bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiopoietin-like protein 4 and cardiovascular function in COPD
Authors: Waschki B , Kirsten AM , Holz O , Meyer T , Lichtinghagen R , Rabe KF , Magnussen H , Welte T , Watz H , Janciauskiene S 
Published: November 2016

IntroductionThe coexistence of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) is frequent and might be inter-related through inflammation-related processes reflected by specific markers. Here, we studied angiopoietin-like protein 4 (ANGPTL4), an upcoming cardiovascular marker, in stable COPD, and its relationship to cardiovascular function with respect to well-known CVD risk factors.MethodsIn a prospective COPD cohort study, we investigated serum ANGPTL4 levels, vascular status (ankle–brachial index (ABI)) and cardiac function (N-terminal pro-B-type natriuretic peptide (NT-proBNP)) as well as airflow limitation, objectively measured physical activity, the metabolic syndrome, high-sensitive C reactive protein (hs-CRP) and other CVD risk factors at 2 time points. We initially studied 74 stable COPD patients and 18 controls. For internal validation, we additionally studied 160 COPD patients of a former visit.ResultsANGPTL4 was significantly elevated in COPD patients compared with controls (p=0.026). After correction for traditional CVD risk factors, including hs-CRP, higher levels of ANGPTL4 were independently associated with lower ABI (p=0.023) and higher NT-proBNP (p<0.001). These findings were confirmed in the internal validation analysis, which included echocardiographic assessments.ConclusionsSerum ANGPTL4 is independently associated with cardiovascular function in COPD and might qualify as a biomarker reflecting a pathogenic link between COPD and CVD.
Research priorities of international sporting federations and the IOC research centres
Authors: Finch Caroline F , Talpey Scott , Bradshaw Ashley , Soligard Torbjorn , Engebretsen Lars 
Published: November 2016

Background/aimTo be fully effective, the prevention of injury in sport and promotion of athlete's health needs to be both targeted and underpinned by scientific evidence. This study aimed to identify the research priorities of International Sporting Federation (ISFs) compared to the current research focus of the International Olympic Committee Research Centres (IOC-RCs).MethodsOnline survey of ISF Medical Chairpersons (n=22, 69% response) and IOC-RC Directors (n=7, 78% response). Open-ended responses relating to injury/illness priorities and specific athlete targets were thematically coded. Ratings were given of the need for different research types according to the Translating Research into Injury Prevention Practice (TRIPP) Framework stages. Results are presented as the frequency of ISFs and IOC-RCs separately.ResultsBoth ISFs and IOC-RFs prioritised research into concussion (27%, 72%, respectively), competitive overuse (23%, 43%) and youth (41%, 43%). The ISFs also ranked catastrophic injuries (14%), environmental factors (18%), elite athletes (18%) and Paralympic athletes (14%) as important. The IOC-RCs gave higher priority to preventing respiratory illness (43%), long-term health consequences of injury (43%) and recreational athletes (43%). There was a trend towards ISFs valuing TRIPP stage 5/6 research more highly and for the IOC-RCs to value TRIPP stage 1/2 research.ConclusionsThere are clear opportunities to better link the priorities and actions of the ISFs and IOC-RCs, to ensure more effective practice-policy-research partnerships for the benefit of all athletes. Setting a mutually-agreed research agenda will require further active engagement between researchers and broader ISF representatives.
EGFL6 Regulates the Asymmetric Division, Maintenance, and Metastasis of ALDH+ Ovarian Cancer Cells
Authors: Bai Shoumei , Ingram Patrick , Chen Yu-Chih , Deng Ning , Pearson Alex , Niknafs Yashar S. , O'Hayer Patrick , Wang Yun , Zhang Zhong-Yin , Boscolo Elisa , Bischoff Joyce , Yoon Euisik , Buckanovich Ronald J. 
Published: November 2016

