunocytochemistry and angiogenesis factor expression profile of this ANGM5 cell line were studied. The cell line has been grown continuously for more than 200 serial passages in standard culture media presenting no sign of cell senescence. The cultured cells are elongated or multipolar in shape and the population doubling time is 28 hours. The karyotype is complex and the chromosomal number varied between 46 and 48. The cell line is resistant to Temozolomide, cisplatin, vincristine and etoposide. This chemoresistance could be explained by the overexpression of the breast cancer resistance protein (BCRP) which found to be overexpressed by this cell line. Immunocytochemistry also showed that this cell line exhibited several characteristic features of glioblastomas, analysis of glial markers demonstrated that cells are positive for glial fibrillary acidic protein (GFAP), and negative for nestin and calbindin. Protein microarray analysis showed very high production of TIMP2 as well as other factors that are important for the invasiveness and aggressiveness of glioblastoma. This glioblastoma cell line is a useful addition to the cell lines currently available for study of the pathobiology and chemoresistance properties of glioblastoma multiforme as well as for antitumour drug discovery.
Citation Format: Ahmed M. Al-Shammari, Ahmed A. Al-Juboory, Asmaa A. Al-Mukhtar, Amal M. Ali, Zaid A. Al-Hili, Nahi Y. Yaseen. Establishment and characterization of a chemoresistant glioblastoma cell line from an Iraqi patient. [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 1221. doi:10.1158/1538-7445.AM2014-1221
Abstract 1224: A patient derived xenograft (PDX) platform for development of next generation KIT kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors (GIST)
Authors: Mullins Chelsea , Ricono Jill , Carson Patrick , Habets Gaston , Shellooe Rafe , Nguyen Hoa , Broudy Thomas , Mirsaidi Cyrus , Nair Praveen 
Published: May 2015

Abstract
Despite best efforts in the treatment of gastrointestinal stromal tumors (GIST), patients continue to face a poor prognosis. That said, introduction of imatinib into clinical practice has vastly improved outcomes for KIT positive patients. However, as with many kinases, resistance has developed into a clinical dilemma, rendering the drug ineffective. A number of resistance mutations have previously been identified including the well known D816 activating mutation. To overcome this challenge, we have established a set of GIST patient derived xenograft models to recapitulate the original patient tumor, including genetics of resistance. In this work, we show four primary GIST samples which were selected based on mutational and clinical profile. PDX models were developed in immunocompromised mice and were further characterized by immunohistochemistry, additional sequencing and pharmacological efficacy. We then evaluated the efficacy of chemotherapeutic agents in these models. We describe imatinib resistance mutations, and demonstrate in vivo efficacy of dasatinib over imatinib in the resistant GIST PDX model. Take together, this data validates these GIST PDX models as a novel platform for the evaluation of new drug candidates to better delay and circumvent resistance now found in the clinic.
Citation Format: Chelsea Mullins, Jill Ricono, Patrick Carson, Gaston Habets, Rafe Shellooe, Hoa Nguyen, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair. A patient derived xenograft (PDX) platform for development of next generation KIT kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors (GIST). [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 1224. doi:10.1158/1538-7445.AM2014-1224
Abstract 1235: Targeting the DNA binding domain of the androgen receptor as a potential therapy for prostate cancer
Authors: Dalal Kush , Li Huifang , Moniri Mani R. , Ban Fuqiang , Sharma Aishwariya , Cherkasov Artem , Rennie Paul S. 
Published: May 2015

