bluuebunny/crossref_metadata_2025 huggingface dataset:
Causes of Genome Instability
Authors: Aguilera Andrés , García-Muse Tatiana
Published: August 2013

Genomes are transmitted faithfully from dividing cells to their offspring. Changes that occur during DNA repair, chromosome duplication, and transmission or via recombination provide a natural source of genetic variation. They occur at low frequency because of the intrinsic variable nature of genomes, which we refer to as genome instability. However, genome instability can be enhanced by exposure to external genotoxic agents or as the result of cellular pathologies. We review the causes of genome instability as well as how it results in hyper-recombination, genome rearrangements, and chromosome fragmentation and loss, which are mainly mediated by double-strand breaks or single-strand gaps. Such events are primarily associated with defects in DNA replication and the DNA damage response, and show high incidence at repetitive DNA, non-B DNA structures, DNA-protein barriers, and highly transcribed regions. Identifying the causes of genome instability is crucial to understanding genome dynamics during cell proliferation and its role in cancer, aging, and a number of rare genetic diseases.
The Tevatron Collider Physics Legacy
Authors: Grannis Paul D. , Shochet Melvyn J.
Published: August 2013

The proton–antiproton Tevatron Collider at Fermilab began physics operation in 1988, and by its shutdown in 2011 it had delivered more than 10 fb−1 of data to the two general-purpose detectors CDF and D0. Thus far, these experiments have published more than 800 papers studying the character of the strong nuclear force, measuring the properties of hadrons containing heavy quarks, elucidating the nature of the electroweak force, discovering and measuring the properties of the top quark, seeking evidence for the Higgs boson, and searching for new phenomena beyond the standard paradigm of particle physics. We summarize the results that define the physics legacy of the Tevatron program.
Cardiac sympathetic dysfunction in the prehypertensive spontaneously hypertensive rat
Authors: Shanks Julia , Manou-Stathopoulou Sotiria , Lu Chieh-Ju , Li Dan , Paterson David J. , Herring Neil
Published: August 2013

Recent studies in prehypertensive spontaneously hypertensive rats (SHR) have shown larger calcium transients and reduced norepinephrine transporter (NET) activity in cultured stellate neurons compared with Wistar-Kyoto (WKY) controls, although the functional significance of these results is unknown. We hypothesized that peripheral sympathetic responsiveness in the SHR at 4 wk of age would be exaggerated compared with the WKY. In vivo arterial pressure (under 2% isoflurane) was similar in SHRs (88 ± 2/50 ± 3 mmHg, n = 18) compared with WKYs (88 ± 3/49 ± 4 mmHg, n = 20). However, a small but significant ( P < 0.05) tachycardia was observed in the young SHR despite the heart rate response to vagus stimulation (3 and 5 Hz) in vivo being similar (SHR: n = 12, WKY: n = 10). In isolated atrial preparations there was a significantly greater tachycardia during right stellate stimulation (5 and 7 Hz) in SHRs ( n = 19) compared with WKYs ( n = 16) but not in response to exogenous NE (0.025–5 μM, SHR: n = 10, WKY: n = 10). There was also a significantly greater release of [3H]NE to field stimulation (5 Hz) of atria in the SHR (SHR: n = 17, WKY: n = 16). Additionally, plasma levels of neuropeptide Y sampled from the right atria in vivo were also higher in the SHR (ELISA, n = 12 for both groups). The difference in [3H]NE release between SHR and WKY could be normalized by the NET inhibitor desipramine (1 μM, SHR: n = 10, WKY: n = 8) but not the α2-receptor antagonist yohimbine (1 μM, SHR: n = 7, WKY: n = 8). Increased cardiac sympathetic neurotransmission driven by larger neuronal calcium transients and reduced NE reuptake translates into enhanced cardiac sympathetic responsiveness at the end organ in prehypertensive SHRs.
Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats
Authors: Xing Wenjuan , Li Youyou , Zhang Haifeng , Mi Chunjuan , Hou Zuoxu , Quon Michael J. , Gao Feng
Published: August 2013

Exercise training lowers blood pressure and is a recommended nonpharmacological strategy and useful adjunctive therapy for hypertensive patients. Studies demonstrate that physical activity attenuates progression of hypertension. However, underlying mechanisms remain elusive. Vascular insulin resistance and endothelial dysfunction plays a critical role in the development of hypertension. The present study investigated whether long-term physical exercise starting during the prehypertensive period prevents the development of hypertension via improving vascular insulin sensitivity. Young (4 wk old) prehypertensive spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) control rats were subjected to a 10-wk free-of-loading swim training session (60 min/day, 5 days/wk). Blood pressure, mesenteric arteriolar vasorelaxation, G protein-coupled receptor kinase-2 (GRK2) expression and activity, and insulin-stimulated Akt/endothelial nitric oxide synthase (eNOS) activation were determined. SHRs had higher systolic blood pressure, systemic insulin resistance, and impaired vasodilator actions of insulin in resistance vessels when compared with WKY rats. Systolic blood pressure in SHRs postexercise was significantly lower than that in sedentary rats. Vascular insulin sensitivity in mesenteric arteries was improved after exercise training as evidenced by an increased vasodilator response to insulin. In addition, exercise downregulated vascular GRK2 expression and activity, which further increased insulin-stimulated vascular Akt/eNOS activation in exercised SHRs. Specific small interfering RNA knockdown of GRK2 in endothelium mimicked the effect of exercise-enhanced vascular insulin sensitivity. Likewise, upregulation of GRK2 by Chariot-mediated delivery opposed exercise-induced vascular insulin sensitization. Taken together, our results suggest that long-term exercise beginning at the prehypertensive stage improves vascular insulin sensitivity via downregulation of vascular GRK2 that may help to limit the progression of hypertension.
A three-microphone acoustic reflection technique using transmitted acoustic waves in the airway
Authors: Fujimoto Yuki , Huang Jyongsu , Fukunaga Toshiharu , Kato Ryo , Higashino Mari , Shinomiya Shohei , Kitadate Shoko , Takahara Yutaka , Yamaya Atsuyo , Saito Masatoshi , Kobayashi Makoto , Kojima Koji , Oikawa Taku , Nakagawa Ken , Tsuchihara Katsuma , Iguchi Masaharu , Takahashi Masakatsu , Mizuno Shiro , Osanai Kazuhiro , Toga Hirohisa
Published: August 2013

