bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2727: Predicting lung cancer risk based on a novel proteomic signature of bronchial lesions
Authors: Rahman S.M. Jamshedur , Gonzalez Adriana L. , Seeley Erin H. , Zimmerman Lisa J. , Zhang Xueqiong J. , Li Ming , Kikuchi Takefumi , Chaurand Pierre , Manier M. Lisa , Olson Sandy , Shah Ronak , Miller Aloson , Putnam Joe B. , Miller York E. , Franklin Wilbur A. , Carbone David P. , Shyr Yu , Caprioli Richard A. , Massion Pierre P. 
Published: February 2011

Abstract
A biomarker signature to identify individuals at-risk for lung cancer would be of great clinical value. We hypothesized that the bronchial epithelium expresses a subset of proteins that once increased confer an elevated risk for lung cancer. We have therefore developed a proteomic approach to assess the risk for lung cancer. From our previous studies, we selected 11 matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) features to distinguish normal bronchial epithelium and low grade preinvasive lesions from high grade preinvasive lesions and invasive lung tumors. We tested this signature in an independent validation set consisting of bronchial specimens from 60 patients. The prediction accuracy was 78% with 73% sensitivity and 81% specificity. There was a 19-fold increased risk of having lung cancer for individuals with a signature intensity above the third quartile (95% CI, 5.65-64.81). We identified 10 of the 11 features corresponding to 7 proteins, thymosin ß4, ubiquitin, acyl-coA binding protein, cystatin A, S100A11, cytochrome c and macrophage migration inhibitory factor. The identity of these proteins was validated by immunohistochemistry, Western blotting and MALDI imaging mass spectrometry (IMS). MALDI IMS localized the candidate biomarker proteins specifically to high grade preinvasive lesions and invasive tumors. This novel proteomic signature may facilitate the selection and monitoring of high risk individuals for lung cancer early detection and chemoprevention strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2727.
Abstract 273: Exosome targeted receptor activation (ExTRAcrine) signaling: A new mode of EGF receptor ligand signaling
Authors: Beckler Michelle Demory , Higginbotham James N. , Gephart Jonathan , Coffey Robert J. 
Published: February 2011

Abstract
Epidermal growth factor receptor (EGFR) ligands have been shown to act in an autocrine, paracrine and juxtacrine manner. We report a new mode of signaling - via exosomes. Exosomes are 30-100 nm nano-vesicles that are produced by intralumenal budding into multivesicular bodies (MVB); they are released from many cell types after fusion of the MVB with the plasma membrane. Our studies showed that human breast and colorectal cancer cell lines differ in the composition of EGFR ligands in exosomes isolated from conditioned medium by established methods. By fluorescent-activated vesicle sorting (FAVS; Mol Cell Proteomics 7: 1651-1667, 2008), we show that a single HCA-7-derived exosome contains TGF-α, amphiregulin (AR) and HB-EGF. Ligands localized in exosomes are signaling competent with the ectodomains presented on the outside and cytoplasmic tails on the inside, and exist as stable transmembrane proteins. To explore the biological function of individual ligands, we isolated exosomes from MDCK cells individually stably expressing TGF-α, AR or HB-EGF. We assessed the invasive capacity of these exosomes by incubating them with a breast cancer-derived cell line (LM2-4175) in a Boyden chamber assay and measured the number of invading cells 72 hours later. Exosomes purifed from MDCK cells singly expressing AR induced invasion of LM2-4175 recipient cells 4-fold more than TGF-α or HB-EGF exosomes and 15-30-fold more than recombinant ligands TGF-α, HB-EGF or AR). The number of invading cells exposed to AR exosomes was significantly inhibited by an AR neutralizing antibody, suggesting that the invasive capacity of recipient cells is dependent upon exosomal AR engagement with recipient cell EGFR. Fixed and live cell imaging by confocal microscopy showed that AR exosomes are internalized by recipient cells. Further analysis showed that exosomes isolated from mutant KRAS DLD-1 colon cancer cells increased invasion of LM2-4175 cells 5-fold more than exosomes isolated from cells in which mutant KRAS was eliminated by homologous recombination (DKs-8 cells) and this correlated with increased levels of exosomal AR present in DLD-1 cells compared to DKs-8 cells. We provide the first evidence that EGFR ligands are present in exosomes and demonstrate that AR exosomes confer a greater invasive effect on recipient cells than TGF-α and HB-EGF exosomes or recombinant EGFR ligands. We propose ExTRAcrine signaling as a novel mode of EGFR ligand signaling with important diagnostic and therapeutic implications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 273.
Abstract 2735: Diagnosis of prostate cancer without tumor cells using differentially expressed genes in the tumor microenvironment
Authors: Jia Zhenyu , Wang Yipeng , McClelland Michael , Sawyers Anne , Yao Huazhen , Rahmatpanah Farahnaz , Xia Xiao-Qin , Xu Qiang , Koziol James , Carpenter Philip , Wang-Rodriquez Jessica , Simoneau Anne , Meyskens Frank , Sutton Manuel , Lernhardt Waldemar , Beach Thomas , Mercola Dan 
Published: February 2011

