bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccine-Instructed Intratumoral IFN-γ Enables Regression of Autochthonous Mouse Prostate Cancer in Allogeneic T-Cell Transplantation
Authors: Hess Michelini Rodrigo , Manzo Teresa , Sturmheit Tabea , Basso Veronica , Rocchi Martina , Freschi Massimo , Listopad Joanna , Blankenstein Thomas , Bellone Matteo , Mondino Anna 
Published: June 2013

Abstract
Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematologic malignancies, but the basis for this synergy is not understood to the degree where such approaches could be effective for treating solid tumors. We investigated this issue in a transgenic mouse model of prostate cancer treated by transplantation of a nonmyeloablative MHC-matched, single Y chromosome–encoded, or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here, we report that tumor-directed vaccination after allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion is essential for acute graft versus tumor responses, tumor regression, and prolonged survival. Vaccination proved essential for generation of CD8+ IFN-γ+ tumor-directed effector cells in secondary lymphoid organs and also for IFN-γ+ upregulation at the tumor site, which in turn instructed local expression of proinflammatory chemokines and intratumoral recruitment of donor-derived T cells for disease regression. Omitting vaccination, transplanting IFN-γ–deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-γ–driven inflammation and lymphocyte infiltration, abolishing antitumor responses and therapeutic efficacy of the combined approach. Our findings argue that posttransplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation. Cancer Res; 73(00); 4641–52. ©2013 AACR.
Proteomic and Lipidomic Signatures of Lipid Metabolism in NASH-Associated Hepatocellular Carcinoma
Authors: Muir Kyle , Hazim Antonious , He Ying , Peyressatre Marion , Kim Do-Young , Song Xiaoling , Beretta Laura 
Published: June 2013

Abstract
Nonalcoholic steatohepatitis (NASH) is a common preneoplastic condition of hepatocellular carcinoma (HCC). Mice with hepatocytic deletion of Pten develop NASH and HCC later in life. This model is highly valuable for studies aimed at identifying the molecular mechanism by which metabolic disorders contribute to tumor development. We applied proteomic and lipidomic profiling approaches to Pten-null NASH liver and tumors. Circulating fatty acid composition was also characterized in these mice. The relevance to human NASH and HCC was further validated. This integrative proteomic and lipidomic study from mouse to human and from liver to blood identified the following disease signatures: (i) an HCC signature: upregulated hepatic scd1/scd2, fads2, and acsl5:acsl1 ratio, elevated vaccenic and erucic acids, and reduced margaric and linoleic acids in both liver and plasma; (ii) a NASH signature that correlates with tumor burden: upregulated hepatic elovl6, elevated oleic, adrenic, and osbond acids, and reduced cervonic acid in liver and plasma; and (iii) a NASH signature: reduced hepatic and circulating lignoceric and eicosapentaenoic acids. Altogether, these results show the role of lipid-modifying enzymes converting saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA) in HCC and the importance of an increased ratio of long chain n6-polyunsaturated fatty acids over n3-polyunsaturated fatty acids in NASH and HCC risk. They also highlight the relevance of the Pten-null model for studies related to NASH and HCC and show that circulating lipid metabolome provides a direct read of lipid changes in the liver. Most importantly, novel candidate targets for HCC diagnosis, therapy, risk assessment, and prevention were identified. Cancer Res; 73(15); 4722–31. ©2013 AACR.
Peroxiredoxin-2 Represses Melanoma Metastasis by Increasing E-Cadherin/β-Catenin Complexes in Adherens Junctions
Authors: Lee Doo Jae , Kang Dong Hoon , Choi Mina , Choi Yang Ji , Lee Joo Young , Park Joo Hyun , Park Yoon Jung , Lee Kyung Wha , Kang Sang Won 
Published: June 2013