The acoustic reflection technique noninvasively measures airway cross-sectional area vs. distance functions and uses a wave tube with a constant cross-sectional area to separate incidental and reflected waves introduced into the mouth or nostril. The accuracy of estimated cross-sectional areas gets worse in the deeper distances due to the nature of marching algorithms, i.e., errors of the estimated areas in the closer distances accumulate to those in the further distances. Here we present a new technique of acoustic reflection from measuring transmitted acoustic waves in the airway with three microphones and without employing a wave tube. Using miniaturized microphones mounted on a catheter, we estimated reflection coefficients among the microphones and separated incidental and reflected waves. A model study showed that the estimated cross-sectional area vs. distance function was coincident with the conventional two-microphone method, and it did not change with altered cross-sectional areas at the microphone position, although the estimated cross-sectional areas are relative values to that at the microphone position. The pharyngeal cross-sectional areas including retropalatal and retroglossal regions and the closing site during sleep was visualized in patients with obstructive sleep apnea. The method can be applicable to larger or smaller bronchi to evaluate the airspace and function in these localized airways.
A Two-Tube Multiplex Reverse Transcription PCR Assay for Simultaneous Detection of Sixteen Human Respiratory Virus Types/Subtypes
Authors: Li Jin , Qi Shunxiang , Zhang Chen , Hu Xiumei , Shen Hongwei , Yang Mengjie , Wang Ji , Wang Miao , Xu Wenbo , Ma Xuejun
Published: August 2013

There is a need for the development of a rapid and sensitive diagnosis of respiratory viral pathogens. With an intended application in provincial Centers for Diseases Control and Prevention, in this study, we present a two-tube multiplex RT-PCR assay (two-tube assay) using automatic electrophoresis to simultaneously detect sixteen common respiratory viruses. The specificity and the sensitivity of the assay were tested. The assay could detect 20–200 copies per reaction when each viral type was assayed individually, 2000 copies with 9 premixed viral targets in the multiplexed assay in tube 1, and 200 copies with 8 premixed templates in tube 2. A total of 247 specimens were used to evaluate the two-tube assay, and the results were compared with those obtained from the Luminex xTAG RVP Fast assay. The discordant results were confirmed by sequencing or by the Seeplex RV15 ACE detection kit. There were no false positives, but six false negatives occurred with the two-tube assay. In conclusion, the two-tube assay is demonstrated to have great potential for routine surveillance of respiratory virus infection in China.
SOX10 Ablation Arrests Cell Cycle, Induces Senescence, and Suppresses Melanomagenesis
Authors: Cronin Julia C. , Watkins-Chow Dawn E. , Incao Art , Hasskamp Joanne H. , Schönewolf Nicola , Aoude Lauren G. , Hayward Nicholas K. , Bastian Boris C. , Dummer Reinhard , Loftus Stacie K. , Pavan William J.
Published: August 2013

The transcription factor SOX10 is essential for survival and proper differentiation of neural crest cell lineages, where it plays an important role in the generation and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, but a role in disease progression has not been established. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1Tg) transgenic mouse model. Stable SOX10 knockdown in human melanoma cells arrested cell growth, altered cellular morphology, and induced senescence. Melanoma cells with stable loss of SOX10 were arrested in the G1 phase of the cell cycle, with reduced expression of the melanocyte determining factor microphthalmia-associated transcription factor, elevated expression of p21WAF1 and p27KIP2, hypophosphorylated RB, and reduced levels of its binding partner E2F1. As cell-cycle dysregulation is a core event in neoplastic transformation, the role for SOX10 in maintaining cell-cycle control in melanocytes suggests a rational new direction for targeted treatment or prevention of melanoma. Cancer Res; 73(18); 5709–18. ©2013 AACR.
ERG Is a Critical Regulator of Wnt/LEF1 Signaling in Prostate Cancer
Authors: Wu Longtao , Zhao Jonathan C. , Kim Jung , Jin Hong-Jian , Wang Cun-Yu , Yu Jindan
Published: August 2013

