bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5038: Why is rapamycin effective against Kaposi sarcoma? An analysis of molecular pathways reveals posttranslational silencing of PTEN
Authors: Dittmer Dirk , Roy Debasmita , Krown Susan E. , Damania Blossom ,   AIDS Malignancy Consortium (AMC)
Published: June 2012

Abstract
Background: Rapamycin (RAPA) and its derivatives target the mTOR kinase within the PI3K/Akt/mTOR pathway. RAPA induced regression of transplant-associated Kaposi sarcoma (KS), but it is unclear why this cancer and selected others are responsive to mTOR inhibitors, whereas many others are not. KS requires infection with the KS-associated herpesvirus (KSHV). We hypothesized that because of its viral etiology, the PI3K/Akt/mTOR pathway in KS would be activated post-translationally and reversibly rather than by mutation and thus more responsive to small molecule inhibitors.
Material and methods: The AMC conducted a pilot study of RAPA in HIV-associated KS and several partial responses were observed. We used immuno- histochemistry and molecular methods to study the PI3K/Akt/mTOR pathway in sequential biopsies from patients on this trial, as well as in a larger collection of KS biopsies assembled into a TMA, tumor cell lines and tumors from RAPA-treated mice bearing KS xenografts.
Results: Ribosomal protein S6 and Akt were consistently phosphorylated in KS. At the same time PTEN was expressed. We found no evidence for PTEN mutations, rather it was phosphorylated. RAPA inhibited mTORC1 signaling in HIV-KS patients and murine xenografts as determined by loss of S6 phosphorylation. Akt remained consistently activated and we saw no changes in phosphorylation at either the mTORC-independent S308 or mTORC2-dependent T473, i.e. there was no evidence for compensatory upregulation of mTORC2.
Conclusions: Rapamycin inhibits the mTORC1 pathway in HIV-KS. KS can be considered representative of tumors in which PTEN is epigenetically inactivated and which may be most susceptible to mTOR inhibition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5038. doi:10.1158/1538-7445.AM2011-5038
Abstract 5069: Comprehensive mutational analysis of epidermal growth factor receptor, EML4-ALK, and KRAS identifies four distinct disease entity in never-smoker patients with non-small cell lung cancer
Authors: Kim Hye Ryun , Shim Hyo Sup , Chung Jin-Haeng , Lee Young Joo , Ha Sang-Jun , Kim Se Kyu , Kim Joo Hang , Cho Byoung Chul 
Published: June 2012

Abstract
Purpose: To determine the proportions of major oncogenic mutations and examine the survival in genotype-specific subsets in non-small-cell lung cancer (NSCLC) from never-smokers.
Patients and Methods: We concurrently analyzed mutations in epidermal growth factor receptor (EGFR), EML4-ALK, and KRAS in 229 never-smokers with NSCLC. The ALK rearrangements was identified by using fluorescent in situ hybridization and confirmed by immunohistochemistry. The EGFR (exons 18 to 21) and KRAS (codon 12/13) mutations were determined by direct sequencing.
Results: Of 229 tumors, the frequency of EGFR mutation, ALK rearrangement, KRAS mutation, and wild-type for aforementioned genes (WT/WT/WT) were 48.0%, 8.3%, 3.5%, and 40.2%. All mutations were mutually exclusive. The progression free survival to EGFR tyrosine kinase inhibitors (TKIs) was 12.8, 6.3, 2.1, and 1.6 months in EGFR mutant, WT/WT/WT, KRAS mutant, and EML4-ALK, respectively. In a logistic regression model, the adjusted hazard ratio for the risk of disease progression to EGFR TKIs was 0.59 (95% CI, 0.40 to 0.87; P = .008) for EGFR mutant, 4.58 (95% CI, 2.07 to 10.15; P &lt; .001) for EML4-ALK, 4.23 (95% CI, 1.65 to 10.8; P &lt; .003) for KRAS mutant, respectively. Overall survival was also significantly different among genotypes.
Conclusion: This is the first comprehensive and concurrent analysis of three major oncogenic mutations in the largest-ever cohort of East Asian never-smokers with NSCLC. Since survival outcome is different among genotypes and drugs are now available to target these mutations, genetic profiling is needed to identify genotype-specific subsets and successfully treat them with appropriate kinase inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5069. doi:10.1158/1538-7445.AM2011-5069
Abstract 5079: A mathematical approach to earlier cancer detection: Using blood biomarker assays to monitor growth of a tumor from a single cell
Authors: Hori Sharon S. , Gambhir Sanjiv S. 
Published: June 2012

