bluuebunny/crossref_metadata_2025 huggingface dataset:
APOBEC3 versus Retroviruses, Immunity versus Invasion: Clash of the Titans
Authors: Sheehy Ann M. , Erthal Julie
Published: June 2012

Since the identification of APOBEC3G (A3G) as a potent restriction factor of HIV-1, a tremendous amount of effort has led to a broadened understanding of both A3G and the APOBEC3 (A3) family to which it belongs. In spite of the fine-tuned viral counterattack to A3 activity, in the form of the HIV-1 Vif protein, enthusiasm for leveraging the Vif : A3G axis as a point of clinical intervention remains high. In an impressive explosion of information over the last decade, additional A3 family members have been identified as antiviral proteins, mechanistic details of the restrictive capacity of these proteins have been elucidated, structure-function studies have revealed important molecular details of the Vif : A3G interaction, and clinical cohorts have been scrutinized for correlations between A3 expression and function and viral pathogenesis. In the last year, novel and unexpected findings regarding the role of A3G in immunity have refocused efforts on exploring the potential of harnessing the natural power of this immune defense. These most recent reports allude to functions of the A3 proteins that extend beyond their well-characterized designation as restriction factors. The emerging story implicates the A3 family as not only defense proteins, but also as participants in the broader innate immune response.
Development of a Cloud‐Point Extraction Method for Cobalt Determination in Natural Water Samples
Authors: Jamali Mohammad Reza , Gholinezhad Mohammad , Balarostaghi Saiedeh , Rahnama Reyhaneh , Rahimi Seyed Hojjat Allah
Published: June 2012

A new, simple, and versatile cloud‐point extraction (CPE) methodology has been developed for the separation and preconcentration of cobalt. The cobalt ions in the initial aqueous solution were complexed with 4‐Benzylpiperidinedithiocarbamate, and Triton X‐114 was added as surfactant. Dilution of the surfactant‐rich phase with acidified ethanol was performed after phase separation, and the cobalt content was measured by flame atomic absorption spectrometry. The main factors affecting CPE procedure, such as pH, concentration of ligand, amount of Triton X‐114, equilibrium temperature, and incubation time were investigated and optimized. Under the optimal conditions, the limit of detection (LOD) for cobalt was 0.5 μg L−1, with sensitivity enhancement factor (EF) of 67. Calibration curve was linear in the range of 2–150 μg L−1, and relative standard deviation was 3.2% (c = 100 μg L−1; n = 10). The proposed method was applied to the determination of trace cobalt in real water samples with satisfactory analytical results.
Vav3-Rac1 Signaling Regulates Prostate Cancer Metastasis with Elevated Vav3 Expression Correlating with Prostate Cancer Progression and Posttreatment Recurrence
Authors: Lin Kai-Ti , Gong Jianli , Li Chien-Feng , Jang Te-Hsuan , Chen Wen-Ling , Chen Huei-Jane , Wang Lu-Hai
Published: June 2012

Prostate cancer remains the second leading cause of cancer death in men in the Western world. Yet current therapies do not significantly improve the long-term survival of patients with distant metastasis. In this study, we investigated the role of the guanine nucleotide exchange factor Vav3 in prostate cancer progression and metastasis and found that Vav3 expression correlated positively with prostate cancer cell migration and invasion. Stimulation of the receptor tyrosine kinase EphA2 by ephrinA1 resulted in recruitment and tyrosine phosphorylation of Vav3, leading to Rac1 activation as well as increased migration and invasion in vitro. Reduction of Vav3 resulted in fewer para-aortic lymph nodes and bone metastasis in vivo. Clinically, expression of Vav3 and EphA2 was elevated in late-stage and metastatic prostate cancers. Among patients with stage IIB or earlier prostate cancer, higher Vav3 expression correlated with lower cumulative biochemical failure-free survival, suggesting that Vav3 may represent a prognostic marker for posttreatment recurrence of prostate cancer. Together, our findings provide evidence that the Vav3-mediated signaling pathway may serve as a therapeutic target for prostate cancer metastasis. Cancer Res; 72(12); 3000–9. ©2012 AACR.
Dishonorable Discharge: The Oncogenic Roles of Cleaved E-Cadherin Fragments
Authors: David Justin M. , Rajasekaran Ayyappan K.
Published: June 2012

Strong cell–cell interactions represent a major barrier against cancer cell mobility, and loss of intercellular adhesion by E-cadherin is a fundamental change that occurs during the progression of cancer to invasive disease. However, some aggressive carcinomas retain characteristics of differentiated epithelial cells, including E-cadherin expression. Emerging evidence indicates that proteolysis of E-cadherin generates fragments that promote tumor growth, survival, and motility, suggesting that E-cadherin cleavage converts this tumor suppressor into an oncogenic factor. In this review we discuss the emerging roles of cleaved E-cadherin fragments as modulators of cancer progression, and explore the translational and clinical implications of this research. Cancer Res; 72(12); 2917–23. ©2012 AACR.
Targeting of a Conformationally Exposed, Tumor-Specific Epitope of EGFR as a Strategy for Cancer Therapy
Authors: Gan Hui K. , Burgess Antony W. , Clayton Andrew H. A. , Scott Andrew M.
Published: June 2012