Chromosomal translocations juxtaposing the androgen-responsive TMPRSS2 promoter with the ETS-family transcription factor ERG result in aberrant ERG upregulation in approximately 50% of prostate cancers. Studies to date have shown important roles of ERG in inducing oncogenic properties of prostate cancer. Its molecular mechanisms of action, however, are yet to be fully understood. Here, we report that ERG activates Wnt/LEF1 signaling cascade through multiple mechanisms. ERG bound to the promoters of various Wnt genes to directly increase ligand expression. Consequently, ERG overexpression increased active β-catenin level in the cells and enhanced TCF/LEF1 luciferase reporter activity, which could be partially blocked by WNT-3A inhibitor IWP-2. Most importantly, our data defined LEF1 as a direct target of ERG and that LEF1 inhibition fully abolished ERG-induced Wnt signaling and target gene expression. Furthermore, functional assays showed that Wnt/LEF1 activation phenocopied that of ERG in inducing cell growth, epithelial-to-mesenchymal transition, and cell invasion, whereas blockade of Wnt signaling attenuated these effects. Concordantly, LEF1 expression is significantly upregulated in ERG-high human prostate cancers. Overall, this study provides an important mechanism of activation of Wnt signaling in prostate cancer and nominates LEF1 as a critical mediator of ERG-induced tumorigenesis. Wnt/LEF1 pathway might provide novel targets for therapeutic management of patients with fusion-positive prostate cancer. Cancer Res; 73(19); 6068–79. ©2013 AACR.
Abstract 40: Arsenic exposure in pregnancy increases the risk of adverse birth outcomes of newborns in Taiwan.
Authors: Chou W.C. , Chuang C.Y. , Huang P.C. , Wang C.J. , Chen H.Y. , Chuang Y.D. , Wang S.L.
Published: August 2013

Background: Previous studies have reported that arsenic (As) exposure in pregnancy induces DNA damage and increased risk of fetal health and development. However, the associations between As-induced DNA damage and adverse birth outcomes in newborns have yet to be established. We aimed to elucidate the association between As exposure and DNA damages in pregnant women, and link it to the increased risks of adverse birth outcomes in newborn.

Methods: A birth cohort study of 309 mother-newborn pairs was recruited during 2001-2002. We collected maternal urine samples in the third trimester of pregnancy for measurements of metabolites of inorganic arsenic (iAs) using high-performance liquid chromatography/ inductively coupled plasma mass spectrometry, and DNA damage biomarkers by liquid chromatography tenden mass spectrometer. Information of birth weight, birth length, head circumference, chest girth and Apgar score of newborns were collected to assess newborn health.

Results: We found a significant correlation between maternal As exposure and increased levels of 8-OHdG (β=0.39, p<0.001) and N7-MeG (β=0.26, p<0.001) in pregnant women. The significant increased risk of low Apgar score at 1st min (<7) in newborns were associated with increased levels of urinary iAs (OR: 1.03, 95% confidence interval (CI): 1.01-1.06) and N7-MeG (OR: 1.24, 95% CI: 1.10-1.25).

Conclusions: These findings suggest that maternal As exposure may contribute to the formation of DNA damages and affect fetal and infant health. DNA methylation altered by arsenic exposure was hypothesized and tested.

Citation Format: W.C. Chou, C.Y. Chuang, P.C. Huang, C.J. Wang, H.Y. Chen, Y.D. Chuang, S.L. Wang. Arsenic exposure in pregnancy increases the risk of adverse birth outcomes of newborns in Taiwan. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 40.
Abstract 51: Prospective study of LINE-1 hypomethylation in peripheral leukocyte DNA and colorectal cancer risk.
Authors: Huang Wen-Yi , Su L. Joseph , Berndt Sonja I. , Moore Lee E. , Katki Hormuzd A. , Yegnasubramanian Srinivasan , Purdue Mark P.
Published: August 2013

Background: The family of long interspersed nuclear elements (LINE-1) retrotransposons is reportedly hypomethylated in many cancers and reflects global methylation status in the genome. Global hypomethylation in peripheral blood leukocyte DNA has been increasingly studied and associated with increased risk of cancer, including colorectal cancer and adenoma in cross-sectional studies.

Methods: To minimize disease- and/or treatment-related effects, we studied LINE-1 methylation levels in prospectively collected blood specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in relation to subsequent colorectal cancer risk. In a nested study of 398 cases and 519 controls who were cancer-free at blood collection, the extent of LINE-1 hypomethylation was measured by using the McrBC methylation specific restriction enzyme to cut methylated but not unmethylated DNA, followed by real-time PCR of the undigested/unmethylated LINE1 promoter sequences. We estimated the association between colorectal cancer risk and LINE-1 methylation categories by computing odds ratios (ORs) and 95% confidence intervals (CIs) through multivariable logistic regression modeling.

Results: Overall, we observed no clear association between colorectal cancer and LINE-1 methylation categories (lowest tertile vs. highest: OR=1.06, 95% CI=0.74-1.52; P trend=0.72). However, we observed a nearly significant trend of decreasing LINE-1 methylation (hypomethylation) associated with increasing colorectal cancer risk, after excluding cases diagnosed within 1 year (lowest tertile vs. highest: OR=1.40, 95% CI=0.87-2.27; P trend=0.14) and 5 years (OR=2.65, 95% CI=0.96-7.36; P trend=0.07) following the blood collection. We noted no significant risk modification by folate intake or other suspected risk factors of colorectal cancer, such as smoking, obesity, and aspirin/ ibuprofen use in analyses including all subjects or excluding cases diagnosed within 5 years following blood collection (P interaction ranged between = 0.12 to 0.98).

