bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B40: Suppression of Stat3 inhibits the invasive potential of malignant squamous cell carcinoma by interfering with the HGF/cmet/Stat3 signaling pathway
Authors: Syed Zanobia , Yin Weihong , Gill Jennifer , Hughes Kendall , Clifford John L.
Published: May 2012

Cancer cell invasion and induction of the metastatic cascade are often the consequence of deregulated cell adhesion and migration. There is substantial evidence for the involvement of Stat3 in cell motility, migration, and invasion under normal and pathological situations. Stat3 activation is required for induction of genes encoding MMP-1, MMP-2, and MMP-9, key components of tumor invasion. Through binding to its receptor, cmet, hepatocyte growth factor (HGF) can regulate cell survival, growth, migration, and angiogenesis. cmet is often constitutively active in human tumors and HGF/cmet signaling is at least partially mediated by Stat3. Overall, these observations suggest that positive feedback signals in the HGF/cmet/Stat3 signaling pathway contribute to tumorigenesis.

To explore the role of Stat3 in skin cell malignancy in a human cell culture model, our lab has overexpressed a dominant negative form of Stat3β in the tumorigenic SCC cell line, SRB12-p9. We established SRB12-p9 cell clones expressing FLAG-tagged Stat3β-Y705F (S3DN). Suppression of Stat3 activity impaired the ability of these cells to scatter upon stimulation with HGF, diminished their capacity to invade, and enhanced adhesion in vitro. S3DN cells also showed suppressed HGF-induced activation of cmet, as revealed by a phospho-specific cmet antibody. We next assessed the role of Stat3 in tumor invasion using in vivo mouse tumorigenicity experiments. When injected subcutaneously into immune-deficient mice, S3DN cells produced tumors that were less locally invasive, though WT tumors were more differentiated as indicated by K10 immunostaining. Upon further examination of these tumors, we found that those arising from WT cells had more intense membrane staining for total cmet and phospho-cmet than S3DN cells, indicating stronger cmet activity in these tumors. This pattern of cmet staining correlated with increased phospho-Stat3 membrane staining in the WT tumors. Western blotting revealed a decrease in MMP-2, MMP-9, and cmet expression in the S3DN cells. These results are consistent with those from the in vitro experiments. Finally, we show that S3DN may interfere with Stat3/cmet interaction, as evidenced by co-immunoprecipitation experiments, preventing the activation of cmet at the cell membrane. Ongoing studies will further address the effect of S3DN expression on cmet signaling and the effect this has on the HGF/c-met/Stat3 signaling loop and tumor cell invasion.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B40.
Abstract B47: External Qi of Yan Xin Qigong induces cell cycle arrest and apoptosis in colon cancer cells through regulation of multiple signaling pathways
Authors: Yan Xin , Shen Hua , Jiang Hongjian , Hu Dan , Zhang Chengsheng , Wang Jun , Wu Xinqi
Published: May 2012

The concept external Qi of Qigong refers to the technology and ability of “Qi deployment” therapy and health preservation of traditional Chinese medicine (TCM). External Qi therapy of TCM has long been one of the medical practices in China. Long-term clinical observations and ongoing studies have shown positive effects of external Qi of Yan Xin Qigong (YXQ-EQ) on patients of various types of cancer. The molecular and cellular mechanisms underlying YXQ-EQ's antitumor effects have recently begun to be addressed. In the present study we investigated YXQ-EQ's effects on the growth and apoptosis of human colon carcinoma HT-29 cells. We show that YXQ-EQ treatment reduced the viability and inhibited clonogenic growth of HT-29 cells. In agreement, YXQ-EQ induced cell cycle G1 arrest and apoptosis in HT-29 cells. YXQ-EQ induced apoptosis is accompanied by DNA fragmentation and cleavage of procaspase-3 and -9 and poly(ribose-ADP) polymerase. YXQ-EQ inhibited phosphorylation of Akt and GSK3β, decreased the levels of cyclin D1 and hyper-phosphorylated Rb, and repressed the expression of antiapoptic proteins Bcl-XL, XIAP, and survivin. Concomitantly, YXQ-EQ increased the expression of cyclin-dependent kinase inhibitor p21CIP1/WAF1. These findings suggest that YXQ-EQ may induce cell cycle arrest and apoptosis in colon cancer cells through regulation of multiple signaling pathways that play important roles in cell proliferation, survival and apoptosis.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B47.
Abstract B51: Discovery of novel genomic targets in the NRF2-mediated antioxidant response pathway by ChIP-on-chip and ChIP-seq
Authors: Campbell Michelle R. , Chorley Brian N. , Wang Xuting , Cho Hye-Youn , Kleeberger Steve R. , Bell Douglas A.
Published: May 2012

