bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-487: Pim protein kinase inhibitors induce the unfolded protein response and sensitize prostate cancer cells to killing by ABT-737-mediated apoptosis
Authors: Song Jin H. , Kraft Andrew S. 
Published: August 2012

Abstract
Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet anticancer efficacy of Pim kinase inhibitors on prostate cancer is unknown. We demonstrate for the first time that a genetically engineered decrease in Pim kinase levels or the addition of Pim kinase small molecule inhibitors (e.g. SMI-4a) to human prostate cancer cells, including LNCaP and PC-3, causes ER stress and activates the unfolded protein response (UPR) stimulating increases in eIF-2α phosphorylation, ATF-4, CHOP proteins, and cleavage of XBP-1. Because (1) Bcl-2 family proteins reside on the ER lumen and play an important role in regulation of XBP-1 splicing, (2) Bcl-2 family members are over expressed in prostate cancer to enhance Pim kinase anti-cancer activity, and (3) Pim kinase inhibitors decrease Mcl-1 and increase Noxa protein, we treated prostate cancer cell lines with SMI-4a plus the Bcl-2 family antagonist ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′-cap dependent translation and decreasing protein half life. Additionally, Pim inhibition transcriptionally increased levels of the BH3 protein Noxa by activating the UPR, lead to eIF2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 protein activity. Notably, these specific protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. We find that the Pim kinase inhibitors and ABT-737 are highly synergistic in killing prostate cancer both in vitro and when used together in a subcutaneous animal model of prostate cancer therapy. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-487. doi:1538-7445.AM2012-LB-487
Abstract LB-489: MDM2 alternative splicing: fine-tuning the p53 damage response
Authors: Jacob Aishwarya G. , Singh Ravi K. , Bebee Thomas W. , Chandler Dawn S. 
Published: August 2012

Abstract
Cell survival is dependent upon precise control of the activity of the tumor suppressor p53. p53 is a transcription factor and is known to control a number of biological processes including cell cycle arrest and apoptosis by transactivating downstream genes. Several proteins are reported to affect p53 activity but the murine double-minute protein, MDM2, and a closely related family member, MDM4, are two of the most critical regulators of p53. In previous work, we have identified alternative splicing of both the MDM2 and MDM4 genes in response to UV damage implicating alternative splicing in the cell's normal surveillance mechanism. However, the role of the splice variants in the DNA damage pathway remains elusive. To determine the role the alternative splice forms play in the p53 damage response, overexpression of the UV-induced isoforms, MDM2-ALT1 and MDM4-ALT2, was performed. Both MDM2-ALT1 and MDM4-ALT2 are capable of negatively regulating the full-length MDM2 and MDM4 full-length proteins thereby increasing p53 levels. Interestingly, each splice variant activates a distinct and unique subset of p53 target genes. An additional type of cellular stress, hypoxia, induces alternative splicing of MDM2 as well, but generates a different splice form known as MDM2-ALT2. This splice form activates a third unique profile of p53 target genes. Hence, the splicing status of the MDM2 and MDM4 genes is capable of dictating unique p53 programs. We are also currently investigating p53-independent functions for the damage-induced splice variants to better understand their role in the damage response and tumorigenesis. This work elucidates regulated splicing as a novel mechanism by which cellular injury can control the activity of p53 within the cell. By producing specific alternatively spliced variants of both MDM2 and MDM4, yet another layer of p53 regulation is initiated in order to fine-tune the cell's response to damage. Because MDM2 and MDM4 alternative splice variants are characteristic of numerous cancer types, this work indicates that the status of MDM2 and MDM4 splicing could be a consideration in determining treatment options for cancers for which p53 activation is a therapeutic strategy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-489. doi:1538-7445.AM2012-LB-489
Abstract LB-49: Surviving by empowerment
Authors: Togbo Judy 
Published: August 2012

