bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3113: Primate-specific miR-663 suppresses glioblastoma progression and predicts patient prognosis
Authors: Shi Yu , Ping Yi-fang , Bian Xiu-wu 
Published: August 2015

Abstract
Purpose: miRNAs (microRNAs) have recently been recognized as important regulators of cancer biological behavior. However, the expression patterns and prognostic significance of miRNAs in GBM remain elusive due to the lack of large pools of clinical specimens for screening. This study was performed to identify miR-663 as a potential regulator of glioblastoma (GBM) malignant behaviors from miRNA profiles. The prognostic significance of miR-663 in GBM, its effect in tumor progression and the underlying mechanism were determined.
Methods: Specimens from 256 cases of glioma patients, including 239 patients with follow-up information, were used to analyze the association between miR-663 and patients’ prognosis by Kaplan-Meier and multivariate Cox regression analyses. The effects of miR-663 on GBM cell proliferation and invasion were examined both in vitro and in vivo. Bioinformatics prediction and signal network analysis were applied to identify the putative targets of miR-663, which were further verified by luciferase reporter assay, rescue experiments as well as the immunohistochemistry (IHC) and Western blotting examination of downstream effectors. Quantitative reverse transcriptase-PCR (qRT-PCR) and IHC were applied to investigate the clinical association between miR-663 and its target in human GBM specimens.
Results: miR-663 was identified from miRNA profiles and inversely correlated with glioma grades but positively correlated with patients’ survival. Furthermore, two distinct subgroups of GBM patients with different prognoses were identified based on miR-663 expression in our specimens and that from TCGA database. Overexpression of miR-663 significantly suppressed the proliferation and invasion of GBM cells in vitro and in vivo. Mechanistically, we discovered PIK3CD as a direct target of miR-663 and found that phosphorylated AKT and three key downstream effectors of PIK3CD, were down-regulated by miR-663 overexpression. Moreover, PIK3CD was inversely correlated with miR-663 in GBM specimens and predicted poor prognosis of GBM patients.
Conclusion: miR-663 is a novel prognostic biomarker and a potential therapeutic candidate for GBM.
Citation Format: Yu Shi, Yi-fang Ping, Xiu-wu Bian. Primate-specific miR-663 suppresses glioblastoma progression and predicts patient prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3113. doi:10.1158/1538-7445.AM2015-3113
Abstract 3125: miR-9-3p plays a tumor-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells
Authors: Higashi Takaaki , Hayashi Hiromitsu , Takeyama Hideaki , Kaida Takayoshi , Arima Kota , Taki Katsunobu , Okabe Hirohisa , Nitta Hidetoshi , Hashimoto Daisuke , Chikamoto Akira , Beppu Toru , Baba Hideo 
Published: August 2015

Abstract
Background: Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. Despite recent advance in cancer treatment including the development of molecular target drugs, the prognosis in patients with hepatocellular carcinoma (HCC) still remains poor.
The inactivation of the Hippo-pathway lead to TAZ/YAP overexpression, and is associated with worse prognostic outcomes in various cancers including hepatocellular carcinoma (HCC). While there are several reports of miR targeting for YAP, miR targeting for TAZ remains unclear. The aim of this study is to identify the miR targeting TAZ expression in HCC.
Methods: miR expression was analyzed using the Human miFinder 384HC miScript miR PCR Array and was compared between low and high TAZ expression cell lines. Then, we extracted miR-9-3p as a tumor-suppressor miR targeting TAZ using miRBase. We examined the functional role of miR-9-3p targeting TAZ using miR-9-3p mimic and inhibitor in HCC cell lines (HLF and HuH1 with high and low TAZ expressions, respectively).
Results: In HCC cell lines and HCC clinical samples, there was the inverse correlation between miR-9-3p and TAZ expressions by real-time PCR. By western blotting, TAZ expression was induced by treatment of miR-9-3p inhibitor and was downregulated by treatment of miR-9-3p mimic. TAZ nuclear localization was indeed inhibited with a treatment with miR-9-3p mimics in HLF cells, and was inversely accelerated with a treatment of miR-9-3p inhibitors in HuH1 cells.
Treatment of miR-9-3p mimic inhibited cell proliferative ability by downregulating the phosphorylation of Erk1/2 and Akt signals in HLF. Inversely, treatment of miR-9-3p inhibitor accelerated cell growth compared to control in HuH1. On the other hand, cell invasiveness was not affected by miR-9-3p.
Conclusions: miR-9-3p was identified as the tumor-suppressor miR targeting TAZ expression in HCC cells. miR-9-3p played a crucial role in cell proliferation, but not in invasion, via Akt and Erk1/2 signals in HCC cells.
Citation Format: Takaaki Higashi, Hiromitsu Hayashi, Hideaki Takeyama, Takayoshi Kaida, Kota Arima, Katsunobu Taki, Hirohisa Okabe, Hidetoshi Nitta, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hideo Baba. miR-9-3p plays a tumor-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3125. doi:10.1158/1538-7445.AM2015-3125
Abstract 3128: MicroRNA-mediated reprogramming of myeloid cells by targeting TGFβ signaling and its associated molecular network
Authors: Vodnala Suman K. 
Published: August 2015