Conclusion: Findings from this prospective investigation offer further support for a potential dose-dependent relationship between LINE-1 hypomethylation in leukocyte DNA and subsequent colorectal cancer risk.

Citation Format: Wen-Yi Huang, L. Joseph Su, Sonja I. Berndt, Lee E. Moore, Hormuzd A. Katki, Srinivasan Yegnasubramanian, Mark P. Purdue. Prospective study of LINE-1 hypomethylation in peripheral leukocyte DNA and colorectal cancer risk. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 51.
Abstract 62: A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population.
Authors: Shiraishi Kouya , Kunitoh Hideo , Daigo Yataro , Takahashi Atsushi , Goto Koichi , Sakamoto Hiromi , Ohnami Sumiko , Shimada Yoko , Ashikawa Kyota , Saito Akira , Watanabe Shun-ichi , Tsuta Koji , Kamatani Naoyuki , Yoshida Teruhiko , Nakamura Yusuke , Yokota Jun , Kubo Michiaki , Kohno Takashi
Published: August 2013

Adenocarcinoma is the most common type, comprising ˜40% of all lung cancer cases, and its incidence is increasing both in Asian and Western countries. The development of lung adenocarcinoma is more weakly associated with smoking than other histological types of lung cancer, such as squamous and small cell carcinomas, indicating that the mechanisms of carcinogenesis differ among these types. A better understanding of the genetic factors underlying lung adenocarcinoma development is strongly needed to elucidate the disease etiology and to identify high-risk individuals for targeted screening and/or prevention. To identify genetic factors that influence the risk of lung adenocarcinoma, we conducted a genome-wide association study and two validation studies in the Japanese population that consisted of a total of 6,029 lung adenocarcinoma cases and 13,535 controls (Shiraishi et al, Nat Genet, 2012).

Associations of two previously reported loci, 5p15.33 (rs2853677 in TERT; PCombined = 2.8x10-40, odds ratio (OR) = 1.41) and 3q28 (rs10937405 in TP63; PCombined = 6.9x10-17, OR = 1.25) (Landi et al, AJHG, 2009; Miki et al, Nat Genet, 2010), were validated. In addition, we identified two new susceptibility loci, 17q24.3 (rs7216064 in BPTF; PCombined = 7.4x10-11, OR = 1.20) and 6p21.3 (rs3817963 in BTNL2; PCombined = 2.7x10-10, OR = 1.18). BPTF encodes a chromatin remodeling factor that regulates transcription via specific recognition of methylated histone proteins. BPTF mRNA levels in noncancerous lung tissues were different depending on the genotype of the rs7216064 SNP (P = 0.02), implying a low expression from the risk allele. The BTNL2 gene encodes a T cell co-stimulatory molecule, and associations between BTNL2 SNPs and risk have been reported in several immune-related diseases. These data provide further evidence supporting genetic susceptibility to the development of lung adenocarcinoma.

Citation Format: Kouya Shiraishi, Hideo Kunitoh, Yataro Daigo, Atsushi Takahashi, Koichi Goto, Hiromi Sakamoto, Sumiko Ohnami, Yoko Shimada, Kyota Ashikawa, Akira Saito, Shunichi Watanabe, Koji Tsuta, Naoyuki Kamatani, Teruhiko Yoshida, Yusuke Nakamura, Jun Yokota, Michiaki Kubo, Takashi Kohno. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 62.
Abstract IA05: Integrative approaches for understanding the functional relevance of cancer susceptibility loci.
Authors: Fridley Brooke L.
Published: August 2013

Genome-wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) that confer susceptibility to a variety of cancers. However, as with the vast majority of common genetic variants, the functional rationale underlying cancer risk is largely unknown. In addition, other variants, which failed to reach genome-wide significance, remain undiscovered. Understanding the functional rationale underlying the cancer susceptibility loci is complex, requiring an integrated approach that combines epidemiology, biostatistics, next generation genomics, and cell biology. In this presentation, I will discuss a variety of integrative statistical and bioinformatics approaches being applied to determine the functional relevance of confirmed loci and approaches to discover additional risk loci.

Citation Format: Brooke L. Fridley. Integrative approaches for understanding the functional relevance of cancer susceptibility loci. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA05.
Abstract IA11: Extracting predictive networks from high-dimensional data.
Authors: Quackenbush John
Published: August 2013

Two trends are driving innovation and discovery in biological sciences: technologies that allow holistic surveys of genes, proteins, and metabolites and the growing realization that analysis and interpretation of the resulting requires an understanding of the complex phenotypic and environmental data regarding the samples from which they were derived. The growing body of biological and biomedical information in the public domain provides outstanding opportunities for leveraging what we already “know” in a systematic way to understand the problems we are studying. Here, I will provide an overview of some of the methods we are using to investigate the complexities of human cancers and to explore how we can use biological data to uncover the cellular networks and pathways that underlie human disease, building predictive models of those networks that may help to direct therapies.