Abstract
Little is known about the factors that regulate the asymmetric division of cancer stem–like cells (CSC). Here, we demonstrate that EGFL6, a stem cell regulatory factor expressed in ovarian tumor cells and vasculature, regulates ALDH+ ovarian CSC. EGFL6 signaled at least in part via the oncoprotein SHP2 with concomitant activation of ERK. EGFL6 signaling promoted the migration and asymmetric division of ALDH+ ovarian CSC. As such, EGFL6 increased not only tumor growth but also metastasis. Silencing of EGFL6 or SHP2 limited numbers of ALDH+ cells and reduced tumor growth, supporting a critical role for EGFL6/SHP2 in ALDH+ cell maintenance. Notably, systemic administration of an EGFL6-neutralizing antibody we generated restricted tumor growth and metastasis, specifically blocking ovarian cancer cell recruitment to the ovary. Together, our results offer a preclinical proof of concept for EGFL6 as a novel therapeutic target for the treatment of ovarian cancer. Cancer Res; 76(21); 6396–409. ©2016 AACR.
Chemotherapy, Genetic Susceptibility, and Risk of Venous Thromboembolism in Breast Cancer Patients
Authors: Brand Judith S. , Hedayati Elham , Humphreys Keith , Ludvigsson Jonas F. , Johansson Anna L.V. , Bergh Jonas , Hall Per , Czene Kamila 
Published: November 2016

Abstract
Purpose: Venous thromboembolism (VTE) is highly heritable and a serious complication of cancer and its treatment. We examined the individual and joint effects of chemotherapy and genetic susceptibility on VTE risk in patients with breast cancer.
Experimental Design: A Swedish population-based study including 4,261 women diagnosed with primary invasive breast cancer between 2001 and 2008 in Stockholm, followed until 2012. Risk stratification by chemotherapy and genetic susceptibility [a polygenic risk score (PRS), including nine established VTE loci] was assessed using Kaplan–Meier and flexible parametric survival analyses, adjusting for patient, tumor, and treatment characteristics.
Results: In total, 276 patients experienced a VTE event during a median follow-up of 7.6 years. Patients receiving chemotherapy [HR (95% CI) = 1.98; 1.40–2.80] and patients in the highest 5% of the PRS [HR (95% CI) = 1.90; 1.24–2.91] were at increased risk of developing VTE. Chemotherapy and PRS acted independently on VTE risk and the 1-year cumulative incidence in patients carrying both risk factors was 9.5% compared with 1.3% in patients not having these risk factors (P &lt; 0.001). Stratified analyses by age showed that the risk-increasing effect of PRS was stronger in older patients (P interaction = 0.04), resulting in an excess risk among genetically susceptible patients receiving chemotherapy aged ≥ 60 years (1-year cumulative incidence = 25.0%).
Conclusions: Risk stratification by chemotherapy and genetic susceptibility identifies patients with breast cancer at high VTE risk, who could potentially benefit from thromboprophylaxis. Our results further suggest that genetic testing is more informative in older patients with breast cancer. Clin Cancer Res; 22(21); 5249–55. ©2016 AACR.
Simultaneous In Vivo Fluorescent Markers for Perfusion, Protoporphyrin Metabolism, and EGFR Expression for Optically Guided Identification of Orthotopic Glioma
Authors: Elliott Jonathan T. , Marra Kayla , Evans Linton T. , Davis Scott C. , Samkoe Kimberley S. , Feldwisch Joachim , Paulsen Keith D. , Roberts David W. , Pogue Brian W. 
Published: November 2016

