bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3644: C-Jun N-terminal kinases and autophagy promote adenoviral and ectopic tumor-associated antigen presentation
Authors: Klein Sarah Renee 
Published: May 2015

Abstract
Adenoviruses are innately immunogenic; thus, targeted immunotherapy with recombinant, oncolytic adenoviruses is under investigation for the treatment of cancer. Evidence indicates adenoviruses induce autophagy that is required for cancer cell lysis. Importantly, autophagy is known to promote the presentation of self and foreign antigens for immune cell activation. The molecular regulation of autophagy and antigen presentation in adenovirus- infected cells remains undefined. Our data indicates adenovirus infection triggered phosphorylation of c-Jun N-terminal kinases (JNK) in vitro and in vivo, which was essential for autophagy. JNK-dependent B cell lymphoma-2 (Bcl-2) phosphorylation stimulated the dissociation of Bcl-2/beclin 1 heterodimers, enabling beclin 1 to initiate autophagy. Additionally, our data demonstrated for the first time that adenoviral epitopes were presented at the surface of infected cells through JNK- and autophagy-dependent mechanisms, as infected JNK- and autophagy-deficient cells were unable to activate splenocytes from adenovirus-immunized mice. Rapamycin, a chemical activator of autophagy, was able to enhance adenoviral antigen presentation. Contrary to starvation-induced autophagy, inhibiting adenovirus-mediated autophagy and antigen presentation required genetic knock-out of both JNK1 and JNK2 isoforms. We propose this unique mechanism for the processing of adenoviral antigens and consequent activation of immune cells can be leveraged in developing recombinant adenoviruses for the advancement of anti-tumor immunotherapy. Thus, we developed a novel adenovirus that expresses a chimeric fiber protein containing the cancer-specific, immunogenic epitope from the epidermal growth factor receptor variant III (EGFRvIII). We confirmed that the EGFRvIII epitope was presented at the surface of cells in an autophagy-dependent manner that could be enhanced by the pro-inflammatory cytokine, interferon gamma. Thus, we discovered molecular events regulating adenovirus-mediated autophagy and antigen presentation that differs from the conventional paradigm which could be employed for the advancement of adenovirus-based vaccines.
Citation Format: Sarah Renee Klein. C-Jun N-terminal kinases and autophagy promote adenoviral and ectopic tumor-associated antigen presentation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3644. doi:10.1158/1538-7445.AM2014-3644
Abstract 3649: Significance of HIV viral load and CD4 count on Kaposi sarcoma in the era of highly active antiretroviral therapy
Authors: King Gentry T. , Garg Shivani 
Published: May 2015

Abstract
Background: Approximately 20% of patients with HIV will have Kaposi Sarcoma (KS) and about half will die within 3 months of diagnosis. Incidence and outcomes of KS have traditionally been linked to CD4 counts &lt;350. More recently, KS has been increasingly described in higher CD4 counts and variable presentations in the era of Highly-Active-Antiretroviral-Therapy (HAART). No studies have established the role of Viral Load (VL) on KS.
Objective: To determine the effect of CD4 count and HIV VL on KS presentation and outcomes.
Methods: Retrospective review of KS patients with HIV admitted over 12 years (2000-2012). KS patients without HIV infection were excluded. Patients were divided into 4 groups based on CD4 count (≥200 or 100,000 or &lt;100,000). Groups were analyzed with regards to KS severity (good vs poor risk), extent (soft tissue vs visceral), receipt of HAART and survival (6months). Statistical analysis was done via Chi-Square test.
Results: 43 patients were included. KS affected predominantly young (30-40yrs), male (93%) HIV patients with VL &gt;100,000 (85%) and CD4 counts 100,000 had a statistically significant increased incidence for visceral involvement (96%, p100,000 ((66.7% with good risk), increased survival (59.4% survived &gt;6months) and less use of HAART (20%). Although, these differences were statistically insignificant.
Conclusion: HIV VL of &gt;100,000 is correlated with increased severity and extent of KS. Though statistically insignificant, CD4 counts &lt;200 showed a trend for less severe disease and increased survival despite less use of HAART. Larger prospective studies are warranted to elucidate on these differences.
Citation Format: Gentry T. King, Shivani Garg. Significance of HIV viral load and CD4 count on Kaposi sarcoma in the era of highly active antiretroviral therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3649. doi:10.1158/1538-7445.AM2014-3649
Abstract 3653: Nanoparticle-delivered T7-synthesized siRNA enhances cell killing in HER-2 (+) breast cancer
Authors: Alonso-Valenteen Felix , Medina-Kauwe Lali K. 
Published: May 2015

