bluuebunny/crossref_metadata_2025 huggingface dataset:
Convergence Analysis of Wireless Remote Iterative Learning Control Systems with Dropout Compensation
Authors: Huang Li-xun , Fang Yong
Published: April 2013

The wireless remote iterative learning control (ILC) system with random data dropouts is considered. The data dropout is viewed as a binary switching sequence which obeys the Bernoulli distribution. In order to eliminate the effect of data dropouts on the convergence property of output error, the signal at the same time with the lost one but in the last iteration is used to compensate the data dropout at the actuator. With the dropout compensation, the convergence property of output error is analyzed by studying the element values of system transition matrix. Finally, some simulation results are given to illustrate the validity of the proposed method.
Carica papayaLeaves Juice Significantly Accelerates the Rate of Increase in Platelet Count among Patients with Dengue Fever and Dengue Haemorrhagic Fever
Authors: Subenthiran Soobitha , Choon Tan Chwee , Cheong Kee Chee , Thayan Ravindran , Teck Mok Boon , Muniandy Prem Kumar , Afzan Adlin , Abdullah Noor Rain , Ismail Zakiah
Published: April 2013

The study was conducted to investigate the platelet increasing property ofCarica papayaleaves juice (CPLJ) in patients with dengue fever (DF). An open labeled randomized controlled trial was carried out on 228 patients with DF and dengue haemorrhagic fever (DHF). Approximately half the patients received the juice, for 3 consecutive days while the others remained as controls and received the standard management. Their full blood count was monitored 8 hours for 48 hours. Gene expression studies were conducted on the ALOX 12 and PTAFR genes. The mean increase in platelet counts were compared in both groups using repeated measure ANCOVA. There was a significant increase in mean platelet count observed in the intervention group (P<0.001) but not in the control group 40 hours since the first dose of CPLJ. Comparison of mean platelet count between intervention and control group showed that mean platelet count in intervention group was significantly higher than control group after 40 and 48 hours of admission (P<0.01). The ALOX 12 (FC  =  15.00) and PTAFR (FC  =  13.42) genes were highly expressed among those on the juice. It was concluded that CPLJ does significantly increase the platelet count in patients with DF and DHF.
Dynamical Behaviors of Stochastic Hopfield Neural Networks with Both Time-Varying and Continuously Distributed Delays
Authors: Zhou Qinghua , Zhang Penglin , Wan Li
Published: April 2013

This paper investigates dynamical behaviors of stochastic Hopfield neural networks with both time-varying and continuously distributed delays. By employing the Lyapunov functional theory and linear matrix inequality, some novel criteria on asymptotic stability, ultimate boundedness, and weak attractor are derived. Finally, an example is given to illustrate the correctness and effectiveness of our theoretical results.
Optimal Management of Rechargeable Biosensors in Temperature-Sensitive Environments
Authors: Osais Yahya , Yu F. Richard , St-Hilaire Marc
Published: April 2013

Biological sensors (biosensors, for short) are tiny wireless devices attached or implanted into the body of a human or animal to monitor and detect abnormalities and then relay data to physician or provide therapy on the spot. They are distinguished from conventional sensors by their biologically derived sensing elements and by being temperature constrained. Biosensors generate heat when they transmit their measurements and when they are recharged by electromagnetic energy. The generated heat translates to a temperature increase in the tissues surrounding the biosensors. If the temperature increase exceeds a certain threshold, the tissues might be damaged. In this paper, we discuss the problem of finding an optimal policy for operating a rechargeable biosensor inside a temperature-sensitive environment characterized by a strict maximum temperature increase constraint. This problem can be formulated as a Markov Decision Process (MDP) and solved to obtain the optimal policy which maximizes the average number of samples that can be generated by the biosensor while observing the constraint on the maximum safe temperature level. In order to handle large-size MDP models, it is shown how operating policies can be obtained using Q-learning and heuristics. Numerical and simulation results demonstrating the performance of the different policies are presented.
Common Fixed Point Theorems for α-ψ-Contractive Type Mappings
Authors: Hassanzadeasl Jalal
Published: April 2013

Recently, Samet et al. (2012) introduced the notion of α-ψ-contractive type mappings. They established some fixed point theorems for these mappings in complete metric spaces. In this paper, we introduce the notion of a coupled α-ψ-contractive mapping and give a common fixed point result about the mapping. Also, we give a result of common fixed points of some coupled self-maps on complete metric spaces satisfying a contractive condition.
Analysis of the Reynolds Equation for Lubrication in Case of Pressure-Dependent Viscosity
Authors: Marušić-Paloka Eduard , Marušić Sanja
Published: April 2013

We study the Reynolds equation, describing the ow of a lubricant, in case of pressure-dependent viscosity. First we prove the existence and uniqueness of the solution. Then, we study the asymptotic behavior of the solution in case of periodic roughness via homogenization method. Some interesting nonlocal effects appear due to the nonlinearity.
Comparison of Conventional Polyethylene Wear and Signs of Cup Failure in Two Similar Total Hip Designs
Authors: Pace Thomas B. , Keith Kevin C. , Alvarez Estefania , Snider Rebecca G. , Tanner Stephanie L. , DesJardins John D.
Published: April 2013

