bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adherence to Cancer Prevention Guidelines and Cancer Risk in Low-Income and African American Populations
Authors: Warren Andersen Shaneda , Blot William J. , Shu Xiao-Ou , Sonderman Jennifer S. , Steinwandel Mark D. , Hargreaves Margaret K. , Zheng Wei 
Published: March 2016

AbstractBackground: The American Cancer Society (ACS) publishes behavioral guidelines for cancer prevention, including standards on body weight, physical activity, nutrition, alcohol, and tobacco use. The impact of these guidelines has been rarely studied in low-income and African American populations.Methods: The study included 61,098 racially diverse, mainly low-income adults who participated in the Southern Community Cohort Study and were followed for a median of 6 years. Cox models were used to estimate HRs for cancer incidence associated with behaviors and with an ACS physical activity/nutrition 0-to-4 compliance score indicating the number of body weight, physical activity, healthy eating, and alcohol guidelines met.Results: During the study period, 2,240 incident cancers were identified. Significantly lower cancer incidence was found among never smokers and non/moderate alcohol drinkers, but not among those meeting guidelines for obesity, physical activity, and diet. The ACS compliance score was inversely associated with cancer risk among the 25,509 participants without baseline chronic disease. HRs for cancer incidence among those without baseline chronic diseases and who met one, two, three, or four guidelines versus zero guidelines were 0.93 (95% confidence intervals, 0.71–1.21), 0.85 (0.65–1.12), 0.70 (0.51–0.97), and 0.55 (0.31–0.99), respectively. Associations were consistent in analyses stratified by sex, race, household income, and smoking status.Conclusions: Meeting the ACS smoking and body weight/physical activity/dietary/alcohol guidelines for cancer prevention is associated with reductions in cancer incidence in low-income and African American populations.Impact: This study provides strong evidence supporting lifestyle modification to lower cancer incidence in these underserved populations. Cancer Epidemiol Biomarkers Prev; 25(5); 846–53. ©2016 AACR.
HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma
Authors: Zheng Hong , Zhao Weipeng , Yan Cihui , Watson Crystina C. , Massengill Michael , Xie Mengyu , Massengill Chris , Noyes David R. , Martinez Gary V. , Afzal Roha , Chen Zhihua , Ren Xiubao , Antonia Scott J. , Haura Eric B. , Ruffell Brian , Beg Amer A. 
Published: March 2016

Abstract
Purpose: A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g., ∼20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies that increase T-cell infiltration to tumors can be efficacious in enhancing immunotherapy response.
Experimental Design: We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms.
Results: We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T-cell infiltration, and T-cell–dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells.
Conclusions: These results provide evidence for a novel role of HDACs in modulating T-cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacologic induction of T-cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment. Clin Cancer Res; 22(16); 4119–32. ©2016 AACR.
Constitutive Activation of DNA Damage Checkpoint Signaling Contributes to Mutant p53 Accumulation via Modulation of p53 Ubiquitination
Authors: Frum Rebecca A. , Love Ian M. , Damle Priyadarshan K. , Mukhopadhyay Nitai D. , Palit Deb Swati , Deb Sumitra , Grossman Steven R. 
Published: March 2016

Abstract
Many mutant p53 proteins exhibit an abnormally long half-life and overall increased abundance compared with wild-type p53 in tumors, contributing to mutant p53's gain-of-function oncogenic properties. Here, a novel mechanism is revealed for the maintenance of mutant p53 abundance in cancer that is dependent on DNA damage checkpoint activation. High-level mutant p53 expression in lung cancer cells was associated with preferential p53 monoubiquitination versus polyubiquitination, suggesting a role for the ubiquitin/proteasome system in regulation of mutant p53 abundance in cancer cells. Interestingly, mutant p53 ubiquitination status was regulated by ataxia–telangectasia mutated (ATM) activation and downstream phosphorylation of mutant p53 (serine 15), both in resting and in genotoxin-treated lung cancer cells. Specifically, either inhibition of ATM with caffeine or mutation of p53 (serine 15 to alanine) restored MDM2-dependent polyubiquitination of otherwise monoubiquitinated mutant p53. Caffeine treatment rescued MDM2-dependent proteasome degradation of mutant p53 in cells exhibiting active DNA damage signaling, and ATM knockdown phenocopied the caffeine effect. Importantly, in cells analyzed individually by flow cytometry, p53 levels were highest in cells exhibiting the greatest levels of DNA damage response, and interference with DNA damage signaling preferentially decreased the relative percentage of cells in a population with the highest levels of mutant p53. These data demonstrate that active DNA damage signaling contributes to high levels of mutant p53 via modulation of ubiquitin/proteasome activity toward p53.
Implication: The ability of DNA damage checkpoint signaling to mediate accumulation of mutant p53 suggests that targeting this signaling pathway may provide therapeutic gain. Mol Cancer Res; 14(5); 423–36. ©2016 AACR.
Mast Cell-Targeted Strategies in Cancer Therapy
Authors: Ammendola Michele , Sacco Rosario , Sammarco Giuseppe , Luposella Maria , Patruno Rosa , Gadaleta Cosmo Damiano , De Sarro Giovambattista , Ranieri Girolamo 
Published: March 2016

