bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging and modeling of acute pressure-induced changes of collagen and elastin microarchitectures in pig and human resistance arteries
Authors: Bloksgaard Maria , Leurgans Thomas M. , Spronck Bart , Heusinkveld Maarten H. G. , Thorsted Bjarne , Rosenstand Kristoffer , Nissen Inger , Hansen Ulla M. , Brewer Jonathan R. , Bagatolli Luis A. , Rasmussen Lars M. , Irmukhamedov Akhmadjon , Reesink Koen D. , De Mey Jo G. R. 
Published: April 2017

The impact of disease-related changes in the extracellular matrix (ECM) on the mechanical properties of human resistance arteries largely remains to be established. Resistance arteries from both pig and human parietal pericardium (PRA) display a different ECM microarchitecture compared with frequently used rodent mesenteric arteries. We hypothesized that the biaxial mechanics of PRA mirror pressure-induced changes in the ECM microarchitecture. This was tested using isolated pig PRA as a model system, integrating vital imaging, pressure myography, and mathematical modeling. Collagenase and elastase digestions were applied to evaluate the load-bearing roles of collagen and elastin, respectively. The incremental elastic modulus linearly related to the straightness of adventitial collagen fibers circumferentially and longitudinally (both R2 ≥ 0.99), whereas there was a nonlinear relationship to the internal elastic lamina elastin fiber branching angles. Mathematical modeling suggested a collagen recruitment strain (means ± SE) of 1.1 ± 0.2 circumferentially and 0.20 ± 0.01 longitudinally, corresponding to a pressure of ~40 mmHg, a finding supported by the vital imaging. The integrated method was tested on human PRA to confirm its validity. These showed limited circumferential distensibility and elongation and a collagen recruitment strain of 0.8 ± 0.1 circumferentially and 0.06 ± 0.02 longitudinally, reached at a distending pressure below 20 mmHg. This was confirmed by vital imaging showing negligible microarchitectural changes of elastin and collagen upon pressurization. In conclusion, we show here, for the first time in resistance arteries, a quantitative relationship between pressure-induced changes in the extracellular matrix and the arterial wall mechanics. The strength of the integrated methods invites for future detailed studies of microvascular pathologies. NEW & NOTEWORTHY This is the first study to quantitatively relate pressure-induced microstructural changes in resistance arteries to the mechanics of their wall. Principal findings using a pig model system were confirmed in human arteries. The combined methods provide a strong tool for future hypothesis-driven studies of microvascular pathologies.
MK5 haplodeficiency attenuates hypertrophy and preserves diastolic function during remodeling induced by chronic pressure overload in the mouse heart
Authors: Nawaito Sherin Ali , Dingar Dharmendra , Sahadevan Pramod , Hussein Bahira , Sahmi Fatiha , Shi Yanfen , Gillis Marc-Antoine , Gaestel Matthias , Tardif Jean-Claude , Allen Bruce G. 
Published: April 2017