Abstract
Tumor derived soluble factors result in accumulation of Gr-1+CD11b+ immature myeloid cells at tumor site and premetastatic organ. These cells are known to promote tumor progression and metastasis. Gr-1+CD11b+ immature myeloid cells and tumor-associated macrophages display a type 2 phenotype (M2) and produce immune suppressive cytokines including TGFβ. We have previously shown that immature myeloid cells are vicious producers of TGFβ ligand and express high levels of TGFβR2 receptor for eliciting immune suppressive function. Specific deletion of TGFβR2 in myeloid cells resulted in increased antitumor immunity and decreased metastasis in the lungs of cancer mouse models. microRNAs (miRs) are abundant class of small non-coding RNAs that have recently emerged as powerful epigenetic regulators of gene expression in pathophysiological conditions. One of the critical properties of miR is to target a large number of genes frequently within the context of a network, making them very efficient in regulating distinct biological cell processes. In the current project, we have identified three miRs that target myeloid TGFβR2 associated molecular network including p38 and cAMP pathways, which are critical in type 2 cytokine production. We have successfully transduced bone marrow stem cells with lentivirus expressing these miRs driven by a myeloid specific promoter CD11b. Transplantation of these modified bone marrow into lethally irradiated mice decreased breast cancer metastasis. The underlying mechanisms involve the reduction in type 2 cytokines such as IL-4, IL-10 and IL-13 and activation of IFN producing CD8 cytotoxic lymphocytes. Interestingly, the miRNAs are also differentially regulated by TGFβ signaling in TGFβR2+/+ and TGFβR2−/− myeloid cells, suggesting a feedback loop between TGFβ and miRNA. These results demonstrate that the candidate miRNA can reprogram tumor-associated myeloid cells by altering the cytokine milieu and enhance host antitumor immunity. Our work points out that endogenous miRNA targeting myeloid TGFβ signaling and its molecular network provides an important therapeutic option.
Note: This abstract was not presented at the meeting.
Citation Format: Suman K. Vodnala. MicroRNA-mediated reprogramming of myeloid cells by targeting TGFβ signaling and its associated molecular network. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3128. doi:10.1158/1538-7445.AM2015-3128
Abstract 3133: Deciphering the novel role and underlying mechanism of let-7i repression in stem-like properties of head and neck cancer cells
Authors: Liao Tsai-Tsen , Yang Muh-Hwa 
Published: August 2015

Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is one of the major male cancers worldwide, and the main therapeutic strategies include surgery, radiotherapy and chemotherapy. Cancer stem cells are a small population of tumor cells that are responsible for tumorigenesis, tumor recurrence and treatment resistance. let-7 family microRNAs have been shown to function as a tumor suppressor. Here we aim to investigate the role of let-7i in regulating stem cell properties in HNSCC. Methods: Luciferase reporter assay were used to identify the targets of let-7i; Western blot to analysis the correlation between ARID3B and Oct4; ChIP assay confirm the binding of ARID3B to Oct4 proximal promoter; Quantitative RT-PCR to analyzed the level of ARID3B, Oct4, and let-7i in the 52 pairs of samples containing primary tumor tissues and adjacent normal epithelium from head and neck cancer patients with different stage receiving surgery.
Results: ARID3B, a member of the AT-rich interaction domain family proteins which plays an essential role during embryogenesis, is a bona fide target of let-7i. ARID3B promotes stem-like properties of HNSCC cells and upregulates a panel of stemness genes, and Oct4 is one of the most prominent ones to be upregulated. ARID3B direct binds to the AT-rich region of Oct4 promoter to activate its transcription. Downregulation of let-7i in HNSCC samples correlates with a corresponding upregulation of Oct4 and ARID3B.
Conclusions: We propose a mechanism of let-7i repression-mediated stem-like properties through releasing the suppression of a novel let-7i target ARID3B, which leads to transcriptional activation of stemness genes. Let-7i coordinates the function of ARID3B through repressing targets related to ARID3B activity, such as ARID3A and KPNA4. Furthermore, we elucidate of the regulatory mechanism of the stemness factors by ARID3B through epigenetic regulation. The results provide useful information in elucidating the mechanism of HNSCC progression and also provide potential targets in developing HNSCC-specific treatment.
Citation Format: Tsai-Tsen Liao, Muh-Hwa Yang. Deciphering the novel role and underlying mechanism of let-7i repression in stem-like properties of head and neck cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3133. doi:10.1158/1538-7445.AM2015-3133
Abstract 3142: Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptors
Authors: O'Brien Shaun , Wang Liang-Chuan , Newick Kheng , Thomas Rajan M. , Wells Andrew , Albelda Steven M. 
Published: August 2015

Abstract
Recent success of adoptive transfer of T cells expressing chimeric antigen receptors (CARs) in patients with blood-borne malignancies has resulted in growing enthusiasm to apply the same approach to treat solid tumors. CAR-expressing T cells, however, will likely face many challenges that will limit their efficacy in solid tumors. One possible obstacles will be the intrinsic negative feedback systems that prevent continuing T cell responses. The transcription factor Ikaros which has been shown to suppress endogenous T effector functions through epigenetic remodeling of cytokine gene loci may be one such negative regulator. Here we show that anti-mesothelin CAR (mesoCAR) T cells with reduced levels of Ikaros consistently mediate better in vitro cell killing and in vivo tumor regression than their wild-type counterparts. This increased anti-tumor activity was accompanied by increased persistence of mesoCAR T cells, as well as increased IFN-g. Enhanced cytolytic activity was also evidenced in mesoCAR T cells with reduced Ikaros, which could be partially explained by increased CD107a upregulation and Granzyme B production. Reduction in the Ikaros level in mesoCAR T cells did not affect T cell receptor and CAR signaling, but was able to render them more resistant to soluble inhibitory factors like TGF-B and adenosine. In summary, inhibition of the transcriptional repressor Ikaros in CAR T cells could be an attractive strategy to overcome immunosuppressive tumor microenvironments and enhance their tumoricidal capacity. Further clinical development is warranted.
Citation Format: Shaun O'Brien, Liang-Chuan Wang, Kheng Newick, Rajan M. Thomas, Andrew Wells, Steven M. Albelda. Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3142. doi:10.1158/1538-7445.AM2015-3142
Abstract 3144: Development of immunotherapy for anaplastic large cell lymphoma (ALCL) using CSF1R retargeted human T lymphocytes
Authors: Achkova Daniela , Spicer James , Maher John 
Published: August 2015