Mast cells (MCs) are cells that originate in the bone marrow from pluripotent CD34+ hematopoietic stem cells. Precursors of MCs migrate through the circulation to their target tissues, completing their maturation process into granulated cells under the influence of several microenvironment growth factors. The most important of these factors is the ligand for the c-Kit receptor (c-Kit-R) namely stem cell factor (SCF), secreted mainly by fibroblasts and endothelial cells (ECs). SCF also regulates development, survival and de novo proliferation of MCs. It has already been demonstrated that gain-of-function mutations of gene c-Kit encoding c-Kit-R result in the development of some tumors. Furthermore, MCs are able also to modulate both innate and adaptive immune response and to express the high-affinity IgE receptor following IgE activation. Among the other IgE-independent MC activation mechanisms, a wide variety of other surface receptors for cytokines, chemokines, immunoglobulins, and complement are also described. Interestingly, MCs can stimulate angiogenesis by releasing of several pro-angiogenic cytokines stored in their cytoplasm. Studies published in the last year suggest that angiogenesis stimulated by MCs may play an important role in tumor growth and progression. Here, we aim to focus several biological features of MCs and to summarize new anti-cancer MC-targeted strategies with potential translation in human clinical trials.
Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci
Authors: Zhao Yuqi , Chen Jing , Freudenberg Johannes M. , Meng Qingying ,   CARDIoGRAM Consortium, Rajpal Deepak K. , Yang Xia 
Published: March 2016

Objective—
Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations.

Approach and Results—

We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls. The networks and top-ranked regulators according to these data-driven criteria were further queried against literature, experimental evidence, and drug information to evaluate their disease relevance and potential as drug targets. Our analysis uncovered several potential novel regulators of CAD such as
LUM
and
STAT3
, which possess properties suitable as drug targets. We also revealed molecular relations and potential mechanisms through which the top CAD loci operate. Furthermore, we found that multiple CAD-relevant biological processes such as extracellular matrix, inflammatory and immune pathways, complement and coagulation cascades, and lipid metabolism interact in the CAD networks.

Conclusions—
Our data-driven integrative genomics framework unraveled tissue-specific relations among the candidate genes of the CAD genome-wide association studies loci and prioritized novel network regulatory genes orchestrating biological processes relevant to CAD.
Modulation of Kinin B2 Receptor Signaling Controls Aortic Dilatation and Rupture in the Angiotensin II–Infused Apolipoprotein E–Deficient Mouse
Authors: Moran Corey S. , Rush Catherine M. , Dougan Tammy , Jose Roby J. , Biros Erik , Norman Paul E. , Gera Lajos , Golledge Jonathan 
Published: March 2016

Objective—
Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Activity of the local kallikrein–kinin system may be important in cardiovascular disease. The effect of kinin B2 receptor (B2R) agonist and antagonist peptides on experimental AAA was investigated.

Approach and Results—
AAA was induced in apolipoprotein E–deficient mice via infusion of angiotensin II (1.0 μg/kg per minute SC). B2R agonists or antagonists were given via injection (2 mg/kg IP) every other day. The B2R agonist (B9772) promoted aortic rupture in response to angiotensin II associated with an increase in neutrophil infiltration of the aorta in comparison to controls. Mice receiving a B2R/kinin B1 receptor antagonist (B9430) were relatively protected from aortic rupture. Neutrophil depletion abrogated the ability of the B2R agonist to promote aortic rupture. Progression of angiotensin II–induced aortic dilatation was inhibited in mice receiving a B2R antagonist (B9330). Secretion of metalloproteinase-2 and -9, osteoprotegerin, and osteopontin by human AAA explant was reduced in the presence of the B2R antagonist (B9330). B2R agonist and antagonist peptides enhanced and inhibited, respectively, angiotensin II–induced neutrophil activation and aortic smooth muscle cell inflammatory phenotype. The B2R antagonist (B9330; 5 μg) delivered directly to the aortic wall 1 week post-AAA induction with calcium phosphate in a rat model reduced aneurysm growth associated with downregulation of aortic metalloproteinase-9.