MAPK-activated protein kinase-5 (MK5) is a protein serine/threonine kinase that is activated by p38 MAPK and the atypical MAPKs ERK3 and ERK4. The physiological function(s) of MK5 remains unknown. Here, we examined the effect of MK5 haplodeficiency on cardiac function and myocardial remodeling. At 12 wk of age, MK5 haplodeficient mice (MK5+/−) were smaller than age-matched wild-type littermates (MK5+/+), with similar diastolic function but reduced systolic function. Transverse aortic constriction (TAC) was used to induce chronic pressure overload in 12-wk-old male MK5+/− and MK5+/+ mice. Two weeks post-TAC, heart weight-to-tibia length ratios were similarly increased in MK5+/− and MK5+/+ hearts, as was the abundance of B-type natriuretic peptide and β-myosin heavy chain mRNA. Left ventricular ejection fraction was reduced in both MK5+/+ and MK5+/− mice, whereas regional peak systolic tissue velocities were reduced and isovolumetric relaxation time was prolonged in MK5+/+ hearts but not in MK5+/− hearts. The TAC-induced increase in collagen type 1-α1 mRNA observed in MK5+/+ hearts was markedly attenuated in MK5+/− hearts. Eight weeks post-TAC, systolic function was equally impaired in MK5+/+ and MK5+/− mice. In contrast, the increase in E wave deceleration rate and progression of hypertrophy observed in TAC MK5+/+ mice were attenuated in TAC MK5+/− mice. MK5 immunoreactivity was detected in adult fibroblasts but not in myocytes. MK5+/+, MK5+/−, and MK5−/− fibroblasts all expressed α-smooth muscle actin in culture. Hence, reduced MK5 expression in cardiac fibroblasts was associated with the attenuation of both hypertrophy and development of a restrictive filling pattern during myocardial remodeling in response to chronic pressure overload. NEW & NOTEWORTHY MAPK-activated protein kinase-5 (MK5)/p38-regulated/activated protein kinase is a protein serine/threonine kinase activated by p38 MAPK and/or the atypical MAPKs ERK3 and ERK4. MK5 immunoreactivity was detected in adult ventricular fibroblasts but not in myocytes. MK5 haplodeficiency attenuated the progression of hypertrophy, reduced collagen type 1 mRNA, and protected diastolic function in response to chronic pressure overload.
Increased amplitude of inward rectifier K+ currents with advanced age in smooth muscle cells of murine superior epigastric arteries
Authors: Hayoz Sebastien , Pettis Jessica , Bradley Vanessa , Segal Steven S. , Jackson William F. 
Published: April 2017

Inward rectifier K+ channels (KIR) may contribute to skeletal muscle blood flow regulation and adapt to advanced age. Using mouse abdominal wall superior epigastric arteries (SEAs) from either young (3–6 mo) or old (24–26 mo) male C57BL/6 mice, we investigated whether SEA smooth muscle cells (SMCs) express functional KIR channels and how aging may affect KIR function. Freshly dissected SEAs were either enzymatically dissociated to isolate SMCs for electrophysiological recording (perforated patch) and mRNA expression or used intact for pressure myography. With 5 mM extracellular K+ concentration ([K+]o), exposure of SMCs to the KIR blocker Ba2+ (100 μM) had no significant effect ( P > 0.05) on whole cell currents elicited by membrane potentials spanning −120 to −30 mV. Raising [K+]o to 15 mM activated Ba2+-sensitive KIR currents between −120 and −30 mV, which were greater in SMCs from old mice than in SMCs from young mice ( P < 0.05). Pressure myography of SEAs revealed that while aging decreased maximum vessel diameter by ~8% ( P < 0.05), it had no significant effect on resting diameter, myogenic tone, dilation to 15 mM [K+]o, Ba2+-induced constriction in 5 mM [K+]o, or constriction induced by 15 mM [K+]o in the presence of Ba2+ ( P > 0.05). Quantitative RT-PCR revealed SMC expression of KIR2.1 and KIR2.2 mRNA that was not affected by age. Barium-induced constriction of SEAs from young and old mice suggests an integral role for KIR in regulating resting membrane potential and vasomotor tone. Increased functional expression of KIR channels during advanced age may compensate for other age-related changes in SEA function. NEW & NOTEWORTHY Ion channels are integral to blood flow regulation. We found greater functional expression of inward rectifying K+ channels in smooth muscle cells of resistance arteries of mouse skeletal muscle with advanced age. This adaptation to aging may contribute to the maintenance of vasomotor tone and blood flow regulation during exercise.
Low-frequency blood pressure oscillations and inotrope treatment failure in premature infants
Authors: Vesoulis Zachary A. , Hao Jessica , McPherson Christopher , El Ters Nathalie M. , Mathur Amit M. 
Published: April 2017