Abstract
Anaplastic large cell lymphoma (ALCL), a type of T/null-cell lymphoma, represents about 20-30% of paediatric lymphomas and has an aggressive clinical course with frequent relapse. Recently, high-level expression of CSF1R on malignant cells in ALCL has been linked to shorter progression free survival, providing a rationale to test adoptive C28ζ-mediated T-cell therapy. This approach encompasses the genetic modification of T-cells to express a chimeric antigen receptor (CAR) named C28ζ, a fusion receptor coupling the recognition of CSF1R on the tumour cell surface to the delivery of tailored T-cell activation signal provided by a fused CD28+CD3ζ endodomain. To optimize this approach for human translation, the C28ζ CAR was co-expressed with the chimeric cytokine receptor 4αβ (combination termed “C4”), which allows for selective expansion and enrichment of CAR-transduced T-cells using IL-4. PBMCs of healthy donors were isolated and activated using anti-CD3/CD28 beads. Following retroviral T-cell transduction and 14 days expansion of C4+ T-cells in the presence of IL-4, co-cultures with a panel of ALCL cell lines (2 ALK positive and 2 ALK negative ALCL cell lines) were set up to test C4 efficacy in vitro. Successful re-targeting of C4+ T-cells was confirmed by monitoring target cell destruction. Conditioned media was collected and analysed for IFN-γ and IL-2 production. Cytotoxicity, cytokine release and T-cell proliferation data demonstrated Ag-specific activation of the C4+ cells, which contrasted with T-cells expressing a control CAR with truncated endodomain. This data provides for the first time the basis for successful application of CAR-based immunotherapy against CSF1R-expressing malignancies.
Citation Format: Daniela Achkova, James Spicer, John Maher. Development of immunotherapy for anaplastic large cell lymphoma (ALCL) using CSF1R retargeted human T lymphocytes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3144. doi:10.1158/1538-7445.AM2015-3144
Abstract 3147: Generation of exhaustion-resistant memory CD8 T-cells by simultaneous downmodulation of mTORC1 and PD-1 in activated CD8 T-cells
Authors: Berezhnoy Alexey , Levay Agata , Rajagopalan Anugraha , Puplampu-Dove Yvonne , Gilboa Eli 
Published: August 2015

Abstract
CD8 memory T cells play a crucial role in controlling chronic infections and certain malignancies. It is possible to expand the population redirecting early-activated T-cells toward memory differentiation by altering intracellular signaling of mTORC1 pathway. Indeed, treatment with mTORC1 inhibitor rapamycin increased formation of memory cells as published previously; however, animals treated with the drug exhibited signs of immune suppression and rapamycin-generated CD8 memory T-cells failed to protect animals against melanoma challenge. We introduced highly efficient RNAi-based method to downmodulate mTORC1 signaling specifically in target cells. siRNA against raptor, a critical component of the signaling complex, was delivered in vivo into activated T-cells by conjugating to the 4-1BB-binding RNA aptamer resulting in expansion of CD8+ memory T-cells formation.
Memory T-cells are generally resistant to immune suppression, yet in vivo, the population suffers from the gradual attrition mediated by PD-1 signalling. We developed the conjugate with two highly effective siRNAs against raptor and PD-1 linked to the same 4-1BB aptamer molecule. In vitro, both siRNAs efficiently dissociated from the conjugate inside target cells and simultaneously downregulated its respective mRNAs. In vivo, using OT-I adoptive transfer model, we demonstrated that treatment with 4-1BB-raptor-PD1 conjugates increased formation of memory CD8+ T-cells (as measured by absolute number of OT-1 cells 30 days after the treatment) in a rate similar to the 4-1BB-raptor conjugate. There was, however, qualitative difference between two populations, as CD8+ memory T-cells expanded with 4-1BB-raptor-PD1 conjugates expressed significantly less PD-1 on cell surface, and were, therefore, resistant to PD-1-mediated immune suppression. Thus, we introduced a new method to generate memory cells with enhanced functional potential and currently exploring its therapeutic usefulness in various models.
Citation Format: Alexey Berezhnoy, Agata Levay, Anugraha Rajagopalan, Yvonne Puplampu-Dove, Eli Gilboa. Generation of exhaustion-resistant memory CD8 T-cells by simultaneous downmodulation of mTORC1 and PD-1 in activated CD8 T-cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3147. doi:10.1158/1538-7445.AM2015-3147
Abstract 3158: Ex vivo expansion and activation of human lymphocytes with a selective activator of effector cells
Authors: Lopes Jared E. , Fisher Jan L. , Losey Heather C. , Ernstoff Marc S. , Alvarez Juan C. 
Published: August 2015