Abstract
Over one million prostate biopsies are performed in the U.S. every year. However, pathology examination is not definitive in a significant percentage of cases due to missing the tumor or equivocal structures. Given that the tissue near tumors will experience expression changes, biopsies could reveal the presence of a nearby tumor even if the biopsy contains no tumor. In order to identify reliable examples of such genes we compared gene expression profiles (Affymetrix U133plus2) from 15 volunteer biopsy specimens to 13 specimens containing largely tumor-adjacent stroma. More than a thousand significant expression changes were found and thereafter filtered to eliminate possible aging-related genes and genes also expressed at detectable levels in tumor cells. Classifiers were constructed based on 114 unique candidate genes (131 Affymetrix probe sets) and tested on 380 independent cases, including 255 tumor-bearing cases, 125 nontumor cases (normal biopsies, normal autopsies, remote stroma as well as pure tumor adjacent stroma). The classifier predicted the tumor status of patients with an average accuracy of 97.4% (sensitivity = 98.0% and specificity = 89.7%). These results indicate that the prostate cancer microenvironment exhibits reproducible changes useful for detecting “presence of tumor”.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2735.
Abstract 2736: Overexpression of L-type amino acid transporter-1 in breast cancer cells and tissues: potential association with growth and progression of tumors
Authors: Liang Zhongxing , Cho Heidi T. , Liang Ke , Zhu Aizhi , Huang Ke , Wu Hui , Hong Samuel , Goodman Mark M. , Shim Hyunsuk 
Published: February 2011

Abstract
For a tumor to constantly proliferate, malignant cells require nutrients, especially glucose and amino acids. There is abundant evidence that tumor growth depends heavily on glucose uptake. The L-type amino acid transporter 1 (LAT1) is a major nutrient transport system responsible for the transport of large neutral essential amino acids. In the present study, we analyzed expression levels of LAT1 mRNA and protein with RT-PCR, Western blot and immunohistochemical staining. The results showed that normal breast tissues or low malignant cell lines expressed low levels of LAT1 mRNA and protein, while LAT1 was overexpressed in highly malignant cancer cell lines and high grade breast cancer tissues. In addition, we found higher expression levels of LAT1 in breast cancer tissues were consistent with high stages of breast cancer. Furthermore, we demonstrated that blockade of LAT1 with its inhibitor, 2-amino-bicyclo[2.2.1]heptane-2-carboxylic acid (BCH), or knockdown of LAT1 with transfection of specific siRNA inhibited proliferation of breast cancer cells. A variety of 11C- and 18F-labeled amino acids have been studied for potential use in positron emission tomography (PET) oncology. A non-natural, not-metabolizable leucine analog, anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid ([18F]FACBC), has shown superior tumor/normal brain ratio. We tested whether [18F]FACBC would also be an excellent PET tracer for malignant breast cancer imaging using an orthotopic breast cancer animal model and an experimental animal model of breast cancer metastasis. Our results support that [18F]FACBC could be a useful PET tracer for non-invasive imaging of breast cancer. These findings suggest that overexpression of LAT1 is necessary for proliferation of breast cancer cells and may contribute to progression of tumors. LAT1 may represent a potential target for diagnosis of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2736.
Abstract 274: Cited2, a novel EGFR-induced coactivator, plays a key role in lung cancer progression
Authors: Chou Yu-Ting , Hsu Chiung-Fang , Kao Yu-Rung , Wu Cheng-Wen 
Published: February 2011