Abstract
Men's Health Network (MHN) is a national non-profit organization whose mission is to reach men, boys, and their families where theylive, work, play, and pray with health prevention messages and tools, screening programs, educational materials, advocacy opportunities, and patient navigation. MHN was founded in 1992 by a group of men's activists, therapists, and writers interested in improving the health and well-being of men, boys and families. It is a nonprofit incorporated in the District of Columbia. MHN has also been designated as a tax exempt organization under Section 501(c)(3) of the U.S. Internal Revenue Service code. MHN has received the highest rating (4 stars) from Charity Navigator. Men's Health Network (MHN) is undertaking a series of free state symposia on the health of men and their families around the country. MHN is presenting these symposia as an effort to educate health professionals and the public-at-large about significant family health issues. The symposia create awareness of such issues with state policy leaders, elected officials, and healthcare leaders as they deal with the reality of rising health care costs. These state symposia also create opportunities for additional networking for community outreach organizations throughout the state, as well as encourage preventative health measures and physician and patient dialogue. Among those invited to participate are: local, regional, and state public health department officials, key legislators, advocacy groups, medical associations, patient advocacy organizations, churches/parishes, community health leaders, and healthcare providers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-49. doi:1538-7445.AM2012-LB-49
Abstract LB-491: PD-1 expression level on T cell subsets is a crucial factor forming a novel mechanism for designing immune therapeutic approaches using PD-1 binding ligand
Authors: Mkrtichyan Mikayel , Najjar Yana G. , Raulfs Estella C. , Liu Linda , Langerman Solomon , Khleif Samir N. 
Published: August 2012

Abstract
A significant barrier to tumor regression in the setting of a successful immune response is tumor-mediated immunosuppression. Programmed death receptor-1 (PD-1) is an important signaling molecule and in the context of the tumor microenvironment may inhibit T cell immunity when bound to its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), by inducing T cell apoptosis and anergy. Recently we demonstrated that combination of anti-PD-1 antibody with vaccine and low-dose of cyclophosphamide (CPM), that reduces the number and function of Treg cells, significantly enhances antigen-specific immune responses, decreases tumor burden and increases survival of treated mice, suggesting that targeting multiple immune checkpoint inhibitors is a promising strategy for tumor immunotherapy. Here we tested the anti-tumor immune effect of B7-DC-Ig, a recombinant protein that binds and target PD-1. It is composed of the extracellular domain of B7-DC, fused to the Fc portion of murine IgG2a. We demonstrated that B7-DC-Ig can enhance the therapeutic efficacy of a peptide based cancer vaccine when combined with CPM. We showed that this combination significantly enhances antigen-specific immune responses and leads to complete eradication of established tumors in 60% of mice and that this effect is CD8 dependent. Importantly, we found that unlike anti-PD-1 antibody, B7-DC-Ig does not block the suppressive PD-1/PD-L1 interaction as its primary mechanism, and identified a novel mechanism by which B7-DC-Ig exerts its therapeutic effect. We demonstrate, for the first time, that there are significant differences between levels and timing of surface PD-1 expression on different T cell subsets. We found that these differences play a critical role in the anti-tumor effects exhibited by B7-DC-Ig through inhibiting proliferation of dysfunctional PD-1high CD4 T cells, for both Treg and FoxP3−T cells, leading to a significant decrease in levels of tumor infiltration by dysfunctional T cells. In addition, we showed that treatment with B7-DC-Ig also leads to a decrease in PD-1highCD8 T cells, tipping the balance towards non-exhausted, functional PD-1lowCD8 T cells. Aside from presenting a promising anti-tumor immunotherapeutic approach, we demonstrated that the level of PD-1 expression on different T cells subsets determines the “effective target zone” of B7-DC-Ig. We believe that this represents an important parameter that needs to be considered to favorably alter the tumor microenvironment when designing PD-1 targeting immune therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-491. doi:1538-7445.AM2012-LB-491
Abstract LB-492: CD44 binding peptide attached to an engineered matrix prevents the formation of CSC tumorspheres
Authors: Yang Xiaoming , He Xuezhong , Jabbari Esmaiel 
Published: August 2012