Epidermal growth factor receptor (EGFR) and its most common extracellular mutant, EGFRvIII, are important therapeutic targets in multiple cancer types. A number of monoclonal antibodies and small-molecule inhibitors against these receptors are now used for anticancer treatments. New insights into the structure and function of these receptors illustrate how they can be targeted in novel ways, with expected improvements in the therapeutic efficacy. Monoclonal antibody 806 (mAb806) is an antibody that targets a conformationally exposed epitope of wild-type EGFR when it is overexpressed on tumor cells or in the presence of oncogenic mutations such as EGFRvIII. The mechanism of action of mAb806, which allows for EGFR inhibition without normal tissue toxicity, creates opportunities for combination therapy and strongly suggests mAb806 will be a superior targeted delivery system for antitumor agents. Targeting of the epitope for mAb806 also appears to be an improved strategy to inhibit tumors that express EGFRvIII. This concept of conformational epitope targeting by antibodies reflects an underlying interplay between the structure and biology of different conformational forms of the EGFR family. Cancer Res; 72(12); 2924–30. ©2012 AACR.
The Oncogenic Lung Cancer Fusion Kinase CD74-ROS Activates a Novel Invasiveness Pathway through E-Syt1 Phosphorylation
Authors: Jun Hyun Jung , Johnson Hannah , Bronson Roderick T. , de Feraudy Sebastien , White Forest , Charest Alain
Published: June 2012

Patients with lung cancer often present with metastatic disease and therefore have a very poor prognosis. The recent discovery of several novel ROS receptor tyrosine kinase molecular alterations in non–small cell lung cancer (NSCLC) presents a therapeutic opportunity for the development of new targeted treatment strategies. Here, we report that the NSCLC-derived fusion CD74-ROS, which accounts for 30% of all ROS fusion kinases in NSCLC, is an active and oncogenic tyrosine kinase. We found that CD74-ROS–expressing cells were highly invasive in vitro and metastatic in vivo. Pharmacologic inhibition of CD74-ROS kinase activity reversed its transforming capacity by attenuating downstream signaling networks. Using quantitative phosphoproteomics, we uncovered a mechanism by which CD74-ROS activates a novel pathway driving cell invasion. Expression of CD74-ROS resulted in the phosphorylation of the extended synaptotagmin-like protein E-Syt1. Elimination of E-Syt1 expression drastically reduced invasiveness both in vitro and in vivo without modifying the oncogenic activity of CD74-ROS. Furthermore, expression of CD74-ROS in noninvasive NSCLC cell lines readily conferred invasive properties that paralleled the acquisition of E-Syt1 phosphorylation. Taken together, our findings indicate that E-Syt1 is a mediator of cancer cell invasion and molecularly define ROS fusion kinases as therapeutic targets in the treatment of NSCLC. Cancer Res; 72(15); 3764–74. ©2012 AACR.
Inhibitory Roles of Signal Transducer and Activator of Transcription 3 in Antitumor Immunity during Carcinogen-Induced Lung Tumorigenesis
Authors: Ihara Shoichi , Kida Hiroshi , Arase Hisashi , Tripathi Lokesh P. , Chen Yi-An , Kimura Tetsuya , Yoshida Mitsuhiro , Kashiwa Yozo , Hirata Haruhiko , Fukamizu Reiko , Inoue Ruriko , Hasegawa Kana , Goya Sho , Takahashi Ryo , Minami Toshiyuki , Tsujino Kazuyuki , Suzuki Mayumi , Kohmo Satoshi , Inoue Koji , Nagatomo Izumi , Takeda Yoshito , Kijima Takashi , Mizuguchi Kenji , Tachibana Isao , Kumanogoh Atsushi
Published: June 2012

Stat3 mediates a complex spectrum of cellular responses, including inflammation, cell proliferation, and apoptosis. Although evidence exists in support of a positive role for Stat3 in cancer, its role has remained somewhat controversial because of insufficient study of how its genetic deletion may affect carcinogenesis in various tissues. In this study, we show using epithelium-specific knockout mice (Stat3Δ/Δ) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3Δ/Δ mice did not show any lung defects in terms of proliferation, apoptosis, or angiogenesis, they exhibited reduced urethane-induced tumorigenesis and increased antitumor inflammation and natural killer (NK) cell immunity. Comparative microarray analysis revealed an increase in Stat3Δ/Δ tumors in proinflammatory chemokine production and a decrease in MHC class I antigen expression associated with NK cell recognition. Consistent with these findings, human non–small cell lung cancer (NSCLC) cells in which Stat3 was silenced displayed an enhancement of proinflammatory chemokine production, reduced expression of MHC class I antigen, and increased susceptibility to NK cell–mediated cytotoxicity. In addition, supernatants from Stat3-silenced NSCLC cells promoted monocyte migration. Collectively, our findings argue that Stat3 exerts an inhibitory effect on antitumor NK cell immunity in the setting of carcinogen-induced tumorigenesis. Cancer Res; 72(12); 2990–9. ©2012 AACR.
Molecular Signature of Smoking in Human Lung Tissues
Authors: Bossé Yohan , Postma Dirkje S. , Sin Don D. , Lamontagne Maxime , Couture Christian , Gaudreault Nathalie , Joubert Philippe , Wong Vivien , Elliott Mark , van den Berge Maarten , Brandsma Corry A. , Tribouley Catherine , Malkov Vladislav , Tsou Jeffrey A. , Opiteck Gregory J. , Hogg James C. , Sandford Andrew J. , Timens Wim , Paré Peter D. , Laviolette Michel
Published: June 2012

