bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1831: Interrogating HER2+ plasticity and lapatinib resistance with MicroEnvironment MicroArrays
Authors: Watson Spencer , Korkola James , Rantala Juha , Gray Joe 
Published: May 2015

Abstract
Treatment of HER2+ breast cancer with the targeted therapeutic lapatinib has shown promising results, but faces the major obstacles of de novo and acquired resistance in clinical use. Much of this resistance can be attributed to intratumoral heterogeneity, giving rise to drug resistant cell populations. An important factor of intratumoral heterogeneity is spatial heterogeneity of cancer cells, which results in differential contact with extra cellular matrix (ECM) proteins, stromal cells, and growth factors and signaling molecules within the tumor microenvironment. This can variably alter the intracellular signaling network of cancer cells, modulating cellular plasticity and drug response.
To assess the effect cellular interactions with the microenvironment has on lapatinib resistance, we are utilizing MicroEnvironment MicroArrays (MEMA), which consist of combinations of functional ECMs, growth factors, and cytokines printed onto a solid surface, allowing for the simultaneous interrogation of thousands of unique microenvironments in a single assay. We have grown HER2+ breast cancer cells on the MEMA spots, treated with lapatinib, and measured functional response to each protein combination by immunofluorescent assay and high throughput image acquisition and analysis. By focusing on markers of proliferation, apoptosis, and cellular subtype differentiation, we have identified protein combinations that confer resistance to lapatinib. One of the combinations that came out of this preliminary screen is the desmosome protein Desmoglein II and the growth factor HGF, which continued to drive proliferation of HER2+ cells in the presence of lapatinib. Validation experiments found that on their own these two proteins could modulate the differentiation status of HER2+ cells, and combined to provide resistance to lapatinib treatment in traditional cell culture assays. In addition, the extent of drug resistance provided by protein interaction was found to be strongly linked to the differentiation status of the HER2+ cells. Both HGF and Desmoglein II are reported to be important in the progression of breast cancer, but their effect in combination is a novel finding from the use of MEMA analysis.
We plan to utilize RNAseq analysis to inform a probabilistic computational model of network signaling to determine what pathways are enhanced by the microenvironment factors, and siRNA knockdown or small molecule inhibitors of identified pathway nodes can then determine which interactions can be targeted to restore drug sensitivity.
Citation Format: Spencer Watson, James Korkola, Juha Rantala, Joe Gray. Interrogating HER2+ plasticity and lapatinib resistance with MicroEnvironment MicroArrays. [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 1831. doi:10.1158/1538-7445.AM2014-1831
Abstract 1844: Novel HER3 neutralizing antibody, patritumab abrogates cetuximab resistance mediated by a heregulin-autocrine loop in colorectal cancer
Authors: Kawakami Hisato , Okamoto Isamu , Yonesaka Kimio , Okamoto Kunio , Kuwata Kiyoko , Morita Yume , Yamaguchi Haruka , Nishio Kazuto , Nakagawa Kazuhiko 
Published: May 2015

Abstract
Purpose
Acquired resistance to cetuximab is a major problem in the treatment of colorectal cancers. We previously showed that the HER3/HER4 ligand heregulin induced resistance to cetuximab by increasing the association between HER2 and HER3, and subsequent activation of downstream targets. We have now investigated strategies to overcome such resistance, using patritumab, a novel neutralizing HER3 antibody.
Experimental design
We established DiFi cells that stably express heregulin (DiFi-HRG cells) as a result of retroviral infection, and examined the antitumor effect of cetuximab, patritumab, and the combination of both in these cells in vitro and vivo.
Results
DiFi-HRG cells secreted large amount of heregulin and exhibited resistance to cetuximab. Cetuximab alone down-regulated ERK phosphorylation, whereas it had no effect on AKT phosphorylation, suggesting that continuous AKT activation underlain underlies resistance to cetuximab in these cells. In contrast, Patritumab in combination with cetuximab markedly reduced the level of phosphorylation of HER2 HER3 and AKT, as well as ERK, and induced apoptosis that was accompanied by upregulation of BIM and by downregulation of survivin in vitro. Furthermore, the combination therapy also markedly inhibited the growth of DiFi-HRG tumors in nude mice to a greater extent than did treatment with either drug alone.
Conclusion
Our data indicate that HER2/HER3 signaling activated by a heregulin-autocrine loop confers resistance to cetuximab, and that patritumab restored sensitivity to cetuximab by inhibition of HER3 phosphorylation that is stimulated by heregulin.
Citation Format: Hisato Kawakami, Isamu Okamoto, Kimio Yonesaka, Kunio Okamoto, Kiyoko Kuwata, Yume Morita, Haruka Yamaguchi, Kazuto Nishio, Kazuhiko Nakagawa. Novel HER3 neutralizing antibody, patritumab abrogates cetuximab resistance mediated by a heregulin-autocrine loop in colorectal 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 1844. doi:10.1158/1538-7445.AM2014-1844
Abstract 1864: Reptin as a tumor-associated antigen of epithelial ovarian cancer
Authors: Lee Eun-ju , Cho Hanbyoul , Shin Ha-Yeon , Yang Wookyeom , Kwon Hyunja , Kim Sol , Kim Jae-Hoon 
Published: May 2015

