bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of the Stem-like Cell Regulator CD44 by Rho Kinase Inhibition Contributes to the Maintenance of Colon Cancer–Initiating Cells
Authors: Ohata Hirokazu , Ishiguro Tatsuya , Aihara Yuki , Sato Ai , Sakai Hiroaki , Sekine Shigeki , Taniguchi Hirokazu , Akasu Takayuki , Fujita Shin , Nakagama Hitoshi , Okamoto Koji 
Published: September 2012

Abstract
The difficulty in expanding cancer-initiating cells in vitro is one of major obstacles for their biochemical characterization. We found that Rho kinase (ROCK) inhibitors as well as blebbistatin, a myosin II inhibitor, greatly facilitated the establishment of spheroids from primary colon cancer. The spheroid cells expressed cancer stem cell markers, showed the ability to differentiate, and induced tumors in mice. The spheroids were composed of cells that express various levels of CD44, whereas CD44high cells were associated with increased sphere-forming ability, expression of the activating form of β-catenin, and elevated levels of glycolytic genes, CD44−/low cells showed increased levels of differentiation markers and apoptotic cells. The spheroid cells expressed variant forms of CD44 including v6, and the induction of the variants was associated with the activating phosphorylation of c-Met. As expected from the predicted hierarchy, CD44high cells differentiated into CD44−/low cells. Unexpectedly, a fraction of CD44−/low cells generated CD44high cells, and the ROCK inhibitor or blebbistatin primed the transition by inducing CD44 expression. We propose that the transition from CD44−/low to CD44high state helps to maintain a CD44high fraction and the tumorigenic diversity in colon cancer. Cancer Res; 72(19); 5101–10. ©2012 AACR.
Microenvironmental Regulation of Epithelial–Mesenchymal Transitions in Cancer
Authors: Gao Dingcheng , Vahdat Linda T. , Wong Stephen , Chang Jenny C. , Mittal Vivek 
Published: September 2012

Abstract
The evolution of the cancer cell into a metastatic entity is the major cause of death in patients with cancer. Activation of the epithelial-to-mesenchymal transition (EMT) endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs. The observation that in many cancers distant metastases resemble the epithelial phenotype of primary tumors has led to speculation that the disseminated tumor cells recruited to the target organs undergo mesenchymal-to-epithelial transition (MET). However, the MET cascade has not been recapitulated in vivo, and the cellular and molecular regulators that promote MET remain unknown. In a recent report, using a model of spontaneous breast cancer, we have shown that bone marrow–derived myeloid progenitor cells in the premetastatic lung secrete the proteoglycan versican, which induces MET of metastatic tumor cells and accelerates metastases. This review summarizes recent progress in MET research, outlines a unique paracrine cross-talk between the microenvironment and the cancer cells, which promotes tumor outgrowth in the metastatic organ, and discusses opportunities for novel antimetastatic approaches for cancer therapy. Cancer Res; 72(19); 4883–9. ©2012 AACR.
Identification of FoxM1/Bub1b Signaling Pathway as a Required Component for Growth and Survival of Rhabdomyosarcoma
Authors: Wan Xiaolin , Yeung Choh , Kim Su Young , Dolan Joseph G. , Ngo Vu N. , Burkett Sandra , Khan Javed , Staudt Louis M. , Helman Lee J. 
Published: September 2012

Abstract
We identified Bub1b as an essential element for the growth and survival of rhabdomyosarcoma (RMS) cells using a bar-coded, tetracycline-inducible short hairpin RNA (shRNA) library screen. Knockdown of Bub1b resulted in suppression of tumor growth in vivo, including the regression of established tumors. The mechanism by which this occurs is via postmitotic endoreduplication checkpoint and mitotic catastrophe. Furthermore, using a chromatin immunoprecipitation assay, we found that Bub1b is a direct transcriptional target of Forkhead Box M1 (FoxM1). Suppression of FoxM1 either by shRNA or the inhibitor siomycin A resulted in reduction of Bub1b expression and inhibition of cell growth and survival. These results show the important role of the Bub1b/FoxM1 pathway in RMS and provide potential therapeutic targets. Cancer Res; 72(22); 5889–99. ©2012 AACR.
Inflammation Modulates Murine Venous Thrombosis Resolution In Vivo
Authors: Ripplinger Crystal M. , Kessinger Chase W. , Li Chunqiang , Kim Jin Won , McCarthy Jason R. , Weissleder Ralph , Henke Peter K. , Lin Charles P. , Jaffer Farouc A. 
Published: September 2012

Objective—
Assessment of thrombus inflammation in vivo could provide new insights into deep vein thrombosis (DVT) resolution. Here, we develop and evaluate 2 integrated fluorescence molecular-structural imaging strategies to quantify DVT-related inflammation and architecture and to assess the effect of thrombus inflammation on subsequent DVT resolution in vivo.

