bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B21: Immune-based treatment of ovarian cancer in a mouse model with attenuated Toxoplasma gondii.
Authors: Fiering Steven , Baird Jason R. , Fox Barbara , Lizotte Patrick , Sanders Kiah , Conjeo-Garcia Jose , Bzik David 
Published: August 2014

Abstract
Ovarian cancer is generally diagnosed at stage 3 or 4 metastatic disease. The disease course of ovarian cancer is characterized by a remission period following surgery and chemotherapy, but the remission generally only lasts 1-2 years and the relapse is very difficult to treat, so the disease has very poor 5 year survival rates. Effective stimulation of an antitumor immune response during the remission period could eliminate occult metastatic disease and therefore developing immunotherapy approaches for ovarian cancer that can be applied during the remission period is of considerable interest. We have utilized the ID8 based ovarian cancer model in the form of the highly aggressive ID8/Vegf/Defb29 subline to test the ability of an attenuated strain of T. gondii (cps) to stimulate an anti-tumor immune response. We show that following establishment of the tumor by IP injection of tumor cells, introduction of cps into the peritoneal cavity significantly slows the development of the disease. cps predominantly invades immunosuppressive phagocytes in the tumor microenvironment and modifies these and newly recruited phagocytes to be immunostimulatory. The phagocytes are now much more efficient antigen processers and presenters, the immune system is freed from immunosuppression, and the antitumor immune response is activated. The treatment efficacy is associated with a large increase of tumor antigen-specific CD8 T cells and these T cells demonstrate antitumor activity in a transfer experiment and tumor challenge. cps is nontoxic, even in animals with no adaptive immune system, and is a fully attenuated but highly effective platform for developing cancer treatment vaccines. Further developed and applied, cps could be the basis for an autologous tumor vaccine approach that has the potential to improve ovarian cancer outcomes.
Citation Format: Steven Fiering, Jason R. Baird, Barbara Fox, Patrick Lizotte, Kiah Sanders, Jose Conjeo-Garcia, David Bzik. Immune-based treatment of ovarian cancer in a mouse model with attenuated Toxoplasma gondii. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B21.
Abstract B30: Cross-priming of CD8+ T cells is controlled by dipeptidyl peptidase 3 and thimet oligopeptidase 1 present in necrotic cells.
Authors: Gamrekelashvili Jaba , Kapanadze Tamar , Wissing Josef , Ma Chi , Jaensch Lothar , Korangy Firouzeh , Greten Tim F. 
Published: August 2014

Abstract
Cross-priming of CD8+ T cells and generation of effector immune responses is pivotal for tumor immunity, successful anticancer vaccination and therapy. We have discovered a novel molecular mechanism operating in antigen donor cells, which regulates cross-priming of CD8+ T cells during primary sterile necrosis and thereby controls adaptive immune responses. We show that cellular peptidases, dipeptidyl peptidase 3 (DPP-3) and thimet oligopeptidase 1 (TOP-1) present in non-immunogenic necrotic cells eliminate proteasomal degradation products and block antigen cross-presentation. While sterile necrotic tumor cells fail to induce CD8+ T cell responses, their non-immunogenicity can be reversed in vitro and in vivo by inactivation of peptidases, DPP-3 and TOP-1. Thus control of cross-priming and thereby immunogenicity of primary sterile necrosis relies on the proteasome dependent oligopeptide generation and functional status of peptidases in antigen donor cells.
Citation Format: Jaba Gamrekelashvili, Tamar Kapanadze, Josef Wissing, Chi Ma, Lothar Jaensch, Firouzeh Korangy, Tim F. Greten. Cross-priming of CD8+ T cells is controlled by dipeptidyl peptidase 3 and thimet oligopeptidase 1 present in necrotic cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B30.
Abstract IA13: Phase I trial of targeted therapy with PSA-TRICOM vaccine (V) and ipilimumab (ipi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Gulley James L. , Madan Ravi A. , Tsang Kwong Y. , Jochems Caroline , Dahut William L. , Schlom Jeffrey 
Published: August 2014