Cigarette smoking is the leading risk factor for lung cancer. To identify genes deregulated by smoking and to distinguish gene expression changes that are reversible and persistent following smoking cessation, we carried out genome-wide gene expression profiling on nontumor lung tissue from 853 patients with lung cancer. Gene expression levels were compared between never and current smokers, and time-dependent changes in gene expression were studied in former smokers. A total of 3,223 transcripts were differentially expressed between smoking groups in the discovery set (n = 344, P < 1.29 × 10−6). A substantial number of smoking-induced genes also were validated in two replication sets (n = 285 and 224), and a gene expression signature of 599 transcripts consistently segregated never from current smokers across all three sets. The expression of the majority of these genes reverted to never-smoker levels following smoking cessation, although the time course of normalization differed widely among transcripts. Moreover, some genes showed very slow or no reversibility in expression, including SERPIND1, which was found to be the most consistent gene permanently altered by smoking in the three sets. Our findings therefore indicate that smoking deregulates many genes, many of which reverse to normal following smoking cessation. However, a subset of genes remains altered even decades following smoking cessation and may account, at least in part, for the residual risk of lung cancer among former smokers. Cancer Res; 72(15); 3753–63. ©2012 AACR.
Best Practices in Cancer Nanotechnology: Perspective from NCI Nanotechnology Alliance
Authors: Zamboni William C. , Torchilin Vladimir , Patri Anil K. , Hrkach Jeff , Stern Stephen , Lee Robert , Nel Andre , Panaro Nicholas J. , Grodzinski Piotr
Published: June 2012

Historically, treatment of patients with cancer using chemotherapeutic agents has been associated with debilitating and systemic toxicities, poor bioavailability, and unfavorable pharmacokinetics. Nanotechnology-based drug delivery systems, on the other hand, can specifically target cancer cells while avoiding their healthy neighbors, avoid rapid clearance from the body, and be administered without toxic solvents. They hold immense potential in addressing all of these issues, which has hampered further development of chemotherapeutics. Furthermore, such drug delivery systems will lead to cancer therapeutic modalities that are not only less toxic to the patient but also significantly more efficacious. In addition to established therapeutic modes of action, nanomaterials are opening up entirely new modalities of cancer therapy, such as photodynamic and hyperthermia treatments. Furthermore, nanoparticle carriers are also capable of addressing several drug delivery problems that could not be effectively solved in the past and include overcoming formulation issues, multidrug-resistance phenomenon, and penetrating cellular barriers that may limit device accessibility to intended targets, such as the blood–brain barrier. The challenges in optimizing design of nanoparticles tailored to specific tumor indications still remain; however, it is clear that nanoscale devices carry a significant promise toward new ways of diagnosing and treating cancer. This review focuses on future prospects of using nanotechnology in cancer applications and discusses practices and methodologies used in the development and translation of nanotechnology-based therapeutics. Clin Cancer Res; 18(12); 3229–41. ©2012 AACR.
Genetic Polymorphisms in MicroRNA-Related Genes as Predictors of Clinical Outcomes in Colorectal Adenocarcinoma Patients
Authors: Lin Moubin , Gu Jian , Eng Cathy , Ellis Lee M. , Hildebrandt Michelle A. , Lin Jie , Huang Maosheng , Calin George A. , Wang Dingzhi , DuBois Raymond N. , Hawk Ernest T. , Wu Xifeng
Published: June 2012

Purpose: To evaluate the effects of single-nucleotide polymorphisms (SNP) in microRNA-related genes on clinical outcomes in patients with colorectal cancer (CRC) receiving first-line fluoropyrimidine-based chemotherapy.

Experimental Design: Forty-one SNPs in 26 microRNA-related genes were genotyped in 1,097 patients with CRC recruited at the University of Texas MD Anderson Cancer Center (Houston, TX). Patients were enrolled between 1990 and 2008 and last follow-up was in 2010. The associations between genotypes and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) stratified by clinical stage were analyzed in 741 newly diagnosed patients (diagnosed within 1 year) and replicated the findings in an additional 356 patients.

Results: In patients with stage III disease, mir608: rs4919510 was associated with increased risk for both recurrence [HR, 2.72; 95% confidence interval (CI), 1.38–5.33] and death (HR, 3.53; 95%CI, 1.42–8.73). The associations were confirmed in the replication set, and the combined HRs for training and replication sets were 1.65 (95% CI, 1.13–2.41) for recurrence and 1.96 (95% CI, 1.19–3.21) for death, respectively. The mir219-1:rs213210 showed consistent association with death in the training set (HR, 3.86; 95% CI, 1.33–11.22), the replication set (HR, 3.33; 95% CI, 1.39–7.98), and combined data set (HR, 3.22; 95% CI, 1.70–6.10). In combined analysis of these two SNPs, patients carrying the variant genotypes at both sites exhibited a 5.6-fold increased risk of death.

Conclusion: Genetic polymorphisms in the microRNA pathway may predict prognosis in patients with stage III CRC treated with fluoropyrimidine-based chemotherapy. Clin Cancer Res; 18(14); 3982–91. ©2012 AACR.
Analysis of Receptor Tyrosine Kinase ROS1-Positive Tumors in Non–Small Cell Lung Cancer: Identification of a FIG-ROS1 Fusion
Authors: Rimkunas Victoria M. , Crosby Katherine E. , Li Daiqiang , Hu Yerong , Kelly Meghan E. , Gu Ting-Lei , Mack Jennifer S. , Silver Matthew R. , Zhou Xinmin , Haack Herbert
Published: June 2012

Purpose: To deepen our understanding of mutant ROS1 expression, localization, and frequency in non–small cell lung cancer (NSCLC), we developed a highly specific and sensitive immunohistochemistry (IHC)-based assay that is useful for the detection of wild-type and mutant ROS1.

Experimental Design: We analyzed 556 tumors with the ROS1 D4D6 rabbit monoclonal antibody IHC assay to assess ROS1 expression levels and localization. A subset of tumors was analyzed by FISH to determine the percentage of these tumors harboring ROS1 translocations. Using specific and sensitive IHC assays, we analyzed the expression of anaplastic lymphoma kinase (ALK), EGFR L858R, and EGFR E746-A750del mutations in a subset of lung tumors, including those expressing ROS1.

