bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A34: Characterization of tumor infiltrating lymphocytes in human breast cancer by infrared imaging
Authors: Verdonck Magali , Garaud Soizic , Buisseret Laurence , Duvillier Hugues , Desmedt Christine , Wind Roland de , Sotiriou Christos , Willard-Gallo Karen , Goormaghtigh Erik
Published: October 2015

In human breast cancer spatially organized Tumor Infiltrating Lymphocytes (TILs) have been associated with effective therapeutic responses and favorable clinical outcomes.[1-3] This study investigates the potential for using InfraRed (IR) imaging to identify and characterize infiltrating lymphocytes in breast tumors, focusing on CD4+, CD8+ T lymphocytes and B lymphocytes (CD20+). Fourier Transform InfraRed (FTIR) spectroscopy coupled with microscopy is an emerging tool in cancer research and diagnosis.[4,5] IR imaging can probe the chemical composition and molecular structure of cells and tissues, thereby providing a global and unique signature for all cellular constituents. Compared with standard techniques used for identification and characterization of immune cells in tissue sections, IR imaging has numerous advantages, including no requirement for staining or automation. In this study, infrared spectra of lymphocyte subpopulations were recorded for lymphocytes in FFPE tissue sections from tonsils and breast tumors. Samples were deposited on a BaF2 window and the spectroscopic imaging data acquired in transmission mode using a Hyperion imaging system (Bruker) equipped with a focal plane array detector. The specific lymphocyte subpopulations present in each region were evaluated using hematoxyline & eosin (HE) and immunofluorescent (IF) staining of adjacent tissue sections. Statistical analyses indicate that IR spectra obtained from the CD4+, CD8+ or CD20+ lymphocyte subpopulations in tonsils are significantly different and identifiable relative to the other subpopulations. These data suggest that FTIR imaging can be used to identify specific lymphocyte subpopulations in tissues based on their spectral features. Our current work is testing this hypothesis to examine immune infiltrates in breast tumor tissue and these data will be presented at the meeting.

[1] C. Gu-Trantien et al. 2013. J. Clin. Invest. 2013, 123(7) pp. 2873–2892.

[2] C. Gu-Trantien and K. Willard-Gallo. Oncoimmunol. 2013, 2(10):e26066.

[3] C. Denkert et al., J. Clin. Oncol. 2010, 28(1), pp. 105-113.

[4] G. Bellisola and C. Sorio, Am J. Cancer Res. 2012, 2(1), pp. 1-21.

[5] J. Nallala et al., Cytometry A. 2013, 83(3), pp. 294-300.

Citation Format: Magali Verdonck, Soizic Garaud, Laurence Buisseret, Hugues Duvillier, Christine Desmedt, Roland de Wind, Christos Sotiriou, Karen Willard-Gallo, Erik Goormaghtigh. Characterization of tumor infiltrating lymphocytes in human breast cancer by infrared imaging. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A34.
Abstract A68: Local tumor treatments to simulate systemic antitumor immune responses
Authors: Lizotte Patrick , Sheen Mee Rie , Wen Amy M. , Steinmetz Nicole F. , Fiering Steven
Published: October 2015

The generation of effective systemic antitumor immune response is the central goal of tumor immunotherapy. The majority of efforts are focused on systemic treatments that inject therapeutic reagents IV. This is an excellent approach and will be a central facet of tumor immunotherapy, however there is also an opportunity to develop therapies that involve direct intratumoral treatments of recognized tumors with the goal of stimulating systemic antitumor immune responses. Such approach can be used in conjunction with systemically applied therapies and have advantages because of the greater ability to control reagent concentrations that are intratumorally injected. We will present data from recent studies that utilize attenuated microorganisms, known TLR agonists and hyperthermia alone or in combinations to treat murine melanoma and ovarian cancer.

Citation Format: Patrick Lizotte, Mee Rie Sheen, Amy M. Wen, Nicole F. Steinmetz, Steven Fiering. Local tumor treatments to simulate systemic antitumor immune responses. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A68.
Abstract A69: The immunological environment in triple negative breast cancer; impact on clinical outcomes towards a prognostic clinical test
Authors: Gigoux Mathieu , Gruosso Tina , Bertos Nicholas , Saleh Sadiq , Omeroglu Atilla , Zhao Hong , Souleimanova Margarita , Meterissian Sarkis , Hallett Michael , Park Morag
Published: October 2015

It is now accepted that changes in the normal cells that constitute the tumor microenvironment (TME) play important roles in determining cancer progression and ultimate outcome. We and others have established that an immune signature, and more recently that the ability of CD8+ T cells to infiltrate the tumor bed, are correlated with good outcome in triple negative breast cancer. Importantly, since the cytotoxic effector functions of CD8+ T cells are mainly contact-dependent, the tumor microenvironment may act to inhibit access to the epithelial tumor bed, leading to uncontrolled tumor growth. Therefore, in order to determine the role that the TME plays on mediating the entry of CD8+ T cells into the epithelial tumor bed, our group performed laser-capture microdissection to separate the tumor epithelial compartment from the surrounding tumor-associated stroma from the primary tumor of 56 triple negative breast cancer patients and followed by gene expression profiling. Our aims are to provide clinical validation of predicted CD8+ T cell localisation based on our bioinformatic analysis, test our predictions that the identified stroma signature correlates with CD8+ T cell retention in other cohort of TN breast cancer patients and develop suitable markers of this stroma, and develop a muliplex based assay integrating CD8+ T cell localisation with stromal markers suitable for a retrospective study to validate predictions with outcome. Using gene expression profiling, our data have identified a canonical gene expression signature which correlates with retention of CD8+ T cells in the stroma and poor outcome. Thus, our results demonstrate that gene expression analysis of clinical triple negative breast cancer samples can predict the location of CD8+ T cells within the tumor and in turn the outcome.