Multiple factors have been identified as contributing to polyethylene wear and debris generation of the acetabular lining. Polyethylene wear is the primary limiting factor in the functional behavior and consequent longevity of a total hip arthroplasty (THA). This retrospective study reviewed the clinical and radiographic data of 77 consecutive THAs comparing in vivo polyethylene wear of two similar acetabular cup liners. Minimum follow-up was 7 years (range 7–15). The incidence of measurable wear in a group of machined liners sterilized with ethylene oxide and composed of GUR 1050 stock resin was significantly higher (61%) than the compression-molded, GUR 1020, O2-free gamma irradiation sterilized group (24%)(P=0.0004). Clinically, at a 9-year average followup, both groups had comparable HHS scores and incidence of thigh or groin pain, though the machined group had an increased incidence of osteolysis and annual linear wear rate.
Identification of Fuzzy Inference Systems by Means of a Multiobjective Opposition-Based Space Search Algorithm
Authors: Huang Wei , Oh Sung-Kwun
Published: April 2013

We introduce a new category of fuzzy inference systems with the aid of a multiobjective opposition-based space search algorithm (MOSSA). The proposed MOSSA is essentially a multiobjective space search algorithm improved by using an opposition-based learning that employs a so-called opposite numbers mechanism to speed up the convergence of the optimization algorithm. In the identification of fuzzy inference system, the MOSSA is exploited to carry out the parametric identification of the fuzzy model as well as to realize its structural identification. Experimental results demonstrate the effectiveness of the proposed fuzzy models.
A New User Authentication Protocol for Wireless Sensor Networks Using Elliptic Curves Cryptography
Authors: Shi Wenbo , Gong Peng
Published: April 2013

User authentication in wireless sensor networks (WSNs) is a critical security issue due to their unattended and hostile deployment in the field. Since sensor nodes are equipped with limited computing power, storage, and communication modules, authenticating remote users in such resource-constrained environments is a paramount security concern. To overcome the weaknesses of Yeh et al.'s protocol, we proposed a new authentication protocol for wireless sensor networks using elliptic curves cryptography. The comparisons show that our protocol is more suitable for WSNs.
Predatory Search Strategy Based on Swarm Intelligence for Continuous Optimization Problems
Authors: Wang J. W. , Wang H. F. , Ip W. H. , Furuta K. , Kanno T. , Zhang W. J.
Published: April 2013

We propose an approach to solve continuous variable optimization problems. The approach is based on the integration of predatory search strategy (PSS) and swarm intelligence technique. The integration is further based on two newly defined concepts proposed for the PSS, namely, “restriction” and “neighborhood,” and takes the particle swarm optimization (PSO) algorithm as the local optimizer. The PSS is for the switch of exploitation and exploration (in particular by the adjustment of neighborhood), while the swarm intelligence technique is for searching the neighborhood. The proposed approach is thus named PSS-PSO. Five benchmarks are taken as test functions (including both unimodal and multimodal ones) to examine the effectiveness of the PSS-PSO with the seven well-known algorithms. The result of the test shows that the proposed approach PSS-PSO is superior to all the seven algorithms.
Nonscalpel Vasectomy as Family Planning Method: A Battle Yet to Be Conquered
Authors: Garg Pankaj Kumar , Jain Bhupendra Kumar , Choudhary Deepti , Chaurasia Ashish , Pandey Satya Deo
Published: April 2013

Though nonscalpel vasectomy (NSV) technique was introduced in India in 1992 to increase male participation in family planning, it has failed to get adequate momentum and to achieve its goal. We conducted a cross-sectional questionnaire-based survey to get insight into apathy of men towards NSV. The study included 428 respondents. Most of the respondents (97.4%) were aware of NSV as a method for permanent male sterilization. The majority of them (97.2%) knew that NSV is done without any charge and cash incentive is given to the NSV client after the procedure. Though 68.0% respondents agreed that permanent sterilization is a possible option for them, only 34.1% respondents were willing to adopt NSV as a method of family planning. Fear of surgical procedure (40.7%), permanent nature of procedure (22.2%), and religious belief (19.0%) were the common reasons for unwillingness to adopt NSV. We conclude that there is a need to design and develop need-based information, education and communication (IEC) strategy to bridge the existing information gap among the eligible couples regarding NSV to improve its adoption. Involvement of community leaders and satisfied clients and utilization of television and radio would enhance the effectiveness of such interventions.
An Energy-Efficient Cyclic Diversionary Routing Strategy against Global Eavesdroppers in Wireless Sensor Networks
Authors: Ren Ju , Zhang Yaoxue , Liu Kang
Published: April 2013

While many protocols for sensor network security provide confidentiality for message content, contextual information usually remains exposed, which can be critical to the mission of the sensor network. In this paper, we propose an energy-efficient cyclic diversionary routing (CDR) scheme against global eavesdroppers for preserving location privacy and maximizing lifetime of wireless sensor networks (WSNs). To ensure no impact on lifetime of WSNs, we minimize the energy consumption of hotspots and generate abundant diversionary routing paths in areas far from sink. To enhance the location privacy preservation, we theoretically figure out the probability of the cyclic interference routings in different areas of the network and statistically achieve an energy consumption balance in the entire network. Analysis and simulation results show that CDR significantly improves the security in source-location privacy preservation without reducing the network lifetime.
Biharmonic Maps and Laguerre Minimal Surfaces
Authors: Abu Muhanna Yusuf , Ali Rosihan M.
Published: April 2013