Conclusions—
B2R signaling promotes aortic rupture within a mouse model associated with the ability to stimulate inflammatory phenotypes of neutrophils and vascular smooth muscle cells. B2R antagonism could be a potential therapy for AAA.
Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways
Authors: Sun Jian-Yong , Li Chao , Shen Zhu-Xia , Zhang Wu-Chang , Ai Tang-Jun , Du Lin-Juan , Zhang Yu-Yao , Yao Gao-Feng , Liu Yan , Sun Shuyang , Naray-Fejes-Toth Aniko , Fejes-Toth Geza , Peng Yong , Chen Mao , Liu Xiaojing , Tao Jun , Zhou Bin , Yu Ying , Guo Feifan , Du Jie , Duan Sheng-Zhong 
Published: March 2016

Objective—
Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms.

Approach and Results—
Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury. MMRKO reduced intima area and intima/media ratio, Ki67- and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67- and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-β and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages.

Conclusions—
Selective deletion of MR in myeloid cells limits macrophage accumulation and vascular inflammation and, therefore, inhibits neointimal hyperplasia and vascular remodeling. Mechanistically, MR deficiency suppresses migration and proliferation of macrophages and leads to less vascular smooth muscle cell activation. At the molecular level, MR deficiency suppresses macrophage inflammatory response via SGK1-AP1/NF-κB pathways.
Diabetes Mellitus Is Associated With Reduced High-Density Lipoprotein Sphingosine-1-Phosphate Content and Impaired High-Density Lipoprotein Cardiac Cell Protection
Authors: Brinck Jonas W. , Thomas Aurélien , Lauer Estelle , Jornayvaz François R. , Brulhart-Meynet Marie-Claude , Prost Jean-Christophe , Pataky Zoltan , Löfgren Patrik , Hoffstedt Johan , Eriksson Mats , Pramfalk Camilla , Morel Sandrine , Kwak Brenda R. , van Eck Miranda , James Richard W. , Frias Miguel A. 
Published: March 2016

Objective—
The dyslipidemia of type 2 diabetes mellitus has multiple etiologies and impairs lipoprotein functionality, thereby increasing risk for cardiovascular disease. High-density lipoproteins (HDLs) have several beneficial effects, notably protecting the heart from myocardial ischemia. We hypothesized that glycation of HDL could compromise this cardioprotective effect.

Approach and Results—

We used in vitro (cardiomyocytes) and ex vivo (whole heart) models subjected to oxidative stress together with HDL isolated from diabetic patients and nondiabetic HDL glycated in vitro (methylglyoxal). Diabetic and in vitro glycated HDL were less effective (
P
<0.05) than control HDL in protecting from oxidative stress. Protection was significantly, inversely correlated with the degree of in vitro glycation (
P
<0.001) and the levels of hemoglobin A1c in diabetic patients (
P
<0.007). The ability to activate protective, intracellular survival pathways involving Akt, Stat3, and Erk1/2 was significantly reduced (
P
<0.05) using glycated HDL. Glycation reduced the sphingosine-1-phosphate (S1P) content of HDL, whereas the S1P concentrations of diabetic HDL were inversely correlated with hemoglobin A1c (
P
<0.005). The S1P contents of in vitro glycated and diabetic HDL were significantly, positively correlated (both <0.01) with cardiomyocyte survival during oxidative stress. Adding S1P to diabetic HDL increased its S1P content and restored its cardioprotective function.

Conclusions—
Our data demonstrate that glycation can reduce the S1P content of HDL, leading to increased cardiomyocyte cell death because of less effective activation of intracellular survival pathways. It has important implications for the functionality of HDL in diabetes mellitus because HDL-S1P has several beneficial effects on the vasculature.
Association Between Left Atrial Stiffness Index and Atrial Fibrillation Recurrence in Patients Undergoing Left Atrial Ablation
Authors: Khurram Irfan M. , Maqbool Farhan , Berger Ronald D. , Marine Joseph E. , Spragg David D. , Ashikaga Hiroshi , Zipunnikov Vadim , Kass David A. , Calkins Hugh , Nazarian Saman , Zimmerman Stefan L. 
Published: March 2016

Background—
Atrial fibrillation (AF) is associated with significant abnormalities of left atrial (LA) systolic and diastolic function. This study describes a novel measure, LA stiffness index, that estimates LA diastolic function and its association with clinical outcomes of catheter ablation.