The underlying mechanism as to why some hypotensive preterm infants do not respond to inotropic medications remains unclear. For these infants, we hypothesize that impaired vasomotor function is a significant factor and is manifested through a decrease in low-frequency blood pressure variability across regulatory components of vascular tone. Infants born ≤28 wk estimated gestational age underwent prospective recording of mean arterial blood pressure for 72 h after birth. After error correction, root-mean-square spectral power was calculated for each valid 10-min data frame across each of four frequency bands ( B1, 0.005–0.0095 Hz; B2, 0.0095–0.02 Hz; B3, 0.02–0.06 Hz; and B4, 0.06–0.16) corresponding to different components of vasomotion control. Forty infants (twenty-nine normotensive control and eleven inotrope-exposed) were included with a mean ± SD estimated gestational age of 25.2 ± 1.6 wk and birth weight 790 ± 211 g. 9.7/11.8 Million (82%) data points were error-free and used for analysis. Spectral power across all frequency bands increased with time, although the magnitude was 20% less in the inotrope-exposed infants. A statistically significant increase in spectral power in response to inotrope initiation was noted across all frequency bands. Infants with robust blood pressure response to inotropes had a greater increase compared with those who had limited or no blood pressure response. In this study, hypotensive infants who require inotropes have decreased low-frequency variability at baseline compared with normotensive infants, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure.NEW & NOTEWORTHY In this study, we examine patterns of low-frequency oscillations in blood pressure variability across regulatory components of vascular tone in normotensive and hypotensive infants exposed to inotropic medications. We found that hypotensive infants who require inotropes have decreased low-frequency variability at baseline, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure.
Interaction between Tumor Cell Surface Receptor RAGE and Proteinase 3 Mediates Prostate Cancer Metastasis to Bone
Authors: Kolonin Mikhail G. , Sergeeva Anna , Staquicini Daniela I. , Smith Tracey L. , Tarleton Christy A. , Molldrem Jeffrey J. , Sidman Richard L. , Marchiò Serena , Pasqualini Renata , Arap Wadih 
Published: April 2017

Abstract
Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE–PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a nonproteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short timeframe. Our findings demonstrate how RAGE–PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. Cancer Res; 77(12); 3144–50. ©2017 AACR.
Master Transcriptional Regulators in Cancer: Discovery via Reverse Engineering Approaches and Subsequent Validation
Authors: Moran Bruce , Rahman Arman , Palonen Katja , Lanigan Fiona T. , Gallagher William M. 
Published: April 2017

Abstract
Reverse engineering of transcriptional networks using gene expression data enables identification of genes that underpin the development and progression of different cancers. Methods to this end have been available for over a decade and, with a critical mass of transcriptomic data in the oncology arena having been reached, they are ever more applicable. Extensive and complex networks can be distilled into a small set of key master transcriptional regulators (MTR), genes that are very highly connected and have been shown to be involved in processes of known importance in disease. Interpreting and validating the results of standardized bioinformatic methods is of crucial importance in determining the inherent value of MTRs. In this review, we briefly describe how MTRs are identified and focus on providing an overview of how MTRs can and have been validated for use in clinical decision making in malignant diseases, along with serving as tractable therapeutic targets. Cancer Res; 77(9); 2186–90. ©2017 AACR.
Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion
Authors: Chen Hsin-Yu , Larson Peder E.Z. , Bok Robert A. , von Morze Cornelius , Sriram Renuka , Delos Santos Romelyn , Delos Santos Justin , Gordon Jeremy W. , Bahrami Naeim , Ferrone Marcus , Kurhanewicz John , Vigneron Daniel B. 
Published: April 2017

AbstractNew magnetic resonance (MR) molecular imaging techniques offer the potential for noninvasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a three-dimensional dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low- and high-grade tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1, and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans, attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL. This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials. Cancer Res; 77(12); 3207–16. ©2017 AACR.
PD-L1 Expression in Melanoma: A Quantitative Immunohistochemical Antibody Comparison
Authors: Sunshine Joel C. , Nguyen Peter L. , Kaunitz Genevieve J. , Cottrell Tricia R. , Berry Sneha , Esandrio Jessica , Xu Haiying , Ogurtsova Aleksandra , Bleich Karen B. , Cornish Toby C. , Lipson Evan J. , Anders Robert A. , Taube Janis M. 
Published: April 2017