Sulforaphane is a dietary isothiocyanate that has been shown to have anticancer, antidiabetic and antimicrobial properties. Found in cruciferous vegetables, sulforaphane acts primarily as a phase II enzyme inducer through the pathway mediated by nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is the key transcriptional activator in this pathway, binding as a heterodimer with small Maf proteins to cis-acting antioxidant response elements (AREs) found in the promoter regions of downstream oxidative response genes. In Nrf2 knockout mice, oxidative stress exposure causes increased damage to lung, liver and neurological tissue compared to wild type mice. Conversely, an aggressive cancer phenotype has been linked to permanently activated NRF2; indicating NRF2 may directly regulate other pathways unrelated to oxidant defense. In order to investigate NRF2 binding and gene regulation on a genome wide scale, we analyzed chromatin immunoprecipitated (ChIP) NRF2-bound DNA using ChIP-on-chip and ChIP-Seq technologies. Specifically, a human lymphoblastoid cell line (HapMap GM11994) was exposed in triplicate to 10uM sulforaphane, crosslinked, sonicated and immunoprecipitated with NRF2 antibody. NRF2-bound DNA was amplified and hybridized to the Agilent Human Promoter chip, which provides −5.5 to +2.5 kilobase coverage around the majority of gene transcriptional start sites (ChIP-on-chip). Additionally, ChIP NRF2-bound DNA was sequenced using the Solexa GAII second-generation sequencing platform (ChIP-seq). ChIP-on-chip intensity data was input to Agilent's DNA analytics software and 1056 probes in promoter regions of 277 genes displayed sulforaphane - induced NRF2 binding, 20 of which had been previously identified as NRF2-regulated genes. Ingenuity pathway analysis found these 277 genes were involved in oxidative stress, cellular growth and proliferation, cellular development, small molecule biochemistry and other signaling pathways. We cross referenced the ChIP-on-chip data with results from gene expression (induction>1.2-fold/suppression <0.8-fold compared to control, p<2.5X10−6) in 60 sulforaphane-exposed HapMap lymphoblastoid cells lines as determined by Illumina microarray. We identified 32 differentially expressed genes with NRF2 binding, 17 that had not previously been described as regulated by NRF2. Preliminary analysis of the ChIP-seq data has mapped 2.1 million uniquely aligned sequencing reads resulting in 945 bound regions (high quality peaks). Of these, 5% are located near known NRF2-binding regions, and approximately 20% of the regions overlap with the ChIP-on-chip platform. Using both the ChIP-on-chip and ChIP-seq platform in this study has allowed us to investigate NRF2 on a genome-wide scale and identify novel sulforaphane-activated NRF2 gene targets.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B51.
Abstract B87: In vitro DNA binding studies of S- and R-enantiomers of organotin complexes: Antitumor activity of S-enantiomer against human tumor cell lines
Authors: Farukh Arjmand
Published: May 2012

New organotin modulated antitumor drug candidates 1 and 2 derived from R- and S- enantiomer of [4-hydroxy-1-phenylethylimino)pent-2-ol] and 2-amino-2-phenylethanol, respectively were synthesized by de novo synthetic strategy and thoroughly characterized by analytical and various spectroscopic methods. The complexes (S) / (R)−1 and 2 display trigonal bipyramidal and tetrahedral environment, respectively around the tin center. Preliminary complex-DNA interaction studies employing UV-Visible, fluorescence, and viscosity revealed that S-enantiomer displayed more propensities towards the ultimate drug target double helix DNA. This was quantified by Kb and Ksv values of (S)- and (R)-1 and 2, their ligands L and L′ which demonstrated multifold increase in case of S- enantiomer in comparison to their R- enantiomeric form. Nevertheless, both isomers displayed higher Kb values than that of cisplatin. This clearly demonstrates the chiral preference of S- enatiomer over R- enantiomer. Therefore, the in vitro antitumor activity of S-enantiomer of 1 and 2 was evaluated by the Sulforhodamine-B (SRB) assays to assess cellular proliferation against five human cell lines viz, Hop62 (human lung), DWD (human oral), K562 (human leukemia), DU145 (human prostrate) and MCF-7 (human breast). The complex (S)-1 displayed remarkably pronounced and specific activity for K562 (human leukemia) while complex (S)-2 exhibited significant activity towards Hop62 (human lung), DWD(Human oral), DU145 (human prostrate) and MCF-7 (human breast).

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B87.
Abstract CN12-02: Towards the control of melanoma
Authors: Whiteman David C.
Published: May 2012

The incidence of melanoma continues to rise in most fair-skinned populations around the world. This year, 68,720 Americans will be diagnosed with melanoma and more than 8,500 will die from the disease, an enormous toll for a largely preventable cancer. Strategies to control the burden of melanoma include primary prevention, early detection of treatable lesions, and novel therapies for established disease.

Primary prevention requires understanding of the modifiable causal factors, and then developing programs to intervene at the population level to reduce the incidence of new cases. To date, the only modifiable factor yet identified is solar ultraviolet radiation (UVR). Somewhat unusually in cancer research, the most compelling human data for a causal association between sunlight and melanoma come from ecological studies comparing the incidence of melanoma across populations, over time, and following migration. Animal models are limited in number, but mostly confirm that exposure to UVR, particularly early in life, causes melanoma. Data regarding the role of solar UVR from observational epidemiological studies is abundant but inconsistent, and data from intervention trials is almost non-existent. Thus the evidence-base with which to enact primary prevention policies for melanoma is limited. Moreover, recent epidemiologic and molecular findings indicating that melanomas arise through multiple causal pathways pose interesting new challenges for designing primary prevention interventions. Early detection is another approach to reducing the melanoma burden. The strategy to identify and remove threatening melanocytic lesions before harm ensues is widely practiced, although nowhere is this done systematically across entire populations. Several considerations have precluded the formal introduction of melanoma screening programs, particularly the low predictive value of current screening methods and the consequent costs of overdiagnosis of pigmented lesions. Research to improve screening performance, including the identification of high-risk populations using phenotypic and genotypic markers, is currently underway and may lead to new approaches.