Abstract
Background: Immunotherapy is an emerging therapeutic option for mCRPC and has demonstrated improved survival. Immunologic combinations are a logical next step in the clinical development. PSA-TRICOM V, composed of poxviral vectors encoding PSA and 3 costimulatory molecules (ICAM-I, LFA-3, and B7.1), has shown evidence of clinical activity in mCRPC and is being tested in a phase III study (NCT01322490). Ipi, which blocks CTLA-4, a T-cell coinhibitory receptor, has clinical activity in mCRPC as monotherapy and has also been shown to enhance antitumor responses in combination with V in preclinical studies.
Methods: We completed a phase I dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipi in combination with a fixed dose of PSA-TRICOM V. Pts with mCRPC received vaccinia PSA-TRICOM subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of fowlpox PSA-TRICOM starting on day 15. Intravenous ipi was given monthly x 6 starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination.
Results: We completed enrollment with 30 pts (24 of whom were chemotherapy-naïve) and did not identify any dose-limiting toxicity. 21 pts had grade ≥ 2 immune-related adverse events, including diarrhea or colitis, rash, raised aminotransferases, endocrinopathy, and neutropenia. Only 1 of the 6 pts previously treated with chemotherapy had a PSA decline from baseline. Of the 24 pts who were chemotherapy-naïve, 14 (58%) had PSA declines from baseline, of which 6 were &gt; 50%. While the median predicted survival was about 18 months, based on a validated nomogram, actual median OS exceeded 34 months in this phase I study. A previous 32 pt study at the same institution of V alone in the same population (predicted survival 17.4 months) had an OS of 26.6 months.
Conclusions: The use of a V targeting PSA that also enhances costimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipi. There is a suggestion of clinical activity for the combination; however, randomized trials are needed to further assess clinical outcomes of the combination of ipi and V in mCRPC.
ClinicalTrials.gov registry number: NCT00113984
Ref: Madan et al., Lancet Oncology 2012.
Citation Format: James L. Gulley, Ravi A. Madan, Kwong Y. Tsang, Caroline Jochems, William L. Dahut, Jeffrey Schlom. Phase I trial of targeted therapy with PSA-TRICOM vaccine (V) and ipilimumab (ipi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA13.
Abstract IA25: Local immunomodulation at a single site of tumor generates a therapeutic immune response that cures metastatic disease at distant sites, including the brain.
Authors: Marabelle Aurelien , Kohrt Holbrook , Levy Ronald 
Published: August 2014

Abstract
TLR-9 ligand (CpG) injected directly into a tumor can induce a therapeutic immune response. However regulatory T-cells (Tregs) eventually inhibit the anti-tumor immune response and thereby limit the power of cancer immunotherapies. We found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intra-tumoral co-injection of anti-CTLA-4 and anti-OX40 together with CpG depletes tumor-infiltrating Tregs. This in situ immunomodulation performed with low doses of antibodies into a single tumor generates a systemic anti-tumor immune response able to eradicate disseminated disease in mice, including established CNS lymphoma with leptomeningeal metastases, sites usually considered as sanctuaries for conventional systemic therapies.
These results support a paradigm shift in cancer therapy where instead of using monoclonal antibodies to target cancer cells systemically, we use monoclonal antibodies at low doses to target the tumor infiltrative immune cells locally. The consequences of this strategy are the generation of a more potent anti-tumor immune response, and the expectation of less toxicity.
On the basis of our preclinical results we are now opening a Phase I/II clinical trial testing the combination of local low dose radiotherapy with escalating doses of Ibilumimab (anti-CTLA4). Patients with metastatic melanoma, colorectal cancer and lymphoma are eligible. The intention will be to find a safe dose of the antibody when injected locally together with radiotherapy and then to assess the patients for immune responses and for tumor responses at uninjected sites of disease.
Citation Format: Aurelien Marabelle, Holbrook Kohrt, Ronald Levy. Local immunomodulation at a single site of tumor generates a therapeutic immune response that cures metastatic disease at distant sites, including the brain. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA25.
Abstract PR12: Early TCRα expression during T cell development for the generation of enhanced-affinity TCRs for TCR gene therapy.
Authors: Schmitt Thomas M. , Greenberg Philip D. , Aggen David H. , Kranz David , Ochsenreither Sebastian 
Published: August 2014

