bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1161: Detection and identification of a miRNA expression profile from cell-free urine: Potential utility in bladder cancer
Authors: Holway Antonia H. , DeLong Jessica , Harty Niall , Kozinn Spencer , Summerhayes Kelly , Summerhayes Ian C. , Libertino John A. , Rieger-Christ Kimberly M. 
Published: June 2012

Abstract
Introduction/Objective: MicroRNAs are small, non-coding RNAs that have been shown to play an important role in tumorigenesis. There is differential expression of miRNA in cancer progression, and profiling of miRNA is promising for both diagnosis and treatment of malignant tumors. In this study we isolated RNA from cell-free urine in an attempt to characterize miRNA profiles indicating the presence of urothelial carcinoma and its potential use as a non-invasive assay to identify patients with cancer progression.
Methods: Urine was collected from patients diagnosed with bladder cancer and control patients with no history of cancer under an IRB-approved protocol. Urine was centrifuged and total RNA was isolated from the supernatants using the mirVana Paris™ kit. A total of 178 samples were grouped according to grade and stage (healthy controls (35), TaG1 (19), T1G3 (16), ≥T2 (30), carcinoma in situ (CIS; 28) and no evidence of disease following therapy (50). Seven hundred and thirty miRNAs were profiled by qRT-PCR on pooled samples within each group. Validation of selected miRNAs was performed on individual samples using qRT-PCR.
Results: Cell-free RNA was isolated from urine of 35 healthy controls and 143 patients with bladder cancer. Of the 730 miRNAs tested, 236 were detected in at least one of the pooled samples using a Ct cutoff of 35. The number of miRNAs detected in the pooled samples correlated with disease progression where the healthy control group and the ≥T2 group expressed 8 and 228 miRNAs, respectively. qRT-PCR of individual samples revealed a gradual increase of some miRNAs with disease progression. Statistical analysis adjusted for multiple comparisons demonstrated differences between groups based on miRNA expression levels. In addition, a panel of miRNAs was identified which discriminated between cancer and cancer-free patients.
Conclusion: This study demonstrates the successful isolation of miRNAs from cell-free urine. Utilizing non-invasive urine based assays, we identified a miRNA panel that can discriminate between cancer-free patients and patients with urinary carcinoma of the bladder. These findings provide evidence that profiling of miRNAs from cell-free urine holds the promise for the development of valuable clinical tools.
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 1161. doi:10.1158/1538-7445.AM2011-1161
Abstract 1166: Inhibition of tumor growth in mouse models of cancer by systemic delivery of tumor suppressor miRNAs
Authors: Brown David , Daige Chris , Wiggins Jason , Kelnar Kevin , Ruffino Lynnsie , Omotola Michael , Zhou Jane , Bader Andreas 
Published: June 2012

Abstract
Tumor suppressor miRNAs represent an intriguing new class of biomolecules that might be developed into therapeutic candidates for cancer. Based upon its involvement in the p53 pathway and its capacity to regulate cell cycle and apoptosis via multiple oncogenic pathways, miR-34 might be the most intriguing of the tumor suppressor miRNAs. We have developed mimics of the miR-34 tumor suppressor that have been tested for efficacy using xenograft and transgenic mouse models of cancer. When complexed with an effective delivery agent, tail-vein injected miR-34 mimics have proven capable of inhibiting the growth and metastasis of mature tumors. When delivered systemically to BalbC mice, the same complexed miR-34 mimics fail to incease the serum levels of liver, kidney, and heart toxicity markers. Systemically delivered miR-34 mimics also failed to induce cytokines in mice. The development of miR-34 mimics with enhanced pharmacokinetic profiles and a systemic delivery formulation that can be manufactured under cGMP conditions are underway. Preclinical efficacy, PK/PD, and rodent safety data will be presented.
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 1166. doi:10.1158/1538-7445.AM2011-1166
Abstract 1181: Expression studies from the PVT1 region of 8q24
Authors: Huppi Konrad , Pitt Jason , Wahlberg Brady , Jones Tamara L. , Mushinski J. Frederic , Janz Siegfried , Caplen Natasha J. 
Published: June 2012

