bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C35: Rapid assessment of aneuploidy using 5 minute oligo-FISH probes
Authors: McGrath Patricia , Bradley Sean , Aurich-Costa Joan , Ng Carrie , Selvaggio Susan 
Published: May 2012

Abstract
More than 15 years ago, development of non-radioactive FISH probes revolutionized clinical cytogenetics and FISH is now routinely used for mapping genes, detecting pathogenic DNA, and diagnosing cancers and genetic diseases. However, most FISH applications rely on probes generated from large genomic fragments (BAC, YAC or plasmids), cDNA, or PCR generated fragments. The large probe size (200–600bp) results in poor cell penetration necessitating long, 8 to 16 hours hybridization. Furthermore, large BAC probes require high probe concentration and stringent wash conditions.
We recently developed short (30mer), synthetic Oligo-FISH probes targeting highly repetitive sequences which offer several advantages for assessing aneuploidy, including performance in &lt; 10 min compared to 8–16 hours required for BAC probes. In addition, since Oligo-FISH probes hybridize at low stringency, it is possible to perform at least 6 successive 4 probe hybridizations without damaging cellular DNA, making it possible to determine aneuploidy in all 24 chromosomes on the same slide in &lt; 24 hours.
Here we show results using Oligo-FISH probes specific for chromosomes: 7, 3, 9q12, and 17 designed to detect aneuploidy in urothelial cells. After optimizing probe design, we identified sequences available in the human genome database that contain chromosome specific alpha—satellite or satellite sequences. Next, we prepared urothelial slides and optimized denaturation and hybridization times. After establishing optimum Oligo-FISH conditions, we tested urine samples from 5 healthy volunteers. Our results, obtained in &lt; 3 hours show Analytical Sensitivity &gt; 98% and S/N&gt; 2.
Urothelial carcinomas account for more than 90% of all bladder cancers and more than 54% of these newly diagnosed carcinomas are superficial, non-invasive transitional cell carcinomas, which has the highest rate of recurrence and requires life-long diagnostic surveillance. The current standard methods for bladder cancer include cystoscopy and cytology which are invasive, expensive and insensitive.
Citation Information: Cancer Res 2009;69(23 Suppl):C35.
Abstract C36: Using the Rb/E2f3 mutant mouse model to reveal markers for the progression to metastasis
Authors: Vormbrock Kirsten , Schreiber Caroline , Loddenkemper Christoph , Ziebold Ulrike 
Published: May 2012

Abstract
The retinoblastoma tumor suppressor protein (pRb) was the first tumor suppressor to be identified. The E2F family of transcription factors is considered the best-studied class of interaction partners of pRB. Specifically, E2F1-3 are all capable to control re-entry and progression through the S-phase of the cell cycle. The simplified view is that hypo-phosphorylated pRb is bound by E2F and recruits chromatin remodeling complexes to represses the transcription of E2F target genes. Upon cell cycle progression pRb is phosphorylated leading to a release of E2Fs and the subsequent progression through the G1/S-transition.
In order to understand the consequences of deregulation of the pRb/E2F-pathway, a number of groups have established mouse knock-out models of various members of this pathway. Using a combined knockout mouse model it was demonstrated that E2F3 contributes to both the inappropriate proliferation and p53-dependent apoptosis that arises in pRb-deficient embryos. Furthermore, it was shown that absence of E2F3 results on one hand in the attenuation of the growth of pituitary adenomas, on the other hand it promotes the development of medullary thyroid carcinomas (MTCs) yielding metastases at an increased frequency.
Since this is one of the few existing mouse models to study metastasis, we wished to use this model to identify novel markers and mechanisms that regulate this process. We established the whole genomic transcriptional profile of mouse MTCs harvested from Rb/E2f3 mutant mice. The comparison of metastatic MTCs with non-metastatic tumors defined a data set of 123 putative metastatic markers. Among this data set, we identified a cluster of 22 genes that are directly involved in the formation of the kinetochore, establishment of the centromere or play a distinct role in the spindle assembly checkpoint. We validated the expression of these novel metastatic markers using mouse RNA, as well as material from human metastatic MTC biopsies. Importantly, we were able to establish that the same genes were only upregulated in metastatic tumors utilizing immunhistochemistry on sections of human metastatic MTCs but not in non-metastatic counterparts. Moreover, chromatin immunoprecipitation assays support that these genes are direct targets of the pRB/E2F-pathway. In summary we identified novel markers of metastasis. Moreover, these markers are also putative E2F target genes, the fact of which emphasizes the important contribution of E2Fs to tumor progression.
Citation Information: Cancer Res 2009;69(23 Suppl):C36.
Abstract C37: Ensemble survival prediction for breast cancer using microarray data
Authors: Reddy Anupama , Ganesan Shridar , Bhanot Gyan 
Published: May 2012