Abstract
The Androgen Receptor (AR) is a ligand inducible transcription factor that drives expression of genes contributing to the growth, recurrence and metastasis of prostate cancer (PCa). The AR is activated by steroid hormones (androgens) that bind to a C-terminal ligand-binding domain (LBD) and cause the transcription factor to enter the nucleus, dimerize and interact with DNA via its conserved DNA-binding domain (DBD). Accordingly, treatment for PCa involves reducing DHT production or using small molecules (i.e. antiandrogens) to compete with the specific interaction between hormones and the AR-LBD, preventing AR activation. This treatment will eventually fail as recurrent PCa changes into a castration resistant form (CRPC) where AR signalling continues even in the absence of androgens. The occurrence of CRPC is driven, in part, by mutations in the AR-LBD that alter the binding of antiandrogens, or by the presence of constitutively active AR splice variants that lack the LBD, effectively removing the site of action of conventional antiandrogens.
Here, we describe a surface exposed pocket on the AR-DBD, based on its 3D-crystal structure, which may qualify as an alternative target for small molecule inhibitors of AR transcriptional activity. Following virtual screening of many compounds, we characterize the interaction of the AR-DBD with various potential inhibitors and measure the efficacy of these agents to block the transcriptional activity of both full-length and splice variant AR in cell culture. Drug-inhibition was reduced upon site-directed mutagenesis of amino-acid residues in the DBD that are suspected of interacting with the compounds. Biochemical approaches are used to further examine the physical interaction of the purified AR-DBD protein with small molecules and to investigate their effect on protein-DNA interactions in vitro. Lastly, we use confocal microscopy of live PCa cells to investigate the effect of our compounds on the spatial localization and dimerization of fluorescently tagged AR proteins. These results illustrate the feasibility of targeting the AR-DBD to potentially inhibit the reactivation of AR transcriptional activity that is observed in CRPC.
Citation Format: Kush Dalal, Huifang Li, Mani R. Moniri, Fuqiang Ban, Aishwariya Sharma, Artem Cherkasov, Paul S. Rennie. Targeting the DNA binding domain of the androgen receptor as a potential therapy for prostate cancer. [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 1235. doi:10.1158/1538-7445.AM2014-1235
Abstract 124: Effect of RKIP on MMP expression and regulation of breast cancer metastasis
Authors: Datar Ila J. , Feng Jingwei , Ren Gang , Li Zehui , Qiu Xiaoliang , Al-Mulla Fahd , Bitar Milad S. , Yeung Miranda , Yeung Kam 
Published: May 2015

Abstract
Raf Kinase Inhibitory Protein or RKIP was initially identified as a Raf-1 binding protein using the yeast 2-hybrid screen. RKIP inhibits the activation phosphorylation of MEK by Raf-1 by competitively inhibiting the binding of MEK to Raf-1 and thus exerting an inhibitory effect on the Raf-MEK-ERK pathway. RKIP has been identified as a metastasis suppressor gene. Metastasis is a complex multiple-step process. Expression of RKIP is low in cancer metastases. Although primary tumor growth was unaffected, re-expression of RKIP inhibits cancer metastasis. Mechanistically, RKIP constrains metastasis by inhibiting angiogenesis, local invasion, intravasation, and colonization. The molecular mechanism of how RKIP inhibits these individual steps remains undefined. Using an unbiased PCR based screening and by analyzing DNA microarray expression datasets we observed that the expression of multiple metalloproteases (MMP) including MMP1, MMP3, MMP10 and MMP13 were negatively correlated with RKIP expression in breast cancer cell lines and clinical samples. Since expression of MMPs by cancer cells is important for cancer metastasis, we hypothesize that RKIP may mediate suppression of breast cancer metastasis by inhibiting multiple MMPs. In this study we show that the expression signature of RKIP and MMPs is better at predicting high metastatic risk than the individual gene. Using a combination of loss- and gain-of-function approaches, we found that MMP13 is the cause of RKIP-mediated inhibition of local cancer invasion. Interestingly expression of MMP13 alone was not sufficient to reverse the inhibition of breast cancer cells metastasis to the lung due to the expression of RKIP. We found that RKIP negatively regulated MMP13 through the Erk2-Fra1 transcriptional axis and the repression of MMP13 by RKIP requires the presence of the a TPA-responsive element in the MMP13 proximal promoter. Together, our findings indicate that RKIP inhibits cancer cell invasion, in part, via MMP13 inhibition. These data also implicate RKIP in the regulation of MMPs transcription, suggesting a potential mechanism by which RKIP inhibits tumor progression and metastasis.
Citation Format: Ila J. Datar, Jingwei Feng, Gang Ren, Zehui Li, Xiaoliang Qiu, Fahd Al-Mulla, Milad S. Bitar, Miranda Yeung, Kam Yeung. Effect of RKIP on MMP expression and regulation of breast cancer metastasis. [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 124. doi:10.1158/1538-7445.AM2014-124
Abstract 1241: Kaempferol suppresses solar ultraviolet radiation-induced skin cancers by targeting RSK2 and MSK1
Authors: Yao Ke , Chen Hanyong , Lee Mee-Hyun , Langfald Alyssa , Kim Myoung Ok , Yu Dong Hoon , Liu Kangdong , Ma Wei-Ya , Bode Ann M. , Dong Ziming , Dong Zigang 
Published: May 2015

