bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4379: Framing therapeutic opportunities in tumor-activated gametogenic programs.
Authors: Corcoran Kathleen , Taus Patrick , Sinnott Rebecca , Maxfield Kimberly , Wooten Joshua , Whitehurst Angelique 
Published: August 2014

Abstract
Tumors frequently activate genes whose expression is otherwise restricted to testes, and which can invoke a humoral immune response in cancer patients. Given their germline-biased expression pattern, these Cancer-Testes antigens (CT-antigens, CTAs) may afford the potential for an extraordinary therapeutic window, if they are required for tumorigenic behaviors. While the function of CTAs in normal and neoplastic settings remains obscure, mounting evidence suggests that specific CTAs can contribute to tumor cell autonomous behaviors. To generate a more comprehensive understanding of the functional roles of CTAs, we have employed an unbiased, multi-dimensional, loss of function discovery platform to systematically assess the contribution of CT-antigens to a range of tumorigenic signaling pathways and phenotypes. By employing a diverse panel of 11 tumor-derived cell lines to screen 120 CTAs, we find that these tumor-activated genes are required to support a number of the hallmarks of cancer. For example, we reveal multiple MAGE family members that mitigate response to mitotic stress and hypoxia. Additionally, we find that the SPANX family of CTAs contributes to β-catenin signaling. Finally, we reveal a role for GAGE proteins in supporting the viability of a range of tumor types. The diversity of neoplastic settings analyzed in our primary screen allowed for the identification of CTAs that support tumor cell fitness in multiple disease backgrounds. For example, we have uncovered CTAs that contribute to mitochondrial integrity in lung, breast, melanoma and sarcoma. Alternatively, we find that CTAs can display lineage selective dependencies, such as supporting TGFβ signaling in claudin-low breast tumors. Taken together, these observations support the hypothesis that CTAs are frequently integrated into the tumor cell regulatory environment to support cell division, survival and modulate stress responses by regulating key signaling pathways. Thus, CT-antigens present previously unrecognized tumor-specific vulnerabilities that may be exploited for therapeutic intervention.
Citation Format: Kathleen Corcoran, Patrick Taus, Rebecca Sinnott, Kimberly Maxfield, Joshua Wooten, Angelique Whitehurst. Framing therapeutic opportunities in tumor-activated gametogenic programs. [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 4379. doi:10.1158/1538-7445.AM2013-4379
Abstract 438: Establishment of MDA-MB231-derived breast cancer cell lines possessing a higher metastatic activity and a resistance to radiation.
Authors: Hara Takamitsu , Iwadate Manabu , Shiratori Shuichi , Gonda Kenji , Shimura Tatsuo , Nakagami Yoshihiro , Shibata Masahiko , Waguri Satoshi , Takenoshita Seiichi 
Published: August 2014

Abstract
Background and purpose: Metastatic cancer tissues might have characteristics different from their original primary regions, which could affect strategies for radiotherapy. To investigate properties of metastatic cancers and their radiosensitivities, we established MDA-MB231-derived breast cancer cell lines, which were prone to cause metastasis when transplanted into mouse.
Methods: A breast cancer cell line, MDA-MB231 expressing pGL4.5/luciferase were injected into nude mice via left ventricle or mammary gland tissue to form metastatic lesions. The metastatic cells in lymph nodes, bone, and lung were detected by a bioluminescence imaging technique, which were excised, cultured, and transplanted into the next mice in the same way. Such transplantation procedures were repeated 3 times to establish organ-oriented metastasis-prone cell lines. The different characteristics of these cells were examined by morphological analysis, and proliferation, invasion, and migration assays, as well as radiation sensitivity test.
Result: There was no significant difference among cell lines in morphology and proliferative ability. All three metastasis-prone cell lines showed increased activity in migration and invasion compared to the parental cell line. Moreover, they showed lower sensitivities to radiation than the parental cell line, while no difference was found among the metastasis-prone cell lines.
Conclusion: We have established new cell lines that could be used for the study of metastatic breast cancers in relation to the radiotherapy.
Citation Format: Takamitsu Hara, Manabu Iwadate, Shuichi Shiratori, Kenji Gonda, Tatsuo Shimura, Yoshihiro Nakagami, Masahiko Shibata, Satoshi Waguri, Seiichi Takenoshita. Establishment of MDA-MB231-derived breast cancer cell lines possessing a higher metastatic activity and a resistance to radiation. [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 438. doi:10.1158/1538-7445.AM2013-438
Abstract 4384: Discovery of CD146/Latexin as a novel pathway suppressing breast tumor invasion.
Authors: Ouhtit Allal , Abd Elmageed Zakariya Y. , Fernando Augusta , Gaur Rajiv , Gupta Ishita , Shanmuganathan Somya , Al-Riyami Hamad , Raj Madhwa HG 
Published: August 2014