Abstract
RDB 1450 is an engineered fusion protein of circularly permuted IL-2 and IL-2Rα that is selective for the intermediate-affinity IL-2 receptor. The intermediate-affinity receptor is comprised of the IL-2 receptor beta chain (CD122) and common gamma chain (CD132) expressed on lymphocytes with effector function, whereas the high-affinity receptor, which additionally includes the alpha chain (CD25), is expressed primarily on immunosuppressive CD4+CD25+ regulatory T cells (Tregs). Ex vivo proliferation of subsets of human lymphocytes in response to RDB 1450 or rhIL-2 were evaluated. RDB 1450 supports the selective activation and expansion of effector lymphocytes based on higher observed memory CD8 T/Treg and NK/Treg ratios. Both RDB 1450 and IL-2 drive expansion of NK cells, however, a greater proportion of CD25+ NK cells are observed in response to RDB 1450. Furthermore, unlike IL-2, RDB 1450 does not effectively expand highly suppressive ICOS+ Tregs. The immunological profile resulting from the ex vivo treatment of human PBMCs with RDB 1450 supports its use as a novel immunotherapy for cancer.
Citation Format: Jared E. Lopes, Jan L. Fisher, Heather C. Losey, Marc S. Ernstoff, Juan C. Alvarez. Ex vivo expansion and activation of human lymphocytes with a selective activator of effector cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3158. doi:10.1158/1538-7445.AM2015-3158
Abstract 3159: In vitro characterization of third-generation chimeric antigen receptor T cells directed toward GD2-expressing and BRAF-inhibitor resistant melanoma target cells
Authors: Gargett Tessa , Brown Michael P. 
Published: August 2015

Abstract
Advances in the treatment of metastatic melanoma include the recent approval of the immunotherapy ipilimumab, an anti-CTLA-4 monoclonal antibody, and of the targeted therapies vemurafenib, dabrafenib and trametinib, which are mitogen-activated protein kinase (MAPK)-pathway inhibitors. Cancer immunotherapy also includes adoptive transfer of autologous tumor-specific chimeric antigen receptor (CAR) T cells. CAR T cells are responsible for significant tumor responses in leukemia and neuroblastoma patients. We have manufactured third-generation GD2-specific CAR T cells to be used in our open CARPETS Phase I clinical trial of autologous GD2-CAR T cells in patients with advanced GD2-expressing melanoma (ACTRN12613000198729). However, although these promising new targeted- and immuno-therapies can produce complete or partial tumor responses, tumor resistance via alteration or bypass of the targeted molecules inevitably occurs.Combination therapies have been proposed as a way to exploit the high-level but short-term responses associated with kinase-inhibitor therapies and the low-level but longer-term responses associated with immunotherapy, and could potentially overcome tumor resistance by targeting multiple tumor-associated molecules. To this end, we have investigated the effects of vemurafenib, dabrafenib and trametinib on the function of our GD2-CAR T cells and found that dabrafenib does not inhibit effector functions at concentrations equivalent to reported plasma concentrations in treated patients. We have also observed that although GD2-CAR T cells have reduced killing of BRAF inhibitor -resistant melanoma cell lines, their function is not inhibited by PD1 blockade in vitro.These effects depend on whether GD2-CAR T-cell activation occurs via the native TCR or the CAR and upon the nature of apoptosis resistance in the GD2-expressing melanoma target cells.
Citation Format: Tessa Gargett, Michael P. Brown. In vitro characterization of third-generation chimeric antigen receptor T cells directed toward GD2-expressing and BRAF-inhibitor resistant melanoma target cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3159. doi:10.1158/1538-7445.AM2015-3159