Abstract
Ultraviolet (UV) irradiation is the leading factor in the development of skin cancer, which is the most common form of cancer in the United States. Discovering novel chemopreventive agents against this disease is extremely important. Kaempferol, a natural flavonol isolated from tea, broccoli, grapes, apples and other plant sources, is known to have anticancer activity, but its molecular mechanisms and direct target(s) in cancer chemoprevention are still unclear. In this study, our pull-down assay results showed that RSK2 and MSK1 directly interact with kaempferol in both ex vivo and in vitro systems. ATP competition and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations determined that kaempferol acts as an inhibitor of RSK2 and MSK1 kinase activities to attenuate solar UV-induced phosphorylation in mitogen-activated protein kinase signaling cascades in JB6 P+ mouse skin epidermal cells. In a mouse skin tumorigenesis study, kaempferol significantly suppressed solar UV-induced skin carcinogenesis. Further analysis showed that the kaempferol-treated group had a substantial reduction in solar UV-induced phosphorylation of CREB and c-Fos in mouse skin. Taken together, our results identify kaempferol as a safe and novel chemopreventive agent against solar UV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1.
Citation Format: Ke Yao, Hanyong Chen, Mee-Hyun Lee, Alyssa Langfald, Myoung Ok Kim, Dong Hoon Yu, Kangdong Liu, Wei-Ya Ma, Ann M. Bode, Ziming Dong, Zigang Dong. Kaempferol suppresses solar ultraviolet radiation-induced skin cancers by targeting RSK2 and MSK1. [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 1241. doi:10.1158/1538-7445.AM2014-1241
Abstract 1261: Targeting IL-11Rα inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model
Authors: Lewis Valerae O. , Devarajan Eswaran , Hughes Dennis PM 
Published: May 2015

Abstract
Osteosarcoma is the most common primary tumor of bones. In the past three decades treatment paradigms and survival rates have not improved. While osteosarcoma clinical phenotype has been well characterized, the underlying tumor molecular biology remains unclear. We have previously demonstrated that IL-11Rα is overexpressed in primary and metastatic osteosarcoma. Recently investigators identified that IL-11 and IL-11Rα play a role in the development of metastasis in breast and gastrointestinal cancer. However the role of IL-11/IL-11Rα signaling in osteosarcoma is unknown. Using in vitro and in vivo osteosarcoma models we investigated the role of IL-11/IL-11Rα in osteosarcoma metastasis. The purpose of our study is to determine the effect of the knockdown of IL-11Rα in osteosarcoma. We stably knocked down IL-11Rα expression in a highly metastatic osteosarcoma cell line, using a lentiviral short hair-pin (shRNA) based approach. Knockdown of IL-11Rα led to inhibition of STAT-3(Tyr705) protein phosphorylation, cell growth, migration, invasion and colony formation in vitro. To determine the role of IL-11Rα in osteosarcoma tumorigeniesis and metastasis, we used an orthotopic metastatic model. In this model, mice injected with KRIB-IL-11Rα shRNA cells developed significantly less metastasis than control mice injected with KRIB control shRNA (P&lt;0.01). The relevance of our data to human conditions was studied by immunohistochemical staining of IL-11Rα protein in human osteosarcoma biopsy samples containing primary tumor and lesions, significant difference (p&lt;0.01) in expression distribution between primary and metastatic osteosarcoma lesions and a trend toward an impact on survival was noted. In conclusion, we showed that IL-11Rα plays an important role in the development of metastasis in osteosarcoma and blockade of this axis may inhibit the formation of metastasis and may provide an excellent target for the treatment of osteosarcoma.
Citation Format: Valerae O. Lewis, Eswaran Devarajan, Dennis PM Hughes. Targeting IL-11Rα inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model. [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 1261. doi:10.1158/1538-7445.AM2014-1261
Abstract 129: AIP1 suppresses tumor metastasis by regulating tumor microenvironment and metastatic niche
Authors: Min Wang 
Published: May 2015