Abstract
Background:
Reptin is also known as RuvBl2, Tip48, TIP49b, ECP51 and CGI-46, is a member of AAA+ (ATPases associated with diverse cellular activities) superfamily. Reptin is associated with cell viability and development of S. cerevisiae, D. melanogaster, X. laevis, or D. rerio has a lot of functions including transcriptional regulation, DNA damage repair and telomerase activity.
Self-reactive IgG autoantibodies are present on human sera.Each self-reactive IgG autoantibody derived from pre- and post-treatment of ovarian cancer patients is competitively combined with cancer tissue gotten during the operation, self-reactive IgG autoantibodies bound to tumor antigens. As a result, self-reactive IgG autoantibodies may be decreased after treatment. In this study, we have identified and investigated the function of Reptin as an available therapeutic biomarker for ovarian cancer using difference of self-reactive IgG autoantibody amounts.
Method:
We carried out the two-dimensional differential gel electrophoresis analysis of immunoprecipitated tumor antigens (2D-DITA) to compare with expression level of autoantibodies in pre- and post-treatment sera of 14 ovarian cancer patients. Autoantibody differentiated between pre- and post-treatment sera was identified by MALDI-TOF.
We performed qRT-PCR with 8 human ovarian surface epitheliums (HOSEs) and 14 ovarian cancer cell lines for validation studies. Reptin was also detected in other ovarian cancer tissues by immunohistochemistry (IHC). We constructed SKOV-3 cell line for overexpression Reptin using lentiviral system. For investigating function of Reptin, we performed proliferation, wound healing, and invasion assay.
Results:
We identified Reptin as a tumor-associated antigen of epithelial ovarian cancer. Relative mRNA level of Reptin showed higher levels in ovarian cancer cell lines than in HOSEs. Reptin protein levels were significantly upregulated in ovarian cancer tissues than normal, benign, and borderline ovarian tumors. In SKOV-3 cells, overexpression of Reptin induced inhibition of cell proliferation (P&lt;0.0001), migration and invasion (P&lt;0.0001).
Conclusion: Our results demonstrate that Reptin is a tumor -associated antigen of ovarian cancer, i.e. tumor suppressor.
Citation Format: Eun-ju Lee, Hanbyoul Cho, Ha-Yeon Shin, Wookyeom Yang, Hyunja Kwon, Sol Kim, Jae-Hoon Kim. Reptin as a tumor-associated antigen of epithelial ovarian 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 1864. doi:10.1158/1538-7445.AM2014-1864
Abstract 1872: A novel method for efficient and hands-free purification of circulating DNA from human plasma
Authors: White Douglas , Horejsh Douglas , Zeng Zhiyang , Uyeda Tetsuo , Meisenheimer Poncho , Urh Marjeta 
Published: May 2015