Abstract
Aberrant expression and function of epidermal growth factor receptor (EGFR) are reported in most lung cancer cases and are correlated with poor prognosis. However, the role of many downstream effectors associated with abnormal EGFR signaling is not clear in cancer progression. Cited2, a novel transcriptional co-activator was identified to be induced by hyperactive EGFR mutant L858R in lung cancer cells. Overexpression of Cited2 in CL1-0 lung cancer cells allowed cell to survive in serum free condition. Knockdown of Cited2 attenuated cell growth, leading to G1/S cell cycle arrest. Through microarray analysis, we identified that expression of E2F3 and its downstream gene targets were blocked in Cited2-silenced cells. Overexpression of Cited2 enhanced E2F3 expression, supporting that Cited2 regulates E2F3 expression. By chromatin immunoprecipitation assay, we found Cited2 bound to E2F3 promoter. In addition to affecting cell growth, knockdown of Cited2 promoted cell senescence with flat and enlarged cell morphology, and increased senescence-associated ß-galactosidase activity. Through western blot analysis, we found Cited2-silencing induced p53 and p21 expression. Overexpression of Cited2 further enhanced tumor growth in nude mice. Clinical analysis showed that Cited2 was highly expressed in lung cancer but not in normal tissues. These data demonstrate that Cited2 plays a key role in lung cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 274.
Abstract 2745: Expression of immunoglobulin gene in myeloblasts from patients with acute myelogenous leukemia and its distinct VKJK recombination pattern
Authors: Qiu Xiaoyan , Sun Xiaoping , He Zhiqiao , Lin Pei , You M. James , Chen Lei , Dai Chongwen , Yin C. Cameron 
Published: February 2011

Abstract
Immunoglobulin (Ig) gene expression is normally restricted to B lymphocytes and plasma cells. Immunoglobulin gene rearrangement has been used in the diagnosis and monitoring of response to therapy in B-cell lymphoma and leukemia. However, during the last decade, our group and others have found that Ig is also expressed in many non-hematopoietic cells, especially epithelial cancer cells. Moreover, we have reported that non-hematopoietic cancer-derived Ig expression is associated with poor prognosis, though the mechanism of its function in the survival of cancer cells is not yet known.
In this study, we assessed the expression of Ig heavy chain (gamma and mu) and light chain (kappa) in myeloblasts (CD33+CD19-CD138-, sorted by FACs) from 16 patients with acute myelogenous leukemia (AML) and 6 AML cell lines by RT-PCR, ELISA, and immunohistochemistry. As control groups, we also evaluated IgG, IgM and IgK transcripts in monocytes and neutrophils (sorted by FACs) from 15 patients with non-hematopoietic malignancies and 8 healthy individuals. We have found that Ig gamma chain was expressed in 6 of 14 AML patients, but in none of the 23 controls. All of the variable region sequences of AML-derived Ig gamma chain showed diversity, similar to B cells-derived Ig gamma chain. In contrast, Ig mu chain was expressed in 7 of 14 AML cases, 3 of 15 monocytes and 1 of 10 neutrophils from non-hematopoietic cancers, and 4 of 8 monocytes and 2 of 8 neutrophils from healthy controls. All of the variable region sequences of AML-derived mu chain from any individual showed monoclonal pattern, but different individuals showed different sequences. Kappa light chain was expressed in 15 of 16 AML cases, 11 of 15 monocytes and 3 of 10 neutrophils from patients with non-hematopoietic cancers, and 1 of 8 monocytes and 1 of 8 neutrophils from healthy controls. Interestingly, the AML-derived Ig kappa transcripts showed unique VKJK rearrangement pattern with several predominant VKJK usages. In particular, the VK1-5/JK1-3 recombination was observed in 93/155 of VKJK sequences from 15 AML cases.
The frequent expression of Ig in AML cells and the preferential usage of certain VKJK rearrangements by AML-derived Ig kappa light chain suggest a role of Ig in AML pathogenesis and a potential target for AML therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2745.
Abstract 275: The shedding of epidermal growth factor receptor is mediated by MMP-2 or MMP-9 and stimulated by fibronectin in MDA-MB-468 cells
Authors: Vazquez-Quinones Luis E. , Valle Blanca L. , Cabrera-Toro Krizia L. , Torres-Rodríguez Sheila , Ozuna-Vázquez Hazel , Pérez-Torres Marianela , Cora Elsa M. 
Published: February 2011