Abstract
Early cancer detection may eventually be enabled by a quick, highly sensitive assay to monitor abnormal cancer biomarker levels in blood, followed by a localized imaging scan to visualize tumor burden. To improve screening of high-risk patients prior to imaging, blood assay sensitivity/specificity is being increased and biomarker secretion processes are being studied, but it is not clear which strategies will provide better detection of smaller tumors. To address this, we developed a linear 1-compartment model with 9 parameters to describe plasma biomarker kinetics in relation to the growth of cancer, beginning with a single tumor cell. In this model, plasma biomarker levels are dependent on the number of biomarker-secreting cells (cancerous and healthy), the biomarker secretion rate, the percent of biomarker entering plasma from the interstitium, and the elimination rate of plasma biomarker. To exemplify a realistic case, we based parameter values on ovarian cancer and CA125 secretion because CA125 secretion rates and assay sensitivities are readily available in published literature. Gompertzian tumor growth was modeled using published human ovarian carcinoma growth rates. The model predicted that tumor burden must grow to a volume of (20.4 mm)3 to reach plasma biomarker levels that are greater than in 99.9% of healthy patients; this may require &gt;10 years after the birth of the initial tumor cell. These predictions are consistent with published cancer progression timelines recently uncovered from sequencing of metastatic genome data. Furthermore, by perturbing parameter values over log-orders of magnitude, we identified alternative strategies that could allow detection of &lt;1 mm diameter tumors (Table). Applying this model to other cancers and associated biomarkers may pinpoint characteristics of ideal biomarkers and the assays used to detect them, thereby helping to identify cancers at earlier stages, when they can be more effectively treated.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5079. doi:10.1158/1538-7445.AM2011-5079
Abstract 5134: G-Quadruplex structure formation in the proximal promoter region of the human vascular endothelial growth factor gene
Authors: Agrawal Prashansa , Hatzakis Emmanuel , Guo Kexiao , Yang Danzhou 
Published: June 2012

Abstract
The human vascular endothelial growth factor gene, VEGF, is a key regulator of angiogenesis. It plays an important role in tumor survival, growth and metastasis. It is over-expressed in many types of human cancers including glioma and renal cell carcinoma, ovarian and pancreatic cell carcinomas. The VEGF proximal promoter region contains a poly G/poly C rich tract that is essential for basal and inducible VEGF expression. The guanine-rich (G-rich) strand on this tract is shown to form a specific secondary structure, the G-quadruplex. Here we have elucidated the solution structure of the major intramolecular G-quadruplex formed on the G-rich strand of this region in K+ solution by proton Nuclear Magnetic Resonance (NMR) spectroscopy followed by the structural calculation of the G-quadruplex using Distance Geometry Simulated Annealing (DGSA) module of XPLOR-NIH software. It is inferred that this strand adopts a well-defined parallel-stranded G-quadruplex structure, which contains three G-tetrads stabilized by Hoogsteen hydrogen bonding, as well as three double-chain reversal loops containing 1:4:1 bases, a feature important for the formation of the most thermodynamically stable conformation. The size of the 4-base loop plays a critical role in determining the most favored folded pattern of a G-quadruplex. These 4-base loop residues interact with the residues of the 3’ flanking region of VEGF sequence; also, the 1-base double-chain reversal loop on two edges of the tetrad are very stable, which overall contribute in stabilizing the 1:4:1 conformer. We have found that the two cytosines in this central 4-base loop are involved in hydrogen bonding with the 3’ terminal end residues of VEGF, which is a salient feature as this interaction is sequence-specific and differs from that in other parallel-stranded structures, e.g. c-myc, significantly. These results are also supported by the DMS footprinting results by Guo et al. (2008) which show that the guanines involved in the tetrad formation in this major G-quadruplex loop isomer 1:4:1 are well-protected against DMS methylation. Therefore, the knowledge about the secondary structure of this non B-DNA conformation of the VEGF promoter region is essential for using the G- quadruplex as a target for anticancer drugs, which could be a novel approach to anti-angiogenesis drug discovery in cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5134. doi:10.1158/1538-7445.AM2011-5134
Abstract 5154: Serotonin signaling as a novel target of tumor angiogenesis
Authors: Zamani Ali , Zhai Ling , Roy Anshu M. , Li Rongbao , Qu Zhican , Maxuitenko Yulia Y. 
Published: June 2012