A Laguerre surface is known to be minimal if and only if its corresponding isotropic map is biharmonic. For every Laguerre surfaceΦis its associated surfaceΨ=1+u2Φ, whereulies in the unit disk. In this paper, the projection of the surfaceΨassociated to a Laguerre minimal surface is shown to be biharmonic. A complete characterization ofΨis obtained under the assumption that the corresponding isotropic map of the Laguerre minimal surface is harmonic. A sufficient and necessary condition is also derived forΨto be a graph. Estimates of the Gaussian curvature to the Laguerre minimal surface are obtained, and several illustrative examples are given.
The Use of LiDAR Terrain Data in Characterizing Surface Roughness and Microtopography
Authors: Brubaker Kristen M. , Myers Wayne L. , Drohan Patrick J. , Miller Douglas A. , Boyer Elizabeth W.
Published: April 2013

The availability of light detection and ranging data (LiDAR) has resulted in a new era of landscape analysis. For example, improvements in LiDAR data resolution may make it possible to accurately model microtopography over a large geographic area; however, data resolution and processing costs versus resulting accuracy may be too costly. We examined two LiDAR datasets of differing resolutions, a low point density (0.714 points/m2spacing) 1 m DEM available statewide in Pennsylvania and a high point density (10.28 points/m2spacing) 1 m DEM research-grade DEM, and compared the calculated roughness between both resulting DEMs using standard deviation of slope, standard deviation of curvature, a pit fill index, and the difference between a smoothed splined surface and the original DEM. These results were then compared to field-surveyed plots and transects of microterrain. Using both datasets, patterns of roughness were identified, which were associated with different landforms derived from hydrogeomorphic features such as stream channels, gullies, and depressions. Lowland areas tended to have the highest roughness values for all methods, with other areas showing distinctive patterns of roughness values across metrics. However, our results suggest that the high-resolution research-grade LiDAR did not improve roughness modeling in comparison to the coarser statewide LiDAR. We conclude that resolution and initial point density may not be as important as the algorithm and methodology used to generate a LiDAR-derived DEM for roughness modeling purposes.
Asymptotic Behavior of Solutions to Fast Diffusive Non-Newtonian Filtration Equations Coupled by Nonlinear Boundary Sources
Authors: Zejia Wang , Shunti Wang , Chengbin Zhang
Published: April 2013

This paper is concerning the asymptotic behavior of solutions to the fast diffusive non-Newtonian filtration equations coupled by the nonlinear boundary sources. We are interested in the critical global existence curve and the critical Fujita curve, which are used to describe the large-time behavior of solutions. It is shown that the above two critical curves are both the same for the multidimensional problem we considered.
Sobolev Embeddings for Generalized Riesz Potentials of Functions in Morrey Spaces over Nondoubling Measure Spaces
Authors: Sawano Yoshihiro , Shimomura Tetsu
Published: April 2013

Our aim in this paper is to deal with the Sobolev embeddings for generalized Riesz potentials of functions in Morrey spaces over nondoubling measure spaces.
Inhibition of c-Met Reduces Lymphatic Metastasis in RIP-Tag2 Transgenic Mice
Authors: Sennino Barbara , Ishiguro-Oonuma Toshina , Schriver Brian J. , Christensen James G. , McDonald Donald M.
Published: April 2013

Inhibition of VEGF signaling can promote lymph node metastasis in preclinical models, but the mechanism is not fully understood, and successful methods of prevention have not been found. Signaling of hepatocyte growth factor (HGF) and its receptor c-Met can promote the growth of lymphatics and metastasis of some tumors. We sought to explore the contributions of c-Met signaling to lymph node metastasis after inhibition of VEGF signaling. In particular, we examined whether c-Met is upregulated in lymphatics in or near pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice and whether lymph node metastasis can be reduced by concurrent inhibition of VEGF and c-Met signaling. Inhibition of VEGF signaling by anti-VEGF antibody or sunitinib in mice from the age of 14 to 17 weeks was accompanied by more intratumoral lymphatics, more tumor cells inside lymphatics, and more lymph node metastases. Under these conditions, lymphatic endothelial cells, like tumor cells, had strong immunoreactivity for c-Met and phospho-c-Met. c-Met blockade by the selective inhibitor, PF-04217903, significantly reduced metastasis to local lymph nodes. Together, these results indicate that inhibition of VEGF signaling in RIP-Tag2 mice upregulates c-Met expression in lymphatic endothelial cells, increases the number of intratumoral lymphatics and number of tumor cells within lymphatics, and promotes metastasis to local lymph nodes. Prevention of lymph node metastasis by PF-04217903 in this setting implicates c-Met signaling in tumor cell spread to lymph nodes. Cancer Res; 73(12); 3692–703. ©2013 AACR.
A Novel Model for Evaluating Therapies Targeting Human Tumor Vasculature and Human Cancer Stem–like Cells
Authors: Burgos-Ojeda Daniela , McLean Karen , Bai Shoumei , Pulaski Heather , Gong Yusong , Silva Ines , Skorecki Karl , Tzukerman Maty , Buckanovich Ronald J.
Published: April 2013