Abstract
Objective: Cancer recurrence is related to the existence of cancer stem cells (CSCs) in the tumor tissue that are highly resistant to conventional therapies. Self-renewal and differentiation of CSCs are regulated by tumor microenvironment. Naturally derived matrices have been used for immobilization of cancer stem cells but, due to their many ligand-receptor interactions, those matrices cannot isolate the effect of individual factors in the microenvironment on CSCs. We hypothesized that an inert biodegradable hydrogel, conjugated with bioactive peptides, that allow precise control of mechanical, physiochemical, and biological properties are ideal for investigating the effect of microenvironmental on maintenance of CSCs. The objective of this work was to investigate the effect of CD44 binding peptide RLVSYNGIIFFLK conjugated to an engineered inert but permissive gel (SPELA gel) on viability and maintenance of 4T1 CSCs. Methodology: 4T1 cancer cells were cultured in RPMI 1640 medium supplemented with 10% FBS, 100 U/ml PEN and 100 μg/ml STREP. After 70% confluence, 4T1 tumor cells were suspended in DMEM-F12 medium supplemented with 0.4% BSA, 5 μg/ml insulin, 40 ng/ml bFGF, 20 ng/ml EGF, 5% horse serum (CSC medium). Next, 4T1 cells were seeded in ultra-low attachment plates at a density of 100K cells/mL. After 7-10 days, the cultures were analyzed for tumorsphere formation. The acrylamide-terminated CD44-binding peptide RLVSYNGIIFFLK was synthesized in the solid phase by Fmoc chemistry. 4T1 cell-laden SPELA gels were produced by photopolymerization and cultured in CSCS medium. At each time point, samples were analyzed by fluorescent microscopy and mRNA analysis for the formation of CSCs. Data and Results: The 4T1 CSCs were characterized by inoculation in the back of Balb/c mice. 500 CSCs inoculated in mice formed larger tumors in mice than 50,000 tumor cells after 14 days. When tumor cells were encapsulated in the inert SPELA gel matrix, tumorspheres began to form and continued to grow in size with incubation, but tumorsphere formation strongly depended on the gel modulus. For example, tumorsphere size in gels with moduli in the 5-10 kPa range increased from 25 to 100, and 225 after 2, 6, and 10 days of incubation. Interestingly, the covalent attachment of CD44 ligand to the inert gel prevented the formation of tumorspheres and maintenance of CSCs. Inert engineered matrices are very powerful tools for understanding the effect of tumor microenvironment on maintenance of CSCs and tumorsphere formation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-492. doi:1538-7445.AM2012-LB-492
Abstract LB-497: Primary tumor localization determines the metastatic immune profile
Authors: Remark Romain , Crozet Lucile , Lupo Audrey , Alifano Marco , Riquet Marc , Cremer Isabelle , Dieu-Nosjean Marie-Caroline , Goc Jeremy , Mlecnik Bernhard , Cazes Aurelie , Fléjou Jean-François , Gibault Laure , Verkarre Virginie , Oudard Stéphane , Pagès Olivier , Régnard Jean-François , Sautès-Fridman Catherine , Fridman Wolf-Herman , Damotte Diane 
Published: August 2012

Abstract
Primary tumor localization determines the metastatic immune profile Background Most cancer patients die from their metastatic disease and not from their primary tumor. However, little is known on the immune microenvironment of metastatic lesions and on its impact on clinical outcome. Indeed, the immune pattern of the tumor microenvironment has been recently identified as being a major prognostic factor in primary tumors. Thus, a high density of memory T cells with a Th1 and CD8 cytotoxic orientation is beneficial in many cancers. However, there are a few exceptions since CD8+ T cells have been reported to be associated with bad prognosis in renal cell carcinoma. The question of the respective roles of the tumor cell and organ microenvironment to explain these differences has not been addressed. Methods We studied the density and organization of tumor-infiltrating immune cells (CD3+, CD8+, Foxp3+, granzyme B+, NK cells and mature DCs) in retrospective cohorts of primary and lung metastases of colorectal cancer (CRC, n=124) and renal cell carcinoma (RCC, n=55) by immunohistochemistry. We investigated by qPCR the gene expression levels related to immune populations and their functions in the lung metastases from 19 CRC and 12 RCC. Biological data's were compared to clinical data's and patient's outcome. Results The cell composition (CD3+, CD4+ and Foxp3+ T cells, mature DCs and NK cells) and organization (tertiary lymphoid structures) of the immune infiltrate in metastases depend on the origin of the primary tumor. In both cases (colorectal cancer and renal cell carcinoma lung metastases), the density of CD8+ T cells and mature DCs appeared to be strongest prognosticator of patient's survival as reported for many primary tumors, but with opposite impact. High densities of mature DCs and CD8+ cells correlate with good overall survival in lung metastases of colorectal cancer and with poor survival in lung metastases of renal cell cancer. In the latter, a strong Th2 and inflammatory context was present associated with a strong Th1 polarization. Conclusions Altogether, our data demonstrate that the immune pattern depends on the tumor origin and has a major prognostic role in advanced cancer stages with an impact on patient therapeutic management. We demonstrated also the complexity of the immune response polarization and its impact upon tumor immune surveillance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-497. doi:1538-7445.AM2012-LB-497
Abstract LB-50: Street smarts: cancer education and outreach in the homeless community
Authors: Ryan Cynthia 
Published: August 2012