Abstract
In melanoma, transition to the vertical growth phase is the critical step in conversion to a deadly malignant disease. Here, we offer the first evidence that an antioxidant enzyme has a key role in this transition. We found that the antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the metastatic capacity of human melanoma cells. Silencing Prx2 expression stimulated proliferation and migration, whereas ectopic expression of Prx2 produced the opposite effect. Mechanistic investigations indicated that Prx2 negatively regulated Src/ERK activation status, which in turn fortified adherens junctions function by increasing E-cadherin expression and phospho-Y654–dependent retention of β-catenin in the plasma membrane. In murine melanoma cells, Prx2 silencing enhanced lung metastasis in vivo. Interestingly, the natural compound gliotoxin, which is known to exert a Prx-like activity, inhibited proliferation and migration as well as lung metastasis of Prx2-deficient melanoma cells. Overall, our findings reveal that Prx2 is a key regulator of invasion and metastasis in melanoma, and also suggest a pharmacologic strategy to effectively decrease deadly malignant forms of this disease. Cancer Res; 73(15); 4744–57. ©2013 AACR.
Intravital FLIM-FRET Imaging Reveals Dasatinib-Induced Spatial Control of Src in Pancreatic Cancer
Authors: Nobis Max , McGhee Ewan J. , Morton Jennifer P. , Schwarz Juliane P. , Karim Saadia A. , Quinn Jean , Edward Mike , Campbell Andrew D. , McGarry Lynn C. , Evans T.R. Jeffry , Brunton Valerie G. , Frame Margaret C. , Carragher Neil O. , Wang Yingxiao , Sansom Owen J. , Timpson Paul , Anderson Kurt I. 
Published: June 2013

Abstract
Cancer invasion and metastasis occur in a complex three-dimensional (3D) environment, with reciprocal feedback from the surrounding host tissue and vasculature-governing behavior. In this study, we used a novel intravital method that revealed spatiotemporal regulation of Src activity in response to the anti-invasive Src inhibitor dasatinib. A fluorescence lifetime imaging microscopy–fluorescence resonance energy transfer (FLIM-FRET) Src biosensor was used to monitor drug-targeting efficacy in a transgenic p53-mutant mouse model of pancreatic cancer. In contrast to conventional techniques, FLIM-FRET analysis allowed for accurate, time-dependent, live monitoring of drug efficacy and clearance in live tumors. In 3D organotypic cultures, we showed that a spatially distinct gradient of Src activity exists within invading tumor cells, governed by the depth of penetration into complex matrices. In parallel, this gradient was also found to exist within live tumors, where Src activity is enhanced at the invasive border relative to the tumor cortex. Upon treatment with dasatinib, we observed a switch in activity at the invasive borders, correlating with impaired metastatic capacity in vivo. Src regulation was governed by the proximity of cells to the host vasculature, as cells distal to the vasculature were regulated differentially in response to drug treatment compared with cells proximal to the vasculature. Overall, our results in live tumors revealed that a threshold of drug penetrance exists in vivo and that this can be used to map areas of poor drug-targeting efficiency within specific tumor microenvironments. We propose that using FLIM-FRET in this capacity could provide a useful preclinical tool in animal models before clinical translation. Cancer Res; 73(15); 4674–86. ©2013 AACR.
PanIN-Specific Regulation of Wnt Signaling by HIF2α during Early Pancreatic Tumorigenesis
Authors: Criscimanna Angela , Duan Li-Juan , Rhodes Julie A. , Fendrich Volker , Wickline Emily , Hartman Douglas J. , Monga Satdarshan P.S. , Lotze Michael T. , Gittes George K. , Fong Guo-Hua , Esni Farzad 
Published: June 2013

Abstract
Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2α is a potent oncogenic stimulus, but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate KrasG12D and delete Hif2α solely within the pancreas. Surprisingly, loss of Hif2α in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of β-catenin and SMAD4. The relationship among HIF2α, β-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2α resulted in reduced β-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and β-catenin. Cancer Res; 73(15); 4781–90. ©2013 AACR.
Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer
Authors: Kimple Randall J. , Smith Molly A. , Blitzer Grace C. , Torres Alexandra D. , Martin Joshua A. , Yang Robert Z. , Peet Chimera R. , Lorenz Laurel D. , Nickel Kwangok P. , Klingelhutz Aloysius J. , Lambert Paul F. , Harari Paul M. 
Published: June 2013