The final pillar of melanoma control lies in finding better treatments, especially for disseminated melanoma which has proven to be largely resistant to ‘traditional’ cancer therapies. Research into the mutations occurring within melanoma tumors is anticipated to identify novel targets for treatments, as well as lead to better understanding of the causes of melanoma. Limited success has been made with c-Kit; it is hoped that other targets will follow from molecular characterization of these tumors.

This presentation will introduce these concepts, aspects of which will be addressed in more detail by the panel speakers with respect to both melanoma and keratinocyte cancers.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN12-02.
Abstract PR-04: Blood lipid and lipoprotein levels and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition
Authors: van Duijnhoven Fränzel J. , Calligaro Miriam , Jenab Mazda , Pischon Tobias , Jansen Eugène H. , Frohlich Jiri , Ayyobi Amir , Bueno-de-Mesquita H. Bas ,   for the EPIC study group
Published: May 2012

Background: Blood lipids and lipoproteins may affect colorectal cancer (CRC) risk, but results are inconsistent. We examined the relation between serum levels of total cholesterol, high density lipoprotein (HDL), low density lipoprotein, triglycerides, apo lipoprotein A–I (apoA), apo lipoprotein B and the incidence of CRC.

Methods: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 1238 first primary incident colorectal cancer cases were matched to 1238 controls by age, gender, center, time of blood collection and fasting status. Serum levels were quantitatively determined by a colorimetric method. Conditional logistic regression models were used to estimate relative risks (RRs) and 95% confidence intervals (95% CI).

Results: After adjustments, levels of HDL and apoA were inversely associated with colon cancer risk (RR for one standard deviation increase of 0.43 mmol/L in HDL and 0.32 g/L in apoA (95% CI) = 0.78 (0.68–0.89); p<0.01 and 0.82 (0.72–0.94); p<0.01, respectively) and with distal cancer risk (0.79 (0.65–0.96); p=0.02 and 0.83 (0.69–1.01); p=0.07, respectively). Although only slightly weaker, associations with proximal colon cancer risk were not statistically significant (0.82 (0.65–1.03); p=0.09 and 0.86 (0.68–1.07); p=0.18, respectively). Inclusion of other biomarkers or exclusion of the first 2 years of follow-up did not influence the association between HDL and colon cancer risk. No association was observed for rectal cancer risk.

Conclusion: These findings suggest that high HDL levels may decrease colon cancer risk. The mechanism behind this association should be further investigated.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):PR-04.
Abstract PR-07: Skin cancer concerns and genetic risk information seeking in primary care
Authors: Hay Jennifer , Kaphingst Kimberly , Li Yuelin , Baser Raymond , Alford Sharon Hensley , McBride Colleen
Published: May 2012

Skin cancers are among the most rapidly increasing cancers in the United States. The most serious form, melanoma, is relatively common in younger adults and has a high mortality rate if it becomes metastatic. Growing evidence from genome-wide association studies is identifying genetic variants associated with skin cancer risk. Accordingly, it is being suggested that genomic testing for these variants could enable personalized feedback of susceptibility to skin cancer as an innovative approach to motivate adoption of preventive behaviors. Little is known about the receptivity of healthy adults to genetic risk information for common diseases such as cancer. We investigated whether cognitive factors (worry and perceived skin cancer risk), family factors (family health history awareness, family or personal cancer history, family constellation and social influences on health), behavioral factors (sunburn and sunscreen use history), and level of general health information-seeking relate to perceived importance of learning about how genes affect personal health risks. These research questions were examined using baseline assessment data from the Multiplex Initiative, a primary-care based study examining interest and uptake of genetic susceptibility testing for eight common diseases in a large Midwestern health maintenance organization. The sample included 1959 members, ages 25–40, who had not been diagnosed with any of the eight conditions on the genetic test. About 53% of participants were female; 37% were white and 53% black. Most (75%) had at least some college education. Average level of perceived importance of learning about genes was high (X=5.55; 1–7 scale). To highlight interactions between covariates, we used recursive partitioning classification and regression trees (RPART) to identify predictors of perceived importance of learning about genes among white and black respondents. In whites, the tree correctly classified 79% of the participants, such that those participants who perceived that others close to them wanted them to learn more about keeping healthy, were highly worried about skin cancer, and reported lower perceived skin cancer risk were most likely to endorse high levels of perceived importance of learning about genes; other variables did not substantially improve model accuracy. Findings were similar for blacks. This study indicates that the perceived investment of family and friends regarding health-focused information seeking may be a primary motivator for learning about how genes affect health, and that investigation of actual and perceived social support and social influences may improve our understanding of how cognitive and information seeking processes relate to interest and uptake of genetic information in primary care settings.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):PR-07.
The mouse dorsal skinfold chamber as a model for the study of thrombolysis by intravital microscopy
Authors: Rouzaud Marie-Catherine , Loyau Stéphane , Jandrot-Perrus Martine , Bouton Marie-Christine , Boulaftali Yacine , Lamrani Lamia , Ho-Tin-Noé Benoît
Published: May 2012

