bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4392: Targeting HADC-2: Chemopreventive effect of OSU-HDAC42 on rat colon carcinogenesis and APCmin/+ Mice intestinal tumorigenesis.
Authors: Ravillah Durgadevi , Qian Li , Brewer Misty , Zhang Yuting , Biddick Laura , Madka Venkateshwar , Patlolla Jagan M.R. , Mohammed Altaf , Steele Vernon , Rao Chintalapally V. 
Published: August 2014

Abstract
Epigenetic modulators particularly histone deacetylases (HDACs) are valid targets cancer for prevention and Therapy. Recent studies from our laboratory and others suggest that HDAC-2 over-expression is associated with colon tumor progression and potential target for colon cancer prevention. The present study explored the chemopreventive effects of novel HDAC-2 inhibitor, OSU-HDAC42, in a mouse model of familial adenomatous polyposis (FAP). We used a rat colon carcinogenesis model assay, inhibition of aberrant crypt foci (ACF) development, as measure of the dose-response and chemopreventive effects. Colonic ACF were induced by azoxymethane (AOM) (15 mg/kg BW once weekly for 2 weeks by s.c. injection at the age of 8 and 9 weeks). One week after AOM-treatment groups of rats were fed AIN-76A diet containing 0, 75, 150 and 300 ppm OSU-HDAC42 for eight-weeks, and then colonic ACF were evaluated. Six week-old male C57Bl/6J-APCmin/+ and wild type mice were fed AIN-76A diet containing 150 ppm OSU-HADC42 or 300 ppm SAHA for 80 days. At ∼120 days of age, all mice were killed, and the intestines were evaluated for polyps. Dietary administration of OSU-HDAC42 produced a dose-dependent inhibition of AOM-induced colonic ACF formation (by 13-50%, p&lt;0.05 -0.001) and reduced the number of foci with ≥4 crypts/focus (by 25-57%, P&lt;0.05-0.0001) in F344 rats. 150 ppm OSU-HDAC42 significantly inhibited development of small intestinal (&gt;46%, p&lt;0.001) and colon tumors (&gt;26%, P≥0.05) in APCmin/+ mice. Whereas 300 ppm SAHA showed limited non-significant inhibition of intestinal polyp formation in APCmin/+ mice. Further, OSU-HDAC42 showed inhibition in small intestinal polyps size measuring 1-2-mm (P&lt;0.001). Importantly, mice fed with 150ppm OSU-HDAC42 showed significant reduction in HDAC-2, PCNA, CyclinA, CDK2, CDC25C expression pattern and increased p53 expression levels. These observations demonstrate that novel HDAC inhibitor, OSU-HDAC42 potential chemopreventive against the chemically-induced and polyposis models of colon tumorigenesis. {This work is supported by NCI-N01-CN53300}
Citation Format: Durgadevi Ravillah, Li Qian, Misty Brewer, Yuting Zhang, Laura Biddick, Venkateshwar Madka, Jagan M.R. Patlolla, Altaf Mohammed, Vernon Steele, Chintalapally V. Rao. Targeting HADC-2: Chemopreventive effect of OSU-HDAC42 on rat colon carcinogenesis and APCmin/+ Mice intestinal tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4392. doi:10.1158/1538-7445.AM2013-4392
Abstract 44: Tissue image analysis tool to quantify HER2 RNA and protein expression by colorimetric in situ hybridization and immunohistochemistry for breast cancer diagnosis.
Authors: Peljto Mirza , Krueger Joseph , Hagendorn Erik , Young David , Potts Steve , Nguyen Quan , Maqsodi Botoul , Yaoi Takuro , McMaster Gary 
Published: August 2014