Abstract
Patients with human papillomavirus (HPV+)–associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV−) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV− HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV−: 0.59 vs. HPV+: 0.22; P &lt; 0.0001), corresponding with a prolonged G2–M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV− cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P &lt; 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV− HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome. Cancer Res; 73(15); 4791–800. ©2013 AACR.
Parkinson's Disease Genes Do Not Segregate with Breast Cancer Genes' Loci
Authors: Kravitz Efrat , Laitman Yael , Hassin-Baer Sharon , Inzelberg Rivka , Friedman Eitan 
Published: June 2013

Abstract
Background: Breast cancer and skin cancer rates among patients with Parkinson's disease are higher than in non-Parkinson's disease cases, and Jewish-Ashkenazi LRRK2*G2019S mutation carriers have higher breast cancer rates than noncarriers. Because additional Parkinson's disease predisposition genes are implicated in the malignant transformation process, we hypothesized that the association between breast cancer and Parkinson's disease may be related to segregation of breast cancer loci with known Parkinson's disease predisposition loci.
Methods: Data mining for single-nucleotide polymorphisms (SNP), reportedly associated with breast cancer in genome-wide association study (GWAS) that localize to chromosomes bearing known Parkinson's disease predisposition loci: PARK7, PINK1 (chromosome 1); SNCA (chromosome 4); PARK2 (chromosome 6); and LRRK2 (chromosome 12), was carried out.
Results: A total of 188 breast cancer–associated SNPs were identified in 29 eligible manuscripts: 43 SNPs on chromosome 1 (PINK1), 46 SNPs on chromosome 4 (SNCA), 72 SNPs on chromosome 6 (PARK2), and 27 SNPs on chromosome 12 (LRRK2). No breast cancer–associated SNP was located at distance less than 500,000 bp from any of the analyzed Parkinson's disease predisposition genes.
Conclusions: The association between breast cancer and the most common genetic-inherited forms of Parkinson's disease cannot be accounted for by allele cosegregation at the genomic level.
Impact: To elucidate the association between Parkinson's disease and breast cancer, a comprehensive approach that spans beyond a simple genetic association is required. Cancer Epidemiol Biomarkers Prev; 22(8); 1464–72. ©2013 AACR.
Risk Scores of Common Genetic Variants for Lipid Levels Influence Atherosclerosis and Incident Coronary Heart Disease
Authors: Isaacs Aaron , Willems Sara M. , Bos Daniel , Dehghan Abbas , Hofman Albert , Ikram M. Arfan , Uitterlinden André G. , Oostra Ben A. , Franco Oscar H. , Witteman Jacqueline C. , van Duijn Cornelia M. 
Published: June 2013

Objective—
Circulating levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides are recognized risk factors for cardiovascular disease. We tested the hypothesis that the cumulative effects of common genetic variants for lipids are collectively associated with subclinical atherosclerosis and incident coronary heart disease.

Approach and Results—

Participants were drawn from the Erasmus Rucphen Family Study (n=2269) and the Rotterdam Study (n=8130). Linear regression and Cox proportional hazards models were applied to assess the influence of 4 risk scores derived from common genetic variants for lipids (total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglycerides) on carotid plaque, intima-media thickness, incident myocardial infarction, and coronary heart disease. Adjusted for age and sex, all 4 risk scores were associated with carotid plaque. This relationship was the strongest for the LDL-C score, which increased plaque score by 0.102 per SD increase in genetic risk score (
P
=3.2×10
−8
). The LDL-C score was also nominally associated with intima-media thickness, which increased 0.006 mm per SD increase in score (
P
=0.05). Both the total cholesterol and LDL-C scores were associated with incident myocardial infarction and coronary heart disease with hazard ratios between 1.10 and 1.13 per SD increase in score. Inclusion of additional risk factors as covariates minimally affected these results.