Abstract
CD146, also known as melanoma cell adhesion molecule or MUC18, was initially identified as a promoter of melanoma as well as prostate cancer progression and metastasis. Interestingly, however, CD146 appears to be a breast cancer (BC) tumor suppressor. The molecular mechanism of CD146 in cancer are still nascent and controversial. To address this discrepancy, we applied microarray gene expression profiling analysis, using a tetracycline (tet On)-inducible system of CD146 in the MDA-MB-231 BC cell line, and identified latexin (LXN) as a potential CD146-downstream signaling transcriptional target. LXN showed a 7 fold increase, which was confirmed in vitro by both time-course western blotting and RT-PCR analyses. In addition, NF-kappaB was identified as the molecular link between CD146 induction and LXN transactivation.
More interestingly, we established the CD146-tet On inducible system in mouse BC xenograft model, and demonstrated that in vivo induction of CD146-inhibited breast tumor growth. Furthermore, breast tumor tissues from both Omani patients and patients from New Orleans area in Louisiana, were examined by immunohistochemistry for the expression of CD146 and LXN. Strikingly, the results revealed that the expression levels of both CD146 and its downstream target LXN showed parallel inhibition patterns in BC progression, with high expression in both normal and benign but low or no expression in malignant and metastatic breast tumor tissues.
This study is the first to uncover a molecular link and provide evidence for a role of CD146/LXN-signaling in suppressing BC progression. Thus, reactivation of LXN through pharmacological manipulation holds particular promise for guiding the development of novel targeted-therapeutic strategies for BC.
Citation Format: Allal Ouhtit, Zakariya Y. Abd Elmageed, Augusta Fernando, Rajiv Gaur, Ishita Gupta, Somya Shanmuganathan, Hamad Al-Riyami, Madhwa HG Raj. Discovery of CD146/Latexin as a novel pathway suppressing breast tumor invasion. [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 4384. doi:10.1158/1538-7445.AM2013-4384
Abstract 440: The sublethal dose radiation induces cellular senescence and potent bystander effects through c-Myc oncogene.
Authors: Lo Chia-Chien , Chou Yen-Ting , Chiu Su-Jun , Hwang Jeng-Jung , Lee Yi-Jang 
Published: August 2014

Abstract
The sublethal dose radiation may induce cellular senescence and promote secondary maligancy during radiotherapy. However, the molecular mechanisms are unclear. It has been reported that a variety of early response oncogenes can be up-regulated by the low dose radiation. Because oncogene-induced senescence (OIS) has been considered important for tumor development, we are interested in investigating whether the sublethal dose radiation also raises OIS to affect the malignancy. To this end, human diploid fibroblasts WI-38 cells and human non-small lung cancer H1299 cells were exposed to less than 2Gy of X-rays delivered by the RS2000 X-rays machine. Both cell types exhibited senescent phenotypes within a dose-dependent manner using the senescence-associated β-galactosidase (SA-β-gal) staining. Subsequently, we investigated the expression of c-Myc and c-Ras oncogenes, and the results showed that sublethal dose radiation could induce c-Myc, but not c-Ras, in both transcriptional and translational levels. Additionally, up-regulated c-Myc exhibited transcriptional activity as demonstrated by the promoter-based reporter gene assys. Although the sublethal dose radiation caused cellular senescence and growth delay in exposed cells, the collected culture medium could increase the motility of non-irradiated H1299 cancer cells using the wound healing assay. Interestingly, the culture medium obtained from irradiated H1299 cancer cells caused higher motility in non-irradiated cells than that from irradiated WI-38 fibroblasts. Furthermore, the sublethal dose radiation induced senescent phenotype was suppressed in cells treated with siRNA against c-Myc. Meanwhile, the motility of non-irradiated cells was not increased by the cultured medium obtained from irradiated c-Myc silenced cells. Taken together, the current data suggest that the sublethal dose radiation causes a c-Myc oncogene induced senescence, and this event may promote the bystandard effects that influence the motility of non-irradiated cancer cells.
Citation Format: Chia-Chien Lo, Yen-Ting Chou, Su-Jun Chiu, Jeng-Jung Hwang, Yi-Jang Lee. The sublethal dose radiation induces cellular senescence and potent bystander effects through c-Myc oncogene. [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 440. doi:10.1158/1538-7445.AM2013-440
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4401: UCHL1 as a potential therapeutic target in uterine papillary serous carcinoma.
Authors: Kwan Suet Ying , Wong Kwong-Kwok , Schmandt Rosemarie E. , Lu Karen H. 
Published: August 2014