Citation Format: Mathieu Gigoux, Tina Gruosso, Nicholas Bertos, Sadiq Saleh, Atilla Omeroglu, Hong Zhao, Margarita Souleimanova, Sarkis Meterissian, Michael Hallett, Morag Park. The immunological environment in triple negative breast cancer; impact on clinical outcomes towards a prognostic clinical test. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A69.
Abstract A74: Spatial organization of myeloid cells in tumor microenvironment
Authors: Kim Minhyeok , Lee Seon Woo , Kang Suk-Jo , Kang Changwon
Published: October 2015

Myeloid cells infiltrating tumor microenvironment orchestrate immune response to induce cancer progression. From tumor cell proliferation to angiogenesis, invasion, and metastasis, every step of cancer development is controlled by distinct types of immune cells. Tumor-associated macrophages (TAMs), myeloid derived suppressor cells (MDSCs), TIE2-expressing monocytes (TEMs), tumor associated neutrophils (TANs), and sub-population of dendritic cells are examples of tumor promoting myeloid cells. These numerous types of myeloid cells have been identified and characterized but their spatial organization within the tumor microenvironment have not been analyzed thoroughly. To understand their actions and mechanisms on cancer promotion, understanding their organization is required. By using EL4 thymoma syngenic graft model, we analyzed composition of myeloid cells infiltrating EL4 tumor microenvironment and revealed spatial organization of each type of myeloid cells. Dozens of immune cell surface markers were used to comprehensively define and characterize tumor infiltrating myeloid cells. Most of CD11b positive myeloid cells were localized at surrounding matrix of tumor mass. In particular, immunosuppressive immune cells like MDSCs were localized surrounding matrix of tumor and barely infiltrating actual tumor mass. In contrast, TAMs and dendritic cells are integrated with tumor cells inside the tumor mass. Dendritic cells can be subdivided based on CD11b expression level and those two distinct subsets are localized at distinct area of tumor mass. This analysis of spatial localization of immune cells implies division of labor among the cancer promoting myeloid cells. Tumor mass integrated myeloid cells suspected to promote angiogenesis and tumor cell proliferation. Tumor surrounding matrix localized myeloid cells suspected to promote immune suppression, invasion and metastasis.

Citation Format: Minhyeok Kim, Seon Woo Lee, Suk-Jo Kang, Changwon Kang. Spatial organization of myeloid cells in tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A74.
Abstract A92: Small molecules targeting HMGR and HDAC in colorectal cancer
Authors: Wei Tzu-Tang , Lin Yi-Ting , Lin Yu-Chin , Chen Ching-Chow
Published: October 2015

Background and Aims: Colorectal cancer (CRC) is an important cancer with rising annual incidence worldwide, leading to significant morbidity and mortality. The addition of new anti-CRC drugs significantly improves treatment outcome, indicating that it is crucial to develop new drugs. Chemoprevention is another important approach to reduce cancer-related mortality. We first demonstrated statins with a carboxylic acid-containing long chain inhibiting histone deacetylase (HDAC) activity. To further improve their HDAC inhibition, we designed and synthesized three statin hydroxamates (JMF3086, JMF3171 and JMF3173) that potently inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and histone deacetylases (HDACs) simultaneously. Their preventive and therapeutic effects on CRC were investigated.

Methods: The in vitro anticancer activity was evaluated in human cancer cells. Molecular mechanisms were investigated using genome-wide ChIP-on-chip, Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA). Anti-inflammation was examined by Dextran sulfate sodium (DSS)-induced acute colitis in mice. Prevention or therapy for CRC was examined by AOM/DSS mouse model. Anti-metastasis was examined by splenic and tail vein injected mouse models, and colorectal cancer stem cells were generated to investigate the inhibition of stemness.

Results: Statin hydroxamates were effective to inhibit a variety of human cancer cells. ChIP-on-chip analysis demonstrated the down-regulation of inflammatory and stemness genes and up-regulation of tumor suppressor genes. GO and IPA predicted the regulatory role of NF-kB in inflammatory genes and NR3C1 in apoptosis-related genes. The oral administration of JMF3086 prevented DSS-induced colitis and AOM/DSS-induced CRC in mice by inhibiting inflammation. Statin hydroxamates exerted a therapeutic effect in CRC mice by inducing apoptosis. CRC metastasis to the livers and lungs and the propagation of CRC stem cells in vivo were also inhibited by JMF3086. The efficacy of JMF3086 was superior to the combination of lovastatin and SAHA (HDAC inhibitor) with less toxicity.