Human tumor vessels express tumor vascular markers (TVM), proteins that are not expressed in normal blood vessels. Antibodies targeting TVMs could act as potent therapeutics. Unfortunately, preclinical in vivo studies testing anti-human TVM therapies have been difficult to do due to a lack of in vivo models with confirmed expression of human TVMs. We therefore evaluated TVM expression in a human embryonic stem cell–derived teratoma (hESCT) tumor model previously shown to have human vessels. We now report that in the presence of tumor cells, hESCT tumor vessels express human TVMs. The addition of mouse embryonic fibroblasts and human tumor endothelial cells significantly increases the number of human tumor vessels. TVM induction is mostly tumor-type–specific with ovarian cancer cells inducing primarily ovarian TVMs, whereas breast cancer cells induce breast cancer specific TVMs. We show the use of this model to test an anti-human specific TVM immunotherapeutics; anti-human Thy1 TVM immunotherapy results in central tumor necrosis and a three-fold reduction in human tumor vascular density. Finally, we tested the ability of the hESCT model, with human tumor vascular niche, to enhance the engraftment rate of primary human ovarian cancer stem–like cells (CSC). ALDH+ CSC from patients (n = 6) engrafted in hESCT within 4 to 12 weeks whereas none engrafted in the flank. ALDH− ovarian cancer cells showed no engraftment in the hESCT or flank (n = 3). Thus, this model represents a useful tool to test anti-human TVM therapy and evaluate in vivo human CSC tumor biology. Cancer Res; 73(12); 3555–65. ©2013 AACR.
ING5 Is a Tip60 Cofactor That Acetylates p53 in Response to DNA Damage
Authors: Liu Nansong , Wang Jiadong , Wang Jifeng , Wang Rukai , Liu Zhongle , Yu Yao , Lu Hong
Published: April 2013

Posttranslational modification of p53 is a critical event in regulating the expression of its target genes. p53 is acetylated at lysine 120 (K120) by acetyltranferases Tip60 (KAT5) and hMOF (KAT8) in response to DNA damage. Identification of cofactors for these two enzymes will shed light on the mechanism by which cells make a choice between cell-cycle arrest and apoptosis. It has been reported that ING5, a member of the inhibitor of growth (ING) family, is involved in p53-dependent pathways, but its exact role is unknown. In this study, we found that ING5 expression was significantly increased and that ING5 assisted Tip60, but not hMOF, in acetylating p53 at K120 in response to DNA damage. ING5 had no effect on acetylation of p53 at K373/382, but it formed a complex with p53 and Tip60. ING5 was required for acetylation of p53 at K120, and p53 acetylated at K120 subsequently bound to the promoters of its target apoptotic genes, BAX and GADD45, to promote their expression and lead to apoptosis. Mutation of K120 to K120R abolished the effects of ING5 on p53-induced gene expression. Thus, we conclude that ING5 functions as a cofactor of Tip60 in the acetylation of p53 at K120 in response to DNA damage. Cancer Res; 73(12); 3749–60. ©2013 AACR.
Mathematical Modeling of Tumor Cell Proliferation Kinetics and Label Retention in a Mouse Model of Lung Cancer
Authors: Zheng Yanyan , Moore Helen , Piryatinska Alexandra , Solis Trinidad , Sweet-Cordero E. Alejandro
Published: April 2013

Slowly cycling tumor cells that may be present in human tumors may evade cytotoxic therapies, which tend to be more efficient at destroying cells with faster growth rates. However, the proportion and growth rate of slowly cycling tumor cells is often unknown in preclinical model systems used for drug discovery. Here, we report a quantitative approach to quantitate slowly cycling malignant cells in solid tumors, using a well-established mouse model of Kras-induced lung cancer (KrasG12D/+). 5-Bromo-2-deoxyuridine (BrdUrd) was administered to tumor-bearing mice, and samples were collected at defined times during pulse and chase phases. Mathematical and statistical modeling of the label-retention data during the chase phase supported the existence of a slowly cycling label-retaining population in this tumor model and permitted the estimation of its proportion and proliferation rate within a tumor. The doubling time of the slowly cycling population was estimated at approximately 5.7 weeks, and this population represented approximately 31% of the total tumor cells in this model system. The mathematical modeling techniques implemented here may be useful in other tumor models where direct observation of cell-cycle kinetics is difficult and may help evaluate tumor cell subpopulations with distinct cell-cycling rates. Cancer Res; 73(12); 3525–33. ©2013 AACR.
Early B-Cell Differentiation in Merkel Cell Carcinomas: Clues to Cellular Ancestry
Authors: zur Hausen Axel , Rennspiess Dorit , Winnepenninckx Veronique , Speel Ernst-Jan , Kurz Anna Kordelia
Published: April 2013

Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine nonmelanoma skin cancer, which is associated with the Merkel cell polyoma virus (MCPyV). Recently, expression of the terminal deoxynucleotidyl transferase (TdT) and the paired box gene 5 (PAX 5) has been consistently reported in the majority of MCCs. We tested 21 MCCs for the expression of MCPyV, TdT, PAX5, IgG, IgM, IgA, kappa, and lambda by immunohistochemistry and assessed IgH and Igk rearrangement in all 21 MCCs. All of the MCCs revealed specific expression of PAX5 and 72.8% of the MCCs expressed TdT. In addition, most of the MCCs revealed specific expression of one or more Ig subclasses and kappa or lambda. One MCC did reveal monoclonal IgH and Igk rearrangement next to two other MCCs showing Igk rearrangement. As coexpression of TdT and PAX5 under physiologic circumstances is restricted to pro/pre- and pre-B cells we propose, on the basis of our results, that the cell of origin of MCCs is a pro/pre- or pre-B cell rather than the postmitotic Merkel cells. MCPyV infection and transformation of pro-/pre-B cells are likely to induce the expression of simple cytokeratins as has been shown for SV40 in other nonepithelial cells. This model of cellular ancestry of MCCs might impact therapy and possibly helps to understand why approximately 20% of MCCs are MCPyV-negative. Cancer Res; 73(16); 4982–7. ©2013 AACR.
Blood Levels of Folate at Birth and Risk of Childhood Leukemia
Authors: Chokkalingam Anand P. , Chun Danielle S. , Noonan Emily J. , Pfeiffer Christine M. , Zhang Mindy , Month Stacy R. , Taggart Denah R. , Wiemels Joseph L. , Metayer Catherine , Buffler Patricia A.
Published: April 2013

Background: A role for folate in cancer etiology has long been suspected because of folate's function as a cofactor in DNA methylation and maintenance of DNA synthesis. Previous case–control studies examining the association between risk of childhood acute lymphoblastic leukemia (ALL) and mothers' self-reported folate intake and supplementation have been inconclusive.

Materials and Methods: We used a quantitative microbiologic assay to measure newborn folate concentrations in archived dried bloodspots collected at birth from 313 incident ALL cases, 44 incident acute myeloid leukemia (AML) cases, and 405 matched population-based controls.

Results: Overall, we found no difference in hemoglobin-normalized newborn folate concentrations (HbFol, nmol/g) between ALL cases and controls (2.76 vs. 2.77, P = 0.97) or between AML cases and controls (2.93 vs. 2.76, P = 0.32). Null results persisted after stratification by both birth period (1982–94, 1995–98, and 1999–2002) to account for the start of folate fortification of grain products in the United States, and by self-reported maternal prepregnancy supplement use. Similarly, no association was observed for major ALL subgroups.

Conclusions: Our results do not support an association between birth folate concentrations and risk of childhood AML or major ALL subgroups.

Impact: However, they do not rule out a role for folate through exposures after birth or in early stages of fetal development. Cancer Epidemiol Biomarkers Prev; 22(6); 1088–94. ©2013 AACR.
Long-Term Physical Activity Trends in Breast Cancer Survivors
Authors: Mason Caitlin , Alfano Catherine M. , Smith Ashley Wilder , Wang Ching-Yun , Neuhouser Marian L. , Duggan Catherine , Bernstein Leslie , Baumgartner Kathy B. , Baumgartner Richard N. , Ballard-Barbash Rachel , McTiernan Anne
Published: April 2013

Background: Physical activity is associated with reduced mortality and higher quality of life in breast cancer survivors; however, limited data on the prevalence of activity and long-term trends after diagnosis are available.

Methods: A multiethnic cohort of 631 women (18–64 years) with stage 0 to IIIA breast cancer was followed for 10 years. Recreational aerobic activity (MET-h/wk) was ascertained for the year before diagnosis (baseline), 24 months, 5 years, and 10 years after enrollment. Women were classified according to U.S. physical activity guidelines (≥150 min/wk moderate or ≥75 min/wk vigorous activity). The OR for meeting guidelines at 5 and 10 years according to baseline factors was estimated using logistic regression. The change in MET-h/wk was predicted using linear regression.

Results: Prediagnosis, 34% of women met physical activity guidelines; 34.0%, 39.5%, and 21.4% met guidelines at 24 months, 5 years, and 10 years after enrollment, respectively. Less than 8% of survivors met guidelines at all follow-up periods. Over 10 years, recreational aerobic activity decreased by a mean ± SD of 4.3 ± 16.2 MET-h/wk. Meeting guidelines pre-diagnosis was strongly associated with meeting guidelines at 5 years [OR (95% confidence interval; CI): 2.76 (1.85–4.1)] and 10 years [OR (95% CI): 3.35 (2.13–5.28)]. No other demographic or prognostic factors were significantly associated with the 10-year change in MET-h/wk.

Conclusion: The vast majority of early breast cancer survivors do not meet national exercise recommendations 10 years postdiagnosis.

Impact: Physical activity levels are low in breast cancer survivors across the 10 years postdiagnosis; nonetheless, the predictors of activity in this population remain poorly understood. Cancer Epidemiol Biomarkers Prev; 22(6); 1153–61. ©2013 AACR.
Relapsed Classic E-Cadherin (CDH1)–Mutated Invasive Lobular Breast Cancer Shows a High Frequency ofHER2(ERBB2) Gene Mutations
Authors: Ross Jeffrey S. , Wang Kai , Sheehan Christine E. , Boguniewicz Ann B. , Otto Geoff , Downing Sean R. , Sun James , He Jie , Curran John A. , Ali Siraj , Yelensky Roman , Lipson Doron , Palmer Gary , Miller Vincent A. , Stephens Philip J.
Published: April 2013

Purpose: We queried whether comprehensive genomic profiling using a next-generation sequencing–based assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC).

Experimental Design: DNA sequencing (Illumina HiSeq 2000) was conducted for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor-ligated, hybridization-captured libraries using DNA isolated from formalin-fixed paraffin-embedded sections from 22 histologically verified ILC.