Abstract
Thymic selection eliminates T cells expressing TCRs with a high affinity for self-antigen. However, many of the most promising tumor antigens for T cell-based cancer immunotherapies are unmodified self-antigens. Therefore, tumor-specific T cells often have a low avidity for tumor antigens, thus limiting the efficacy of this approach. TCR gene therapy using TCR genes that have been modified for increased affinity can overcome this limitation. The generation of enhanced affinity TCRs generally involves saturation mutagenesis targeting the complementarity determining regions of the TCR genes to be modified. However, this approach requires considerable trial and error, and is still not always successful at generating a higher affinity TCR without promiscuous off-target activity. We have developed a system for selecting high affinity tumor antigen-specific TCRs from a population of T cells selected by agonist signaling during T cell development in vitro.
The αβ/γδ lineage choice is in part dictated by the strength of TCR/pre-TCR signaling during early T cell development, such that the pre-TCR provides a weak signal that drives αβ T cell development while the mature γδ TCR provides a stronger signal that drives γδ T cell development. In TCR transgenic mice, early expression of the transgenic TCRα chain prior to β-selection can also provide a stronger γδ-like signal through the mature αβ TCR, leading to the development of lineage redirected TCRαβ+ CD4/CD8 double negative (DN) γδ wanna-be” cells. The development of these DN TCRαβ+ cells is enhanced in the presence of cognate antigen or TCR crosslinking; suggesting that early expression of an antigen-specific TCRα chain before β-selection could promote the generation of DN TCRαβ+ cells in the presence of antigen, through a process in which the introduced TCRα chain pairs with an endogenous TCRβ chain to produce an αβ TCR with high affinity for the target antigen. To test this hypothesis, the TCRα chain from a tumor antigen-specific TCR was transduced into hematopoietic progenitor cells and a library of TCRβ chains was isolated from the lineage redirected DN TCRαβ+ T cells that developed. Several TCRβchains of varying CDR3 lengths were isolated that confer enhanced affinity for the target antigen when paired with the introduced TCRα chain.
This abstract is also presented as Poster A13.
Citation Format: Thomas M. Schmitt, Philip D. Greenberg, David H. Aggen, David Kranz, Sebastian Ochsenreither. Early TCRα expression during T cell development for the generation of enhanced-affinity TCRs for TCR gene therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr PR12.
Abstract PR3: Myofibroblasts activated upon tissue injury and hypoxia promote development of castration-resistant prostate cancer.
Authors: Ammirante Massimo , Kang Youngjin , Karin Michael 
Published: August 2014

Abstract
Background: Prostate cancer (PCa) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration resistant (CR) metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent (AD) PCa, metastatic CR-PCa is a major complication with high mortality. Cancer associated fibroblasts (CAFs) are a heterogeneous cell population of the tumor microenvironment that play important enabling roles in cancer development and progression. The mechanism resonsible for myofibroblast activation within the tumor microenvironment are not entirely clear and can be cancer-specific and heterogeneous.
Methods: We used the Myc-CaP translpantable model of AD-PCa and the spontaneous mouse PCa model, TRAMP and we examinated how androgen ablation leads to induction of CXCL13 expression, which is critical for recruitment of B cells into tumor remnants and accellerate evolution of CR-PCa. We confirmed our data using human specimens of PCa.
Results: Following castration, many myofibroblasts were present within the tumors remnants, which expressed CXCL13. Ablation of myofibroblasts led to a marked reduction in the infiltration of T, B and dendritic cells into the tumor remnants after the castration, reduced the expression of several chemokines, including CXCL13 and also delayed the re-growth of CR-PCa.
We also found that androgen ablation led to increased expression of TGF-β in the tumor remnants. Inhibition of TGF-β signaling prevented activation of myofibroblasts, infiltration of B cells, induction of CXCL13 expressing myofibroblasts and also delayed the re-growth of CR-PCa. The main source of TGF-β in PCa tumors after castration appeared to be the fibroblast fraction.
After castration, hypoxic areas appeared along with nuclear translocation of HIF-1α. Exposure of inactivated fibroblasts isolated from PCa tumors of non-castrated mice under hypoxic condition induced the expression of CTGF and TGF-β, which was HIF-1α dependent, and converted the fibroblasts into myofibroblasts.
Conclusions: Our data show for the first time that androgen ablation led to hypoxia-induced myofibroblast activation, which is the cell type in the tumor stroma that recruits tumor-infiltrating B cells that allow the re-growth of CR-PCa through the production of lymphotoxin and IKKα nuclear translocation in the prostate epithelial cells.
This abstract is also presented as Poster A75.
Citation Format: Massimo Ammirante, Youngjin Kang, Michael Karin. Myofibroblasts activated upon tissue injury and hypoxia promote development of castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr PR3.
Cardiac Structure and Function and Prognosis in Heart Failure With Preserved Ejection Fraction
Authors: Shah Amil M. , Claggett Brian , Sweitzer Nancy K. , Shah Sanjiv J. , Anand Inder S. , O’Meara Eileen , Desai Akshay S. , Heitner John F. , Li Guichu , Fang James , Rouleau Jean , Zile Michael R. , Markov Valetin , Ryabov Vyacheslav , Reis Gilmar , Assmann Susan F. , McKinlay Sonja M. , Pitt Bertram , Pfeffer Marc A. , Solomon Scott D. 
Published: August 2014

Background—
Abnormalities in cardiac structure and function in heart failure with preserved ejection fraction may help identify patients at particularly high risk for cardiovascular morbidity and mortality.

