bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4890: Diffusion-weighted MRI provides an early assessment of treatment response in a murine model of metastatic prostate cancer to the bone
Authors: Brisset Jean-Christophe , Galbán Stefanie , Rehemtulla Alnawaz , Pienta Kenneth J. , Galbán Craig J. , Ross Brian Dale 
Published: June 2012

Abstract
Ninety percent of patients with advanced prostate cancer develop metastases to the bone1. At present, there is no definitive means for assessing response to therapy, with RECIST identifying tumors in the bone as “unmeasureable”. Diffusion-weighted MRI (DW-MRI) is highly sensitive to microscopic changes in tumor tissue. Our goal is to use DW-MRI to detect and quantify changes in tumor tissue throughout therapy where the magnitude of the change could be related to the effectiveness of the treatment. Human prostate cancer (PC3) cells were implanted by direct intra-tibial injection into male SCID mice, which served as a model for prostate bone metastases. MRI experiments were performed on a 9.4T MRI. Upon identifying a tumor volume of ∼10mm3, animals were randomly distributed into 4 treatment groups: docetaxel 20 mg/kg i.p. dose once a week for 3 doses (qd7×3; N=5), fractionated radiation IR at 2 Gy/day 5x per week for 2 weeks (N=7), combined treatment (N=5) and control (N=6). Animals were imaged by DW-MRI in which the apparent diffusion coefficient was calculated from the DW images. Tumor volume and ADC measurements were acquired pre-treatment and on days 0, 1, 4, 7, and once per week after post-treatment initiation. Animals were removed from the study when the tumor reached a percent increase of 400% (5x the initial tumor volume). Group comparisons in MRI metrics were obtained using an unpaired Student t-test. Mice treated by Dox or IR had significant smaller increase in tumor volume compared to control mice. Combined treatment resulted in improved efficacy over lone therapies. This resulted in a significant decrease in tumor size. The Dox group showed an increase in ADC following the first administration and a slow decline in ADC values following day 4 post-treatment initiations regardless of additional treatments. ADC value for IR treated animals did not elevate above control until day 7. Combined treatment generated increased ADC values that were maintained throughout the treatment cycle. IR and Dox alone and in combination were effective as assessed by anatomical and DW-MRI. Those results demonstrate the potential of quantitative ADC map for assessing early response of metastatic cancer to the bone.
References:
1. Carlin BI et al. Cancer. 2000;88(12):2989-2994. 2. Lee KC et al. Cancer Res. 2007;67(8):3524-3528. 3. Lee KC Neoplasia. 2007;9(12):1003-1011.
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 4890. doi:10.1158/1538-7445.AM2011-4890
Abstract 4895: Tagging endogenous genes with fluorescent reporters using CompoZr® zinc finger nuclease technology
Authors: Zhang Hongyi , Zhang Fan , Zenser Nathan , Vassar Deborah L. , Malkov Dmitry , Davis Gary 
Published: June 2012

Abstract
Zinc finger nucleases (ZFNs) are a class of engineered DNA-binding proteins that facilitate targeted editing of the genome by creating double-strand breaks (DSBs) in DNA at desired locations. DSBs are important for site-specific mutagenesis in that they stimulate the cell's natural DNA-repair processes, namely homologous recombination (HR) and non-homologous end joining (NHEJ). The formation of a DSB increases the rate of HR by a thousand fold between a specific genomic target and a donor plasmid in somatic cells. Sigma-Aldrich CompoZr® ZFN technology is a useful tool to create site specific mutations, and to generate knock-in and knockout model lines for academic and clinical research.
By this approach, we tagged an oncogene, several cytoskeletal genes and a chromatin gene by integrating a fluorescent protein sequence into the desired location (at the sequences encoding either N-terminus or C-terminus of the target protein) in the genome. The integration resulted in endogenous expression of the corresponding fusion proteins (green, red, or blue) that shows their native characteristic pattern. The following five loci were tagged: ERBB2/HER2 (human epidermal growth factor receptor 2, plasma membrane), TUBA1B (α-tubulin 1b, microtubule), ACTB (β-actin, actin stress fibers), LMNB1 (lamin B1, nuclear envelope) and HMGA1 (high mobility group AT-hook 1, nucleus). Single cell clones were isolated in SKOV3, U2OS, and MCF10 cells with one copy of a given gene tagged. Multiplexing was demonstrated by labeling different genes in the same cell line as well as different alleles of the same gene.
We demonstrate that ZFN mediated gene tagging is an efficient way to generate knock-in cell lines to report endogenous gene expression. It provides the basis for development of various high content screening (HCS) assays for compound screening where target gene regulation and corresponding protein function are preserved.
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 4895. doi:10.1158/1538-7445.AM2011-4895
Abstract 4915: Physiologically-based PK modeling of liposomal drug delivery points to a key role of tumor deposition in determining the relative efficacy of liposomal vs. free doxorubicin in breast cancer and Kaposi sarcoma
Authors: Hendriks Bart , Reynolds Joe , Klinz Stephan , Leonard Shannon , Geretti Elena , Lee Helen , Eckelhofer Isabelle , Gaddy Daniel , Wickham Thomas 
Published: June 2012