Citation Format: John Quackenbush. Extracting predictive networks from high-dimensional data. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA11.
Abstract IA21: Using mouse models to identify breast cancer metastasis susceptibility genes.
Authors: Hunter Kent W.
Published: August 2013

Approximately 200,000 women are diagnosed with breast cancer and about 40,000 patients will succumb to this disease per year. The vast majority of these deaths are due to metastatic disease, rather than the primary tumor, so better understanding of the terminal stages of breast cancer is of great importance for the design of improved clinical interventions. Mouse genetic studies from our laboratory previously demonstrated that like susceptibility to the development of breast cancer, a significant inherited component exists for disseminated disease. However, despite the tremendous success of GWAS in identifying inherited variants associated with cancer etiology, significantly less success has been achieved in identifying SNPs associated with disease prognosis. This may be due in part to the complexity of the metastatic process, which involves genetic, epigenetic as well as stochastic somatic events. The ability to directly detect inherited metastasis susceptibility loci in human populations may be further complicated by clinical interventions, including surgical resection, radiation and/or adjuvant therapy which may alter or interrupt the natural progression of the disease in patient cohorts, reducing the power of detection. Therefore to complement human studies of inherited susceptibility to progression, our laboratory has employed a dominant metastatic genetically engineered mouse model and a quantitative trait analysis strategy to identify genes associated with disseminated disease. The results of these studies will be presented in this presentation.

Citation Format: Kent W. Hunter. Using mouse models to identify breast cancer metastasis susceptibility genes. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA21.
Bim Polymorphisms: Influence on Function and Response to Treatment in Children with Acute Lymphoblastic Leukemia
Authors: Gagné Vincent , Rousseau Julie , Labuda Malgorzata , Sharif-Askari Bahram , Brukner Ivan , Laverdière Caroline , Ceppi Francesco , Sallan Stephen E. , Silverman Lewis B. , Neuberg Donna , Kutok Jeffery L. , Sinnett Daniel , Krajinovic Maja
Published: August 2013

Purpose: Corticosteroids induce apoptosis in the malignant lymphoid cells and are critical component of combination therapy for acute lymphoblastic leukemia (ALL). Several genome-wide microarray studies showed major implication of proapoptotic Bim in mediating corticosteroid-related resistance in leukemia cells.

Experimental Design: We investigated Bim gene polymorphisms and their association with childhood ALL outcome, and the mechanism underlying the observed finding.

Results: Lower overall survival (OS) was associated with BimC29201T located in Bcl-2 homology 3 (BH3) domain (P = 0.01). An association remained significant in multivariate model (P = 0.007), was more apparent in high-risk patients (P = 0.004) and patients treated with dexamethasone (P = 0.009), and was subsequently confirmed in the replication patient cohort (P = 0.03). RNA analysis revealed that C29201T affects generation of γ isoforms (γ1) that lack proapoptotic BH3 domain. The phenotypic effect was minor suggesting the influence of additional factors that may act in conjunction with Bim genotype. Combined analysis with Mcl gene polymorphism (G-486T) revealed profound reduction in OS in individuals with both risk genotypes (P < 0.0005 in discovery and P = 0.002 in replication cohort) and particularly in high-risk patients (P ≤ 0.008).

Conclusions: Increased expression of prosurvival Mcl1 and presence of Bim isoforms lacking proapoptotic function might explain marked reduction of OS in a disease and dose-dependent manner in ALL patients carrying Bim- and Mcl1-risk genotypes. Clin Cancer Res; 19(18); 5240–9. ©2013 AACR.
Natural Regulatory T Cells Limit Angiotensin II–Induced Aneurysm Formation and Rupture in Mice
Authors: Ait-Oufella Hafid , Wang Yu , Herbin Olivier , Bourcier Simon , Potteaux Stephane , Joffre Jeremie , Loyer Xavier , Ponnuswamy Padmapria , Esposito Bruno , Dalloz Marion , Laurans Ludivine , Tedgui Alain , Mallat Ziad
Published: August 2013

Objective—

Abdominal aortic aneurysm is an inflammatory disease leading to destructive vascular remodeling and ultimately to lethal aortic rupture. Despite its frequent association with atherosclerosis, compelling studies have shown striking differences and potentially opposite roles of T-cell helper responses in aneurysm as compared with atherosclerosis, casting doubt on the relevance and suitability of T-cell–targeted therapies in this context.

Approach and Results—

Here, we show that selective depletion of T regulatory (Treg) cells using a CD25-specific monoclonal antibody significantly enhances the susceptibility of C57Bl/6 mice to angiotensin II–induced abdominal aortic aneurysm and promotes aortic rupture (n=25–44 mice/group). Similar results are observed in angiotensin II–treated
Cd80
−/−
/Cd86
−/−
or
Cd28
−/−
mice with impaired Treg cell homeostasis (n=18–23 mice/group). Treg cell depletion is associated with increased immune cell activation and a blunted interleukin (IL)-10 anti-inflammatory response, suggesting an immunoinflammatory imbalance. Interestingly,
Il-10
−/−
mice (n=20 mice/group) show increased susceptibility to angiotensin II–induced abdominal aortic aneurysm and aortic rupture and are insensitive to Treg cell depletion. Finally, reconstitution of
Cd28
−/−
Treg-deficient mice with Treg cells (n=22 mice/group) restores a balance in the immunoinflammatory response, rescues the animals from increased susceptibility to aneurysm, and prevents aortic dissection.