Conclusions: Statin hydroxamates with dual inhibition on HMGR and HDACs show great preclinical efficacy in prevention and treatment of CRC through inhibiting inflammation and inducing apoptosis.

Citation Format: Tzu-Tang Wei, Yi-Ting Lin, Yu-Chin Lin, Ching-Chow Chen. Small molecules targeting HMGR and HDAC in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A92.
Abstract B18: Adoptive T-cell transfer combined with murine cytokine-armed adenoviruses for the treatment of melanoma
Authors: Siurala Mikko , Havunen Riikka , Bramante Simona , Saha Dipongkor , Tähtinen Siri , Vähä-Koskela Markus , Hemminki Akseli
Published: October 2015

Adoptive cell transfer (ACT) has shown promising results in clinical trials for melanoma, with response rates ranging from 40% to 72%. We aimed to enhance the efficacy of ACT by coupling it with adenoviruses coding for immunostimulatory cytokines. The non-replicating adenoviruses that were constructed (Ad5-CMV-mIFNg, Ad5-CMV-mIL2, Ad5-CMV-mIFNb and Ad5-CMV-mTNFa) were confirmed to produce biologically active murine cytokines in vitro. These viruses were then used in combination with adoptive transfer of OT-1 TCR transgenic T-cells to treat C57BL/6 mice bearing B16-OVA melanoma tumors. The animals were administered intraperitoneally with 1.5 x 106 CD8+-enriched OT-1 cells with or without intratumoral injections of cytokine-coding adenoviruses (1 x 109 viral particles/tumor). Combination treatment with Ad5-CMV-mIL2 and OT-1 resulted in statistically significant antitumor efficacy when compared with either monotherapy and untreated control (combination vs. virus, p=0.026; combination vs. OT1, p=0.003; combination vs. mock, p<0.001). Similar results were obtained with other cytokine-coding virus and OT-1 combinations, except for mIFNb. In further experiments a triple combination of Ad5-CMV-mIL2 + Ad5-CMV-mTNFa (1:1 ratio) and OT-1 T-cells were used to treat B16-OVA; improved antitumor efficacy was observed with the triple combination over dual agent therapies (triple combination vs. Ad5-CMV-mIL2 + OT-1, p=0.001; triple combination vs. Ad5-CMV-mTNFa + OT-1, p=0.049). In summary, these results support the further development of a novel immunotherapeutic approach for the treatment of melanoma.

Citation Format: Mikko Siurala, Riikka Havunen, Simona Bramante, Dipongkor Saha, Siri Tähtinen, Markus Vähä-Koskela, Akseli Hemminki. Adoptive T-cell transfer combined with murine cytokine-armed adenoviruses for the treatment of melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B18.
Abstract B26: Translation of cancer vaccine strategies from mice to clinical trials
Authors: Berzofsky Jay A. , Terabe Masaki , Wood Lauren V.
Published: October 2015

We have developed several cancer vaccine strategies and translated them from mice to humans. We used “epitope enhancement” to modify an epitope of the TARP prostate cancer antigen to increase affinity for HLA-A2 and immunogenicity in HLA-A2-transgenic mice. This and another high affinity TARP epitope elicited human T cells killing human tumor cells. We translated these into a vaccine trial in stage D0 prostate cancer, in which patients after primary disease treatment have rising PSA. Patients received TARP peptides either in montanide or pulsed onto autologous DCs. No difference was seen between arms. 72% of vaccinees at 24 wks and 74% at 48 wks had a decreased PSA velocity (p= 0.0004), a validated measure of tumor growth. 77% of vaccinees made a specific IFNγ ELISpot response, but there was no correlation with clinical effect, suggesting that the quality of the T cells is critical. Accordingly, a phase II randomized placebo-controlled clinical trial is being opened. We also developed an adenovirus vaccine expressing the extracellular & transmembrane domains of HER2, which cured almost all mice with large (up to 2 cm) established tumors and lung metastases. The protection in mice is purely antibody-dependent. We translated this to a clinical trial with autologous DCs transduced with an adenovirus expressing human HER2 domains. The first part is a dose-escalation in patients with any type of cancer expressing 1+ to 3+ HER2 by IHC who are naïve to HER2-targeted therapies. In 1 of 2 patients so far at the 2nd dose level for which we have data, we have an indication of a partial response. Thus, translation of cancer vaccine strategies from mice to humans is beginning to show promising results.

Citation Format: Jay A. Berzofsky, Masaki Terabe, Lauren V. Wood. Translation of cancer vaccine strategies from mice to clinical trials. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B26.
Abstract B35: Use of random peptide array to discover cancer neo-antigens for vaccines and diagnostics
Authors: Stafford Phillip , Richer Josh , Johnston Stephen Albert , Shen Luhui
Published: October 2015

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR10) of the Conference Proceedings.