Abstract
Purpose: While extent of tumor resection is an important predictor of outcome in glioma, margin delineation remains challenging due to lack of inherent contrast between tumor and normal parenchyma. Fluorescence-guided surgery is promising for its ability to enhance contrast through exogenous fluorophores; however, the specificity and sensitivity of the underlying contrast mechanism and tumor delivery and uptake vary widely across approved and emerging agents.
Experimental Design: Rats with orthotopic F98 wild-type and F98 EGFR-positive (EGFR+) gliomas received in vivo administration of IRDye680RD, 5-aminioleuvulinic acid, and ABY-029—markers of perfusion, protoporphyrin metabolism, and EGFR expression, respectively. Ex vivo imaging demonstrates the contrast mechanism–dependent spatial heterogeneity and enables within-animal comparisons of tumor-to-background ratio (TBR).
Results: Generally, ABY-029 outperformed PpIX in F98EGFR orthotopic tumor margins and core (50% and 60% higher TBR, respectively). PpIX outperformed ABY-029 in F98wt margins by 60% but provided equivalent contrast in the bulk tumor. IRDye680RD provided little contrast, having an average TBR of 1.7 ± 0.2. The unique spatial patterns of each agent were combined into a single metric, the multimechanistic fluorescence-contrast index (MFCI). ABY-029 performed best in EGFR+ tumors (91% accuracy), while PpIX performed best in wild-type tumors (87% accuracy). Across all groups, ABY-029 and PpIX performed similarly (80% and 84%, respectively) but MFCI was 91% accurate, supporting multiagent imaging when tumor genotype was unknown.
Conclusions: Human use of ABY-029 for glioma resection should enhance excision of EGFR+ tumors and could be incorporated into current PpIX strategies to further enhance treatment in the general glioma case. Clin Cancer Res; 23(9); 2203–12. ©2016 AACR.
Abstract A022: Computational pipeline for a personalized genomic vaccine trial
Authors: Rubinsteyn Alexander , Hodes Isaac , O'Donnell Timothy , Mondet Sebastien F. , Finnigan John P. , Friedlander Philip , Sabado Rachel , Bhardwaj Nina , Hammerbacher Jeffrey 
Published: November 2016

Abstract
PGV-001 (Personalized Genomic Vaccine) is a Phase I clinical trial at Mount Sinai testing the safety, feasibility, and immunogenicity of a neoantigen + Poly-ICLC vaccine derived from exome and RNA sequencing [1]. The personalized component of the vaccine consists of ten peptides (25 amino acids in length) predicted to contain highly expressed mutated cytotoxic T-cell epitopes. Selecting peptides for each patient requires a number of standard bioinformatics tasks such as somatic variant calling, sequence-based HLA typing, and class I peptide-MHC binding prediction, as well as new methods to determine the coding sequence for each identified mutation, quantify the RNA support for each variant allele, and scoring each vaccine peptide. We present the overall design of PGV, its implementation as an open source computational pipeline, and several independently useful libraries that implement aspects of mutant epitope prediction.
One of the unique characteristics of the PGV pipeline is that the amino acid sequence of a candidate vaccine peptide is determined from RNA reads overlapping a variant [2]. Consequently, variants which lack any evidence in RNA cannot be used in PGV. Determining a coding sequence from RNA allows us to capture atypical splicing around a mutation as well as phase somatic variants with nearby germline variants. Once a mutant coding sequence is established, candidate vaccine peptides are ranked by combining their predicted Class I MHC binding affinity with allele-specific expression [3]. We demonstrate the impact of different ranking criteria on vaccine efficacy using a tumor mouse model.
Execution and dependency management of the PGV pipeline is orchestrated using a a novel workflow engine [4, 5] which allows us to run complex tools across many machines with fault tolerance and reproducibility. The pipeline can be run on single machines, local clusters, or on public infrastructure using the Google Cloud Platform. We hope that by making the PGV pipeline and its underlying components available as open source software we can facilitate faster experimentation in the design of personalized cancer vaccines.
[1] https://clinicaltrials.gov/ct2/show/NCT02721043
[2] https://github.com/hammerlab/isovar
[3] https://github.com/hammerlab/vaxrank
[4] https://github.com/hammerlab/ketrew
[5] https://github.com/hammerlab/biokepi
Citation Format: Alexander Rubinsteyn, Isaac Hodes, Timothy O'Donnell, Sebastien F. Mondet, John P. Finnigan, Philip Friedlander, Rachel Sabado, Nina Bhardwaj, Jeffrey Hammerbacher. Computational pipeline for a personalized genomic vaccine trial [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A022.
Abstract A029: A vaccine-induced, antigen-specific TH9 immune response blocks tumor cell engraftment
Authors: Abdul-Wahid Aws , Prodeus Aaron , Cydzik Marzena , Alwash Mays , Gariepy Jean 
Published: November 2016