Although intravital microscopy models of thrombosis in mice have contributed to dissect the mechanisms of thrombus formation and stability, they have not been well adapted to study long-term evolution of occlusive thrombi. Here, we assessed the suitability of the dorsal skinfold chamber (DSC) for the study of thrombolysis and testing of thrombolytic agents by intravital microscopy. We show that induction of FeCl3-induced occlusive thrombosis is achievable in microvessels of DSCs, and that thrombi formed in DSCs can be visualised by intravital microscopy using brightfield transmitted light, or fluorescent staining of thrombus components such as fibrinogen, platelets, leukocytes, and von Willebrand factor. Direct application of control saline or recombinant tissue-plasminogen activator (rtPA) to FeCl3-produced thrombi in DSCs did not affect thrombus size or induce recanalisation. However, in the presence of hirudin, rtPA treatment caused a rapid dose-dependent lysis of occlusive thrombi, resulting in recanalisation within 1 hour after treatment. Skin haemorrhage originating from vessels located inside and outside the FeCl3-injured area was also observed in DSCs of rtPA-treated mice. We further show that rtPA-induced thrombolysis was enhanced in plasminogen activator inhibitor-1-deficient (PAI-1−/−) mice, and dropped considerably as the time between occlusion and treatment application increased. Together, our results show that by allowing visualization and measurement of thrombus lysis and potential bleeding complications of thrombolytic treatments, the DSC provides a model for studying endogenous fibrinolysis and for first-line screening of thrombolytic agents. Furthermore, using this system, we found that thrombin and clot aging impair the thrombolytic action of rtPA towards FeCl3-produced thrombi.
Clinical Outcome of Catheter Ablation in Patients With Nonparoxysmal Atrial Fibrillation
Authors: Chao Tze-Fan , Tsao Hsuan-Ming , Lin Yenn-Jiang , Tsai Chin-Feng , Lin Wei-Shiang , Chang Shih-Lin , Lo Li-Wei , Hu Yu-Feng , Tuan Ta-Chuan , Suenari Kazuyoshi , Li Cheng-Hung , Hartono Beny , Chang Hung-Yu , Ambrose Kibos , Wu Tsu-Juey , Chen Shih-Ann
Published: May 2012

Background—

Catheter ablation of atrial fibrillation (AF) became an effective therapy for patients with drug-refractory AF, and the indications have broadened to include nonparoxysmal AF patients. However, data about the long-term effectiveness of ablation in patients with nonparoxysmal AF are lacking. The aim of the present study was to investigate the long-term outcomes of catheter ablation in patients with nonparoxysmal AF.

Methods and Results—

A total of 88 nonparoxysmal AF patients who received a stepwise catheter ablation (isolation of the pulmonary veins plus substrate modification) from 2006 to 2008 were enrolled. Freedom of recurrence was defined as the absence of atrial arrhythmias without using any antiarrhythmic agents after the catheter ablation. There were 63 patients (71.6%) with recurrences (47 patients with AF and 16 patients with atrial flutter/atrial tachycardia) after the initial procedure during a median follow-up period of 36.8 months. A CHADS
2
score of ≥3 and the left atrial (LA) diameter were significant predictors of recurrences in the multivariable analysis. Of the patients with CHADS
2
scores of ≥3 and an LA dimension ≥44 mm, all had recurrences within 1 year after the initial procedure. The overall recurrence-free rate could increase to 47.7% after the second procedure and 51.1% after the third procedure.

Conclusions—

The long-term recurrence-free rate of ablation in nonparoxysmal AF was only 28.4% after a single procedure, and multiple procedures were necessary to raise the recurrence-free rate. The CHADS
2
score and LA dimension may help us to identify patients who will have recurrences after catheter ablations of nonparoxysmal AF.
National Surveillance Definitions for Hypertension Prevalence and Control Among Adults
Authors: Crim Matthew T. , Yoon Sung Sug (Sarah) , Ortiz Eduardo , Wall Hilary K. , Schober Susan , Gillespie Cathleen , Sorlie Paul , Keenan Nora , Labarthe Darwin , Hong Yuling
Published: May 2012

Background—

Clear and consistent definitions of hypertension and hypertension control are crucial to guide diagnosis, treatment, and surveillance. A variety of surveillance definitions are in frequent use, resulting in variation of reported hypertension prevalence and control, even when based on the same data set.

Methods and Results—

To assess the variety of published surveillance definitions and rates, we performed a literature search for studies and reports that used National Health and Nutrition Examination Surveys (NHANES) data from at least as recent as the 2003 to 2004 survey cycle. We identified 19 studies that used various criteria for defining hypertension and hypertension control, as well as different parameters for age adjustment and inclusion of subpopulations. This resulted in variation of reported age-standardized hypertension prevalence from 28.9% to 32.1% and hypertension control from 35.1% to 64%. We then assessed the effects of varying the definitions of hypertension and hypertension control, parameters for age adjustment, and inclusion of subpopulations on NHANES data from both 2007 to 2008 (n=5645) and 2005 to 2008 (n=10 365). We propose standard surveillance definitions and age-adjustment parameters for hypertension and hypertension control. By using our recommended approach with NHANES 2007 to 2008 data, the age-standardized prevalence of hypertension in the United States was 29.8% (SE, 0.62%) and the rate of hypertension control was 45.8% (SE, 4.03%).