Citation Format: Phillip Stafford, Josh Richer, Stephen Albert Johnston, Luhui Shen. Use of random peptide array to discover cancer neo-antigens for vaccines and diagnostics. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B35.
Abstract B42: Cyclic dinucleotides (CDNs) activated DC and NK cells in antitumor immunotherapy
Authors: Fu Juan , Zhen Qi , Pardoll Drew , Dubensky Tom , Kim Young
Published: October 2015

Abstract Our laboratory developed cell based cancer vaccines (STINGVAX) that was formulated with cyclic dinucleotides that and sensed by STING to phosphorylate interferon regulatory factor3 (IRF3) and nuclear factor kappa-light-chain-enhancer (NF-κB) to induce B cells and myeloid cells to secrete IFN-β. IFN-β can active NK cells through Tyk2-STAT1 signaling pathway, and we found increased number of activated NK cells in tumor bearing mice treated with STINGVAX. In the context of formulation with GM-CSF secreting cellular vaccines, the anti-tumor effect of CDN was dependent on IFNα/β receptors. We found that CDN activated NK cells both in vitro and in vivo, and at the molecular level, CDN increased TYK2-STAT1 signaling. When we tested STINGVAX's anti-tumor efficacy with NK depletion, its anti-tumor effect was abrogated.

Citation Format: Juan Fu, Qi Zhen, Drew Pardoll, Tom Dubensky, Young Kim. Cyclic dinucleotides (CDNs) activated DC and NK cells in antitumor immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B42.
Abstract B48: Homer3 regulates the establishment of neutrophil polarity
Authors: Wu Julie , Pipathsouk Anne , Keizer-Gunnink A , Alkema Wynand , Fusetti Fabrizia , Liu Shanshan , Atschuler Steve , Wu Lani , Kortholt Arjan , Weiner Orion
Published: October 2015

Neutrophils migrate towards developing tumors where they promote angiogenesis, setting the stage for metastasis. Investigating neutrophil migration should lead to novel drug targets to prevent neutrophil accumulation in tumors. Neutrophils and other cells rely on activation of the heterotrimeric G-protein Gai to regulate directional cell migration, but few links from Gai to chemotactic effectors are known. Through affinity chromatography using primary neutrophil lysate, we identify Homer3 as a novel Gai2-binding protein. RNAi-mediated knockdown of Homer3 in neutrophil-like HL-60 cells impairs chemotaxis and the establishment of polarity of the actin cytoskeleton. Most previously-characterized proteins that are required for cell polarity are needed for actin assembly or activation of core chemotactic effectors such as the Rac GTPase. In contrast, Homer3 knockdown cells show a normal magnitude and kinetics of chemoattractant-induced activation of PI3K and Rac effectors. Chemoattractant-stimulated Homer3 knockdown cells also exhibit a normal initial magnitude of actin polymerization, but they fail to polarize actin assembly and are defective in the initiation of cell polarity and motility. Our data suggest that Homer3 acts as a scaffold that spatially organizes actin assembly to support neutrophil polarity and motility downstream of GPCR activation.

Citation Format: Julie Wu, Anne Pipathsouk, A Keizer-Gunnink, Wynand Alkema, Fabrizia Fusetti, Shanshan Liu, Steve Atschuler, Lani Wu, Arjan Kortholt, Orion Weiner. Homer3 regulates the establishment of neutrophil polarity. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B48.
Abstract IA05: Breaking immune privilege in pancreatic cancer
Authors: Vonderheide Robert H.
Published: October 2015

Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. Certain tumors, especially pancreatic ductal adenocarcinoma (PDA), are fully refractory to these antibodies. Using a genetically engineered mouse model of PDA in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients. Tumor T cells express PD-1 as prominently as in classical models of chronic infection, but treatment with PD-1 mAb, with or without CTLA-4 mAb, fails in well-established tumors, recapitulating clinical results. Two “vaccine strategies” can be used to induce T cell immunity and reverse resistance of PDA to PD-1 and CTLA-4. These approaches include hypofractionated radiation or chemotherapy in conjunction with a CD40 agonisitc antibody. Data suggest that in non immunogenic tumors, manifesting as immune privilege in PDA, baseline refractoriness to checkpoint inhibitors may be rescued by the priming of a T cell response.

Citation Format: Robert H. Vonderheide. Breaking immune privilege in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA05.
Abstract IA09: Molecular mechanisms controlling the T cell-inflamed tumor microenvironment: Implications for therapy
Authors: Gajewski Thomas
Published: October 2015

Two major categories of melanoma metastases have been observed based on gene expression profiling and confirmatory technologies. One subgroup of patients has T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN gene signature. In contrast, the other major subset lacks this phenotype and these tumors show a behavior of immune “exclusion”. The optimal immunotherapeutic intervention may be distinct for these two general subsets. The T cell-inflamed tumor microenvironment subset contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3+ Tregs, and evidence for T cell-intrinsic anergy has also emerged. In addition, the mechanism of induction of these inhibitory mechanisms has been elucidated—PD-L1 and IDO are induced by IFN-γ, and Tregs are largely recruited by chemokines such as CCL22, produced by activated CD8+ effector T cells. Preclinical experiments have confirmed a critical role for all 4 of these mechanisms in limiting anti-tumor T cell efficacy in vivo, giving a mechanism base for translation back into the clinic. These include anti-PD-1/PD-L1 mAbs, IDO inhibitors, and approaches to deplete CD25+ Tregs and/or reverse anergy. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous to overcome compensatory effects. Preclinical data indicated synergy between anti-CTLA-4 +/- anti-PD-L1 +/- IDO inhibition. The mechanism of synergy is striking, as it correlates with a marked improvement of IL-2 production and proliferation of tumor-infiltrating CD8+ T cells. Clinical translation of these combination immunotherapies is promising and ongoing. In contrast to the T cell-inflamed melanomas, a new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Recent work has indicated that successful innate immune sensing of tumors involves the STING pathway and type I IFN production. Therefore, STING agonists are being developed to promote effective innate immune activation and generation of an adaptive immune response. Molecular mechanisms that explain the presence or absence of a T cell-inflamed tumor microenvironment in patients are being elucidated, which is opening up new concepts for therapies that may overcome immune exclusion and render patients responsive to immunotherapies.