Abstract
Circulating or Cell-Free DNA in plasma can be used to detect biomarkers that show great promise for diagnosis and monitoring of cancer, and is already being used as a non-invasive method to detect trisomy in fetuses. There is currently great interest in the discovery of new cancer biomarkers and their potential clinical application. However, reproducible and efficient purification of these highly fragmented and low-concentration species represents a major challenge. Here we will present a novel method which is completely automated and allows parallel purification of circulating nucleic acid from plasma and serum using a medium-throughput robot. Sixteen samples can be processed simultaneously. The method was optimized to produce high-quality DNA that is suitable for use in quantitative PCR and next generation sequencing. In addition, the absence of any pre-processing steps improves reproducibility and lowers the risk of contamination.Initial characterization on plasma from pregnant women showed that fetal DNA could be detected as early as 4 weeks into gestation and could be tracked throughout pregnancy. Further characterization showed that the system was able to reliably detect less than 25 copies/ml plasma of fragmented DNA that was spiked into the sample. Subsequent work on plasma from patients with colorectal cancer showed that the system was able to detect DNA containing both wild-type and mutated EGFR, suggesting that this method can be a useful tool when screening plasma samples for biomarkers of interest.
Citation Format: Douglas White, Douglas Horejsh, Zhiyang Zeng, Tetsuo Uyeda, Poncho Meisenheimer, Marjeta Urh. A novel method for efficient and hands-free purification of circulating DNA from human plasma. [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 1872. doi:10.1158/1538-7445.AM2014-1872
Abstract 1886: Highly sensitive detection of circulating tumor DNA in plasma as a biomarker of colorectal cancer
Authors: Wiggin Matthew , Perkins Jaryn , Mai Laura , Vysotskaia Valentina , Marziali Andre 
Published: May 2015

Abstract
Circulating tumor DNA (ctDNA) from the blood of cancer patients is a promising biomarker of certain types of colorectal cancer, with potential use in screening, treatment selection, therapy response monitoring, minimal residual disease detection, and surveillance.
We present results demonstrating that the OnTarget ctDNA detection assay can be used as an indicator of the presence of genomic variants associated with colorectal cancer in patients prior to treatment. The study includes three cohorts of individuals: young normal controls, age-matched normal controls, and colorectal cancer patients whose blood was drawn prior to treatment or surgery, and whose diagnosis confirms the presence of a colorectal tumor. Tissue from the primary tumor biopsy was also collected and analyzed with the OnTarget assay.
Using Boreal Genomics' OnTarget 46-mutation panel, we find high correlation between the tumor mutational profile and the plasma mutation profile even for early stage patients demonstrating high sensitivity (88% plasma-tissue concordance to date) of the assay. By applying the same assay in the normal population we demonstrate extremely low false positive rates, highlighting the potential of the assay as a tool for therapy monitoring, surveillance, or screening.
The OnTarget assay is capable of single molecule sensitivity, specificity to ≤0.01% mutation abundance versus wild-type, and multiplexing of over 100 mutations in a single test from a single plasma sample. The OnTarget technology employs a combination of Next Generation DNA Sequencing and a proprietary target selection process that removes wild-type DNA prior to amplification to greatly improve signal to noise and reduce the error rate of sequencing.
We present an overview of the technology and results from an ongoing study to demonstrate the potential clinical utility of ctDNA as an effective biomarker to guide management of colorectal cancer.
Citation Format: Matthew Wiggin, Jaryn Perkins, Laura Mai, Valentina Vysotskaia, Andre Marziali. Highly sensitive detection of circulating tumor DNA in plasma as a biomarker of colorectal 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 1886. doi:10.1158/1538-7445.AM2014-1886
Abstract 1896: Clinicopathologic characteristics for elevated microsatellite alterations at selected tetranucleotie repeats (EMAST) in colorectal cancer of Korean patients
Authors: Ihn Myong Hoon , Kim Duck-Woo , Lee Hye Seung , Park Kyoung Un , Lee Soo Young , Oh Heung-Kwon , Kang Sung-Bum 
Published: May 2015