Abstract
We have previously developed the recombinant fusion protein, HerPBK10, for ligand-directed targeting and penetration of HER2+ breast cancer. HerPBK10 contains a ten lysine (K10) carboxy [C] -terminal tail that allows it to non-covalently bind anionic payloads, such as nucleic acids, by electrophilic interaction. In this study, a modified siRNA capable of both gene silencing and immunostimulation is the payload. Here, we test the hypothesis that ligand-directed, protein-based nanoparticles delivering siRNA launch a three-pronged attack on tumors by combining missile-like targeting (known as “transductional targeting”) with siRNA-mediated gene silencing, and cytokine-mediated cell death. The latter effect will be accomplished by taking advantage of the normally undesirable cytokine-mediated cytotoxicity induced by epigenetic modifications on certain forms of siRNA, and delivering this to tumors. Here we will deliver siRNA produced by T7 phage polymerase transcription, which introduces a 5′ triphosphate cap that triggers cytokine-mediated toxicity within host cells. So far, in vitro data has shown that this approach is more effective in reducing cell proliferation than synthetic siRNA against the same gene. Furthermore, in vivo xenograft data shows that this strategy can control and ablate the growth of HER2+ tumors. Future directions include IHC investigation of resected tumors and testing this hypothesis in an immunocompetent in vivo setting where we envision this immune-sensitive strategy having even greater efficacy.
Citation Format: Felix Alonso-Valenteen, Medina-Kauwe. Nanoparticle-delivered T7-synthesized siRNA enhances cell killing in HER-2 (+) breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3653. doi:10.1158/1538-7445.AM2014-3653
Abstract 3654: The role of structure-specific endonuclease MUS81 in the induction of cytosolic DNA in tumor cells
Authors: Ho Samantha , Gasser Stephan 
Published: May 2015

Abstract
Genomic DNA is constantly damaged by endogenous and exogenous agents. The DNA damage response (DDR) is vital for recognizing DNA damage and instigating DNA repair reactions to ensure genome stability. MUS81 is a structure-specific endonuclease that is required for resolving stalled replication forks at sites of DNA damage to initiate Homologous Recombination repair. Our preliminary data suggests that the potentially detrimental DNA structures cleaved by MUS81 accumulate in the cytosol of many tumor cells. Furthermore, we found that DNA cleaved by MUS81 induces type I interferon expression in a STING-dependent manner, and initiates an innate immune response in vivo. Cytosolic DNA in tumor cells was also abrogated upon inhibition of DNA damage sensors, ATM/ATR and PARP1. In addition, genetic inhibition of Mus81 in different tumor cells lines impaired expression of cytosolic DNA and type I interferon. In summary, our data suggest that the structure-specific endonuclease MUS81 cleaves damaged nuclear DNA leading to accumulation of genomic DNA in the cytosol of tumor cells, activating immunosurveillance mechanisms.
Citation Format: Samantha Ho, Stephan Gasser. The role of structure-specific endonuclease MUS81 in the induction of cytosolic DNA in tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3654. doi:10.1158/1538-7445.AM2014-3654
Abstract 3657: Cross-regulation between the two subsets of NKT cells is dependent on interferon-gamma
Authors: Izhak Liat , Kato Shingo , Parish Stanley T. , Terabe Masaki , Berzofsky Jay A. 
Published: May 2015

Abstract
Overcoming the suppression of tumor immunity has been a major challenge in the fight against cancer. Suppression of tumor immunity is being regulated by different kinds of suppressor cells and depleting or blocking their function has been the target of immunotherapy development. One subset of immune suppressors is type II NKT cells. We have previously shown that, upon simultaneous stimulation, type I NKT cells that can promote tumor immunity and type II NKT cells cross regulate each other in vitro as well as in vivo. In some tumor models it was found that activation of type II NKT cells by sulfatide can completely abrogate the protective affect of type I NKT cell activation by alpha-galactosylceramide, leading to tumor progression and reduced survival. However the mechanism for this suppression has not been understood. By co-stimulating NKT cells in vitro, we found that type II NKT cells can inhibit the proliferation of type I NKT cells. By blocking a variety of immunregulators, we found that this suppression is dependent on interferon-gamma (IFNg). Blocking IFNg or its receptor reversed the suppression of type I NKT cell proliferation in vitro. In addition suppression was not observed in IFNgKO C57BL/6 NKT cells. It was also found that exogenous IFNg reduces the proliferation of type I NKT cells after stimulation, suggesting that IFNg is necessary for the suppression of type I NKT cells by type II NKT cells. This was unexpected as IFNg is also an effector cytokine secreted by type I NKT cells. The mechanism is under investigation. Blocking the ability of type II NKT cells to suppress type I NKT cells could shift the balance toward immune protection leading to a better tumor outcome.
Citation Format: Liat Izhak, Shingo Kato, Stanley T. Parish, Masaki Terabe, Jay A. Berzofsky. Cross-regulation between the two subsets of NKT cells is dependent on interferon-gamma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3657. doi:10.1158/1538-7445.AM2014-3657
Abstract 366: Translational modeling of docetaxel-thalidomide combination treatment in metastatic, castrate-resistant prostate cancer: predicting clinical response using preclinical data
Authors: Fernandez Eric , Mistry Hitesh , Brightman Frances , Orrell David , Dahut William L. , Figg William D. , Stein Wilfried D. , Chassagnole Christophe 
Published: May 2015