Citation Format: Thomas Gajewski. Molecular mechanisms controlling the T cell-inflamed tumor microenvironment: Implications for therapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA09.
Abstract PR01: The heat shock protein-CD91 pathway is necessary for tumor immunosurveillance
Authors: Zhou Yu Jerry , Binder Robert J.
Published: October 2015

Many tumors are capable of generating immune response in the bearing host. Since tumors lack the typical (foreign) PAMPs that provide signal 2 for T cell priming, the mechanism of how concomitant immunity is established remains a mystery. We provide evidence here that, heat shock proteins (HSPs), when released into the tumor microenvironment, is the immunogen necessary for tumor immunosurveillance. This response requires CD91- the endocytic and signaling receptor for the immunogenic HSPs. In our study, we generated CD11c-specific CD91 knockout mice and showed that transplantable tumors grew faster in those knockout mice, compared to wild type mice. In addition, we abrogated the interaction of tumor-derived HSP with CD91 in vivo by over-expression of Receptor Associated Protein (RAP), an endogenous inhibitor of CD91. The loss of CD91 funtion through antagonism or its deletion was shown to negatively affect cross-priming. While initial studies were performed on transplantable tumors, these experiments have now been carried out in chemically induced tumor models. In summary, our study demonstrates that the HSP-CD91 pathway is critical for establishment tumor immunity. Considering that elevated RAP levels have been reported in colon cancer patients, we propose a novel mechanism of immune evasion for tumors expressing competing ligands for immune receptors such as CD91.

Citation Format: Yu Jerry Zhou, Robert J. Binder. The heat shock protein-CD91 pathway is necessary for tumor immunosurveillance. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr PR01.
Set-Shifting Ability Is Associated with Gray Matter Volume in Older People with Mild Cognitive Impairment
Authors: Tsutsumimoto Kota , Makizako Hyuma , Shimada Hiroyuki , Doi Takehiko , Suzuki Takao
Published: October 2015

Background/Aims: An understanding of the association between gray matter volume and executive functioning could provide strategies to reduce dementia risk in older people with mild cognitive impairment (MCI). Methods: In a cross-sectional analysis, we assessed executive functioning in 83 older people with MCI using three standard neuropsychological tests: set shifting (difference between Trail Making Test Parts B and A), working memory (difference between Digit Span forward and backward from the Wechsler Adult Intelligence Scale-IV), and selective attention/response inhibition (difference between the second and third conditions of the color- and picture-word Stroop test). Gray matter volume was computed from brain MRIs and SIENAX from FSL software. Results: Gray matter volume was significantly associated with set-shifting performance after accounting for age, gender, body mass index, education, and global cognition (standardized β = -0.376, p = 0.001), but not with working memory or selective attention/response inhibition. Conclusion: The executive function of set-shifting ability was correlated with gray matter volume in older people with MCI.
The Effect of Aβ1-42 Oligomers on APP Processing and Aβ1-40 Generation in Cultured U-373 Astrocytes
Authors: Ourdev Dimitar , Foroutanpay Bahram V. , Wang Yanlin , Kar Satyabrata
Published: October 2015

Background: Amyloid-β (Aβ) peptides are a family of proteins that are considered to be a principal aspect of Alzheimer's disease (AD), the most common cause of senile dementia affecting elderly individuals. These peptides result from the proteolytic processing of amyloid precursor protein (APP) by sequential cleavage mediated via β- and γ-secretases. Evidence suggests that an overproduction and/or a lack of degradation may increase brain Aβ levels which, in turn, contribute to neuronal loss and development of AD. Objectives: In this study, we seek to determine what effect Aβ has on APP processing in cultured astrocytes. Methods: Using the human astrocytoma cell line U-373, we investigated the effects induced by oligomeric Aβ1-42 treatment on the cellular levels/expression of APP and its products, C-terminal fragments αCTF and βCTF, and Aβ1-40. In conjunction with these experiments, we examined the relative levels and activity of β- and γ-secretases in Aβ-treated astrocytes. Results: We report here that Aβ1-42 treatment of astrocytes increased the expression of APP and its cleaved products including Aβ1-40 in a time-dependent manner. Conclusions: These results suggest that activated astrocytes can contribute to the development of AD by enhancing levels and processing of APP leading to an increased production/secretion of Aβ-related peptides.
Epigenetics in Clinical Practice: Characterizing Patient and Provider Experiences with MTHFR Polymorphisms and Methylfolate
Authors: Oberg Erica , Givant Chris , Fisk Briana , Parikh Carina , Bradley Ryan
Published: October 2015