Abstract
Activation of the epidermal growth factor receptor (EGFR) is essential for cell proliferation and tissue homeostasis. Alterations in the ERBB signaling pathway have been detected in several human cancers. Soluble isoforms of EGFR generated by proteolytic cleavage of the membrane bound receptor have been identified in several cell lines. The shedding of EGFR in MDA-MB-468 cells generates a fragment of approximately 110 kDa that comprises the extracellular domain plus four amino acids of the transmembrane domain of the full-length receptor. The shedding of EGFR in MDA-MB-468 is activated by two ligands of the receptor (EGF, TGF-alpha), fetal bovine serum, an inhibitor of phosphatases (pervanadate) and by an activator of metalloproteases (i.e. APMA). However, the proteolytic activity that cleaves EGFR is unknown. Studies using metalloprotease inhibitors have suggested that matrix metalloproteases (MMPs) are involved in the shedding of EGFR. Here, we show that the shedding of EGFR increased in MDA-MB-468 cells treated with activated MMP-2 and MMP-9. Similarly, we observed cleavage of the receptor when EGFR (Sigma) or membrane preparations from MDA-MB-468 cells were incubated in vitro with activated MMP-2 or MMP-9. This cleavage was blocked when antibodies against MMP-2 or MMP-9 were included in the incubation mixture. Since fetal bovine serum increases the shedding of EGFR in MDA-MB-468 cells, we evaluated whether other serum components in addition to EGF and TGF-alpha have similar effect. Our results showed that the shedding of EGFR increased when fibronectin (Sigma) was added to MDA-MB-468 cells growing in serum free culture medium. This increase in the shedding of EGFR by fibronectin was dose and time dependent and was abolished when antibodies against α1β5 integrin was added to the incubation medium. Together, these results strongly suggest that the shedding of EGFR is mediated by MMP-2 and MMP-9 and therefore, it is of physiological relevance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 275.
Abstract 2750: ARQ 621, a novel potent and selective inhibitor of Eg5: Preclinical data and early results from a clinical phase 1 study
Authors: Rosen Lee , Chen Lin-Chi , Iyengar Tara , Goldman Jonathan , Lahr Sandra , Chen Chang-rung , France Dennis S. , Chan Thomas C.K. , Schwartz Brian , Abbadessa Giovanni , Von Hoff Daniel D. 
Published: February 2011