Methods and Results—

Murine DVT were created with topical 5% FeCl
3
application to thigh or jugular veins (n=35). On day 3, mice received macrophage and matrix metalloproteinase activity fluorescence imaging agents. On day 4, integrated assessment of DVT inflammation and architecture was performed using confocal fluorescence intravital microscopy. Day 4 analyses showed robust relationships among in vivo thrombus macrophages, matrix metalloproteinase activity, and fluorescein isothiocyanate-dextran deposition (
r
>0.70;
P
<0.01). In a serial 2–time point study, mice with DVT underwent intravital microscopy at day 4 and day 6. Analyses revealed that the intensity of thrombus inflammation at day 4 predicted the magnitude of DVT resolution at day 6 (
P
<0.05). In a second approach, noninvasive fluorescence molecular tomography-computed tomography was used and detected macrophages within jugular DVT (
P
<0.05 versus sham controls).

Conclusion—
Integrated fluorescence molecular-structural imaging demonstrates that the DVT-induced inflammatory response can be readily assessed in vivo and can inform the magnitude of thrombus resolution.
Atorvastatin Delays Murine Platelet Activation In Vivo Even in the Absence of Endothelial NO Synthase
Authors: Ni Ran , Peleg Tal , Gross Peter L. 
Published: September 2012

Objective—
Statins decrease mortality in patients with vascular disorders, and evidence for the pleiotropic effects of statins is accumulating. Statins enhance endothelial NO synthase (eNOS) expression, thereby attenuating platelet activation and thrombus formation. Our goal was to determine whether statins have eNOS-independent effects on platelet activation.

Methods and Results—
Wild-type and eNOS-deficient mice were given a 14-day course of oral atorvastatin, and platelet activation was evaluated in vitro and in vivo. Whereas in wild-type mice atorvastatin inhibited platelet activation in vitro in response to numerous agonists, in eNOS-deficient mice, atorvastatin inhibited only thrombin-induced and protease-activated receptor 4 agonist peptide–induced platelet activation. Consistent with an eNOS-independent effect, atorvastatin inhibited platelet activation in vivo in both wild-type and eNOS-deficient mice.

Conclusion—
Atorvastatin inhibits platelet activation via eNOS-dependent and eNOS-independent mechanisms with the latter restricted to protease-activated receptor 4-induced activation downstream to the receptor.
Upregulation of a Disintegrin and Metalloproteinase With Thrombospondin Motifs-7 by miR-29 Repression Mediates Vascular Smooth Muscle Calcification
Authors: Du Yaoyao , Gao Cheng , Liu Ziyi , Wang Li , Liu Bo , He Fan , Zhang Tao , Wang Yue , Wang Xiujie , Xu Mingjiang , Luo Guan-Zheng , Zhu Yi , Xu Qingbo , Wang Xian , Kong Wei 
Published: September 2012

Objective—
Vascular calcification significantly increases cardiovascular morbidity and mortality. We recently reported that the deficiency of cartilage oligomeric matrix protein (COMP) leads to vascular mineralization. We characterized the COMP-degrading metalloproteinase, a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7). Here, we tested whether ADAMTS-7 facilitates vascular calcification.

Methods and Results—
ADAMTS-7 expression was markedly upregulated in calcifying rat vascular smooth muscle cells (VSMCs) in vitro, calcified arteries of rats with chronic renal failure in vivo, and radial arteries of uraemic patients. Silencing of ADAMTS-7 markedly reduced COMP degradation and ameliorated VSMC calcification, whereas ectopic expression of ADAMTS-7 greatly enhanced COMP degradation and exacerbated mineralization. The transcriptional activity of ADAMTS-7 promoter was not altered by high phosphate. We used bioinformatics and quantitative polymerase chain reaction analysis to demonstrate that high-phosphate upregulated ADAMTS-7 mRNA and protein via miR-29a/b repression, which directly targeted the 3′ untranslated region of ADAMTS-7 in VSMCs. MicroRNA (MiR)-29a/b mimic markedly inhibited but miR-29a/b inhibitor greatly enhanced high-phosphate–induced ADAMTS-7 expression, COMP degradation, and subsequent VSMC calcification. ADAMTS-7 silencing significantly diminished miR-29a/b repression–exaggerated VSMC calcification.