Abstract
For the chemotherapeutic, doxorubicin, liposomal encapsulation simultaneously (i) protects the heart from doxorubicin-induced cardiotoxicity, (ii) results in passive tumor accumulation via the enhanced permeability and retention effect and (iii) increases its circulation life-time. Clinically, pegylated-liposomal doxorubicin (PLD) shows a dramatic benefit to Kaposi sarcoma (KS) patients relative to free doxorubicin. In contrast, PLD does not show any survival benefit relative to free doxorubicin in patients with metastatic breast cancer. We hypothesized that the differential efficacy observed might be explained by differences in tumor cell exposure to drug. To better understand the effects of liposomal encapsulation on drug exposure, we developed a mechanism-based PK model of liposome biodistribution. The model consists of superimposed PK models for free and liposomal doxorubicin with a common central blood compartment which are then connected to a physiologically-based tumor tissue compartment. The tumor tissue compartment includes vascular, interstitial and cell space and captures rates of blood flow, tumor deposition into the interstitial space, doxorubicin release from the liposomes and the trafficking of free doxorubicin into and out of cells. The model parameters were extensively validated against literature data from in vitro studies, mouse xenografts and human clinical data. With our model we are able to simulate total tumor doxorubicin and DNA-bound doxorubicin in tumors, reproducing observed mouse xenograft data for free vs. liposomal doxorubicin. Analysis of the model revealed dramatically different dynamics in tumor exposure for free vs. liposomal doxorubicin delivery. Further, rates of tumor deposition were rate-limiting for overall tumor cell exposure for liposomally-delivered doxorubicin. Upon scaling the model to reflect human physiology, we demonstrate that the clinically observed liposome accumulation in KS tumors can quantitatively explain the dramatic increase in efficacy relative to free doxorubicin. Furthermore, the model indicates that the lower rates of liposome tumor deposition seen in breast cancer patients result in no survival benefit relative to free doxorubicin, consistent with clinical trial results.
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 4915. doi:10.1158/1538-7445.AM2011-4915
Abstract 4922: A single-cell TGFbetaR-JUND dichotomy and its role in basal-like breast cancer
Authors: Wang Chun-Chao , Jamal Leen , Atkins Kristen A. , Janes Kevin A. 
Published: June 2012

Abstract
Basal-like carcinoma is a subtype of breast cancer with poor prognosis that is characterized by pronounced cell-to-cell non-uniformities. Intratumor heterogeneity could involve sporadic single-cell activation of key pathways implicated in cancer progression, but it has not been possible to identify such pathways in an unbiased way. Our lab has developed a new approach for globally identifying coregulated, heterogeneously expressed genes among single cells (Nat Methods 7:311 [2010]). In a 3D in vitro culture model of a basal-like breast epithelial cell line (MCF10A), we stochastically profiled 4557 transcripts for heterogeneity and identified 547 that were predicted to be strongly dichotomous among extracellular matrix (ECM)-attached cells in the developing acinus. Hierarchical clustering of the heterogeneous transcripts revealed a group of ∼15 biosynthetic genes that contained the transcription factor, JUND, and the basal-cell cytokeratin, KRT5. In the same dataset, we identified a second group of genes-containing a transforming growth factor-beta (TGF-beta) family ligand (GDF11), a TGF-beta receptor (TGFBR3), and a TGF-beta marker protein (TGFBI)-with strong sampling fluctuations that were opposite to those of JUND cluster. Here, we show that perturbation of JUND or TGFBR3 expression profoundly disrupts 3D morphogenesis. Constitutive JUND expression causes stable cribiform-like bridges across the acinar lumen, whereas TGFBR3 knockdown induces a ductal-branching phenotype. These perturbations further revealed that JUND and TGFBR3 are reciprocally coupled by interlinked positive and negative feedback loops that could give rise to asynchronous oscillations during morphogenesis. Live-cell imaging with a fluorescently tagged Smad2 revealed sporadic pulses of TGF-betaR signaling in matrix-attached cells during morphogenesis. Last, in clinical specimens of breast cancer with dichotomous basal cytokeratin expression, we find that junD and Krt5 proteins are correlated in ECM-attached cells. Interestingly, junD and Krt5 are anticorrelated in cells not directly in contact with stromal ECM, and this regulation is mimicked in 3D culture of MCF10A cells. Together, our results raise the possibility that heterogeneous basal-like breast cancers switch between two states that depend critically on the ECM context.
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 4922. doi:10.1158/1538-7445.AM2011-4922
Abstract 4924: Gene network inference models reveal novel key mediators of mammary tumorigenesis
Authors: Brock Amy , Li Hu , Krause Silva , Collins James J. , Ingber Donald E. 
Published: June 2012