Abstract
Uterine papillary serous carcinoma (UPSC) comprises less than 10% of all endometrial cancers but accounts for a disproportionately high number of deaths. Due to its rarity, few prospective studies have been conducted which focus on this aggressive subtype, and it has been difficult to establish optimal treatment strategies. With poor survival rates and high recurrence rates, the identification of novel therapeutic targets would aid in the management of UPSCs. RNAseq data from The Cancer Genome Atlas (TCGA) was analyzed using Significant Analysis of Microarrays to identify genes that were differentially expressed between 81 cases of grade 2 endometrioid endometrial carcinoma (EEC) and 41 cases of UPSC. A gene of interest was then selected based on its subcellular location, correlation with survival and normal tissue specificity. The findings were validated by immunohistochemical staining of UPSC paraffin sections. All patient samples were obtained and stored in accordance with human subject research protocols approved by the Institutional Review Board. All paraffin sections were reviewed by a pathologist. By comparing the RNAseq profiles of UPSCs and EECs, we identified 242 genes that were differentially expressed (q&lt;0.005). Among these, ubiquitin C-terminal hydrolase 1 (UCHL1) showed higher expression in UPSCs compared to EECs, with an increase of over 6-fold. UCHL1 was chosen for further studies as Kaplan-Meier analysis of all endometrial cases in the TCGA database revealed that UCHL1 expression also correlated significantly with poorer disease-free survival (p&lt;0.05). Preliminary immunohistochemical studies also show higher expression of UCHL1 in UPSCs than in ECCs. Interestingly, contrast analysis of TCGA data for breast cancer indicates that basal-like breast tumors also show significantly higher UCHL1 expression compared to the other breast cancer subtypes (p&lt;0.005). Both basal-like breast cancer and UPSC have a high rate of p53 mutation (80% and 90%); this shared upregulation of UCHL1 suggests that a possible mechanism by which UCHL1 contributes to pathogenesis is through stabilization of mutant p53. In conclusion, our data identifies UCHL1 as a gene that is upregulated in UPSCs and is associated with poor disease-free survival. UCHL1 is a possible novel therapeutic target for the management of UPSCs. Further studies are needed to elucidate the underlying mechanisms in which it contributes to tumorigenesis.
Citation Format: Suet Ying Kwan, Kwong-Kwok Wong, Rosemarie E. Schmandt, Karen H. Lu. UCHL1 as a potential therapeutic target in uterine papillary serous carcinoma. [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 4401. doi:10.1158/1538-7445.AM2013-4401
Abstract 4405: RNases: Approaching RNA as a target for cancer therapy.
Authors: Strong Laura E. , Kink John , Mei Baigen , Shahan Mark , Raines Ronald T. 
Published: August 2014