Abstract
Several SNPs in the area surrounding the PVT1 noncoding gene region on human chromosome 8q24 have recently been found by Genome Wide Association (GWA) to be associated with susceptibility to a number of malignancies including Hodgkin's Lymphoma and other diseases including Type II Diabetes and End Stage Renal Disease in Type I Diabetes. This genetically unstable region is one of the most frequent targets of retroviral integration of the Human Papilloma Virus Type 18 (HPV18 in Cervical Carcinoma) and is the frequent target of chromosomal translocation in lymphoid malignancies such as Non-Hodgkin's Lymphoma [incl. Burkitt's Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBL)]. Gene amplification in carcinomas such as breast, prostate, ovarian, colon, pancreatic, esophageal, as well as osteogenic sarcoma usually encompasses the proximal region of PVT1 along with its well-known neighboring transcript, MYC, whereas chromosomal deletion (in hematodermic NK lymphoma) affects the distal segment of PVT1. In a search for functionality to PVT1, many laboratories (including our own) have cloned and sequenced transcripts from the PVT1 region from many species in addition to human, with the conclusion that PVT1 is a noncoding or lincRNA with many alternatively spliced isoforms. We have systematically documented these isoforms with a particular focus on promoter and regulatory elements that are found in the region. Our laboratory has also identified a cluster of at least 6 miRNAs (miR-1204∼1208) that span the PVT1 region adding yet another level of complexity to the locus. To begin to assign some function to PVT1 based transcripts in these disease phenotypes, we have made 4th generation (CMV promoter with WPE enhancer) over-expressing lentiviral constructs containing either a large segment of PVT1 (Exons 1b-10) or the most proximal and abundant miRNA, miR-1204. These constructs follow earlier studies with a 3rd generation lentivirus (CMV promoter) containing miR-1204 that rapidly generated DLBL in cooperation with MYC or IL6 transgenes (∼16 days or 82 days respectively). While these results pointed to over-expression of miR-1204 playing a specific role in the development of B cell malignancy, additional studies with the LentiCMV-miR-1204 construct in other tumor cell lines (prostate and breast) also revealed potential phenotypic changes in cell proliferation and migration. With the new 4th generation constructs, experiments are now underway in cell lines and mouse models to determine if over-expression of miR-1204 or PVT1 alone is sufficient to induce phenotypic changes.
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 1181. doi:10.1158/1538-7445.AM2011-1181
Abstract 1192: Regulation of CCND2, HMGA2, and the IGF pathway by LIN28B in HPV negative head and neck squamous cell carcinoma (HNSCC)
Authors: Alajez Nehad M. , Wong Dennis , Shi Wei , Lenarduzzi Michelle , Liu Fei-Fei 
Published: June 2012

Abstract
Background: Lin28 and Lin28B have recently been implicated in the post-transcriptional regulation of Let-7/miR-98 biogenesis. While Lin28B over-expression has been associated with worse clinical outcome in several human cancers, the prognostic significance of Lin28B expression and the molecular mechanism(s) by which it drives tumour progression remains largely unknown.
Methods: Let-7-Resist Lin28B-expression plasmid was stably transfected into the FaDu human hypopharyngeal squamous cell carcinoma line. MicoRNA expression profiling was conducted using the Nanostring nCounter Analysis System. Genome-wide micro-array and in silico analyses were utilized to identify Let-7/miR-98 targets. Cell viability and apoptosis were measured using MTS assay and flow cytometry, respectively. In vivo experiments were conducted using SCID mice.
Results: qRT-PCR analysis of genes involved in the miRNA biogenesis pathway (DICER, LIN28, LIN28B, and TUT4) suggested an inverse relationship between the expression of Lin28B and mature Let-7 miRNA. Over-expression of Lin28B mediated significant increase in the migration of FaDu cells in vitro, and tumor growth in SCID mice, which in turn, was associated with marked reduction in the Let-7 family of microRNAs. Using a tri-Pronged approach by combining prediction algorithms, experimentally-derived mRNA profiling, along with gene expression data in primary HNSCC samples identified several upregulated Let-7/miR98 gene targets in Lin28B-FaDu cells, including CCND2, HMGA2, and regulators of the insulin growth factor (IGF) mitogenic pathway. Concordantly, treating FaDu-Lin28B cells with IGF (10-50 nM) led to a 26% and 50% increase in cell viability under stress conditions (serum starvation), whereas treating FaDu-GFP cells with IGF had no effect on viability, suggesting the relevance of the IGF axis in FaDu-Lin28B cells. Furthermore, analyzing publicly available data sets on primary HPV positive vs. HPV negative HNSCC samples revealed a significantly higher expression of HMGA2, and genes that regulate the IGF pathway in the latter group of tumours, suggesting a possible role for Lin28B, Let-7/miR-98 and their downstream targets in mediating the more aggressive behavior of HPV negative HNSCC.
Conclusions: Our data report for the first time, a potentially important role for Lin28B in regulating the IGF mitogenic pathway, as one possible mechanism in driving the biological behaviour of HPV negative HNSCC.
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 1192. doi:10.1158/1538-7445.AM2011-1192
Abstract 1200: BP1 regulates ERα activity in MCF-7 cells
Authors: Berg Patricia E. , Awate Sanket , Kirolikar Saurabh , Schwartz Arnold 
Published: June 2012