Conclusions—

These results identify a critical role for Treg cells and IL-10 in the control of aneurysm formation and its progression to rupture and suggest that therapies targeting Treg responses may be most suited to treat aneurysmal disease.
Reduction in Early Stroke Risk in Carotid Stenosis With Transient Ischemic Attack Associated With Statin Treatment
Authors: Merwick Áine , Albers Gregory W. , Arsava Ethem M. , Ay Hakan , Calvet David , Coutts Shelagh B. , Cucchiara Brett L. , Demchuk Andrew M. , Giles Matthew F. , Mas Jean-Louis , Olivot Jean Marc , Purroy Francisco , Rothwell Peter M. , Saver Jeffrey L. , Sharma Vijay K. , Tsivgoulis Georgios , Kelly Peter J.
Published: August 2013

Background and Purpose—

Statins reduce stroke risk when initiated months after transient ischemic attack (TIA)/stroke and reduce early vascular events in acute coronary syndromes, possibly via pleiotropic plaque stabilization. Few data exist on acute statin use in TIA. We aimed to determine whether statin pretreatment at TIA onset modified early stroke risk in carotid stenosis.

Methods—

We analyzed data from 2770 patients with TIA from 11 centers, 387 with ipsilateral carotid stenosis. ABCD2 score, abnormal diffusion weighted imaging, medication pretreatment, and early stroke were recorded.

Results—

In patients with carotid stenosis, 7-day stroke risk was 8.3% (95% confidence interval [CI], 5.7–11.1) compared with 2.7% (CI, 2.0%–3.4%) without stenosis (
P
<0.0001; 90-day risks 17.8% and 5.7% [
P
<0.0001]). Among carotid stenosis patients, nonprocedural 7-day stroke risk was 3.8% (CI, 1.2%–9.7%) with statin treatment at TIA onset, compared with 13.2% (CI, 8.5%–19.8%) in those not statin pretreated (
P
=0.01; 90-day risks 8.9% versus 20.8% [
P
=0.01]). Statin pretreatment was associated with reduced stroke risk in patients with carotid stenosis (odds ratio for 90-day stroke, 0.37; CI, 0.17–0.82) but not nonstenosis patients (odds ratio, 1.3; CI, 0.8–2.24;
P
for interaction, 0.008). On multivariable logistic regression, the association remained after adjustment for ABCD2 score, smoking, antiplatelet treatment, recent TIA, and diffusion weighted imaging hyperintensity (adjusted
P
for interaction, 0.054).

Conclusions—

In acute symptomatic carotid stenosis, statin pretreatment was associated with reduced stroke risk, consistent with findings from randomized trials in acute coronary syndromes. These data support the hypothesis that statins started acutely after TIA symptom onset may also be beneficial to prevent early stroke. Randomized trials addressing this question are required.
Venetian Trading Networks in the Medieval Mediterranean
Authors: Apellániz Francisco
Published: August 2013

Network analysis can identify the crucial role that such social outcasts as Jews, Greeks, colonial subjects, and uprooted individuals played within the exclusive commercial networks of the Republic of Venice. These lower-rank merchants and brokers were able not only to manipulate legal, cultural, and religious categories to integrate themselves into the Venetian networks but also to abandon those networks when better economic opportunities arose.
Authenticity, Sincerity and Spontaneity: The Mutual Implication of Nature and Religion in China and the West
Authors: Miller James
Published: August 2013

Abstract

Fundamental approaches to ethics and morality in both China and the West are bound up not only with conceptions of religion and ultimate truth, but also with conceptions of nature. One dominant theme in the West is to see nature in terms of an original goodness that precedes human manipulation. This theme is bound up with Biblical views of divine creation by a divine lawmaker. In contrast to this view, Chinese conceptions of sincerity (cheng) and spontaneity (ziran) mitigate against such an abstract conception of the original goodness or authenticity of nature.
Guillaume Postel and the Primordial Origins of the Middle East
Authors: Wheeler Brannon
Published: August 2013

Abstract

Guillaume Postel is often credited as one of the founding fathers of the modern “orientalist” European study of the Middle East, and of Arabic, Islam, and the Quran in particular. He published his most influential work in 1544, calling on the French king to lead a Crusade against the Ottomans and usher in a new, apocalyptic age. Although usually credited as a pioneer in the comparative study of Semitic languages, an influential figure in French-Ottoman relations, and as one of the first Europeans to study the Quran in comparison with the Bible, it was the unique sixteenth-century renaissance combination of apocalyptism, European nationalism, and alchemy behind the specific formation of Postel’s universal linguistic theories that would most influence future scholarship. The following pages examine the historical context in which Postel produced his work with particular attention to the apocalyptism of his religious ideas and the kabbalistic sources of his linguistic scholarship.
A Dual-Polarization Radar Signature of Hydrometeor Refreezing in Winter Storms
Authors: Kumjian Matthew R. , Ryzhkov Alexander V. , Reeves Heather D. , Schuur Terry J.
Published: August 2013