Results: A total of 75 genomic alterations were identified with an average of 3.4 alterations per tumor (range, 1–6), of which 35 were actionable for an average of 1.59 actionable alterations per patient (range, 0–3). Nineteen of 22 (86%) of the ILC samples harbored at least one actionable alteration. Six (27%) cases featured alterations in ERRB2 including 4 (18%) with ERBB2 mutation, 1 (5%) with an ERBB2 gene fusion, and 1 (5%) with an ERBB2 copy number gain (amplification). The enrichment of ERBB2 mutations/fusion in CDH1-mutated ILC (5 of 22, 23%) compared with the 5 ERBB2 mutations in a series of 286 non-CDH1-mutated breast cancers from which the ILC cases were obtained (5 of 286, 2%) was significant (P = 0.0006).

Conclusions: Comprehensive genomic profiling of relapsed CDH1-mutated ILC revealed actionable genomic alterations in 86% of cases, featured a high incidence of ERBB2 alterations, and can reveal actionable alterations that can inform treatment decisions for patients with ILC. Clin Cancer Res; 19(10); 2668–76. ©2013 AACR.
CYP1A1 Regulates Breast Cancer Proliferation and Survival
Authors: Rodriguez Mariangellys , Potter David A.
Published: April 2013

Cytochrome P450-1A1 (CYP1A1) is an extrahepatic phase I metabolizing enzyme whose expression is suppressed under physiologic conditions but can be induced by substrates via the aryl hydrocarbon receptor (AhR). Recent studies have shown that the majority of breast cancer tumors constitutively express CYP1A1. These findings led us to test the hypothesis that CYP1A1 promotes breast cancer progression by evaluating the effects of CYP1A1 knockdown on the proliferation and survival of the MCF7 and MDA-MB-231 lines. Independently of estrogen receptor status, CYP1A1 knockdown decreased colony formation, decreased cell proliferation, blocked the cell cycle at G0-G1 associated with reduction of cyclin D1, and increased apoptosis associated with reduction of survivin. CYP1A1 knockdown markedly increased phosphorylation of AMP-activated protein kinase (AMPK) and decreased phosphorylation of AKT, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and 70-kDa ribosomal protein S6 kinase (P70S6K). AMPK inhibition by compound C partially abrogated the proapoptotic effects of CYP1A1 knockdown, suggesting that effects of CYP1A1 knockdown are mediated in part through AMPK signaling. Consistent with CYP1A1 knockdown, pharmacologic reduction of CYP1A1 levels by the phytopolyphenol carnosol also correlated with impaired proliferation and induced AMPK phosphorylation. These results indicate that reduction of basal CYP1A1 expression is critical for inhibition of proliferation, which is not affected by α-naphthoflavone-mediated inhibition of CYP1A1 activity nor modulated by AhR silencing. This study supports the notion that CYP1A1 promotes breast cancer proliferation and survival, at least in part, through suppression of AMPK signaling and that reduction of CYP1A1 levels is a potential strategy for breast cancer therapeutics. Mol Cancer Res; 11(7); 780–92. ©2013 AACR.
FoxM1 is Overexpressed in Helicobacter pylori–Induced Gastric Carcinogenesis and Is Negatively Regulated by miR-370
Authors: Feng Yimin , Wang Lixiang , Zeng Jiping , Shen Li , Liang Xiuming , Yu Han , Liu Shili , Liu Zhifang , Sun Yundong , Li Wenjuan , Chen Chunyan , Jia Jihui
Published: April 2013

Helicobacter pylori (H. pylori) infections are strongly implicated in human gastric mucosa–associated diseases. Forkhead box M1 (FoxM1), a key positive regulator of cell proliferation, is overexpressed in gastric cancer. MicroRNAs are important post-transcriptional regulators of gene expression. In this study, the effects of H. pylori infection on FoxM1 expression and possible mechanisms of carcinogenesis were explored. The expression of FoxM1 was gradually increased in human gastric specimens from inflammation to cancer. FoxM1 upregulation was time- and concentration-dependent in gastric epithelial-derived cell lines infected with H. pylori. CagA, a key virulence factor of H. pylori, was associated with increased FoxM1 expression. H. pylori and CagA inhibited the expression of p27Kip1 (CDKN1B) and promoted cell proliferation by upregulating FoxM1. The expression of miR-370 was decreased in human gastritis and gastric cancer. FoxM1 was directly downregulated by miR-370 in gastric cell lines. H. pylori and CagA inhibited miR-370 expression, which led to overexpression of FoxM1 and cell proliferation. Furthermore, the overexpression of FoxM1 and reduced expression of miR-370 was confirmed in H. pylori–infected C57BL/6J mice. H. pylori infection and CagA upregulated FoxM1 expression, dependent on miR-370, altered the expression of p27Kip1, and promoted proliferation in gastric cells.