Abstract
A major cause of drug failure in the clinic is that preclinical studies do not predict with sufficient certainty what will happen in clinical practice. Accurately translating information from animal studies to the clinic would have a major impact on attrition rate. We have developed a mathematical model of a tumor cell population called the Virtual Tumour, which has been used extensively to predict the efficacy of single drug or drug combination treatment in preclinical studies. We have now extended and adapted our preclinical model to predict efficacy in the clinic, thus creating the “Virtual Tumour Clinical.” Here we show a comparative study of the preclinical Virtual Tumour calibrated model for prostate tumor xenografts in mice, with a Virtual Tumour Clinical version calibrated with a clinical data set comprising 53 prostate cancer patients treated with thalidomide, 25 treated with docetaxel and 50 treated with a docetaxel and thalidomide combination. PSA measurements were used as proxy for tumor size. We analysed the consistency, the capability and the limitations of the models in translating the effect of the drug combination from the preclinical situation to the clinic.
Citation Format: Eric Fernandez, Hitesh Mistry, Frances Brightman, David Orrell, William L. Dahut, William D. Figg, Wilfried D. Stein, Christophe Chassagnole. Translational modeling of docetaxel-thalidomide combination treatment in metastatic, castrate-resistant prostate cancer: predicting clinical response using preclinical data. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 366. doi:10.1158/1538-7445.AM2014-366
Abstract 3663: Immune suppressive myeloid cells expansion in vitro requires a simulated tumor microenvironment
Authors: Markowitz Joseph , Brooks Taylor R. , Carson William E. 
Published: May 2015

Abstract
Elevated levels of immune suppressor cells induced by tumor derived factors are associated with inhibition of immune responses. One such group of immune suppressor cells is Myeloid Derived Suppressor Cells (MDSCs). They are phenotypically defined in humans as HLADR low or negative and CD33, CD11b, and CD15 or CD14 positive and functionally by their ability to suppress the activation of other immune cells such as T cells. We hypothesized that MDSCs generated in vitro could be propagated but would lose their suppressive ability on the action of T cells in the absence of a simulated tumor microenvironment. MDSCs were first differentiated in vitro from normal donor peripheral blood mononuclear cells (PBMCs) using a simulated tumor microenvironment consisting of either cytokines (GMCSF and IL-6) or tumor cell lines (pancreatic adenocarcinoma SW-1990 or head and neck cancer CAL-27). The MDSCs generated in vitro suppressed T cell proliferation of autologous T cells using the carboxyfluorescein succinimidyl ester (CFSE) assay (31%, 46% and 75% suppression for cytokines, CAL-27 and SW-1990, respectively). Given the MDSCs obtained from co-culture of PBMCs with SW-1990 were the most suppressive on the proliferation of T cells, we attempted to proliferate these cells in vitro to expand the number of MDSC available for experimentation rather than having to purify MDSC from clinical samples. In vitro generated MDSC were propagated using a Rho-associated kinase (ROCK) inhibitor. Generated MDSC collected via magnetic bead isolation (CD33) were cultured with irradiated fibroblast feeder cells (± 3000 rad) in F medium [3:1 (v/v) F-12 Nutrient Mixture (Ham)-Dulbecco's modified Eagle's medium, 5% fetal bovine serum, 0.4 µg/mL hydrocortisone, 5 µg/mL insulin, 8.4 ng/mL cholera toxin, 10 ng/mL epidermal growth factor (or 10 ng/mL GMCSF), and 24 µg/mL adenine]. The ROCK inhibitor was added at 10 µM and the media was exchanged every 3 days. The generated MDSC did propagate as measured by CFSE staining of the generated MDSC; however, the generated MDSCs completely lost their ability to inhibit T cells by day 11 in culture. In conclusion, generated MDSCs can be propagated in culture but lose their ability to suppress T cells in the absence of a simulated tumor microenvironment and the presence of a Rho kinase inhibitor.
Citation Format: Joseph Markowitz, Taylor R. Brooks, William E. Carson. Immune suppressive myeloid cells expansion in vitro requires a simulated tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3663. doi:10.1158/1538-7445.AM2014-3663
Abstract 3666: Tumor microenvironment modulation enhances macrophage polarization and T-cell activation resulting in synergized anti-cancer effect
Authors: Huang Yuhui , Jiang Wen , Kim Betty Y.S. 
Published: May 2015