Abstract
We present an algorithm, “Ensemble Logical Analysis of Survival Data”, for predicting survival of cancer patients based on patterns identified on gene-expression microarray data. A pattern is defined as a combination of expression levels of multiple genes, associated with risk of mortality or metastasis of the tumor. We illustrate our method on several breast cancer microarray datasets, including 286 samples from a study of node negative untreated samples from Wang et al 2005, 347 primary invasive samples from Ivshina et al. 2006, and 255 early-stage samples who received Tamoxifen as adjuvant treatment from Loi et al. 2008. We use the recent molecular stratification of the breast cancers into eight robust subtypes: Luminals: (LA, LB1, LB2, LB3), Basal-like: (BA1, BA2) and Her2+: (Her2+I, Her2+NI) from Alexe et al. 2007 and identify patterns of genes which drive the disease within each of these molecular types. This is followed by an analysis of the genes seen most frequently in patterns to determine the pathways responsible for progression/metastasis/death for each subtype.
At each event time point (event = death/recurrence/metastasis), we identify patterns that separate patients into high/low risk classes. Each pattern is then associated with a score defined as the integral of the Kaplan-Meier survival curve for the samples that satisfy the pattern. Pattern space is not disjoint and a sample can satisfy more than one pattern, even for a given time point. The average of the pattern scores for each patient across all time points defines a patient-specific survival score. All the above steps are computed using an ensemble method: two-thirds of the data is randomly selected, patterns are generated on this random subset, and patient scores are computed. This is repeated 100 times, and patient scores are aggregated over these 100 runs.
We find that these aggregated scores correlate very well with actual survival in the Wang dataset (c-statistic: 86% for LA, 95% for LB1, 88% for LB3, 77% for Basals, and 80% for Her2+). High/low risk class assignment based on the median of the predicted survival score is highly significant (log-rank p-value: 0.01 for LA, 0.0004 for LB1, 0.00006 for LB3, 3.3×10−8 for Basals and 0.0003 for Her2+). The method that we propose is general and can be used for predicting survival for any cancer type. It can also be applied to RT-PCR data, single nucleotide polymorphisms, microRNA data and data on copy number variations. Finally, we show that our risk score is significantly superior to an Oncotype DXTM score inferred for the samples from the gene expression data.
Citation Information: Cancer Res 2009;69(23 Suppl):C37.
Abstract C38: Metformin inhibits cancer cell growth in an AMP kinase-independent and -dependent manner
Authors: Rattan Ramandeep , Giri Shailendra , Hartmann Lynn C. , Shridhar Viji 
Published: May 2012

Abstract
Metformin is the most widely used drug for type 2 diabetes. Metformin activates AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism via its upstream kinase LKB1. Activation of AMPK has been shown extensively to cause growth arrest in multiple tumor types by inhibiting the TSC-mTOR (mammalian target of rapamycin) pathway as well as by inducing cell cycle arrest. Our data indicate that metformin exerts an anti-proliferative effect on several chemo-responsive and -resistant ovarian cancer cell lines (A2780, CP70, C200, OV202, OVCAR3 and SKVO3ip, PE01, PE04), which is accompanied by activation of AMPK and cell cycle arrest. Interestingly, we have also determined that metformin is able to inhibit proliferation of ovarian cancer cells when AMPK is silenced by siRNA, where both the expression and activation of AMPK is significantly reduced. Also, metformin was able to attenuate proliferation of AMPK (−/−) mefs, although to a lesser degree in AMPK (+/+) mefs. Additional results indicate that metformin activates p21 and inhibits cyclinD1 activities partially in AMPK (−/) mefs. These data suggest a novel mechanism of metformin action, namely, an AMPK independent pathway which can modulate proliferation and possibly cell cycle regulated events in ovarian cancer. Whether the AMPK independent effects of metformin require LKB1 activity is currently under investigation. Collectively, our preliminary observations indicate that metformin can modulate proliferation and cell cycle arrest in an AMPK independent manner.
Citation Information: Cancer Res 2009;69(23 Suppl):C38.
Abstract C41: Heme oxygenase-1 and carbon monoxide modulate responses to DNA damage in prostate cancer
Authors: Wegiel Barbara , Bjartell Anders , Harris Clair , Belcher John , Vercellotti Gregory , Gallo Dave , Csizmadia Eva , Helczynski Leszek , Persson Jenny Liao , Otterbein Leo E. 
Published: May 2012