Conclusions—

Surveillance definitions of hypertension and hypertension control vary in the literature. We present standard definitions of hypertension prevalence and control among adults and standard parameters for age-adjustment and population composition that will enable meaningful population comparisons and monitoring of trends.
Use of Tissue-Type Plasminogen Activator Before and After Publication of the European Cooperative Acute Stroke Study III in Get With The Guidelines-Stroke
Authors: Messé Steven R. , Fonarow Gregg C. , Smith Eric E. , Kaltenbach Lisa , Olson DaiWai M. , Kasner Scott E. , Schwamm Lee H.
Published: May 2012

Background—

The European Cooperative Acute Stroke Study (ECASS) III demonstrated benefit to expanding the intravenous tissue-type plasminogen activator (tPA) window from 3 to 4.5 hours for patients with acute ischemic stroke (AIS). We investigated how this trial influenced use of tPA in clinical practice.

Methods and Results—

Using the Get With The Guidelines-Stroke data set, we identified 217 692 patients who presented to the hospital within 4.5 hours of AIS from April 2003 to March 2011, 106 113 before and 111 579 after the publication of ECASS III in September 2008. The proportion of patients with AIS who presented within 4.5 hours and were treated with tPA in the 3- to 4.5-hour window increased from 1.2% before ECASS III to 3.5% after (
P
<0.0001). The proportion of eligible patients with AIS presenting within 3.5 hours and treated within 4.5 hours increased from 19% (18 484/96 208) to 35% (26 888/77 309) (
P
<0.0001). ECASS III appeared to have no adverse affect on the treatment of patients who presented early because the proportion of eligible patients with AIS presenting within 2 hours and treated within 3 hours increased after ECASS III from 57% to 75% (
P
<0.0001), whereas median door-to-needle times in patients treated within 3 hours decreased from 79 to 74 minutes (
P
<0.0001).

Conclusions—

Following publication of ECASS III, there has been a significant increase in the use of tPA between 3 and 4.5 hours without adversely affecting treatment of patients in the <3-hour window. However, there remains substantial opportunity to further improve treatment rates in the later time window.
MMP-2 Regulates Erk1/2 Phosphorylation and Aortic Dilatation in Marfan Syndrome
Authors: Xiong Wanfen , Meisinger Trevor , Knispel Rebecca , Worth Jennifer M. , Baxter B. Timothy
Published: May 2012

Rationale:

Aneurysm and dissection of the ascending thoracic aorta are the main cardiovascular complications of Marfan syndrome (MFS) resulting in premature death. Studies using mouse models of MFS have shown that activation of transforming growth factor-beta (TGF-β) and the concomitant upregulation of matrix metalloproteinases (MMPs) contribute to aneurysm development. Our previous study showed that doxycycline delayed aneurysm rupture in a mouse model of MFS,

Fbn1
mgR/mgR

. Losartan has been shown to prevent aneurysms in another mouse model of MFS,

Fbn1
C1039G/+

, through inhibition of the Erk1/2 pathway. However, the role of MMP-2 in MFS and effect of losartan on the lifespan of MFS mice remain unknown.

Objective:

We investigated the role of MMP-2 in MFS and compared the effects of losartan and doxycycline on aortic dilatation and survival in

Fbn1
mgR/mgR

mice.

Methods and Results:

By life table analysis, we found that losartan and doxycycline improved the survival of

Fbn1
mgR/mgR

mice. Gelatin zymography and Western blot data showed that only doxycycline inhibited MMP-2 expression, whereas both drugs decreased Erk1/2 phosphorylation. When combined, only one of nine mice died within the 30-week study; aortic histology and diameter were normalized and the effects on Smad2 phosphorylation was additive. To further explore the role of MMP-2 in MFS, we created MMP-2–deficient

Fbn1
mgR/mgR

mice. MMP-2 deletion inhibited activation of TGF-β and phosphorylation of Erk1/2 and Smad2 and prolonged the lifespan of the mice.

Conclusions:

These studies demonstrated that inhibition of MMP-2 by doxycycline delayed the manifestations of MFS, in part, through its ability to decrease active TGF-β and the noncanonical signaling cascade downstream of TGF-β. This study further suggested that targeting TGF-β signaling at different points might be a more effective strategy for inhibiting disease progression.
NPHP4
Variants Are Associated With Pleiotropic Heart Malformations
Authors: French Vanessa M. , van de Laar Ingrid M.B.H. , Wessels Marja W. , Rohe Christan , Roos-Hesselink Jolien W. , Wang Guangliang , Frohn-Mulder Ingrid M.E. , Severijnen Lies-Anne , de Graaf Bianca M. , Schot Rachel , Breedveld Guido , Mientjes Edwin , van Tienhoven Marianne , Jadot Elodie , Jiang Zhengxin , Verkerk Annemieke , Swagemakers Sigrid , Venselaar Hanka , Rahimi Zohreh , Najmabadi Hossein , Meijers-Heijboer Hanne , de Graaff Esther , Helbing Wim A. , Willemsen Rob , Devriendt Koen , Belmont John W. , Oostra Ben A. , Amack Jeffrey D. , Bertoli-Avella Aida M.
Published: May 2012

Rationale:

Congenital heart malformations are a major cause of morbidity and mortality, especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs.

Objective:

To identify genetic mutations causing cardiac laterality defects.