Abstract
In response to a year-long investigation of cancer among the homeless in Birmingham, AL, this presenter created an education program called “Street Smarts.” Findings from a focus group consisting of homeless women diagnosed with stage IV breast cancer revealed competing values (poor self-esteem and body image, limited health care resources, etc.) preventing individuals in this population from seeking diagnosis or treatment for cancer, even when free-of-charge options are available. Street Smarts brings together members of this underserved community for a day of pampering while educating them about breast cancer screening and health care alternatives. The program is funded in partnership with the North Central Alabama Susan G. Komen Foundation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-50. doi:1538-7445.AM2012-LB-50
Abstract LB-500: Genomic and RNAi analyses identify diverse oncogenic interactions between breast cancer cells and stromal fibroblasts
Authors: Rajaram Megha , Powers Scott , Egeblad Mikala , Li Jinyu 
Published: August 2012

Abstract
Although it is well established that fibroblasts in the breast cancer microenvironment can promote tumorigenicity, the scope and functional importance of all molecular interactions remains unclear. Here we've undertaken a systematic, genome-wide approach to identify and test genes that play functional roles in these interactions. We have developed an in vitro and in vivo based model system using human fibroblasts and breast cancer cell lines. Using this system, we first discovered a set of genes that are induced in fibroblasts upon co-culture with breast cancer cells and are also upregulated in the stroma of primary human breast cancer. Several of the upregulated genes encode secreted growth factors or cytokines. Using this approach, we also identified several oncogenic pathways upregulated in our model system as well as primary human breast stroma. We then used RNAi analyses and a co-injection tumorigenicity assay to functionally test these candidate genes for their roles in tumor-fibroblast interactions. We determined that the majority of our candidates play important roles in promoting breast cancer. Interestingly, these genes have significant yet diverse mechanisms through which they act. These results establish a wide range of potential targets for therapeutic inhibition of the ability of fibroblasts to promote breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-500. doi:1538-7445.AM2012-LB-500
Abstract LB-503: Pharmacological inhibition of microglia leads to increased survival in a murine model of glioblastoma multiforme in conjunction with ionizing radiation
Authors: Miller Ian S. , Didier Sebastien , Murray David W. , Issaivanan Magimairajan , Coniglio Salvatore J. , Segall Jeffrey E. , Al-Abed Yousef , Symons Marc 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most malignant and lethal form of astrocytoma. GBM patients have a median survival time of approximately one year and therefore it is essential to identify novel targets and effective therapies. There is mounting evidence that microglia (specialized brain-resident macrophages) play a significant role in the development and progression of GBM tumors. We have established a microglia-glioma cell co-culture system consisting of normal microglia from C57Bl/6J mice and syngeneic GL261 glioma cells. We have demonstrated that microglia strongly stimulate the invasive behavior of GL261 cells in this system. Our preliminary data also indicate that the microglia significantly stimulate GL261 cell proliferation and resistance to ionizing radiation (IR) in these conditions. In a search for small molecule inhibitors that block the stimulatory effects of microglia on glioma cells, we have examined CNI-1493, a drug that is known to selectively interfere with macrophage function. We found that CNI-1493 potently inhibits microglia-stimulated GL261 invasion. We also examined the effect of intracranially administered CNI-1493 on orthotopic GL261 tumors in the presence or absence of fractionated whole brain irradiation (10 Gy total). We found that although CNI-1493 only has a marginal benefit in the absence of IR, it strongly stimulates animal survival in combination with IR: whereas IR treatment increases survival by 10 days, IR in combination with CNI-1493 treatment extends survival beyond 40 days. In conclusion, our observations support the notion that pharmacological targeting of microglia may be beneficial as adjuvant therapy in conjunction with ionizing radiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-503. doi:1538-7445.AM2012-LB-503