Methods and Results—

A total of 219 AF patients referred for ablation (59% paroxysmal, mean CHA
2
DS
2
VASc score 1.7±1.4) were enrolled. Atrial pressure and volume loops were prepared from invasive pressure measures and cardiac magnetic resonance imaging volumetric data during sinus rhythm for all patients. An LA stiffness index was created, defined by the ratio of change in LA pressure to volume during passive filling of LA (ΔP/ΔV). Patients were followed prospectively. Mean LA stiffness index for AF patients was 0.6±0.5 mm Hg/mL (paroxysmal AF 0.51±0.4 and persistent AF 0.73±0.6;
P
<0.001). Linear regression analysis showed a rise in the stiffness index with age, increasing at a rate of 0.02 mm Hg/mL per year (
P
<0.001). The LA stiffness index was higher in patients with previous LA ablation(s) for AF (0.51±0.35 versus 0.83±0.70;
P
<0.001). Forty of 160 patients had recurrence after AF ablation with a mean follow-up of 10.4±7.6 months. Patients with recurrence had higher stiffness index than those without recurrence (0.83±0.46 versus 0.40±0.22;
P
<0.001).

Conclusions—
LA stiffness index, a novel measure to assess LA diastolic function, increases with age and is higher in persistent AF and in the setting of repeat AF ablation. Greater LA stiffness index was independently associated with recurrence of AF after LA ablation.
Top–Down Activation of Spatiotopic Sensory Codes in Perceptual and Working Memory Search
Authors: Kuo Bo-Cheng , Nobre Anna Christina , Scerif Gaia , Astle Duncan E. 
Published: March 2016

Abstract
A critical requirement of an efficient cognitive system is the selection and prioritization of relevant information. This occurs when selecting specific items from our sensory inputs, which then receive preferential status at subsequent levels of processing. Many everyday tasks also require us to select internal representations, such as a relevant item from memory. We show that both of these types of search are underpinned by the spatiotopic activation of sensory codes, using both fMRI and MEG data. When individuals searched for perceived and remembered targets, the MEG data highlighted a sensor level electrophysiological effect that reflects the contralateral organization of the visual system—namely, the N2pc. The fMRI data were used to identify a network of frontoparietal areas common to both types of search, as well as the early visual areas activated by the search display. We then combined fMRI and MEG data to explore the temporal dynamics of functional connections between the frontoparietal network and the early visual areas. Searching for a target item resulted in significantly enhanced phase–phase coupling between the frontoparietal network and the visual areas contralateral to the perceived or remembered location of that target. This enhancement of spatially specific phase–phase coupling occurred before the N2pc effect and was significantly associated with it on a trial-by-trial basis. The combination of these two imaging modalities suggests that perceptual and working memory search are underpinned by the synchronization of a frontoparietal network and the relevant sensory cortices.
Late survival and heart failure after transcatheter aortic valve implantation
Authors: Johansson Malin , Nozohoor Shahab , Bjursten Henrik , Ragnarsson Sigurdur , Götberg Matthias , Kimblad Per Ola , Zindovic Igor , Sjögren Johan 
Published: March 2016

Background Short-term survival in patients undergoing transcatheter aortic valve implantation is favorable. Our aim was to evaluate late survival and composite clinical endpoints specified by the Valve Academic Research Consortium-2, including rehospitalization for congestive heart failure. Methods Between January 2008 and April 2014, 166 consecutive patients with severe symptomatic aortic stenosis underwent 168 transcatheter aortic valve implantation procedures at our facility. This cohort was compared with propensity score-matched aortic valve replacement patients. Event rates were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox regression analysis was performed to determine predictors of outcome. Results Although 30-day mortality rates following both procedures were similar (4.2% and 4.8%; p = 0.81), significant differences were seen in corresponding rates of survival (51.7% ± 5.8% vs. 72.3% ± 4.3%; p < 0.001) and cumulative rehospitalization for congestive heart failure (41.3% ± 7.2% vs. 23% ± 4.3%; p = 0.006). New York Heart Association functional class IV preoperative status was an independent risk factor for rehospitalization due to congestive heart failure ( p = 0.015). Conclusions This study confirms the merit of transcatheter aortic valve implantation in high-risk patients with aortic stenosis, although late survival proved inferior to that of aortic valve replacement in propensity score-matched subjects. Early safety was excellent for both treatment groups, however, patients undergoing transcatheter aortic valve implantation had a higher incidence of rehospitalization for congestive heart failure and myocardial infarction during follow-up. Patients with severe congestive heart failure should be carefully monitored and aggressively treated to improve outcomes.