Background: Observational research associating 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms with risk of autism, depression, cancer, and cardiovascular disease has led to increased diagnoses of MTHFR; however, doctors lack knowledge about safety, effectiveness, and clinical implications of MTHFR treatment. Treatment strategies are hypothetical and mechanistically based, including methylfolate with or without other B vitamins. Aims: This study was designed to formally describe patient and health care provider experiences with the diagnosis and clinical management of MTHFR. Methods: Guided by a structured interview guide, a qualitative study queried patients' and providers' observations regarding: testing indications, reaction to results, treatment protocols, and clinical response including adverse effects. Results: Thirty patients and 8 doctors participated. Patient themes included emotionality associated with diagnosis, classification of signs and symptoms, and challenges with treatment. They expressed confusion over their diagnosis, and frustration with the state of knowledge their providers had regarding MTHFR. Testing indications included: fatigue (21%), hormone imbalances (13%), and neurological symptoms (13%) including brain fog (8%). Patients reported improvements in physical (60%) and mental/behavioral symptoms (36%) following treatment. A minority of participants reported side effects, but they occurred in almost every body system and ranged in severity. Doctors relied on trial and error to determine treatment doses, frequency and components. Conclusions: MTHFR testing results in variable clinical processes in domains related to delivery of diagnosis and prognosis, and therapeutic options. However, patients report largely positive experiences. Clinicians and patients would benefit from therapeutic algorithms based on rigorous research.
Cross-Cultural Adaptation, Validity and Reliability of the Arabic Version of the Falls Efficacy Scale-International (FES-I)
Authors: Halaweh Hadeel , Svantesson Ulla , Rosberg Susanne , Willen Carin
Published: October 2015

Objective: The aim of this study was to evaluate the validity and reliability of an Arabic language version (Ar) of the Falls Efficacy Scale-International (FES-I) with respect to its use with Arabic-speaking elderly subjects. Subjects and Methods: For cross-cultural adaptation, the translation of the original English version of the scale was conducted based on the protocol of the Prevention of Falls Network Europe (ProFaNE). The FES-I (Ar) was administered via face-to-face interviews to 108 community-dwelling elderly Palestinians (61 women and 47 men, aged 60-84 years). Statistical analyses were used to determine group differences with respect to age, gender and fall history. To assess validity, Spearman's rank correlation coefficient was used to examine the correlation between the total scores of FES-I (Ar) and the Timed Up and Go (TUG) test, gait speed and balance. Test-retest reliability between the two test occasions was assessed in accordance with Svensson's method. Results: The FES-I (Ar) total scores were positively correlated with TUG (rs = 0.641, p < 0.001) and negatively correlated with gait speed (rs = -0.670, p < 0.001) and balance (rs = -0.592, p < 0.001). All items of the FES-I (Ar) indicated a high percentage agreement (from 88 to 93%), and the relative position ranged from 0.01 to 0.06. Conclusion: In this study, the FES-I (Ar) was shown to be a comprehensible, valid and reliable measure of the concern about falling among community-dwelling elderly subjects. In clinical practice and future research, the FES-I (Ar) instrument could be used to effectively assess concern about falling in Arabic-speaking elderly persons.
Abnormal Left Ventricular Mechanics of Ventricular Ectopic Beats
Authors: Potfay Jonathan , Kaszala Karoly , Tan Alex Y. , Sima Adam P. , Gorcsan John , Ellenbogen Kenneth A. , Huizar Jose F.
Published: October 2015

Background—

Left ventricular (LV) dyssynchrony caused by premature ventricular contractions (PVCs) has been proposed as a mechanism of PVC-induced cardiomyopathy. We sought to understand the impact of different PVC locations and coupling intervals (prematurity) on LV regional mechanics and global function of the PVC beat itself.

Methods and Results—

Using our premature pacing algorithm, pentageminal PVCs at coupling intervals of 200 to 375 ms were delivered from the epicardial right ventricular apex, RV outflow tract, and LV free wall, as well as premature atrial contractions, from the left atrial appendage at a coupling interval of 200 ms in 7 healthy canines. LV short-axis echocardiographic images, LV stroke volume, and dP/dt
max
were obtained during all ectopic beats and ventricular pacing. LV dyssynchrony was assessed by dispersion of QRS-to-peak strain (earliest—last QRS-to-peak strain) between 6 different LV segments during each of the aforementioned beats (GE, EchoPac). LV dyssynchrony was greater during long-coupled rather than short-coupled PVCs and PVCs at 375 ms compared with rapid ventricular pacing at 400 ms (
P
<0.0001), whereas no difference was found between PVC locations. Longer PVC coupling intervals were associated with greater stroke volume and dP/dt
max
despite more pronounced dyssynchrony (
P
<0.001).

Conclusions—

PVCs with longer coupling intervals demonstrate more pronounced LV dyssynchrony, whereas PVC location has minimal impact. LV dyssynchrony cannot be attributed to prematurity or abnormal ventricular activation alone, but rather to a combination of both. This study suggests that late-coupled PVCs may cause a more severe cardiomyopathy if dyssynchrony is the leading mechanism responsible for PVC-induced cardiomyopathy.
Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart
Authors: Mohsin Sadia , Troupes Constantine D. , Starosta Timothy , Sharp Thomas E. , Agra Elorm J. , Smith Shavonn , Duran Jason M. , Zalavadia Neil , Zhou Yan , Kubo Hajime , Berretta Remus M. , Houser Steven R.
Published: October 2015

Rationale:

Adoptive transfer of multiple stem cell types has only had modest effects on the structure and function of failing human hearts. Despite increasing the use of stem cell therapies, consensus on the optimal stem cell type is not adequately defined. The modest cardiac repair and functional improvement in patients with cardiac disease warrants identification of a novel stem cell population that possesses properties that induce a more substantial improvement in patients with heart failure.