Abstract
Solid cancer microenvironment is heterogeneous in nature, comprised of many stromal cell types that work in concert with malignant tumor cells for its maintenance and growth. Among these cell types, tumor-associated macrophages (TAMs) represent a dominant cell population with immunosuppressive and proangiogenic properties. Present in most human cancers, histologic evidence of increased TAMs is often associated with poorer prognosis. Here, we show that the immunosuppressive properties of TAMs can be overcome by modulating tumor microenvironmental parameters. By restoring tumor vascular network and tissue perfusion via anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, significant reduction of tumor tissue hypoxia and acidosis can be accomplished. Alteration of these local environmental factors directly results in the polarization of TAMs from an immune inhibitory (M2-like) towards immune stimulatory (M1-like) phenotype. In addition, the restoration of aberrant and dysfunctional tumor vessels leads to changes in local cytokine and protein expression profiles that favor the recruitment of immune effector cells, including increased CXCL9 expression. As a result, both CD4+ helper and CD8+ cytotoxic T cell populations were significantly increased within the tumor. Based on these findings, we tested the utility of combining the optimal dose of anti-VEGFR2 antibody therapy with B7-H4 blockade in breast cancer models. Our preliminary data suggests that such treatment enhanced TAM polarization to an anti-tumor phenotype, increased tumor immune cell infiltration and decreased T-cell inhibition, resulting in synergized anti-cancer effects. Therefore, these results suggest that tumor microenvironment modulating therapy provides a new and interesting strategy to augment active immunotherapy for breast as well as other cancer types.
Citation Format: Yuhui Huang, Wen Jiang, Betty Y.S. Kim. Tumor microenvironment modulation enhances macrophage polarization and T-cell activation resulting in synergized anti-cancer effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3666. doi:10.1158/1538-7445.AM2014-3666
Abstract 368: Inferred regulatory interaction network from prostate cancer reveals potential regulators coordinating progression and metastasis
Authors: Dai Xudong , Gong Yixuang , Galsky Matthew D. , Schadt Eric E. , Oh William K. , Zhu Jun 
Published: May 2015

Abstract
Introduction: Significant genomic reprogramming occurs when prostate cancer cells acquire androgen receptor (AR) independent growth and metastasize to remote sites. Recent whole genome sequencing studies have noted recurrent gene deletion, amplification, fusion and widespread chromoplexy associated with prostate cancer progression. Synchronizing such a multistep multicomponent process, involving both cancer cells and tumor microenvironment, to gain growth advantage is challenging without a master coordinator. Genome-wide siRNA screenings have been undertaken to identify regulators driving such a reprogramming process affecting cancer cell themselves, but not the necessary interaction with host tissue. Thereby a novel approach was developed in the current work to uncover potential regulators that coordinate major cancer hallmarks and tumor-host interactions leading to prostate cancer progression. Methods: A network of potential regulatory interactions among genes was derived from matched prostate cancer expression profiles and copy number variation (CNV) datasets. The relevance of the inferred network was examined by experimentally derived AR target networks and literature mining- based cancer gene interaction networks. Subsequently, a network topology-based matrix, critical node index, was established to identify network modules significantly associated with biochemical recurrence—a clinical surrogate marker representing prostate cancer progression. Results: When bench-marked with established prostate cancer gene sets, the critical node downstream modules were more significantly enriched for individual genes with strong prognostic power (P&lt;1E-5). Furthermore, compounds, which are capable of reversing expression patterns of individual top critical node downstream modules, either inhibited cancer cell growth or tumor progression in public datasets and literature. More importantly, overexpression or knock down of individual critical nodes in LNCaP, 22RV1, and PC3 prostate cancer cell lines demonstrated the potential of critical nodes to coordinate AR-independent growth through regulating host tissue immune interactions. Conclusion: Our preliminary results imply the existence of network modules that can synchronize the effects of genomic reprogramming during prostate cancer progression and metastasis.
Note: This abstract was not presented at the meeting.
Citation Format: Xudong Dai, Yixuang Gong, Matthew D. Galsky, Eric E. Schadt, William K. Oh, Jun Zhu. Inferred regulatory interaction network from prostate cancer reveals potential regulators coordinating progression and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 368. doi:10.1158/1538-7445.AM2014-368