Conclusions—
Common genetic variants with small effects on lipid levels are, in combination, significantly associated with subclinical and clinical cardiovascular outcomes. As knowledge of genetic variation increases, preclinical genetic screening tools might enhance the prediction and prevention of clinical events.
Infant Ventricular Fibrillation After ST-Segment Changes and QRS Widening
Authors: Miyake Christina Y. , Davis Andrew M. , Motonaga Kara S. , Dubin Anne M. , Berul Charles I. , Cecchin Frank 
Published: June 2013

Background—
Ventricular arrhythmia–related sudden cardiac arrest in infants with structurally normal hearts is rare. There have been no previously published reports of infants <3 months of age with ventricular fibrillation in which a primary diagnosis could not be defined.

Methods and Results—
Retrospective chart review of 3 unrelated infants <2 months of age from 3 different tertiary care centers within the United States and Australia was conducted. All 3 infants survived sudden cardiac arrest secondary to multiple episodes of polymorphic ventricular tachycardia and ventricular fibrillation. Each infant demonstrated unique and transient ECG findings consisting of ST changes and QRS widening before arrhythmia onset, which have not been previously reported. Amiodarone, sedation, sodium channel–blocking agents, and ventricular pacing were effective in suppressing acute events. Despite thorough investigation, including genetic testing, the cause of ventricular arrhythmias in each of these infants remains unclear.

Conclusions—
This is the first report of idiopathic ventricular fibrillation in young infants preceded by stereotypical transient ECG changes. These findings may represent a new, potentially treatable cause of sudden infant death. Recognition of these prodromal changes may be important in future management and survival of these infants.
FGF23 Modifies the Relationship Between Vitamin D and Cardiac Remodeling
Authors: Ky Bonnie , Shults Justine , Keane Martin G. , Sutton Martin St. John , Wolf Myles , Feldman Harold I. , Reese Peter P. , Anderson Cheryl A. , Townsend Raymond R. , Deo Rajat , Lo Joan , Gadegbeku Crystal , Carlow Dean , Sulik Michael J. , Leonard Mary B. 
Published: June 2013

Background—
There is growing evidence to support an important role for vitamin D and related hormones, parathyroid hormone and fibroblast growth factor 23 (FGF23), on cardiac remodeling in chronic kidney disease. Our objective was to determine the relationships between vitamin D and cardiac remodeling in chronic kidney disease and the effects of parathyroid hormone and FGF23 on these associations.

Methods and Results—

In 1431 participants from the Chronic Renal Insufficiency Cohort study, we measured 25-hydroxyvitamin D (25(OH)D), 1,25-dihyroxyvitamin D (1,25(OH)
2
D), FGF23, and parathyroid hormone and performed quantitative echocardiography. Using linear regression methods, we determined significant negative interactions between 25(OH)D and FGF23 on left ventricular (LV) mass (
P
=0.016), end-diastolic volume (
P
=0.029), and end-systolic volumes (
P
=0.021). In participants with an FGF23 level greater than the median of 123.5 RU/mL, each doubling of 25(OH)D was associated with a 2.5% (95% confidence interval, −4.8, −0.2) lower LV mass. This association was less pronounced with FGF23 levels less than the median (0.4%; 95% confidence interval, −1.9, 2.7). Conversely, in participants with deficient 25(OH)D levels <20 ng/mL, each doubling of FGF23 was associated with a 3.4% (95% confidence interval, 1.2, 5.6) greater LV mass compared with only a 1.6% (95% confidence interval, −0.2, 3.5) difference in participants with sufficient 25(OH)D. Similar findings were observed with 25(OH)D and volumes (
P
<0.05), and 1,25(OH)
2
D and LV mass and volumes (
P
<0.005). There was no effect modification by parathyroid hormone.