Abstract
Microsatellite instability (MSI) is a hallmark of tumors with mismatch repair deficiency. Recently, a different type of instability, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been reported in colorectal cancers. EMAST was reported to be associated with various clinicopathologic characteristics, including MSI status, race, tumor progression, and morphology and differentiation of tumor. However, contrary to MSI status which is well known prognostic and predictive marker in CRC, clinical implication of EMAST in CRC is still unclear. We evaluated EMAST and MSI status in 88 sporadic CRC cases using five markers (MYCL1, D9S242, D20S85, D8S321, and D20S82) for EMAST and Bethesda panel for MSI status, respectively. Clinicopathologic data of the patients were collected and analyzed. Tumors showing frameshifts in at least two or more EMAST markers were classified as EMAST-positive. Among 88 tumors, EMAST-positive tumors were 22 (25.0%) and MSI-H tumors were 32 (36.4%). EMAST-positive tumors showed proximal location of tumor (90.9% vs. 66.7%, p=0.029), less frequent loss of thymidylate synthase expression (4.5% vs. 34.8%, p=0.005), MSI-H (81.8% vs. 21.2%, p&lt;0.001), nuclear heterogeneity of hMSH3 expression (77.3% vs. 51.5%, p=0.046) when compared with non-EMAST tumor. The other variables including age, gender, gross type and differentiation of tumor, a presence of stromal reaction, and tumor stage were not associated with EMAST status. In addition, overall and disease-free survival rate were similar between EMAST and non-EMAST tumor. In this study, MSI-H tumors showed very high frequency of EMAST-positive and clinical characteristics of EMAST and non-EMAST tumor were definitely different.
Citation Format: Myong Hoon Ihn, Duck-Woo Kim, Hye Seung Lee, Kyoung Un Park, Soo Young Lee, Heung-Kwon Oh, Sung-Bum Kang. Clinicopathologic characteristics for elevated microsatellite alterations at selected tetranucleotie repeats (EMAST) in colorectal cancer of Korean patients. [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 1896. doi:10.1158/1538-7445.AM2014-1896
Abstract 1903: Personalized diagnostics: Receptor specific gold nanorods used for accurate diagnosis of EGFR expression in human tumor tissues
Authors: Caldwell Chuck , Zambre Ajit , Suresh Dhananjay , Arthur Gerald , Kannan Raghuraman 
Published: May 2015

Abstract
Objective: The purpose of this study was to apply the enhanced surface chemistry and imaging properties of gold nanorods to the area of tumor protein diagnostics in order to give an accurate, quantifiable interpretation of a patient's biomarker status. The epidermal growth factor receptor (EGFR; HER1) is a cell surface receptor that regulates cell migration, adhesion, and proliferation. EGFR is commonly overexpressed in a variety of cancers. EGFR expression testing has been mandated by insurance companies in many areas before therapy can be given. Current methods of EGFR evaluation have been shown to be unreliable, thus EGFR was chosen as a target of interest for our studies.
Methods: Gold nanorods (GNR) of aspect ratio 3:4 were prepared using an established seed-mediated growth method. The GNR were then PEGylated and conjugated with a unique modified peptide that has shown specific affinity for the EGF receptor. The product was characterized to show stability and presence of surface-bound peptide. The compound known as GNR-1070 was used to examine correlations between EGFR expression and gold present on the membranes of human cell lines and paraffin-embedded tissue samples.
Results: In cell lines that are known to express EGFR, gold particles were identified bound to the membranes. The amount of bound gold correlated with the degree of EGFR expression of each cell line. Histochemical analysis of paraffin-embedded human tissue lines also correlated with the amount of gold bound to the membranes of the tissues.
Conclusion: Gold nanorods conjugated with receptor-specific peptides can be used to give an accurate evaluation of protein expression in human cell lines and tissue samples.
Citation Format: Chuck Caldwell, Ajit Zambre, Dhananjay Suresh, Gerald Arthur, Raghuraman Kannan. Personalized diagnostics: Receptor specific gold nanorods used for accurate diagnosis of EGFR expression in human tumor tissues. [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 1903. doi:10.1158/1538-7445.AM2014-1903
Abstract 1914: Functional characterization of oncogenic-induced dedifferentiation in neurons and astrocytes using DP-seq
Authors: Friedmann-Morvinski Dinorah , Bhargava Vipul , Gupta Shakti , Verma Inder M. , Subramaniam Shankar 
Published: May 2015