Polarimetric radar measurements in winter storms that produce ice pellets have revealed a unique signature that is indicative of ongoing hydrometeor refreezing. This refreezing signature is observed within the low-level subfreezing air as an enhancement of differential reflectivity ZDR and specific differential phase KDP and a decrease of radar reflectivity factor at horizontal polarization ZH and copolar correlation coefficient ρhv. It is distinct from the overlying melting-layer “brightband” signature and suggests that unique microphysical processes are occurring within the layer of hydrometeor refreezing. The signature is analyzed for four ice-pellet cases in central Oklahoma as observed by two polarimetric radars. A statistical analysis is performed on the characteristics of the refreezing signature for a case of particularly long duration. Several hypotheses are presented to explain the appearance of the signature, along with a summary of the pros and cons for each. It is suggested that preferential freezing of small drops and local ice generation are plausible mechanisms for the appearance of the ZDR and KDP enhancements. Polarimetric measurements and scattering calculations are used to retrieve microphysical information to explore the validity of the hypotheses. The persistence and repetitiveness of the signature suggest its potential use in operational settings to diagnose the transition between freezing rain and ice pellets.
An Observation-Based Investigation of Nudging in WRF for Downscaling Surface Climate Information to 12-km Grid Spacing
Authors: Bullock O. Russell , Alapaty Kiran , Herwehe Jerold A. , Mallard Megan S. , Otte Tanya L. , Gilliam Robert C. , Nolte Christopher G.
Published: August 2013

Previous research has demonstrated the ability to use the Weather Research and Forecasting model (WRF) and contemporary dynamical downscaling methods to refine global climate modeling results to a horizontal grid spacing of 36 km. Environmental managers and urban planners have expressed the need for even finer resolution in projections of surface-level weather to take into account local geophysical and urbanization patterns. In this study, WRF as previously applied at 36-km grid spacing is used with 12-km grid spacing with one-way nesting to simulate the year 2006 over the central and eastern United States. The results at both resolutions are compared with hourly observations of surface air temperature, humidity, and wind speed. The 12- and 36-km simulations are also compared with precipitation data from three separate observation and analysis systems. The results show some additional accuracy with the refinement to 12-km horizontal grid spacing, but only when some form of interior nudging is applied. A positive bias in precipitation found previously in the 36-km results becomes worse in the 12-km simulation, especially without the application of interior nudging. Model sensitivity testing shows that 12-km grid spacing can further improve accuracy for certain meteorological variables when alternate physics options are employed. However, the strong positive bias found for both surface-level water vapor and precipitation suggests that WRF as configured here may have an unbalanced hydrologic cycle that is returning moisture from land and/or water bodies to the atmosphere too quickly.
Observed Tropical Cyclone Eye Thermal Anomaly Profiles Extending above 300 hPa
Authors: Durden Stephen L.
Published: August 2013

As recently pointed out by Stern and Nolan, much of our knowledge of the warm core structure of the tropical cyclone eye has come from composites of in situ data taken from multiple aircraft studies of three storms in the late 1950s and 1960s. Further observational confirmation of eye thermal structure has been lacking, since much of the dropsonde data analyzed to date have been limited to pressure levels of 500 hPa or lower. However, there exist a number of dropsonde eye profiles extending to near 250 hPa; these profiles were acquired from NASA aircraft during various field campaigns. Here, the author uses these data to calculate eye temperature anomaly profiles. These data are supplemented by several surface-based radiosonde releases in tropical cyclone eyes over the period 1944–2003. The author finds that the pressure altitude of the maximum anomaly varies between 760 and 250 hPa. The author also finds positive correlations between the maximum anomaly level and storm intensity, size, upper-level divergence, and environmental instability.
Objective Tropical Cyclone Intensity Estimation Using Analogs of Spatial Features in Satellite Data
Authors: Fetanat Gholamreza , Homaifar Abdollah , Knapp Kenneth R.
Published: August 2013

An objective method for estimating tropical cyclone (TC) intensity using historical hurricane satellite data (HURSAT) is developed and tested. This new method, referred to as feature analogs in satellite imagery (FASI), requires a TC's center location to extract azimuthal brightness temperature (BT) profiles from current imagery as well as BT profiles from imagery 6, 12, and 24 h prior. Instead of using regression techniques, the estimated TC intensity is determined from the 10 closest analogs to this TC based on the BT profiles using a k-nearest-neighbor algorithm. The FASI technique was trained and validated using intensity data from aircraft reconnaissance in the North Atlantic Ocean, where the data were restricted to include storms that are over water and south of 45°N. This subset comprised 2016 observations from 165 storms during 1988–2006. Several tests were implemented to statistically justify the FASI algorithm using n-fold cross validation. The resulting average mean absolute intensity error was 10.9 kt (50% of estimates are within 10 kt, 1 kt = 0.51 m s−1) or 8.4 mb (50% of estimates are within 8 mb); its accuracy is on par with other objective techniques. This approach has the potential to provide global TC intensity estimates that could augment intensity estimates made by other objective techniques.
Witness to Christ’s Dominion: The political service of the Church
Authors: Ziegler Philip G.
Published: August 2013

Bonhoeffer had a specifically theological interest in politics. In politics, as elsewhere, Christians struggle to discern how any given situation wins its reality in and from God in order to orient themselves in the moral field within which political life takes place. Bonhoeffer’s own political theology asks how Christians are constituted as agents of political truth and what form their political service should thus take. It is proclamation – the exercise of Christian freedom for fearless witness to the gospel and the claim of Christ – which proves decisive. The essential political activity of the Christian community is to offer a full proclamation of Christ’s graceful reign by means of which both state and society are drawn into new humane freedom. In this way it attests the reality of God’s revolutionary reconciliation of all things in Christ.
Study on the electrical and rheological percolation threshold of single-walled carbon nanotube-reinforced thermoplastic elastomer based on polypropylene/ethylene–propylene–diene monomer nanocomposite
Authors: Narimani Amir , Hemmati Mahmood
Published: August 2013