Implications: These findings delineate the mechanisms governing FoxM1 regulation and the role of H. pylori in the process of gastric carcinogenesis. Mol Cancer Res; 11(8); 834–44. ©2013 AACR.
Single-Variant and Multi-Variant Trend Tests for Genetic Association with Next-Generation Sequencing That Are Robust to Sequencing Error
Authors: Kim Wonkuk , Londono Douglas , Zhou Lisheng , Xing Jinchuan , Nato Alejandro Q. , Musolf Anthony , Matise Tara C. , Finch Stephen J. , Gordon Derek
Published: April 2013

As with any new technology, next-generation sequencing (NGS) has potential advantages and potential challenges. One advantage is the identification of multiple causal variants for disease that might otherwise be missed by SNP-chip technology. One potential challenge is misclassification error (as with any emerging technology) and the issue of power loss due to multiple testing. Here, we develop an extension of the linear trend test for association that incorporates differential misclassification error and may be applied to any number of SNPs. We call the statistic the linear trend test allowing for error, applied to NGS, or LTTae,NGS. This statistic allows for differential misclassification. The observed data are phenotypes for unrelated cases and controls, coverage, and the number of putative causal variants for every individual at all SNPs. We simulate data considering multiple factors (disease mode of inheritance, genotype relative risk, causal variant frequency, sequence error rate in cases, sequence error rate in controls, number of loci, and others) and evaluate type I error rate and power for each vector of factor settings. We compare our results with two recently published NGS statistics. Also, we create a fictitious disease model based on downloaded 1000 Genomes data for 5 SNPs and 388 individuals, and apply our statistic to those data. We find that the LTTae,NGS maintains the correct type I error rate in all simulations (differential and non-differential error), while the other statistics show large inflation in type I error for lower coverage. Power for all three methods is approximately the same for all three statistics in the presence of non-differential error. Application of our statistic to the 1000 Genomes data suggests that, for the data downloaded, there is a 1.5% sequence misclassification rate over all SNPs. Finally, application of the multi-variant form of LTTae,NGS shows high power for a number of simulation settings, although it can have lower power than the corresponding single-variant simulation results, most probably due to our specification of multi-variant SNP correlation values. In conclusion, our LTTae,NGS addresses two key challenges with NGS disease studies; first, it allows for differential misclassification when computing the statistic; and second, it addresses the multiple-testing issue in that there is a multi-variant form of the statistic that has only one degree of freedom, and provides a single p value, no matter how many loci.
Population Genetics of Rare Variants and Complex Diseases
Authors: Maher M. Cyrus , Uricchio Lawrence H. , Torgerson Dara G. , Hernandez Ryan D.
Published: April 2013

Objectives: Identifying drivers of complex traits from the noisy signals of genetic variation obtained from high-throughput genome sequencing technologies is a central challenge faced by human geneticists today. We hypothesize that the variants involved in complex diseases are likely to exhibit non-neutral evolutionary signatures. Uncovering the evolutionary history of all variants is therefore of intrinsic interest for complex disease research. However, doing so necessitates the simultaneous elucidation of the targets of natural selection and population-specific demographic history. Methods: Here we characterize the action of natural selection operating across complex disease categories, and use population genetic simulations to evaluate the expected patterns of genetic variation in large samples. We focus on populations that have experienced historical bottlenecks followed by explosive growth (consistent with many human populations), and describe the differences between evolutionarily deleterious mutations and those that are neutral. Results: Genes associated with several complex disease categories exhibit stronger signatures of purifying selection than non-disease genes. In addition, loci identified through genome-wide association studies of complex traits also exhibit signatures consistent with being in regions recurrently targeted by purifying selection. Through simulations, we show that population bottlenecks and rapid growth enable deleterious rare variants to persist at low frequencies just as long as neutral variants, but low-frequency and common variants tend to be much younger than neutral variants. This has resulted in a large proportion of modern-day rare alleles that have a deleterious effect on function and that potentially contribute to disease susceptibility. Conclusions: The key question for sequencing-based association studies of complex traits is how to distinguish between deleterious and benign genetic variation. We used population genetic simulations to uncover patterns of genetic variation that distinguish these two categories, especially derived allele age, thereby providing inroads into novel methods for characterizing rare genetic variation driving complex diseases.
Cardiovascular Tissue Engineering Research Support at the National Heart, Lung, and Blood Institute
Authors: Lundberg Martha S.
Published: April 2013

Tissue engineering aims at building 3-dimensional living substitutes that are equal to or better than the damaged tissue to be replaced. The development of such a tissue replacement requires a multidisciplinary approach and careful attention to the optimal cell source, the interactions of growth factors and extracellular milieu, and the scaffolding design. This article is a review of the tissue engineering programs of the National Heart, Lung, and Blood Institute, which support research efforts to translate novel approaches for the treatment of cardiovascular disease. Recent progress is discussed, which highlights some major questions relevant to cardiovascular tissue engineering. The National Heart, Lung, and Blood Institute has a strong interest in tissue engineering and will continue to foster the practical, clinical, and commercial development of research discoveries in this emerging field.
mir-17–92 Cluster Is Required for and Sufficient to Induce Cardiomyocyte Proliferation in Postnatal and Adult Hearts
Authors: Chen Jinghai , Huang Zhan-Peng , Seok Hee Young , Ding Jian , Kataoka Masaharu , Zhang Zheng , Hu Xiaoyun , Wang Gang , Lin Zhiqiang , Wang Si , Pu Willam T. , Liao Ronglih , Wang Da-Zhi
Published: April 2013

Rationale:

Cardiomyocytes in adult mammalian hearts are terminally differentiated cells that have exited from the cell cycle and lost most of their proliferative capacity. Death of mature cardiomyocytes in pathological cardiac conditions and the lack of regeneration capacity of adult hearts are primary causes of heart failure and mortality. However, how cardiomyocyte proliferation in postnatal and adult hearts becomes suppressed remains largely unknown. The miR-17–92 cluster was initially identified as a human oncogene that promotes cell proliferation. However, its role in the heart remains unknown.