Abstract
AIP1 (also called DAB2IP, a new member of RAS-GAP family protein) is downregulated in a variety of human cancer tissues. We and others have recently reported that AIP1 functions as a tumor suppressor in prostate cancer models. However, the role of AIP1 in regulating tumor microenvironment and metastatic niche is not known. In the present study, we implanted tumor cells with the same genetic background into C57BL/6 wild type (WT) and AIP1-deficient (AIP1-KO) mice to address this question. In subcutaneous (SQ) allograft models using B16 melanoma and LLC Lewis lung carcinoma, tumor growth and metastasis to multiple organs including lymph node, lung, liver, spleen and bone marrow were significantly enhanced in AIP1-KO host, suggesting AIP1 in tumor microenvironment limits tumor metastases. However, a direct intravenously injection of tumor cells resulted in no differences in tumor metastasis between WT and AIP1-KO mice, indicating AIP1 in host regulates tumor metastasis at steps prior to extravasation to target tissues. We examined effects of AIP1 deletion on the induction of local inflammation, tumor cell epithelial-mesenchymal transition (EMT), generation of metastatic routes (formation of new blood and lymphatic vessels) and establishment of pre-metastatic niche in distance tissues. SQ tumors in AIP1-KO host showed more profound increases in macrophage infiltration, tumor cell EMT, intratumoral angiogenesis and peri-tumoral lymphangiogenesis as well as lymphangiogenesis in lymph nodes prior to the detection of metastatic tumor cells. Finally, SQ tumor induced an establishment of pre-metastatic niche in lung as indicated by increased immunostaining for fibronectin and accumulation of VEGFR1, c-Kit and CXCR-positive cells which were augmented in AIP1-KO mice. Importantly, WT recipient with AIP1-KO bone marrow-derived cells showed similar phenotype to AIP1-KO mice in tumor growth and metastasis. Taken together, our data suggest that AIP1 functions as tumor metastasis suppressor by regulating tumor microenvironment, metastatic routes and pre-metastatic niche.
Citation Format: Wang Min. AIP1 suppresses tumor metastasis by regulating tumor microenvironment and metastatic niche. [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 129. doi:10.1158/1538-7445.AM2014-129
Abstract 1293: Familial melanoma by histology and age guiding clinical genetic counseling: joint data from five Nordic countries
Authors: Fallah Mahdi , Pukkala Eero , Sundquist Kristina , Tretli Steinar , Olsen Jørgen H. , Tryggvadottir Laufey 
Published: May 2015

Abstract
Background: We aimed to estimate lifetime cumulative risk of melanoma (CRM) in relatives of patients with melanoma by histology and age at diagnosis in patients and relatives.
Methods: A population-based cohort of 238,724 first-degree relatives of 46,091 melanoma patients diagnosed in 1955-2010 in Nordic countries was followed for cancer incidence.
Findings: The CRM (0-79 years) in first-degree relatives of a patient with superficial spreading (SSM), nodular (NM), or lentigo maligna (LMM) melanoma was quite similar, ranging from 2.5% to 2.9%, which represents about 2-fold increase over the general population risk. When one melanoma patient in the family was diagnosed before age 30, the CRM was 3.2%. When there were ≥2 melanoma patients diagnosed before age 30 in a family, CRM for relatives was 13.8%, 5.8% for diagnoses at age 30-59, and 4.8% for diagnoses at age 60 or older. Depending on age at diagnosis of same-sex twins (not known whether monozygotic or dizygotic), their CRM was 7.4-21.3%. Although no familial case of concordant histological types of acral lentiginous/desmoplastic/compound nevus/spindle cell melanomas or malignant blue nevus (MBN) was found, familial risks of discordant histological types of melanoma were interchangeably high for most of the types, e.g. higher risk of SSM when a first-degree relative had NM [standardized incidence ratios (SIR)=2.6, 95%CI=2.1-3.3, n=72] or ALM (4.0, 95%CI=1.5-8.8, n=6) and vice versa. There was a tendency toward concordant age at diagnosis of melanoma among relatives of melanoma patients.
Interpretation: This study provides clinically relevant absolute and relative risk estimates for family members of melanoma patients by age at diagnosis in patients and relatives. Our finding may suggest that the role of genetic or environmental factors in the differentiation of histological types of melanoma is not as strong as its role in the development of melanoma as such.
Citation Format: Mahdi Fallah, Eero Pukkala, Kristina Sundquist, Steinar Tretli, Jørgen H. Olsen, Laufey Tryggvadottir. Familial melanoma by histology and age guiding clinical genetic counseling: joint data from five Nordic countries. [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 1293. doi:10.1158/1538-7445.AM2014-1293