Abstract
Heme oxygenase (HO) and carbon monoxide (CO), a product of HO activity generated during heme catalysis, exert differential effects on the apoptotic response dependently on the environmental milieu and cell types involved. The role of HO-1 and CO in modulating chemotherapeutic treatment in prostate cancer has not been tested. Our focus in this work explored the role of HO-1 and CO in modulating PCa cell death via DNA damage mechanisms. We examined HO-1 expression in PCa samples from 482 patients and found strong nuclear staining in moderately differentiated tumors (Gleason grade 3). Treatment of PCa cells with the chemotherapeutic agents, camptothecin or doxorubicin increased HO-1 activity in the cytosol, which correlated with increased cell death. Nuclear translocation of HO-1 resulted in decreased enzymatic activity. Low activity of HO-1 in the nucleus may confer resistance to chemotherapy due to the antiapoptotic effects of HO-1. Overexpression of cytosolic and active HO-1 or exogenous delivery of CO at low non-toxic concentrations (250 parts per million) in combination with a chemotherapeutic led to enhanced tumor cell death via caspase-3 activation. CO exposure of mice with established PC3 xenografts delayed tumor growth via accelerated apoptosis (TUNEL staining) and mitotic catastrophe of cancer cells as well as strong inhibition of angiogenesis (CD31 staining). Further, CO sensitized tumors to doxorubicin treatment with enhanced apoptosis and blockage of mitosis. In contrast, CO blocked chemotherapeutic-induced cell death in normal cells supporting a new function for HO-1/CO as cellular sensors of DNA damage. Taken together, our data demonstrate the importance of cellular localization of HO-1 in PCa progression and importantly that CO, in part regulates cellular sensitivity to DNA damaging agents. We propose a novel strategy to overcome resistance to chemotherapy as well as reducing the chemotherapeutic burden by employing CO at safe, non-toxic concentrations that permits preservation of normal cells and tissue.
Citation Information: Cancer Res 2009;69(23 Suppl):C41.
Abstract C45: Somatostatin receptor activation by agonist-like antibodies can reverse neuroendocrine tumor BON cell dedifferentiation and increase cell death
Authors: Leu Frank , Nandi Minesh , Wong Chung 
Published: May 2012

Abstract
The somatostatin receptors (SSTR) are effective therapeutic targets for treating neuroendocrine tumors, primarily achieved through the inhibition of both cellular proliferation and hormone secretion. SSTR are comprised of five major subtypes, namely subtypes 1, 2 (A and B), 3, 4 and 5. The somatostatin signaling also works as a determinant in the TGF-β dependent neuroendocrine-mesenchymal transition (NMT) process. NMT is similar to the epithelial-mesenchymal transition (EMT), but has the opposite cellular differentiation response to TGF-β. For instance, TGF-β promotes cell dedifferentiation in EMT but promotes cell differentiation in NMT. The process of EMT is a critical morphogenic event during the progression of epithelial tumors. Recently, in epithelial tumors, the micro RNA 200c (miR-200c) has been found to negatively regulate E-cadherin's transcriptional repressor ZEB1 and capable of keeping the EMT invasiveness in check. In our study, the miR-200c repressor (Oligoengine Inc. designed by Todd Hauser) has been successful in up-regulating ZEB1 and ultimately driving the neuroendocrine tumor BON cells into the dedifferentiated mesenchymal state. The miR-200c repressor induces changes in the tumor metastasis markers, such as the ZEB1 increase, E-cadherin decrease, and ultimately with both Vimentin and Twist increases. Our anti-SSTR antibodies raised against receptor's ectodomain region (anti-SSTR ECL2 antibodies) were able to reverse the BON cell from its mesenchymal state back to the differentiated neuroendocrine state. Our results suggest that similar to EMT, both miR-200c and ZEB1 are also involved in the NMT dedifferentiation programming. In summary, we conclude that miR-200c/ZEB1 signaling can be regulated by the SSTR activation. This is evident because anti-SSTR agonist-like SSTR2, 3 and 5 antibodies are capable of overcoming neuroendocrine tumor's miR-200c commitment to metastasis. Furthermore, we also found that these anti-SSTR antibodies can sensitize tumor cells to death.
Citation Information: Cancer Res 2009;69(23 Suppl):C45.
Abstract C47: 21-OH 6,19-epoxyprogesterone: A new dissociated glucocorticoid with anti-inflammatory properties but without antiapoptotic effects on chemotherapeutically treated mouse mammary tumor cells
Authors: Orqueda Andres J. , Veleiro Adriana , Joffé Elisa Bal de Kier , Kordon Edith , Burton Gerardo , Pecci Adali 
Published: May 2012