Objective:

To test the hypothesis that miR-17–92 participates in the regulation of cardiomyocyte proliferation in postnatal and adult hearts.

Methods and Results:

We deleted miR-17–92 cluster from embryonic and postnatal mouse hearts and demonstrated that miR-17–92 is required for cardiomyocyte proliferation in the heart. Transgenic overexpression of miR-17–92 in cardiomyocytes is sufficient to induce cardiomyocyte proliferation in embryonic, postnatal, and adult hearts. Moreover, overexpression of miR-17–92 in adult cardiomyocytes protects the heart from myocardial infarction-induced injury. Similarly, we found that members of miR-17–92 cluster, miR-19 in particular, are required for and sufficient to induce cardiomyocyte proliferation in vitro. We identified phosphatase and tensin homolog, a tumor suppressor, as an miR-17–92 target to mediate the function of miR-17–92 in cardiomyocyte proliferation.

Conclusions:

Our studies therefore identify miR-17–92 as a critical regulator of cardiomyocyte proliferation, and suggest this cluster of microRNAs could become therapeutic targets for cardiac repair and heart regeneration.
The Common Good: Theoretical Content, Practical Utility
Authors: Galston William A.
Published: April 2013

Despite skepticism about the common good, the idea has both theoretical content and practical utility. It rests on important features of human life, such as inherently social goods, social linkages, and joint occupation of various commons. It reflects the outcome for bargaining for mutual advantage, subject to a fairness test. And it is particularized through a community's adherence to certain goods as objects of joint endeavor. In the context of the United States, these goods are set forth in the Preamble to the Constitution – in general language, subject to political contestation, for a people who have agreed to live together in a united political community. While the Preamble states the ends of the union, the body of the Constitution establishes the institutional means for achieving them. So these institutions are part of the common good as well. These are the enduring commonalities – the elements of a shared good – that ceaseless democratic conflict often obscures but that reemerge in times of crisis and civic ritual.
Can the Judicial Branch be a Steward in a Polarized Democracy?
Authors: Rosen Jeffrey
Published: April 2013

At the beginning of his first term as Chief Justice, John Roberts pledged to try to persuade his colleagues to consider the bipartisan legitimacy of the Court rather than their own ideological agendas. Roberts had mixed success during his first years on the bench, as the Court handed down a series of highprofile decisions by polarized, 5–4 votes. In the health care decision, however, Roberts did precisely what he said he would do, casting a tie-breaking vote to uphold the Affordable Care Act because he thought the bipartisan legitimacy of the Court required it. But the reaction to the health care decision – which Democrats approved and Republicans did not – suggests that Roberts's task of preserving the Court's bipartisan legitimacy is more complicated than he may have imagined, and that his success in the future will depend on the willingness of his colleagues to embrace his vision. Given the Court's declining approval ratings, an increase in partisan attacks on the Court, and a growing perception that the Court decides cases based on politics rather than law, the Chief Justice's vision of the Court as a bipartisan steward is more difficult – and also more urgently needed – than ever.
“Self-Interest Well Understood”: The Origins & Lessons of Public Confidence in the Military
Authors: Hill Andrew A. , Wong Leonard , Gerras Stephen J.
Published: April 2013

In recent decades, the U.S. military has enjoyed high levels of public confidence. We argue that the rise (and sustainment) of public confidence in the military reflects two phenomena. First, the public has a high regard for the military and its mission, arising from a shift to a professional (nonconscript) force that is perceived to be competent, fair, and accountable. Second, the public has little fear of military abuses in the domestic arena, owing chiefly to the reduced domestic presence of the military in the post – World War II era, with less emphasis on the physical defense of the homeland; and to the military's careful cultivation of an apolitical culture since Vietnam. We conclude with a brief discussion of the military's efforts to develop and encourage public-mindedness among its members, and the challenges to replicating the military approach in other institutional settings.
The Challenges Facing Civic Education in the 21st Century
Authors: Jamieson Kathleen Hall
Published: April 2013

This essay explores the value and state of civics education in the United States and identifies five challenges facing those seeking to improve its quality and accessibility: 1) ensuring that the quality of civics education is high is not a state or federal priority; 2) social studies textbooks do not facilitate the development of needed civic skills; 3) upper-income students are better served by our schools than are lower-income individuals; 4) cutbacks in funds available to schools make implementing changes in civics education difficult; and 5) reform efforts are complicated by the fact that civics education has become a pawn in a polarized debate among partisans.
The American Corporation
Authors: Gomory Ralph , Sylla Richard
Published: April 2013

The United States from its earliest years led the world in making the corporate form of business organization widely available to entrepreneurs. Starting in the 1790s, corporations became key institutions of the American economy, contributing greatly to its remarkable growth. This essay reviews the evolution of corporations across several eras of the country's history. The most recent era is marked by a shift away from a stakeholder view of corporate interests and purposes to one dominated by profit and shareholder-value maximization. We strongly question whether this shift has been beneficial to the country as a whole. If our assessment is correct, there is a need to find ways of inducing corporations to act in ways that produce better societal outcomes. We therefore explore ways – including some suggested by the history of U.S. corporations – in which corporate interests and the public interest might become better aligned.