Objective:

To characterize and compare surface marker expression, proliferation, survival, migration, and differentiation capacity of cortical bone stem cells (CBSCs) relative to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs), which have already been tested in early stage clinical trials.

Methods and Results:

CBSCs, MSCs, and CDCs were isolated from Gottingen miniswine or transgenic C57/BL6 mice expressing enhanced green fluorescent protein and were expanded in vitro. CBSCs possess a unique surface marker profile, including high expression of CD61 and integrin β4 versus CDCs and MSCs. In addition, CBSCs were morphologically distinct and showed enhanced proliferation capacity versus CDCs and MSCs. CBSCs had significantly better survival after exposure to an apoptotic stimuli when compared with MSCs. ATP and histamine induced a transient increase of intracellular Ca
2+
concentration in CBSCs versus CDCs and MSCs, which either respond to ATP or histamine only further documenting the differences between the 3 cell types.

Conclusions:

CBSCs are unique from CDCs and MSCs and possess enhanced proliferative, survival, and lineage commitment capacity that could account for the enhanced protective effects after cardiac injury.
Summary of Evidence on Early Carotid Intervention for Recently Symptomatic Stenosis Based on Meta-Analysis of Current Risks
Authors: De Rango Paola , Brown Martin M. , Chaturvedi Seemant , Howard Virginia J. , Jovin Tudor , Mazya Michael V. , Paciaroni Maurizio , Manzone Alessandra , Farchioni Luca , Caso Valeria
Published: October 2015

Background and Purpose—

This study aimed to assess the evidence on the periprocedural (<30 days) risks of carotid intervention in relation to timing of procedure in patients with recently symptomatic carotid stenosis.

Methods—

A systematic literature review of studies published in the past 8 years reporting periprocedural stroke/death after carotid endarterectomy (CEA) and carotid stenting (CAS) related to the time between qualifying neurological symptoms and intervention was performed. Pooled estimates of periprocedural risk for patients treated within 0 to 48 hours, 0 to 7 days, and 0 to 15 days were derived with proportional meta-analyses and reported separately for patients with stroke and transient ischemic attack as index events.

Results—

Of 47 studies included, 35 were on CEA, 7 on CAS, and 5 included both procedures. The pooled risk of periprocedural stroke was 3.4% (95% confidence interval [CI], 2.6–4.3) after CEA and 4.8% (95% CI, 2.5–7.8) after CAS performed <15 days; stroke/death rates were 3.8% and 6.9% after CEA and CAS, respectively. Pooled periprocedural stroke risk was 3.3% (95% CI, 2.1–4.6) after CEA and 4.8% (95% CI, 2.5–7.8) after CAS when performed within 0 to 7 days. In hyperacute surgery (<48 hours), periprocedural stroke risk after CEA was 5.3% (95% CI, 2.8–8.4) but with relevant risk differences among patients treated after transient ischemic attack (2.7%; 95% CI, 0.5–6.9) or stroke (8.0%; 95% CI, 4.6–12.2) as index.

Conclusions—

CEA within 15 days from stroke/transient ischemic attack can be performed with periprocedural stroke risk <3.5%. CAS within the same period may carry a stroke risk of 4.8%. Similar periprocedural risks occur after CEA and CAS performed earlier, within 0 to 7 days. Carotid revascularization can be safely performed within the first week (0–7 days) after symptom onset.
Parallel Computation in Word Formation
Authors: López Luis
Published: October 2015

Taking the Distributed Morphology model as a starting point, this article presents and develops the hypothesis that parallel computations drive some word formation processes. Along the way, some Distributed Morphology assumptions, particularly those concerning contextual allomorphy, are revised. It is argued that event structure is a syntactic head independent of the presence of a vP. Nominalizations in Spanish, which often exhibit verbal thematic vowels between the root and the nominalizing affix, turn out to be an ideal testing ground for theoretical hypotheses.
In Support of the PHAVE Analysis of the Double Object Construction
Authors: Harley Heidi , Jung Hyun Kyoung
Published: October 2015

Pylkkänen ( 2002 , 2008 ) and Bruening (2010a) present several arguments against the ‘‘small clause’’ approach to the double object construction in English, building on the predictions that that proposal makes with respect to the transfer-of-possession entailment, Goal-oriented depictives, nominalizations, subextraction, quantifier scope, and idioms. We argue that the small clause analysis proposed by Harley ( 1995 , 2002 ) in fact makes correct predictions in all these cases. In addition, we point out the existence of previously overlooked parallels between double object structures and have-sentences with respect to depictives, eventive DP complements, and quantifier scope. This motivates an analysis that links these different behaviors to the properties of a single PHAVE element common to both.
Church and Christ in the Work of Stanley Hauerwas
Authors: Lorrimar Victoria
Published: October 2015