Conclusion—
Our data reveal a novel mechanism by which ADAMTS-7 upregulation by miR-29a/b repression mediates vascular calcification, which may shed light on preventing cardiovascular morbidity and mortality.
Genetic and Pharmacological Inhibition of Dimethylarginine Dimethylaminohydrolase 1 Is Protective in Endotoxic Shock
Authors: Nandi Manasi , Kelly Peter , Torondel Belen , Wang Zhen , Starr Anna , Ma Yue , Cunningham Philip , Stidwill Raymond , Leiper James 
Published: September 2012

Objective—
The overproduction of vascular NO contributes toward the circulatory collapse observed in patients with septic shock. Dimethylarginine dimethylaminohydrolase (DDAH), which has 2 isoforms, metabolizes asymmetrically methylated arginines (asymmetric mono- or di-methylarginine), endogenously produced NO synthase inhibitors. We wished to investigate whether reducing DDAH1 activity, using genetic and pharmacological approaches, is protective during lipopolysaccharide-induced endotoxic shock.

Methods and Results—

Experiments were conducted in DDAH1 heterozygous knockout mice (DDAH1
+/−
) or naive rats treated with a synthetic pharmacological DDAH inhibitor (L-257). We demonstrate for the first time that L-257 is DDAH1 selective using recombinant human DDAH proteins. DDAH1 mRNA was expressed in aortic but not macrophage cDNA, and consistent with this expression profile, L-257 selectively inhibited NO production from lipopolysaccharide-treated aorta but not macrophages, in culture. Conscious and anesthetized cardiovascular hemodynamics were monitored using implanted radiotelemetry devices or invasive catheters, respectively. Lipopolysaccharide was administered intravenously to model endotoxemia, and all animals presented with circulatory shock. DDAH1
+/−
mice or L-257–treated rats displayed attenuation in the rate of developed hypotension compared with wild-type littermates or vehicle control animals, respectively.

Conclusion—
Pharmacological and genetic reduction of DDAH1 activity is protective against the vascular changes observed during endotoxic shock.
Trafficking of Endogenous Smooth Muscle Cell Cholesterol
Authors: Pessolano Lawrence G. , Sullivan Christopher P. , Seidl Stephanie E. , Rich Celeste B. , Liscum Laura , Stone Phillip J. , Sipe Jean D. , Schreiber Barbara M. 
Published: September 2012

Objective—
Intracellular cholesterol distribution impacts cell function; however, processes influencing endogenous cholesterol trafficking remain largely unknown. Atherosclerosis is associated with vascular inflammation and these studies address the role of inflammatory mediators on smooth muscle cell cholesterol trafficking.

Methods and Results—

Interestingly, in the absence of an exogenous cholesterol source, serum amyloid A increased [
14
C] oleic acid incorporation into cholesteryl ester in rat smooth muscle cells, suggesting endogenous cholesterol trafficking to the endoplasmic reticulum. [
3
H] cholesteryl ester accumulated in cells prelabeled with [
3
H] cholesterol, confirming that serum amyloid A mediated the movement of endogenous cholesterol. Cholesterol movement was dependent upon functional endolysosomes. The cholesterol oxidase–sensitive pool of cholesterol decreased in serum amyloid A−treated cells. Furthermore, the mechanism whereby serum amyloid A induced cholesterol trafficking was determined to be via activation of expression of secretory phospholipase A
2
, group IIA (sPLA
2
) and sPLA
2
–dependent activation of sphingomyelinase. Interestingly, although neither tumor necrosis factor-α nor interferon-γ induced cholesterol trafficking, interleukin-1β induced [
14
C] cholesteryl ester accumulation that was also dependent upon sPLA
2
and sphingomyelinase activities. Serum amyloid A activates smooth muscle cell interleukin-1β expression, and although the interleukin-1–receptor antagonist inhibited the interleukin-1β−induced cholesterol trafficking, it had no effect on the movement of cholesterol mediated by serum amyloid A.