Abstract
Early cancer diagnosis and risk assessment are powerful drivers in discovery of oncology biomarkers for diagnostic tests and simultaneous improvement of already identified biomarkers. Molecular tools such as RNA Colorimetric in situ hybridization (CISH) and immunohistochemistry (IHC) combined with conventional histopathology promise to increase the sensitivity and specificity of cancer staging and overall survival prediction. Changes in oncogene and proto-oncogene expression are a hallmark of cancer. For this reason, simultaneous quantification of mRNA and protein expression using RNA CISH and IHC combined with image-analysis is of interest. One such proto-oncogene is HER2, which is encoded by ERBB2 gene located at the long arm of human chromosome 17 (17q12). Here, we combine RNA CISH and IHC with image-analysis to develop a reliable quantitative HER2 assay that enables quantification of HER2 mRNA and protein expression in the context of human breast cancer. Since HER2 is only over-expressed in a subset of human breast cancers, we initially focused our analysis by screening tissue microarrays (TMAs) using RNA CISH and IHC. TMAs containing 20 normal and 20 breast tumor tissues were tested and whole-slide imaging was used to obtain CISH and IHC signals. HER2 mRNA and protein expression were analyzed, quantified, and compared both at tissue- and individual cell-levels using proprietary image-analysis based tools. Moreover, we compared heterogeneity of RNA and protein expression and further extended our studies to several other cancer-related genes. Finally, since oncogene expression plays a role in cancer pathologies, successful quantification of oncogene in situ expression in human cancer tissues may prove to be beneficial to further understanding of cancer pathology, for drug screening and development of biomarkers and ultimately diagnostic tests.
Citation Format: Mirza Peljto, Joseph Krueger, Erik Hagendorn, David Young, Steve Potts, Quan Nguyen, Botoul Maqsodi, Takuro Yaoi, Gary McMaster. Tissue image analysis tool to quantify HER2 RNA and protein expression by colorimetric in situ hybridization and immunohistochemistry for breast cancer diagnosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 44. doi:10.1158/1538-7445.AM2013-44
Abstract 4404: Multicellular tumor spheroid models to evaluate drugs targeting cell cycle checkpoints in 3D.
Authors: Ducommun Bernard , Lobjois Valérie , Laurent Jennifer , Frongia Céline , Mondesert Odile , Cazales Martine 
Published: August 2014

Abstract
MultiCellular Tumor Spheroid (MCTS) mimic the organization of a tumor and is considered as an invaluable model to study cancer cell biology and to evaluate new antiproliferative drugs. We report how the characteristics of MCTS in association with new technological developments can be used to explore the regionalization, the dynamics of cell cycle checkpoints and the effects of anticancer drugs in 3D. Spheroids expressing fluorescent reporters were engineered and used to explore cell cycle distribution and regionalization during growth. In these models we monitored cell cycle arrest in response to checkpoint activation after growth factor starvation, DNA injury or treatment with chemotherapeutic agents. The kinetics and regionalized aspects of the response were investigated both on fixed sections and on live spheroids using light sheet microscopy. All together, our data demonstrate the power of the combination of spheroids made of genetically modified cells expressing cell cycle reporters with both classical antibody-based detection and the use of innovative 3D imaging strategy. This study paves the way for the investigation of the molecular aspects of checkpoint response in 3D models and the dynamic studies of the 3D response to novel antiproliferative agents.
Citation Format: Bernard Ducommun, Valérie Lobjois, Jennifer Laurent, Céline Frongia, Odile Mondesert, Martine Cazales. Multicellular tumor spheroid models to evaluate drugs targeting cell cycle checkpoints in 3D. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4404. doi:10.1158/1538-7445.AM2013-4404
Abstract 4501: Diverse microtubule stabilizers cause differential expression of mitotic kinases leading to distinct centrosomal and mitotic defects.
Authors: Rohena Cristina C. , Peng Jiangnan , Johnson Tyler A. , Crews Phillip , Mooberry Susan L. 
Published: August 2014