Abstract
Cancer is a developmental disease, requiring the concerted switching of multiple cellular gene programs. Here we ask whether we can use computational network inference models in a systems biology-driven approach to identify changes in connectivity within the underlying gene regulatory network during cancer progression, as well as novel key mediator genes that are central to altered disease state networks. To investigate this hypothesis, we reverse engineered the gene regulatory networks of mammary glands within normal mice and transgenic C3(1)-SV40Tag mice that undergo mammary gland transformation and tumor progression. RNA was isolated from the mammary glands of transgenic mice at 8, 12, 16 and 20 weeks of age; wild type mice were analyzed at 8 weeks. Whole genome microarray profiles were obtained for each stage. A network inference algorithm was trained on a set of 3000 genome-wide gene expression signatures from public databases. A Mode-of-action Network Inference (MNI) algorithm was used to identify key mediator genes at each stage of the gene regulatory network during different stages of cancer progression in the transgenic mouse mammary gland based on z-score significance. From this initial set of candidates, we focused on key mediator genes classified by gene ontology analysis as transcription factors. To experimentally assess the functional relevance of genes identified by this computational approach, key mediator genes were silenced in vitro in three-dimensional (3D) cultures of mouse mammary tumor epithelial cells derived from the transgenic animals. In contrast to normal mammary epithelial cells, tumor cells failed to form polarized structures containing a lumen in 3D spheroid culture. Importantly, siRNA knockdown of key mediator genes induced these cancer cells to revert to a normalized phenotype in 3D culture. These data demonstrate the feasibility of using genome reverse engineering approaches to identify genes that can potentially induce cancer reversal.
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 4924. doi:10.1158/1538-7445.AM2011-4924
Abstract 4946: Aberrant methylations of microRNA-9s in lung cancers
Authors: Muraoka Takayuki , Toyooka Shinichi , Sou Junichi , Maki Yuho , Ueno Tsuyoshi , Tanaka Norimitsu , Aokage Keiju , Asano Hiroaki , Tsukuda Kazunori , Yamane Masaomi , Takahiro Oto , Miyoshi Shinichiro 
Published: June 2012

Abstract
Background: microRNAs (miRNAs) represent a new class of small non-coding RNAs regulating gene expression by inducing messenger RNA degradation or interfering with translation. miRNAs regulate many cellular processes and have been shown to be associated with cancer development. Recent study showed that miR-9s consisting of mir-9-1,9-2, 9-3 regulates E-cadherin. On the other hand, it has been reported that that methylation of miR-9s are associated with metastasis or poor prognosis of some type of human cancers. In this study, we examined the methylation status of miR -9-1, 9-2, 9-3 in lung cancer to find that miR-9 methylation seems to be associated with lymph node metastasis in lung cancer(LC).
Material and methods: We collected 152 LC tumor DNAs which resected in our institute during 2007 to 2008. After bisulfate conversion, we determined the methylation status of miR-9-1, 9-2 and 9-3 by combined bisulfite restriction analysis method.
Results: Aberrant methylations of either miR-9 were shown in 52 out of 152 cases (34%). Methylation of either miR-9 was present in 39 %, 26 %, 34 %, 42 % of males, females, never-smokers, and ever-smokers, respectively. Methylation of either miR-9s were detected in 35 % of adenocarcinomas, 33 % of squamous cell carcinomas, and 63 % of other LCs. Of note, miR-9 methylation was significantly more frequent in pathological stage I cases (39 %, n = 119) than in the other stage (II to IV) cases (18 %, n = 33; p = 0.028). While 4 cases were methylated in lymph node metastasis cases (17%, n =24), 48 cases were methylated in cases without lymph nodal metastasis (38 %, n =128 : p=0.06).
Conclusion: Aberrant hypermetylation of miR-9s were associated with early pathological stage and /or non-lymph nodal metastasis, suggesting that miR-9s, which relate to aggressiveness and metastasis, might be sliced by abbarent methylation in early stage LCs.
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 4946. doi:10.1158/1538-7445.AM2011-4946
Abstract 4949: microRNA (miR) analysis as a tool for discovering platinum resistance mechanisms in non-small cell lung cancer (NSCLC)
Authors: Bar Jair , Perez-Iratxeta Carolina , Gorn-hundermann Ivan , Stefanie Reid , Goss Glenwood D. , Dimitroulakos Jim 
Published: June 2012