Abstract
Ribonucleases (RNases) are a unique class of anti-cancer drugs that target the RNA in cancer cells without the complications of delivering RNA. Efficacious RNases have diminished binding to the naturally occurring RNase inhibitor protein in the cytosol of cells. Since human RNase I binds tightly to the inhibitor, changes to the amino acid residues in the contact region were made and resulted in the lead candidate referred to as QBI-139. This variant maintains 95% sequence identity with the wild type human RNase 1.
Broad efficacy and a strong therapeutic window were seen across multiple tumor types in xenograft models and QBI-139 was advanced to an ongoing Phase I clinical trial. For the Investigational New Drug application package, rat and dog toxicology studies were used to aid in selection of the starting dose for humans. Exposure levels (pharmacokinetics, PK) are an important factor in evaluating whether toxicity and efficacy will be comparable across the species. A complicating issue in the evaluation of the results is the range of routes of administration across species, specifically intraperitoneal injection (mice), intravenous injection (rat and dog) and intravenous infusion (human). One parameter that is consistent is rapid clearance, which is likely due to the small size of QBI-139 (15 kiloDaltons). With preliminary results from the early stage clinical trial, the exposure levels across the experiments will be compared. The results demonstrate that the exposure profiles in the clinic where the route of administration is intravenous infusion, is most similar to that in the mouse efficacy models, which is intraperitoneal injection.
A human RNase variant, called QBI-139 provides an innovative drug development approach to targeting RNA. In model systems, QBI-139 has shown broad in vivo anti-tumor activity alone and in combination with standard of care therapies and a strong tolerability profile. The knowledge gained about the impact of PK on therapeutic effect will be valuable as the method of administration is selected and confirmed in the next stage of clinical trials.
Citation Format: Laura E. Strong, John Kink, Baigen Mei, Mark Shahan, Ronald T. Raines. RNases: Approaching RNA as a target for cancer therapy. [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 4405. doi:10.1158/1538-7445.AM2013-4405
Abstract 4407: Structural and biochemical analysis of ERBB4 mutations in cancer.
Authors: Kurppa Kari , Denessiouk Konstantin , Johnson Mark S. , Elenius Klaus 
Published: August 2014

Abstract
Genes encoding the ErbB receptor tyrosine kinases (EGFR/ERBB1, ERBB2, ERBB3, and ERBB4) are key regulators of cellular proliferation, survival, and differentiation, and thus represent potent proto-oncogenes. In particular, mutations or copy number variations of EGFR or ERBB2 are present in human malignancies and serve as biomarkers for targeted therapies. Recently, somatic mutations of the ERBB4 gene have been identified in various cancer types, such as non-small cell lung cancer and melanoma, indicating a role for mutated ERBB4 as a potential drug target. However, the structural and functional consequences of the ERBB4 mutations remain to be fully elucidated.
We used both a structural as well as a biochemical approach to address the functional effects the ERBB4 mutations for ErbB4 signaling. The structural effects of the mutations were assessed in both active and inactive ErbB4 conformation in silico. The biochemical effects of the mutations on ErbB4 signaling were analyzed in vitro using assays measuring the kinase activity of ErbB4 as well as activation of downstream signaling pathways.
Although all structural subdomains of ERBB4 have been reported to be affected by somatic mutations, our analyses indicated that the mutations cluster to regions important for activation of the receptor, such as the dimerization interface and the kinase domain active site. Some of the mutations were structurally non-hazardous and probably represent passenger mutations. Consistently, the biochemical analyses indicated for the presence of both activating and functionally non-significant mutations.
These observations suggest for the presence of both driver as well as passenger mutations of ERBB4 in human cancer.
Citation Format: Kari Kurppa, Konstantin Denessiouk, Mark S. Johnson, Klaus Elenius. Structural and biochemical analysis of ERBB4 mutations in 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 4407. doi:10.1158/1538-7445.AM2013-4407
Abstract 4412: S1 and gossypol induce NOXA through increased reactive oxygen species or cytoplasmic calcium and sensitize to ABT-737.
Authors: Soderquist Ryan S. , Bates Darcy J. P. , Eastman Alan 
Published: August 2014