Abstract
Background: ARQ 621 is an allosteric, potent and selective inhibitor of Eg5, a microtubule-based ATPase motor protein involved in cell division. Eg5 inhibition is recognized as a potential therapeutic strategy in cancer supported by the observation that over-expression of Eg5 causes genomic instability and tumor formation in mice. In this clinical trial we sought to evaluate the safety and pharmacokinetics of ARQ 621 in patients with solid tumors.
Methods: Patients (pts) are being enrolled into this multi-cohort phase 1 trial at the initial i.v. dose of 10 mg/m2/week. Drug is administered weekly intravenously over 1-2 hours. Cohorts of 3 or 6 patients are based on a 3+3 dose escalation schedule and dose is increased according to a modified Fibonacci scheme. Treatment continues until disease progression or unacceptable toxicity.
Results: Recently expanded preclinical data with ARQ 621 shows anti-tumor activity with potencies in the low nanomolar range across a much wider range of human cancer cell types than previously reported, including colon, NSCLC, gastric, and hematologic cancer cell lines. Furthermore, no evidence of bone marrow toxicity and DNA damage is evident with ARQ 621 as we have seen with a leading Eg5 inhibitor. As of November 19, 2009, 18 pts (60% male; median age 60 yrs, ECOG PS 0 (N=3), PS 1 (N=13), PS 2 (N=2) were enrolled. The most common tumors treated with ARQ 621 were colorectal (N=6) and breast (N=2). Treatment-emergent adverse events (TEAEs) were reported in 13 pts. The most common (&gt; 10%) include fatigue (27%), redness at infusion site 3 (16%), and anemia 3 (16%). Three pts experienced serious AEs (1 each of anemia, sepsis, pneumonia) reported as not drug related. Three pts (cholangiosarcoma, liposarcoma and colorectal carcinoma) remained stable for &gt; 4 months.
Conclusions: Preclinical studies continue to elucidate the potential indications for Eg5 inhibition as well as the combinability of ARQ 621 with other molecularly targeted therapeutics. To date, therapy with ARQ 621 appears well tolerated, with no dose-limiting toxicity observed at doses and frequencies much higher than those achieved with the leading Eg5 inhibitors of comparable potencies. Dose-limiting toxicity has not been reached, and recruitment continues to identify the maximum tolerated dose and a recommended Phase 2 dose. Additional safety, pharmacokinetic, and preliminary efficacy data will be available for presentation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2750.
Abstract 2753: Change in tumor size by RECIST correlates linearly with progression-free and overall survival in phase I studies
Authors: Jain Rajul K. , Lee J. Jack , Hong David , Gong Jing , Naing Aung , Wheler Jennifer , Kurzrock Razelle 
Published: February 2011

Abstract
INTRODUCTION: The Response Evaluation Criteria in Solid Tumors (RECIST) sets cutoff values for complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The efficacy of novel anticancer therapies is traditionally described as the percentage of patients with responses in each of these 4 categories. However, the boundary values defining these categories are arbitrarily set. We therefore study the relationship between change in tumor size by RECIST and both progression-free and overall survival (PFS and OS), and evaluate if boundaries exist or if alternatively the relationship is a continuous parameter.
METHODS: We analyzed 468 participants on 24 phase I trials at MD Anderson from 10-1-04 to 6-30-08. Best response (best change by RECIST while on study) is correlated with PFS and OS by Somers' rank correlation. Kaplan-Meier survival curves of patients binned by response are also calculated (Table). Finally, a Cox model with no covariates is fit to the survival data, and analysis of best response versus the model residual is conducted.
RESULTS: Rank order testing demonstrated a correlation between best response and survival (Dxy = −0.56 for PFS and −0.34 for OS). Kaplan-Meier analysis also demonstrated a strong correlation (p &lt; 1×10−6, Table). Residual analysis of the Cox model (Methods) demonstrated a near linear relationship between changes in tumor size from −100% to +25% and survival; patients with a change of +25% or greater did uniformly poorly. Landmark analyses at multiple time points demonstrated identical trends regardless of the landmark.
CONCLUSION: Given the linear relationship between best response to treatment and both PFS and OS, evaluating specific patient responses, for example through mechanisms such as waterfall plots, may be more valuable than aggregate CR, PR, SD, and PD rates. Additionally, the cutoffs for CR, PR, SD, and PD as defined by RECIST may not have special significance regarding survival in this population.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2753.