Results: In our NSCLC cohort of Chinese patients, we identified 9 (1.6%) tumors expressing ROS1 and 22 (4.0%) tumors expressing ALK. FISH identified tumors with ALK or ROS1 rearrangements, and IHC alone was capable of detecting all cases with ALK and ROS1 rearrangements. ROS1 fusion partners were determined by reverse transcriptase PCR identifying CD74-ROS1, SLC34A2-ROS1, and FIG-ROS1 fusions. Some of the ALK and ROS1 rearranged tumors may also harbor coexisting EGFR mutations.

Conclusions: NSCLC tumors with ROS1 rearrangements are uncommon in the Chinese population and represent a distinct entity of carcinomas. The ROS1 IHC assay described here is a valuable tool for identifying patients expressing mutant ROS1 and could be routinely applied in clinical practice to detect lung cancers that may be responsive to targeted therapies. Clin Cancer Res; 18(16); 4449–57. ©2012 AACR.
Emerging Roles of Angiopoietin-like 4 in Human Cancer
Authors: Tan Ming Jie , Teo Ziqiang , Sng Ming Keat , Zhu Pengcheng , Tan Nguan Soon
Published: June 2012

Angiopoietin-like 4 (ANGPTL4) is best known for its role as an adipokine involved in the regulation of lipid and glucose metabolism. The characterization of ANGPTL4 as an adipokine is largely due to our limited understanding of the interaction partners of ANGPTL4 and how ANGPTL4 initiates intracellular signaling. Recent findings have revealed a critical role for ANGPTL4 in cancer growth and progression, anoikis resistance, altered redox regulation, angiogenesis, and metastasis. Emerging evidence suggests that ANGPTL4 function may be drastically altered depending on the proteolytic processing and posttranslational modifications of ANGPTL4, which may clarify several conflicting roles of ANGPTL4 in different cancers. Although the N-terminal coiled-coil region of ANGPTL4 has been largely responsible for the endocrine regulatory role in lipid metabolism, insulin sensitivity, and glucose homeostasis, it has now emerged that the COOH-terminal fibrinogen-like domain of ANGPTL4 may be a key regulator in the multifaceted signaling during cancer development. New insights into the mechanistic action of this functional domain have opened a new chapter into the possible clinical application of ANGPTL4 as a promising candidate for clinical intervention in the fight against cancer. This review summarizes our current understanding of ANGPTL4 in cancer and highlights areas that warrant further investigation. A better understanding of the underlying cellular and molecular mechanisms of ANGPTL4 will reveal novel insights into other aspects of tumorigenesis and the potential therapeutic value of ANGPTL4. Mol Cancer Res; 10(6); 677–88. ©2012 AACR.
Resveratrol Helps Recovery from Fatty Liver and Protects against Hepatocellular Carcinoma Induced by Hepatitis B Virus X Protein in a Mouse Model
Authors: Lin Hsiu-Ching , Chen Yi-Fan , Hsu Wen-Hsin , Yang Chu-Wen , Kao Cheng-Heng , Tsai Ting-Fen
Published: June 2012

Resveratrol is a natural polyphenol that has beneficial effects across species and various disease models. Here, we investigate whether resveratrol is effective against hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) using HBV X protein (HBx) transgenic mice. We found that resveratrol (30 mg/kg/d) has a therapeutic effect on HBx-induced fatty liver and the early stages of liver damage. Resveratrol decreased intracellular reactive oxygen species and transiently stimulated hepatocyte proliferation. Interestingly, resveratrol inhibited LXRα and downregulated the expression of the lipogenic genes, Srebp1-c and PPARγ. The decrease in Srebp1-c seems to further downregulate the expression of its target genes, Acc and Fas. In addition, resveratrol stimulated the activity of Ampk and SirT1. Thus, resveratrol has a pleiotropic effect on HBx transgenic mice in terms of the downregulation of lipogenesis, the promotion of transient liver regeneration, and the stimulation of antioxidant activity. Furthermore, at the later precancerous stages, resveratrol delayed HBx-mediated hepatocarcinogenesis and reduced HCC incidence from 80% to 15%, a 5.3-fold reduction. Resveratrol should be considered as a potential chemopreventive agent for HBV-associated HCC. Cancer Prev Res; 5(7); 952–62. ©2012 AACR.
Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy
Authors: Kalra Sukirti , Knatko Elena V. , Zhang Ying , Honda Tadashi , Yamamoto Masayuki , Dinkova-Kostova Albena T.
Published: June 2012