Conclusions—

We identified significant interactions among 25(OH)D, 1,25(OH)
2
D, and FGF23 on cardiac remodeling. Increased LV mass and cavity dilatation were observed with low 25(OH)D and high FGF23. Our findings suggest that consideration of both hormones is crucial to understanding the role of either in cardiac remodeling, and may have important therapeutic implications.
Quantification of Incomplete Revascularization and its Association With Five-Year Mortality in the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) Trial Validation of the Residual SYNTAX Score
Authors: Farooq Vasim , Serruys Patrick W. , Bourantas Christos V. , Zhang Yaojun , Muramatsu Takashi , Feldman Ted , Holmes David R. , Mack Michael , Morice Marie Claude , Ståhle Elisabeth , Colombo Antonio , de Vries Ton , Morel Marie-angèle , Dawkins Keith D. , Kappetein Arie-Pieter , Mohr Friedrich W. 
Published: June 2013

Background—
The residual Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) Score is an objective measure of the degree and complexity of residual stenosis after percutaneous coronary intervention (PCI).

Methods and Results—

In the randomized PCI cohort of the SYNTAX Trial (n=903), the baseline and residual SYNTAX Scores were calculated. Subjects with a residual SYNTAX Score of 0 were defined as having undergone complete revascularization (CR), and a residual SYNTAX Score >0 as incomplete revascularization (ICR). Five-year clinical outcomes were stratified by CR and ICR (tertiles of the residual SYNTAX Score: >0–4, >4–8, and >8). In the PCI cohort, the mean baseline and residual SYNTAX Scores were 28.4±11.5 and 4.5±6.9, respectively. The mean Δ SYNTAX Score (representative of the burden of disease removed by PCI) was 23.8±10.9. The residual SYNTAX Score was distributed as follows: CR, 0 (n=386, 42.7%); ICR, >0 to 4 (n=184, 20.4%), >4 to 8 (n=167, 18.5%), >8 (n=153, 16.9%). A progressively higher residual SYNTAX Score was shown to be a surrogate marker of increasing clinical comorbidity and anatomic complexity. Subjects with CR or residual SYNTAX Scores ≤8 had comparable 5-year mortality (CR, 8.5%; residual SYNTAX Score >0–4, 8.7%; >4–8, 11.4%;
P
=0.60). A residual SYNTAX Score >8 was associated with 35.3% all-cause mortality at 5-years (
P
<0.001). Stratified analyses in the predefined medical treated diabetic and left main subgroups yielded similar results.

Conclusions—
The residual SYNTAX Score was shown to be a powerful indicator of 5-year mortality in the SYNTAX Trial. The residual SYNTAX Score may aid in determining a reasonable level of revascularization.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00114972.
Aëtius, Achilles, Epicurus and Lucretius on the Phases and Eclipses of the Moon
Authors: Bakker Frederik A. 
Published: June 2013

AbstractAlthough chapter 2.29 of Aëtius’Placitaclaims to be dealing with lunar eclipses, several of its lemmas are actually concerned with the moon’s ‘monthly concealment’, i.e. new moon. This paper will show that, save for one obvious transposition, all lemmas in the first part of the chapter are in fact concerned with the new moon, while only those at the end deal with lunar eclipses. This is best explained on the assumption that in Aëtius 2.29 two separate chapters have been conflated, the first dealing with the phases of the moon, and the other with lunar eclipses. It is further shown that while the first portion is virtually complete, the second is not, preserving only lemmas which presuppose that the moon reflects the light of the sun. A doxographical passage in Ach.Isag. 21, where new moon and the lunar eclipse are similarly confused, suggests that the conflation must have been already present in its and Aëtius’ commonVorlage. On the other hand, Epicurus and Lucretius, believed to have culled their astronomical theories from doxographical works, clearly distinguish the two phenomena and provide useful clues as to the lemmas missing from Aëtius 2.29.