Abstract
Introduction. BP1 is a member of the homeobox gene family of transcription factors. Our recent studies have shown that BP1 may play a role in breast cancer cell survival, aggressiveness and metastasis. BP1 protein (pBP1) is expressed in 80% of invasive ductal breast tumors, and is associated with estrogen receptor negativity – 100% of ERα negative (hereafter called ER-) tumors expressed BP1, while 73% of ER positive (ER+) tumors expressed BP1; this difference was statistically significant (p=0.03). Initially most tumors are hormone dependent and are sensitive to antiestrogens. Over time, many tumors progress to hormone-independence. One possible mechanism by which this might occur is reduction of ER protein. Here we present data indicating that high BP1 expression decreases ER protein levels in ER+ cells grown in the absence of serum. Since it is not currently understood what factors may cause ER+ cells to become more ER negative, it is important to determine the role of BP1 in reducing ER protein levels. Results. Our data suggest that MCF-7 ER+ cells engineered to overexpress BP1, when grown in the absence of serum, exhibit decreased ER protein compared with control cells containing an empty vector and grown under the same conditions. This is not a transcriptional effect since there was no change in ER mRNA levels in the presence of high levels of BP1. There was also a decrease in ER immunostaining in cells overexpressing BP1 grown without serum. Decreased ER protein levels correlated with decreased expression of pS2, a known downstream target of ER, demonstrating that there is less functional ER protein in cells overexpressing BP1 when grown in the absence of serum. We speculate that regulation of ER levels by BP1 is post-translational. Several pathways that control ER protein stability are being evaluated in cells grown with or without serum. Phosphorylation of Akt on Ser473, the site that is known to phosphorylate and stabilize ER protein, is being investigated to determine whether BP1 regulates phospho Akt levels. MAPK signaling can result in activation of ER in the absence of estrogen, but we did not see any evidence that BP1 is involved in the MAPK pathway. p300 is known to acetylate and stabilize ER protein; experiments are underway to determine whether BP1 directly regulates p300 expression since there are two potential BP1 binding sites in the p300 gene. Conclusions. We hypothesize that BP1 overexpression leads to reduced ER protein in ER positive cells. This could result in decreased sensitivity to antiestrogens in those 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 1200. doi:10.1158/1538-7445.AM2011-1200
Abstract 1202: DCA induces EGFR internalization by a mechanism that is distinct from EGF or UDCA
Authors: Martinez Jesse , Li Qiang 
Published: June 2012