Chronic treatment with azathioprine, a highly effective anti-inflammatory and immunosuppressive agent, profoundly increases the risk for development of unusually aggressive cutaneous squamous cell carcinoma. Its ultimate metabolite, 6-thioguanine (6-TG) nucleotide, is incorporated in DNA of skin cells, and upon exposure to UVA radiation, causes oxidative stress, followed by damage of DNA and associated proteins. The acetylenic tricyclic bis(cyano enone) TBE-31 is a strong inhibitor of inflammation and a potent inducer of the Keap1/Nrf2/ARE pathway, which orchestrates the expression of a large network of cytoprotective genes. We now report that long-term (five days per week for four weeks) topical daily applications of small (200 nmol) quantities of TBE-31 cause a robust systemic induction of the Keap1/Nrf2/ARE pathway and decreases the 6-TG incorporation in DNA of skin, blood, and liver of azathioprine-treated mice, indicating extraordinary bioavailability and efficacy. In addition, TBE-31, at nanomolar concentrations, protects cells with 6-TG in their genomic DNA against oxidative stress caused by UVA radiation through induction of the Keap1/Nrf2/ARE pathway. At the same 6-TG DNA levels, Keap1-knockout cells, in which the pathway is constitutively upregulated, are highly resistant to UVA radiation–induced oxidative stress. The protective effects of both the Keap1-knockout genotype and TBE-31 are completely lost in the absence of transcription factor Nrf2. Our findings suggest that compounds of this kind are excellent candidates for mechanism-based chemoprotective agents against conditions in which oxidative stress and inflammation underlie disease pathogenesis. Moreover, their potential skin patch incorporation for transdermal delivery is an exciting possibility. Cancer Prev Res; 5(7); 973–81. ©2012 AACR.
Common Variation in Fatty Acid Genes and Resuscitation From Sudden Cardiac Arrest
Authors: Johnson Catherine O. , Lemaitre Rozenn N. , Fahrenbruch Carol E. , Hesselson Stephanie , Sotoodehnia Nona , McKnight Barbara , Rice Kenneth M. , Kwok Pui-Yan , Siscovick David S. , Rea Thomas D.
Published: June 2012

Background—

Fatty acids provide energy and structural substrates for the heart and brain and may influence resuscitation from sudden cardiac arrest (SCA). We investigated whether genetic variation in fatty acid metabolism pathways was associated with SCA survival.

Methods and Results—

Subjects (mean age, 67 years; 80% male, white) were out-of-hospital SCA patients found in ventricular fibrillation in King County, WA. We compared subjects who survived to hospital admission (n=664) with those who did not (n=689), and subjects who survived to hospital discharge (n=334) with those who did not (n=1019). Associations between survival and genetic variants were assessed using logistic regression adjusting for age, sex, location, time to arrival of paramedics, whether the event was witnessed, and receipt of bystander cardiopulmonary resuscitation. Within-gene permutation tests were used to correct for multiple comparisons. Variants in 5 genes were significantly associated with SCA survival. After correction for multiple comparisons, single-nucleotide polymorphisms in
ACSL1
and
ACSL3
were significantly associated with survival to hospital admission. Single-nucleotide polymorphisms in
ACSL3, AGPAT3, MLYCD,
and
SLC27A6
were significantly associated with survival to hospital discharge.

Conclusions—

Our findings indicate that variants in genes important in fatty acid metabolism are associated with SCA survival in this population.
Cardiovascular Remodeling in Response to Long-Term Exposure to Fine Particulate Matter Air Pollution
Authors: Wold Loren E. , Ying Zhekang , Hutchinson Kirk R. , Velten Markus , Gorr Matthew W. , Velten Christina , Youtz Dane J. , Wang Aixia , Lucchesi Pamela A. , Sun Qinghua , Rajagopalan Sanjay
Published: June 2012

Background—

Air pollution is a pervasive environmental health hazard that occurs over a lifetime of exposure in individuals from many industrialized societies. However, studies have focused primarily on exposure durations that correspond to only a portion of the lifespan. We therefore tested the hypothesis that exposure over a considerable portion of the lifespan would induce maladaptive cardiovascular responses.

Methods and Results—

C57BL/6 male mice were exposed to concentrated ambient particles <2.5
µ
m (particulate matter, PM or PM
2.5
) or filtered air (FA), 6 h/d, 5 d/wk, for 9 months. Assessment of cardiac contractile function, coronary arterial flow reserve, isolated cardiomyocyte function, expression of hypertrophic markers, calcium handling proteins, and cardiac fibrosis were then performed. Mean daily concentrations of PM
2.5
in the exposure chamber versus ambient daily PM
2.5
concentration at the study site were 85.3 versus 10.6
µ
g/m

3

(7.8-fold concentration), respectively. PM
2.5
exposure resulted in increased hypertrophic markers leading to adverse ventricular remodeling characterized by myosin heavy chain (MHC) isoform switch and fibrosis, decreased fractional shortening (39.8 ± 1.4 FA versus 27.9 ± 1.3 PM, FS%), and mitral inflow patterns consistent with diastolic dysfunction (1.95 ± 0.05 FA versus 1.52 ± 0.07 PM, E/A ratio). Contractile reserve to dobutamine was depressed (62.3 ± 0.9 FA versus 49.2 ± 1.5 PM, FS%) in response to PM
2.5
without significant alterations in maximal vasodilator flow reserve. In vitro cardiomyocyte function revealed depressed peak shortening (8.7 ± 0.6 FA versus 7.0 ± 0.4 PM, %PS) and increased time-to-90% shortening (72.5 ± 3.2 FA versus 82.8 ± 3.2 PM, ms) and relengthening (253.1 ± 7.9 FA versus 282.8 ± 9.3 PM, ms), which were associated with upregulation of profibrotic markers and decreased total antioxidant capacity. Whole-heart SERCA2a levels and the ratio of
α
/
β
-MHC were both significantly decreased (
P
<0.05) in PM
2.5
-exposed animals, suggesting a switch to fetal programming.

Conclusions—

Long-term exposure to environmentally relevant concentrations of PM
2.5
resulted in a cardiac phenotype consistent with incipient heart failure.
Mechanistic Evaluation of Echocardiographic Dyssynchrony Indices
Authors: Lumens Joost , Leenders Geert E. , Cramer Maarten J. , De Boeck Bart W. L. , Doevendans Pieter A. , Prinzen Frits W. , Delhaas Tammo
Published: June 2012

Background—

The power of echocardiographic dyssynchrony indices to predict response to cardiac resynchronization therapy (CRT) appears to vary between indices and between studies. We investigated whether the variability of predictive power between the dyssynchrony indices can be explained by differences in their operational definitions.