Abstract
Metastatic cancer remains the main cause of cancer-related mortality. Therapies are needed to address this significant unmet medical need. The implantation of cancer cells resulting in metastatic foci is the consequence of a multistep process that is seldom diagnosed or targeted for therapeutic intervention. In light of its adhesive properties and deregulated overexpression by cancer cells, the carcinoembryonic antigen (CEA) has been identified as a molecular determinant linked to cellular events defining the metastatic cascade including their attachment to the ECM and to the formation of micrometastases. Herein, we report that a vaccination strategy yielding an antigen-specific TH9 response induces long term host surveillance and prevents the engraftment of circulating cancer cells. Specifically, we show that vaccination with a recombinant CEA IgV-like N domain, formulated with the TLR3 ligand poly I:C, elicits a CEA-specific TH9 response, wherein IL-9 secreting TH cells act in concert with CEA N domain-specific antibodies as well as activated mast cells in preventing tumor cell engraftment. Vaccine-imparted protection was reversed upon depleting CD3+ T cells, neutralizing serum IL-9, pharmacologically stabilizing or by depleting of CD117+ mast cells, in vivo. The development of this immune response was dependent on TLR3, since interference with the TLR3-dsRNA complex formation led to a reduction in vaccine-imparted protection and a shift in the resulting immune response toward a TH2 response. These results highlight the first instance of a vaccine induced tumor antigen-specific TH9 immune response and points to the existence of an alternate tumor eradication mechanism that may be exploited for developing anti-metastasic immunotherapies. (Supported by OCIR-IPDC,CBCF and CIHR)
Citation Format: Aws Abdul-Wahid, Aaron Prodeus, Marzena Cydzik, Mays Alwash, Jean Gariepy. A vaccine-induced, antigen-specific TH9 immune response blocks tumor cell engraftment [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A029.
Abstract A030: Development of acid responsive microparticles for cytotoxic T-lymphocyte based antitumor immunotherapy
Authors: Huang Xuefei , Kavunja Herbert , Lang Shuyao , Sungsuwan Suttipun , Yin Zhaojun 
Published: November 2016

Abstract
Cytotoxic T lymphocytes (CTL) can have remarkable abilities to kill tumor cells. However, the establishment of successful CTL based anticancer therapy has met many challenges, which include 1) difficulties in generating highly functional CTLs targeting endogenous tumor associated CTL epitopes; 2) the existence of antigen-loss variant subpopulation within cancer cells, which fail to express the targeted antigen and can escape the immune pressure bestowed by the specific CTLs; and 3) the reduced expression of major histocompatibility complex class I (MHC-I) molecules on tumor cells due to immune editing. To address these difficulties, a new approach is developed to deliver foreign high affinity CTL epitopes to tumor tissues utilizing pH responsive “smart” microparticles (MPs). These MPs could encapsulate CTL peptide, release the peptide under acidic condition encountered in tumor tissues, and enhance CTL activation. Mice bearing existing solid tumor were administered intratumorally with MPs containing the CTL peptide, which showed 100% survival following the treatment. In contrast, all control mice died from tumor. Significant protection from tumor induced death was also observed with systemic administration of CTL peptide-MPs. The therapeutic efficacy can be attributed to enhanced delivery of the epitope to tumor tissues, presentation of the epitope by tumor cells as well as tumor stromal cells and/or generation of epitope specific CTLs by the peptide containing MPs. These findings offer a promising new direction for treating established solid tumor using CTL therapy.
Citation Format: Xuefei Huang, Herbert Kavunja, Shuyao Lang, Suttipun Sungsuwan, Zhaojun Yin. Development of acid responsive microparticles for cytotoxic T-lymphocyte based antitumor immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A030.
Abstract A060: The effects of tumor-associated calreticulin mutants on antigen presentation
Authors: Arshad Najla , Cresswell Peter 
Published: November 2016