Abstract
Secondary bile acids have long been thought to influence the etiology of colon tumorigenesis however, the mechanism of their action remains unclear. Our previous studies focused on deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) because they appear to have the opposite effect at the molecular and the biological level. DCA stimulates mitogenic signaling by activating the EGF receptor and can promote tumorigenesis in mouse models, whereas UDCA suppresses EGFR-related mitogenic signaling and has been shown to inhibit colon tumorigenesis in clinical trials. In previous studies we showed that both bile acids act on the cell membrane and this resulted in stimulation of EGFR activity by DCA, but resulted in suppression of receptor signaling by UDCA. In this work, the effect of DCA and UDCA on EGFR internalization in Hct116 cells was investigated using reverse biotinylation. Both DCA and UDCA were found to induce ligand independent internalization of EGFR. However, UDCA treatment resulted in rapid degradation of EGFR whereas DCA caused internalization and stabilization of the receptor in an apparently activated state. To examine this further we pretreated the cells with Methyl-β-cyclodextrin to deplete cholesterol from the plasma membrane, or with chlorpromazine to inhibit endocytosis through clatherin coated pits (CCP). We also suppressed functioning of caveolae or CCPs using caveolin-1 shRNA, or clathrin heavy chain shRNA. We found that EGFR internalization induced by UDCA is cholesterol and caveolin dependent. However, none of these treatments affected the rate of EGFR internalization induced by DCA, suggesting that DCA induced EGFR internalization by a mechanism which is different from that of either EGF or UDCA. This may explain the distinct biological activities exhibited by these two bile acids.
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 1202. doi:10.1158/1538-7445.AM2011-1202
Abstract 1208: Elucidating possible functional implications of osteosarcoma risk-associated genetic level alterations in IGF2R
Authors: Piperdi Sajida , Cao Yu , Gorlick Richard 
Published: June 2012

Abstract
To address the need for novel osteosarcoma (OS) treatment regimens with greater efficacy and less toxicity, attention has been focused on developing antibodies that target components of the insulin-like growth factor (IGF) pathway, particularly insulin-like growth factor 1 receptor tyrosine kinase (IGF1R). IGF1R and its two ligands, insulin-like growth factor 1 (IGF1) and insulin-like growth factor 2 (IGF2), are known to be over-expressed in several cancers including OS and have roles in regulating cellular growth and proliferation. Clinical trials of IGF1R-inhibiting antibody therapies in OS, however, have returned mixed results. Studies aimed at elucidating the biologic basis of this differential clinical sensitivity to IGF1R-targeting therapeutic agents are currently underway. Interestingly, recent studies from our lab show that IGF2R is consistently over-expressed, relative to other known transmembrane receptors, on the cell surface, across 4 standard and 10 patient-derived OS cell lines. Coupled with results from concurrent experiments suggesting a lack of IGF1R copy number amplification in the majority of tested patient-derived OS samples and xenograft models, we chose to focus our next set of studies on IGF2R_aiming to characterize significant genetic variations within this gene and any functional implications, thereby elucidating the link, if any, between IGF2R's mutational status and its cell surface expression in OS. Relative quantification studies, done via real-time PCR, demonstrated variable IGF2R gene expression across 27 patient-derived OS samples, 4 xenograft models, and 4 standard cell culture (serum-starved) lines. Using the CaCo-2 cell line as the calibrator, 12 out of 27 patient-derived OS samples showed increased IGF2R gene expression, while none of the xenograft models or the standard OS cell lines did. Ongoing studies will examine the relationship between genetic level alterations in IGF2R and its patterns of expression; common IGF2R SNPs will be genotyped, first in the four available OS xenograft models. Findings will be correlated with known patterns of clinical response/sensitivity to IGF1R-targeted therapy tested on these models. The same SNPs will then be genotyped in the patient-derived OS samples and standard cell culture lines. Depending on the results obtained from these initial studies, further experiments can be designed to sequence/genotype other suspect coding regions on the IGF2R gene that may contain functionally significant mutations.
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 1208. doi:10.1158/1538-7445.AM2011-1208
Abstract 1209: Concurrent administration of doxorubicin and lapatinib worsens doxorubicin-induced cardiac dysfunction in mice
Authors: Goukassian David , Sasi Sharath , Lee Juyong , Budiu Daniela , Lawson Christopher , Maysky Michael , Hlatky Lynn , Carrozza Joseph , Morgan James P. , Yan Xinhua 
Published: June 2012