Abstract
Background: NSCLC is the most common cause of cancer-related death in the world. Platinum-based chemotherapy is the mainstay of treatment both in the adjuvant and the metastatic settings, but platinum resistance is common. A variety of mechanisms have been reported to underlie platinum-resistance. miRs are short non-coding RNA molecules, each regulating a large number of genes. We hypothesized that in platinum-resistant NSCLC cells, a small number of differentially expressed miRs modulating an abundance of gene products, activate in concert a large number of platinum-resistance mechanisms.
Aim: To uncover mechanisms of platinum-resistance in NSCLC, by indentifying miRs differentially expressed in platinum resistant cells.
Methods: Platinum-resistant cell lines were created by cisplatin selection of Calu6 and NCI-H23, NSCLC cell lines. RNA was hybridized to Affymetrix miR arrays, followed by TargetScan algorithm analysis. Levels of specific miRs were quantified by RT-PCR (ABI) and were modulated by miR inhibitors (Ambion).
Results: Two sets of sensitive (S) and platinum-resistant (R) cell lines were created, each set consisting of a parental S line and several R sub-lines. miR array analysis was performed on the S and R lines. miRs that were significantly more abundant in each of four R lines compared to the corresponding S lines were compiled. Genes predicted to be targeted by each of those miRs with a p value &lt; .05 were tabulated. Surprisingly, only 16 genes were common to those four gene lists, including CDK6, an important G1-S cell cycle regulator. mRNA and protein levels of CDK6 were higher in S compared to R lines, and accordingly, growth rate of R lines was slower. miR145, one of the miRs upregulated in the R lines, is predicted to target CDK6. Transfection of a miR145 inhibitor resulted in a mild increase in mRNA levels of CDK6, supporting its role as a regulator of CDK6.
Conclusions: Utilizing a number of biological systems (sets of cells lines) that model the same phenotype (platinum resistance) allows for a robust analysis of the involved molecules. miR profiling of multiple systems can identify genes that are commonly regulated in different systems by different miRs. Using this approach we discovered upregulation of miRs, including miR145, resulting in downregulation of CDK6, as a potential mechanism of platinum resistance in NSCLC.
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 4949. doi:10.1158/1538-7445.AM2011-4949
Abstract 4963: An integrated approach for functional analysis of 11q13 amplification target genes in HNSCC
Authors: Lepikhova Tatiana , Pehkonen Henna , Louhimo Riku , Chen Ping , Peitsaro Nina , Nieminen Anni , Imai Misa , Klefstrom Juha , Hautaniemi Sampsa , Monni Outi M. 
Published: June 2012

Abstract
Gene amplification is one of the most common mechanisms for oncogenic activation in human cancer. Some genomic regions are more frequently amplified than others. For example, amplification of 11q13 occurs at high frequencies in several human cancers, such as lung, bladder, breast and ovarian carcinomas, as well as head and neck squamous cell carcinoma (HNSCC). Approximately 40% of HNSCC are affected by this specific amplification, which is associated with the presence of lymph node metastasis and poor prognosis. Distinct core regions of amplified areas within the 11q13 locus have been identified, and these can be amplified independently or concurrently in various combinations. A number of oncogenes or potential cancer-related genes have been mapped to the 11q13 chromosomal region, however it is still not known whether these genes, that undergo co-amplification and over-expression, cooperate in promoting tumorigenesis. We have used a complementary approach to comprehensively characterize the functional basis for selection and maintenance of 11q13 amplification in HNSCC. To facilitate this approach, each of the 15 HNSCC cell lines used in this study has undergone molecular characterization for genomic and transcriptomic alterations. We performed a loss-of-function screen on 11q13 positive HNSCC cell lines to identify the genes essential for growth and survival. Next we applied gain-of-function analysis using ORFs for CTTN, FADD, PPFIA1, ORAOV1, CCND1 on 11q13 negative HNSCC cell lines. A single or multiple genes mapping to the amplicon were stably co-overexpressed in different combinations and related phenotypes were analysed in several in vitro and in vivo assays for growth, invasion and sensitivity/resistance to drugs. In addition, changes associated with overexpression of those genes were analysed by exon arrays in order to identify deregulated signaling pathways associated with 11q13 amplification. Our preliminary data suggests that this integrated approach is an efficient method at identifying genes that co-operate due to their location in the same amplicon. Such information is particularly valuable for elucidating oncogenic drivers and addressing the relevance of 11q13 amplification to drug sensitivity/resistance in 11q13 positive 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 4963. doi:10.1158/1538-7445.AM2011-4963