Conclusion—
These data support a role for inflammation in endogenous smooth muscle cell cholesterol trafficking from the plasma membrane to the endoplasmic reticulum.
Endogenous IRAK-M Attenuates Postinfarction Remodeling Through Effects on Macrophages and Fibroblasts
Authors: Chen Wei , Saxena Amit , Li Na , Sun Jinyu , Gupta Amit , Lee Dong-Wook , Tian Qi , Dobaczewski Marcin , Frangogiannis Nikolaos G. 
Published: September 2012

Objective—
Effective postinfarction repair requires timely suppression of innate immune signals to prevent the catastrophic consequences of uncontrolled inflammation on cardiac geometry and function. In macrophages, interleukin-1 receptor-associated kinase (IRAK)-M acts as a functional decoy preventing uncontrolled toll-like receptor /interleukin-1–mediated responses. Our study investigates the role of IRAK-M as a negative regulator of the postinfarction inflammatory response and as a modulator of cardiac remodeling.

Methods and Results—

In wild-type mouse infarcts IRAK-M was upregulated in infiltrating macrophages and fibroblasts exhibiting a biphasic response. When compared with wild-type animals, infarcted IRAK-M
−/−
mice had enhanced adverse remodeling and worse systolic dysfunction; however, acute infarct size was comparable between groups. Adverse remodeling in IRAK-M
−/−
animals was associated with enhanced myocardial inflammation and protease activation. The protective actions of IRAK-M involved phenotypic modulation of macrophages and fibroblasts. IRAK-M
−/−
infarcts showed increased infiltration with proinflammatory CD11b+/Ly6C
hi
monocytes; leukocytes harvested from IRAK-M−null infarcts exhibited accentuated cytokine expression. In vitro, IRAK-M expression was upregulated in cytokine-stimulated murine cardiac fibroblasts and suppressed their matrix-degrading properties without affecting their inflammatory activity.

Conclusion—
Endogenous IRAK-M attenuates adverse postinfarction remodeling suppressing leukocyte inflammatory activity, while inhibiting fibroblast-mediated matrix degradation.
Expression of the Irisin Precursor FNDC5 in Skeletal Muscle Correlates With Aerobic Exercise Performance in Patients With Heart Failure
Authors: Lecker Stewart H. , Zavin Alexandra , Cao Peirang , Arena Ross , Allsup Kelly , Daniels Karla M. , Joseph Jacob , Schulze P. Christian , Forman Daniel E. 
Published: September 2012

Background—

Exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (
FNDC5
) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and because PGC-1α and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF.

Methods and Results—

Systolic HF (left ventricular ejection fraction ≤40%) patients underwent cardiopulmonary exercise testing to evaluate aerobic performance. High versus low aerobic performance was assessed using oxygen consumption (peak V
o
2
[>14 versus ≤14 mL O
2
·kg
−1
·min
−1
]) and ventilatory efficiency (VE/V
co
2
slope [<34 versus ≥34]). Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression. Twenty-four patients were studied. FNDC5 (5.7±3.5 versus 3.1±1.2,
P<0
.05) and PGC-1α (9.9±5.9 versus 4.5±1.9,
P
<0.01) gene expressions were greater in the high-peak V
o
2
group; correlation between FNDC5 and PGC-1α was significant (
r
=0.56,
P
<0.05) only in the high-peak V
o
2
group. Similarly, FNDC5 and PGC-1α gene expression was greater in the high-performance group based on lower VE/V
co
2
slopes (5.8±3.6 versus 3.3±1.4,
P
<0.05 and 9.7±6 versus 5.3±3.4,
P
<0.05); FNDC5 also correlated with PGC-1α (
r
=0.55,
P
<0.05) only in the low VE/V
co
2
slope group.

Conclusions—
This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients.
Rapid Estrogen Receptor Signaling Is Essential for the Protective Effects of Estrogen Against Vascular Injury
Authors: Bernelot Moens Sophie J. , Schnitzler Gavin R. , Nickerson Moriah , Guo Huiming , Ueda Kazutaka , Lu Qing , Aronovitz Mark J. , Nickerson Heather , Baur Wendy E. , Hansen Ulla , Iyer Lakshmanan K. , Karas Richard H. 
Published: September 2012

Background—
Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which, when bound to estrogen, can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a rapid nonnuclear signaling cascade. However, the biological significance of this rapid signaling pathway has been unclear.

Methods and Results—
In the present study, we develop a novel transgenic mouse in which rapid signaling is blocked by overexpression of a peptide that prevents ERs from interacting with the scaffold protein striatin (the disrupting peptide mouse). Microarray analysis of ex vivo treated mouse aortas demonstrates that rapid ER signaling plays an important role in estrogen-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of estrogen to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the disrupting peptide mouse after carotid artery wire injury.