Methods and Results:

We performed a genome-wide linkage analysis in patients with cardiac laterality defects from a consanguineous family. The patients had combinations of defects that included dextrocardia, transposition of great arteries, double-outlet right ventricle, atrioventricular septal defects, and caval vein abnormalities. Sequencing of positional candidate genes identified mutations in
NPHP4
. We performed mutation analysis of
NPHP4
in 146 unrelated patients with similar cardiac laterality defects. Forty-one percent of these patients also had laterality defects of the abdominal organs. We identified 8 additional missense variants that were absent or very rare in control subjects. To study the role of
nphp4
in establishing L-R asymmetry, we used antisense morpholinos to knockdown
nphp4
expression in zebrafish. Depletion of
nphp4
disrupted L-R patterning as well as cardiac and gut laterality. Cardiac laterality defects were partially rescued by human
NPHP4
mRNA, whereas mutant
NPHP4
containing genetic variants found in patients failed to rescue. We show that
nphp4
is involved in the formation of motile cilia in Kupffer's vesicle, which generate asymmetrical fluid flow necessary for normal L-R asymmetry.

Conclusions:

NPHP4
mutations are associated with cardiac laterality defects and heterotaxy. In zebrafish,
nphp4
is essential for the development and function of Kupffer's vesicle cilia and is required for global L-R patterning.
Risk Factors for Progression of Carotid Intima-Media Thickness and Total Plaque Area
Authors: Herder Marit , Johnsen Stein Harald , Arntzen Kjell Arne , Mathiesen Ellisiv B.
Published: May 2012

Background and Purpose

Data on risk factors for progression of intima-media thickness (IMT) and plaque are scarce. The objective was to determine long-term risk factors for total plaque area (TPA) and IMT as well as risk factors for progression (ΔTPA and ΔIMT).

Methods

Subjects were 1307 men and 1436 women who participated in a longitudinal population-based study with ultrasound examination of the right carotid artery at baseline and after 13 years of follow-up. Total cholesterol, high-density lipoprotein cholesterol, blood pressure, body mass index, and information about smoking habits, prevalent diabetes, and cardiovascular disease were obtained at baseline. Carotid atherosclerosis was assessed as TPA and mean IMT of plaque-free segments of the common carotid artery. Associations between z-scores of risk factors and carotid atherosclerosis were assessed in multiple linear regression models.

Results

In multivariable models, total cholesterol, systolic blood pressure, and smoking were stronger predictors of follow-up TPA than of IMT, whereas sex and age were stronger predictors of IMT. Total cholesterol (standardized β=0.081), systolic blood pressure (standardized β=0.062), and smoking (standardized β=0.107) were significant predictors of ΔTPA, whereas only total cholesterol (standardized β=0.084) was an independent predictor of ΔIMT. The variance explained by traditional cardiovascular risk factors was somewhat greater for TPA than for IMT.

Conclusions

The cardiovascular risk factors total cholesterol, smoking, and systolic blood pressure were stronger long-term predictors of TPA and TPA progression than for IMT and IMT progression.
Traditional Cardiovascular Risk Factors Explain the Minority of the Variability in Carotid Plaque
Authors: Kuo Frank , Gardener Hannah , Dong Chuanhui , Cabral Digna , Della-Morte David , Blanton Susan H. , Elkind Mitchell S.V. , Sacco Ralph L. , Rundek Tatjana
Published: May 2012

Background and Purpose—

Subclinical atherosclerotic plaque is an important marker of increased vascular risk. Identifying factors underlying the variability in burden of atherosclerotic carotid plaque unexplained by traditional vascular risk factors may help target novel preventive strategies.

Methods—

As a part of the carotid substudy of the Northern Manhattan Study (NOMAS), 1790 stroke-free individuals (mean age, 69±9; 60% women; 61% Hispanic, 19% black, 18% white) were assessed for total plaque area (TPA) burden using 2-dimensional carotid ultrasound imaging. Multiple linear regression models were constructed. Model 1 used prespecified traditional risk factors: age, sex, low-density lipoprotein cholesterol, diabetes mellitus, pack-years of smoking, blood pressure, and treatment for blood pressure; and Model 2, an addition of socioeconomic and less traditional risk factors. The contributions of the components of the Framingham heart risk score and the NOMAS Global Vascular Risk Score to the TPA were explored.

Results—

Prevalence of carotid plaque was 58%. Mean TPA was 13±19 mm
2
. Model 1 explained 19.5% of the variance in TPA burden (
R
2
=0.195). Model 2 explained 21.9% of TPA burden. Similarly, the Framingham heart risk score explained 18.8% and NOMAS global vascular risk score 21.5% of the TPA variance.

Conclusions—

The variation in preclinical carotid plaque burden is largely unexplained by traditional and less traditional vascular risk factors, suggesting that other unaccounted environmental and genetic factors play an important role in the determination of atherosclerotic plaque. Identification of these factors may lead to new approaches to prevent stroke and cardiovascular disease.
Children Writers: Methodology of the Rights-Based Approach
Authors: Habashi Janette
Published: May 2012

The paper examines the rights-based approach utilized in research with children. This approach aims to encourage children’s participation in every stage of the research process (planning, monitoring, evaluating, and writing up the results) on issues that impact their lives. The rights-based framework is more inclusive than the traditional approach that limits children’s participation to the data collection segment of the study. The traditional approach of research excludes children’s perspectives in the research agenda and therefore the implementation of the findings in social policy. Alternatively, this paper discusses the Palestinian journaling project as a prototype of transformation utilizing the rights-based approach whereby children create possibility for ownership over the agenda and the process of research. These concepts could transform child research participants from co-researchers to writers, as well as highlight the possibilities of including children at the conceptual stage of the research process.
Comparing Tropical Forest Projections from Two Generations of Hadley Centre Earth System Models, HadGEM2-ES and HadCM3LC
Authors: Good Peter , Jones Chris , Lowe Jason , Betts Richard , Gedney Nicola
Published: May 2012