Abstract
The phenomenon of antigen processing and presentation aids the immune system in distinguishing between normal and malignant cells. In cancer cells, Major Histocompatibility Complex (MHC) proteins present tumor- associated antigens (TAAs) that may serve as targets of immunotherapy. Antigen presentation by MHC class I-β2m heterodimers (MHC-I) requires peptide association to occur in in the ER. Binding is facilitated by the Peptide Loading Complex (PLC), which consists of the TAP transporter, tapasin, the thiol-oxidoreductase ERp57, and a lectin chaperone, calreticulin (CRT). CRT associates with MHC-I via the single, conserved, glycan present on MHC-I, drawing it into the PLC to facilitate peptide loading.
CRT is comprised of an N-terminal lectin domain, a proline-rich central P domain, and a negatively charged C-terminal domain (CTD) that is also contains an ER retention motif. Two recent studies report a mutant CRT associated with myeloproliferative neoplasms (MPNs). These MPNs carry a somatic frame-shift CRT mutation (CRTFS) that generates a novel CTD that lacks the ER-retention signal and renders it positively charged. Previous studies have shown that ablation of CRT expression in mouse embryonic fibroblast cells result in decreased surface expression of MHC-I, which is reversed on reconstitution of full-length CRT. Interestingly, reconstitution of CRT lacking the CTD did not restore MHC-I expression, indicating a role for the CTD in MHC-I expression. We therefore suspect that antigen presentation in MPNs carrying the CRTFS is altered.
To address the role of CRTFS in antigen presentation in a human cell line, we have generated a CRT knockout of HEK293T cells using CRISPR/Cas9 technology. The CRT−/− cells exhibit reduced surface levels of MHC-I. We used these calreticulin-deficient cells to generate stable cell lines expressing CRT or CRTFS. We find that expression of CRT restores surface MHC-I, but expression of CRTFS does not. We are currently assessing the reason behind the alterations in MHC-I expression in these cell lines using various biochemical techniques. Future experiments include analysis of the peptide repertoire displayed on the surface of these cells as well as changes in the molecular interactions of the mutant CRT with other members of the PLC. After a preliminary study in HEK293T cells, we will study the effect of CRTFS in antigen presentation in MPN cell lines to identify unique TAAs to facilitate the specific targeting of these cells by immunotherapy.
Citation Format: Najla Arshad, Peter Cresswell. The effects of tumor-associated calreticulin mutants on antigen presentation [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A060.
Abstract A070: The role of the centrosome in cytotoxic T cell function
Authors: Tamzalit Fella , Kepecs Ariella , Bazzi Hisham , Anderson Kathryn , Huse Morgan 
Published: November 2016

Abstract
Cytotoxic T lymphocytes (CTLs) are essential for productive immune responses and recent studies have demonstrated their strong clinical potential as immunotherapeutic agents against established tumors. Cytotoxic responses in CTLs are induced by the T cell receptor, which recognizes cognate peptide-major histocompatibility complex molecules on the surfaces of infected or transformed cells, which induces the formation the immunological synapse. Synapse formation is accompanied by a series of actin and microtubule remodeling events, the most striking of which is the dramatic reorientation of the centrosome to a position just beneath the center of the contact site. It has been proposed that lytic granules containing perforin and granzyme cluster around the centrosome in activated CTLs. This polarization toward the synapse promotes the selective fusion of these granules with the synaptic membrane, leading to directional release of their contents toward the target cell.
In order to study more precisely how the centrosome influences secretory responses and how these contributions affect CTL activity, we have developed an approach using OT-I mice bearing a conditional allele of both p53 (p53flox) as well as SAS4 (SAS4flox), a scaffolding protein that is absolutely required for the formation and maintenance of the centrosome. OT-I SAS4−/−p53−/− cells were generated by transducing SAS4flox/floxp53flox/flox cells with a retrovirus expressing Cre. Using gamma-tubulin and pericentrin staining, we were able to show that SAS4 deletion effectively eliminates interphase centrosomes in CTLs. OT-I SAS4−/− p53−/− cells exhibited a marked defect in target cell killing after 24h, implying a crucial role of the centrosome in cytotoxic responses. This killing defect was accompanied by a decrease in both granzyme B and perforin production. IFN-gamma production and secretion were not altered by the loss of the centrosome. Importantly, TCR induced signaling was normal in these cells.
In summary, we were able to show that centrosome deletion impairs target cell killing without altering their overall magnitude. Given the importance of centrosome polarization for lytic granules delivery, we can assume that the centrosome ablation selectively alters cytotoxic efficiency by disrupting the directional synaptic secretion.
Citation Format: Fella Tamzalit, Ariella Kepecs, Hisham Bazzi, Kathryn Anderson, Morgan Huse. The role of the centrosome in cytotoxic T cell function [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A070.