Abstract
Microtubule stabilizers are some of the most useful and successful drugs used to treat adult solid tumors. However, the molecular events responsible for their antimitotic actions are not yet fully understood. In this study we evaluated the mitotic defects and signaling events initiated by three structurally and biologically different microtubule stabilizers; taccalonolide AJ, laulimalide/fijianolide B and paclitaxel. These microtubule stabilizers cause the formation of aberrant, but morphologically distinct mitotic spindles leading to the hypothesis that they initiate distinct mitotic signaling events. Each microtubule stabilizer caused different patterns of expression of key mitotic signaling proteins. Taccalonolide AJ caused centrosome separation failure to a much greater extent than paclitaxel or laulimalide. Taccalonolide AJ is also unique in that it was the only stabilizer to cause centrosome disjunction failure. These observations were consistent with the different defects in expression and activation of Plk1 and Eg5 caused by each stabilizer. Localization studies revealed that TPX2 and Aurora A are associated with each spindle aster formed by each stabilizer, which suggests a common mechanism of aster formation. However, taccalonolide AJ was the only stabilizer evaluated that caused pericentrin accumulation on every spindle aster. Pericentrin's localization to every spindle aster could facilitate the maintenance and stability of the highly focused asters formed by taccalonolide AJ. Laulimalide and paclitaxel caused completely different patterns of expression and activation of these proteins, as well as phenotypically different spindle phenotypes. Elucidating how chemically distinct microtubule stabilizers disturb mitotic signaling could identify key proteins involved in controlling sensitivity and resistance to the antimitotic actions of these agents.
Citation Format: Cristina C. Rohena, Jiangnan Peng, Tyler A. Johnson, Phillip Crews, Susan L. Mooberry. Diverse microtubule stabilizers cause differential expression of mitotic kinases leading to distinct centrosomal and mitotic defects. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4501. doi:10.1158/1538-7445.AM2013-4501
Abstract 4506: Photocaged molecules in targeted drug delivery.
Authors: Mitra Deboleena , Dcona Martin Michael , Hartman Matthew C.T. 
Published: August 2014

Abstract
We have developed a new targeted therapy that uses light to deliver cytotoxic agents into cancer cells. This strategy is based on the concept of photocaging in which a biologically active molecule is made inactive by the attachment of a light-cleavable blocking group. Upon exposure to UV radiation the photocleavable entity is removed and the biologically active molecule is released. Using this concept we have designed a prodrug that consists of a cell impermeable hydrophilic photocage attached to doxorubicin. The hydrophilic moiety makes the entire prodrug cell impermeable in the dark. Upon irradiation with non-toxic doses of UV light, the photosensitive group is removed and cytotoxic doxorubicin is released into the cells. In the presence of light the IC50 has been found to be 1.6 ±1.0 μM in JH-Eso-Ad1 cells. The FACS studies further confirmed that the cytotoxicity was due to light triggered release of free doxorubicin from the cell impermeable prodrug. This concept has been further developed by attaching a receptor binding molecule to the photocaged drug to enhance specificity. Specifically, we have attached folic acid and the PSMA binding ligand, DUPA to the photocaged doxorubicin. These targeting groups enable cancer cell selective drug delivery with light.
Citation Format: Deboleena Mitra, Martin Michael Dcona, Matthew C.T. Hartman. Photocaged molecules in targeted drug delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4506. doi:10.1158/1538-7445.AM2013-4506
Abstract 4542: Towards the identification of PKR-like endoplasmic reticulum kinase (PERK) inhibitors.
Authors: Park Jihyun , Wang Qiantao , Ren Pengyu , Dalby Kevin N. 
Published: August 2014

Abstract
During tumorgenesis cancer cells must tolerate cellular stresses such as DNA damage, hypoxia, and oxidative stress. In order to adapt to and overcome such stresses, tumor cells remodel transcriptional and translational programs by activating pro-survival signaling pathways. PERK (PKR-like endoplasmic reticulum kinase) is one of the key components of the unfolded protein response (UPR). Many studies report that the UPR is activated in a variety of tumor types. Previous studies demonstrated that cells with a compromised PERK-eIF2α-ATF4 signaling pathway are sensitive to hypoxic stress in vitro and form tumors that grow more slowly in vivo. Together, these data suggest a substantial role for PERK and the UPR in tumor cell survival and adaptation to stress. Thus, selective inhibitors of PERK activity may be useful therapeutic candidates for the treatment of cancer. Using a high-throughput screening (HTS) approach a number of lead compounds were identified with demonstrated ability to inhibit PERK kinase autophosphorylation and activity in cells. Using a publically available structure of Apo PERK a PERK-ATP complex structure was generated by means of molecular dynamics (MD) simulation. Evidence is presented to support the notion that the simulation-generated structure represents a useful model for computer-aided lead optimization.
Citation Format: Jihyun Park, Qiantao Wang, Pengyu Ren, Kevin N. Dalby. Towards the identification of PKR-like endoplasmic reticulum kinase (PERK) inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4542. doi:10.1158/1538-7445.AM2013-4542
Abstract 4578: Deep targeted sequencing of 12 breast cancer loci in 4,700 women across four different ethnicities.
Authors: Lindström Sara , Chapman Brad , Chen Gary , Chen Constance , Ablorh Akweley , Le Marchand Loic , Henderson Brian , Hofmann Oliver , Mirel Daniel , Haiman Christopher , Kraft Peter 
Published: August 2014