Abstract
Angiogenesis is a well-controlled process that is regulated by multiple factors that are secreted by the cancer cells as well as other cells within the tumor microenvironment. Angiogenesis inhibitors are showing therapeutic efficacy in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are transitory and are followed by resistance and a restoration of tumor growth and progression. Therefore, novel anti-angiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. Activation of platelets and blood coagulation frequently occurs in cancer patients. Apart from VEGF, platelets contain several other angiogenic growth factors and inhibitors that are released upon activation and promote tumor neoangiogenesis. Although considerable attention has been focused on platelet peptide growth factors, little is known about the mitogenic effects of nonpeptide platelet products such s serotonin (5-HT), considering that 99% of 5-HT in blood is found in platelets and is released at blood clotting sites. In previous studies, we have shown that endothelial cells express 5-HT receptors and 5-HT has growth stimulatory effcts on multiple types of endothelial cells. We have also demonstrated that 5-HT binds to inhibitory type of G-protein coupled receptors and stimulates the phosphorylation of PYK2/PI3K/AKT/mTOR signaling pathway, the same signaling pathway, which has been activated by most angiogenic factors, including VEGF. In our recent studies, we explored angiogenic promoting activity of 5-HT in the mouse matrigel plug assay (in vivo angiogenesis model system) and antiangiogenic potential of antagonists against 5-HT receptors in xenograft-CAM assay (ex vivo tumor angiogenesis model system). The most importantly, an antagonist against a specific 5-HT receptor demonstrated the synergistic effect in blocking tumor-induced new blood vessel formation when it was applied in combination with Sutent, a FDA approved antiangiogenic drug against VEGF receptor. The results of this study suggest that 5-HT signaling pathway constitute a novel target of tumor angiogenesis in anticancer therapeutic development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5154. doi:10.1158/1538-7445.AM2011-5154
Abstract 5218: Basigin-2 (EMMPRIN), a prognostic marker, is a dynamic portal of entry into cancer cells
Authors: Ancheta Leonardo R. , Lappi Douglas A. 
Published: June 2012

Abstract
Basigin-2 (EMMPRIN) is a marker for prognosis of several tumor types. With the identification of the internalization of basigin-2 in response to antibody binding, we now further explore the possibility of its use as a dynamic portal of entry for molecules into cancer cells. We also wish to identify a correlation between number of basigin-2 on the cell surface and half maximal effective concentration (EC50) of a targeted toxin by examining eleven tumor cell lines which encompass various tumor types such as breast (MCF-7, BT549), leukemia (K562, HL-60), multiple myeloma (RPMI-8226), neuroblastoma (SH-SY5Y), non-small cell lung (A549, NCI-H23, NCI-H522), and prostate (PC3).
In this investigation, we employed the use of flow cytometry to characterize each cell line according to mean fluorescence as well as to determine the number of basigin-2 molecules expressed on the cell surface through a surface quantification assay. This was visualized by staining with a monoclonal antibody directed to basigin-2 ECD with comparison of results against a standard with known Antibody Binding Capacity (ABC) and standardizing the results into Molecules of Equivalent Soluble Fluorochromes (MESF; Bangs Laboratories, Inc.).
Last year at this meeting we showed the ability of an antibody to basigin-2 ECD to cause internalization of secondary targeted toxins to cause cell death. We now report on the activity of a primary toxin: the ribosome-inactivating protein saporin attached directly to an antibody to basigin-2.
Cytotoxicity assays yielded an EC50 range of 3.5-420 pM while surface quantification assays resulted in expression that ranged from 1-4 million basigin-2 molecules per cell. Cell lines showing potent EC50 values were characterized to have higher surface expression of basign-2 when compared to cell lines with less potent EC50 values.
Preliminary results suggest a correlation between EC50 and basigin-2 surface expression such that more basigin-2 available on the cell surface would facilitate greater opportunity for a primary toxin to bind and enter into the cell and cause cell death. These data suggest the use of basigin-2 as a means to identify an entry system for molecules into cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5218. doi:10.1158/1538-7445.AM2011-5218
Abstract 5225: Quantification of circulating tumor cell aggregates in breast cancer patient blood using an enrichment-free detection method
Authors: Cho Edward H. , Sok Devin , Marrinucci Dena , Luttgen Madelyn , Kolatkar Anand , Yoshioka Craig , Wendel Marco , Matrone Michael A. , Lazar Daniel , Yang Xing , Malchiodi Michael , Lamy Rachelle , Torrey Melissa , Bethel Kelly , Kuhn Peter 
Published: June 2012