Methods and Results—

In 132 CRT-candidates (left ventricular [LV] ejection fraction, 19 ± 6%; QRS width, 170 ± 22 ms), 4 mechanical dyssynchrony indices (septal systolic rebound stretch [SRSsept], interventricular mechanical dyssynchrony [IVMD], septal-to-lateral peak shortening delay [Strain-SL], and septal-to-posterior wall motion delay [SPWMD]) were quantified at baseline. CRT response was quantified as 6-month percent change of LV end-systolic volume. Multiscale computer simulations of cardiac mechanics and hemodynamics were used to assess the relationships between dyssynchrony indices and CRT response within wide ranges of dyssynchrony of LV activation and reduced contractility. In patients, SRSsept showed best correlation with CRT response followed by IVMD, Strain-SL, and SPWMD (
R
=−0.56, −0.50, −0.48, and −0.39, respectively; all
P
<0.01). In patients and simulations, SRSsept and IVMD showed a continuous linear relationship with CRT response, whereas Strain-SL and SPWMD showed discontinuous relationships characterized by data clusters. Model simulations revealed that this data clustering originated from the complex multipeak pattern of septal strain and motion. In patients and simulations with (simulated) LV scar, SRSsept and IVMD retained their linear relationship with CRT response, whereas Strain-SL and SPWMD did not.

Conclusions—

The power to predict CRT response differs between indices of mechanical dyssynchrony. SRSsept and IVMD better represent LV dyssynchrony amenable to CRT and better predict CRT response than the indices assessing time-to-peak deformation or motion.
Constitutively Active TRPC Channels of Adipocytes Confer a Mechanism for Sensing Dietary Fatty Acids and Regulating Adiponectin
Authors: Sukumar Piruthivi , Sedo Alicia , Li Jing , Wilson Lesley A. , O'Regan David , Lippiat Jonathan D. , Porter Karen E. , Kearney Mark T. , Ainscough Justin F.X. , Beech David J.
Published: June 2012

Rationale:

Calcium entry is pivotal in the heart and blood vessels, but its significance and mechanisms in adipose tissue are largely unknown. An important factor produced by adipocytes is adiponectin, which confers myocardial protection, insulin-sensitization, and antiatherosclerotic effects.

Objective:

To investigate the relevance of calcium channels to adipocytes and the production of adiponectin.

Methods and Results:

Microarray analysis led to identification of transient receptor potential canonical (TRPC)1 and TRPC5 as channel subunits that are induced when adipocytes mature. Both subunits were found in perivascular fat of patients with atherosclerosis. Intracellular calcium and patch-clamp measurements showed that adipocytes exhibit constitutively active calcium-permeable nonselective cationic channels that depend on TRPC1 and TRPC5. The activity could be enhanced by lanthanum or rosiglitazone, known stimulators of TRPC5 and TRPC5-containing channels. Screening identified lipid modulators of the channels that are relevant to adipose biology. Dietary ω-3 fatty acids (eg, α-linolenic acid) were inhibitory at concentrations that are achieved by ingestion. The adipocyte TRPC1/TRPC5-containing channel was functionally negative for the generation of adiponectin because channel blockade by antibodies, knock-down of TRPC1–TRPC5 in vitro, or conditional disruption of calcium permeability in TRPC5-incorporating channels in vivo increased the generation of adiponectin. The previously recognized capability of α-linolenic acid to stimulate the generation of adiponectin was lost when calcium permeability in the channels was disrupted.

Conclusions:

The data suggest that TRPC1 and TRPC5 contribute a constitutively active heteromultimeric channel of adipocytes that negatively regulates adiponectin and through which ω-3 fatty acids enhance the anti-inflammatory adipokine, adiponectin.
Endothelial Cell–Specific FGD5 Involvement in Vascular Pruning Defines Neovessel Fate in Mice
Authors: Cheng Caroline , Haasdijk Remco , Tempel Dennie , van de Kamp Esther H. M. , Herpers Robert , Bos Frank , Den Dekker Wijnand K. , Blonden Lau A.J. , de Jong Renate , Bürgisser Petra E. , Chrifi Ihsan , Biessen Erik A.L. , Dimmeler Stefanie , Schulte-Merker Stefan , Duckers Henricus J.
Published: June 2012

Background—

New vessel formation contributes to organ development during embryogenesis and tissue repair in response to mechanical damage, inflammation, and ischemia in adult organisms. Early angiogenesis includes formation of an excessive primitive network that needs to be reorganized into a secondary vascular network with higher hierarchical structure. Vascular pruning, the removal of aberrant neovessels by apoptosis, is a vital step in this process. Although multiple molecular pathways for early angiogenesis have been identified, little is known about the genetic regulators of secondary network development.

Methods and Results—

Using a transcriptomics approach, we identified a new endothelial specific gene named FYVE, RhoGEF, and PH domain–containing 5 (FGD5) that plays a crucial role in vascular pruning. Loss- and gain-of-function studies demonstrate that FGD5 inhibits neovascularization, indicated by in vitro tube-formation, aortic-ring, and coated-bead assays and by in vivo coated-bead plug assays and studies in the murine retina model. FGD5 promotes apoptosis-induced vaso-obliteration via induction of the hey1-p53 pathway by direct binding and activation of cdc42. Indeed, FGD5 correlates with apoptosis in endothelial cells during vascular remodeling and was linked to rising p21
CIP1
levels in aging mice.