Abstract
Genome-wide association studies (GWAS) have identified multiple genetic loci associated with breast cancer risk. However, the underlying genetic structure in these regions is not fully understood and it is likely that the index GWAS signal originates from one or more yet unidentified causal variants within the region. We used next-generation sequencing to characterize 12 GWAS-discovered breast cancer loci in a total of 2,300 breast cancer cases and 2,300 controls across four ethnic populations. Study subjects were women from the Nurses’ Health Study (NHS) and the Multiethnic Cohort (MEC). Region intervals spanned between 46kb and 973kb and we hybrid-captured and sequenced a total of 5.5Mb. On average, we were able to capture 82% of the non-repetitive sequence in the targeted regions, and the average fraction of captured bases sequenced with a depth %gt20x was more than 95%. After single nucleotide variant (SNV) calling and quality control, a total of 138,898 SNVs remained for analysis. 87.4% of those had a minor allele frequency less than 0.5% and 50.2% were private mutations. Across all regions, a total of 81 SNVs showed evidence for association with breast cancer (P&lt0.001) but we did not find unequivocal association evidence supporting a causal role for any individual SNV. However, in two of the regions (2q35 and 11q13), we were able to refine the GWAS signal and identify a high posterior probability (&gt90%) set including less than 15 SNVs. We also conducted burden tests of rare variants (MAF&lt0.005) but did not identify any significant associations after adjusting for number of tests. However, rare variants in FGFR2 and a second gene at 10q26 were nominally associated with breast cancer (P&lt0.05). We are currently imputing existing breast cancer GWAS using this sequencing data as a reference panel which will triple our current sample size. These results stress the importance of large study samples when attempting to refine GWAS signals and illustrate the challenges facing post-GWAS fine-mapping studies.
Citation Format: Sara Lindström, Brad Chapman, Gary Chen, Constance Chen, Akweley Ablorh, Loic Le Marchand, Brian Henderson, Oliver Hofmann, Daniel Mirel, Christopher Haiman, Peter Kraft. Deep targeted sequencing of 12 breast cancer loci in 4,700 women across four different ethnicities. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4578. doi:10.1158/1538-7445.AM2013-4578
Abstract 4589: Overexpression of RAD51 promotes brain metastases from breast cancer.
Authors: Woditschka Stephan , Palmieri Diane , Duchnowska Renata , Jassem Jacek , Badve Sunil , Sledge George W. , Steeg Patricia S. 
Published: August 2014