Abstract
Background: Concurrent use of chemotherapy drug doxorubicin (DOX) and Trastuzumab, a monocloncal antibody that blocks HER2, induced cardiac dysfunction in 27% of patients. Clinical trials have shown that the incidence of symptomatic heart failure was much lower (0.3%) in patients sequentially treated with DOX and lapatinib, an EGFR and HER2 tyrosine kinase inhibitor. More studies are necessary to determine the safety of concurrent DOX and lapatinib treatment, which is important for developing more effective cancer therapy. Here, we tested the effect of concurrent DOX and lapatinib administration on cardiac function in mice. Methods: A well-established subacute murine DOX heart failure model was used. 10-12 week old C57BL/6 mice were treated with a single dose of DOX (20 mg/kg, i.p.), or DOX concurrently with lapatinib (100 mg/kg, oral gavage, daily). Survival was analyzed by the Kaplan-Meier method. Cardiac function was monitored by hemodynamic measurements. Results: Ten days after the treatment, survival was significantly lower in DOX+lapatinib vs. DOX mice (13 vs. 0 %, n=7-8 /group, P&lt;0.001). Five to seven days after the treatment, cardiac contractile function was significantly lower in DOX+lapatinib vs. control mice [left ventricular systolic pressure (LVSP): 83 ± 2 vs. 93 ± 2 mmHg, P&lt;0.05; dP/dtmin: 4020 ± 360 vs. 7112 ± 580 mmHg/sec, P&lt;0.05; cardiac output (CO): 1236 ± 266 vs. 2734 ± 209 unit/min, P&lt;0.05, n=5 per group]; however, these indices were maintained in DOX mice at this point (LVSP: 99 ±4 mmHg; dP/dtmin: 7787 ± 965 mmHg/sec; CO: 2315 ± 366 unit/min, P=NS vs. control, n=5-6 per group). Conclusions: These results have shown that concurrent DOX and lapatinib administration exacerbates DOX-induced cardiac dysfunction in mice, suggesting that concurrent use of DOX and lapatanib may not be safe in patients. This study strongly suggests that cardiac function must be closely monitored in patients treated with DOX and HER2 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 1209. doi:10.1158/1538-7445.AM2011-1209
Abstract 1210: Activation of heterogeneous nuclear ribonucleoprotein K (HNRNPK) by ERBB2/ERBB3
Authors: Patel Nirav M. , Xiang Jie , Warren Carmen , Avliyakulov Nurali , Haykinson Michael , Landgraf Ralf 
Published: June 2012

Abstract
ERBB2 (HER2/neu) amplification constitute one of the most prominent oncogenic amplification event in breast cancer, and ERBB2 overexpression is well established as a predominantly proliferation and metastasis favoring signaling input. It is consequently the object of different targeted therapies (e.g. Trastuzumab, Pertuzumab or Lapatinib).
We carried out 2-D difference gel electrophoresis based proteomics studies (DIGE) of early posttranslational protein modifications in MCF7 breast cancer cells in response to ligand induced activation. These studies have identified heterogeneous nuclear ribonucleoprotein K (HNRNPK) as a target for rapid tyrosine phosphorylation after ERBB2/ERBB3 activation by neuregulin β1. Upregulation of protein levels coupled with cytoplasmic accumulation of HNRNPK has been found to be associated with its oncogenic role in several types of cancer, and HNRNPK overexpression enhances the tumorigenicity of breast cancer cells in cell culture models. Previous studies have shown that HNRNPK levels are reduced in breast cancer cells after prolonged treatment with EGFR or ERBB2 directed therapeutic antibodies. However, while molecular mechanistic data exist on HNRNPK from a variety of model systems, we currently lack a coherent mechanistic framework of the crosstalk of ERBB2 and HNRNPK signaling in breast cancer.
Following our DIGE analysis, we found that ligand induced and ERBB2/ERBB3 mediated tyrosine phosphorylation of HNRNPK in MCF7 cells is mediated by members of the SRC kinase family. Following ligand dependent stimulation, activation of HNRNPK coincides with a cytoplasmic relocalization of a relatively small portion of the predominantly nuclear HNRNPK pool. We compared our observations of ligand induced activation with the status of HNRNPK in ERBB2 over expressing breast cancer cell lines in presence or absence of ERBB2 targeted inhibitors. These studies are aimed at elucidating the interplay of HNRNPK and constitutive ERBB2 signaling in breast cancer cells and its role in cellular transformation.
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 1210. doi:10.1158/1538-7445.AM2011-1210