The rheological and electrical percolation threshold of single-walled carbon nanotube (SWNT)-reinforced thermoplastic elastomer based on polypropylene/ethylene–propylene–diene monomer (PP/EPDM; 80/20) nanocomposite was investigated by melt-mixing process. The rheological properties revealed that the addition of SWNT increased the shear stress and shear viscosity. Both PP/EPDM and its nanocomposites exhibited non-Newtonian behavior. It was also found that the materials experience a fluid–solid transition at 0.5 wt% SWNT. The steady shear behaviors and die swell decreased with increasing temperature. The maximum flow activation energy corresponding to the minimum die swell was also observed. The scanning electron microscopic morphology of the PP/EPDM/SWNT nanocomposites showed that the EPDM particles were dispersed through PP and the size of dispersed phase decreased with the introduction of SWNT to 0.5 wt%. The electrical percolation threshold was formed at approximately 1 wt% of SWNT. In addition, difference between electrical and rheological percolation thresholds was observed due to the nanotube–nanotube distance after the formation of the percolating network.
Rail vehicle response to lateral carbody excitations imitating crosswind
Authors: Thomas Dirk , Berg Mats , Stichel Sebastian , Diedrichs Ben
Published: August 2013

Repeatable field tests to measure the vehicle response to unsteady crosswinds are not practical due to safety and economic reasons. Simulations are therefore necessary to gather information on the vehicle response to crosswind. However, in turn, these simulations need to be validated. This study presents results of measured quasi-static and dynamic responses of a stationary rail vehicle due to defined lateral carbody excitations imitating unsteady crosswind, which are reflected by multibody simulations. The vehicle responses are measured in terms of suspension deflections, lateral carbody accelerations and vertical wheel/rail forces. The vehicle dynamic response to a gust-like event results in an overshoot of wheel unloading. In general the measurements and simulations show good agreement. However, the simulations partly overestimate the responses slightly and an influence due to airspring levelling can be observed in the measured values of quasi-static load cases.
Analysis of the rotation angle of a coupler used on heavy haul locomotives
Authors: Xu Ziqiang , Ma Weihua , Wu Qing , Luo Shihui
Published: August 2013

Increases in train length and axle loads have significantly increased in-train forces for heavy haul trains. These forces when combined with the rotation behavior of the coupler can exert an adverse effect on the operational safety of trains. This paper analyzes the rotation behavior of a coupler resulting from the application of a compressive force. A suitable free-rotation angle for the coupler and a stabilization mechanism are also presented. Simulations were performed using a dynamic model of a train consisting of three heavy haul locomotives and two couplers. The obtained results indicate that trains with free-rotation angles of the coupler of 6°have a better dynamic safety and lower levels of wheel tread wear than trains with an initial free-rotation angle of 8°. Variation of the locomotive’s structural parameters, including the secondary stop free clearance, the distance between front and rear stops and the distance between secondary stop and coupler pin, affects the maximum rotation angle of the coupler and, in turn, the operational safety of the train. The matching of the locomotive’s structural parameters and the free-rotation angle of the coupler should be considered when selecting a heavy haul coupler and buffer system so as to avoid safety problems caused by excessive rotation behavior of the coupler.
Reduced agglomeration in solid propellants containing porous aluminum
Authors: Yavor Yinon , Rosenband Valery , Gany Alon
Published: August 2013

The effects of using porous aluminum particles in solid propellants were studied, with emphasis on the agglomeration phenomena. Burning strands containing either regular (as-received) or porous aluminum were photographed by a high-speed camera, and particulate combustion products were analyzed in a laser particle analyzer. Results obtained from experiments conducted in a pressure-range of 1–34 atmospheres show that porous aluminum particles produce smaller agglomerates than regular aluminum. The median diameter of agglomerates resulting from porous aluminum reached, on average, 70% of the one originating from regular aluminum. This reduction in agglomerate diameter corresponds to a substantial volume (and hence, mass) decrease of approximately 65%. It is assumed that the high-specific area of the porous aluminum particles (10–18 m2/g, similar to that of nano-Al) results in high reactivity, leading to shorter ignition time and hence to the formation of smaller agglomerates.
Endocrine and metabolic abnormalities among HIV-infected patients: A current review
Authors: Kibirige Davis , Ssekitoleko Richard
Published: August 2013

Multiple endocrine and metabolic abnormalities have been reported among human immunodeficiency virus (HIV) patients since the pre-antiretroviral therapy era. These abnormalities present with either subclinical or overt clinical features. Endocrine and metabolic abnormalities primarily occur due to the direct destructive effects of HIV, malignancies and opportunistic infections on the varied endocrine glands and antiretroviral therapy-associated toxicities. This article offers a broad review on the commonly encountered endocrine and metabolic abnormalities among HIV-infected patients. Timely endocrine or metabolic evaluations should be performed among patients suspected with endocrine or metabolic dysfunction and appropriate treatment instituted since the majority of these conditions pose an increased risk of mortality if undiagnosed or untreated.