Abstract
The DNA double-strand break (DSB) repair gene RAD51 was found to be overexpressed (1.5-fold, p=0.001) at the mRNA level in resected brain metastases compared to primary breast tumors from the same patients. RAD51 was also overexpressed (1.4-fold, p=0.008) specifically in brain metastases from breast cancer compared to systemic (bone/lung) metastases. We therefore hypothesize that RAD51 promotes brain metastasis development in breast cancer patients and investigated RAD51 as functional driver of brain metastases, independent of its recognized role in resistance to DNA-damaging chemotherapy.
RAD51 was overexpressed at physiologically relevant levels in brain-metastatic variants of human MDA-MB-231 breast carcinoma cells (231-BR) and 4T1 murine mammary carcinoma cells (4T1-BR). In vitro, RAD51 overexpression results in a 35-40% (p&lt;0.0001) reduction Gamma-H2AX foci during S-phase, a DNA DSB marker. Furthermore, using a Homologous Recombination (HR) assay we found that the frequency of HR was significantly increased (1.7-fold, p=0.002) in RAD51 overexpressers compared to vector controls. No effects on proliferation, motility or invasion were observed with RAD51 overexpression.
In intracardiac-injected mice, overexpression of RAD51 increased formation of large brain metastases, the equivalent of clinically detectable lesions, (3.3-fold, p=0.005; 3.3-fold, p=0.02) and micro-metastases (3.1-fold, p=0.01; 2.0-fold, p=0.04), compared to vector controls in 231-BR and 4T1-BR models, respectively. ShRNA-mediated RAD51 knockdown in 4T1-BR cells had the opposite effect, reducing large brain metastases (2.5-fold, p=0.001) and micro-metastases (2.5-fold, p=0.01). RAD51 modulation had no effect on lung metastasis development in tail-vein injected mouse models of 231-BR or 4T1-BR cells.
To distinguish between roles for RAD51 in initiation vs. outgrowth of brain metastasis, we quantified iron-labeled 231-BR cells in the brain microenvironment at 3, 7 and 12 days post-injection. On day 12, we observed significantly more RAD51-overexpressing single cells compared to vector controls, with a clear trend discernable by day 7 (fold-changes over vector: 1.1-fold, p=0.8; 2.4-fold, p=0.07 and 2.8-fold, p=0.001 for days 3, 7 and 12, respectively).
Together these data suggest that RAD51 drives initiation of brain metastases from breast cancer.
Citation Format: Stephan Woditschka, Diane Palmieri, Renata Duchnowska, Jacek Jassem, Sunil Badve, George W. Sledge, Patricia S. Steeg. Overexpression of RAD51 promotes brain metastases from breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4589. doi:10.1158/1538-7445.AM2013-4589
Abstract 460: Delicate balance among three types of T cells in concurrent regulation of tumor immunity.
Authors: Izhak Liat , Ambrosino Elena , O'Konek Jessica J. , Kato Shingo , Parish Stanley T. , Xia Zheng , Venzon David , Berzofsky Jay A. , Terabe Masaki 
Published: August 2014

Abstract
Various immunosuppressive cells, such as Tregs and type II NKT cells, mediate the immune regulation of cancer. Many studies have demonstrated the importance of regulatory cells; however, it is still not clear why different suppressive cells play a dominant role in different models. Here, we examined the relative role of two suppressors - Tregs and type II NKT cells – in a subcutaneous CT26 tumor model in three strains of mice: wild-type, NKT cell-deficient CD1dKO mice and Jα18KO, which lack type I NKT cells but still retain type II NKT cells. Tumors grew in all three strains, but Treg blockade by anti-CD25 mAb (PC61) led to tumor rejection in WT and CD1dKO but not in Jα18KO mice, suggesting that in Jα18KO mice, Tregs are not necessary for immune suppression. We hypothesized that cross regulation between type I and type II NKT cells in wild-type mice leaves Treg cells as primary suppressors, whereas in mice lacking type I NKT cells, unopposed type II NKT cells can suppress tumor immunity even when Tregs are blocked. We confirmed this hypothesis in PC61-treated Jα18KO mice by blocking type II NKT cells using anti-CD1d mAb (1B1) or by adoptive transfer of type I NKT cells combined with Treg blockade. These results support our hypothesis that it is necessary to block both suppressors, type II NKT cells and Tregs, in order to achieve protection. Also, activation of type II NKT cells by sulfatide in PC61-treated wild-type mice abrogated the protective effect of Treg blockade, indicating that shifting the balance between the two types of NKT cells toward immunosuppressive type II NKT cell dominance suppresses tumor immunity even in the absence of Tregs. We conclude that both Tregs and type II NKT cells can concurrently suppress tumor immunity and the balance between these is controlled in part by a third T cell, the type I NKT cell, regulating the regulators. Finally as cancer patients often have deficient type I NKT cell function somewhat like the Jα18KO mice, managing this delicate balance among three T cells may be critical for the success of immunotherapy of human cancer.
Citation Format: Liat Izhak, Elena Ambrosino, Jessica J. O'Konek, Shingo Kato, Stanley T. Parish, Zheng Xia, David Venzon, Jay A. Berzofsky, Masaki Terabe. Delicate balance among three types of T cells in concurrent regulation of tumor immunity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 460. doi:10.1158/1538-7445.AM2013-460