Conclusion—

We have identified FGD5 as a novel genetic regulator of vascular pruning by activation of endothelial cell–targeted apoptosis.
Maternal Experience of Interactions With Providers Among Mothers With Milk Supply Concern
Authors: Flaherman Valerie J. , Hicks Katherine G. , Cabana Michael D. , Lee Kathryn A.
Published: June 2012

Background.

Milk supply concern is the most common reason given by mothers for discontinuing breastfeeding.

Objectives.

To describe maternal experiences of interactions with health care providers related to milk supply.

Patients and methods.

Ten focus groups (N = 56 participants) were conducted among mothers who had had milk supply concern in the first month after birth. Group sessions were audio-recorded, transcribed, coded, and analyzed to identify themes.

Results.

Interactions regarding milk supply concern evoked strong emotions, including gratitude, guilt, disappointment, and fear, and measurement of infant weight was frequently reported as a trigger for these emotions. Some mothers reported that experiencing “pressure” and “guilt” when providers emphasized exclusive breastfeeding led to suboptimal breastfeeding choices.

Conclusions.

Interactions with providers about milk supply concern evoke strong emotions among mothers. Providers should be aware that how they communicate routine advice regarding infant weight and formula may have unintended consequences, including discontinuation of breastfeeding.
The Rise of Outsiders in Latin America, 1980–2010
Authors: Carreras Miguel
Published: June 2012

One of the most significant developments in Latin American democracies since the beginning of the third wave of democratization is the rise to political prominence of outsider candidates in presidential elections. I use an original database of political outsiders in Latin America to examine the institutional factors that contribute to the emergence of political outsiders. Using a fixed effects variance decomposition (FEVD) model, I find that, in addition to the favorable conditions already identified in the literature—legitimacy crisis of traditional political parties and negative socioeconomic conditions—the rise of political outsiders is determined by institutional factors, such as nonconcurrent elections, compulsory voting rules, and reelection provisions.
Reaching a vanishing point? Reflections on the future of neutrality norms in Sweden and Finland
Authors: Lödén Hans
Published: June 2012

This rejoinder article takes the contributions in the Special Issue of Cooperation and Conflict – Vol. 46(3) – on Neutrality and ‘Military Non-Alignment’ as point of departure for a discussion of some of the problems former neutrals face in shaping their foreign and security policies. The author argues that current and future developments regarding neutrality norms are dependent on internal factors such as national identity and public opinion, and on external factors such as the military non-aligned states’ relationships to EU, NATO and, not least, the UN. The possibility of a ‘Second Option’ of full-scale military cooperation if a preferred neutral position fails is discussed. Increased UN activism, for example, connected with the R2P concept and the tendency to outsource major UN-mandated military operations to NATO, is touched upon as well as the Libya crisis of 2011 and some of its implications for European foreign and security policy cooperation. Special attention is given to current Swedish debates on military non-alignment and NATO membership.
Statistical Methods Used in Gifted Education Journals, 2006-2010
Authors: Warne Russell T. , Lazo Maria , Ramos Tammy , Ritter Nicola
Published: June 2012

This article describes the statistical methods used in quantitative and mixed methods articles between 2006 and 2010 in five gifted education research journals. Results indicate that the most commonly used statistical methods are means (85.9% of articles), standard deviations (77.8%), Pearson’s r (47.8%), χ2 (32.2%), ANOVA (30.7%), t tests (30.0%), and MANOVA (23.0%). Approximately half (53.3%) of the articles included reliability reports for the data at hand; Cronbach’s alpha was the most commonly reported measure of reliability (41.5%). Some discussions of best statistical practice and implications for the field of gifted education are included.
Twice-Exceptional Students Enrolled in Advanced Placement Classes
Authors: Schultz Susan M.
Published: June 2012

Twice-exceptional students, those who have disabilities and display areas of gifts or talents, frequently spend their high school years with a focus on their disabilities. Using semistructured interviews, this study explores the perceptions of parents, teachers, and guidance counselors regarding participation of twice-exceptional students in Advanced Placement (AP) and for-college-credit classes. The supports and barriers for students with disabilities participating in AP and for-college-credit classes were identified. Additionally, participants included six college students who had taken AP and/or for-college-credit classes while still in high school. The results of this study indicated that school culture and early placement decisions affect enrollment in AP and for-college-credit classes for the twice-exceptional student. Inconsistencies between students’ goals and transition planning and inconsistent implementation of test and environmental accommodations were documented.
The Capability of Static and Dynamic Features to Distinguish Competent From Genuinely Expert Practitioners in Pediatric Diagnosis
Authors: Loveday Thomas , Wiggins Mark W. , Searle Ben J. , Festa Marino , Schell David
Published: June 2012

Children’s Hospital at Westmead, Sydney, Australia Objective:

The authors describe the development of a new, more objective method of distinguishing experienced competent nonexpert from expert practitioners within pediatric intensive care.

Background:

Expert performance involves the acquisition and use of refined feature-event associations (cues) in the operational environment. Competent nonexperts, although experienced, possess rudimentary cue associations in memory. Thus, they cannot respond as efficiently or as reliably as their expert counterparts, particularly when key diagnostic information is unavail- able, such as that provided by dynamic cues.

Method:

This study involved the application of four distinct tasks in which the use of relevant cues could be expected to increase both the accuracy and the efficiency of diagnostic performance. These tasks included both static and dynamic stimuli that were varied systematically. A total of 50 experienced pediatric intensive staff took part in the study.

Results:

The sample clustered into two levels across the tasks: Participants who performed at a consistently high level throughout the four tasks were labeled experts, and participants who performed at a lower level throughout the tasks were labeled competent nonexperts. The groups differed in their responses to the diagnostic scenarios presented in two of the tasks and their ability to maintain performance in the absence of dynamic features.