Future changes in atmospheric greenhouse gas concentrations and associated influences on climate could affect the future sustainability of tropical forests. The authors report on tropical forest projections from the new Hadley Centre Global Environmental Model version 2 Earth System configuration (HadGEM2-ES) and compare them to results from the previous generation model [third climate configuration of the Met Office Unified Model in lower resolution with carbon cycle (HadCM3LC)], which had projected near-complete dieback of the Amazon rain forest for a business as usual scenario. In contrast, HadGEM2-ES projects minimal change in Amazon forest extent. The main aim of this study is a preliminary investigation of this difference between the two models. It is found that around 40% of the difference in forest dieback projections is associated with differences in the projected change in dry-season length. Differences in control climatologies of temperature and dry-season length, projected regional warming, and the forest response to climate and CO2 also all contribute to the increased survival of forest in HadGEM2-ES. However, HadGEM2-ES does not invalidate HadCM3LC: Amazon dieback remains a possible scenario of dangerous change that requires further understanding. The authors discuss the relevance to assessments of dieback risk and future work toward narrowing uncertainty about the fate of the Amazon forest.
Ocean–Atmosphere Characteristics of Tropical Instability Waves Simulated in the NCEP Climate Forecast System Reanalysis
Authors: Wen Caihong , Xue Yan , Kumar Arun
Published: May 2012

The NCEP Climate Forecast System Reanalysis (CFSR) represents a new effort with the first guess from a high-resolution coupled system and offers prospects for improved simulation of mesoscale air–sea coupled variability. This study aims to describe the characteristics of ocean–atmosphere covariability associated with tropical instability waves (TIWs) in the Pacific for the CFSR, and to assess how well they agree with in situ and satellite observations.

Multiyear daily high-resolution CFSR data are used to describe variability associated with TIWs. Results show that TIW-induced SST variations exhibit pronounced seasonal and interannual variability that are tightly connected with cold tongue variations. The analysis illustrates coherent patterns associated with TIWs, both in the ocean and the atmosphere. Moisture and air temperature maximums are located west of SST maximums, leading to downstream displacement of surface pressure minimums relative to SST maximums. Surface winds accelerate (decelerate) over warm (cold) water, and a thermally direct circulation is created. Significant signals are observed in low-level cloud cover, which are closely in phase with surface wind convergences. The magnitudes of TIW-induced surface wind, surface pressure, and cloud cover perturbations agree well with in situ and satellite observations. Further analysis shows that surface net heat flux perturbations are dominated by latent heat fluxes and have a large negative feedback on TIW SST variability (~40 W m−2 °C−1). Water vapor perturbation is the primary factor contributing to changes in latent heat fluxes, while SST-induced wind perturbation plays a secondary role. The analysis presented here highlights that the CFSR provides an unprecedented opportunity to study the physical mechanisms for the TIWs, as well as their influences on climate variability.
On the Annual Cycle, Variability, and Correlations of Oceanic Low-Topped Clouds with Large-Scale Circulation Using Aqua MODIS and ERA-Interim
Authors: Kubar Terence L. , Waliser Duane E. , Li J.-L. , Jiang Xianan
Published: May 2012

Eight years of Aqua Moderate Resolution Imaging Spectroradiometer (MODIS) level-3 cloud data in conjunction with collocated Interim ECMWF Re-Analysis are used to investigate relationships between isolated low-topped cloud fraction (LCF) and dynamics/thermodynamics versus averaging time scale. Correlation coefficients between LCF and −SST exceed 0.70 over 56% of ocean regions from 25°S to 25°N for 90-day running means and exceed 0.70 between LCF and 500-hPa omega (ω500) for over one-third of oceans from 50°S to 50°N. Correlations increase most dramatically by increasing the averaging time scale from 1 day to about 15, owing to the large LCF synoptic variability and random effects that are suppressed by averaging. In five regions selected with monthly mean SSTs between 291 and 303 K, SST decreases by −0.13 K %-1 low-cloud cover increase. Monthly LCF is also correlated with estimated inversion strength (EIS), which is SST dominated in low latitudes and free tropospheric temperature dominated in the northeast Atlantic, Pacific, and midlatitudes, though SST and stability are poor predictors of LCF over the southern oceans.

Where the fraction of variance explained by the annual LCF harmonic is high, maximum LCF tends to lead minimum SST by ~15–30 days such that clouds can amplify the SST annual cycle, especially when LCF maxima coexist with insolation minima. Monthly mean LCF tends to scale with ω500 exponentially over the convective margins and offshore of the Pacific Northwest, but daily climatology relationships indicate that LCF levels off and even diminishes for ω500 > 0.05 Pa s−1, suggesting a limit through, perhaps, a too strong suppression of boundary layer heights. This suggests the need for dynamic-regime analysis in diagnosing low cloud/circulation feedbacks.
Ocean Heat Transport and Water Vapor Greenhouse in a Warm Equable Climate: A New Look at the Low Gradient Paradox
Authors: Rose Brian E. J. , Ferreira David
Published: May 2012

The authors study the role of ocean heat transport (OHT) in the maintenance of a warm, equable, ice-free climate. An ensemble of idealized aquaplanet GCM calculations is used to assess the equilibrium sensitivity of global mean surface temperature and its equator-to-pole gradient (ΔT) to variations in OHT, prescribed through a simple analytical formula representing export out of the tropics and poleward convergence. Low-latitude OHT warms the mid- to high latitudes without cooling the tropics; increases by 1°C and ΔT decreases by 2.6°C for every 0.5-PW increase in OHT across 30° latitude. This warming is relatively insensitive to the detailed meridional structure of OHT. It occurs in spite of near-perfect atmospheric compensation of large imposed variations in OHT: the total poleward heat transport is nearly fixed.