Methods and Results—
Cardiac structure and function were assessed by echocardiography in a blinded core laboratory at baseline in 935 patients with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and related to the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest, and its components. At a median follow-up of 2.9 years, 244 patients experienced the primary outcome. Left ventricular hypertrophy (adjusted hazard ratio, 1.52; 95% confidence interval, 1.16–2.00), elevated left ventricular filling pressure (E/E′; adjusted hazard ratio 1.05 per 1 integer increase; 95% confidence interval, 1.02–1.07), and higher pulmonary artery pressure assessed by the tricuspid regurgitation velocity (hazard ratio, 1.23 per 0.5 m/s increase; 95% confidence interval, 1.02–1.49) were associated with the composite outcome and heart failure hospitalization alone after adjusting for clinical and laboratory variables. The risk of adverse outcome associated with left ventricular hypertrophy was additive to the risk associated with elevated E/E′.

Conclusions—
Among heart failure with preserved ejection fraction patients enrolled in TOPCAT, left ventricular hypertrophy, higher left ventricular filling pressure, and higher pulmonary artery pressure were predictive of heart failure hospitalization, cardiovascular death, or aborted cardiac arrest independent of clinical and laboratory predictors. These features, both alone and in combination, identify heart failure with preserved ejection fraction patients at particularly high risk for cardiovascular morbidity and mortality.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00094302.
The Origins of Vortex Sheets in a Simulated Supercell Thunderstorm
Authors: Markowski Paul , Richardson Yvette , Bryan George 
Published: August 2014

AbstractThis paper investigates the origins of the (cyclonic) vertical vorticity within vortex sheets that develop within a numerically simulated supercell in a nonrotating, horizontally homogeneous environment with a free-slip lower boundary. Vortex sheets are commonly observed along the gust fronts of supercell storms, particularly in the early stages of storm development. The “collapse” of a vortex sheet into a compact vortex is often seen to accompany the intensification of rotation that occasionally leads to tornadogenesis. The vortex sheets predominantly acquire their vertical vorticity from the tilting of horizontal vorticity that has been modified by horizontal buoyancy gradients associated with the supercell’s cool low-level outflow. If the tilting is within an ascending airstream (i.e., the horizontal gradient of vertical velocity responsible for the tilting resides entirely within an updraft), the vertical vorticity of the vortex sheet nearly vanishes at the lowest model level for horizontal winds (5 m). However, if the tilting occurs within a descending airstream (i.e., the horizontal gradient of vertical velocity responsible for tilting includes a downdraft adjacent to the updraft within which the majority of the cyclonic vorticity resides), the vortex sheet extends to the lowest model level. The findings are consistent with the large body of prior work that has found that downdrafts are necessary for the development of significant vertical vorticity at the surface.
Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma
Authors: Kummetha Venkata Jagadish , An Ningfei , Stuart Robert , Costa Luciano J. , Cai Houjian , Coker Woodrow , Song Jin H. , Gibbs Kiwana , Matson Terri , Garrett-Mayer Elizabeth , Wan Zhuang , Ogretmen Besim , Smith Charles , Kang Yubin 
Published: August 2014

Key Points
SK2 is overexpressed in myeloma cells and contributes to myeloma cell survival and proliferation. SK2-specific inhibitor promotes proteasome degradation of Mcl-1 and c-Myc and inhibits myeloma growth in vitro and in vivo.
Crust and uppermost mantle structure beneath central Japan inferred from receiver function analysis
Authors: Igarashi Toshihiro , Iidaka Takashi , Iwasaki Takaya , Shibutani Takuo , Ueno Tomotake ,   Japanese University Group of the Joint Seismic Observation at the Niigata-Kobe Tectonic Zone
Published: August 2014

AbstractWe apply the receiver function method to estimate the structure of the crust and the uppermost mantle at an area that traverses central Japan including the Niigata-Kobe Tectonic Zone (NKTZ). The resultant receiver function images show clear seismic discontinuities, such as the subducting Philippine Sea plate, the Moho in the overriding plate, and other discontinuities inside the crust around the NKTZ. We also address station corrections for shallow structures using a synthetic receiver function. Crustal discontinuities seem to be complicated at the south side from the northern limit of the NKTZ. The dip of the discontinuities changes around the Atotsugawa active fault located in the NKTZ. The Moho discontinuity in the overriding plate is continuous and gradually dips to the south. The depths of the Moho discontinuity in the receiver function image exceed 40 km at the southern part of the profile line, and are 5–10 km deeper than that indicated by an explosion analysis of the same profile line. It seems that the differences between the estimated depths obtained by the two methods indicate complicated structures around the Moho discontinuity.