Conclusion:

Experienced pediatricians can be decomposed into two groups on the basis of their capacity to acquire and use cues; these groups differ in their diagnostic accuracy and in their ability to maintain performance in the absence of dynamic features.

Application:

The tasks may be used to identify practitioners who are failing to acquire expertise at a rate consistent with their experience, position, or training. This information may be used to guide targeted training efforts.
Autonomous work groups and the challenge of inter-group coordination
Authors: Ingvaldsen Jonas A , Rolfsen Monica
Published: June 2012

In work systems based on autonomous work groups, the effort of different autonomous groups needs to be coordinated to produce desirable system-wide effects. The existing literature on organizational structures for inter-group coordination is limited. In this article, the authors explore two different structures for inter-group coordination, which are alternatives to traditional hierarchical control. These structures are rotating group spokespersons and shared leadership. The main conclusion of this article is that inter-group coordination becomes a major challenge when groups enjoy high levels of autonomy. Our argument builds on a case study of a manufacturing company, analysed through the lens of modern socio-technical theory. The difficulties associated with inter-group coordination have implications for debates on organizational performance and may help explain why autonomous work groups are not widely used in industry.
Electoral Rules and the Democratic Progressive Party’s Performance in the 2004 and 2008 Legislative Elections in Taiwan
Authors: O’Neill Daniel C
Published: June 2012

The Democratic Progressive Party (DPP) in Taiwan increased its vote share in each legislative election from 2001 to 2008. Nevertheless, the 2004 and 2008 elections were widely viewed as major defeats for the party. Through an analysis of the DPP’s performance in these elections, this article considers the effects of electoral rules on election outcomes and the perception of those outcomes. In Taiwan, under both the previous single non-transferable vote (SNTV) and the current mixed member majoritarian (MMM) systems, the mechanical effect of how electoral rules translate votes into seats and the psychological impact this has on voter and party behavior have influenced party electoral performance, and the perception of it, by causing vote and seat shares to diverge. In addition, this article analyzes whether recent redistricting in Taiwan structurally disadvantages the DPP.
Dentin Regeneration Using Deciduous Pulp Stem/Progenitor Cells
Authors: Zheng Y. , Wang X.Y. , Wang Y.M. , Liu X.Y. , Zhang C.M. , Hou B.X. , Wang S.L.
Published: June 2012

Reparative dentin formation is essential for maintaining the integrity of dentin structure during disease or trauma. In this study, we investigated stem/progenitor cell-based tissue engineering for dentin regeneration in a large animal model. Porcine deciduous pulp stem/progenitor cells (PDPSCs) were mixed with a beta-tricalcium phosphate (β-TCP) scaffold for dentin regeneration. Different concentrations of PDPSCs were tested to determine the optimal density for dentin regeneration. Aliquots of 5×105 PDPSCs in 1 mL resulted in the highest number of cells attached to the scaffold and the greatest alkaline phosphatase activity. We labeled PDPSCs with green fluorescent protein (GFP) and used the optimal cell numbers mixed with β-TCP to repair pulp chamber roof defects in the premolars of swine. Four weeks after transplantation, GFP-positive PDPSCs were observed in PDPSC-embedded scaffold constructs. At 16 weeks after transplantation, the PDPSCs mixed with β-TCP significantly regenerated the dentin-like structures and nearly completely restored the pulp chamber roof defects. This study demonstrated that the PDPSC/scaffold construct was useful in direct pulp-capping and provides pre-clinical evidence for stem/progenitor cell-based dentin regeneration.
Caries Resistance as a Function of Age in an Initially Caries-free Population
Authors: Wen A. , Goldberg D. , Marrs C.F. , Weyant R.J. , Marazita M.L. , Srinivasan U. , Zhang L. , Crout R. , McNeil D.W. , Foxman B.
Published: June 2012

Using data from the Center for Oral Health Research in Appalachia Study, we examined variability in susceptibility to dental caries among children and adolescents in rural Appalachia. Among 210 participants who were caries-free at the initial visit, age at the baseline visit can be used as a proxy for the degree of caries resistance; probability of caries development at the tooth level decreased as age at the baseline visit increased. Participants who stayed caries-free for a longer period during childhood and adolescence experienced less extensive caries, as measured by the number of carious teeth. However, the probability of becoming caries-positive did not correlate with age at the baseline visit. For children between 1 and 18 years of age, there was not a “threshold age” after which a caries-free child’s risk of caries onset is significantly reduced.
Teacher Groups’ Conceptions and Uses of Student-Learning Data
Authors: Slavit David , Nelson Tamara Holmlund , Deuel Angie
Published: June 2012

This article measures and discusses six teacher groups’ (a) time spent working with data and (b) time devoted to particular kinds of inquiry activities, and explores various contextual factors that influence these results. The authors make use of a framework useful in describing and analyzing the stance taken by teachers when they engage with student-learning data. Their findings suggest that most teacher groups spend the vast majority of their time collecting and analyzing data, with little time devoted to exploring potential data sources and reflecting on implications of their data analysis. Furthermore, “time on task” is less important than stance in determining the nature of the inquiry activity. Implications of these results are explored.
The 21st Century Teacher
Authors: Rueda Robert , Stillman Jamy
Published: June 2012

In this article, the authors focus on the disciplinary divides between multicultural, bilingual, and special education. Existing issues that inhibit closer integration of these areas are highlighted, and a focus on the issue of culture is examined. Problematic ways that this key area has been treated in the past are described, and a proposal for a cultural focus on all students is described.