Stanley Hauerwas has attracted much criticism for his ecclesiocentric approach to theology. As a result of his emphasis on the faithful practice of virtues in community for salvation, he has been accused of Pelagianism. He has also been charged with showing interest in Jesus primarily as an exemplar, rather than for himself. The adequacy of Hauerwas’ ecclesiology is tested here against its implications for Christology. Hauerwas conceives of Jesus primarily as the autobasileia, and emphasises the importance of his entire life and teachings in addition to his death and resurrection. Two questions concerning Hauerwas’ Christology are explored: (1) What did Christ achieve at the cross? (2) What constitutes salvation and how is it mediated to ensuing generations? This paper examines whether the church does indeed usurp the place of Christ in salvation in Hauerwas’ thought, as suggested by Healy.
Splanchnonema-like species in Pleosporales: introducing Pseudosplanchnonema gen. nov. in Massarinaceae
Authors: Chethana Thilini , Liu Mei , Ariyawansa Hiran A. , Konta Sirinapa , Wanasinghe Dhanushka N. , Zhou Ying , Yan Jiye , Camporesi Erio , Bulgakov Timur S. , Chukeatirote Ekachai , Hyde Kevin D. , Bahkali Ali H. , Liu Jianhua , Li Xinghong
Published: October 2015

In this paper we introduce a new genus Pseudosplanchnonema with P. phorcioides comb. nov., isolated from dead branches of Acer campestre and Morus species. The new genus is confirmed based on morphology and phylogenetic analyses of sequence data. Phylogenetic analyses based on combined LSU and SSU sequence data showed that P. phorcioides formed a distinct clade within the family Massarinaceae and is sister to Massarina eburnea, the type species of Massarina. The new genus Pseudosplanchnonema differs from Massarina in having ascomata without clypei, a thick peridium and larger, 1-septate, guttulate, dark brown ascospores. The new genus is compared with genera in the family Massarinaceae and a detailed description and illustrations of the species P. phorcioides, including its asexual morph, is provided.
Seed morphology of Boschniakia sensu lato (Orobanchaceae) and its taxonomical implications
Authors: Piwowarczyk Renata
Published: October 2015

Seeds of 25 samples of 4 species of the holoparasitic genus Boschniakia sensu lato were investigated using light and scanning electron microscopy. Previous phylogenetic and morphological evidence indicated the division of Boschniakia s.l. into three genera: Boschniakia, Kopsiopsis, and Xylanche. However, results of the recent phylogenetic analysis are that Kopsiopsis hookeri and K. strobilacea are sister taxa in one lineage and Boschniakia himalaica and B. rossica are sister taxa in a different lineage. Differences in seed size and sculpture can be very auxiliaries in determining the taxonomic position of these species. In this study, analysis of the morphology of seeds showed the presence of three types of seed. The most significant is differences between the distinct type of seed B. rossica and B. himalaica. The usefulness of micromorphological studies on seeds is demonstrated. A comparison of the main characteristics distinguishing the seeds of Boschniakia s.l. is also presented and discussed.
Relationship Between Pain and CEAP C Categories of Chronic Venous Disease
Authors: Radak D. J. , Tanaskovic S. Z. , Vlajinac H. D. , Marinkovic J. M. , Maksimovic M. Z.
Published: October 2015

In this study, we investigated whether the occurrence and intensity of leg pain are related to C class of the clinical, etiological, anatomical, and pathophysiological (CEAP) classification for chronic venous disease (CVeD). This cross-sectional study, conducted in Serbia, included 2841 patients: 2027 (71.3%) women and 814 (28.7%) men with CVeD diagnosed by general practitioners. For the first time, the Numeric Rating Scale of 0 to 5 units was used to assess the intensity of pain. For the analysis, univariate and multivariate logistic and linear regressions were applied. Pain in the legs was reported by 90.5% of the patients. The occurrence of pain significantly ( P < .001) increased with increasing C class. Of the patients who reported pain in the legs, 42.0% had moderate pain, 23.7% had moderate to severe pain, 22.8% had light pain, 11.2% had severe pain, and 0.3% had very severe pain. Severity of pain differed significantly ( P < .001) according to C class. Light and moderate pain gradually decreased and severe pain gradually increased from C0 to C6 class. These associations remained significant after adjustment for age, body mass index, and family history of CVeD.
The Roles of Power, Passing, and Surface Acting in the Workplace Relationships of Female Leaders With Disability
Authors: Boucher Carlene
Published: October 2015

This article describes how female managers with physical impairment negotiate their relationships in the workplace. It locates discussion of physical impairment and disability within an Interactional Model of Disability. Drawing on 20 interviews, this research identifies the factors that are central to the experience of female managers with disability in the workplace, including power, passing, and surface acting. When dealing with others who had power over them (such as their superiors), the leaders adopted approaches such as passing, in an attempt to minimize the visibility of both their impairment and their disability. This involved the leaders using surface acting to present an optimistic demeanor even when their actual feelings were very different. It will be argued that the use of surface acting and the reliance on passing begins to explain why people with disability are invisible in the workplace leadership literature and why this is damaging to diversity agendas in organizations.