Abstract
Circulating tumor cells (CTCs) have been implicated as a potential population of cells that may seed metastasis in cancer patients. In order to characterize and understand this population of cells, an enrichment-free immunofluorescence detection method was developed by our lab. This method take whole patient blood and classifies cells based on cytokeratin (CTCs) and CD45 (WBCs) antibody staining. Using this CTC detection method, a population of cells residing in tumor cell aggregates was observed in blood draws from Stage IV breast cancer patients. It was previously observed in ex vivo mouse experiments that homotypic aggregate formation of tumor cells may increase metastatic efficiency (Glinsky, et al., Cancer Research, 2003). In this work, we seek to determine if a significant proportion of CTCs reside in homotypic aggregates in patient blood by enumerating CTC aggregates from the blood draws of 23 Stage IV breast cancer patients and 16 healthy donor patients. Preliminary analysis measuring associations of CTCs with other nucleated cells found in patient blood draws revealed that ∼43% of cytokeratin-positive (CK+) cells found in breast cancer patient samples localize with either other CK+ or white blood cells (WBCs) versus 14% in healthy donor patient samples. Furthermore, ∼19% of WBCs were found to be associated with either CK+ or other WBCs in breast cancer patient samples versus ∼7% in healthy donor patient samples. Pathological review confirming CK+ cells as CTCs revealed that of the CTCs detected in patient blood after pathological review, ∼2% of CTCs were found as homotypic aggregates versus ∼0.07% in healthy donor samples (p=0.0005). Four breast cancer patients were found to have no CTC aggregates. Two breast cancer patients had significantly higher than average CTC aggregate percentages (∼6% and ∼7%). Patients will continue to be monitored to measure any differences in disease outcome of patients with high incidence of CTC aggregates versus patients with low incidence of CTC aggregates and healthy donors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5225. doi:10.1158/1538-7445.AM2011-5225
Abstract 5287: Non-invasive imaging of tumor cell death using a Hsp90 ligand
Authors: Park Danielle , Don Anthony , Massamiri Tania , Karwa Amol , Warner Beth , Hemenway Christine L. , Naik Arati D. , Kuan Kah-Tiong , Dilda Pierre J. , Wong Jason , Chinen Lori , Dyszlewski Mary , Hogg Philip J. 
Published: June 2012

Abstract
Cell death plays an integral role in physiology, including turnover of cells in the gastrointestinal tract, the menstrual cycle and the immune system. Imbalance of this process is also associated with disease. Excessive cell death is characteristic of vascular disorders, neurodegenerative diseases, myelodysplastic syndromes, ischemia/reperfusion injury and organ transplant rejection, among others.
Cell death also plays a role in the treatment of disease. In cancer for example, most chemotherapeutics, radiation treatments and anti-hormonal agents act by inducing death of cancer cells. Given the prevalence of cell death in normal physiology and disease, non-invasive imaging of this process is likely to have wide application in biological research and ultimately in patient diagnosis and management.
Common to apoptotic and necrotic death cell is eventual loss of plasma membrane integrity. We have developed a small, synthetic organoarsenical compound (4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid) that rapidly accumulates in the cytosol of dying cells, coincident with loss of plasma membrane integrity. The compound is retained in the cytosol predominantly by covalent reaction with the 90-kDa heat shock protein (Hsp90), the most abundant molecular chaperone of the eukaryotic cytoplasm. The organoarsenical was tagged with either optical or radioisotope reporting groups to image cell death in cultured cells and in murine tumors ex vivo and in situ. Tumor cell death in mice was non-invasively imaged by SPECT/CT using an 111In-tagged compound.
This versatile compound has the advantage of chemical stability, exquisite selectivity for dying cells and versatility with respect to the reporting group. The nature and abundance of its cytosolic target, Hsp90, also bodes well for its suitability for the imaging of cell death in most experimental settings.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5287. doi:10.1158/1538-7445.AM2011-5287
Abstract 5295: Near-infrared fluorescence in vivo tumor imaging using SNAP-tag technology
Authors: Gong Haibiao , Kovar Joy , Zhang Aihua , Correa Ivan R. , Xu Ming-Qun , Olive Michael 
Published: June 2012

Abstract
The SNAP-tag is a small protein derived from the human DNA repair protein O6-alkylguanine-DNA-alkyltransferase (hAGT). It reacts with fluorescent dye conjugated benzylguanine (BG) substrate, leading to covalent labeling of the fluorescent dye on the SNAP-tag®. This property makes the SNAP-tag a valuable tool for fluorescence imaging. In this study, we extended the SNAP-tag technology to near-infrared (NIR) fluorescence imaging using IRDye® 800CW conjugated BG substrate (BG-800). Compared to the visible spectrum, fluorescence in the NIR spectrum has the advantage of low light absorption and reduced autofluorescence, which is highly desirable for in vivo imaging. We created HEK293, MDA-MB-231, SK-OV-3 and SK-BR-3 cells stably expressing SNAP-ADRB2 fusion protein. The ADRB2 potion of the protein directs the localization of the protein to the cell membrane. The expression of SNAP-ADRB2 was confirmed by the reaction between BG-800 substrate and the cell lysate. Microscopic examination confirmed that SNAP-ADRB2 was localized on the cell membrane. The signal intensity of the stable cells after reaction with the substrate BG-800 was dependent on the BG-800 concentration. In vivo imaging study showed that BG-800 could visualize xenograft tumors established with SNAP-ADRB2 overexpressing SK-OV-3 cells. These results demonstrated that the application of SNAP-tag technology could be extended to in vivo imaging when combined with NIR fluorescent fluorophores.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5295. doi:10.1158/1538-7445.AM2011-5295