Abstract
The upregulation of anti-apoptotic BCL2 family members enhances the survival of cancer cells, such as in chronic lymphocytic leukemia (CLL). A class of inhibitors (termed BH3 mimetics) has been developed to inhibit BCL2 proteins and selectively kill cancer cells. These inhibitors function by occupying the groove through which BCL2 proteins interact with their binding partners. ABT-737 is a high affinity inhibitor of BCL2 and BCLXL, and navitoclax, which has a similar binding profile, has shown efficacy in clinical trials. However, resistance occurs when the cancer cells rely on additional BCL2 members, such as MCL1 or BFL1, which are not inhibited by ABT-737. Using leukemia cell lines, we compared several BH3 mimetics reported to inhibit multiple BCL2-family proteins (including MCL1 and BFL1), with the goal of enhancing the efficacy of ABT-737. We found that none of these compounds functioned as true BH3 mimetics. Instead, the compounds induced ER stress and upregulated the pro-apoptotic protein NOXA. Furthermore, two of these compounds, S1 and gossypol, sensitized leukemia cells to ABT-737 in a NOXA-dependent manner. NOXA induced by S1 or gossypol is dependent on increased reactive oxygen species or increased cytoplasmic calcium, respectively. We also tested these drug combinations in CLL cells ex vivo. S1 and gossypol combined with ABT-737 to selectively kill CLL cells but not normal lymphocytes. Interaction between CLL cells and stroma in patients promotes resistance to BCL2 inhibitors through the upregulation of MCL1 and BFL1. Co-incubation of CLL cells ex vivo with CD40 ligand-expressing stroma mimics the resistance to BCL2 inhibitors seen in patients. Importantly, this resistance was overcome when S1 or gossypol was combined with ABT-737. Our results show two novel mechanisms for upregulating NOXA and sensitizing leukemia cells to ABT-737. These combinations also kill CLL cells exposed to stroma, and may therefore target residual CLL cells in vivo, thus improving clinical outcome.
Citation Format: Ryan S. Soderquist, Darcy J. P. Bates, Alan Eastman. S1 and gossypol induce NOXA through increased reactive oxygen species or cytoplasmic calcium and sensitize to ABT-737. [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 4412. doi:10.1158/1538-7445.AM2013-4412
Abstract 4416: A reporter mouse to measure drug myelotoxicity in time.
Authors: Rizzi Nicoletta , Manni Isabella , Mancini Laura , Roncoroni Chiara , Brunialti Electra , Oliva Paolo , Gentileschi Maria Pia , Di Giovine Stefano , Pesenti Enrico A. , Piaggio Giulia , Maggi Adriana , Ciana Paolo 
Published: August 2014

Abstract
Myelotoxicity is the well known side effect of most anti-cancer treatments, thus the study of the myelosuppressive effect of a given treatment is tested routinely during the preclinical phase of investigation. Current ethodologies require the use of a very large number of animals to measure the effect of the investigated compound in time and the study is generally carried out by bone marrow dissection and subsequent analysis with a myeloid clonogenic assay. The goal of our study was to apply non invasive imaging technologies to generate a novel, simple and robust assay to test the state of proliferation of bone marrow reducing the number of animals to be sacrificed and increasing the power of the analysis thanks t the possibility to follow in time, in the same animal the effect of the treatment. To this aim, we have utilized a trangenic mouse, the repTOP™mitoIRE reporter mouse recently developed to image proliferative events in vivo (Goeman et al 2012, Oliva et al 2012). This transgenic mouse carries a luciferase reporter gene under the transcriptional control of a minimal human cyclin B2 promoter.Our in vitro and in vivo results show that the luciferase expression and photon emission in the different body regions of the repTOP™mitoIRE is strictly proportional to the proliferative state of the cells in the tissues examined. Our results demonstrate that the extent of bone marrow proliferation can be measured by in vivo imaging photon emission of femur and sternum in each mouse prior the treatment and then monitored during the longitudinal study.
The repTOP™mitoIRE mouse model, was successfully applied to the study of the differential immunosuppressive potential of several well known anti-neoplastic treatments demonstrating the validity of the novel test over currently available methodologies: we measured the differential effects on immunosuppression and on regeneration of 5-fluorouracil, docetaxel, bortezomid, temozolomide and radiotherapy in dose-response experiments. The results led us to conclude that the imaging-based test here proposed is reproducible and provides a reliable measure of bone marrow cell proliferation in time and to propose it as a routine test in for the pre-clinical of novel anti-neoplastic compounds.
Citation Format: Nicoletta Rizzi, Isabella Manni, Laura Mancini, Chiara Roncoroni, Electra Brunialti, Paolo Oliva, Maria Pia Gentileschi, Stefano Di Giovine, Enrico A. Pesenti, Giulia Piaggio, Adriana Maggi, Paolo Ciana. A reporter mouse to measure drug myelotoxicity in time. [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 4416. doi:10.1158/1538-7445.AM2013-4416