Abstract
Glucocorticoids (GCs) are widely used as coadyuvants in the treatment of solid tumors with chemotherapics such as paclitaxel (PXL) and doxorubicin (DOXO). However, clinical evidence supports the idea that GCs may induce resistance to these antitumor therapies. To improve cancer treatment quality, intense efforts are being made to design new dissociated steroids (steroid receptor glucocorticoid modulators (SRGMs). These compounds should mimic only the beneficial aspects of glucocorticoid therapy without inducing the undesired side effects in cancer patients. We have previously shown that dexamethasone (Dex), a well-known synthetic GC, inhibits PXL or DOXO induced apoptosis in breast tumor cells through a mechanism involving Bcl-XL and Bcl-2 induction. Here, our goal was to compare Dex effects with those triggered by 21-OH-6,19-epoxyprogesterone (21-OH-6,19-OP), which is a rigid steroid considered a passive GC antagonist. Molecular dynamic simulation studies predicted that 21-OH-6,19OP is unable to induce GR/21-OH-6,19-OP complex homodimerization and/or binding to coactivators, making these complex incapable to directly activate gene transcription (Alvarez et al J Med Chem. 2008. 13:1352). The effects of 21-OH-6,19-OP on apoptosis induced by DOXO or PXL in the epithelial mouse mammary tumor cell line LM3 was determined by analyzing Caspase-3 activity and gene and protein expression of antiapoptotic members of the Bcl family, i.e. Bcl-2 and Bcl-XL. The results show that, contrary to Dex, 21-OH-6,19-OP cannot reverse apoptosis induced by DOXO or PXL in LM3 cells. In fact, 21-OH-6,19-OP and Dex differentially regulate Bcl-2 and Bcl-XL expression. Dex's reversion on chemotherapic induced apoptosis (Dex+DOXO o Dex+PXL) correlates with an increase in Bcl-XL levels, while 21-O-H-6, 19-OP does not affect neither cell death nor Bcl-XL levels. The relevance of Bcl-XL involvement in DOXO resistance of cells treated with Dex was confirmed by knocking-down Bcl-XL with specific siRNA. Silencing Bcl-XL expression directly implicated loss of antiapoptotic GC effects. On the other hand, 21-OH-6,19-OP antiinflammatory action was also evaluated on the lung epithelial tumor cell line A549 by determining Interleukin-8 (IL-8) and Cyclooxygenase-2 (COX-2) expression in the presence of the Tumor Necrosis Factor-alpha (TNF-α). Expression levels of IL-8 and COX-2, measured by qRT-PCR, indicate that 21-OH-6,19-OP may have antiinflammatory effects as it reverses these inflammation markers expression induced by TNF-α in lung epithelial cells. Together, these findings suggest that 21-OH-6,19-OP is a SRGM that keeps glucocorticoid antiinflammatory properties without antiapoptotic effects, thus becoming a novel candidate for treatment of solid tumors as breast cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):C47.
Abstract C48: Antiangiogenic properties of rare earth nanoparticles: Implications in ovarian cancer
Authors: Giri Shailendra , Rattan Ramandeep , Karakoti Ajay , Seal Sudeepta , Shridhar Vijayalakshmi 
Published: May 2012