Conclusions—
Taken together, these results support the concept that rapid, nonnuclear ER signaling contributes to the transcriptional regulatory functions of ER and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents.
A Randomized, Placebo‐Controlled Trial of Omega‐3 Fatty Acids for Inhibition of Supraventricular Arrhythmias After Cardiac Surgery: The FISH Trial
Authors: Sandesara Chirag M. , Chung Mina K. , Van Wagoner David R. , Barringer Thomas A. , Allen Keith , Ismail Hassan M. , Zimmerman Bridget , Olshansky Brian 
Published: September 2012

Background
Omega‐3 polyunsaturated fatty acids (n3‐PUFAs) might have antiarrhythmic properties, but data conflict on whether n3‐PUFAs reduce rates of atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG). We hypothesized that n3‐PUFAs would reduce post‐CABG AF, and we tested this hypothesis in a well‐powered, randomized, double‐blind, placebo‐controlled, multicenter clinical trial.

Methods and Results

Patients undergoing CABG were randomized to pharmaceutical‐grade n3‐PUFAs 2 g orally twice daily (minimum of 6 g) or a matched placebo ≥24 hours before surgery. Gas chromatography was used to assess plasma fatty acid composition of samples collected on the day of screening, day of surgery, and postoperative day 4. Treatment continued either until the primary end point, clinically significant AF requiring treatment, occurred or for a maximum of 2 weeks after surgery. Two hundred sixty patients were enrolled and randomized. Before surgery, n3‐PUFA dosing increased plasma n3‐PUFA levels from 2.9% to 4% and reduced the n6:n3‐PUFA ratio from 9.1 to 6.4 (both
P
<0.001). Similar changes were noted on postoperative day 4. There were no lipid changes in the placebo group. The rate of post‐CABG AF was similar in both groups (30% n3‐PUFAs versus 33% placebo,
P
=0.67). The post‐CABG AF odds ratio for n3‐PUFAs relative to placebo was 0.89 (95% confidence interval 0.52–1.53). There were no differences in any secondary end points.

Conclusions
Oral n3‐PUFA supplementation begun 2 days before CABG did not reduce AF or other complications after surgery.

Clinical Trial Registration

URL:
www.clinicaltrials.gov
Unique identifier: NCT00446966.

(
J Am Heart Assoc
. 2012;1:e000547 doi: 10.1161/JAHA.111.000547.)
Reduction of Long‐Term Care Dependence After an 8‐Year Primary Care Prevention Program for Stroke and Dementia: The INVADE Trial
Authors: Bickel Horst , Ander Karl‐Heinz , Brönner Monika , Etgen Thorleif , Gnahn Hans , Gotzler Othma , Poppert Holger , Pürner Klaus , Sander Dirk , Förstl Hans 
Published: September 2012

Background

Stroke and dementia are the major causes for long‐term care (
LTC
) dependence in old age. This intervention trial compared a multidomain prevention program for stroke and dementia with usual medical care in reducing the need for
LTC
.

Methods and Results

The Intervention Project on Cerebrovascular Disease and Dementia in the District of Ebersberg (
INVADE
) was a general practice–based 8‐year trial in 2 defined catchment areas in Upper Bavaria, Germany. All 11 317 insurants of a statutory health insurance plan who were ≥55 years of age and lived in the intervention district were offered the opportunity to participate in a prevention program; 3908 enrolled. The 13 301 insurants in the reference district received usual medical care. The intervention consisted of the systematic identification and evidence‐based treatment of vascular risk factors. The primary clinical end point was incidence of
LTC
dependence according to external assessment by a special medical service in the framework of the statutory German
LTC
insurance. Age‐ and sex‐specific incidence rates from the reference district were used to calculate the expected number of cases of
LTC
dependence under usual medical care. The expected number was compared with the observed number of cases in the intervention district. Analysis was by intention to treat. During the 5 years after completion of the recruitment period, significantly fewer incident cases of
LTC
dependence arose in the intervention district than expected (χ
2
=13.25;
P<
0.001). In women, the incidence was reduced by 10% (
P<
0.01). In men, the incidence was reduced by 9.6% (
P<
0.05).

Conclusions

Our results support the feasibility and effectiveness of a primary care prevention program for stroke and dementia to reduce the risk of developing
LTC
dependence.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
01107548. (

J Am Heart Assoc.

2012;1: e000786 doi: 10.1161/
JAHA
.112.000786.)