Abstract
Purpose: PD-L1 expression in the pretreatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.
Experimental Design: PD-L1 IHC was performed on 34 formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3, and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies.
Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R2 = 0.81–0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/H-scores strongly correlated with percentage of PD-L1(+) cells (R2 &gt; 0.78, all clones).
Conclusions: The 5H1, SP142, 28-8, 22C3, and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/H-score in chromogenic PD-L1 IHC assays. Clin Cancer Res; 23(16); 4938–44. ©2017 AACR.
Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth
Authors: Kach Jacob , Long Tiha M. , Selman Phillip , Tonsing-Carter Eva Y. , Bacalao Maria A. , Lastra Ricardo R. , de Wet Larischa , Comiskey Shane , Gillard Marc , VanOpstall Calvin , West Diana C. , Chan Wen-Ching , Griend Donald Vander , Conzen Suzanne D. , Szmulewitz Russell Z. 
Published: April 2017

Abstract
Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect androgen receptor (AR) signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR–expressing, but not in low GR–expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective nonsteroidal SGRMs potently inhibit GR activity and prostate cancer growth despite AR pathway inhibition, demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC. Mol Cancer Ther; 16(8); 1680–92. ©2017 AACR.
Progression of Coronary Artery Calcium and Incident Heart Failure: The Multi‐Ethnic Study of Atherosclerosis
Authors: Bakhshi Hooman , Ambale‐Venkatesh Bharath , Yang Xiaoying , Ostovaneh Mohammad R. , Wu Colin O. , Budoff Matthew , Bahrami Hossein , Wong Nathan D. , Bluemke David A. , Lima João A.C. 
Published: April 2017

Background

Although the association between coronary artery calcium (
CAC
) and future heart failure (
HF
) has been shown previously, the value of
CAC
progression in the prediction of
HF
has not been investigated. In this study, we investigated the association of
CAC
progression with subclinical left ventricular (
LV
) dysfunction and incident
HF
in the Multi‐Ethnic Study of Atherosclerosis.

Methods and Results

The Multi‐Ethnic Study of Atherosclerosis is a population‐based study consisting of 6814 men and women aged 45 to 84, free of overt cardiovascular disease at enrollment, who were recruited from 4 ethnicities. We included 5644 Multi‐Ethnic Study of Atherosclerosis participants who had baseline and follow‐up cardiac computed tomography and were free of
HF
and coronary heart disease before the second cardiac computed tomography. Mean (±
SD
) age was 61.7±10.2 years and 47.2% were male. The Cox proportional hazard models and multivariable linear regression models were deployed to determine the association of
CAC
progression with incident
HF
and subclinical
LV
dysfunction, respectively. Over a median follow‐up of 9.6 (interquartile range: 8.8–10.6) years, 182 participants developed incident
HF
.
CAC
progression of 10 units per year was associated with 3% of increased risk of
HF
independent of overt coronary heart disease (
P
=0.008). In 2818 participants with available cardiac magnetic resonance images,
CAC
progression was associated with increased LV end diastolic volume (β=0.16;
P
=0.03) and LV end systolic volume (β=0.12;
P
=0.006) after excluding participants with any coronary heart disease.

Conclusions

CAC
progression was associated with incident
HF
and modestly increased LV end diastolic volume and LV end systolic volume at follow‐up exam independent of overt coronary heart disease.
Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia
Authors: Pase Matthew P. , Himali Jayandra J. , Beiser Alexa S. , Aparicio Hugo J. , Satizabal Claudia L. , Vasan Ramachandran S. , Seshadri Sudha , Jacques Paul F. 
Published: April 2017

Background and Purpose—
Sugar- and artificially-sweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar- or artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort.

Methods—
We studied 2888 participants aged >45 years for incident stroke (mean age 62 [SD, 9] years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 [SD, 6] years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991–1995), 6 (1995–1998), and 7 (1998–2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer’s disease).

Results—
After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer’s disease dementia. When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26–6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18–7.07) for Alzheimer’s disease. Sugar-sweetened beverages were not associated with stroke or dementia.

Conclusions—
Artificially sweetened soft drink consumption was associated with a higher risk of stroke and dementia.