Abstract
A substantial body of evidence suggests an association between vascular endothelial growth factor (VEGF) and the neovascularization that occurs with ovarian carcinogenesis. VEGF expression has been directly related to ascites accumulation. Phase II clinical trials in ovarian cancer using single-agent bevacizumab (a monoclonal antibody directed against VEGF) showed promising results, clearly highlighting the importance of anti-angiogenesis based-targeted therapies in ovarian cancer. One of the ways that VEGF mediates angiogenesis is by activating NADPH oxidase-ROS pathway. We have developed and engineered nanoparticles (NP) of cerium oxide (Nanoceria, NCe), a rare earth oxides, which have been tested for their ability to serve as free-radical scavengers to provide protection against chemical, biological, and radiological insults that promote the production of free radicals. Here we show for the first time that treatment of human umbilical vascular endothelial cells (HUVECs) with NCe resulted in inhibition of proliferation, capillary tube formation and VEGF165 induced activation of VEGFR2 and MMP2. Additionally, NCe treatment inhibited growth factor induced migration and invasion of ovarian cancer cells. Collectively, these results indicate that cerium oxide based NP could potentially be used as an antiangiogenic therapeutic agent in ovarian cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):C48.
Abstract C49: AKT inhibitor has potent antitumor activity in human lung cancer xenograft models
Authors: Banu Naheed , Hiran Tej , Fadela K. Chafai , Menon Krishna 
Published: May 2012

Abstract
Lung cancer accounts for more than 215,000 new cases annually in the United States, and is the single largest cause of cancer death accounting for more than 130,000 deaths each year. Non-small cell lung cancer (NSCLC) accounts for 80% of all bronchogenic neoplasms with 90% of diagnosed patients dying within five years; therefore, new therapies are strongly desired. Effective therapies will come from a more detailed understanding of the molecular mechanisms underlying both the disease and the clinical response. We are developing a novel molecule, termed Kevetrin™, which was effective in reducing tumor growth in human lung cancer xenograft models while being well-tolerated. Kevetrin appeared to exert its anti-tumor activity by lowering levels of activated AKT also known as protein kinase B, of the AKT signal transduction pathway resulting in reduced tumor cell survival. Activated AKT was measured by a sandwich ELISA specific for phosphorylated AKT protein. Kevetrin was also evaluated for anti-tumor activity in vivo in the NCI-H1975 and A549 lung xenograft tumor models. Tumor-bearing nude mice were treated intravenously (IV) with either 200 mg/kg Kevetrin three times every other day or 22 mg/kg paclitaxel four times every other day. After Kevetrin was incubated with cells in vitro, phosphorylated AKT levels were reduced leading us to test for anti-tumor activity in vivo. Results with NCI-H1975 tumors showed that Kevetrin significantly delayed median tumor growth by 34 days (142%) in the first experiment and 28 days (156%) in a repeat experiment compared to controls, whereas the tumor growth delay (TGD) of paclitaxel was just 4 days (17%) and 14 days (78%), respectively. No weight loss occurred during treatment with Kevetrin. Results with A549 tumors showed that Kevetrin significantly delayed median tumor growth by 11 days (33%) in the first experiment and 30 days (111%) in a repeat experiment compared to controls, whereas the TGD of paclitaxel was just 0 days (0%) and 3 days (11%), respectively. In this study, Kevetrin resulted in &lt;5% weight loss during treatment. These results showed that Kevetrin exerted potent anti-tumor activity against two human lung xenograft tumor models, NCI-H1975 and A549, at a dose and schedule that was well-tolerated as indicated by a small transient weight loss during treatment. NCI-H1975 have the T790M and L858R mutations in epidermal growth factor receptor (EGFR) and A549 have the K-ras mutation and overexpress STAT3 and Nrf2; these mutations are associated with resistance to standard chemotherapy. The reduction of activated AKT may be a mechanism by which Kevetrin overcame resistance and showed efficacy in these tumor models. These studies demonstrate that Kevetrin has promising potential for the treatment of lung carcinoma, particularly in cases where tumors have become resistant to standard chemotherapy.
Citation Information: Cancer Res 2009;69(23 Suppl):C49.