Abstract
Glioblastoma (GBM) is the most common and lethal form of intracranial tumor. Using a Cre-inducible lentiviral GBM mouse model we recently showed that gliomas can originate from dedifferentiation of mature neurons and astrocytes. Expression analysis of the known markers (of the differentiated cell-types) showed diminished expression while the expression of the undifferentiated state markers were significantly up-regulated in the dedifferentiated transformed neurons and astrocytes. In this study, we performed whole transcriptome analysis of these cells along with mouse pluripotent embryonic stem cells (mESC), neural stem cells (NSC), neurons and astrocytes to characterize the undifferentiated state of these cells. Our analysis revealed that dedifferentiated cell-types shared traits with neurons and NSCs at the global transcriptome level suggesting that they have retained memory of their cell-of-origin and share markers of undifferentiated cells with NSCs. Functional analysis of the transcriptomics data revealed involvement of the Wnt signaling, cell cycle and the focal adhesion pathways in defining the state of the dedifferentiated cell-types. Our analysis further revealed conservation of a gene interaction network in both dedifferentiated cell-types. This network exhibited a modular architecture, connecting components of the cell cycle pathway to Wnt signaling and the focal adhesion pathways. One of these components, Osteopontin (OPN), also known as Spp1, is highly expressed and secreted by the tumors and dedifferentiated transformed neurons and astrocytes. Attempts to inhibit the action of OPN, either by using a neutralizing antibody or silencing the OPN gene (shRNA), blocked the formation of tumorspheres and diminished their proliferating capacity. We are currently assessing the effects of the inhibition of OPN function in vivo.
Further genetic perturbation of additional interacting partners and/or the abolishment of the interactions can help elucidate the regulatory mechanism of this network in maintaining the dedifferentiated state of the transformed neurons and astrocytes.
Citation Format: Dinorah Friedmann-Morvinski, Vipul Bhargava, Shakti Gupta, Inder M. Verma, Shankar Subramaniam. Functional characterization of oncogenic-induced dedifferentiation in neurons and astrocytes using DP-seq. [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 1914. doi:10.1158/1538-7445.AM2014-1914
Abstract 1917: Re-thinking the concept of cancer stem cells: Polyploid giant cancer cells as mother cancer stem cells
Authors: Liu Jinsong , Mercado-Uribe Imelda , Niu Na , Sun Baocun , Kuang Jian , Zhang Shiwu 
Published: May 2015

Abstract
Polyploid giant cancer cells (PGCCs) have been observed by pathologists for over a century. PGCCs contribute to solid tumor heterogeneity, but their functions are largely undefined. Little attention has been given to these cells, largely because PGCCs have been generally thought to originate from repeated mitosis/cytokinesis failure and have no capacity for long-term survival and cell proliferation. Our group has recently reported that we successfully purified and cultured PGCCs from human ovarian cancer cell lines and primary ovarian cancer. These cells are highly resistant to oxygen deprivation and could form through endoreduplication or cell fusion, generating regular-sized cancer cells quickly through budding or burst. They are positive for normal and cancer stem cell markers, divided asymmetrically and cycled slowly. They can differentiate into adipose, cartilage, and bone. A single PGCC formed cancer spheroids in vitro and generated tumors in immunodeficient mice. PGCC-derived tumor gained a mesenchymal phenotype with increased expression of cancer stem cell markers CD44 and CD133 and become more resistant to the treatment of cisplatin and also form tissue organ-like structure. Together, our results reveal that the PGCCs present a resistant form of human cancer that behaves like mother cancer stem cells that can contribute to generation of daughter cancer stem-like cells and formation of tissue organ structure. These cells can be induced in response to hypoxia and play a fundamental role in regulating tumor heterogeneity, stemness, and chemoresistance in human cancer. In contrast to the phenotype unstable cancer stem cells selected by cell surface markers, PGCCs can be stably passaged and maintained, thus these cells provide reproducible experimental system to study mechanisms involved in generation of cancer stem cells. The key references related this concept are listed below. we will provide a most updated data to support this new concept that PGCCs as mother cancer stem cells at this meeting.
Zhang S et al, Oncogene 2013, March online publication; Zhang S et al, Int J Cancer. 2013 Feb 1;134(3):508-18; Zhang S el al, Cancer Lett. 2013 Jun 10;333(2):205-12.
Citation Format: Jinsong Liu, Imelda Mercado-Uribe, Na Niu, Baocun Sun, Jian Kuang, Shiwu Zhang. Re-thinking the concept of cancer stem cells: Polyploid giant cancer cells as mother cancer stem cells. [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 1917. doi:10.1158/1538-7445.AM2014-1917