The warming results from a convective adjustment of the extratropical troposphere. Increased OHT drives a shift from large-scale to convective precipitation in the midlatitude storm tracks. Warming arises primarily from enhanced greenhouse trapping associated with convective moistening of the upper troposphere. Warming extends to the poles by atmospheric processes even in the absence of high-latitude OHT.

A new conceptual model for equable climates is proposed, in which OHT plays a key role by driving enhanced deep convection in the midlatitude storm tracks. In this view, the climatic impact of OHT depends on its effects on the greenhouse properties of the atmosphere, rather than its ability to increase the total poleward energy transport.
A Simple Groundwater Scheme for Hydrological and Climate Applications: Description and Offline Evaluation over France
Authors: Vergnes J.-P. , Decharme B. , Alkama R. , Martin E. , Habets F. , Douville H.
Published: May 2012

Despite their potential influences on surface water and climate, groundwater processes are generally not represented in climate models. Here, a simple groundwater scheme including two-dimensional flow dynamics and accounting for groundwater–river exchanges is introduced into the global Total Runoff Integrated Pathways (TRIP) river routing model coupled to the Météo-France climate model. This original scheme is tested in offline mode over France at high () and low (0.5°) resolution against a dense network of river discharge and water table observations over the 1970–2010 period, and is compared to the fine-tuned Système d’Analyze Fournissant des Renseignements Atmosphériques à la Neige (SAFRAN)–Interactions between Soil, Biosphere, and Atmosphere (ISBA) coupled hydrometeorological model (MODCOU). In addition, the simulated terrestrial water storage (TWS) variations are compared to the TWS estimates from the Gravity Recovery and Climate Experiment (GRACE) satellite mission. The aquifer basins over France are defined using the World-wide Hydrogeological Mapping and Assessment Programme (WHYMAP) groundwater resources map, a simplified French lithological map, and the International Geological Map of Europe (IGME). TRIP is forced by daily runoff and drainage data derived from a preexisting simulation of the ISBA land surface scheme driven by the high-resolution SAFRAN meteorological analysis. Four simulations are carried out with or without groundwater at both resolutions. Results show that the groundwater scheme allows TRIP to better capture the spatiotemporal variability of the observed river discharges and piezometric heads. Summer base flows are particularly improved over the main rivers of France. Decreasing the horizontal resolution has a limited impact on the simulated discharges, while it slightly degrades the simulation of water table variations.
First-Order Scaling Law for Potential Vorticity Extraction due to Wind
Authors: Deremble Bruno , Dewar W. K.
Published: May 2012

Surface sources and sinks of potential vorticity (PV) have been examined recently in various publications. These are normally identified as the mechanical and buoyant PV fluxes with the former scaled according to wind stress and the latter from buoyancy flux. The authors here examine a PV source that is often overlooked: namely, the diabatically forced source due to wind-driven deepening.

Based on an idealized model of the mixed layer, the rate of deepening of the mixed layer due to wind is translated into PV extraction. The authors propose the first-order scaling law as an estimate of the net PV flux due to diabatic wind effects in the absence of other buoyancy effects. This law is verified and calibrated in several numerical experiments. Then, the authors compare the magnitude of the PV extraction due to wind to the other factors responsible for PV input/output: namely, air–sea heat flux, freshwater flux, and Ekman wind-driven currents. Finally, to illustrate the impact of the mixing induced by wind, the authors conclude with a global air–sea PV budget in the North Atlantic basin. The wind-driven diabatic PV flux is found to be comparable to all other sources in all cases and is distinguished by acting only to extract PV.
SSH Wavenumber Spectra in the North Pacific from a High-Resolution Realistic Simulation
Authors: Sasaki Hideharu , Klein Patrice
Published: May 2012

Following recent studies based on altimetric data, this paper analyses the spectral characteristics of the sea surface height (SSH) using a new realistic simulation of the North Pacific Ocean with high resolution ( in the horizontal and 100 vertical levels). This simulation resolves smaller scales (down to ≈10 km) than altimetric data (limited to 70 km because of the noise level). In high eddy kinetic energy (EKE) regions (as in the western part), SSH spectral slope almost follows a k−4 (with k the wavenumber) or slightly steeper law in agreement with altimeter studies. The new result is that, unlike altimeter studies, such a k−4 slope is also observed in low EKE regions (as in the eastern part). In these regions, this slope mostly concerns scales not well resolved by altimetric data. Such k−4 SSH spectral slopes are weaker from what is expected from quasigeostrophic turbulence theory but closer to surface quasigeostrophic (SQG) turbulence theory. The consequence is that the small scales concerned by these spectral slopes, in particular in low EKE regions, may significantly affect the larger ones because of the inverse kinetic energy cascade. These results need to be confirmed using a longer numerical integration. They also need to be corroborated by high-resolution observations.